Pharma Book Final

INDEX
S
CONTEN PAGE
R.
TS NO.
N
O.
SITE MASTER FILE (SMF) 6
VALIDATION MASTER PLAN (VMP) 7
QUALITY MANUAL (QM) 8
CHANGE CONTROL 9
DEVIATION 13
MARKET COMPLAINT 18
PRODUCT RECALL 29
CAPA 32
MANAGEMENT NOTIFICATION 34
NPI 35
REGULATORY UPDATES 36
PLANT QUALITY REVIEW MEETING 37
SHELF INSPECTION 38
VENDOR MANAGEMENT 39
CLEANING VALIDATION 43
PRODUCT QUALITY REVIEW (PQR) 51
PROCESS VALIDATION 54
QUALITY RISK MANAGEMENT 57
STABILITY STUDIES 66
ANALYTICAL METHOD VALIDATION 70
OUT OF SPECIFICATION 79
MICRO 84
Page 2 of 270
INDEX
S
INDEX
CONTEN PAGE
R. S
TS NO. CONTEN PAGE
N R.
O. TS NO.
N
O.
2 TRAINING 87
3. 43. DIFFRENCE BEWTWEEN OOS AND OOS 167
0 2
2 MEDICAL CHECKUP 89 44. DIFFRENCE BEWTWEEN CHANGE CONTROL AND DEVIATION 167
4. 0
0
45. DIFFRENCE BEWTWEEN SOP AND PROTOCOL 167
2 PEST CONTROL 89 0
5.
0 46. CHANGE ROOM AND LINE CLEARANCE CONCEPT 168
0
2 RODENT CONTROL 90
6. 47. BATCH RECORD 169
0 0
2 HEALTH 90 48. PASS BOX 170

7. 0
0 49. EQUIPMENT AND PROCESS 171
2 HYGIENE 91 0
8. 50. BALANCE CALIBRATION 203
0 0
2 QUALIFICATION 92 51. IPQA 204
9. 0
0
52. ONLINE SYSTEM FLOW 215
3 HVAC SYSTEM 94 0
0.
0 53. SAP 216
0
3 RLAF/LAF 107
1. 54. HOLD TIME STUDY 218
0 0
3 WATER SYSTEM 109 55. MVTR 221

2. 0
0 56. HANDLING OF LABORTORY INCIDENT / DISCREPANCY 223
3 COMPRESSED AIR 131 0
3. 57. CONTRACT TESTING LABORATORY 225
0 0
3 ENGINEERING 139 58. RELEASE OF INTERMEDIATE AND FINISHED PRODUCTS 227
4. 0
0
59. FAILURE INVESTIGATION AND ROOT CAUSE ANALYSIS 230
3 PREVENTIVE MAINTENANCE 147 0
5.
0 60. HANDLING OF PHARMACOPEIAL CHANGES 238
0
61. GOOD MANUFACTURING PRACTICES (GMP) 240
Page 3 of 270 Page 4 of 270
INDEX PHARMA BOOK
S
CONTEN PAGE SR. QUESTION ANSWER
R.
TS NO. NO.
N
O. 1.0
SITE MASTER FILE (SMF)
6 VARIATION FILE 249
5. What is SMF
0
6 CLINICAL TRIALS 253 1. Site Master File is Full information about the site.
6. 1
0 be used for establishing registration in various countries.
6 MARKETING AUTHORISATION 257 Which Guideline follow for preparation of SMF
7.
0 1.
2 PIC/S and EU Guideline (Eudralex Volume-4).
6 EUDRALEX 262
8. Preparation
0
1.
3 SMF is Prepared by Quality Assurance and Reviewed by Plant Head and Authorised by Head QA.
Contents of SMF
1. General Information
2. Personnel
3. Premises and Equipment
1. 4. Documentation
4 5. Production
6. Quality Control
7. Contract Manufacture and Analysis
8. Distribution, Complaints and Product Recall.
9. Self Inspection
Review Period
Any changes after approval of SMF shall be recorded in Annexure-II for keeping a track of
changes taken place. All such changes shall be collated and amended in the next revision.
1.
5
Site Master File shall be revised at end of every calendar year or as and when required through change
control management system
Storage Period
Site Master File shall be store by QA department for 10 years.

1.
6

PHARMA BOOK PHARMA BOOK
SR.QUESTION SR. QUESTION ANSWER

NO.ANSWER NO.
2.0VALIDATION MASTER PLAN (VMP) Review Period
Any changes after approval of VMP shall be recorded in Annexure-II for keeping a track of
What is VMP changes taken place.
Brief information about Qualification, Validation and calibration of Equipment, Instrument and System. VMP shall be revised at end of every calendar year, or as and when required through change control
2. management system.
2.
1 4
details of and timescales for the validation work to be performed. Responsibilities relating to the Validation master plan is prepared at the initial stage of commissioning of a facility after the civil
plan should be stated. design, type, drawings are established.
Which Guideline follow for preparation of VMP The VMP shall be prepared by QA, it should be reviewed by Department Head and approved
by Plant Head and QA Head.
2.
2 PIC/S (PI 006), WHO TRS 961, Eudralex Volume 4
Storage Period
Contents of VMP. 2.
5 Validation Master Plan shall be store by QA department for perpetual.
Cover Page, Table of contents
Approval of document
3.0QUALITY MANUAL (QM)
Introduction, Objective, Scope
Quality policy What is QM
Validation policy 3.
Quality Risk Management 1 organization.
Policy Responsibility
Validation / Qualification Schematic Flow Which Guideline follow for preparation of QM
Validation and Qualification approach 3.
Eudralex Volume 4 (Chapter 1 Pharmaceuticals Quality System), ICH Q8, Q9 and Q10, Schedule
Revalidation and Requalification approach 2
M.
Qualification Activity Contents of QM
Facility Qualification Introduction, Scope, Basics of Quality Management System
Qualification and Validation of Utilities Quality Policy, Quality Objective Quality Risk Management
2. Equipment Qualification Policy Company Profile, Organization, Regulatory Basics
3 Laboratory Instruments and Equipment Documentation For The Quality Management System
Personnel Qualification Document Structure Production of Quality Management
Products and Process Validation 3.
System Accompanying Quality Management System
Exhibit batches process 3
Design/Project Management, Qualification and Validation
validation Cleaning Validation Maintenance, Health requirements, Personnel hygiene requirements, including clothing
Analytical Method Complaints, Product Recall, Customer Management
Validation Hold Time Study Product Documentation, Labeling And Packaging Control
Computerized System Product Quality Review, References
Validation Vendor Qualification Review Period
Program 3.
Change Control, SOP, Training, Environment Monitoring, Preventive Maintenance / 4 Every Two Years
calibration Storage Period
Terms and
3. Perpetual
Definitions List of
5
Annexure Revision
History
Page 7 of 270
Page 8 of 270
SR.
SR. QUESTION ANSWER NO.
QUESTION
NO. ANSWER
4.0
CHANGE CONTROL
CLASSIFICATION OF TYPICAL CHANGES
What is change control
Type of change Critical Major
A Process which ensures that changes to procedures, materials, methods, equipment, and software are
properly documented, approved, validated and traceable. Change in systems
Change in manufacturing formula/process / New Products
CHANGE CONTROL PROCEDURE:
Change in expiry (related to stability)
DEFINATION: Change in critical Raw Material/solvent
Change Control: A formal system by which qualified representative of appropriate disciplines Change in specifications and test method
review proposed or actual changes that might affect the validated status of facility, systems, Change in SOP for addition / deletion
equipments or processes.
Change in equipment
Temporary Change: A change (departure from any established procedure/system/process) initiated Modification in critical equipment
for the evaluation of proposed procedure/system/process, which has been taken with prior approval to
Modification / Up gradation in facility
achieve the desired output, allowed for one time change and limited to a particular batch. For example
change in batch size, manufacturing equipment, etc. Change in stability program
Change in key raw material source or supplier
Permanent change: A change initiated based upon scientific rational or historical GMP data or
data generated through temporary changes. Change in storage conditions
Change in primary packing material
Major Change: Changes, proposed for improvements to process, materials, product and procedures Change in secondary packing material
which may have impact upon the identity, quality, purity, strength, stability, safety and efficacy or
physical characteristic of the product. Notification to agency required. Change in packing style
4. Change in printed text on label
1 Minor Change: Changes, which does not have impact on the quality attributes like identity,
quality, purity, strength, stability, safety, efficacy or physical characteristic of the product. Change in manufacturing location/site
Change in manufacturing Batch Size
Changes are divided into two types:
Change in packing batch size
1) Permanent Change
Change in control systems i.e. computers, Data Collection
2) Temporary Change
Formats and internal labels
The change control approval or rejection process shall require to be completed within 30 Deletion of a product
working days from the date of initiation of the change control.
Note: The list can be elaborated based on practical changes occurring at the locations.
Change control preferably closed within 90 working days after Head QA approval.
Product Change : Change in key RM/Solvent, BOM, Process Parameters, In-process
control, pack style, packing material, introduction of New Product etc
98. Initiating department Head shall review the extension request
and write justification for delay with impact assessment. QA shall assess the impact of delay in
Engineering Change : Change in Facility design, equipment type, Maintenance parameters,
action completion and approve / reject the Period extension request. Period extension shall be
utilities.
allowed for two times only. After this new change control shall be initiated.
System Change : Change in software/firmware or its configuration etc.
Change control trending shall be carried out monthly
Documentation Change: Change in SOP, STP, Document control procedures etc.

SR.
QUESTION S QUESTION
NO.
ANSWER R.
N ANSWER
RECOMMENDED SUPPORTING STUDIES FOR CHANGE (S)
Type of change Recommendations
Change in systems Training, Change in relevant documents, and/or

validation wherever required.
Validation of three consecutive batches, with
Change in manufacturing formula/process / stability studies, method validation, specification,
New Products STP, Cleaning Validation verification in facility.
Information and pre-approval from
customer/regulatory authorities (as applicable)
Change in specifications Stability studies on the changed specifications.
Updating of SAP. Registration Dossier updation.
Change in test methods Analytical Method validation, Updating of TDS,
Registration Dossier updation.
Change in SOP for addition / deletion of
instructions/formats/labels Training, Change in relevant documents.
Change in expiry Stability studies, Change in relevant documents,

intimation to concerned departments. Registration
Change/modification in equipment/ New Dossier updation.
equipment Equipment qualification. SOP preparation, Training,
Equipment list updation
Changes made for Marketing Authorization
Modification/Up gradation in facility Process related / system related.
Change in stability program Facility qualifications, SMF update
Change in critical raw material source Stability studies in change conditions.
Vendor approval as per SOP
Change in storage conditions Stability studies in changed conditions, Change in
relevant documents/labels
Change in primary packaging material Stability study, Change in relevant documents/BPR,
Specification updation.
Change in pack style Change in relevant documents/BPR, intimation to
concerned departments.
Change in printed text Change in relevant documents/BPR. Intimation to
concerned departments.
Change in manufacturing batch size, Partial validation of three consecutive batches,
manufacturing site/location accelerated/long term stability studies depending on
the change.
Change in control systems i.e. computers,
configuration of software/firmware, etc. Validation of the new control system.
Note: This list is not exhaustive and can be extended based on practical changes occurring at
the locations.
Page 12 of 270
Page 11 of 270
S QUESTION
R.
N ANSWER
5.0DEVIATION
SR. QUESTION ANSWER
NO.
Initiator shall do the initial assessment and shall take suitable immediate action according to the nature
of deviation and inform to department head and concern QA person.
DEFINATION: Initial impact assessment shall be done by the observing department head / designee and designated
DEVIATION: person QA. Recommendation for continuation of process / discontinue the process shall be given by
Deviation is an unexpected event that occurs during the on-going operation / Activity / Documentation head of department and Head QA or designee.
/ Entries at any stage of Receipt, Storage and Manufacturing, Analysis and Distribution of Drug
Products / Intermediates / Raw Materials / Packing materials. Deviations are to be reported as Based on nature of deviation, initial assessment and immediate action taken, Head of initiating
and when they occur and to be investigated for impact assessment. department shall approve the deviation for further evaluation of QA.
Critical Deviation: Deviation that could have significant impact on the product quality or GMP After approval of deviation from head of initiating department deviation form shall be forwarded
system. Examples of critical deviations are given below but not limited to: to QA for evaluation.
Cross contamination or product mix up in a During evaluation, designated QA person shall verify whether the deviation is quality relevance or not
product. Failure to process step during and whether deviation is a repeat occurrence or not.
manufacturing.
Use of obsolete batch document / test method. If it is quality relevance, impact shall be assessed on other areas/departments.
Filter integrity failure.
And if it is a repeat occurrence, impact assessment shall extend to verify the effectiveness of previous
Major Deviations: Deviation that could have a moderate to considerable impact on the product CAPA taken.
quality or GMP system. Examples of major deviations are given below but not
limited to: After evaluation categorizes deviation into critical, major or minor based on the evaluation of impacted
areas and product quality impact.
Machine breakdown during processing
5. Mix ups of cartons of same product with different strength. If deviation is categorized as Critical or Major, Cross Functional Team comprising of technical
1 experts from different department (as per the nature of deviation) shall be form to investigate the root
Minor Deviations: Deviation unlikely to have a detectable impact on product quality or GMP system. cause of deviation.
Examples of minor deviations are given below but not limited to:
Minor errors in batch records or document that not affecting the If deviation is minor, investigation shall be carried out jointly by designated QA person along with
integrity of data. a person from department where deviation happened.
Spillage of material during dispensing.
Failure to meet environmental condition during batch processing. Failure Investigation and Root Cause identifications shall be carried out by the investigation team using
PROCEDURE: investigational methodologies.
All deviation shall be documented, investigated, tracked and trended. All deviation shall be reported Upon identification of root cause of failure, the probable root cause of failure shall be documented.
as when they occur.
Corrective actions and preventive actions shall be recommended to prevent the reoccurrence of the
The person who observes the deviation shall inform the immediate supervisor or concern department same.
head/designee and to Quality Assurance.
The deviation including investigation report (wherever applicable) shall be closed within 30
As per the severity of deviation and stage of process, the process may be stopped for initial working days of the initiation date. The initiation date is the date of observation of deviation.
assessment.
per SOP No. QAD 098. Initiating department Head shall review the extension request and write
assigning deviation number justification for delay with impact assessment. QA shall assess the impact of delay in action
The initiator shall fill the details (like Product / Material / Equipment / Document / Other If any and completion and approve / reject the Period extension request.
Deviations shall be closed only when all relevant actions in the CAPA log are completed.
Batch No. / A.R.No. If applicable) in deviation control form.

SR.
NO.
QUESTION SR. QUESTION ANSWER
ANSWER NO.
Activity / Document Examples of Deviations

Continuous trending of deviations shall be carried out on monthly basis
QA shall carry out trend analysis for all the deviation in the whole year at the beginning of the next year Data entries Calculation error, missing of critical reading
by using monthly trend data. A copy of trend analysis shall be forwarded to Head CQA.
Signatures / Approvals Inconsistent dates / initials, in appropriate approvals
The record retention for all closed deviation and investigation reports shall be not less than 7 years or as Equipment / Area cleaning, Line Inappropriate cleaning, Line clearance failure,
otherwise agreed with concerned regulatory body. clearance, sterilization and Sanitation questionable house-keeping.
All deviation and investigation reports shall be kept in custody of QA and QA shall maintain the Validation / Qualification related Failure to meet validation/ qualification
Deviation register. deviation requirements, non-validated equipment,
unapproved protocol
Example of Deviation: Testing not performed within established
Activity / Document Examples of Deviations Testing
timeframe, testing not performed
Documents 1) No pallet identification number on pallet.
Wrong version, data missing or incorrect
2) Case/carton/Label/Product/Lot not identified,
Procedures (SOPs) Product Identification Discrepancy Status is incomplete or incorrect.
data. Procedure not followed. 3) A lot number discrepancy either physical or
systemic between what is expected and what is
Batch records (BMR / BPR) Steps not followed, Steps skipped. received.
More than one lot on a single pallet without proper
Incoming Materials requiring QA Deviations reported by receiving department Mixed Lots on Pallet
placard and separation.
release including damaged or incorrect shipment, missing or
questionable label or documentation 1) Potential product has a deviation other than
Damaged or incorrect shipment, incomplete or incorrect Packaging and labelling
Sampling of incoming materials Potential Product Defect
2) Temperature Deviation Temperature goes outside
documentation
the specified range
Material and their status Incorrect or unapproved material used, questionable
release 1) Incorrect / defective packaging supply- Supplies
that do not meet specification.
Batch Yield Established yield or reconciliation is not met 2) Third Party Vendor Error An error by third
Third Party / Vendor or Supplier
party vendor that effects product identity,
Process Control Parameters issues
Parameters not in control and / or not followed. safety, stability
3) Transportation error An error made by a carrier of
Sampling Improper sampling technique or frequency, our products.
Sample identity mix- up 1) Lot status discrepancy The status of a lot is not
Material Holding time and holding the same in all computer systems. A situation
conditions Holding time or conditions not met, incorrect vessel used.
Lot Status Issues where the true lots status in question.
Environmental controls 2) Improperly Placard Placards do not reflect actual
Parameters exceed limits
product status
Calibration Equipment/ instrument out of calibration or tolerance, A Mechanical deviation within the unit that results in a
Mechanical Failure
log or sticker missing possible GMP deviation.
Equipment function / Facility issues Equipment/ instrument failure, incorrect equipment/ area
used
Quality Failures errors reprocessing, reinsertion

S QUESTION SR. QUESTION ANSWER
R. NO.
N ANSWER 6.0
O. MARKET COMPLAINT
DEFINATION:
MARKET COMPLAINTS
A complaint is any expression of dissatisfaction with a product or service marketed.
Any written/ genuine verbal communication received directly from any customer, retailer, distributor,
healthcare professional, regulatory agency, patient (Consumer) or field staff, regarding the safety,
identity, strength, purity, efficacy, quality, shortages or any other such complaints shall be considered
as a Market Complaint.
PROCEDURE:
All the market complaints shall be received by marketing department (Domestic/International) at Head
Office.
Concern marketing person shall record all the details of complaint product, name and address of
complainant and nature of complaint in "Market Complaint Form and forward the same to Head-CQA.
Head-CQA/Designee shall ensure that all information available in the "Market Complaint Form"
6. concerning the particular complaint. Ensure that all required information is entered and all required
1 information for complaint investigation is received and if not, then Head-CQA shall ask to send
required information to marketing department.
In case of quality/efficacy related complaint, Head-CQA/Designee shall request the

complainant/marketing department for complaint sample. Head-CQA/Designee shall follow up for
complaint sample up to 15 days from the date of complaint.
If marketing department is unable to provide the required information (Details of complaint) and
complaint sample to Head-CQA then the same complaint shall treated as non-justified complaint and
closed.
If the required information provided by marketing department/complainant, Head - CQA shall
shall be forwarded to Head-QA/Designee at site.
Head-QA/Designee shall enter the complaint details in market complaint log
After logging of complaint, Head-QA/Designee shall start the investigation of compliant based on
guideline provided

SR.
SR. QUESTION ANSWER NO.
QUESTION
NO. ANSWER
Sr. No.
Example of Suggested investigation
Sr. No.Example
Suggested
of Complaint
investigation
2. Complaint
1.Ineffectiveness
History/ of
Poor
theQuality
product.
/ Inadequate response of the drug product. Physical inspection of complaint & control sample,
Physical inspection of complaint & control sample. Review of batch document for, Less content in capsules/ For,
API calculation. tablet
Qty. added of API & excipients (dispensing slip/raw material requisition against bill of material. Minor crack.
Source of material. Improper sealing.
Dispensing precautions: e.g. API dispensing & storage in the dedicated polybag or container etc. Processing precautions, low light, and nitrogen flushing or any other. Condition of container label & / or carton to
Processing parameters. eliminate possibility of leakage.
In process checks by production & QA. Review of batch manufacturing record
Any deviation, which has direct or indirect impact on product quality. for, API calculation.
Qty. added of API & excipients (dispensing
In process quality control data.
slip/raw material requisition against bill of
Review of FP analytical report & trend. Review of stability data.
material.
Complaint & control sample analysis for, Weight variation, Hardness & friability. Content uniformity. In process checks by production &
Dissolution. Assay. QA. Yield & reconciliation of the
Degradation. Moisture content. Biological assay. batch.
Storage condition. In process & FP quality control data.
Audit of distributors, C & F agent or retailer etc. Equipment usage logbooks of compression or
capsule filing machine for breakdown.
Complaint & control sample analysis for,
Average weight
Dissolution.
Content uniformity.
Assay.
Degradation.
Weight variation.
3. Bulging of
strip/blister pockets. History of the product.
Physical inspection of control & complaint sample.
Review of storage condition.
Review of stability data.
Analysis of complaint &/or control sample
for, Assay.
4. Presence of foreign matter Degradation.
(Living / non living). History of the product.
Physical inspection of complaint & control sample.
Physical inspection of particular AR No. of RM
used for manufacturing of the batch.
Review of batch manufacturing record.
Cleaning record of mfg equipments &
area. Environmental monitoring data.
Analysis of complaint sample for,
Assay, Degradation.
Microbial contamination test.
Training record of visual inspectors.
Page 19 of 270
Page 20 of 270
SR. QUESTION ANSWER SR.
NO. NO.
QUESTION
ANSWER
Sr. No.Example of Complaint

Suggested investigation
Sr. No. Example of Suggested investigation
5.Adverse reactions (e.g.Review
vomiting,
of complaint
severe cramps,
history.
rashes
Review
etc)history of the patient. Review of package insert.
Complaint
Microbiological analysis of complaint sample. Pharmacology of the API & related formulations. History of the product. 9. Physical inspection of control & complaint sample
Physical inspection of complaint & control sample Review of batch manufacturing record for, Product or batch mix for physical appearance of primary pkg. material of
Special precautions required during processing e.g. controlled humidity/ light sensitive & temperature etc. up. two products under question.
Cleaning record of granulation, compression and coating equipments & area. Review of system followed to ensure proper segregation
In process checks by production & QA during manufacturing & packing. product at different stages.
6. Discoloration
Analysis of tablets
of control & / or complaint sample for, Assay, Degradation, Stability data Review of logbooks of machine at every stage to know
/capsules.
Storage condition. the previous or next product taken on the same machine &
Physical inspection of complaint & control sample. Review of batch manufacturing record for, precautions taken to ensure absence of same /similar
Visual inspection record product in the surrounding area.
Temp. & humidity conditions Review of other products packed on the same day on
Capsule filling machine setting parameters In process checks during manufacturing & packing by QA & production. the nearby labelling machine or packing line of product
Vendor of EHG capsule. under question.
Equipment logbook of capsule filling machine for breakdown. Review of batch manufacturing record for,
Training of the visual checkers. Machine & line clearance record at different
Compatibility study of empty hard gelatine capsule with excipients. stages.
Reconciliation of packaging materials.
Reconciliation of bulk & FP.
Analysis of control &/or complaint sample for,
7.Damaged / broken / leakage in capsule Identification test of two products under question.
Identification test of preservative.
Wrong labelling/ packing.
Training record of checker and packers.
History of the production
10.
Physical inspection of control & / or complaint sample.
Poor quality of cap Vendor of packing (cap) material.
Compatibility study
Review of stability data.
History of the product.
11.
Comparison of complaint sample with control sample fo
appearance of strip/ label (font size of letters, printed text
Faulty product (Product
matter, size of the pocket, gap between the two pockets,
Counterfeiting)
knurling pattern, logo of the company, movement of tab or
8 Broken tab. History of the product. cap in the pocket etc).
. Physical inspection of complaint & control
Comparison of complaint sample with control sample fo
sample. Review of batch manufacturing appearance of tablet or capsule (size or dimensions, colour,
record for, imprint, embossing, edge type etc).
In process checks by production & Analysis of complaint & / or control sample.
QA during manufacturing &
packing.
Visual inspection record.
Review of trend of processing, in process
& FP Parameters and Handling of the
bulk product.
Training record of the visual checkers & strip/blisters
SR.
NO.
ANSWER NO.
Head-QA/Designee shall write the complaint product details and categorize the complaint as
Critical/Major/Minor in "Market Complaint Investigation Form
Sr. No. Example of Complaint Suggested investigation Critical Complaint:

12. Empty primary container Physical inspection of control &/or complaint sample. A complaint that strongly indicates the purity, identity, safety or efficacy of a product may have been
(Bottle / pocket of strip or compromised and has the potential to cause a life threatening or serious health situation.
Logbooks of striping or blistering machine
blister) for breakdown.
Major Complaint:
Working of Non Fill Detector (NFD) or
A complaint that indicates the purity, identity, safety or efficacy of a product may have been
Blister Inspection system (BIS)
compromised, but does not present as a life threatening or serious health risk.
Review of batch document for,
In process checks by production & QA during
Minor Complaint:
filling. Leak test record.
A complaint that is neither critical nor serious
Visual inspection record.
In process checks by production & QA during
If complaint is categorized as critical, Head-QA shall intimate (within 24 hours from the receipt of the
packing (e.g. on line compressed air flow or any other
complaint) to Head - Marketing/Distribution for the immediately stoppage of the further sale and
system followed to remove empty plastic container or
distribution of the batch till the completion of investigation
empty pocket in strip or blister).
Yield & reconciliation of the batch & comparison with
trend. Head-CQA / QA shall communicate to FDA / Regulatory Affairs / Customer / MA holder / QP /
Customer regarding market complaint based on nature of market complaint
Balance or checkweigher performance & calibration
check record.
The investigation shall be carried out by a team of representatives from QC, QA, Production,
Weight variation record of packed cartons
Engineering, R&D, ADL, Marketing, RA and etc. (as per nature of complaint).
&/or shippers.
Proper segregation of packed & empty
The investigation shall involve, but not restricted to, examining reserve samples, complaint
boxes. Training record of the visual
samples and other samples, review of batches of complaint product, review of batch
13. Receipt of product in inspectors. documents and other related logbooks and documents etc.
different carton/ having Complaint sample observation.
different label. Physical inspection of control sample. If complaint sample is received along with the market complaint, it should be thoroughly
Previous & next product packed on the same machine. examined for the integrity of the pack, physical appearance and evidence of deterioration if any.
Appearance of packing material of two products under Complaint sample needs to be checked for detection of counterfeiting. Check for counterfeit
question. sample shall be
Review of batch document for,
Line clearance (by packing & QA) record.
Reconciliation of packing material. In case of quality testing related complaint, QA shall send the complaint sample (if available) or
Machine & line clearance record. reserve sample of the complaint batch to quality control department for analysis.
In process checks by packing & QA.
Storage of packing material in the store & in pkg. Depending on the nature of complaint, the reserve sample and complaint sample is to be analyzed for
Dept. the relevant test parameters specified by Head-QA. Analysis of the sample is to be carried out as per
Procedure to be followed for the left over pkg. the specification by which the product was registered.
Material after completion of packing.
Inspection of remaining stock of PM of the After completion of analysis, QC shall send the analytical report to QA for further investigation.
products under question.
Training of checker and packers. The Head-QA/Designee shall review the analytical report for compliance to specification that may be
relevant to the complaint.
If the results of reserve samples and complaint samples are complying with the specification or either
of samples complying with specification, probable root cause shall be identified with the help of
guideline
Page 24 of 270
Page 23 of 270
SR. QUESTION ANSWER
NO.
SR. QUESTION ANSWER
NO.
If any OOS observed in the control samples, then investigate as per "OOS" SOP No. QCG 034. Head-QA and other members of investigation team shall suggest corrective and preventive actions
against the identified root cause and investigation report shall forward to Head-Manufacturing.
QA shall ensure the storage of remaining complaint sample in secured manner under desired storage
conditions till the closure of complaint. Head-Manufacturing shall review and recommend suggested corrective and preventive actions.
Complaint samples received shall be destroyed during of closure of complaint. Finally Head-QA shall review and approve the investigation report and CAPA. In case
the
Head - QA shall decide for the extension of the investigation if similar complaints for the product or investigation reveals nature of complaint as Critical, Head-QA shall initiate recall of the
other products have been received. complaint
Head - QA shall form an Investigation team, comprising of technical persons from requisite
departments such as QA, QC, Production, Stores, Engineering, R&D, ADL, RA and Marketing Head-QA/Designee shall send the investigation report to all concerned persons with the corrective and
depending upon the nature of complaint. preventive actions in detail along with target completion date of actions.
Investigation team shall investigate the complaint to identify the root cause and to take necessary
CAPA. TIME LINES FOR INVESTIGATION:
Investigation shall be completed within 7 working days for critical complaint and 30 working days for
For investigation methodology/to Major/Minor (or as per Technical Agreement requirement or Regulatory Agency requirement where
appropriate) and same shall be sent to marketing department immediately after investigation.
addition, guidelines as mentioned in Annexure-VI shall be followed.
If the complaint is from regulatory agency / MA holder, investigation shall be completed according to
The complaint investigation may include the concerned Analytical Report, Batch Manufacturing their timelines.
Record, Batch Packing Record, instruments/equipments logbooks, Training Records, Stability
Records, Cleaning Records, Calibration records, Environmental Monitoring Records of various stages Approved Market Complaint Investigation report shall be forwarded to Marketing department, who in
of processing, Storage, Dispatch and distribution of the batch and other related documents such as any turn send response to the complainant.
deviation in concerned batch.
In case of complaints from export market, QA/RA shall check the regulatory impact. While reviewing
Previous and next batches of the product shall also be investigated in case of same raw materials / the impact, QA/RA shall consider the specific requirements mentioned in Technical Agreement as
packing materials are used for the batch. well as country specific requirements.
The investigation shall extend to other batches of the same drug product and other drug products if Wherever applicable, the regulatory agency / MA Holder / QP shall be informed if action is being
investigation shows the possibility of similar defects in other batches/products. considered following possible faulty manufacturing, product deterioration, detection of
counterfeiting, or any other serious quality problems with a product that could result in a recall or
If required, observations of stability study samples and review of data to be carried out. abnormal restriction on supply.
If required, help of R&D - Formulations shall be taken in case of process related problems. The corrective and preventive actions for all the complaints shall be tracked as per the SOP No.
QAD
Take Medical department opinion (if any) from medical experts as a part of investigation for clinical
related complaint.
Investigation team shall identify the root cause of complaint based on the observations made during The acknowledgement from the complainant for the receipt of the response shall be obtained against
investigation. the
Annexure-VIII. If complainant provides acknowledgment
Manager- through email / letter / fax, same shall be documented.
shall
be forwarded to Head-QA for impact assessment as per root cause identified. The complaint shall be treated as "Closed" after receiving feedback from the
MAH/Customer/Complainant. The time period for receiving feedback from the customer is 30 days.
Page 25 of 270
Page 26 of 270
SR. QUESTION ANSWER
NO.
S QUESTI
R. ON
N ANSWER
Implementation of suggested corrective and preventive actions shall be verified by Head-QA/Designee.
Designated QA person shall ensure that all correspondence related to complaint is available at site
before closure of complaint. Correspondence if made by the Marketing department / Medical
department shall also be requested from the respective department.
In case of receipt of any complaints through a legal route, the investigation findings shall be
communicated by Medley legal department in consultation with Head Quality / QA. A copy of
the response shall be kept with the complaint record at QA Daman.
Handling of Counterfeit Samples:

In case if the received complaint samples is suspected to be counterfeit, then it shall be examined as
follows:
In Comparison of packaging / labeling of the complaint sample with reserve
sample. Check the coding style / printing of the batch details.
Quality of the packaging components.
Organoleptic properties of the drug in comparison with reserve sample.
If the comparison of the packaging components, coding style and organoleptic examination does not
reveal the conclusive evidence then perform the analysis of the complaint sample along with reserve
samples.
During the course of investigation, if the complaint sample received found to be counterfeit then
Head- QA shall inform to marketing and Medley representative in countries where the company's
products are marketed for appropriate action through Head-CQA.
REVIEW AND TRENDING OF COMPLAINTS:
Head - QA shall review the complaint status every quarter to evaluate specific or recurring
problems which require further attention.
Designated QA person shall prepare complaint yearly trends. Trends shall be reviewed by Head -
QA and required action shall be taken accordingly.
The records of all market complaints for drug products and the follow -up / related records shall be
kept for one year from the date of expiry of the batch for which the complaint has been received.

SR. QUESTION ANSWER SR. QUESTION ANSWER
NO. NO.
7.0 In case of product recall, Head-QA or his designee shall intimate to the members of Recall Co-
PRODUCT RECALL
ordination Committee (RCC) and organize for a meeting.
DEFINATION: The RCC members shall evaluate the known information on the nature and extent of the health risk
taking inputs from Head-Medical department
PRODUCT RECALL:
Removal or correction of marketed products for the reasons relating to deficiencies in quality, safety or Based on the evaluation, the RCC members shall classify the recall as Class I, Class II and Class III to
efficacy, including labeling considered to be in violation of the laws. indicate the relative degree of health hazard of the product being recalled or considered for recall.
Class I Recall:
PROCEDURE:
These are recalls which result from quality defects of medicinal products which are potentially life
Any batch of a product not meeting the defined quality standards has to be recalled from the market.
threatening or could cause serious risk to health.
Recall can be of two types; Voluntary Recall and Statutory Recall.
Class II Recall:
Voluntary Recall: Voluntary recall can be triggered by any incident that affects the quality, safety and
These are recalls due to quality defects which may cause mistreatment or harm to the patient but it
efficacy of the batch/product in question such as
is not life threatening or serious.
If the batch or batches are found to be not complying with the regulatory specifications Class III Recall:
during the post marketing stability study
These are recalls due to quality defects which are unlikely to cause harm to the patient, and the pose
a significant hazard to health but where a recall has been initiated for other reasons, such as non-
If the batch is found to be defective during investigation of market complaint. compliance with the marketing authorization or specification.
During any failure investigation, if it is observed that the failure under investigation might have Levels of Recall:
adverse quality impact on already released batch. The level (or depth) of recall of a product/batch shall be determined based on recall classification
7. and level to which distribution has been taken place.
1 If any unusual observation is noted during visual inspection of reserve samples which There are three levels of recall such as consumer /user, retail and wholesale.
indicate an impact on quality of the product after investigation.
Consumer or User Level: This may vary with product, including any intermediate wholesale or
If the post marketing surveillance reports /pharmacovigilance reports indicates that there is retail level. Consumer or user may include individual consumers, patients, physicians and hospitals.
serious safety risk associated with the product. Retail Level: Recall to the level immediately preceding consumer or user level. It includes retail
shops, pharmacies, hospital pharmacies, dispensing physician, institutions such as clinics and
nursing homes, etc.
Statutory Recall: Statutory recall can be triggered in response to the direction or mandate by the Drug
Regulatory Authorities. Wholesale Level: All distribution levels between the manufacturer and retailer.
To recall the drug product/batch, considered to be in violation of the laws, it administers Class I Recall: Notification and acknowledgement of receipt of recall notification within
such as not of standard quality etc. 24hrs. Class II Recalls: Notification and acknowledgement of receipt of recall notification
To recall the banned drugs. within 48 hours. Class III Recalls: Notification and acknowledgement of receipt of recall
Labeling and / or Promotional materials that are considered to be in violation of law. notification within 5 days.
Mock recall shall be done to evaluate the effectiveness of arrangements periodically to recall the
Recall Logging: Once a potential product recall situation is identified Head-QA/designee shall products from EU / US / Australia / other export markets and domestic markets. Mock recall is
enter the details in Product Recall log applicable only to markets where product is already marketed.
Designated QA person shall assign a product recall number to the same Frequency of Mock Recall shall be once in two years or as per MA Holder / Contract giver
requirement.

R. NO.
N ANSWER 8.0
O. CAPA
Correction
Immediate action to correct
Corrective Action
Action required to correct and prevent a re-occurrence for something that happened yesterday
Preventive Action
Action required to prevent an occurrence of something that may happen tomorrow
Root Cause Analysis :

Root cause analysis is a problem solving technique for identifying the basic or cause factor (s) that
underlie the occurrence or possible occurrences of an adverse event in a process similar to diagnosis
of disease with the goal always in mind of preventing reoccurrence.
CAPA Identification
The source of quality problems leading to CAPA could be following, but not limited to:
Change Control and its trends
Deviations/Incidents and its
Trend Market Complaints and
its Trend
Out of Specification Results and its Trend
8. Stability Results, Out of Trends
1 Product Recalls and/or Field Actions, such as Field Alert Reports
Material / Batch Failure, Self Inspection/Audits
Regulatory Audit and Commitments
(Query/deficiency received post submission to any regulatory agency)
Audit by Contract Giver
Technology Transfer Document
PQR, Environment and its
Safety Quality Control Stability
Reports
Return Goods, Other Non
Conformances Risk Assessment
Recommendation of Executed Validation
Adverse Reaction Reported, Supplier Non Conformance
Process Control Data Review
Instrument/Equipment Service Data Review
Calibration Review, Management Review Results
Scrap, Yield or Rework Data
Any Assessment of Quality data that reveals a negative trend, undesirable condition, out of control
situation or other Quality problem may result in a CAPA.
All CAPA form shall be maintained separately with CAPA log by designated QA person, for easy
traceability.

S QUESTION
R.
N ANSWER SR. QUESTION ANSWER
O. NO.
FLOW CHART OF CAPA 9.0
MANAGEMENT NOTIFICATION
9.1

S QUESTION S QUESTION
R. R. ANSWER
N ANSWER
10.0NPI N
REGULATORY UPDATES
O.
FLOW CHART OF NPI 11

.0
S NAME OF THE
R WEBSITES
.
N REGULATORY AGENCY
O
.
1 DCGI (India) www.cdsco.nic.in
2 WHO www.who.int
3 ICH
4 PICs www.picscheme.org
5 USFDA www.fda.gov/drugs
6 Health Canada (Canada) www.hc-sc.gc.ca
7 MHRA (Europe) www.mhra.gov.uk

10
.1 8 EMEA (Europe) www.ema.europa.eu
9 EDQM (Europe)
11 1 MCC (South Africa) www.mccza.com

.1 0
1 TGA (Australia) www.tga.gov.au
1
1 ANVISA www.anvisa.gov.br/eng/index.htm
2
Head QA/designee shall subscribe to receive the periodic updates and changes of regulatory guidance
from various regulatory agencies at the following web addresses, where such subscription is not
available, specific website shall be checked for any updates.
Regulatory guidance updates shall be reviewed and downloaded by visiting the web sites mentioned
above. Latest regulatory guidance/addendum to guidance can be downloaded from publications/news
centers/consumer updates/public health notifications/latest press etc.
Head QA/designee shall compile the updates and relevant changes and communicate to all affecting
departments once in a month

S QUESTI SR. QUESTION ANSWER
R. ON NO.
N ANSWE 13.0
O. R SHELF INSPECTION
Affecting departments head shall share the gap analysis details with Head-QA and implement the
changes through change control procedure.
Head QA shall share regulatory updates/news letters, gap analysis and its implementation to Head-
CQA on monthly basis.
Head-QA/designee shall provide training to the concern department about the regulatory
updates/changes before its implementation, where applicable.
12. PLANT QUALITY REVIEW MEETING

0
It is a meeting conducted every month at location of Medley pharmaceuticals Ltd, Daman to discuss the
key performance indicators (KPIs) of total Quality Management tools with the help of prepared
metrics. the actions of KPIs.
A schedule for Plant Quality Review Meeting (PQRM) shall be followed every year as per the
Annexure- I. This review meeting shall be held on every month within the second week. The
Annual schedule shall be prepared by Manger- QA and approved by Head- QA.
The meeting shall emphasize effective understanding of Quality GMP issues that shall result in
effective decision out come.
Based on the discussion held in the plant quality review meeting action plan, responsible person and
target completion date shall be decided by the user departments Head and shall be documented in
minutes of meeting
Head QA/Designee shall share the outcome and minutes of meeting with the all respective
12.1 department head and to Senior Management on agreed actions.
A systematic inspection program to detect any short comings in the implementation of cGMP and to
recommend necessary corrective actions.
Manager QA/Head QA shall nominate the Self Inspection team.
Team shall be a cross functional team comprising of persons from different departments such as
Quality Assurance, Quality Control, Production, Warehouse, Engineering and Personnel and
Administration department . QA must be a part of the team.
Internal auditor shall be trained with Auditor certification Training program.
Educational Qualification: Graduate in Science, Pharmacy, Engineering and other respective

disciplines.
Experience: Preferably 5 years of experience in pharmaceutical industry, GMP knowledge,

professional and practical experience related to GMP. Understanding of National, Local and Global
legislation GMP.
Designate QA person shall prepare a schedule (for the next year ) at the end of the calendar
year The frequencies for audit shall be scheduled as twice in a year

13
The actual audit date may vary by ± 15 working days from the tentative date or depend on the
.1
availability of Audit team.
The Self Inspection team shall summarize the audit observations and discuss the observations
among the team members.
The team shall classify the audit observations as Critical, Major or Minor based on following.
The concerned HOD shall submit the response within 10 working days of receipt of "Self Inspection
observation report" which includes compliance to audit observations, action plan for CAPA with target
completion date.
The self-audit team members shall review the compliance report and verify the implementation as
stated in the compliance report.
On verification of implementation, the self-audit team members shall close the report and submit
the report along with Audit summary (Annexure II) to Head - QA.
Head - QA/ Designee shall review and ensure that the observation reports are closed properly
Designated person from QA shall store the report in documentation cell for 6 years.

NO. NO.
14.0 Purchase department shall ask the vendor for pre-purchase samples of at least one batch depending
VENDOR MANAGEMENT
upon the along with its certificate of analysis and shall be sent to Formulation Development and/or
Quality Control for analysis.
DEFINATION:
Formulation Development and/or Quality Control shall evaluate the source material lots and on
New Vendor: Manufacturer identified by Formulation Development or purchase department as a compliance of the sample as per specification and shall confirm the suitability as per specification to
manufacturer to supply of a specific material from a specific manufacturing site. purchase department.
Approved Vendor: Manufacturer of raw material, primary and printed packaging material, which has Formulation Development and/Quality Control will intimate the purchase and QA for suitability of
been approved by QA to supply a specific material from specific site, based on the satisfactory cGMP sample.
history as well as compliance of material to specification.
Based on the assessment report from Formulation Development and/Quality Control satisfactory
evaluation of data provided by the vendor, the new vendor shall be considered as a
PROCEDURE:
VENDOR DEVELOPMENT The vendor list contains Material Code, Material Name, Synonym/ Storage Condition, Manufacturer
Name and Site Address, Suppliers Name and Address and current approval status. The vendor list
The requirement of new raw & packing materials and their profiles shall be given by the formulations shall be prepared, reviewed and approved. A separate vendor list shall be prepared for US/UK market
development department. and others.
In charge-purchase (Vendor development) shall identify the vendors with the available information Once vendor is temporary approved, vendor code is to be assigned to the particular vendor as well as
based on specifications provided by formulations development department. material code in SAP is to be generated by purchase department in co-ordination with SAP department.
APPROVED VENDORS
ASSESSMENT OF NEW VENDOR ( S) FOR NEW / EXISTING Temporary ap -
14
.1
MATERIAL TEMPORARY APPROVED VENDORS For Manufacturer
Another Two commercial lots supplied by Temporary approved vendors are analysed and passed.
quality history is required. Purchase department shall collect and maintain information of the new In case of API/ Primary packing material, vendor questionnaire is filled and vendor audit is done and
vendor through the vendor registration form for manufacturer and for supplier or Trade. complied.
Purchase department will get technical information regarding the material through vendor questionnaire In case of excipients and secondary packing material questionnaire is completed.(if required, audit to be
from the vendor which includes the brief manufacturing process, TSE/BSE free declaration, impurity carried out)
profile, residual solvent information, GMO free declaration, Melamine free declaration, Gluten free
declaration and stability data/shelf life statement etc. as applicable depending upon the type of material. When manufacturing site audit is required, it shall be carried out by site QA/CQA to assess
compliance with cGMP requirements.
GMO : Genetically Modified Organism
The manufacturing site of the vendor shall be audited as per the checklist.
Note: For non-critical excipients requirement of impurity profile, residual solvent information,
stability data, GMO/Melamine/Gluten free declarations are not mandatory. Based on the audit findings, a detailed report shall be classified as critical(C), Major (M) and minor
Purchase department shall ask the vendor for analytical method and analytical method (N) as described under definitions.
validation data for the materials claiming residual solvents.
The purchase department shall send the site audit report prepared by site QA/CQA to the vendor.
Based on the evaluation of above information and vendor registration form, Purchase/Formulation
development department shall ensure that vendor is ready to supply material of required grade with The vendor should respond in a period of 30 days after receipt of the audit report from purchase
specific requirement, if any. department.

SR. QUESTION ANSWER
NO.
S QUESTION
R.
N ANSWER
FLOW CHART OF VENDOR APPROVAL
The audit compliance report received from the new vendor shall be evaluated by the audit team
members and recommendations shall be given to approve or reject the vendor by head QA.
Re-audit may be required for ensuring compliance in case of critical deficiencies observed during the
audit.
QA shall update the vendor list once in 6 months to include or exclude approved vendor and to reflect
the change in the status of vendors.
PERIODIC EVALUATION OF APPROVED VENDORS
quality issues, if
any Yearly trending of all API from the Vendor shall be carried out of quality issues, if
any.
Reassessment of quality systems shall be carried out if the rejection rate on quality grounds is higher
than 20%.
nd primary packing materials shall be audited once in three years.
The vendor should respond with audit compliance report in a period of 30 days after receiving the audit
report from purchase department.
If the compliance is not satisfactory, then the vendor rating will be downgraded or disapproved and
deleted from the list. QA will update the vendor list accordingly and communication of the same shall
be sent to QC, warehouse and purchase department.
DISQUALIFICATION OF VENDORS
Vendors failing to meet the GMP requirements and those consistently (up to three lots) failing to meet
quality standards shall be disqualified and blocked for supply of material by QA. However vendor can
immediately be disqualified, Incase of any critical failure e.g. failing in potency (Assay below 80 %),
microbial test (failure in pathogens).
If the satisfactory corrective actions are taken by the vendor to resolve the quality problems and non-
compliances, the vendor shall be re-approved for the supply.

NO. NO.
15.0 Cleanability of API shall be mentioned as per following Table:
CLEANING VALIDATION
Approximate volume of solvent
Solubility Cleanability
Index in milliliters per gram of solute
Food Branch Inspectorate Cleaning Validation Guideline-Health Canada.
Very soluble Less than 1 part (< 1) Easily
cleanable Freely soluble From 1 to 10

Cleaning validation is documented evidence that an approved cleaning procedure will provide equipment which is suitable for processing medicinal products.
parts (1 : 10) Easily cleanable
Soluble From 10 to 30 parts (10 : 30) Easily cleanable

ts Sparingly soluble From 30 to 100 parts (30 : 100) Hard to
f the previous product Biological - Microorganisms
matter From 100
clean Slightly soluble
to 1000 parts
be mentioned as per following Table: Hard to clean
(100 : 1000)
Approximate volume of solvent in milliliters per Very slightly From 1000 to 10000 parts
Solubil gram of solute soluble (1000 : 10000)
Mechanical water forced
ity required
Very soluble Less than 1 part (< 1) Practically
insolub More than 10000 parts (> 10000) Mechanical water forced required
Freely soluble From 1 to 10 parts (1 : 10) le
Soluble From 10 to 30 parts (10 : 30)
Sparingly soluble From 30 to 100 parts (30 : 100) All equipments parts shall be identified as per rational criteria and categories as per bellow
Slightly soluble From 100 to 1000 parts (100 : 1000)
Hard to clean
Very slightly soluble From 1000 to 10000 parts (1000 : 10000)
Direct contact with product
Practically insoluble More than 10000 parts (> 10000)
No direct contact with
LD50 of API shall be mentioned as per following Table: product

Probable oral Lethal Included
dose descriptive
for humans (Mg/ kg) SAMPLING TECHNIQUES
>15000 Practically non Visual Inspection (Method For Validation of Cleaning of Equipments):
toxic After cleaning of the equipment visual inspection shall be done using a torch held inclined to the
5000- surface being inspected, and a mirror (attached to stainless steel rod) to inspect the surface of
15000 Slightly toxic
equipment. Visual inspection shall be done by unaided naked eye.
500- Moderately toxic
For visual cleaning;
5000 Very toxic
Verify the cleanliness of the product contact surfaces.
50-500
Verify the cleanliness of hard to clean areas.
Extremely toxic
Verify all the product contact dismantled parts before and after assembling.

S
R. QUESTI
ON
N ANSWER
O.
Sampling Procedure:
Surface sampling is identified as a sampling method considering the design, size and number of
equipment.
After the completion of equipment cleaning, visual inspection shall be done.
In case, the surface of equipment is difficult to inspect, a mirror attached to a stick shall be used to
inspect the cleanliness of equipment.
Complete product contact surface area shall be sampled for critical hard to clean area/ critical
accessories like spray gun, punch, dies, and butter fly valve etc.
Swab Sampling for Chemical analysis:

After visual inspection is found satisfactory swab sampling shall be carried out.
Wear hand gloves and nose mask before commencing swab sampling.
The swab must be wetted in purified water or suitable diluents.
Swab area shall be measured with the help of template for swabbing and the area must be 5cm x
5cm or as per protocol.
Swabbing shall be done by parallel horizontal and then tilt the swab and do vertical strokes as
described below to assure that the entire area is swabbed.
5 cm
5 cm 5 cm
Horizontal strokes Vertical strokes
After swabbing, place the swab into a stoppered test tube, wrap with aluminum foil and label the
test tube for identification of swab sample.
Swab samples must be collected from different areas of equipment as stated in the cleaning validation
protocol.
Send the stoppered test tube with swab to Quality Control Laboratory for analysis.
Swab sampling for Microbial analysis:

Wear sterile hand gloves and nose mask before commencing swab sampling to avoid the
microbiological contamination.
Sterile cotton swab shall be used for swabbing.
S QUESTI
R. ON
N ANSWE
O. R
The sterile cotton swab shall be soaked in sterile saline.
Swabbing shall be done by parallel horizontal and then tilt the swab and do vertical strokes as
described below to assure that the entire area is swabbed.
5 cm
6 cm 6 cm
Horizontal strokes
Swab area shall be measured for swabbing and the area must be 5cm x 6cm.
Microbial swab sample shall be collected before chemical swab.
Swabbing shall be done on the surface of equipments and the area is different from the area of
swab taken for chemical analysis.
After swabbing, place the swab into a sterilized stoppered test tube and label the test tube for
identification of swab sample.
Swab samples must be collected from different areas of equipment as stated in the cleaning validation
protocol.
Send the sterile stoppered test tube with swab to Quality Control Microbiology Laboratory
for analysis.
Rinse Sampling Procedure:
After visual inspection is found satisfactory, the equipment shall be rinsed with the volume of rinsing
solvent (purified water) as described in respective cleaning validation protocol (rinse sample shall be
performed whenever necessary).
Rinse sample shall be collected in the bottles used for the collection of routine purified water samples.
After the collection of rinse sample, (stopper) close the bottle and label it for identification of rinse
sample.
Send the rinse sample bottle to Quality Control Laboratory for analysis.

SR. QUESTION ANSWER S QUESTION
NO. R.
N ANSWER
O.
MANUFACTURING VESSEL LID GASKET Method of analysis:
Methods of analysis used for determination of possible contaminant residues must be specific and
sensitive.
The selection of analytical methods shall be validated for at least below mentioned parameters based
on at least the following but not limited to;
Precisi
on,
Specifi
city
Linearity and
Range, Limit of
Detection, Limit of
Quantification,
Stability of
solutions,
Recovery from Equipment Surface.
FOR WORST CASE APPROACH;
10 PPM Criteria:
MACO = [Mac10] x [Swab Area]

[Shared equipment surface area between products]
Where,
Mac10
Dose Criteria:
MFG VESSEL LID PRODUCT CONTAINER LID MACO = S.F x [SRDD (A) in mg] x [MBS (B) in mg] x [Swab Area]
[LRDD (B) in mg] x [shared equipment surface area between
products]

SR. QUESTION ANSWER
NO.
Re-validation:
Re-validation shall be performed in case of any change, (at least the following but not limited to)
Introduction of a new facility, equipment, process or product.
Change in cleaning procedure.
Change in cleaning agent used for cleaning.
Reduction in minimum batch size and lowest dose of the product i.e change in MACO limit.
Major Modification in processing

equipment. Periodic revalidation after
every three years. Change in regulatory
MBS (B) requirements.
Dirty Equipment Hold Time (DEHT) The time from the end of manufacturing till the beginning of
The Hold Time Study of Dirty Equipments shall be carried out by keeping equipment in idle for a
LIMITS:
period of 24 hours in dirty condition. (The Maximum possible hold period under normal conditions) to
evaluate microbial contamination on equipment surface and effectiveness of cleaning process.
n criteria: No quantity of residue should be visible to naked eyes on the equipment after cleaning procedures are performed (i.e. less than 100 mcg /25 cm2).
Clean Equipment Hold Time (CEHT) The time from the end of equipment cleaning till
Not more than 10ppm of active pharmaceutical ingredient of previous product is permitted in next product. subsequent use of equipment (subsequent use includes product manufacturing).
visual inspection by keeping equipment in idle clean condition up to 72 hours to

eria: Not more than 1/1000 of minimum daily therapeutic dose of the previous product in the maximum daily dose of the next product establish the expiry of cleaning in view of microbiology.
After the equipments surfaces are found visually clean, sampling and testing shall be carried out for
Microbiological enumeration Tests and residual determination (chemical analysis) on the cleaned
y limits for microbiological sample shall be determined based on; equipment surfaces at 0 hour interval, then sampling and testing shall be carried out only for
Microbiological enumeration Tests at rest intervals as per the sampling plan. (i.e., after 24 hours, 48
Limit Dirty Equipment Limit Cleaned Equipment hours and 72 hours).
Parameters
Surfaces Surfaces
Total Aerobic Microbial
NMT 1000 cfu/swab NMT 100 cfu/ swab
(TAMC)
Dirty Equipment Hold Time Period : 24 Hours
Total Combined Yeasts
Less Than 10 cfu/swab Less Than 10 cfu/ swab
Cleaned Equipment Hold Time Period : 48 Hours

NO.ANSWER NO.
16.0 PRODUCT QUALITY REVIEW (PQR)
Process Capability (CpK) shall be carried out for critical analytical parameters e.g. Assay.
DEFINATION:
CpK= USL-X or X -LSL
PRODUCT QUALITY REVIEW (PQR): 3*SD 3*SD
Documented regular periodic or rolling quality reviews of all licensed medicinal products with the Where LSL = Lower specification limit
objective of verifying the consistency of the existing manufacturing process to highlight any trends
and to identify product and process improvements or weaknesses for licensed medicinal products the USL = Upper specification
appropriateness of current specifications for both starting materials and finished products is included limit X = mean
SD = Standard Deviation
PROCEDURE: This calculation helps to understand how close the process is producing outcomes compared to what
th specification is.
PQR shall be prepared for each product manufactured and tested in a calendar year from January to
December. Interpretation:
CpK < 1.0 i.e. process is not capable
st
The Final PQR shall be prepared before the end of first quarter of the next year i.e. 31 March. CpK 1.00 to 1.33 i.e. product is barely
Interim PQR shall be prepared as trend of critical parameter on every four months i.e. January- manufactured CpK 1.34 to 3.00 i.e. process is
April, May-August, September December. good
Trend data for critical in process parameters, finished product, analytical parameters and process CpK 3.0 i.e. Process is excellent
parameters shall be prepared and reviewed. Critical parameters such as, Note: Minimum 10 batches are required to calculate the Process Capability (CpK).
16
.1 In-Process Parameter includes (but not limited to), Storage Period
Average weight, pH, Water Content, Hardness, DT & Friability, and Assay etc. All PQR is to be stored for the period of six years.
Finish Product Tests includes (but not limited to),

Assay, Water / Loss on Drying, Identification, Description, PH, Fill volume, related substance What is PQR :
Dissolution, etc.
Which name is using in MHRA/USA PQR/APQR
Process parameters includes (but not limited to),
Blending time, mixing time, RPM of compression machine, details of yield reconciliation of total batche
manufactured in the year. Which guideline
Graphical representation for trend data of in process Parameters, Finished product analytical EudraLex Volume 4
parameter and Process Parameters shall be made.Following statistical quality review shall be performed Health Science Authorities
on critica parameters e.g. (HSA) PICS
Minimum, Maximum & Mean value of analytical
parameter. Standard Deviation
If OOT found then
Relative Standard Deviation If any abnormal trend of the data observed during the compilation and review, it shall be commented
Process Capability (CpK) in the report, if required the investigation shall be done.

S
R. QUESTION SR. QUESTION ANSWER
NO.
N ANSWER 17.0
O. PROCESS VALIDATION
CONTENTS
Review of starting material

Review of packing material
Review of critical in-process
controls Review of finished
product results Review of process
parameters
Review of all batches that failed to meet established specification and their investigation
Review of significant deviations or non-conformance.
Review of changes
Review of marketing authorization variation
Review of stability monitoring program and adverse trends
Review of quality related complaint/recall /any investigation conducted.
Review of adequacy of any other previous product process/equipment corrective actions
Review of new marketing authorization and variations and review of post marketing commitments
Review of qualification status of relevant equipments and utilities
Review of technical agreements
Review of process validation
Review of control sample
evaluation
Review of environmental and water quality status
Process capability
Summary
Conclusion
Recommendat
ion
List of Annexures Attached
Reference
Abbreviations
DEFINATION:
Process Validation: Process validation is establishing documented evidence which provides a high
degree of assurance that a specific process will consistently produce a product meeting its pre-
determined specifications and quality characteristics.
Types of Validation
Prospective Validation
Concurrent Validation
Retrospective
Validation Revalidation
Prospective Validation:
Validation carried out during the development stage by means of a risk analysis of the
production process, which is broken down into individual steps. These are then evaluated on the
basis of past experience to determine whether they may lead to critical situation.
Concurrent Validation:
Validation carried out during routine production of product intended for sale on at least one batch.
17 Retrospective validation (Based on Historical data):

.1
This approach to validation shall be undertaken on products already in commercial distribution
and have a long history of compliance to established standards.
Re-validation: A repeat of the process validation to provide an assurance that changes in the
process/equipment introduced in accordance with change control procedures do not adversely affect
process characteristics and product quality.
PROCEDURE:
Process Validation shall be carried out in the following cases :
New product introduction
Change in manufacturing formula
Change in approved vendor source of active pharmaceutical ingredient
Change in Batch size. Change in Equipment. Change in Manufacturing
site
Any other change as deemed necessary for validation through change management
system The Process validation shall be performed on at least three successful commercial
batches or as per

SR. QUESTION ANSWER S QUESTI
NO. R. ON
N ANSWE
O. R
In case where the circumstances demands single or two batches, the process validation shall be
carried out covering all the variables [Critical quality attributes (CQA) and critical process parameters Any Out of Specifications encountered during the process validation execution shall be
(CPP)] and a final report shall be prepared based on the single or two batches data.
investigated and the process validation program shall be modified if required.
In case where the process validation is planned for three batches but circumstances demands batch
release prior to completion of all three validation batches then an interim report shall be prepared
REVALIDATION
Prior to progression of exhibit / process validation studies, ensure the following availabilities: Change in Batch Size.
All instruments are calibrated.
Change in location of product manufacturing site.
All equipments, utilities and area are
qualified. All personnel are trained and Change in Major Equipment or major part of the equipment impacting the product quality.
qualified.
Change in manufacturing formula.
Process validation protocol is approved.
If there is any change in the Regulatory requirements.
Contents
Product Details Change in API source.
Protocol Approval Sheet
Contents of process validation As per review recommendation in APR.
protocol Introduction,
Objective,
Scope
Responsibili
ties
Number of Process Validation
batches Design Plan
Reference
Documents List of
Equipments
Qualification of Equipment
In-process testing instrument details
Process Flow Chart
Manufacturing Process
Scientific justification for critical process parameters
Composition
Sampling plan
Certificate of
Analysis Acceptance
Criteria
Change control and revalidation criteria
Deviation
Summary Report, Conclusion and
Approval List of Annexure

NO. NO.
18.0
QUALITY RISK MANAGEMENT Quality risk management team shall be a cross functional team comprise of experts from
different areas (such as Head-QA/designee (as a team Leader), Quality Assurance, Quality
Control, Production, Warehouse, Engineering departments, P&A, Regulatory affairs, ADL,
DEFINATION: R&D and Marketing department) in addition to individuals who are knowledgeable about the
quality risk management process.
Risk Assessment: A systematic process of organizing information to support a risk decision to be
made within a risk management process. It consists of the identification of hazards and the analysis Risk Identification:
and evaluation of risks associated with exposure to those hazards. Risk may be identified by anyone working in his/her respective workplace with the systematic use of
information.
General Quality Risk Management Process Risk Analysis :
Initiate Team shall analyze the risk linking the likelihood of occurrence, detection and severity of harm using
qualitative descriptor such as "High", "Medium" and "Low".
Quality Risk Management process
Relative Risk Description
Risk Assessment
The Operation / Practice /Equipment/ Condition / System/ Documents/
Risk Identification Materials etc. that may have direct impact on product quality/ safety.
Failure of the system which may result in an inappropriate
High decision or action related to product quality/ safety.
Risk Analysis There is no other system to check or verify the product
quality/ safety.
The system can have an indirect impact on product quality/ safety.
Risk Evaluation
Failure of the system may result in an inappropriate decision or
18 Unacceptable Medium action relative to supporting processes or systems that have direct
impact on
.1
product quality/safety.
Risk Control 1) The system does not have an impact on product quality. Failure of
the system may result into changes in practices, Procedure,
Risk Reduction Low SOP modification etc with no risk to product quality/ safety.
Risk Acceptance Risk Evaluation :

Risk shall be evaluated by considering the probability of occurrence, detectability and severity of
the harm covered under Risk Management Tools.
Output / Results of the
t Risk Control
Quality Risk Management process Quality Risk management team shall decide the steps to control the risk by considering the
following: Is the risk estimated in the assessment above an acceptable level?
Risk Review What can be done to reduce or eliminate the risk?
What is the appropriate balance among benefits, risk and
Review Events resources? Are new risks introduced due to identified risk being
controlled?
Based on the criticality or level of risk, specific corrective actions should be developed to prevent
recurrence of instances where there have been deviations from established risk control measures,
especially for high risks
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Page 58 of 270
SR. QUESTION ANSWER
NO. S QUESTI
R. ON
Risk Acceptance: N ANSWE
O. R
If it is not possible to entirely eliminate the risk, decision shall be taken to accept the risk assuring Quality Risk Management Methodology
to reduce it to acceptable level. This acceptable level will depend on many parameters and should
be decided on a case to case basis.
Basic risk management facilitation methods (flowcharts, check sheets etc.)
Failure Mode Effects Analysis (FMEA)
The Quality risk management team shall identify the corrective actions for the identified failure or
failure. Failure Mode, Effects and Criticality Analysis
(FMECA) Fault Tree Analysis (FTA)
The Quality risk management team shall draw out the conclusion at the end of the quality risk Hazard Analysis and Critical Control Points (HACCP)
assessment study. Hazard Operability Analysis (HAZOP)
Preliminary Hazard Analysis
Risk Communication: Risk communication is information sharing session between risk (PHA) Risk ranking and filtering
management team and other concern department involved with different functions. Once approved, Supporting statistical tools
quality risks shall be communicated to the relevant department Heads to implement the suggested
actions to mitigate / avoid risks. Training shall be given to the concern to mitigate/ avoid risks. If
required, risk shall be communicated to the suppliers/customers. The output / results of the risk
management shall be appropriately communicated and documented. Failure Mode Effects Analysis (FMEA) :
Risk Review: Risk assessment reports along with supporting documents (if any) shall be forwarded Selection of the process:
to respective head of the department for review. Further same reports shall be forwarded to Head The first thing is, select the process to be analyzed.
QA for review and approval.
Review of the process:
Identified quality risks through Planned Risk assessment (e.g. change control, temporary change The selected process shall be analyzed and described in a flowchart and flow of the process shall be
etc.) and Unplanned Risk assessment (e.g. deviation, complaint, OOS etc) shall be logged and studied thoroughly for the efficient output. And attach the same to the FMEA.
tracked in "Risk Management Log..
Brainstorm potential failure modes:
Risk assessment reports and risk management log shall be maintained by QA. Look at Each stage of the process and identify the ways it could potentially fail or the things that
might go wrong.
As an ongoing part of quality management process, risk management shall be reviewed to take into
account new knowledge and experience. List of potential effects of each failure mode: List the potential effect of each failure next to the
failure. If a failure has more than one effect, mention all. To identify the effects and the causes of
Once Quality risk management process has been initiated, the process shall be utilized continuously the
by QRM team, for events that might impact the original quality risk management decision whether
these events are planned (e.g. results of product review, change controls, inspections, audits) or
unplanned (e.g. Root cause from failure investigation, recall, deviations, complaints). Assign a severity rating for each effect:
Give each effect its own severity
Rating Severityrating (from 1 to 5, with 5 being the most hazardous effect).
The QRM team shall review and verify for the effectiveness of the process of risk assessment for
planned as well as unplanned risks. 1 No Effect on output
2 Minor Effect
3 Moderate Effect
4 Serious Effect
5 Hazardous Effect
Page 59 of 270
Page 60 of 270
SR.QUESTION
NO.ANSWER
e mode: Prioritize the failure modes for action:

he failure of the product. Using this information, determine how likely it is for a failure to occur and assign an appropriate
Depending
rating (from
upon 1calculation
to 5, withand
5 being
analysis
the almost
carriedcertain).
out, decide the priority order. Give the priority to the items with high RPN value or high severit
Acceptance Criteria:
Rating Occurrence In case of calculated RPN rating is greater than 50 that particulars failures are not accepted and recommended solution shall required.
1 Very rare
If the RPN rating is between 25 and 50, recommended solution may be required if the detectability is 5.
2 Unlikely Possible
3 Likely
If For RPN rating < 25, no recommended solution is required.
4
5 Almost Certain (every time) Recommended solution is required if any of the individual severity, occurrence and detectability is high i.e. 5 (even if RPN is within the acceptan
ating for each failure mode and effect: Sr. RPN Rating RPN Category
ently in place to prevent each effect of a failure from occurring and assign a detection rating for each item (from 1 to 5, with 5 being a lack of detection). No.
1 76 to < 125 Critical
Rating Detectability 2 51 to 75 Major
1 Always detected 3 26 to 50 Moderate
2 Will detect failure 4 Up to 25 Minor
3 Might detect failure Action to eliminate or reduce the high risk failure modes:
4 Almost Certain not to detectThe action to be taken for each high risk failure and a person shall be assigned to implement the action /change.
failure
5 Lack of detection control
Considering acceptance criteria, detailed recommended solutions to be drawn with responsibility. Implementation should be through appropriate CAPA and change control procedure
Calculation of the risk priority number (RPN) for each effect:

Compliance of recommendation shall be monitored by Quality Assurance department.
Calculate the RPN by multiplying the severity rating with that of occurrence rating and detection rating.
FMEA shall be reviewed after six months till all RPN are reduced to < 25 or risks are reduced to acceptable level.
Occurrencex Severity x Detectability
Frequency of
driven by the number of trials

Degree of belief
Past Today Future
Page 62 of 270
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SR. QUESTION ANSWER
NO.
SR. QUESTION ANSWER
NO.
Hazard Analysis and Critical Control Points (HACCP): The flow chart for Hazard Analysis and Critical Control Points is as follows:
HACCP is a systematic, proactive and preventive tool for assuring product quality, reliability
and safety. Initiate HACCP
It is a structured approach that applies technical and scientific principles to analyze, evaluate, Risk Assessment = Hazard
prevent and control the risk or adverse consequence(s) of hazard(s) due to the design, development,
production and use of products.
Analysis Identify Hazards
HACCP is most useful when product and process understanding is sufficiently comprehensive to
support identification of critical control points.
Determine Critical
The output of a HACCP analysis is risk management information that facilitates monitoring of
critical points not only in the manufacturing process but also in other life cycle phases.
Determine Critical Limits
HACCP consists of the following seven steps:
Conduct a hazard analysis and identify preventive measures for each step of the process.
Determine the critical control points Unacceptable
Establish critical limits Risk Control = Critical Control
Establish a system to monitor the critical control points to reduce risk to acceptable level.
Establish the corrective action to be taken when monitoring indicates that the critical control Point System to monito
points are not in a state of control.
Establish system to verify that the HACCP system is working effectively;
Establish a record-keeping system. Corrective Action if CCP is out of Control
Potential Areas of Use(s) are following but not limited to:

Material receipt Output / Results of the HACCP
Sampli Q g
ng
Analysi Risk Review = Effectiveness
s
Release Verification Verification that process works
Dispens
ing effectively
Manufacturing Process
Packaging Process
In-process analysis
Finished product Basic Risk Management Facilitation Method :
analysis Finished
goods storage Simple techniques that are commonly used to structure risk management by gathering/
Dispatch of finished product organizing data and facilitating decision making are as follows :
Flowcharts:
Pictorial presentation of a process and breaking the process down into its constituent steps.
Check sheets:
Present information in an efficient format which can be accomplished with a simple listing of items.
SR.
QUESTION
NO.
ANSWER
19.0
STABILITY STUDIES
DEFINATION:
be selected based on unit operations and their interrelation can be shown. Complex processes and associated risks shall be analyzed systematically.
What is stability studies
Example:DispensingSieving GranulationDryingBlending The ability of a pharmaceutical product to retain its physical and chemical properties within specified
limits throughout its shelf life.
Packaging Coating Compression
TYPES OF STABILITY STUDIES
Cause and Effect Diagram (Ishikawa / Fish Bone Diagram): Long term testing
The Ishikawa/Fish Bone Diagram is used to associate multiple possible causes with single effect. Stability studies under the recommended storage condition for the re-test period or shelf life proposed
(or approved) for labeling.
Methods / Process Machine/Equipment Material Intermediate testing

Studies conducted at 30°C/65% RH and designed to moderately increase the rate of chemical
Major Branch degradation or physical changes for a drug substance or drug product intended to be stored long term at
25°C.
Accelerated testing
Studies designed to increase the rate of chemical degradation or physical change of a drug substance or
drug product by using exaggerated storage conditions as part of the formal stability studies. Data from
Minor Branch
these studies, in addition to long term stability studies, can be used to assess longer term chemical effects
19.1 at non-accelerated conditions and to evaluate the effect of short term excursions outside the label storage
Mother Nature Man/Personnel Measurement conditions such as might occur during shipping. Results from accelerated testing studies are not always
predictive of physical changes.
ary branch represents the effect, major branch corresponds the major causes and minor branch corresponds to more detailed causal factors. Climatic zones
The four zones in the world that are distinguished by their characteristic prevalent annual climatic
conditions.
Climati Storag
Definition Areas covered under the zone
c e
Zone Conditi
No. on
Temperate 21°C & United Kingdom, Northern
I
climate 45% Europe,
RH. Canada, Russia, United states, Japan etc.
Subtropical
25°C/6 United States, Southe Eur
II and
0% (Portugal- rn ope
Mediterrane
an RH Greece) etc.
climate
Hot & dry 30°C/35 Australia, Argentina, Egypt,
II
climate % Iran, Iraq, Sudan, India etc.
I
RH
Hot & Brazil, Ghana, Indonesia,
I 30°C/65 Nicaragua, Srilanka, Vietnam,
humid
Page 65 of 270 V % Philippines, Uganda,
climate
A Thailand, India etc.
Hot & very
I 30°C/75 Brazil, Asian countries etc.
humid climate
V %
B
P
a
g
e
6
6
o
f
2
7
0
SR.
S QUESTI QUESTION
NO.
R. ON ANSWER
N ANSWER
Sampling for Stability
O.
Study
Factors affecting stability of the product
QA shall inform to QC regarding type of stability study to be performed.
Temperature:
The rate of chemical reaction increases exponentially for each 10°C increase in temperature. This QC shall calculate the sample quantity and shall inform to QA.
relationship has been observed for nearly all drug hydrolysis and some drug oxidation reaction.
Total sample quantity per batch shall be equivalent to 1.5 times of the quantity required for single
Light: complete or partial analysis & based on number of stations plus additional one station (since stability
Exposure to primarily, UV illumination may cause oxidation (photo oxidation) and scission testing has to be continued for 12 month beyond the expiry).
(Photolysis) of covalent bonds.
Incubation of Stability Samples and Storage conditions
Air:
Presence of oxygen, nitrogen. Samples shall be incubated as per below guideline.
Humidity (Moisture): Identify the storage conditions based on the Pharmacopoeial data or literature information or
Esters & beta-lactoms are the chemical bonds that are most likely to hydrolyze in the presence of water. R&D information. For add on batch use long term storage conditions.
E.g. the acetyl ester in aspirin is hydrolyzed to acetic acid and salicylic acid in the presence of
moisture, but in a dry environment the hydrolysis of aspirin is negligible.
at the time of submission and shall be continued for a period of time sufficient to cover the proposed
shelf life.
Selection of Batches
For new drug product, samples of at least three consecutive validation batches shall be kept for Long term, accelerated, and, where appropriate, intermediate storage conditions for drug products are
accelerated and long-term stability. detailed in the sections below.
For routine stability study, one commercial batch shall be kept for long term stability on every year. Minimum time period
Study Storage condition
covered
by data at submission
25°C ± 2°C / 60% RH ± 5% RH or
Testing frequency Long term 12 months
Testing frequency shall be determined based on condition at which stability is performed. 30°C ± 2°C / 65% RH ± 5% RH
Accelerated Intermediate* 30°C ± 2°C / 65% RH ± 5% RH 6 months

Accelerated stability shall be conducted at 0,1,2,3 and 6 months.
Accelerated 40°C ± 2°C / 75% RH ± 5% RH 6 months
Long term
Long-term stability studies shall be carried out at the intervals of, * If 30°C ± 2°C / 65% RH ± 5% RH is the long -term condition, there is no intermediate condition.
Every three months on first year 0, 3, 6,9,12,
Every six months on second year 12, 18, 24 If long-
Every year thereafter through the proposed shelf life 24, 36, 48 and 60 the accelerated storage condition, additional testing at the
Eg: 0, 3,6,9,12,18,24,36,48 and 60 months. intermediate storage condition should be conducted and evaluated against significant change criteria.
-month study at the
Intermediate intermediate storage condition.
Intermediate stability studies (minimum four time points, including initial and final points)
shall be carried out at 0,3,6,9 and 12 months or up to 60 months. Temperature & Humidity of stability incubator shall be monitored on daily basis. If incubation of the
stability samples is delayed by 30 days or more from the release date of the batch, initial (0 month)
analysis shall be performed again before incubation.

SR.QUESTION
R.QUESTION NO.ANSWER
NO.ANSWER 20.0 ANALYTICAL METHOD VALIDATION
nalysis of the sample shall be performed on the due date or if not possible, then complete within below tolerance limit from due date.
DEFINATION:
Tolerance
Sr. No. Stability Station Analytical Method Validation:
(From due date of analysis)
1M , 2M, 3M Accelerated, Validation of an analytical procedure is the process by which it is established, by laboratory studies,
3M long term, 07 days that the performance characteristics of the procedure meet the requirements for the intended
3M Intermediate term 6M Accelerated analytical applications.
6M, 9M, 12M long term.
Specificity:
6M, 9M, 12M Intermediate term. 15 days
Ability to assess unequivocally the analyte in the presence of components which may be expected to be
3 18M & onwards of long term. ± 30 days present (impurities, degradants, matrix). It is a measure of the degree of interference from such things
. as other active ingredients, excipients, impurities, and degradation products, ensuring that a peak
response is due to a single component only.
o meet specification (significant change) in stability analysis, results shall be intimated to Head QC. Precision:
The precision of an analytical procedure expresses the closeness of agreement (degree of scatter)
between a series of measurements obtained from multiple sampling of the same homogeneous
ut of trend (OOT) results according to the SOP No. QAD 087 of OOT. sample under the prescribed conditions. Precision may be considered at three levels: repeatability,
intermediate precision and reproducibility.
ocess or site:
process, Sample from batches produced under each change shall be added to stability program (one batch). Repeatability (Method Precision):
Repeatability expresses the precision under the same operating conditions over a short interval of time.
Repeatability is also termed intra-assay precision.
20
process, collect the samples from the new batches (three batches) and perform the stability like new product. In such a case the protocol and report procedure number shall be changed.
.1
Intermediate precision (Ruggedness):
Intermediate precision expresses within-laboratories variations: different days, different analysts,
ate the affect on stability of the drug product by keeping one batch for stability.
different equipment, etc.
Accuracy:
The accuracy of an analytical procedure expresses the closeness of agreement between the value
which is accepted either as a conventional true value or an accepted reference value and the value
found.
Linearity:
The linearity of an analytical procedure is its ability (within a given range) to obtain test results
which are directly proportional to the concentration (amount) of analyte in the sample.
Range:
The range of an analytical procedure is the interval between the upper and lower concentration
(amounts) of analyte in the sample (including these concentrations) for which it has been
demonstrated that the analytical procedure has a suitable level of precision, accuracy and linearity.
Detection Limit (DL):

The detection limit of an individual analytical procedure is the lowest amount of analyte in a sample
which can be detected but not necessarily quantitated as an exact value.
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Page 70 of 270
S QUESTI
R. ON
N ANSWE
O. R
Quantitation Limit (QL):
The quantitation limit of an individual analytical procedure is the lowest amount of analyte in a
sample which can be quantitatively determined with suitable precision and accuracy. The
quantitation limit is a parameter of quantitative assays for low levels of compounds in sample
matrices, and is used particularly for the determination of impurities and/or degradation products.
Robustness:
The robustness of an analytical procedure is a measure of its capacity to remain unaffected by small,
but deliberate variations in method parameters and provides an indication of its reliability during
normal usage.
PROCEDURE
The typical process that is followed in an analytical method validation is chronologically listed below,
Planning and deciding on the method validation experiments
Preparation and approval of method validation protocol
Execution of the method validation activity
Reporting the analytical method validation.
Finalizing the analytical method.
Analytical methods to be revalidated in following circumstances;

Changes in the composition of a finished product (Drug
product). Changes in the Analytical method.
During the optimization of the drug product process, significant changes were introduced into
the process. To ensure that the analytical method will still be able to analyze the potentially
different profile of the drug product, revalidation may be necessary.
The degree of revalidation required depends on the nature of the changes. Certain
other changes may require validation as well.
Types of analytical procedure to be validated,

Category I : Limit test of the active moiety in samples of drug substance or drug
product or other selected component (s) in the product.
Category II:Quantitative tests for impurities content and Limit tests for the control
of impurities;
Category III: Determination of performance characteristic (e.g. Dissolution, drug release)
Category IV: Identification Test
S
R. QUESTION
N ANSWER
O.
Requirem
Analytic ent
al Categor Category II Category Category
performa yI III IV
nce Testing for Impurities Dissolutio Identificati
Assay Quantitat Limit
paramete n, on
rs ion Tests drug test
release
Accuracy Yes / # Yes / # Yes / #
Precision
-System
precision Yes Yes Yes
- Repeatability
Intermed
iate
Precision
Specificity Yes / # Yes / # Yes Yes / # Yes
Detection limit No* Yes
Quantitation Yes
limit
Linearity Yes Yes Yes
* May be required, depending on the nature of the specific test.
# To be performed if the analytical procedure is compendial (Pharmacopoeial)
SPECIFICITY/SELECTIVITY
For identification test
Analyze the finished product sample along with reference standard or certified working standard or
reference material and analyze the finished product sample which do not containing the analyte
(Placebo), compare the results.
For assay and impurity tests

For chromatographic procedure the specificity shall be demonstrated by resolution of the
two closest eluting compounds and their peak purity and blank determination.
For non-chromatographic procedure (e.g. titration) combination of assay and a suitable test for
impurities can be used.
Spike the finished product or drug substance with impurities and/or excipients as per
specification level and analyze it along with unspiked finished product or drug substance.
Check that the all the spiked components are resolved from each other according to the
acceptance criteria.
Acceptance criteria:
System suitability should pass.
No interfering peaks shall be eluted at the retention time of analyte.
The resolution between analyte peak and any closely eluting peak should be more than 2.0.
Page 71 of 270
Page 72 of 270
SR.
NO.
ANSWER NO.
Acceptance criteria: % RSD of results of two different sets (method precision and intermediate
PRECISION precision) should not be more than 6.0 %.
Precision is measured as the percent relative standard deviation (% RSD) for significant number of samples. ACCURACY
For the assay of the finished product:
System precision: Analyze the synthetic mixtures of finished product components (placebo) spiked with known
Carry out minimum 5 determinations of standard /reference solution at 100% of test concentration quantities of drug substance to be analyzed.
(concentration of compound of interest given in analytical method).
Prepare the sample in the range of 80,100,120% of label claim and analyze it in triplicate at each
Acceptance criteria: The relative standard deviation of five replicate injections of standard/reference concentration.
solution should not be more than 2.0%.
If it is not possible to prepare placebo due to non-availability of other components then add known
Repeatability (Method precision): quantities of analyte to the finished product. (4.1.2 b of ICH Q2 (R1))
For Assay/Related substances: Prepare 6 different sample preparations as per concentration of compound
of interest given in analytical method from a sample of one batch and determine the results from these six- Accuracy may be inferred once precision, linearity and specificity have been established.
sample preparation.
For impurities test (quantitation):
Acceptance criteria: Analyze the finished product sample spiked with known amounts of impurities at the specification level.
% of Analyte in Sample % RSD
0.001 to 2 % More than 2 % to 10 % Should not be more than 10 %.
More than 10 % to 100 % should not be more than 5 % should not be more than 2 % Prepare the sample in the range of 80%, 100%, and 120% of specification level and analyze it in
triplicate at each concentration.
For dissolution: Add known amount of standard to that of placebo (above and below the nominal
level) at 3 different levels i.e. 70%, 100% and 130% to cover both above and below the nominal
For Dissolution: Prepare 2 sets of 6 units as per concentration of compound of interest given in levels. Calculate the data as % of label claim, mean and % RSD at each concentration.
analytical method from a sample of one batch and determine the results from 12 units preparation Report the data as the percent recovery by the assay of the known added amount of analyte in the
sample or as the difference between the mean and the accepted true value together with confidence
Acceptance criteria: Over all % RSD of % release of two sets should not be more than 6.0 %. intervals.
Intermediate precision:
For Assay / Related substances: Analyze the sample of single batch six times by different analysts on
different days using different instrument and where applicable use different column or electrode. Acceptance criteria: For Assay / Related substances
System suitability should pass.
Acceptance criteria: The % RSD of results of two different sets (method precision and intermediate Recovery should not less than 90.0
precision) should be as per shown in below table. %. For % RSD of recovery for all
% of Analyte in % RSD levels,
Sample
0.001 to 2 % Should not be more than 10 % of Analyte in Sample % RSD
%.
0.001 to 2 % Should not be more than
More than 2 % to 10 % should not be more than 5
% 10 %. More than 2 % to 10 % should not be more than
More than 10 % to 100 should not be more than 2
% % 5%
More than 10 % to 100 % should not be more than 2 %

For Dissolution: Analyze the sample of single batch (6 units) two times by different analysts on
different days using different instrument.
Acceptance criteria: Dissolution

SR.
NO.
ANSWER NO.
LINEARITY AND
RANGE: Based on the Standard Deviation of the Response and the Slope:
Linearity should be evaluated by visual inspection of a plot of signals as a function of analyte concentration or Determine the slope of calibration curve by analyzing the samples at different concentration in the
content. range of detection limit.
The below table details the methodology to perform linearity and range parameter.
Detection Limit (DL) = 3.3 x Standard deviation (SD) of response
Minimum concentration to be prepared Slope of calibration curve
Type of method Range
10, 30, 50, 80, 100, 120 & 200 % of the

Assay 7 LIMIT OF QUANTITATION (applicable only for impurity
test concentration.
Content 5 70 to 130 % of the test methods): Based on Visual Evaluation:
uniformity Measurement by visual evaluation for non-instrumental methods (e.g. TLC/titration);
concentration. 20 % of the
Dissolution 5
testing specified range. Determined the quantitation limit by the analysis of samples with known concentrations of analyte.
Impurity 5 From quantitation limit to 120% of
Prepare a sample at lowest concentration of analyte and establish minimum level at which analyte
specification
Assay & impurity can be quantified with acceptable accuracy and precision.
are performed 5 From quantitation limit to 120% of the assay
together specification.
as one test Based on Signal-to-Noise:
Demonstrate the linearity by the use of correlation coefficient, y- intercept, and slope of the regression Measurement by signal to noise ratio for instruments which exhibit baseline noise;
line.
Analyze minimum 6-sample solution at decreasing concentration in the expected range of
Acceptance criteria: quantitation limit.
The correlation coefficient should not be less than 0.99 for Assay method and for impurity quantification
method the correlation coefficient should not be less than 0.98. Determine the signal-to-noise ratio by comparing measured signals from samples with known
lowest concentrations of analyte with those of blank samples and establish the minimum
concentration at which the analyte can be consistently quantified. And measure the signal-to-noise
LIMIT OF DETECTION (applicable only for impurity methods): ratio.
It is a limit test that specifies whether or not an analyte is above or below certain value which can not be
quantified as an exact value. Acceptance criteria: A signal to noise ratio 10:1 is required.
Based on Visual Evaluation

Measurement by visual evaluation for non-instrumental methods (e.g. TLC/titration); Based on the Standard Deviation of the Response and the Slope:
Determine the slope of calibration curve by analyzing the samples at different concentration in the
Determined the detection limit by the analysis of samples with known concentrations of analyte. range of quantitation limit.
Prepare a sample at lowest concentration of analyte and establish the minimum level at which the Quantitation Limit (QL) = 10 x Standard deviation (SD) of response
analyte can be consistently detected. Slope of calibration curve
Based on Signal-to-Noise: Precision at Quantitation Limit (QL):

Measurement by signal to noise ratio for instruments which exhibit baseline noise; Prepare a sample solution at the QL concentration determined by adapting any of above method and
analyze it for six times and measured the precision (%RSD) at this concentration.
Determine the signal-to-noise ratio by comparing measured signals from samples with known lowest The acceptance criteria for precision shall be complied the requirement given under acceptance
concentrations of analyte with those of blank samples and establish the minimum concentration at criteria of precision point no.5.9.3.2.
which the analyte can be consistently detected. And measure the signal-to-noise ratio. Acceptance
Criteria: A signal-to-noise ratio between 2:1 or 3:1 is required.

SR. QUESTION ANSWER
S QUESTI NO.
R. ON
N ANSWE
O. R
ROBUSTNESS:
The robustness of the method shall be performed by varying some or all conditions given STAGES RESPONSIBILITY
below; By changing pH of buffer/ mobile phase by ± 0.2.
By changing the flow rate by ± 50% Pre experiment trials before start of
By changing the organic phase of mobile phase composition ± 30 % relative but can Analyst
not be exceed 10% absolute or 2 % absolute.
By changing the columns (Different lots and/or
suppliers) By changing the column oven temperature Development of protocol Section Head
by ±10 C
By changing the extraction time (if applicable)
Protocol approval Department Head
Analyze the sample solution for each condition and compare the data with the data of method precision
Acceptance criteria: Protocol authorization Head

The system suitability should pass for each variation.
The overall % RSD (with method precision) should not be more than 2.0 for assay,
5.0 for dissolution and 10.0 for individual experiment of impurities.
QA Execution of method validation
STABILITY STUDY OF ANALYTICAL SOLUTION:

Stability study of analytical solution shall be performed for at least 24 hours for chromatographic
assay and impurity tests, addition time interval can be extended.
Analyst
For assay & dissolution, prepare the standard (where applicable) and sample solution according to the
proposed method, analyzes initially and at different time interval and find out the cumulative %RSD.
Review of data Analyst
Acceptance criteria: The cumulative %RSD should not be more than 2.0.
For impurity test, spike the sample solution with known amount of impurities, analyze it initially and Preparation of method validation Analyst /Section
different time intervals and find out the cumulative %RSD. Head report
Acceptance criteria: a. The cumulative %RSD should not be more than 10.0.
b. No new peak should elute.
Review of report Department Head/designee
When measurements are susceptible to variations in analytical conditions, the analytical conditions
should be suitably controlled or a precautionary statement should be included in the procedure
Approval of report Head QA
System suitability testing
System suitability parameters are to be followed as given in STP.
Use the method for routine testing Analyst /Section Head
After the laboratory work
After completion of the laboratory work and documentation of the data, QC-officer shall review the
complete data for correctness of calculation and methodology.
Page 77 of 270
Page 78 of 270
NO. R.
21.0 N ANSWER
OUT OF SPECIFICATION O.
DEFINATION :
Out Of Specification (OOS) results:
Test results that does not comply with the pre-determined acceptance criteria (e.g. filed application,
approved marketing submission, official compendia or internal acceptance criteria).
Test results that fall outside of established acceptance criteria which have been established in official
compendial and/or by company documentation (i.e. raw material specification, In process/final product
testing etc).
PROCEDURE :
After completion of analysis, analyst must check the data and results for compliance with
specifications, When any out of specification results observed in laboratory and if no obvious
explanation exists, then follow as mentioned below;
Do not discard the Standard and Test
Preparations Retain all Glassware and Sample
Check the analytical raw data sheet and chromatogram
21 Check the whole analysis for compliance (Self-check)
.1
Based on the request of section incharge of QC, QA person shall enter the details of out of
specification in OOS log (Annexure-II) and issue the OOS investigation report (Annexure-I) QC
for investigation.
Incase OOS is logged, where necessary, QA shall inform to respective QP's/ MA Holder/
Regulatory bodies within 3 working days and customers based on technical agreements after the
OOS is logged. After completion of OOS investigation, the same shall be communicated to
respective QP's / MA Holder/ Regulatory bodies and Customers based on technical agreements.
Handling OOS results during Stability Studies
During stability study any adverse change or OOS observed and confirmed in physical or chemical
parameters shall be brought to the attention of Head- QA, Manufacturing, RA, R&D. Head-QA shall
do investigation on the affected batch along with all other batches manufactured at the same time
period and same shall be communicated to concern regulatory agencies through Head RA.
If OOS found valid for stability samples, the stability study shall be continued for testing samples of
further stations. If the result of the next station sample is also found to be failing with respect to the
test for which OOS was reported, the stability study shall be discontinued.

S QUESTION
R.
N ANSWER
S QUESTI
R. ON
N ANSWER

S QUESTION
R.
N ANSWER
S QUESTI
R. ON
N ANSWER
22.0 MICRO
22.1

SR. QUESTION ANSWER
NO.
SR. QUESTION ANSWER
NO.
The prepared plates of Soyabean casein digest agar are pre-incubated at 30°C to 35°C for 24 hours. Contaminant shall be identified from its colony morphological characteristics if required,
gram
The prepared plates of Sabouraud Chloramphenicol Agar are pre-incubated at 20°C to 25°C staining shall be carried out to differentiate Gram positive from Gram negative organism
as per the SOP No. QCG 151.
for 24 hours. Before start the plate exposure ensure the cleaning, sanitization, AHU operation and activity of
the area.
Active Air sampling by Air sampling
Passive Air sampling by settle plate If results of microbiological environmental monitoring obtained out of alert limit,
Microbiologist should inform to Head Microbiology, Quality Control & Head QA or his
Active Air sampling by Air sampler designee. Start the Out Of limit (OOL) investigation
Autoclave the sampling head of the Air-Sampler by covering it with aluminum foil or hydrophobic
paper. Acceptance criteria
Limits for settle plate of Manufacturing Area, Sampling Area, Dispensing Area and Packing Hall.
Mark each plate with Date of Exposure, Name of Location or Location No.
Keep all the SCDA plate, 70% IPA & hand gloves in sampling box
Plates Alert Limit Action Limit
Enter in the respective areas by following the proper entry (gowning) procedure.
Total Bacterial Count NMT 60 cfu / plate NMT 100 cfu /
Open the sterile media plate and place it in the sampler subsequently by placing sterile
plate Total Fungal Count < 1 cfu / plate < 1 cfu / plate
sampling head of the Air-sampler over the media plate.
Sample 1000 liters of air from a designated sampling point refer Annexure-XII
Limits for settle plate of RLAF in Sampling and Dispensing Area
During sequential sampling; disinfect the air sampling head with filtered 70%
IPA. Plates Alert Limit Action
After sampling open the head of Air sampler and take out the agar plate from the sampler. Limit Total Bacterial Count < 1 cfu /
Cover the plate with lid immediately and put it into the sampling box. plate
Exit from respective area by following the exit procedure. Total Fungal Count < 1 cfu / plate
Incubate the exposed plate in an inverted position in the BOD incubator at 20-25°C for 72
hrs followed by 30-35°C for 48 hrs. Limits for Air sampling of Manufacturing Area, Sampling Area, Dispensing Area and Packing Hall.
Control test: Keep same lot of unexposed media plate in BOD Incubator with exposed plate
Plates
as a negative control. Total Bacterial
After incubation record the observations in respective Annexure. 3
Count NMT 200 cfu
3 /M
Total Fungal Count < 1 cfu /
M
Passive Air sampling by settle plate
Mark each plate with Date of Exposure, Name of Location or Location No. Limits for Air sampling of RLAF in Sampling and Dispensing
Keep all the SCDA & SCA plate, 70% IPA & hand gloves in sampling box
Enter in the respective areas by following the proper entry (gowning) Area Plates
3
procedure. Total Bacterial Count < 1 cfu / M
3
Total Fungal Count < 1 cfu /
Place the marked Soyabean casein digest agar and Sabouraud Chloramphenicol Agar Plates to its M
respective location as per annexure-I.
Open the lid of the plate, keep the lid supported with edge in such a way that the lid Should Limit for Surface Monitoring of Reverse Laminar Air Flow (RLAF)
placed at slight vertical position.
Expose the plates in designated areas for 4 hours. Plates Maximum Allowable Limit cfu / contact
At the end of exposure time, close the plates and transfer to the SS petriplates plate Total Bacterial Count NMT 3 cfu / contact plate (Including
container. Exit from respective area by following the exit procedure. Floor) Total Fungal Count < 1 cfu / contact plate
Transfer the plates to microbiology laboratory.
Incubate the exposed Sabouraud Chloramphenicol agar plates in BOD Incubator at 20°C to Frequency
25°C for 5 days and Incubate the soyabean casein digest agar plates at 30°C to 35 °C for 48 For Settle Plate: Once in a Month (Every first week of the month cover all the sampling point)
hours. For Air sampling: Twice in a Month
Page 85 of 270
Page 86 of 270
SR. QUESTION ANSWER
DEFINATION:
NO.
23.0 Training is a process of teaching or learning a skill through instructions.
TRAINING
INDUCTION TRAINING
The induction training shall be given based on induction manual by Head Personnel &
Administration or his designee about the company, HR rules / policies, organization structure,
various department & their functioning, EHS policies, etc.
ON JOB SOP TRAINING

On satisfactory completion of induction training new employee shall fill his / her detail in signature
log (e.g. name, date of joining, designation, full signature and short signature (initials) in the
specimen signature log.
The New employee shall read and understand the SOP of his department as per training
matrix (Annexure- -IV. If there
is any query
regarding any SOP, it shall be explained or clarified by department head / designee.
After understanding of the entire SOP, the department head shall sign the Annexure IV and
introduce the new employee to the section head where he / she will work.
23 The section head shall identify the task/work for where he / she will work. And accordingly, the new
.1 employee shall perform the task by himself / herself in presence of section head.
The evaluation should be done by question or answer on relevant topic.
Acceptance criteria for the assessment of training are specified under the section of Training assessment
criteria.
After completion of the on job training, if the performance of the new employee found satisfactory,
then work authorization certificate shall be issued to the new employee for the activity by section
head and HOD and it is filed in his/her respective training file. Refer Annexure-V.
Exemption should consider in case of HOD or higher position where on job training is not required
cGMP TRAINING PROGRAM

cGMP training program shall be given in two mode,
1. Basic cGMP training program
2. Refresher cGMP training program
CLASS ROOM TRAINING
The training shall be conducted either as a classroom training or demonstration on the job or self
learning by reading and understanding of the SOPs
The training of each employee should conduct as per the Annual Training calendar
S QUESTI
R ON
. ANSWE
N R
O.
NEED BASED TRAINING IDENTIFICATION
The section head shall identify the training needs of the employees appropriate to his / her job
requirements
External Training Program

The external training comprises of two elements, one where the external trainer or organization are
brought into the site to conduct training - , the other where the trainee is sent to
an external course out side the facility .
The trainer shall be nominated by the head of the department in co-ordination with Head -QA based
on at least the following but not limited to:
Educational qualification: Graduate in Pharmacy, Science or Engineering or Management.
Working Experience.
Working knowledge of GMP in National, Local, and Global legislation
GMP. Skills on preparation and delivery of training modules and Good
communication.
The qualification shall comprise the Medley Authorized Certificate (Refer Annexure-XI) that the
person is an authorized trainer.
DOCUMENTATION:
Training Matrix (Annexure-III) shall be prepared at the end of the year for the next year.
cGMP Training Planner (Annexure-VIII) shall be prepared at the end of every year for the next
year.(Eg: cGMP Training planner for the year of 2013 shall be prepared on December, 2012.)
Annual Training Calendar (Annexure-IX) shall be prepared at the end of every year for the next
year. Check list for Authorized trainer (Annexure-XII) shall be maintained department wise.
List of Authorized trainer (Annexure-XIII) shall be prepared at the end of every year for the next year
maintained department wise.
Individual file:
Work authorization certificate, Training Evaluation Report, Employee training Card.
Certificate for authorized trainer.( In case of Trainer)
P&A Department
Induction Training schedule.

NO. NO.
24.0
MEDICAL CHECKUP
S Name of pesticide and Active Used for Mode of use
Every new recruit should under go medical examination before joining the company. r. recommended ingredi control of
n concentration ent
Get the medical check up done for all employees once in a year through registered medical practitioners o. (organ
only. o
phosphates )
The general medical check-up include the following examination(s) i.e. Physical examination i.e. blood 1. Chlopryriphos - 20 % Diethyl Crawling and 100m1 to
pressure, pulse rate, height, weight, physical abnormality, contagious skin disease, blood test. phosphorthoat flying insects 200 ml (as
e required) Of
Chest X-ray for personnel working in production area who are directly exposed to the products and 2. Cypermenthrin - 10 % Cypermenthrin Crawling and the
eye check-up (Power and color blindness) for personnel engaged in visual inspection of products flying insects concentrated
and analysis in quality control laboratory. 3. Cyfluthrin 2.45% Beta cyfluthrin Crawling and Chemical be
24
flying insects mixed with
.1
Employee should not report to the work if they are infected with any disease or they have any open 4. Permethrin 25% Permethrin Crawling and Liters of
lesions.
26.0 RODENT CONTROL
About illness, employee should report to his/her department head. Department Head would decide Red color rectangle painted on floor / wall indicates point where rodent trap boxes shall be placed.
about his /her continuation of the days work. The Rodent trap box point shall be numbered as RB XX where RB= Rodent trap box, XX= serial
number starting from "01"
Any employee remaining off the duty for more than 3 days on medical ground, he/she shall be
allowed to work only after reviewing his/her Medical Fitness Certificate. Rodent control trap box will be placed as per layout.
House keeping Supervisor / Asst. Security Supervisor / Supervisor shall check the entire rodent trap
26 for any Rodent trapped, on daily basis.
25.0 PEST CONTROL .1
If any rodent is found in the Rodent trap box, concerned supervisor will carefully put rodent in
poly bag and will handover to external agency for destroying the rodent outside the factory
Pest control shall be carried out by spraying the required concentration of pesticides premises.
Spraying shall be done all over the outside periphery of the building and at all entry points as per the If no rodent is trapped in the Trap box; feed of the trap shall be replaced by contractor after
lay out every 7 days.
27.0 HEALTH
Pest control shall be carried out on weekly basis (i.e. on every Friday)
FIRST AID TREATMENT : In case of exposure to skin , inhalation and ingestion, Good health of all the employees is one of the most important responsibilities of the
If in EYES - Immediately flush with plenty of water for at least 15 minutes. In case of redness, organization. The organization has policy for maintaining the good health of all the employees.
2 itching and burning sensation immediate seek medical advice.
5. For all employees an annual medical check up shall be conducted by a registered medical
1 practitioner on contract.
If SWALLOWED - If the patient is conscious, wash out mouth with water. Vomiting should be
induced under the direction of physician. If spontaneous vomiting occurs, have victim lean forward 27
with head down to avoid breathing in of vomit, rinse mouth and administer water. .1 This annual medical check up includes any apparent illness, physical examination and test for
eyesight, physico-chemical examination of blood and urine, test for any infectious disease.
If INHALED - Remove victim to fresh air. Apply artificial respiration if breathing has ceased or
shows signs of failing. Obtain medical attention.
employee is declared medically fit then only he / she shall be allowed for joining the company.
If ON SKIN - Wash material off the skin with plenty of water. If redness, itching or burning
sensation develops, obtain medical attention.
Page 89 of 270
Page 90 of 270
NO. R.
28.0 N ANSWER
HYGIENE O.
29.0 QUALIFICATION
All employees working either in production or non-production area shall observe a high degree of
personal hygiene. What is Qualification
Establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined sp
All employees shall take bath everyday.
All employees shall cut their nails and hair regularly. URS
All employees shall trim their mustache and shave the face regularly.
Possibility checked by vendor
If an employee is with beard, he has to cover the beard with the beard
mask. All employees shall wear clean street cloths and street wear
Purchase order raised by production
everyday.
All employees shall wash their hands after using the toilets every time.
Any employee having any open lesion on the skin or suffering from any contagious disease shall FDS (Function Design Specification) by Vendor
immediately inform his / her department head.
Weekly check of Personnel health and hygiene shall be done and the same shall be recorded in the DQ (Design Qualification) by Vendor to Plant
-I. With the consultation of head personnel and
administration the employee shall be relieved from the duties till recovery. Plant / Purchase Approval
Chewing of tobacco, pan, gutkha etc. and cigarette / bidi smoking is strictly prohibited within company
premises. The security officer shall physically check every employee for the presence of above restricted FAT (Factory Acceptance Test) vendor Visit
28 materials carrying with them. The violation of this shall call for a disciplinary action.
.1
SAT (Site Acceptance Test)
IQ (Installation Qualification)
OQ (Operational Qualification)
PQ (Performance Qualification)
USER REQUIREMENT SPECIFICATION (URS)

It is an documented evidence in which user department provide sufficient information to the manufacturer regarding the equipment
DESIGN QUALIFICATION (DQ)

Documented evidence that the premises, supporting utilities, equipment and processes have been designed in accordance with the re
INSTALLATION QUALIFICATION (IQ)

IQ is the documentary evidence to verify that the equipment has been built and installed in compliance with design specifications.

S QUESTION
R.
N ANSWER
O.
OPERATIONAL QUALIFICATION (OQ)
OQ is the documentary evidence to verify that the equipment operates in accordance with its
design specifications in its normal operating range and performs as intended throughout all
anticipated operating ranges.
PERFORMANCE QUALIFICATION (PQ)

PQ is the documentary evidence which verifies that the equipment or system operates
consistently and gives reproducibility within defined specifications and parameters
for prolonged periods.
Validation and qualification are essentially components of the same concept. The term qualification is
normally used for equipment, utilities and systems, and validation for processes
30. What is HVAC? SR. QUESTION ANSWER
1 Heating Ventilation and Air condition NO.
30.0
Why Required? HVAC SYSTEM
30. To prevent any cross contamination. For better working environment.
2
Difference between AHU and HVAC?
AHU, which is Air Handling Unit is an appliance used to circulate air
HVAC is Heating, Ventilating and Air Conditioning system. HVAC is the central unit to which AHU is
30. connected. AHU is only a part of HVAC
3 HVAC mainly refers to the technology of automotive environmental comfort. The Heating,
Ventilating and Air Conditioning system uses the principles of fluid mechanics, thermodynamics and
heat transfer. The discoveries of by Michael faraday, Nikolay Lvov, Reuben Trane, William Rankine
Wills Carrier, James Joule and Sadi Carnot
Type of test for HVAC qualification.
1. Air Velocity / Air Changes

2. Integrity Test Of HEPA Filters
3. Air borne non-viable particle monitoring
4. Recovery test
30. 5. Smoke test (air flow direction)
4 6. Measurement of light intensity
7. Measurement of sound level
8. Pressure differential, temperature and relative humidity test
9. Air borne viable particle monitoring by settle plate
10. Air borne viable particle monitoring by air sampler
AIR VELOCITY / AIR CHANGES

30.
5 Instruments: Fan type Anemometer, Hot wire anemometer and Capture Hood.
AIR VELOCITY / AIR CHANGES BY CAPTURE HOOD:

OBJECTIVE :
To verify that the HVAC system is capable of delivering required airflow velocities, airflow
volumes and providing required number of air changes.
30.6
PROCEDURE :
Take the each filter CFM by capture hood
Calculate the number of air changes per hour and record in the raw data format. To calculate the air
changes per hour use the following formulas:
Page 93 of 270
Page 94 of 270
SR. QUESTION ANSWER
NO.
SR. QUESTION ANSWER
NO.
INTEGRITY TEST OF HEPA FILTERS

Total Room CFM X 60
Air Changes per Hour of a Room = Objective:
Room Volume in Cubic Feet To verify the integrity of HEPA filters.
Attach the reports of air velocities supplied by the party as an attachment
Test Apparatus:
PAO Aerosol generator, Photometer
ACCEPTANCE CRITERIA:
Not less than 20 ACPH Procedure:
Introduce the aerosol into the air supplied to the filter.
Scan the entire face of each filter including the filter frame using slightly overlapping strokes of the
AIR VELOCITY / AIR CHANGES BY HOT WIRE/FAN TYPE ANEMOMETER: probe, at a traverse rate of NMT 10 feet / minute when using a round probe.
Ensure that the probe is held approximately 2.5 cm / 1 inch from the filter face during scanning.
Objective: Record the observations of PAO leak test in the raw data format.
To verify that the HVAC system is capable of delivering required airflow velocities, airflow 30 Attach the reports of PAO leak test supplied by the party as
volumes and providing required number of air changes. .8 attachment. Seal the leakages by using silicon sealant.
The extent of filter face observed by silicon sealant should be less then 5% of the filter area, if more
Procedure: is Description
sealed the filter must be rejected and new oneCorrective
of leakage shall be installed.
action to be taken
Different
Leak fromtypes
theofframe
leakages and 1.
their corrective
Tightening theactions to be taken
filter frame aresides
from all mentioned in the following table.
Ensure that the probe for checking the air velocities is positioned at a distance of not more than and
15 cm (6 in.) from the filter face. the filter 2. If the leak continues to occur, observe the condition of the
gasket. If the gasket is damaged, replace the gasket and
Measure air velocity from V1 V2 5 locations including four corners and one perform the test again.
center.
V3
V4 V5 Acceptance Criteria:
Leakage should be NMT 0.01%
30.
7 AIR BORNE NON-VIABLE PARTICLE MONITORING:
Record the data in a tabulated form and find the average air velocity.
VA = (V1 + V2 + V3 + V4 + V5 ) / m Objective
To establish that at different locations within the core process areas, a count of less than specified
Where, m : Number of Samples location Taken number of particles per cubic meter of air of 0.5 m or larger is maintained.
VA : Average air velocity in FPM
Test Apparatus
Air Flow volume in CFM = Average Velocity x Filter Size Air borne particulate counter
Calculate the number of air changes per hour and record in the raw data format. To calculate 30
.9 Procedure:
the air changes per hour use the following formulas: The minimum number of sampling point locations is decided as per ISO14644-1, which is detailed as
Total Room CFM follows:
X 60 Air Changes per Hour of a Room =
Derive the minimum number of sampling point locations from the formula: -
Room Volume in Cu Ft NL
Where:
NL=The minimum number of sampling locations (Rounded up to a whole number)
2
Not less than 20 ACPH

SR.
SR. QUESTION ANSWER QUESTION
NO.
NO. ANSWER
Numbe
r of
2 3 4 5 6 7-9
Where only one sampling location is required, take a minimum of three single sample volumes at individ
that location and calculate and record the average value of the sampled data for each considered ual
particle size. averag
es
The single sampling volume in the individual locations is determined by equation
t0.95 6.3 2. 2.4 2.1 2.0 1.9
Vs = (20 X 1000) / Cn.m 9
When the number of locations is greater than 9, the calculation of a UCL is not required.
Where,
Vs : is the minimum single sampling volume (in liters) / location
Cn.m : is the class limit (no of particles / m³ of air) for the largest considered particle size As per ISO 14644-1 If measurements are made at more than one considered particle size, each largest
specified for the relevant class. particle diameter shall be at least 1.5 times the next smaller particle diameter. Hence 0.5 µ & 5 µ particle
should be considered.
Defined no of particles that could be counted if the particle concentration were at the class limit.
Particle count reading at different sampling point locations recorded and the location point to be The result of the 95% UCL calculation may fail to meet the specified ISO designation due to the
indicated in room layout drawing. noncompliance caused by a single non random outlier value resulting from an erroneous measurement
(due to procedural error or equipment malfunction) or from an unusually low particle concentration (due
Record the results of each sampling measurement as the concentration of each of considered to exceptionality clean air), the outlier may be excluded from the calculation, provided that:
particle size appropriate to the relevant classification of air cleanliness.
The calculation is repeated, including all remaining sampling locations.
Determine the overall mean average by the equation
At least three measurement values remain in the calculation;
No more than one measurement value is excluded from the calculation;
Where,
The suspected cause of the erroneous measurement or low particle concentration is investigated and
X : is the overall mean of location averages
documented.
M : is the number of individual location averages
Xl.1 to Xl.m : individual location readings
Acceptance criteria:
Determine the standard deviation of the location averages by the equation Max. concentration limits (particles / m³ of air)
ISO Classification for particles equal to or larger than the
S = Square Root (Xl.1 - X)² + (Xl.2 - - X)² / (m-1) considered sizes
Number
Where, 0.5 5µm
S : is the standard deviation of the location averages. µm
m : is the number of location taken. ISO 7
352,000 2
9
ISO 8 3
When the 0
averages, standard deviation and 95 % Upper Confidence Limit (UCL) from the average particle
concentrations for all the location, determine the 95 % upper confidence limit (UCL) for the overall
mean using the Equation SMOKE TEST (AIR FLOW DIRECTION):
95 % UCL = X + t0.95 ( S ) Objective:

m 30.10 To visualize airflow pattern of process area operation and to prove that there is no cross contamination
from one area to the other.
t0.95 represent the 95 percentile of the distribution with m 1 degree of freedom
Test Apparatus:
Camera to record the airflow pattern of smoke generator, from third party.
Page 97 of 270
Page 98 of
270
SR. QUESTION ANSWER
S QUESTI NO.
R. ON
N ANSWE MEASUREMENT OF LIGHT INTENSITY:
O. R
Procedure: Objective:
Air flow should be stabilize by running the system for 30 minutes. To verify the light intensity in different rooms.
Generate smoke at the air inlet to the room specified (Most critical room has been selected out of Test Apparatus:
the rooms catered by a single AHU). Calibrated Lux meter.
30.
12
Video shooting or photographs shall be taken to cover the sweeping direction of airflow. Procedure:
Operate the Lux meter as per SOP. Measure the light intensity and record the in test data sheet.
Attach the photographs or preserve the CD for reference duly controlled by quality
Acceptance Criteria:
assurance. Acceptance Criteria: Not Less than 500 Lux
a. The smoke/fog should be diffused uniformly at supply grill/risers and pass through return MEASUREMENT OF SOUND LEVEL:
terminals.
b. There should not be any short-circuiting of airflow, dead pockets and the flow of air Objective:
should be unidirectional i.e. from supply to return. To verify the sound level in different rooms.
c. Smoke/fog should pass from area under positive pressure to area under negative pressure
Test Apparatus:
Calibrated Sound Level meter.
RECOVERY TEST (OR DECONTAMINATION TIME): 30.
Procedure:
13
Objective:
To determine whether the core process area is capable of returning to its reference specified Operate the sound level meter as per the SOP. Measure the sound level when there is activity in the
class within a finite time. areas and record the in test data sheet.
Test Apparatus: Acceptance Criteria:

Calibrated Air borne particle Not more than 80 db
counter Thermometers and
Hygrometers Magnehelic Gauge PRESSURE DIFFERENTIAL, TEMPERATURE AND RELATIVE HUMIDITY TEST:
Objective:
Procedure: To demonstrate the capability of the HVAC System to consistently maintain Differential Pressures,
Temperatures and Relative Humidity in different rooms.
30.
Hold the isokinetic probe of particle counter at the highest particle count location obtained under at rest
11 Test Apparatus:
conditions in each room.
Magnehelic Gauge, Thermometers and Hygrometers
Take the particle count and ensure that the particle count is under the specified limit and not the time 30.
Continue the particle count and shut down the AHU. Generate the particle count with fogger machine. Procedure:
14
This test shall be performed after the HVAC System has been operated and the conditions have been
When particle count goes out of the specified limit (at least 100 times or more than 100 times) note stabilized. All the doors in the facility must be closed.
the time. Continue the particle count and start the AHU. Note the time when the particle count of the
area reaches to the specified limit. Record the Pressure Differential, Temperature and Relative Humidity for a period of 72 hours as per
the SOP (Initially at every one hour interval for 8 hrs. and if the observations are within the
Attach the reports of recovery studies. acceptance criteria continuously for 8 hrs, than record the readings at every four hour interval for
remaining 64 hrs.)
Acceptance criteria: and record the observation in raw data format.
Page 99 of 270
Page 100 of 270
SR. QUESTION ANSWER
NO.
SR. QUESTION ANSWER
NO.
Air Borne Viable Particle Monitoring By Settle Plate :
Objective:
To determine the viable particle levels in environment of controlled area by settle plate.
Test Instrument/Sampling aids:

Media plates
Procedure:
Test shall be performed at operation condition by the microbiologist.
Prepare the SCDA and SCA plate and enter in to the respective area as per Entry and Exit
procedure. Expose the plates at various locations as per the settle plate location layout.
30.
15 The plate exposure shall be carried out for the controlled area for three consecutive days after taking the
particle count.
After completion of plate exposure, SCDA Plate incubate at 30-35°C for 48 hours and SCA
plate incubate at 20-25°C for 5 days.
After incubation observe the results and record in the data sheet.
Acceptance Criteria
Plates Alert Limit Action Limit
Total Bacterial Count NMT 60 cfu / NMT 100 cfu / plate

plate
Total Fungal Count < 1 cfu / plate < 1 cfu / plate
Air Borne Viable Particle Monitoring By Air Sampler :
Objective:
To determine the viable particle levels in environment of controlled area by Air Sampler.
Test Instrument/Sampling aids:

Air Sampler (Hi Media)
Procedure:
Test shall be performed at operation condition by the microbiologist.
Prepare the SCDA plate and enter in to the respective area as per Entry and Exit
procedure. Place the SCDA plate on air sampler and operate the air sampler as per SOP
30.
16 No. QCG 179. Take sampling volume 1000 liter of air as per sampling plan.
After completion of sampling incubate the SCDA plate at 20-25ºC for 72 hours and further
transfer at 30-35ºC for 48 hours.
After incubation observe the results and record in the test data sheet.
Acceptance Criteria
3
Class A < 1 cfu /
M
3
Class B <10 cfu / M
3
Difference between Settle Plate and Air sampling Class C <100 cfu / M
3
Settle Plate Passive Class D <200 cfu / M
30.
17
Particle Air Sampling
Active sampling
Which Guideline follows
30.
18 ISO 146441
Re-Qualification Frequency
30.
19 1 year ± 30 Days
If out of limit
30.
Deviation to be raised, Deviation trough failure investigation, investigation trigger CAPA, through
20
CAPA change control to be raised (if required).
Page 101 of 270
Page 102 of 270
S QUESTI
R. ON
N ANSWER
SR. QUESTION ANSWER
NO.
GENERAL FLOW Filtration Rating
Each AHU with 10 micron fresh air filter, 10 micron pre filters, 3 micron intermediate filters, Terminal
30.
HEPA 0.3 micron filters efficiency of 99.997% in core areas and HEPA filter in return. Exhaust HEPA
23
Filter.
Air Circulation
30.
90% and 10% fresh air.
24
At In
Difference between RestISO and EU particle count Operation
As per
Class federal Particle
0.5 µmcount 5.0 µm
100 0 100 0
1,000 1,000 7 10,000 70
30.21 10,000 10,00 7 1,00,000
0 0
At In Operation
Rest
As per ISO
Class Particle count
0.5 µm 5.0 µm
ISO 29 29
CLASS 5
ISO 35,200 293 3,52,000 2930
CLASS 6
30.
25
30.22
Page 103 of 270

Page 104 of 270
SR. QUESTION ANSWER
NO.
Action in case of power failure
30. SR. QUESTION ANSWER
26 10 minutes NO.
Total AHU
30. Total 41 AHU
27
Cooling system
30.
Condensing unit and chiller system
28
HVAC Limit
ACPH NLT 20.

HEPA filter Integrity NMT 0.01%
Sound level should not be more than 80
db. Light intensity should not be less than
500 lux.
Particle count At In Operation

Rest
Class 0.5 µm 5.0 µm
30. ISO 3,52,00 2930 35,20,00 29,300
29 CLASS 7 0 0
25± 2°C for processing and secondary packing area

NMT 25°C for Quarantine and Empty Capsule store
area
55 ± 5% for processing area. NMT 60% for Quarantine and 35% to 60% for Empty Capsule store
area
Viable particle count

LIMITS ALERT ACTION
BACTERIAL 60 CFU/Plate 100
CFU/Plate FUNGAL < 1 cfu /
plate < 1 cfu / plate
Filter Cleaning 30.33
Clean with 1.5 kg/cm2 filtered air and wash with potable water and dry with potable
water Frequency : Pre filter Weekly
30. Micro V Filter Monthly
30
Return Filter At the time of time B cleaning by production or when area is idle for 10 days
Equipment Filter Monthly
Differential Pressure across filter

30. Differential Pressure across 10µ filter should be in range 2 to 12 mm of wc
31 Differential Pressure across 3µ filter should be in range 2 to 15 mm of wc
HEPA filter replacement frequency
30.
32 24 month ± 1 month
Page 105 of 270

Page 106 of 270
SR. QUESTION ANSWER
NO. SR. QUESTION ANSWER
31.0 NO.
RLAF/LAF
Test Limit :
What is RLAF / LAF
31
.1 RLAF - Reverse Laminar Air Flow Air Velocity 90 + 20 FPM
LAF - Laminar Air Flow HEPA filter Integrity NMT 0.01%
Sound level should not be more than 80 db. Light intensity should not be less than 500 lux.
Difference between RLAF/LAF
31
.2 Particle count At In Operation
Rest
Which Guideline
Class 0.5 µm
31 ISO 3520 2 3520 29
.3 ISO 146441
Air Circulation By Settle Plates / Contact Plates

31 Plates Alert Limit Action Limit
.4 Total Bacterial Count < 1 cfu / plate < 1 cfu / plate
Filtration Rating Total Fungal Count < 1 cfu / plate < 1 cfu / plate
31 Each RLAF was found affixed with 10 micron pre filters, 3 micron intermediate filters, final HEPA
.5 filters and 20 Micron return filters. By Air Sampler
3
Qualification Frequency Class A < 1 cfu / M
31 31.9
.6 6 Month ± 30 Days
Test
31 1. Air velocity, 2.Integrity of HEPA filters, 3.Particle count at rest, 4. Sound Level test, 5. Light
.7 intensity test, 6. Viable Particle Monitoring. 7. Recovery Test 8. Smoke Test (Air Flow Direction)
RLAF/ LAF Manometer Pressure Reading

31
.8 7-15 mm of water column
Page 107 of 270

Page 108 of 270
NO. NO.
32.0 WATER SYSTEM pH
Dosing
Make : Thermax Ltd.
FILTE
Source of Water - Bore
32
R RO
.1 well Depth of bore well
E
150 ft.
3 3, D
Capacity : EDI 3.5 M / Hr , Under Ground Storage Tank : 27 M Purified Water storage Tank : 7
KL I
Return line temperature
32 U
SANITIZATION AOBVE 85, GENERAL AMBIENT (25 -30)
.2
V
Sanitization frequency
Conductivity
32 EDI and Distribution
.3 Weekly RO 15 Days Temperature
Preventive maintenance Indicator

32
.4 MONTHLY
HYPOCHLORITE DOSING SYSTEM
Revalidation criteria: Hypochlorite solution dosing can be done on line in the raw water with help of dosing pump for
disinfection. 10% Solution of Hypochlorite is available of which is dissolved in permeate water.
3 Years ± 1 Month
or any significant change in
32 Water treatment system -Design MULTI GRADE SAND FILTER ( MGSF )
.5 Location Filtration of water for removal of suspended impurities
Capacity
Regulatory requirement
SODIUM METABISULFITE DOSING:
If any instruments Failure then? Sodium Metabisulfite Dosing is dosed in this water to dechlorinate the water.
32
.6
Out of limit what will happen SOFTENER :
32 Softener to remove the heavy metals & minerals.
.7
Use of Equipment
ANTI SCALANT DOSING (FOR SCALE PREVENTION)
Hypochlorite dosing An Antiscalant Chemical Permacare - 191 dosed on line in the Filtered Water by Dosing Pump to
Garnet Filter prevent the formation of Scale on the surface of Membrane elements It extend the solubility of
32 sparingly salts like : CaSO4, CaCO3 & BaSO4 etc.
Sodium Metabisulfite Dosing
.8
Anti Scalant Dosing (For Scale Prevention)
Acid Dosing
Page 109 of 270 Page 110 of 270
SR. QUESTION ANSWER
NO.
SR. QUESTION ANSWER
NO.
CHEMICAL CAUSTIC SODA DOSING ( FOR PH ADJUSTMENT)
To adjust pH of raw water upto 7.5 caustic soda (NaOH ) dosing is done on line by means
of Metering Type dosing pump with inbuilt pH meter.
Caustic soda ( NaOH ) solution is prepared by taking 45 liters permeate water in the solution
preparation tank & dissolving 22 gm. caustic soda (100 % Flakes) for 24 Hrs operation. The solution
on line at the flow rate of 2.0 Liters per hour or as required in the clean & clear Raw Water flowing at
the rate of 1.0 M3/Hr.
CEDI (CONTINUOUS ELECTRO- DEIONIZATION):

CEDI system is well established water purification technology by electro-dialysis & ion-exchange
resin. Deionization Consistently produces purified water of very low conductivity. Conductivity
of water of outlet of CEDI module is between 0.1 to 1.0 micron siemens/cm.
UV STERILIZER
This has been provided to control microbial growth in the water. This unit will operate at the flow rate
of 2800 LPH and it will emit the UV rays of 254 nm. It will give out put of three-log reduction. UV
will be switched off during sanitization.
SANITIZATION SYSTEM:
If the microbial load is higher than the alert limit, the loop system needs to be sanitized. For
sanitization purpose, a steam heat exchanger is provided. The storage and distribution system is
sanitized at 85°-90° C for one hour (to be established). The frequency of hot water sanitization is
once in a week (to be established) or whenever the microbial counts exceed the alert limit.
PRESSURE TEST
Hydro test followed by flushing of piping system with chlorine free water (preferably DM water) to
remove dirt and other foreign particles. Pressure test will be done 1.5 times the operating pressure
Pressure drop is observed during the test for the duration & based on pressure drop it is concluded
acceptable or not acceptable
CLEANING AND PASSIVATION

Cleaning medium is compatible with 0.5micron surface finish. Cleaning is mandatory. Passivation is
mandatory. Use of 1% volume/volume Nitric acid solution in water and is circulated for 8-10 hours
and operated according to a written pre-approved procedure. On line pickling/passivation is carried
out as per written pre-approved procedure and the same is documented.
RINSING
The system will be filled with the purified water and circulated at 15 minutes and will be flushed at
each user point outlet and equipment connection thoroughly. Then again the system is rinsed with
purified water until the pH is balanced with inlet pH and conductivity the range of supply
conductivity.
WELD JOINTS
All the weld joints will be butt-welded by Manual TIG welding without external filler wire (butt
welded). For purging, Argon gas with a purity of min. 99.9998% will be used. Ferrous material, tools
or equipment (carbon steel cutting tools) in the fabrication or installation of system will not be
used.
TOC ANALYZER
The Thornton 5000TOC Total Carbon Sensor and 770MAX meter measures the amount of organic
carbon in high purity waters by organic carbon to CO2 with appropriate UV radiation. The
resulting increase between two temperature compensated conductivity measurements of the sample
flow stream at points before and after oxidation is used to calculate the amount of organic carbon
present.
Test
Instrument
Verification Piping
Verification Welding
Surface Finish
32
.9
Deadleg
Measurement
Slope
Measurement
Hydro Test
Passivation
Sanitization
WELDING
OBJECTIVE
To establish a Standard Operating Procedure for Orbital Welding.
SCOPE
This shall be applicable to the Piping of PFW Storage & Distribution System.
RESPONSIBILITY
To do : Manufacturer.
32.1
0 To Check : User company
ACCEPTANCE CRITERIA
All joints shall be argon welded wherever
possible. The welder is qualified / certified.
Weld Numbers and TC joints to be indicated on the as-built Isometric.
WELDING (Standard Operating Procedure)
Page 111 of 270

Page 112 of 270
SR. QUESTION ANSWER
NO.
SR. QUESTION ANSWER
NO.
ALIGNMENT OF TUBING SURFACE FINISH MEASUREMENT Ra
To do welding secure tubing in pipe stand or tripod etc. using two stands per OBJECTIVE:
tube. Use SS Shims and do not allow direct contact of tubing with carbon steel To establish a Standard Operating Procedure for Ra Value Measurement.
material.
SCOPE:
Following rules should be followed during alignment: This shall be applicable to Ra Value Measurement of the PFW Storage & Distribution system.
Make alignment so that welding will be done in horizontal position. RESPONSIBILITY:

To do :
Manufacturer. To
matching faces are in contact with no perceptible gap. Check : User company
TACKING ACCEPTANCE CRITERIA:

To hold pieces together for final orbital welding, pre-tacking will be done. Internal surface of piping, fittings, tank, etc. shall be electro polished and Ra Value shall be less than
Tacking should be small to allow them to be completely integrated into the final weld. or equal to 0.8 micrometer.
Observe penetration and crack at tacking.
Clean OD only with fine k-2 pest / scotch bright just prior to the final weld. External surface of piping, fittings, tank, etc. shall be less than or equal to 1.2 micrometer.
PROCEDURE:
WELDING General Check.
Clamp the welding head at position of welding joint. Check the Power Supply.
Connect the display unit to single phase power supply through AC adaptor. (Input AC 240V, 50 Hz,
Centre the tungsten tip over the weld joint contact 9W Output DC 9V, 500mA)
Then connect drive /detector unit to display unit with the help of a connecting cable.
surface.
Press the ON/OFF DATA SWITCH on the Display Unit, which will switch ON the screen where
Attach the purge gas source to the open end of the system being welded. Probably that point is the lowest we can check the following parameters to measure the Ra Value:-
point & purge gas vent point at the opposite end to the gas source point. Check parameter is
Ra. Unit of
Check the Argon gas (99.99%) flow rate to head and to purging. parameter is m. Cut-
off length is 0.8.
Check the programming which includes the speed, current, overlapping, turn, pulse, pre gas purging Insert the detector. Attach the support feet as per the surface to be
time, post gas purging time & the strike current and compare that selected program to the pipe sample measured. Set the detector parallel to the surface to be measured.
joint. Set the direction of the lay, if any, square to the measuring
direction. Be sure to set the skid in contact with the surface to be
measured.
Press the START/STOP button and the measurement is initiated after error checking, string
CHECK POINTS goes out, segment by segment indicating detector travel during measurement.
Once the travel is completed for the specified traversing length, the measured value is displayed
Weld should be fully penetrated around the entire weld parameter with no crevices or entrapment on the screen and the detector returns to the initial point and stops.
sites. Weld shall be smooth uniform, complete and flat, not concave on the outside.
1.
Weld shall have a uniform and complete weld bead width on the inside with no Convexity.
things and the after rectification starts again.
There shall be no visible signs of oxidation discoloration of the inner weld There shall be
no porosity, pinhole and cracking. 2. Poor connection of the connector.
Re welding of defective weld shall not be carried out in case of above defects. 3. Faulty detector installation.
4. Measure the reading when the Input data exceeds the measurable range.
5. Measure the reading surface at any given point and get the value as the final Ra Value.
Page 113 of 270 Page 114 of 270

SR. QUESTION ANSWER
NO.
SR. QUESTION ANSWER
NO.
DEAD LEG MEASUREMENT:
SLOPE MEASUREMENT
OBJECTIVE:
To establish a Standard Operating Procedure for dead leg measurement. OBJECTIVE:
To establish a Standard Operating Procedure for Slope measurement.
SCOPE:
This shall be applicable to dead leg measurement for PFW Storage & Distribution System SCOPE:
This shall be applicable to Slope Measurement of PFW Storage & Distribution System.
RESPONSIBILITY:
To do :
Manufacturer. To RESPONSIBILITY:
Check : User company To do :
Manufacturer. To
PROCEDURE: Check : User company
Dead leg measurement (main pipe and branch having equal diameter)
PROCEDURE:
Measure the distance from inner surface of main pipe to the farthest end of the branch (till the dead
end, in case of valve consider till center point of valve body) GENERAL:
Make a continuous water column in a transparent and flexible U-tube.
Dead leg measurement (main pipe and branch having unequal diameter)Measure the distance from
inner surface of main pipe to the farthest end of the branch (till the dead end, in case of valve consider Keep one end of the U-tube at the starting point of the subjected tubing/line, such that the water
till center point of valve body) meniscus should be leveled with the axis of the subjected tubing/line.
NOTE: RECORD THE ABOVE RESULTS OBTAINED Keep other end of the U-tube at the end point of the subjected tubing/line.
ACCEPTANCE CRITERION: Measure the distance between the starting point & the end point of the subjected tubing/line(X).
The dead leg shall be less than or equal to 3d (d stands for diameter of branch tapping)
Measure the distance between the tubing /line axis & the water meniscus at the end point(Y).
Now calculate the ratio of Y: X. the ratio should be more than 1:100.
If the ratio is less than the desired value, then the level of the subjected section should be adjusted
accordingly.
Slope of the line : Slope should not be more than 1:100 in any section of line.
Page 115 of 270 Page 116 of 270

SR. QUESTION ANSWER
NO.
SR. QUESTION ANSWER
NO.
PASSIVATION
HYDROTEST
OBJECTIVE:
OBJECTIVE: To establish a Standard Operating Procedure for Passivation.
To establish a Standard Operating Procedure for Hydro test.
SCOPE:
SCOPE: This shall be applicable to Passivation of tubes, for PFW Storage & Distribution System.
This shall be applicable to Hydro test of the PFW Distribution Line.
RESPONSIBILITY:
RESPONSIBILITY: To do :
To do : Manufacturer. To
Manufacturer. To Check : User company
Check : User company
PROCEDURE:
PROCEDURE:
GENERAL
GENERAL This specification covers requirement for cleaning, and to passivate of all stainless steel or alloys
Fill Purified water in the tank up to 40% of the total Tank Volume of the storage. Close all the drain containing more than 12% Cr.
points & the POUs in the system.
All the welding flux and weld spatter shall be removed by initial cleaning.
Select the system in manual mode.
Select the Pump & start it in manual mode. INITIAL CLEANING

Take 25-50% volume of water in the Storage Tank (of the water quality chlorine content less than
Slowly close the return line of the diaphragm valve and then close the pump discharge valve. 5ppm). Re-circulate the water for a period of 30 minutes.
Meanwhile stop the pump and see that there is pressure rise in the line.
Drain the water in the Storage Tank by opening the drain valve and in the System by opening the
Pressurize the entire loop with the help of Hydro pump (1.5 times the operating lowest point valves.
Pressure). Set the pressure as per requirement. PASSIVATION

The composition of the passivating Bath shall be as follows:-
Wait for 1 hour and check the pressure. If there is no drop in pressure, the loop Hydro test is 1. 1 % concentrated Nitric acid,
successful. If there is pressure drop then rectify it and repeat the Hydro test as per the above point. 2. 99% Purified Water
3. 1.5 times the hold up volume of the distribution piping, and
4. 1.5 times the hold up volume of the equipment in the loop (except tanks) OR
ACCEPTANCE CRITERIA 25% volume of the Storage Tank whichever is Higher
Tank pipes and other equipments shall be filled with the solution. The solution shall be held in the
There should not be any leakage. & There should not be any pressure drop during hold time. equipment or re-circulated. Atmospheric 8-10 hours
Stop the recirculation.
Drain the acid solution in the Storage Tank by opening the drain valve and in the System by
opening the lowest point valves.
Flush the system with fresh Purified water till the whole acid solution is flushed out.
Page 117 of 270 Page 118 of 270

SR. QUESTION ANSWER
NO.
SR. QUESTION ANSWER
NO.
FINAL CLEANING
Take 25-50% volume of water in the Storage Tank (of water quality chlorine content less than
1ppm). Re-circulate the water for a period of 30 minutes.
Drain the water in the Storage Tank by opening the drain valve and in the System by opening
the lowest point valves.
Repeat the above procedure (4.4.1 & 4.4.2) till the Conductivity gets to <3.o
2
s/cm This will end the cleaning cycle.
WATER QUALITY TEST DURING FLUSHING
Check the Conductivity and HNO3 Concentration of supply line of water and return line of
water. pH of the water should be between 5 to 7 and feed and drain water pH should match.
After line-flushing pH at loop return shall match with in feed water quality.
SANITIZATION
OBJECTIVE:
To sanitization the loop and Storage Tank.
SCOPE:
This shall be applicable to the sanitization of PFW Distribution Piping and Storage Tank.
PFW water Temperature shall not be less than 80 °c
PFW water Circulation time should be no less than 30 minutes.
PROCEDURE:
Purified water storage & distribution system has been designed for Hot Water sanitization @ 85ºC.The
frequency of the sanitization shall be determined during Phase-I and Phase-II trials but would normally
be once every week. (Description Will Be provided in OQ)
Sanitization of loop :
Hot water sanitization should be done by recirculation PFW water in system. First raised PFW temp to
80
° and maintain it above 80 ° with help of Plant steam heating at tank jacket. Recirculation time should
not be less than 30 minutes.
Dead leg (As per Guideline)
USF
32. DA
11 MH
RA
Schedule M
WHO
IP/BP/USP Purified Water Specification
32.
pH (5-7 at 25ºC), Micro (NMT100cfu/ml)
12
Specification Criteria (Feed Water, Purified Water)
Feed Water
pH 6.5 to 8.5
TDS 2000 ppm
32.
Hardness 600 ppm
13
Chloride 1000 ppm
Conductivity
Purified Water
Page 119 of 270 Page 120 of 270

SR. QUESTION ANSWER
NO.
SR. QUESTION ANSWER
NO.
TYPES OF WATER
Following types of water are used in the factory premises
FLOW OF WATER SYSTEM
Raw Water:
Raw water may be used in the early stages of cleaning of pharmaceutical manufacturing
equipments. It is the prescribed source feed water for the production of purified waters.
Chemical formula: H2O
32.
Drinking Water
14
Raw water (potable water) is used for drinking purpose and stored in water Cooler through Aqua
Guard Water Purification system.
Purified Water
Purified water is used as an excipient in pharmaceutical formulations beside its application in 32.
cleaning of equipment,area etc. 21
Total Sampling/User Point
32. Sampling Point 36

15 User Point 21 (Tablet - 9, Liquid -9, QC 3)
Sanitization
32.
Once in a week at not les than 85° C.
16
The microbial limit
Preparation of chemicals
32.
NMT 100 CFU/ml
17
Sodium Hypo chloride
Phase wise Validation
(NaOCl)
Phase I Every sampling point on daily basis for one 80 liters water +1.2 kg Sodium Hypochlorite Adjust the strokes 55% (i.e. 3.3 LPH) to get the
32. 0.5 to 1- PPM free residual chlorine
month Phase II - Every sampling point on weekly basis
18
for 3 month Phase III - Every sampling point on
fortnightly basis for 1 year Sodium meta bi sulphite (SMBS)
Loop System 80 liters water +360 grams Sodium Meta Sulphite 55% (i.e 3.3 LPH) to achieve ORP meter reading
32.
less than 500 mV.
32. 22
Zero dead leg
19 Hydrochloric Acid (HCl)
Tank Cleaning frequency 80 liters water + 47.6 grams Hydrochloric Acid dosing rate 55% (i.e 3.3 LPH) to achieve RO
inlet pH 5.0 to 6.0.
32.
Once in month
20 Antiscalent
80 liters water + add 960 grams Antiscalent 55% (i.e 3.3 LPH) stroke rate
Sodium Hydroxide
80 liters water + 685 grams Caustic. Set the dosing rate to achieve RO II inlet pH 7.0 to 8.0.
Page 121 of 270

Page 122 of 270
NO. NO.
Maintenance of water system
Monthly
UV Light Replaced after 7500 running
32.
hours Cartridge Filter - once in a three
23
months.
Vent Filter - once in a six months.
User Point General Check Up Frequency is once in a six months.
32.25
32.
24
32.26
Page 123 of 270 Page 124 of 270

NO. NO.
32.
29
32.
27
32.
30
32.
28
32.
31
Page 125 of 270 Page 126 of 270

NO. R. ON
WATER ANALYSIS: N ANSWER
O.
MICRO
Sterilize screw cap glass bottle of 250 ml capacity by autoclaving at 121 C and 15 lbs pressure
for 30 min. LIQUID / TABLET LOOP
Put sterilized sampling bottles, gloves, nose mask and filtered 70% IPA bottle in cleaned and dried SS Select sanitization mode.
sampling box and take it to sampling point.
Start the boiler to generate heat, open steam supply valve to the jacketed purified water distribution
Wear gloves and nose mask. tank.
Clean the hands after wearing the hand gloves with filtered 70 % IPA solution.
32.
32 Open the sampling valve completely and drain 10 to 15 liter of water. Open sterile bottle and fill up Check and record the temperature of purified water in the return loop after every 15 minutes. It
to 250 ml mark close the screw cap immediately.
should be not less then 85°C.
Check and record the temperature in Annexure-I.

CHEMICAL
Rinse the bottles & stopper or cap three to four times with water. Collect the water sample
Circulate the hot water above 85°C for 60
approximately 650 ml) in sampling glass bottle. Close the container with stopper.
minutes. Stop the purified water pump.
For TOC testing, collect the sample in dry and clean 100 ml of volumetric flask (previously rinse with
concentrated hydrochloric acid and water).
Open drain valve (V37) and drain the water.
SANITIZATION OF PURIFIED WATER DISTRIBUTION Close the drain valve (V37) and start RO-II.
LOOP PRE-START
Hot water sanitize of purified water storage distribution system is normally carried out when there is no Collect the 2000 liters purified water into Purified water storage
production activity.
tank. Start the purified water pump and circulate the water through
If there is any production activity then inform the concerned production officer not to operate the
user point. the loop. Circulate the purified water for 15 minutes.
Check the water level in purified water distribution tank on distribution panel. It should be more Stop the purified water pump.
than 2000 liters.
Open the drain valve (V37) and drain the water.
There shall be two booster pump (P-3 & P-4) are available for liquid loop and booster pump (P-1 &
32. P-2) are available for Tablet loop.
33 Close drain valve, user points and take loop in
For Liquid loop. If booster pump (P-3) is selected, then open valves V35 and close valves V36,
use. Update the record the sanitization details.
V37. If booster pump (P-4) is selected, then open valves V36 and close valves V35, V37.
Frequency for sanitization is once in a week.
For Tablet loop. If booster pump (P-1) is selected, then open valves V33 and close valves V34, V37.
If booster pump (P-2) is selected, then open valves V34 and close valves V33, V37.
Close all the user points.
Open lid of purified water distribution tank and check the functioning of spray ball, Rectified it, if
required.
Page 127 of 270 Page 128 of 270

SR. QUESTION ANSWER
NO.
SR. QUESTION ANSWER
NO.
Check and record the chemical consumption for RO sanitization in Annexure-II.
RO
MEMBRANE Frequency for RO membrane sanitization is once in a fifteen days.
PRE START
Ensure valve V3, V5 are open and valve V4, V6, V7 are close.
EDI SANITIZATION
Start RO-II and open valve (V32) to collect water in hot water tank.
Collect the 300 liters of raw water in cleaning tank. Switch on heater by pressing START button.
Connect one end of hosepipe at the outlet of cleaning tank after 5 micron cartridge filter and another Ensure that valve V28, V29, V30 & V31 is open.
end to the inlet side of reject line of RO system with the help of clamp.
When temperature will reach at 75°C, Switch ON the booster pump by pressing START button.
Connect one end to the inlet side of reject line of RO and another end to the cleaning tank.
After start of pump the water will circulate from the Electro de-ionization unit and hot water
PRE-START tank. After 30 minutes of circulation. Stop the booster pump.
Each 10 minutes interval check and record the temperature in Annexure III. It should be more than
75°C.
Ensure valve V3, V7, V15 are open and valve V4, V5, V6, V13, V14 are close.
Re adjust all the manual valves and then start system in operation
Connect the one end of hosepipe at the outlet of drain valve V15 and another end to the cleaning tank.
mode. Frequency for Electro de-ionization sanitization is weekly.
Switch on the booster pump (Raw water pump) by pressing START button.
Collect the 300 liters of portable water in cleaning tank up to the level marking.
Prepare 0.5 % solution of Hydrogen peroxide in cleaning tank, as per mention below.
Sanitizer: Hydrogen Peroxide (30 %), Add 5 liters of 30 % hydrogen peroxide in to the
cleaning tank.
Ensure valve V3, V5 are open and valve V4,V6, V7 are close.
Switch ON the booster pump (Raw water pump) by pressing START button.
After start of pump the solution will circulate from the cleaning tank to the RO membrane for 60
minutes.
After 60 minutes of circulation. Stop the water
pump. Then close V4, V5, V6 and open valve
V7.
Page 129 of 270 Page 130 of 270

What is compressed Air and why required
33
Compressed air system is designed to supply oil free (Non lubricated) compressed air to the various use
.1
points.
Make - Chicago Pneumatic.
33
.2 Capacity - 275 CFM (2 Nos)
General Flow
2
The Air compressor is required to prepare compressed air at about 6.5 Kg/cm which is used in
the production department
as utility for equipments and as an instrument air. Atmospheric air is sucked
33 through air suction and pass through 20 micron filter. The filtered air is feed to compressor
.3 to
2
compress the air from atmospheric pressure to about 6.5 to 7.2 Kg/Cm . The compress air
generated
is passes through coolant to cool the compressed air which is delivered by the air
compressor. Moisture gets condensed and moisture is separated out in moisture separator. The
compressed air filtered through 0.5 µ and 0.2 µ filter, where the viable and non viable contamination
removed. The receiver is used to store the compressed air generated by the compressor. The compress
air is then passes
through air dryer unit to remove moisture before sending to the plant at the user point.
33
.4
SR. QUESTION ANSWER
NO.
SR. QUESTION ANSWER
NO.
33.0
COMPRESSED AIR
33.5
33.6
Page 131 of 270

Page 132 of 270
SR. QUESTION ANSWER
NO.
SR. QUESTION ANSWER
NO.
Test
Method for Compressed air test kit for air detector
In house validation was performed for Microbial test. Analysis for specific
parameters i.e. CO, tube Testing parameter for detector tube of
CO2,
NO/N different test.
33.
7 O2,
SO2, Parameter for Water vapour content
Oil mist,
Water Gastec Tube No : 6
Vapour, Measuring Range : 0 to 18 mg/Ltr
Dew point
Non viable particle count test were performed by External agency. Sampling Volume : 100 ml
Sampling Rate : 100 ml/minutes
Method for Dew Point Test Sampling Time : 01 minutes
Colour Change : Green to Purple
Dew Point test kit having following component.
Closed Glass
Chamber Parameter for oil traces.
Condenser Pipe Gastec Tube No : 109AD
Digital Measuring Range : 0.2 to 5.0 mg/m³
Thermometer Sampling Volume : 20,000 ml
Sampling Rate : 1 Ltr/minutes
Take carefully and place the dew point testing kit at sampling point. 33.
9 Sampling Time : 20 minutes
Connect the compressed air line with the air compression port of dew point testing kit. Colour Change : Pale Red to Pale Blue
Open the compressed air line valve.

Parameter for Oxygen Content.
Transfer the acetone in the condenser pipe.
Gastec Tube No : 31 B La
33.
Place the thermometer probe in the condenser pipe and ensure the probe proper in the acetone Measuring Range : 6 % to 24 %
8
Sampling Volume : 50 ml
solution. Slow add the dry ice in the acetone to decrees the temperature inside the condenser tube. : 50 ml/minute
Sampling Rate
Carefully observe the surface of condenser tube inside the glass chamber for condense of Sampling Time : 1 minute
compressed air water. Colour Change : Black to White
When observe condense on surface of condenser tube recorded the temperature which is dew point. Parameter for Carbon Dioxide.
Gastec Tube No : 2LC
Repeat the test for two times more on same sampling point.
Measuring Range : 200 to 3000 ppm
Note down the dew point and take average. Sampling Volume : 150 ml
Sampling Rate : 100 ml/minute
Sampling Time : 1.5 minute
Colour Change : Pale Blue to Purple
Page 133 of 270

Page 134 of 270
S QUESTIO SR. QUESTION ANSWER
R. N NO.
N ANSWER
O.
Open the compressed air valve to control the required pressure of compressed air at compressed air
Gastec Tube No : 1LC inlet.
Parameter for Carbon Monoxide.
Measuring Range : 5 to 50 ppm Maintain the required air pressure by air pressure controller valve.
Set the air pressure (2 Kg/cm²) by using the air pressure controller regulator.
Sampling Time : 3 minute Set the air flow by using the air flow meter with regulator as per requirement of test (See detector tube
Colour Change : Yellow to Dark Brown literature)
Break the detector tube from the both end and place the detector tube in tube holder pipe.
Gastec Tube No : 11 L Connect the holder pipe with detector tube at outlet of flow meter.
Parameter for Nitric oxide and Nitrogen Dioxide.
Measuring Range : 0.2 to 0.5 ppm
Sampling Volume : 200 ml Start the stop watch for take reading of time as per test requirement.
Remove the gas detector tube from outlet of flow meter after completion of sampling.
Sampling Time : 2 minute
Colour Change : White to Yellowish Orange Check and record the reading on gas detector tube for reference.
Mark the observation on the detector tube for reference.
Parameter for Sulfer Dioxide.

Method for Total Microbial Count (TMC)
Gastec Tube No : 5 La
Measuring Range : 2 to 30 ppm Test for bioload (by membrane filtration method)
Media used: Soyabean casein digest broth. ( Transfer 100 ml of SCDB in a 250 ml conical flask
Sampling Rate : 100 ml/minute cover the pipette ends with aluminium foil and sterilize.
Sampling Time : 2 minute
Colour Change : Blue to Yellow Preparation of SCDA plates.
Equipments.
Conical flask 250 ml
Compressed air testing kit is having following component. capacity. Flow meter.
Compressed air connection port. Membrane filtration unit with sterile 0.22 um membrane filter.
Compressed air pressure controller regulator to control the pressure of compressed air at
compressor air inlet. Sampling Procedure.
Pressure gauge. Only trained and evaluated personnel should collect the samples.
Air flow meter with
regulator Air detector Precaution to be taken by the microbiologist while connecting inlet of compressed air to the
tube holder pipe. Stop sterile flask. Nose mask and gloves to be worn.
watch.
Carry the flask in respective areas.
All components are permanently adhered to SS plate except stop watch.
External surfaces of all sampling points are to be sprayed with 70 % v/v IPA
Take carefully and place the testing kit at sampling point where the quality of compressed air to be
tested.
Page 135 of 270 Page 136 of 270

NO. R.
-determined points. N ANSWER
O.
Carefully insert the outlet of flow meter in to the flask containing broth.
AIR COMPRESSOR
Set the flow rate 50 Ltrs/minute and bubble the air for 20 minute so as to sample 1,000 liters of
air. On completion of sampling remove the tubing from the flask and cover the ends with
aluminium foil.
Identify each flask with proper status label indicating sampling point, sampling date and bring to the
microbiology department.
Method of testing.
Test to be carried out in clean room under laminar flow only.
Use filter cone with membrane filter and transfer the sample from the conical flaskto the filter
holder. Follow the membrane filtration technique.
After completion of filtration remove the membrane filter using sterile forceps and place it on pre-
incubated SCDA plate.
Incubate the inverted plate at 30ºC to 35ºC for 72 hours.
At the end of incubation count the number of colonies. Calculate the TAMC/1,000 Ltrs of
compressed air.
If any microbial growth is there after incubation identify the colonies morphologically.
MOISTURE RECEIVER TANK
Limits:
Using autoclaved media prepare negative controls for each days testing. Growth
promotion test to be performed for positive control. TAMC/1000 LTS OF COMPRESED
AIR NMT 5 CFU.
Page 137 of 270 Page 138 of 270

R. NO.
N ANSWER
34.0 ENGINEERING 34.2
O. ELECRICAL
ETP:
POLE STRUCTURE
34
.1
VACUUM CIRCUIT BREAKER
Page 139 of 270

Page 140 of 270
S QUESTION
S QUESTION
R.
R. ANSWER
ANSWER N
N
O. DG:
TRANSFORMER
BOILER
PANEL ROOM
Page 141 of 270 Page 142 of 270

S QUESTION
R.
N ANSWER
SR. QUESTION ANSWER
NO.
CHILLER PLANT
STOPPING:
Clean the filter cleaning bin with portable water.
CLEANING OF AHU AND FDV FILTERS
Open the filter section door of the

AHU/FDV. Ensure that the is in stop
condition.
Remove the filters one by one by unscrewing the filter holding clamps and put it into the clean
polythene bag and tie with cable tie.
Internally clean the filter section area of AHU/FDV with the Dry
Cloth. Take the dirty filters from hatch for cleaning to filter cleaning
room.
Remove from the polythene bag and stage the filters on dirty filter rack.
10 MICRON FILTERS
Place the filter in the cleaning unit & start the vacuum pump.
Clean the filter by blowing filtered compressed air in the direction opposite to the
normal airflow direction.
Clean the filter with potable water.
Dry the filter by blowing filtered compressed air in the direction opposite to the normal air flow
ER CLEANING : direction.
Visually inspect the filter, if found damaged replace with new.
Keep the cleaned filter in infrared dryer for drying. Chocked and requires cleaning or replacement.
k and Ensure that the filter cleaning equipments are clean. Before cleaning of filters the following precaution to be Taken:
Clean or replace the filter as per filter cleaning SOP ENG 047 .
person carrying out filter cleaning should wear the following.
After drying Put the cleaned filter in fresh polythene bag and transfer it to the concern area
n
e Mask
ber gloves. AHU/FDV & refix the Grill / pre filter as per their respective ID No.
the Vacuum pump and check air is sucked from the filter cleaning bin. Ensure that compressed air pressure should be 2.0 to 2.5 kg/cm2. Close the doors of AHU/FDV and check they are locked.
p the filters in filter washing bin and start cleaning the filter with filtered compressed Air & Portable water.
p the cleaned filter in infrared dryer for drying at about 80°C. -I.
Frequency: Monthly / whenever Mangnehaulic gauges readings are deflated i.e. for 10 µ Limit
is 2 to 15 mm of hg.
r drying, remove the filter, place it in new polythene bag and stage it on rack.
3 MICRON (MICRO-V) FILTERS

Clean the filter by blowing filtered compressed air in the direction opposite to the
normal airflow direction.
Put the cleaned filter with fresh polythene bag and transfer it to the concern area & refix the Grill /
Page 143 of 270 Page 144 of 270

SR. QUESTION ANSWER
NO.
SR. QUESTION ANSWER
NO. Close the doors of dust extraction unit and check
Close the doors of AHU and locked. locked. Switch ON the Dust Extraction unit.
-IV.
nnexure-I. Frequency: Weekly
Frequency: Monthly / whenever Mangnehaulic gauges readings are deflated i.e for 3µ limit is 2 to RLAF/LAF FILTER
12 mm of hg.
Open the back door of RLAF of dispensing & sampling area / LAF of microbiology department and
DUST EXTRACTION UNIT
remove the pre-filters & intermediate filters and put into the clean polythene bag and carry to filter
cleaning room.
Close the compressed air inlet valve of dust extraction Place the filter in the cleaning bin & start the vacuum pump.
Clean the filter by blowing filtered compressed air in the direction opposite to the normal airflow
unit Open the door of the Dust Extraction Unit. direction.
Clean the filter with portable water.
Remove the filter and put into the clean polythene bag. Dry the filter by blowing filtered compressed air in the direction opposite to the normal air flow
direction.
Collect the powder in polythene bag from bottom tray and handover to ETP for disposal. Keep the cleaned filter in infrared dryer for drying.
Place the filter in the cleaning bin & start the vacuum pump. Take the cleaned filter in a new polythene bag and stage on the cleaned filter rack.
Put the cleaned filter with fresh polythene bag and transfer to the concern area & refix the filter as
Clean the filter by blowing filtered compressed air in the direction opposite to the normal airflow per their respective ID No.
direction.
Clean the filter with potable water. -I.
Dry the filter by blowing filtered compressed air in the direction opposite to the normal air flow Frequency: Monthly
direction.
Note: Filter cleaning is being scheduled on monthly basis or depends on magnehelic gauge.
Keep the cleaned filter in infrared dryer for drying.
Dust Collector.
Cleaned the filters mounting Frame by dry cloth.
After cleaning with dry cloth, cleaned with wet
cloth.
After properly cleaning, remove the polythene bags of filters and label & refix the cleaned filters as per
Page 145 of 270 Page 146 of 270
PHARMA BOOK Page 147 of 270
SR. QUESTION ANSWER

NO.
35.0
PREVENTIVE MAINTENANCE
Maintenance means is a procedure of inspecting, testing and reconditioning a system at regular

intervals according to specific instruction and, intended to prevent break down or deterioration.
Preventive Maintenance shall be carried out as per respective preventive maintenance report of
individual equipments
Preventive Maintenance of the equipment to be carried out within + 7 days from the schedule date
otherwise deviation has to be raised.
35 WHY PLANNED PREVENTIVE IS REQUIRED

.1
PURPOSE OF PREVENTIVE MAINTENANCE:
To avoid accidents & probable machine breakdowns.
Reduction of the down time.
Prevention of rejection during processing in order to meet the cGMP compliances.
Reporting the status of deterioration of equipment to the management so that further
necessa to be taken in order to prevent defects in products to meet the cGMP compliance.
3
6 CALCULATION
.
0 Area = Lxw Volume : LxWxH

Area of Plane Shapes
Triangle
Square
Area = 2
a
a = length of side
h = vertical height
Rectangle Parallelogram Area = b × h b = base

h = vertical height
w = width h = height
36.1
Trapezoid (US) Trapezium (UK) Circle

2
h = vertical height r = radius

Sector Area = ½r 2 r = radius
radians
Ellipse
S QUESTION
R.
37.0 PHARMACODE
O. NO.
a1=Width of thin code bar b1 =Width of thick code bar

c1=Gap between the code bars of the main code
Pharmacode:
d1=Gap between the main code bar and the supplementary code bar e1=Height of code bar
Pharmacode, also known as Pharmaceutical Binary Code, is a barcode standard, used in the
z1 =Width of colour code bar = Width b1
pharmaceutical industry as a packing control system. A Pharmacode is a series of thick and thin bars,
which are read using a code camera / laser scanner / single beam sensor head / packaging machine
code readers for product/component security, and also serves important security system during
production by avoiding any mixing of packaging materials like cartons, labels and inserts.
Pharmacode numbers are used as unique security identifies on packaging material.
There are two versions of Pharmacode: a one - track and two track code. There are standard and . Standar Minimum Maximum
miniature variations of the one track Pharmacode. d
Miniature codes shall be used where restricted space is available (e.g. small labels, narrow carton a1 0.5 mm 0.4 mm 0.7 mm
flaps, etc.).
b1 1.5 mm 1.3 mm 2.5 mm
Standard/Miniature (whichever applicable) codes shall be used for Carton and Pack inserts.
However the combination of thin and thick bars will be same as that of the standard code appearing c1 1.0 mm 0.9 mm 2.5 mm
on the labels of that particular product/strength.
d1 1.5 mm 1.2 mm 2.5 mm
Each component to have a unique number. e1 8.0 mm Application Specific Application Specific
Pharmacode tolerances are checked on artwork proofs by Packaging Development and Quality z1 1.5 mm 1.3 mm 2.5 mm
3
Assurance Department.
7. b1/ 3 - -
1 a1
All Foil, Carton, Inserts and Labels used for Indian market and export market will have
combination of thin and thick bars.
Standard Pharmacode:
Page 149 of 270

Page 148 of 270
S QUESTI
R. ON
N ANSWER
O. SR. QUESTION ANSWER
NO.
Miniature Pharmacode:
Calculation of Pharmacode values

Pharmacode may contain minimum 3 bars and maximum of 16 bars which are read from right to left. There shall be at least 1 thick and thin bar
The values associated with each bar are summed to overall value of the code. Minimum code value is 4 and maximum code value is 131069.
The chart is described as below.

Position
Thin bar value

Thick bar
1 1 1 9 8 value7 6 5 4 3 2 1
2 1 0
2 1 5 6 3 1 8 4 2 1
0 0 1
4 2 2
4 2 6
8 4
1 6 3 8 4 2
a2 =Width of thin code bar b2 =Width of thick code bar
4 2 10 2 4 2
c2 =Gap between the code bars of the main code 8
d2 =Gap between the main code bar and the supplementary code bar e2 =Height of code bar
z2 =Width of colour code bar = Width b2
Standar Minimum Maximum

d
a2 0.35 mm 0.3 mm 0.45 mm
32 32 8 8 2 2
b2 1.0 mm 0.9 mm 1.7 mm
c2 0.65 mm 0.55 mm 1.65 mm Example:Pharmacode No = 32 +32+ 8 + 8 + 2 + 2 = 84
d2 1.0 mm 0.8 mm 1.7 mm
e2 6.0 mm Application Specific Application Specific
z2 1.0 mm 0.9 mm 1.7 mm
b2 / =3 - -
a2
Page 150 of 270

Page 151 of 270
S
R
QUESTION S QUESTI
. ANSWER R. ON
N N ANSWE
O
O. R
.
SAMPLING PROCEDURE
3 SAMPLING PROCEDURE FOR IP/FG: For visual examination, the Sample quantity is as per below mentioned table
8 Total No. of batches Nos. of batches to be visually inspected
. The total sample of blend shall be 20gm per batch per batch for in process analysis. manufactured
1-5 All batches
0 Compressed tablets sample shall be withdrawn from container as per table No. 1. 6-15 Any 05 batches including first and last batch.
Total nos. of Nos. of containers to be sampled 16 and
containers 1-5 above
All containers Samples shall be examined visually for evidence of deterioration or any physical change in the
6-15 product once in a year up to the expiry.
Any 05 containers including first and the Last container
16 and above If material is powder, capsule/tablets, it shall be immersed in half filled bucket of water and slurry
is the Total nos. of HDPE containers) shall be sent for disposal to the effluent treatment plant. If the material is liquid, it shall be diluted in
half filled bucket of water and shall be sent to effluent treatment plant fo r disposal.
Collect sample from containers in self-sealing polybag. The total sample of tablets shall be approx 100 tablets per Raw material Sampling device Sample collection container
batch for in process analysis and shake this polybag gently to get composite sample of the entire batch. RM SAMPLING:
For chemical analysis SS Spatula or SS Sampling Amber coloured glass
rod. bottle or polyethylene bag.
Collect sample from containers in self-sealing polybag. The total sample of tablets / capsules shall be
approx 100 units per batch
For microbial analysis Sterile SS Spatula or SS Sterile amber coloured glass bottle.
Collect the liquid syrup samples into the glass bottles from the S.S.Tank. The total sample of liquid Sampling rod.
38.1 syrup shall be 2 bottles for in process analysis. Solvent SS sampler/ Glass pipette Amber coloured glass bottle.
Collect the complete pack of liquid syrup during carton packing. The total sample of liquid syrup
shall be 12 bottles per batch for finished product analysis and 2 bottles from start and end of
packing operation for microbial analysis.
For Active raw material: Draw the sample from all received
containers. For excipient,
I. All containers should be sampled if number of container are less than or equal to 5.
Reserve Sample:
An appropriately identified samples representative of each lot or batch of finished drug product retained II. If the number of container is 5 to 16, draw the sample from 5 containers.
and stored consistent with product labeling III. If the number of container are more than 16 number, it should be sampled by using the
The reserve sample shall be stored in the same immediate container closure system in which the drug Where, n = number of container received.
product is marketed or in one that has essentially the same characteristic. For UK and USA product raw material, Active and excipient raw material sampling shall be done for all
received containers (i.e.100 % sampling plan).
Reserve samples shall be collected as a whole (complete pack) by IPQA Officer during entire run of
final packing. A sticker label as "RESERVE SAMPLE" shall also be pasted on it for identification
(Annexure-V) such as that it shall not hide important details on the carton (eg. Label claim, batch
details, storage conditions etc.) PACKING MATERIAL:
The quantity of reserve sample for finished product shall be twice the quantity required for the complete Number of Containers Received Number of containers to be
analysis. For Tablets and Capsules sample approximately 400 units. For Liquid orals below 50 ml pack
size sample 20 bottles, for 50 ml to 100 ml sample 10 bottles and above 100 ml pack size sample 5 opened 1 to 5 All
bottles.
6 to 16 5
Page 152 of 270 Page 153 of 270

NO. NO.
39.0 NOTE:
OUT OF TREND i. By any circumstances if the cleaned equipment is not used within 48 hrs
then the equipment shall be cleaned as per product change over cleaning
Out of trend: The data that represents abnormal pattern or behavior from normal pattern is called prior to use.
as Out of trend
ii. During continuous production/campaign production on the equipment, the
In case the results are out of trend (alert) observed in commercial batches then the same shall be equipment shall be cleaned as per product changeover cleaning after
39 manufacturing of 10 batches or 10 days which ever is earlier
investigated and report shall be closed. If required, alert values shall be revised with sound
.1
scientific justification.
OOT investigation shall be closed within 30 working days from its discovery. Cover the electrical boards and control panel with poly bag.
Mope the inner and outer surface & body with the help of duster and remove the
40.0EQUIPMENT CLEANING PROCEDURE adhered material from the RMG by scrubbing with Teflon scrubber.
Wash the inside RMG and outside body of RMG thoroughly with potable water.
Charge potable water into the RMG up to the height of chopper blade and operate the RMG
Type C Cleaning for 2 to 3 minutes at slow speed of agitator & chopper. Stop the machine and drain the water
through the discharge port.
Criteria:-At the end of the shift when the same batch is to be continued on next day. Dismantle the chopper assembly. Remove the vent filter, main lid & gasket, small lid &
gasket discharge valve and gasket and take them to the washing area.
Clean the electrical board and control panel with the help of dry lint free duster or vacuum Lift the blade of the agitator. Wash inside and outside body of RMG and agitator with 70-80
cleaner. liters potable water and clean it by scrubbing with nylon scrubber dipped in 0.10% w/v of SLS
Clean/wipe the outer and inner surface of the RMG with the help of dry lint free solution followed by rinsing with 45-50 liters potable water till no residue of any material or
duster. Clean the area as per the procedure for cleaning of production area, SOP surfactant is visible.
No.PSG 010. Put the status label on the machine. Wash the chopper assembly, vent, main lid & gasket, small lid & gasket, discharge valve &
gasket with 15-20 liters potable water and clean it with 0.10% w/v of SLS solution followed
by scrubbing with nylon scrubber. Rinse all the above parts with 10-15 liters potable water till
Type A Cleaning no residue of any material or surfactant is visible.
Criteria:-1. Between batches of same product. Finally rinse the inside and outside body of RMG and all the dismantled parts with 55-65
2. Between batches of lower strength to higher strength of the same product. liters purified water.
Collect rinse water/swab test samples and send it to the QC department for analysis. If traces
Ensure that the area and equipment is free from the materials, containers and documents of found more than the permissible limit then immediately intimate to production head and QA
previous batch/product. head and address it through deviation.
Clean the electrical board and control panel with the help of dry lint free duster or vacuum Wipe out all the dismantled cleaned parts, agitator and inner surface of the body of RMG
cleaner. with a lint free duster dipped in 70 % v/v of IPA.
Remove the adhered material from the RMG by scrubbing with Teflon Dry all the cleaned parts, outside and inside of the body with the help of dry lint free duster
scrubber. Clean/wipe the machine with the help of dry lint free duster. or by using filtered compressed air.
Close the lid of the RMG. Clean the electric board and control panel with dry lint free duster or by using vacuum
Clean the area as per the procedure for cleaning of production area, SOP No. PSG
010. Put the status label on the machine & area. cleaner. Clean the area as per procedure for cleaning of production area, SOP No. PSG
Type B 010.
Cleaning
Criteria: Fill the area and equipment checklist and get it approved by QA after getting the results of
1. Between batches of different product. analysis from quality control department.
2. Between batches of higher strength to lower strength of the same product.
3. Change in colour irrespective of product and strength.
4. After any maintenance work relating product contact part.
Page 154 of 270 Page 155 of 270

SR.
QUESTION SR. QUESTION
NO.
ANSWER NO. ANSWER
41.0
PUNCH AND TOOLING Go and No-Go of punch
Tip diameter of punches head. -
sily.
Check the tip diameter with the help of a Vernier caliper.
Check and set the zero reading of the Vernier caliper.
Place the punch tip in a vertical position. Record the observations in the ANNEXURE I.
Check the fine setting of the Vernier caliper and record the reading in the Annexure-I.
The readings should be within ± 0.1 mm of the standard dimension.
Outer diameter of dies
Set the dial gauge of the inspection kit at zero position with the help of the standard die master
Difference in height of the punches piece.
Set the dial gauge of the inspection kit at zero position with the help of the standard punch height Keep the dies horizontal position one by one over the metal pad (V BLOCK) of the inspection kit
133.60mm. and check the outer dimension deflection from the zero position.
Keep the punches one by one inside the punch holder over the metal pad of the inspection kit and Record the reading in the Annexure II. The standard dimensions and limit are as in table.
check the difference in deflection from the zero position.
Record the difference in Annexure I. Type of tooling Outer diameter of
The difference should not be more than ±0.08 mm of the standard dimension. dies(mm)
38.10 ± 0.1
30.16 ± 0.1
Body diameter of punches
Check the body diameter with the help of a Vernier caliper.
Check and set the zero reading of the Vernier caliper. Height of the die
Check the fine setting of the Vernier caliper and record the reading in Annexure-I. Set the dial gauge of the inspection kit at zero position with the help of the standard die master
The standard dimensions and limit are as in table. piece.
41.1
Place the dies in vertical position one by one over the metal pad of the inspection kit and check
Type of tooling Punch body diameter(mm) the height deflection from the zero position.
25.35 ± 0.1 Record the reading in the Annexure II. Standard dimensions and limit are as in table:
19.0 0.1
Type of tooling Height of dies (mm)
Embossing of punches
Visually check the embossing & enter the remarks in the ANNEXURE I.
Difference in concentricity of punches Difference in concentricity of dies
gauge at zero position over the punch body. the die body.
Rotate the punch in the clockwise direction, take two readings each from the punch (one from the Rotate the die in the clockwise direction, take two readings each from the die (both side) and
top and one from the bottom of the punch body) and record the observations in Annexure I. record the observations in Annexure II.
The deflection should be within ± 0.05 mm of the standard dimension. The deflection should be within ± 0.05 mm.
Frequency: Inspection of punches and dies to be done after receiving of a new punch set and after
gauge at zero position over the highest point on tip diameter. compression of two million tablets per subset.
Rotate the punch in the clockwise direction and record the observations in Annexure I.
The deflection should be within ± 0.025 mm of the stand ard dimension. Note: Check the calibration status of dial gauge, and Vernier caliper before use and record
the same as O.K. /NOT O.K. in the respective annexure. Do not carryout the inspection by
using a dial gauge or Vernier caliper which is due for calibration.
Page 156 of 270 Page 157 of 270

NO. R. ON
N ANSWER
41.
2
There are following types of Tooling available:

-Tooling
- Tooling
-Tooling
- Tooling
Type Of Pu Die Punch Max. Tab.
nch Diameter. Length Size (mm)
Tooling Diameter. (mm)/( inc ( mm)/inch
Following Round/Capsul
definitions for direct terminology for tooling (Punches and dies).
(in h) Head: The end of the punchethat guides it through the cam track of tablet machine during rotation.
mm)
19 30.15/ 133.60 16/19
1.187 Head flat(Dwell Flat): The flat area of the head that receives the compression force from rollers(in upper punches) and determines the weight and ejection height (in lower punches
25.4 38.1/1.50 133.60 25/25

Outside head Angle: The area gets in touch with the roller prior to head flat , while compression.
19 24/0.945 133.60 13/14

Inside Head Angle:This is the area , which pulls down the lower punches after ejection and lifts the upper punches after compression.
25.4 30.15/1.187 133.60 19/19
Neck: The relived area between the head and barrel, which provides clearance for the cams.
Page 158 of 270
Page 159 of 270
Barrel: This area guides the punch (while going up and down) with reference to turret guides.
Stem: The area of the punch opposite the head, beginning at the tip and extending to the point where the full diameter of the barrel begins. If the chamfer is present the barrel usua
NO. R. ON
N ANSWE
O. R
9. Tip face: This area of punch is where the tablet is formed. Good surface finish is required
here to bet quality tablets. Radius
10. Working length: This distance between bottom of the cup and the head flat is called as
working length which determines weight and thickness of the tablet.
11. Overall length: Distance between top of the cup and the head flat.
12. Key Angle: The relationship of the punch key to the tablet shape. The keys position
is influenced by the tablet shape, take-off angle, and turret rotation.
13. Domed Heads: Increases the dwell time and hence help to achieve the better tablet hardness.
14. Dwell time The time punches spends below the pressure roller while rotating in the machine.
Upper Punch Lower Punch

Die
Domed head
Page 160 of 270 Page 161 of 270

R. NO.
N ANSWER
15. Clearance:
Die bore dia punch tip dia = Clearance.
16. Hardness:
follo
ws:
HARDNESS OHNS O1
58-59
HCHC D2 59-60
HCHC D3 61-62
Normally the following combination is used.
For punches AISI O1(OHNS)
For dies AISI D3(HCHC)
Highly abrasive product AISI
D2(HCHC) punches
Die: hardened steel (HCHC) mould to make the shape of a tablet.

Die Terminology:
1. Die.O.D.: The outside diameter of the die, which is compatible with the die pockets in the press.
2. Die Height: The overall height of the die.
-22.225 mm
Page 162 of 270 Page 163 of 270
SR. QUESTION ANSWER
NO.
S QUESTION
R.
N ANSWER
3. Die Bore the
same
form of tablet.
4. Chamfer: Entry angle of the die bore.
6. Taper dies: dies with tapered bore on one or both sides. They are used for easy
ejection of tablets (mainly for double layered tablets.
7. Die Groove: The groove around the periphery of the die, which allows the die to be fixed in
the press.
8. Lined (Insert) Dies: Dies fitted with a linear insert made from a much harder, more
wear- resistant material such as tungsten carbide and ceramic.
Taper in one side
Head Inspection-
NO-
Die Height
Type of product Punch set life
Circular 4 million tablets/set

Other than circular 2 million tablets/set
Double layer 2 million tablets/set Die Outer Diameter
Effervescent Tablet 1 million tablets/set
Page 164 of 270

Page 165 of 270
SR.QUESTION SR.QUESTION
NO.ANSWER NO.ANSWER
42.0DIFFRENCE BEWTWEEN MOISTURE CONTENT AND LOD 43.2DIFFRENCE BEWTWEEN OOS AND OOS
42.1
44.0DIFFRENCE BEWTWEEN CHANGE CONTROL AND DEVIATION
Change Control Deviati
on
It is permanent change It is particular change in
forever. Equip., Process, and
Vendor.
Always required back up Back up not required.
44.1 data other wise not closed.
DIFFRENCE BEWTWEEN CALIBRATION, VALIDATION AND 45.0DIFFRENCE BEWTWEEN SOP AND PROTOCOL
43.0 QUALIFICATION
Protocols
Procedures are documented for one time study to qualify or validate area/ equipment/ process/ system und
Procedures are followed in routine for consistent work performance and quality
out put of the product.
43.1
45.1
Page 166 of 270

Page 167 of 270
SR.QUESTION S QUESTI
NO.ANSWER R. ON
46.0CHANGE ROOM AND LINE CLEARANCE CONCEPT N ANSWE
O. R
SOURCE CONTAMINANT
WHY CHANGE IS REQUIRED?
To reduce intake of dust, dirt, microbes in the processing area. Human Beings : Bacteria, Pathogen, Fibre, Hair, Skin fragments,
SOURCE OF DUST, DIRT & MICROBES ARE : Nail Air : Bacteria, Pathogen, Dust, Gases, Fumes
Man
Material Water : Bacteria, Pathogen suspended matter
Machine
Environ Equipment & Accessories : Previous product traces, material of equipment construction,
ment cleaning Raw Material : Impurities, Residual solvent, Black particles etc.
Primary Packaging : Extraneous matter, Material Bacteria Pathogen
What is Change Room?
Buffer between clean and unclean area
47.0BATCH RECORD
Clean Area :
Has a provision to control dust, dirt and microbes.
Unclean Area : What is Batch Records?

Batch Record is a complete set of documents Containing; Full details of manufacturing & packing
procedures & analytical documents.
LINE / AREA CLEARANCE

46 To ensure that there are no items, packaging components, residues of previous product & any other
Why Batch Record is required?
.1 unwanted material on the line
Batch Record contains Manufacturing procedures, list of Equipment to be used for manufacturing.
Implications
GMP
Violation
It is the only proof for the batches manufactured and packed as per requirement dispatched.
Mix-ups Records provide the history of each batch of the product, including its distribution and also of all other
Contaminati 47.1
relevant information pertinent to the quality of the final product.
ons
Cross
contaminations
It is also required for the investigation in root cause analysis, when ever there is any complaint
Product Failure
received from market.
Market
complaints
It is required to register the products in different countries and regulatory authorities
CONTAMINATION, CROSS CONTAMINATION AND MIX - UP
CONTAMINATION :
In any product, presence of a substance other than product manufacturing formula is called
contamination.
CROSS CONTAMINATION :
Page 168 of 270
Page 169 of 270
NO. R.
N ANSWER
48.0 O. 49.0EQUIPMENT AND PROCESS
PASS BOX
TYPES OF PASS BOX SIFTING
1. Dynamic Pass Box

2. Static Pass Box
DYNAMIC PASS BOX

For Material transfer from unclassified area to classified area.
This Pass box having HEPA filter and UV Light
Frequency of Validation is every six month 49

.1
Test:
1. Air Velocity
2. Filter Integrity
3. Particle count
The purpose of sifting is to grade/obtain a uniform particle size powder of desired range, oversize and
48 undersize particles are separated during this operation.
.1 STATIC PASS BOX
For Material transfer from classified area to classified area. The operation is carried to check for any foreign matter which may come along with the raw material.
The principle of gyratory motion is, if a body is allowed to rotate at high speed around its own axis,
in a plane and it is free to move in all other three planes, the gyratory forces developed are such that
they tend to bring the axis of rotation of the body parallel to the axis of earth
Page 170 of 270 Page 171 of 270

SR. QUESTION ANSWER
NO.
Lid: S.S lid is with charging port to avoid spillage of powder material
Upper hopper Neoprene food grade rubber gaskets
Sieve
Neoprene food grade rubber gaskets
Ring
Lower hopper Note: Sieve /gasket
modified.
Efficiency of the sieving process depends on dimensional accuracy of the apertures of the sieve.
Accurate way of measuring the aperture size is to measure the dimensions of individual apertures in both X and Y direction and use smallest value to give equivalent opening.
In order to asses compliance of sieve with respect to standard, a substantial No. of apertures and wires through out the sieving medium must be measured .
Operator has to hold the sieve against the light / Illuminations and check for any damage.
Absence of any projection on surface of sieves is confirmed by gently moving the gloved hand over both the surfaces of sieve.
Sieve integrity should be checked before and after sifting operation.
S QUESTION
R.
N ANSWER
O.
International Standards used for sieve are ASTM

(USA), JIS (Japan), BSI (U.K.), AFNOR
(France),
Tyler (USA), DIN (Germany)
has two standards ISO 4782 Standard governs metal wire

for industrial wire screens and woven wire cloth ISO 9044
standard governs. industrial wire cloth
Note: these are standards to be followed by sieve
manufacturers.
GRANULATION
Granulation is the process in which powder particles are made to adhere to form
agglomerates called granules.
To prevent segregation of the constituents of the

mix. To improve the flow properties of the mix.
To change the particle size distribution so as to improve the compressibility and to increase
apparent density of the powder.
Granulation of toxic material reduce the hazard associated with handling of toxic dust.
Granulation should be non-friable & have suitable mechanical strength.
Page 172 of 270
Page 173 of 270
S QUESTION
R.
N ANSWER
O.
Granules being compact than the powder occupy lesser volume per unit weight therefore
they are more convenient for storage and shipment.
Granulation can improve or modify drug release profile.
Particle-bonding mechanisms
To form granules, physical/chemical bonds must be formed between particles so that they
adhere.
These bonds must be sufficiently strong to prevent breakdown of the granule to powder in
subsequent handling operations till compression.
There are five primary bonding mechanisms between particles.
Binder
Mechanism of ball growth during granulation

P articles Drying
Of different
s ize
S QUESTION
R
. ANSWER
Page 174 of 270 Page 175 of 270

SR. QUESTION ANSWER
NO.
s used. Wet granulation can roughly divided on the basis of manufacturing process as
chanical compaction or force. Granulation carried out using Planetary Mixer
Granulation carried out using Rapid mixer granulator (RMG).
Granulation carried out using single pot processor.
he mix, is one of the most common method of granulation. The process can be very simple or very complex depending on the characteristics of the powders e.g Hydrophobic mix is difficult for wetting.
an adhesive, instead of by compaction.
Planetary mixer is used for wet mixing of the powders, Powder mixing usually has to be performed
as a separate operation using suitable mixing equipment. The mixed powders are fed into the bowl of
developed between the particles and the tensile strength of bonds increases as amount of liquid added is increased.
the planetary mixer and granulating liquid is added as the paddle of the mixer is responsible for wet
mixing and kneading action required to form the granules. The paddle of planetary mixer has
powder particles using a granulating fluid.The fluid contains a solvent which can be removed by drying, and should be non-toxic. planetary motion. Design of mixer is such that there is a bare minimum clearance between wall of
methylene chloride either alone or in combination. mixer and blades and devoid of any void spaces.
a solvent containing a dissolved binder / suspension / gelatinized binder. (also referred to as a binder or binding agent) which is used to ensure particle adhesion once the granule is dry.
Mixing Arm.
Mixing bowl is in
the lowered
position (This
bowl is raised
on the mixing
arm for
granulation.
Page 177 of 270

Page 176 of 270
SR. QUESTION ANSWER
NO.
S QUESTI
R. ON
N ANSWER
High Speed mixer/granulator
The machines have

a stainless steel
mixing bowl
containing a main
impeller, which Chopper
revolves in the
horizontal plane, Impeller
and a auxiliary
chopper (breaker
blade) which
revolves either in Fluidized Bed Granulator
the vertical or the
horizontal plane.
Page 178 of 270 Page 179 of 270

S QUESTION
R.
N ANSWER
S QUESTI
R. ON
N ANSWER
Spray nozzle
Air flow
simultaneously building particle size.

be encapsulated in a matrix of carrier after the spray granulation. process. Advantage of Fluid bed Granulator.
Rapid
ds) or they are formed within the fluid bed by abrasion (internal seeds). The sprayed liquid is coating the seeds and is wet
dried.massing, agglomeration and drying is carried out in within one unit.
Granulation operation are less laborious and time consuming as compared to other types of wet granulators.
Disadvantages of Fluid bed Granulator.
No adequate mixing of powder components.
bed driers. The powder particles are fluidized in a stream of air, but in addition granulation fluid is sprayed fromThere
a nozzle on to theofbed
is tendency of powder.
demixing especially when there is disparities in particle size and density in the material being processed.
bed of unmixed powder to fluidize the particles and mix the powder; fluidization is actually a very efficient mixing process.
Particles pumped
under from a reservoir
granulation through
has tendency a spray
to stick nozzle
to the positioned
equipment over
filters thisthe bed ofeffective
reduces particles.filter surface area. This also cause product loss and incr
s and powders
Page 180 of 270 Page 181 of 270

SR. QUESTION ANSWER
NO.
SR. QUESTION ANSWER
NO.
Generally water is used as solvent as it is economical, but in case of some drugs water may Roller compactors:
adversely affect drug stability, causing hydrolysis of susceptible products, and even it needs Roller compaction is an alternative gentler method, the powder mix being squeezed
a longer drying time than organic solvents do. between two rollers to form a compressed sheet.
This increases the length of the process and again may affect stability because of the extended The sheet normally is weak and brittle and breaks immediately into
exposure to heat. flakes. These flakes need gentler treatment to break them into granules.
Occasionally non aqueous solvents or solutions that are composed of water or water This can further be milled in to desired particle size.
miscible solvents are used to improve the granulation properties of formulation.
Whenever non aqueous solvents are used in granulation reduced amount of energy is Dry Granulation (Roller compactor)
required for drying.
This gives requirement of proper ventilation and safety precautions against Fire, toxicity and
explosion
Dry Granulation
The dry granulation process is used to form granules without using a liquid solution because the product
to be granulated may be sensitive to moisture and heat.
Forming granules without moisture requires compacting and densifying the powders.
Dry granulation can be conducted on a tablet press using slugging tooling or on a roller compactor
commonly referred to as a When a tablet press is used for dry granulation, the powders may not
possess enough natural flow to feed the product uniformly into the die cavity
The dry granulation process

is used to form granules
without using a liquid
solution because the
product to be granulated To determine End point of granulation.
may be sensitive to Granulation is rather Art than science. There are following ways to determine the granulation
moisture and heat. end point.
Forming granules without To make a ball of granules in fist by applying little pressure. The resultant ball should not be
too hard or soft. It should break after applying little pressure. The remains after breaking of
moisture requires ball should be granules and not fines.
compacting and To measure the
amperage. To measure
densifying the powders. the torque.
Under granulated batch: This batch will have more percentage of fines. This will result into flow
problem.
Sluggers: This batch may have capping, chipping, ejection and hardness problem.
The dry powders can be compressed using a conventional tablet machine or, more usually, a Over Granulated batch may have uneven distribution of fines, hardness and
large heavy-duty rotary press can be used. compressibility problem.
This batch may have uneven colour distribution, DT and dissolution problem.
diameter by about 10
A hammer mill is suitable for breaking the compacts.
Page 182 of 270 Page 183 of 270

NO. R. ON
N ANSWER
Tablets Deep concave (Round/ Capsule shaped) Extra deep.
Modified ball
Definition of Tablets
Tablets can be defined as Solid Pharmaceutical Dosage form containing drug substances with or
without suitable diluents and prepare either by compression or molding methods.
There are various types of Tablets and abbreviations used in referring them are as follows.
1. Compressed Tablets (CT)
2. Sugar-Coated Tablets (SCT)
3. Film-Coated Tablets (FCT)
4. Enteric-Coated Tablets (ECT)
5. Multiple Compressed tablets (MCT) The tablet press is a high-speed mechanical device. It 'squeezes' the ingredients into the required tablet shape with extreme precision.
5.1 Layered Tablets, 5.2 Press-Coated Tablets. It can make the tablet in many shapes, although they are usually round, capsule or oval.
6. Controlled Release tablets.
7. Tablets for Solution / Dispersible Tablets. Monogram/Break-line.
8. Effervescent tablets. Each tablet is made by pressing the granules inside a die cavity made of hardened steel. The die is a disc shape with a hole cut through its
9. Compressed Suppositories or inserts. The powder is compressed under high pressure in the center of the die by upper and lower steel
10. Buccal and Sublingual Tablets. punches that fit into the top and bottom of the die.
11. Vaginal tablets.
12. Lozenges.
13. Implants.
Tablet Tooling
For this purpose different types of punches are

used: Flat- faced bevel- edged.
Shallow concave (Round/ Capsule shaped)
Standard concave (Round/ Capsule shaped)
Page 184 of
270
Page 185 of 270
S QUESTI
R. ON
NO.S ANSWER
QUESTION
R
. ANSWER
Stage I: Top punch is withdrawn from the die

by the upper cam
Bottom punch is low in the die Powder falls in Stage II: Bottom punch moves
through the hole and fills the die. up to adjust the powder weight
it rises and expels some powder
Stage III: Top punch is driven into the die by Stage IV: Top punch is withdrawn by the
Main the upper cam. upper cam
Pressure Bottom punch is raised by the lower cam. Lower punch is pushed up and expels the
Pressure Both punch heads pass between heavy rollers tablet
to compress the powder Tablet is removed from the die surface by the
Roller surface plate
Tabl
et
Eject
ion
Plate
Stage V:
Star
t of
cycl
Page 187 of 270

Page 186 of 270
Causes for Capping Solutions
Tooling Machine Granules
Die Excessive Pressure Excessi Replace dies if found

bores Compression taking ve defective/Polishing/
havin place at lower side lubricati Change the upper
g of die. on. Too punch penetration.
rings. Too much of dry Reduce
Too vibration. granule compression
much s. pressure.
depth Less binder Improve
of in granules / granulation.
conca More fines.
Causes for Sticking/ Picking Solutions
Gran
Tooling Machine u
l
e
s
Wrong Less Excessive Change
design compression moisture. embossing
SR. of pressure. Insuffici
QUESTION ANSWER design. SR. QUESTION ANSWER
NO. embossing Too much heat ent Increase NO.
or break generation due lubricati pressure.
line. Problems in to
Tabletting on 2. Sticking/Picking
1. Capping
Note : Check the Relative Humidity of the area for Humidity sensitive products

Tig Turret running Excessi
ht tight with cam ve
up track Improper moistur
pe feed frame e. Over
r setting. sized
punch Lubrication granule
may be gears or oil may s.
scrappi be contaminating Granules
3.Black marks on Tablets
Causes for Black Marks on Tablets Solutions
Use of dust cups on upp punches.

Rectify machine problem
Set feed frame properly.
ng the the having black Reduce lubrication for upper punches
Cam powder. particles Improve granules qualit
Track prior to
and compression.
Punch
Guide.
Page 188 of 270

Page 189 of 270
NO. NO.
5.Non- Uniform Weight
Causes -Collar Formation on Tablets Solutions

Non- Defective feed Non-Replace/ rectify to found defective. Clean the
uniform frame or uniform,
Reducetoomachine s replace worn-out p and feed
lower improper setting. big, Reduce
too finethe pressur
punch High M/C speed. granules.
Provide uniform Granules.
working
length. Excessive Granules
4.Collar formation Die height vibrations. Worn- sticking to
Causes -Collar Formation on Tablets Solutions is above out weight the lower
the Dozzer. punches.
Tooling Machine Granules standard
In-
dies. fines. Provide
Training to
methods result in polishing 6.Non- Uniform Tablet Thickness
blunt tip corners. operators.
Improve Solutions
Causes- Non-uniform Tablet Thickness
granules.
Non- Worn out Non-uniform,
Replace/ rectify tools, found defective.
uniform pressure too big, too fine machine spee replace worn-out part an
Reduce
lower rollers. granules.Provide uniform Granules.
punch Excessive
working
lengt vibrations. Granules
h. High M/C sticking to the
Worn speed. lower punches
Page 190 of 270 Page 191 of 270

NO. R.
N ANSWER
TABLET COATING O.
Why Coating is required ?
The application of coating to Tablets, which is an additional step in the manufacturing process,
increases the cost of the product; therefore, the decision to coat a tablet is usually based on one or Modern Coating Pan
more of the following objectives
1. To mask the taste, odour, and appearance of the drug.

2. To provide physical and chemical protection for the drug from atmospheric effects,
temperature, humidity and light.
3. Functional coating (Control release, enteric coat, sugar syrup coat). Perforated coating pan
4. To protect the drug from the gastric environment of the stomach with an acid-resistant
enteric coating.
5. To incorporate another drug or formula adjuvant in the coating to avoid
chemical incompatibilities or to provide sequential drug release
6. To improve the Pharmaceutical elegance by use of special colours and contrasting Inlet air
printing, which improves the appearance of the product.
Spray
Conventional Pan coaters Tablet
The pan coaters bed Out let air to

are most
commonly used
for the film exhaust
coating
application.
Page 193 of 270

Page 192 of 270
S QUESTION
R
.S ANSWER
QUESTION
R.
N ANSWER
O.
Fluidized Bed Wurster Coating process
Types of Coating
Sugar
Coating
Film
Coating
Compression Coating
Sugar coating gives excellent appearance to the
tablets. Sugar Coating process involves following
steps:
1. Sealing.
2. Sub coating.
3. Syruping.
4. Finishing
5. Polishing
Page 194 of 270 Page 195 of 270

S QUESTION
R.
N ANSWER
O.
Sugar Coating Process
Film Coating Process
S QUESTION
R
. ANSWER
Page 196 of 270 Page 197 of 270

S QUESTION
R
.S ANSWER
QUESTION
R.
N ANSWER
O.
Twinning Possible Causes:
Too little coating applied

Inadequate Possible Causes:
mixing of tablets during coating
Poor opacitySpray ratepower)
(or hiding too of coating
high of coating
Solids content Pan liquid is too high
speed
Insufficient too of spray guns
number
low
Inappropriate tablet
shape
Tacky
Cracking
coating
cization or excessive pigmentation Core has significantly

form different thermal expansion characteristics than coating Extended elastic recovery of core after compaction
ulation.
Peeling
Possible Causes:
Low mechanical
strength of
coating. Poor
adhesion of
coating to tablet
surface.
Page 198 of 270
e 199 of 270
PHARMA BOOK
S QUESTION
R.
N ANSWER
O.
Possible Causes: Viscosity of coatingliquid too h

Poor atomization
ofcoating liquid
Logo Bridging
Possible Causes: Inadequate adhesion of the film coating

Surface characteristics of the product being coated(e.g. hydrop
Inappropriate design of logo(e.g. too detailed or too fine)
Insufficient plasticizer in
film / high internal stress
Page 200 of 270

S QUESTI
R. ON
N
S ANSWER
QUESTI
R. ON
N ANSWER
Possible Causes:
Possible Causes: Spray rate too high Inadequate drying conditions Low mechanical strength of coating.
Pan speed too low Inadequate atomization of coating liquid Excessive pan speed.
Poor distribution of Low solids content in coating liquid.
Low spray rate.
coating liquid Sharp edges on tablets. Worn tablet punches
Low tablet hardness / friability
Possible Causes: Inherent softness or high friability of core. Excessive pan speed inPossible Causes: Inappropriate design of logo (e.g. too deta
coating process.
Spray rate too low. Low solids content of spray solution. Logo "disappearance" can be due to erosion of tablet surface ar
Premature swelling of hydrophilic super disintegrant in formulation Logo Bridging.
In-filling of logo with spray-
dried coating material.
Page 201 of 270 Page 202 of 270

S QUESTION
R.
O. 50.0BALANCE CALIBRATION NO.
51.0
IPQA
Balance Calibration is one of the most important aspects in Pharmaceutical industry.

The effect of a drug can vary considerably even with very small variations in dosage As per British Pharmacopoeia:
quantities. It is therefore very essential to have a high degree of accuracy in all operations
involving quantisation of dosage forms. Average
Pharmaceutical Dosage forms Tablets (Uncoated and Film Weight 80 mg or less % Deviation 10 %
Coated)
More than 80 mg and 7.5 %
FOR ANALYTICAL BALANCE: les than 250 mg
(I) General Calibration: 250 mg or more Less than 300 mg
5%
Place standard weight as specified one by one on the pan and note down 10 %
the observations in the balance calibration record.
Draw the linearity curve for the above readings and find out the correlation factor. Capsules, Granules (Uncoated single dose) and Powder (Single dose)
Acceptance Criteria: The observed weight should not deviate by 0.1% of actual
weight or 2 x least count which ever is more of the certified weight and the 300 mg or more
Correlation factor should not be less than 0.9999.
FREQUENCY: Quarterly 7 days
As per United States Pharmacopoeia;
(II) Ascentric Calibration:
Place standard weight as specified in four corners and center of the pan one by one and note
down the readings in balance calibration record. Pharmaceutical Dosage forms Average Weight % Deviation
Calculate % RSD.
50 Acceptance Criteria: % RSD- NMT 0.1 %
.1 FREQUENCY: Quarterly 7 days 51.1
Tablets (Uncoated and Film Coated) 130 mg or less 10 %
More than 130 mg 7.5 %
FOR PLATFORM BALANCE: and les than 324
(I) Accuracy: mg
Check the accuracy of the balance by using 5 standard weights.
Place standard weight one by one in the center of the platform and record the observations in the 324 mg or more 5%
balance calibration record. Capsules, Granules (Uncoated single Less than 300 mg 10 %
Acceptance Criteria: The observed weight should not deviate by 0.1% of actual dose) and Powder (Single dose)
weight or 2 x least count which ever is more of the certified weight.
300 mg or more 7.5 %
Frequency: Quarterly 7 days
(II) Corner Load test:
Place standard weight in four corners and center of the balance one by one and note down the
Friability
readings in respective balance calibration record.
Calculate % RSD.
Record the observations in the balance calibration record. For tablets with a unit mass equal to or less than 650 mg, take a sample of whole tablets corresponding as near as to 6.5 gm.
Acceptance Criteria: The observed weight should not deviate by 0.1% of actual
weight or 2 x least count which ever is more of the certified weight.
% RSD : NMT 0.5 % For tablets with a unit mass of more than 650 mg, take a sample of 10 whole tablets.
Frequency: Quarterly 7 days
Friability test is done to withstand the mechanical shocks during manufacturing, packing and shipping.
Friability % =I F X 100
Page 203 of 270
Page 204 of 270
SR. QUESTION ANSWER
S QUESTI NO.
R. ON
N ANSWE
O. R
Complete disintegration is defined as that state in which any residue of the unit, except
I
fragments of insoluble coating or capsule shell remaining on the screen of the test
I : Initial weight of
apparatus or adhering to the lower surface of the discs, if used, is a soft mass having no
tablet F: After
palpably firm core.
friability weight
Disintegration apparatus
The apparatus is common for official pharmacopieas of
Tablet friability Apparatus:
IP,BP,USP. The disintegration apparatus consists of :
Friability test apparatus is common for official pharmacopeias in BP, USP.
The basket-rack assembly

Friability test apparatus consists of:
It consists of 6 open ended transparent tubes each 77.5 ± 2.5 mm long and having
A drum with an internal diameter between 289-291mm and a depth between 36-40 mm, of
inside diameter of 21.85 ± 1.15 mm and a wall 1.9 ± 0.9 mm thick
transparent synthetic polymer with polished internal surface.
The tubes are held in a vertical position by 2 plates, each 90 ± 2 mm in diameter and 6.75 ±
One side of the drum is removable.
1.75 mm in thickness with 6 holes, each 24 ± 2 mm in diameter, equidistant from the center
The tablets are tumbled at each turn of the drum by a curved projection with inside radius
of the plate and equally spaced from one another.
between 75.5-85.5 mm that extends from the middle of the drum to the outer wall.
Attached to the under surface of the lower plate is a woven stainless wire cloth with 2.0 ±
The outer diameter of the central ring is between 24.5-25.5 mm.
0.2 mm mesh appertures.
The drum is attached to the horizontal axis of the device that rotates at 25 ± 1 r/min.
1 liter beaker, 149 ± 11 mm in height and inside diameter of 106 ± 9 mm for the
immersion fluid. A thermostatic arrangement for heating the fluid between 35 °C and 39
°C.
A device for raising and lowering the basket in the immersion fluid at a constant frequency rate
between 29 and 32 cycles per minute, through distance of 55 ± 2 mm.
The volume of the fluid in the vessel is such that at the highest point of the upward stroke
the wire mesh remains at least 15 mm below the surface of the fluid, and descends to not
less than 25 mm from the bottom of the vessel on the downward stroke. At no time should
the top of the basket rack assembly become submerged.
The time required for the upward stroke is equal to the time required for downward stroke,
the change in the stroke direction is a smooth transition rather than abrupt reversal of motion
Discs:
The use of disc is permitted only where specified or
allowed. Each tube is provided with a cylindrical disc with
diameter of
If tablet size or shape causes irregular tumbling, adjust the drum base so that the base forms 20.7 ± 0.15 mm with thickness of 9.5 ± 0.15 mm.
an angle of about 10 with the horizontal and the tablets no longer bind together when lying
next to each other, which prevents them from falling freely. 5 parallel holes extend between the ends of the cylinder with a diameter of 2 ± 0.1 mm.
DISINTEGRATION TEST
Page 205 of 270

Page 206 of 270
NO. NO.
Procedure: Immediate release dosage forms

Place 1 dosage unit in each of the 6 tubes of the basket and if prescribed add a disc.
Operate the apparatus using specified medium maintained at 37 ± 2 ºC as the immersion Level Number tested Acceptance Criteria
fluid. At the end of the specified time lift the basket from the fluid and observe the dosage
units. S1 6 Each unit is not less than Q + 5 percent
Average of 12 units (S1 + S2) is equal to or greater
S2 6
Acceptance criteria: than Q-15 percent
All of the dosage units should have completely disintegrated.
Average of 24 units (S1 + S1 + S1) is equal to or
S3 12 greater than Q , not more than 2 units are less than
If 1 or 2 dosage units fail to disintegrate, repeat the test on 12 additional dosage units. Q-15 percent and no is less than Q-25 percent.
The
Sr.test passes ifType
not less than 16 of the 18 dosage units tested have disintegrated.
of tablet
no Limit
.
1. Uncoated tablets
Not more than 15 Immediate release dosage forms Pooled sample
2. Coated tablets
min Not more
3. Effervescent tablets Level Number tested Acceptance Criteria
than 60 min Not
4. Soluble tablets Average amount dissovled is not less than Q + 10 percent
more than 05 min
5 Dispersible tablets S1 6
Not more than 03
6. Orodispersible tablets
min Not more Average amount dissolved (S1 + S2) is equal to or greater than Q + 5 percent
7. Enteric coated tablets
than 03 min S2 6
Not more than 03 min
In 0.1 M HCL for 2 hrs No Average amount dissolved (S1 + S1 + S1) is equal to or greater than Q .
S3 12
crac In phosphate buffer
solution pH 6 NMT 60 min
DISSOLUTION
Types of dissolution test apparatus:

Basket apparatus
Paddle apparatus
Reciprocating cylinder
apparatus Flow- through cell
The requirements are met if the quantities of active substance dissolved from the dosage
units tested conform to acceptance table. Continue testing through the 3 levels unless the
results
conform at either S1 or S2. The quantity Q, is the specified amount of dissolved active
substance, expressed as a percentage of the labeled content; the 5 per cent, 15 per cent, and
25 per cent values in the acceptance table
Pageare
207percentages
of 270 of the labeled content so that
Page 208 of 270
S QUESTION
R.
N ANSWER
S QUESTI
R. ON
N ANSWER
Page 209 of 270 Page 210 of 270

Uniformity of Dosage Units 4
drug substance among dosage units.
4 The uniformity of dosage units can be demonstrated by either of two methods,
4 Content Uniformity or Weight Variation
4 The test for Content Uniformity is based on the assay of the individual content of drug substance's in a number of individual dosage units to determine whether the in

NO. R. ON
N ANSWE
Dosage Form Type Subtype Dose & Ratio ofDrug STANDARDS FOR TABLETS:-
Substance
IP BP USP
25 mg & <25 mg or
Content of Active Ingredient Content of Active Ingredient
25% <25%
(API) (API)
Tablets Uncoa Fi WV CU
Uniformity of weight Uniformity of weight Weight Variation
ted lm
Coat Ot
Uniformity of Content Uniformity of Content Uniformity of Content
ed her
s
DT DT DT
Capsules H Suspensions WV CU
ar em ulsions, Dissolution Dissolution Dissolution
d gels
S
o
ft CONTENT OF ACTIVE INGREDIENT: -
Assay of Active
20 tabs: - Limits 90% to 110%
TYPES OF TABLET:-
UNIFORMITY OF WEIGHT/WT VARIATION:-
IP BP USP
Uncoated Uncoated Compressed/molded 20 tabs, calculate avg. wt NMT 2 deviate, none twice the limits.
Film Coated Coated Plain Coated
Enteric Coated Gastro Resistant (Enteric Coated) Delayed Release Weight Variation Limits:-
IP/BP Limit USP
Dispersible Tablet Dispersible Tablet Dispersible Tablet 80 mg or less 10% 130mg or less
1) For Tablets
More than 80mg or Less than 250mg 7.5% 130mg to 324mg
Modified Release Tablet Modified Release Tablet Extended Release Tablet 250mg or more 5% More than 324mg
Soluble Tablet Soluble Tablet Soluble Tablet

51.2 2) For Capsule:-
Effervescent Tablet Effervescent Tablet Effervescent Tablet IP Limit
For use in mouth (Chewable, For use in mouth (Chewable, Less than 10%
Chewable/Buccal, 300mg
Lozenges, Sublingual) Lozenges, Sublingual) 300mg or More 7.5%
Sublingu
Orodispersible Orodispersible Orodispersible
Page 211 of 270 Page 212 of 270

S QUESTI
R. ON
N ANSWE
O. R
3) FRIABILITY TEST:-
This test is additional to check crushing strength of tablet by this test one can check Capping &/
Lamination. USP limit is 0.5 to 1%. Rotation: - 25 rpm or 100 rotations in 4 min. LIST OF PHARMACOPEIAS
Sr. Name of Effectiv
Volume Addendum Supplement Remarks
No. Pharmacopeia e Date
4) USP 36 - 905UNIFORMITY OF DOSAGE:-
1st Jan
IP 2014 I,II,III,IV NA NA NA
UNIFORMITY OF CONTENT OR CONTENT UNIFORMITY:-
Under purchase (BP
IP: - Active less than 10mg or Addendum- 1 1st Jan
2013
10%, BP: - Active less than 2 mg BP 2014I,II,III,IV,V (Veternary) NA
available
or 2%, USP: - Active less than )
25mg or 25%.
-10 tabs limit NMT 1 tab deviate 85 115% & none outside 75 125% of the Avg value/IP/BP/USP
Supple ment - I 1st Aug
(Relative Standard Deviation less than or equal to 6%), Supple ment -
NA
USP36I,II,III1st May Addendum
USP
- 1 (2014)
- If 2 or 3 individual values are outside the limits 85 115% of the Avg value, & none 1st Dec
NA
outside 75 125% repeat for 20 tabs.
7.104/2011
- Complies when 30 tabs NMT 3 of the individual values are outside the limit 85 115% of the
Avg value, and none outside 75 125%. 7.0 01/2011 7.207/2011
(Volume -I)
7.301/2012
5) DISINTEGRATION TIME:- Ph.Eu.
7th Addendum- 1
7.404/2012 NA
(2014)
0 0 7.507/2012
Uncoated Tablet NMT 15 min, in water with Disc 37 C ± 2 C 7.0 7.601/2013
(Volume - 01/2011
NMT 30 min, In water with Disc for Film Coated Tab, and NMT 60 min
Coated Tablet Other than Film coated tablet
7.704/2013
7.807/2013
Intact for 1 hr in 0.1 N HCl & disintegrate within 2 hr in Mixed 6.8
Enteric Coated Tab Phosphate buffer. According to USP 1 hr in Simulated gastric
fluid, then in Simulated Intestinal Fluid.
0
C C (BP)
C
Orodispersible Within 1 min

0
5 min in 250 ml water at 20 30 C (IP) & 5 min in 200 ml water at 15-
Effervescent Tab 0
25 C (BP)
S QUESTI
ON
R ANSWE
DT Apparatus:-
Mesh Apperture:- 2mm
(#10), Cycles:- 28 32
5
cycles/min,
1. 50 60 mm distance from bottom &
3 0 0
top, Temp of water 37 C ± 2 C.
If 1 or 2 tabs fail, repeat for 12 tabs.
Page 214 of 270

Page 213 of 270
NO. R.
N ANSWER
52.0 53.0SAP
ONLINE SYSTEM FLOW
SAP stands for Systems, Applications and Products in Data Processing.
SAP is used by companies to plan, organize, integrate and manage their various operations like
accounting, finance, manufacturing and human resources. The main aim is to improve efficiency
and accuracy.
SAP is based on server design and uses a relational database to track all information related to a
company. It is made up of small programs called transactions.
Related transactions together into groups and call them modules. Thus a module is a set of
transactions that deal with the same area of business functionality.
SAP ECC 5.0 computerizes the functions in the following

departments: Inventory
Procurement
Production
Planning Quality
Management
Sales Order Management
52.1
53
.1
Page 215 of 270 Page 216 of 270

S QUESTION
R.
N ANSWER
O.
of commercial software programs (called modules) that are licensed from SAP ECC 5.0. The table below identifies the standard SAP ECC 5.0 modules that have been
54.0HOLD TIME STUDY
OBJECTIVE
To establish the maximum period for which the bulk blend, compressed tablets, coating solution & coated tablets, can be stored prior to compression, coating & packaging operation respectively, whe
Module General Function QS Impact(s)
Name
Material Management Y
e
s
RE QUALIFICATION
Quality Management Y
Any change in the storage conditions Change in formulation
e
s
Production Planning and Control Y
e
BULK BLEND s
Withdraw approximately 300gm of blend for chemical analysis and blend equivalent to 60 gm for microbial limit test and store in sample polybag in an SS container. The lubricated blend can be stored for a maximum period of 60 days. The containers shall be
54.1
Collect 100gm of blend for chemical analysis & 20gm for microbial analysis, carry out the sampling after 15 Days, 30 Days and 60 Days of the storage and sample shall be analyze
Sr. Time of testing Test to be performed

No. intervals
Description, Assay, LOD, Microbial Limit

1. 15 ± 2 days
Test

2. 30 ± 2 days
Test

3. 60 ± 2 days
Test
Page 217 of 270 Page 218 of 270

SR.QUESTION
NO.ANSWER
COATED TABLETS
ample polybag in an SS container. The compressed tablets can be stored for a maximum period of 150 days. The container shall be closed properly and labelled adequately and store at tablet quarantine area at Temperature 25 ± 2ºC & Relative Humidity 55 ± 5%
Withdraw approximately 300 tablets for chemical analysis and tablets equivalent to 60 gm for microbial limit test and store in sample polybag in an SS container. The coated tablets can be stored for a maximum period of 150 days. The container shall be clo
s, 120 Days and 150 Days of the storage and sample shall be analyzed as per test given in below mention sampling plan.
Collect 100 tablets for chemical analysis & tablets equivalent to 20gm for microbial analysis, Carry out the sampling after 90 Days, 120 Days and 150 Days of the storage and sample shall be analyzed as per test given in below mention sampling plan.
Time of testing Test to be performed

intervals
Description, Assay, Related Substances,

Time of testing Test to be performed 1. 90 ±2 days
Microbial Limit Test, Dissolution.
intervals
1 90 ±2 days
Microbial Limit Test. Description, Assay, Related Substances,
. 2. 120±2 days
Microbial Limit Test, Dissolution.
2 120±2 days
Microbial Limit Test.
.
Description, Assay, Related Substances, 3. 150 ±2 days
3 150 ±2 days Microbial Limit Test, Dissolution.
g solution and Microbial Limit Test.
. store in a sterile SS container.
tion (30 ml) at initial, 24 hour, 48 hour and 72 hours of storage as per the in-process sampling procedure and analyze the samples as test given in below mention sampling plan.
HOLD TIME STUDY VALIDATED TIME:
Sr. No. Hold timeTest

Sample After
to be performed Stage Validated
Time
Total aerobic microbial count, Combined Yeast & mould count, Pathogens
1. Total aerobic microbial count, Combined Yeast & mould count, Pathogens
Initial 60 Days
Total aerobic microbial count, Combined Yeast & mould count, Pathogens
Total aerobic microbial count, Combined Yeast & mould count, Pathogens Compressed 150 Days
2. 24 Hours Tablets
Coating Solution 48 Hours
3. 48 Hours Coated Tablets 150 Days
Filled Capsule 150 Days

4. 72 Hours
Bulk Liquid 05 Days
Page 219 of 270 Page 220 of 270

S QUESTION
R.
N ANSWER
SR. 55.0MVTR
QUESTION ANSWER
NO.
Calculate the average rate of moisture permeation in mg per day for each unit-dose blister in each
pack taken by the formula.
MVTR
MOISTURE VAPOUR TRANSMISSION RATE ( 1 / N X ) [ ( W F - W I )- ( C F - C I ) ]
Where,
OBJECTIVE
To determine the moisture-permeation characteristics of the packaging system being utilized for the N : is the number of days expired in the test period (beginning after the initial 24- hour
packing of unit dose products equilibration period);
To evaluate and qualify the suitability of the packaging of products with the USP classification scheme X: is the number of separately sealed units per pack;
to evaluate the moisture-permeation characteristics of single-unit and unit-dose packs as equipment
and operator performance may affect the moisture permeation of a pack. (WF - WI): is the difference in mg between the final and initial weights of each test pack;
To provide a high degree of assurance that the packaging system being utilized for the packing of (CF - CI): is the difference in mg between the average final and average initial weights of
unit dose products are meeting the Good Packaging Practices. the control packs the rates being calculated to two significant figures.
[NOTE: If any indicating pellets turn pink during the procedure or if the average pellet
RE-QUALIFICATION CRITERIA
weight increase in any pack exceeds 10% terminate the test and regard only earlier
Change in packing material and or packing change part such as blister forming/sealing roller
determinations as valid.]
components.
Change in process parameters.

ACCEPTANCE CRITERIA AND CLASSIFICATION OF PACKS
55 Class A: if no pack tested exceeds 0.5 mg per day in average blister moisture permeation rate; Test
.1 period: 28 days.
METHODOLOGY
Preparation of Desiccant
Class B: if no pack tested exceeds 5 mg per day in average blister moisture permeation rate; Test
Dry the desiccant tablets at 110° for one hour prior to use. Use tablets weighing approximately 400
period: 7 days.
mg each. (If necessary due to limited unit dose container size tablet weighing less than 400mg can be
used).
Class C: if no pack tested exceeds 20 mg per day in average blister moisture permeation rate;
Test period: 48 hours.
Procedure
Seal a sufficient number of blister strip (not less than 4 ) with a total of not less than 10 unit-dose
Class D: if the packs tested meet none of the above average blister moisture permeation rate
blisters are tested with 1 pellet in each unit are tested.
requirements. Test period: 24 hours.
Seal a corresponding number of empty packs, each pack containing the same number of unit-dose
blisters as used in the test packs, to provide the controls.
Store all of the pack at 75 ± 3% relative humidity and at a temperature of 23 ± 2°C.
After 24 hours and at subsequent interval specified, remove the packs from the chamber, and allow
them to equilibrate for about 25 minutes.
Record the weights of the individual packs and return them to the chamber.
Weigh the control packs as a unit and divide the total weight by the number of control packs to
obtain the average empty pack weight.
Page 221 of 270 Page 222 of 270

NO. NO.
56.0 Incident Register and issue the incident report to QC for investigation.
LABORATORY DISCREPANCY
The analyst / reviewer shall write the brief of incidence in the incident report and shall attach all
All laboratory incident should require investigation and documentation. relevant data with report.
The source of incidents / discrepancies includes but not limited to the following examples; The Section incharge / Head of the department shall evaluate the incident and suggest the brief
corrective action with justification in the incident report.
System suitability failing during High Performance liquid Chromatography (HPLC), Gas
Chromatography (GC) etc. After investigation, conduct re-analysis through a re-issuance of raw data sheet if applicable.
Wrong integration or integration not properly For the root cause investigation, Investigation tools can be used during the investigation of incident as
Known Laboratory Error: This type of an incident is an error that is known to be caused by the
analyst (such as a spill) or laboratory instrument failure. apparent.
Analysis Carry over observed. The analyst shall report the result obtained and shall attach all relevant data generated during the
Chromatography Ghost peak/peak splitting corrective action. Head of the department shall give the preventive action (if any) in the incident
report.
observed. Any Extraneous peak observed
HPLC/GC system interruption due to leakage problem, connectivity problem and power After completion of QC part, incident report shall be forwarded to quality assurance department, The
failure. Head-QA/Designee shall review the incident, other detail and recommended for additional
investigation if required and give his/her decision on approval of incident.
Virus attack in software or corruption of software, erratic operation
system. Mistake in calculation and in reporting. Under appropriate circumstances corrective and preventive actions must be completed prior to
resumption of laboratory related activities that directly impact product quality.
Wrong labelling of sample/improper transfer of sample and
5
6. sonication Entry miss in logbook Corrective and preventive action commitments are complete upon verification by the Quality
1 Assurance Unit.
Any contamination during sample / standard preparation / storage of
sample. Usage of Instrument before calibration etc ( by mistake). The section incharge shall take approval of the incident report within 30 working days unless
the Quality control manager takes an approval from head QA for an extension of investigation
Glassware breakage with sample or standard during preparation. period of incident as per Annexure-III. The reasons or justification for any extension will be
Sample spills during the test for e.g. Loss on drying, Sulphated Ash or water documented.
content. Power failure or power fluctuation during instrumental analysis or In case where peak response is high and results is not in predetermine specification then it shall be
microbial analysis.
An unexpected or unplanned event happened in/out side of the laboratory. This type of an event Trend of laboratory incidence shall be analysed monthly.
includes, but is not limited to:
Damaged Samples
Power outages or variances
Environment condition out of
limit
Whenever any Incidence/discrepancies is observed, the analyst/reviewer shall intimate to section

incharge, Based on the review of incident, section incharge intimate to QA for login in laboratory
incident register and for issue of incident report.
Page 223 of 270 Page 224 of 270

NO.ANSWER NO.
57.0CONTRACT TESTING LABORATORY
CA. In case compliance report is not satisfactory, carry out re-audit and approve / reject the
same based on re-audit observation.
Contract Testing Laboratory:
Laboratory which is situated outside of the premises of Medley Pharmaceuticals Limited, Daman and The audited contract testing laboratory should have to submit their compliance report within 30 days
authorized by Medley with CONTRACT for analysis of the sample. of time after receipt the audit report from CG.
Selection of Contract Testing Laboratory Upon the approval of the contract testing laboratory, a technical agreement shall be made between the
Head Quality Control / Head QA / CQA shall identify the contract testing laboratory for analysis of CONTRACT GIVER (CG) and CONTRACT ACCEPTOR (CA).
Raw material, Packing Materials, Intermediates , Finished products, Stability Samples and other
tests required to be done in contract testing laboratories when required. If the contract testing laboratory has been rejected, alternate shall be explored.
The sample may be sent to contract testing laboratory in the following Review the performance of the contract testing laboratory every three years three months of the due
month.
cases: In-house testing facility is not available.
Comparative study is when required. Technical agreement procedure
The agreement shall be prepared as per the guidance given in (Annexure -II) but not limited to, if any
further details required same shall be captured.
Failure of any instrument or non-availability of any instrument, reagent or standards.
Approval of agreement
For analysis of all Raw Material, intermediate, Finished Product, stability samples and packing Agreement shall mutually agreed document and shall be signed by both ( CG and CA).
material, Contract Testing Laboratory must be approved by local FDA and NABL.
Agreement shall be reviewed once in every 3 years or as and when required and shall be amended
Selection of contract-testing laboratory based on the requirement of the test and availability of the accordingly by both parties
expertise as per the technical requirement and Initial registration of contract testing laboratory through
a registration questionnaire for contract testing laboratory Results of a test from contract testing laboratory shall be communicated in writing either through
electronic system or hard copy. No verbal communication shall be entertained in this regard.
CONTRACT GIVER (CG) shall forward registration questionnaire to CONTRACT ACCEPTOR
(CA) for detail information of laboratory. CA shall fill registration questionnaire and return back to
CG. On receipt registration questionnaire from CA, CG shall review registration questionnaire and
detail information of laboratory.
After receipt of satisfactory detail information of CA, CG shall carry out audit of the respective contract
testing laboratory facility as per audit checklist to assess their technical & analytical capability.
Head QC and Head QA / CQA shall plan and carry out contract testing laboratory audit to confirm the
in the laboratory function and the auditor must be experienced enough to assess the laboratory and
auditor shall be qualified.
Contract testing laboratory audit check list (Annexure I) shall be used during the audit, but the
audit may be extended to the points given in the check list or as per requirement. Audit findings
shall be categorized into Critical, Major and Minor depending on the nature of the observations.
Audit report shall be sent to the auditee for compliance of the observation noted during
audit.
Head QA/CQA shall approve the contract testing laboratory based on compliance report received from
Page 225 of 270

Page 226 of 270
NO.ANSWER NO.
58.0RELEASE OF INTERMEDIATE AND FINISHED PRODUCTS
Review of Certificate of Analysis and RDS:
Release: Section incharge/Designee shall prepare the COA as per SOP No. QCG 018 "Preparation of
Release is the process of accepting the material if it complies to meet established/approved Certificate of Analysis". The COA shall be signed by Section incharge/Designee at 'Prepared
specification. By' column, Head QC/Designee at "checked by" column.
Release of semi finished goods (SFG stage) Section incharge/Designee shall send the COA along with Raw Data Sheet and all relevant
The following shall be considered as semi finished stage for the respective dosage form. documents to Head-QA/Designee for approval along with the checklist of analytical records as per
Lubricated Blend : Completion of blending stage Annexure II.
Uncoated Tablets : Compressed Tablets

Head-QA/Designee shall verify the COA against specification and analytical results recorded in
Coated Tablets : Completion of Coating stage. RDS, availability of all raw data as per checklist and sign the checklist of analytical records in the
'Checked by' column.
Capsules : Completion of filling operation.
Head-QA/Designee shall ensure prior to signing the COA that any OOS result obtained has been
After completion of the respective SFG stage of a batch, Production Officer/Designee shall update
the lot quantity in SAP using the transaction code MIGO.
If any discrepancy (Non data based) is observed in COA / RDS, it shall be forwarded to Quality
After completion of SAP entry, Production shall intimate to IPQA for sampling of SFG stage. IPQA Control department for compliance.
ng procedure for In-process
and On receipt of corrected COA / RDS, Head-QA/Designee shall cross check the rectified
discrepancies and sign at "Approved by" column in COA.
QC shall perform the finish product analysis at Semi Finished stage.
58
.1 QC personnel shall use the transactions QPR4 for sampling and transactions QE51N for result Finished Goods Release
Once the BPR and COA is reviewed, Head-
Usage decision shall be done by Head-QC/Designee for Semi Finished Goods (SFG) using
Head-QA/Designee shall give the Usage decision of inspection lot in SAP using transaction code
Batch Production Record (BMR/BPR) review:
On completion of the batch, Production officer/Designee shall update the packed quantity of QA further movement.
finished goods (FG) in SAP, using the transaction code MIGO.
Head-QA/Designee shall prepare and approve the Certificate of Conformance (COC) as per
Production officer/Designee shall prepare the 'Finished Good Transfer Note' in duplicate. The annexure-IV or Quality certificate as per annexure-V whenever required as a certification that the
FGTN shall be signed by Production officer/Designee and shall be submitted to Manager- batch is manufactured, packed & tested complying with cGMP. One copy of the COA & COC shall
Production/Designee along with complete batch production record. be attached to BPR.
The completed BPR shall be reviewed by Head-QA/Designee shall forward the COA and COC or Quality Certificate to FG Store for further
dispatch process.
column as an intimation of material transfer from Production to FG stores.
be carried out. The batch quantity shall be
IPQA Officer shall review the BMR/BPR as per "Batch Production Record review check list" transferred to block stock and stored at a designated place till its decision.
Page 227 of 270 Page 228 of 270

SR. QUESTION ANSWER
NO.
S QUESTI
R. ON
N ANSWER
COC CONTENTS : 59. FAILURE INVESTIGATION AND ROOT CAUSE ANALYSIS

Name of Product 0
Finished Product Code, Importing Country An Investigation is a deviation report, which has been identified as requiring more in depth
Marketing Authorization Number/ Product investigation with the involvement of different functional departments.
License No. Strength/ Potency, Dosage Form
Package Size and type, Batch No. Root Cause Analysis: Root Cause Analysis is a problem solving technique for identifying the basic
Date of Completion of Packing, Dispatched Quantity or cause factor(s) that underlie the occurrence or possible occurrences of an adverse event in a process
Batch Manufacturing Record No., Batch Packaging Record similar to diagnosis of disease, with the goal always in mind of preventing reoccurrence.
No. Date of Manufacturing Expiry Date
Name, Address and Authorisation number Failure Investigation and Root Cause Analysis shall be carried out when a product does not meet the
Manufacturing Site Quality Control Site predetermined specification. Failure is defined as any confirmed out of specification (OOS).
Standard Testing Procedure No. Release
Specification No. API Source The Root Cause Analysis is aimed at first generating possible root cause for the problem and then
Finished Product Analytical Raw Data Sheet No. narrowing focus into the most probable cause for the problem.
Analytical Report Number
a. Certificate of GMP compliance Whenever the failure is identified in the product the same shall be brought to the notice of Head-QA or
b. Eudra / MHRA GMP Reference designee.
Number Results of Analysis, Storage
Condition Comments (If Any) Failure Investigation and Root Cause Analysis shall be initiated by concerned department along
[ ] Deviation / [ ] OOS with QA person. QA head will nominate the team for investigation. The documentation shall be
Certification Statement, Person Authorizing for Batch Release done in failure investigation report.
Name and position, Signature and Date
Verified By Head QA, Signature / Date With Seal Carry out Failure Investigation and Root Cause Analysis using the checklist, but it will not be limited
to this checklist and all efforts will be directed to find out the root cause of the failure. Use additional
59.1
sheets for completing the investigation whenever required.
Partial release of finished product:
On packing of a batch, Production Officer shall complete the BPR up to that stage. The investigation shall be extended to all the batches / products which could have possible been
affected by the failure.
Production Officer shall create the partial lot to be released in the SAP and inform to QA and
partial quantity of batch shall be released for dispatch Quarantine any Component(s) / Bulk products / Finished Product which might have been affected
by the failure till investigation is completed and decision is made. Initiate this action through QA.
After analysis, the partial lot of the batch shall be approved and released.
The investigation may include additional testing of the involved batches / products or components.
The remaining quantity of batch shall be released (when required) after the creation of new
inspection lot. Re-analysis of the remaining lot shall be carried out if required by customer. In case
where re- analysis of the remaining lot is not required, the initial analysis data shall be entered by Investigation Steps:
QC in result recording transaction in SAP for remaining lot. The remaining lot shall be released for
dispatch It is the responsibility of the department, where the problem originated, to involve in the
investigation in consultation with the QA Department to ensure adequacy of the investigation.
The failure Investigation and Root Cause Analysis is aimed at first generating possible root cause
In case of SAP failure the following procedure to be followed Head- QA/Designee shall
for the problem and then narrowing focus into the most probable cause for the problem.
-III.
A copy of the release note shall be forwarded to FG Store along with COA and other required The Failure Investigation and Root Cause Analysis is done after an event has occurred. It can be
documents if any. used for preventing problems from occurring.
Finish product release for the market distribution must comply with the requirement of the dossier.
Page 229 of 270 Page 230 of 270
NO. R.
N ANSWER
Investigation team shall perform the investigation using the tools and technique and investigation
O.
checklist.
INVESTIGATION TOOLS: The Second Technique i.e. may be used to identify the root cause of the problem. Th
Based on the information available, identify the probable cause for the non-conformance. If the details of Brainstorming are mentioned below.
probabl cause is not apparent, use following four techniques but not limited to, Brainstorming: One of the creative problem solving method that allows the people to come-up wit
The First Technique to be used for any kind of investigation is . The suggestion / ideas that could solve the problem or help to identify the root cause of the problem.
meaning an procedure of this technique is mentioned below.
1. A meeting with Cross Functional team may be called to brain storm on problem / situation.
2. Relevant people shall ask to think and share their views / suggest ideas to overcome the problem.
the situation.
3. All views and suggestions shall analyse to identify the cause of problem.
Define the problem in detail. Include who, what, when, where and how. Briefly describe why the event i
a problem. This should be a statement of facts.
Third Technique i.e. 5 -WHY technique may be used to identify the cause of problem as per the step
mentioned below.
a) What? Five WHY Technique: It is questions based technique and shall be used for the each possible facto
b) Where? identified for problem. Question shall ask to the right person in right way at right time and place.
c) When? 1. Take the
d) Who? 2.
e) Why?
f) How?
1. Observe the problem / situation first hand, personally (not to rely on the report of other). 3. Repeat question until the primary cause identified.
2. Talk to those at the sharp end (counselling). 4. The cause, when identified should preclude recurrence of the identified non conformance.
3. Explore the contributing visible and invisible factors.
4. Analyze each factor and conclude probability. Fourth technique - (Ishikava diagram) using Fish bone diagram may be
used t identify the root cause of the problem. The steps to use are given below.
Pictorial presentation of fish bone diagram (Refer Annexure-II) of Root cause analysis includes,
Head of Fish: Problem of Effect
Bones of the Fish:
Measurement and Environment/Mother Nature etc. More groups can be added, if necessary. Sub-
Page 231 of 270 Page 232 of 270
S QUESTI
R. ON
NS ANSWER
QUESTI
R. ON
N ANSWER
blem from the following source:
eports, Self Inspection, Deviations, Trend analysis, FMEA, Annual Product Qualit Review.
t Complaints, Quality / Regulatory Audit Reports etc.
ysis team should involve those who are most familiar with the processes and system and include participation of the Department Head, Quality Assurance.
d/Process, Measurement and Environment/Mother Nature.

d identify probable causes, these could be Man, Machine/Equipment, Material Method/Process, Measurement and Environment/Mother Nature.
FISH BONE DIAGRAM / ISHIKAWA DIAGRAM / CAUSE AND EFFECT DIAGRAM
MACHINE / EQUIPMENT
MAN MATERIAL
Sub Causes
Sub Causes Sub Causes

Sub Causes
PROBLEM SUMMARY
Sub Causes
Sub Causes Sub Causes
ENVIRONMENT / MOTHER NATURE METHOD / PROCESS Sub Causes

MEASUREMENT
Analyze the information and identify the actual or hypothesis. Analysis of data must be objective and logical.
Determine the extent of the problem. Is this an isolated occurrence limited to one batch or is this a recurring or potentially system related problem. Evaluate the effects on other process
Propose actions and recommendations for the affected batch(s). Evaluate the following aspect of the batch:
Quality Aspects such as product safety and integrity, product purity and efficacy, product stability, customer perception and potential complaints.
Regulatory Aspects such as deviations from product registration commitments.
Compliance Aspects such as non compliance of GMPs, or deviations from revalidation / requalification requirements.
Page 233 of 270 Page 234 of 270

If an idea fits on more than one branch place it on both, be sure that the causes have a direct, logical relationship to the problem or effect stated at the head of the fish bone. Continue un
eliminate the problem.

Example for Causes / Reasons of non conformance that may be identified by performing investigation is as per Annexure-III.
SR. QUESTION ANSWER

NO.
SR. QUESTION ANSWER
NO.
Inadequate design of manufacturing process (sequence, timing,
1. MATERIAL
complexity) Wrong or inadequate equipment (also see equipment)
Defective material, Wrong item for use
Inadequate definition of steps, critical parameters in batch
Contaminated Material, Wrong specification for
records Process science not understood (also see people)
use
Process is not capable of consistent performance to meet
Wrong test method ( does not evaluate critical material parameters or
specifications Process is not adequately validated; critical parameters
functionality) Outdated material ( also see methods), Mix-up in Material
unknown Improper process/product test methods and/or
Inadequate container or storage
specification,No procedure
Unacceptable consistency ( in or out of specification)
Inadequate design for use (too complicated, too many patches, does not handle
Unacceptable supplier/manufacturer performance (quality, delivery)
expectation, not fail safe where needed, no feedback or communication loops)
Material from Unapproved Sources, Outdated material
Inadequate definition or unclear/understandable instructions (critical steps to reproduce the task
Inadequate Container or Storage, Unacceptable consistency
consistently are not defined in the SOP)
Ownership(individual) of the tasks and results are not defined
2. MAN
Accountability for results not accepted (also see people,
Inadequate instruction or training, Human error
management)
Unauthorized to operate, Unskilled and untrained
Inadequate communication of procedure or results (also see design and
Insufficient number of people, Lack of planning
management) Results of the procedure/process are not
Inadequate resource allocation, Inadequate
measured/trended/communicated
communication
5. MEASUREMENT
3. MACHINE/EQUIPMENT
Procedures not followed, Practices are not the same as written
Equipment design inadequate or obsolete for use (capacity, tolerance,
procedures, Measuring techniques not validated.
speed) Incorrect tool selection, Out of calibration
6. ENVIRONMENT/MOTHER NATURE
Facility / room / area design not adequate for use (size, environment,
Weather extremes (temperature, humidity, rain, wind etc.)
finishes) Facilities or equipment not qualified, capability is unknown or not
Improper monitoring of temperature
documented Facility / room / area fails to maintain specifications(also see
Humidity conditions and storage conditions during handling / transportation
design) Equipment breakdowns (unpredictable); Capability or reliability
7. DOCUMENTS
unknown Equipment not calibrated (also see methods)
Forms missing information, does not reflect task Format confusing and not user-
Lack of or inadequate facility maintenance (unscheduled/reactive, routine, preventive, friendly Obsolete or uncontrolled editions
or predictive maintenance)
8. NON-ASSIGNABLE CAUSE
Lack of or inadequate equipment maintenance (unscheduled/reactive, routine,
preventive, or Predictive) An assignable cause cannot be determined.
4. METHOD/ PROCESS
Page 235 of 270 Page 236 of 270
SR. QUESTION ANSWER SR.QUESTION
NO. NO.ANSWER
60.0HANDLING OF PHARMACOPEIAL CHANGES
Finally list the probable cause and identify the exact root cause or causes among them Look for those
The Pharmacopeia's and supplements shall be procured by the concerned departments within the
shortest possible time of release of the publication.
identified as a cause of the problem than matter shall be further investigated to identify the root cause
to make as error. ADL shall prepare and circulate, within 7 working days in the first month of every year, to R&D, site
production and quality head/s and CQA the release dates, official dates targeted official publications for
Root Cause shall be categorized in to any one or more as per categories guided in Annexure -III
USP/NF and its supplements,
USP-Pharmacopeial Forum (USP-
PF), Ph. Eur. and its supplements,
BP
Develop Corrective / Preventive Actions (CAPA) and document them as per SOP No. QAD 042 on IP and its addendums.
avoid recurrence. Corrective and Preventive actions must be monitored to completion. ADL shall assign a unique tracking number for each requirement/changes.
Corrective Actions emerged from the investigation shall be taken with proper change control if ADL shall intimate to CQA for the drug substance, drug Product and excipients of new/revised
required, and follow up shall be carried out for all the suggested corrective action(s) as per SOP No. monographs and new/revised general chapters from USP, BP, EP, IP or any other applicable
QAD 042 for Corrective Action and Preventive Action. pharmacopeia; within 10 business days of release / receipt of the respective Pharmacopeial
publications,
The Failure Investigations and Root Cause Analysis Report shall be signed by the QA, Production
and any other department involved. The report shall be forwarded to Head-QA for approval. Designated person from CQA shall review the changes and identify the impacted plant /concerned
departments and intimate the same for their evaluation within 5 business days of the receipt of
Head-QA or designee shall take the final decision, based on the investigation findings. 60 intimation from the ADL.
.1
The Failure Investigations and Root Cause Analysis Report shall be maintained in QA-documentation The possible changes are listed in but not limited to the Annexure-II and action shall be taken as
cell with all the supporting data. Designated QA person shall allot the Failure Investigations and Root per annexure-II.
Cause Analysis Report number.
Site-Head QA or designee shall review the monograph/ general chapter in co-ordination with plant
A photocopy of investigation report shall be filed in Batch production record of affected batch (es). QC and production. If the existing product/ material comply with the new requirement the same
shall be intimated back to Head CQA.
The Head-QA or designee shall ensure that the corrected action has been implemented as per the
findings. In case existing product/ materials does not meet requirements or unable to confirm the compliance
due to technical reasons, then QA shall discuss the matter with R&D and CQA to resolve any
The Failure Investigations and Root Cause Analysis shall be completed within 30 working days technical issue. In case of purchased materials, the matter may be referred to Purchase department to
from the initiating date. If investigation could not be completed within stipulated time, mention co-ordinate with manufacturer of the material.
justification and tentative time for the completion of investigation and should be addressed through
the SOP No. The last three batches material received/ product manufactured shall be considered for evaluation
purpose, wherever available.
Samples from the control samples of the validation /Exhibit batches, if available will also be
included for the comparison study for evaluation of the results obtained by monograph method and
those of obtained by In-House method. Whenever applicable, stability samples also shall be
evaluated.
In case evaluation is inconclusive even after discussion with relevant groups or non compliance to the
requirements, the matter shall be referred to R&D through CQA Head in case of manufactured products
Page 237 of 270 Page 238 of 270

SR. QUESTION ANSWER SR.QUESTION
NO. NO.ANSWER
61.0GOOD MANUFACTURING PRACTICES (GMP)
department for further communication to manufacturer with intimation to CQA Head.
R&D shall review the data, which is received from plant and evaluate the product in line with GMP is Part of quality assurance which ensures that products are consistently produced and control to
new/revised monograph or general chapter. quality standards appropriate to their intended use and as required by marketing authorization.
Report on the suitability of the monograph/general chapter will be made by R&D and same shall be GMP was born in Jun 1963 in USA and first guideline on GMP was written and practiced in
submitted to CQA. USA Why GMP? It ensures:
No process deviations, Consistent
Head CQA shall review the suitability studies performed and once found satisfactory, shall quality No product failure, No
communicate to concerned department for implementation through change control procedure. reprocessing
No Product complaint, No Product
Change control system shall identify the activities and impacted documents due to the change or recalls No inspection failures, No
new requirement. Typically following documents may require revision: Specification, STP's, FDA actions
BMR/BPR, MMD Art work, license update and SAP entries (Item codes/Products codes) as Better productivity and therefore, Better profitability, Customer delight
applicable. Regulatory compliance
Any in-house parameter which is part of the existing specification, but is not part of the
proposed monograph, the same shall continue to be part of the specification as an in- S REGULATOR
house parameter. COUNTRY FULL
R Y
NAME
. AUTHORIT
In case of contract manufacturing of formulations, if the evaluation is not feasible at N Y
their location then it shall be evaluated at Medley. Location of evaluation (any of O
Medley's manufacturing location or at R&D) shall be decided by Head-CQA based on
1 USFD United State Food and Drug Administration
the requirements and extent of evaluation in consultation with Contract manufacturing 6 . A
QA. 1. 2 U.K MHRA Medicines and Healthcare Products Regulatory
1 . Agency
However for the APIs, such evaluation shall be conducted at R&D.
3 AUSTRALIA TGA Therapeutic Goods Administration
.
A detailed flow chart of activities with indicative timeline is presented in Annexure-IV. Timeline may
vary based on the criticality of the change requirement. However, the evaluation shall be completed 4 SOUTH MCC Medicine Control Council
. AFRICA
by the proposed implementation date.
5 EUROPE EMEA European Medicines Evaluation Agency
.
6 UGANDA NDA National Drug Authority
.
7 ROMANIA NMA National Medicines Agency
.
National Agency for Food And Drug
8 NIGERIA NAFD
Administration and Control
. AC
9 BRAZIL ANVI Agencia Nacional de Vigiloncia Sanitaria
. SA
MALAYSIA DCA Drug Control Authority
PHILIPPINES BFDA Bureau of Food and Drug Administration
VIETNAM MOH Ministry of Health
THAILAND Food and Drug Authority
Page 239 of 270 Page 240 of 270

S QUESTION S QUESTI
R. R. ON
N ANSWER N ANSWER
62.0 21 CFR (CODE OF FEDERAL REGULATIONS)
O.
63.0 ICH (INTERNATIONAL CONFERENCE HARMONIZATION)
CFR is guideline of USA
ICH stands for International Conference On Harmonisation
21 is no. of USA Rules and
regulations. There are two parts of Harmonization process founded in 1990 (US, EU and Japan)
21 CFR
There are 4 technical Topics
210: Current Good Manufacturing Practices in Manufacturing and
Packing 211: Current Good Manufacturing Practices for Finished
Products.
Safety (S)
Subpart of 211
Efficacy (E)
Subpart A: General Provisions
Subpart B: Personnel and and
Organization Subpart C: Facility
and building Subpart D: Equipment
Multidisciplinary (M)
Subpart E: Control of Container and Product
closer Subpart F: Process control
Subpart G: Packing and labeling
ICH Q-Documents
control Subpart H: Holding and
62 distribution Subpart I: Laboratory Q1. Stability
.1 control
Subpart J: Records and Reports 63.1 Q2. Analytical Validation
Subpart K: Return Products
Q3. Impurities
Q4. Pharmacopeias
Q5. Quality of Biotechnological
products Q6. Specifications
Q7. GMP
Q8.Phamaceutical
Development Q9. Quality Risk
Management
Q10. Pharmaceutical Quality System
Q11.Development and Manufacture of Drug
Substance
Page 241 of 270 Page 242 of 270

NO. R. ON
N ANSWER
DETAILS O.
Q5A
Q1A(R2) Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal
Stability Testing of New Drug Substances and Products (Second Revision) Origin
Q1B Q5B
Stability Testing: Photo stability Testing of New Drug Substances and Products Quality of Biotechnological Products: Analysis of the Expression Construct in Cells Used for
Production of r-DNA Derived Protein Products
Q1C
Stability Testing for New Dosage Forms (Annex to Q1A(R2)) Q5C
Quality of Biotechnological Products: Stability Testing of Biotechnological/Biological Products
Q1D
Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products Q5D
Derivation and Characterization of Cell Substrates Used for
Q1E Production of Biotechnological/Biological Products
Evaluation for Stability Data
Q5E
Q1F Comparability of Biotechnological/Biological Products Subject to Changes in their
Stability Data Package for Registration Applications in Climatic Zones III and IV Manufacturing Process
Q2A Q6A
Text on Validation of Analytical Procedures Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug
Products: Chemical Substances including Decision Trees
Q2B
Validation of Analytical Procedures: Methodology Q6B
Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products
Q3A(R)
Impurities in New Drug Substances (Revised) Q7A
Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients
Q3B(R)
Impurities in New Drug Products (Revised) Q8
Pharmaceutical Development
Q3C
Impurities: Guideline for Residual Solvents Q9
Quality Risk Management
Q3C(M)
Impurities : Guideline for Residual Solvents (Maintenance) Q10
Pharmaceutical Quality Systems
Q4
Pharmacopoeias Q11 (Concept Paper)
Development and Manufacture of Drug Substance
Q4A
Pharmacopoeial Harmonization
Q4B
Regulatory Acceptance of Pharmacopoeial Interchangeability
Page 243 of 270 Page 244 of 270

S QUESTION
R.
N ANSWER SR.
64.0 SCHEDULE M QUESTION ANSWER
O. NO. TYPES OF SCHEDULE
SR.
Schedule M is Schedule of Drugs and Cosmetics Act. SCHEDULE NAME TITLE OF SCHEDULE
NO.
Schedule M is basic guide line of Indian Government for Manufacturing of Pharmaceutical Product 1 SCHEDULE A All Forms
.
Good Manufacturing Practices And Requirements Of Premises, Plant And Fees for test or analysis by the Central Drugs Laboratories or
SCHEDULE B State Drugs Laboratories
Equipment For Pharmaceutical Products 2 Fees for test or analysis by the Pharmacopoeial laboratory for
. SCHEDULE B-1 Indian medicine (PLIM) or the government analysis.
SCHEDULE C Biological and Special Products
3
. SCHEDULE C (1) Other Special Products
SCHEDULE D Class of drugs Extent and conditions of exemption

Information and undertaking required to be submitted by the
manufacturer or his authorized agent with the Application
SCHEDULE D(I) Form for a Registration Certificate. The format shall be
properly filled in for each application in Form 40. The
detailed information,
secret in nature, may be furnished on a Computer Floppy.
4 Information required to be submitted by the manufacturer or
64 . his authorized agent with the Application Form for the
.1 registration of a bulk drug/formulation/special product for its
SCHEDULE D (II) import into India. The format shall be properly filled in and the
detailed information, secret in nature, may be furnished on a
Computer Floppy
Information and undertaking required to be submitted by the
manufacturer or his authorized importer/Distributor/agent with
SCHEDULE D (III) the Application Form for a registration certificate. The format
shall be
properly filled in for each application in Form 42
SCHEDULE-E List of Poisonous substances (Omitted)
5
List of poisonous substances under the Ayurvedic (including
. SCHEDULE-E(1)
Siddha) and Unani Systems of Medicine
Part I to Part XII-A Omitted
PART XII B - Requirements For The Functioning And

Operation Of A Blood Bank And / Or For
Preparation Of Blood Components.
6 SCHEDULE F
PART XII C - I. Requirements For Manufacture Of Blood
.
Products
II. Requirements for manufacture of blood
products From bulk finished products
Page 245 of 270

Page 246 of 270
SR. QUESTION ANSWER
NO.
SR. QUESTION ANSWER
NO.
PART 1 Vaccines ointments, pastes, emulsions, lotions, solutions,

PART II Antisera dusting powders and identical products)
SCHEDULE F(I)
PART III- Diagnostic Antigens
PART IV- General PART 1E- Specific Requirements for manufacture of
SCHEDULE F (II) Standards for surgical dressings Metered- dose- inhalers (mdi)
SCHEDULE F (III) Standards for umbilical tapes PART 1F - Specific requirements of premises, plant and
Materials for manufacture of active
SCHEDULE FF Standards for ophthalmic preparations. Pharmaceutial ingredients (bulk drugs)
SCHEDULE G List PART II- Requirements Of Plant And Equipment

Requirements of factory premises for manufacture of
SCHEDUE M-I
SCHEDULE H Prescription Drugs Homoeopathic preparations
Requirements of factory premises for manufacture of
SCHEDULE M-II
SCHEDULE I Particulars as to proportion of poison in certain cases (Omited) cosmetics
Requirements of factory premises for manufacture of medical
Diseases and ailments (by whatever name described) which a SCHEDULE M-III
devices
SCHEDULE J drug may not purport to prevent or cure or make claims to
List of minimum equipment for the efficient running of a
prevent or 14 CHEDULE N
pharmacy
cure. .0
S
SCHEDULE K Class of Drugs Extent and Conditions of Exemption
1 SCHEDULE O Standard for disinfectant fluids
SCHEDULE L (Omitted) 5.
0
Good Laboratory practices and requirement of
SCHEDULE L 1 premises and equipments SCHEDULE P Life period of drugs
1
Good Manufacturing Practices and Requirements of 6. SCHEDULE P1 Pack sizes of drugs
Premises, Plant and Equipment For Pharmaceutical 0
Products PART I -List of Dyes, colours and Pigments permitted to
be used in Cosmetics and Soaps as given under
IS : 4707 (Part I)-1988 as amended by the
PART 1 - Good manufacturing practices for premises 1 SCHEDULE Q Bureau of Indian Standards
and materials 7.
0 PART II List of Colours permitted to be used in Soaps.
PART IA- Specific requirements for manufacture of sterile
products, parenteral preparations (small volume Standards for condoms made of rubber latex intended for
SCHEDULE R
SCHEDULE M injectables and large Volume parenterals) and single use and other mechanical contraceptives
1
sterile ophthalmic preparations.
8. SCHEDULE R1 Standard Medical Devices
0
PART IB -Specific requirements for manufacture of oral
solid dosage forms (tablets and capsules) 1 SCHEDULE S Standard of cosmetics
9.
PART IC- Specific requirements for manufacture of oral 0
liquids (syrups, elixirs, emulsions and Good manufacturing practices for ayurvedic, Siddha and unani
SCHEDULE T
suspensions) medicines
2 Form for record of utilization of raw material by
0. SCHEDULE T1 ayurvedic, Siddha and unani licensed manufacturing
PART ID- Specific requirements for manufacture of
Page 247 of 270
Page 248 of 270
NO. NO.
I. Particulars to be shown in the manufacturing records:
SCHEDULE U(I) Whilst the list of changes provided is not exhaustive, it is designed to be updated periodically as
II. Records of raw materials:
technical and scientific progress is made. It is anticipated that Variations Classification Guideline
2 SCHEDULE V Standards For Patent Or Proprietary Medicines will evolve over time to capture new and updated types of change, as these are encountered by the
2 CAs/MAHs.
.
0
2 SCHEDULE W (Omitted)
3 WHAT ARE THE VARIATION TYPES AND CATEGORIES?
.
0
Three different variation types are defined by EC Regulation 1234/2008, with intrinsic varying
SCHEDULE X
2 List implications for the type and complexity of the change(s) covered by each and the likely impact of
the change upon the quality, safety or efficacy of the product:
65.0VARIATION FILE
Type IA/IAIN: these are so-
impact, or no impact at all, on the quality, safety or efficacy of the medicinal product concerned
WHAT IS VARIATION: (N.B.: IAIN
The legal definition relating to variation to the terms of Marketing Authorisations (MAs) is:
their very nature, these changes must have been implemented prior to notification of the change to
the CAs;
Type IB: these are so-

classified as minor Type IA variations or major Type II variations (or extensions). Type IB is now
Articles 8 to 12 provide a list of the documentation to be submitted and ultimately approved for any
Marketing Authorisation Application (MAA). the
Once an MA has been granted, the Marketing Authorisation Holder (MAH) has a legal obligation to
ensure that the licence is kept up-to-date as the approved particulars evolve over time. The key Type II: major variations, which are not an extension, and which may have a significant impact
procedure for managing such changes is the EU Variations procedure. upon the quality, safety or efficacy of the medicinal product concerned.
The Variation Classification Guideline specifies a list of variation categories for different types of
65.1 Aformal
variation application basically details a proposed change to approved documentation, providing a
means by which the approved licence details held by the Member State Competent changes to the MA dossier that are frequently proposed by MAHs. For each variation category, the
Authorities Guideline indicates (if applicable) the relevant conditions that must be met to be valid, the
(CAs) for a given medicinal product can be updated. documentation that should be supplied to support the change, and the appropriate variation type
WHAT ARE THE LEGISLATION AND GUIDELINES GOVERNING VARIATIONS IN

THE category B.II.d.1, sub-category a) to g), as a Type IA/IAIN, IB or II, depending upon the exact
EU?
The European variations regulations were revised relatively recently and new rules (EC Regulation nature of requirements, as defined by the Guideline.
1234/2008) describing revised variation details (e.g. variation types, amendment to the default type,
provision of submission information for groupings/worksharing, implementation, etc.) came into The variation application form also specifies an addition
force as of 01 January 2010. that are not foreseen by the Guideline.
In adition to EC 1234/2008, a key revised document was also published, the so- WHAT DOCUMENTATION NEEDS TO BE SUBMITTED WITH A VARIATION?
(Guideline on the details of the various categories of variations to the
terms of marketing authorisations for medicinal products for human use and veterinary medicinal In summary, the core components of a variation package to be submitted to the CAs must include:
products 2010/C 17/01). This document provides details of the classification of variations, by type
and category (see below), for specific defined changes for all sections of the MA dossier A covering letter, stating details of the licence to be amended plus the background to the proposed
Page 249 of 270 Page 250 of 270

SR. QUESTION ANSWER
NO.
SR. QUESTION ANSWER
NO.
A completed application form, describing amongst other information: the submission route 3. Type II 30 days (expedited for safety changes), 60 days (standard) or 90 days (for complex
(national/MRP/DCP/CP); MAH and licence details; the appropriate variation type and category; a changes for example change to therapeutic indication)
In practise there is considerable variation in the actual timescales for any given submission,
explicitly included with the variation application have been made; date of implementation of the depending upon which CAs are involved and any particular local assessment that may exist with the
change(s). CAs at that time.
Updated product information: SmPC, PIL, other labelling (packaging) details. WHAT ASSISTANCE CAN S-CUBED PROVIDE?
Specification of the fee(s)/cost(s) for the application and proof of payment (if Our highly experienced Regulatory Affairs consultants are fully conversant with the requirements
for the preparation and submission of variations, as defined by the new legislation.
appropriate).
The S-cubed team has an in-depth knowledge of EU submission procedures and validation
Additional supporting documentation, where required, depending upon the nature of the change to requirements. We can assist in avoiding simple, yet all too common, pitfalls that may otherwise result
be made, the variation type and category. in the costly time and fee penalties that are inevitably associated with rejected submission.
The above general list is not exhaustive and it should be noted that the overall submission content
will be further defined by the type of variation to be submitted and the exact nature of the change(s)
to be made. CAs/EMA, and these areas of uncertainty vary from EU state to state.
IS THERE A FEE FOR VARIATIONS? In addition to a sound understanding of the formal submission requirements, S-cubed has developed
(and continues to develop) a wealth of practical experience and knowledge from a wide range of
From a pan-European perspective, the fee structures applied by the various CAs vary widely. For different clients and through our interactions with the EU CAs. This additional insight has proven
example, in the UK there is no fee for a Type IA variation, but fees are charged for Type IB and Type invaluable in developing an appreciation of how individual CAs view different aspects of the new
II variations, whereas in France there is a corresponding flat fee for any type of variation. In addition, legislation, and how local differences in interpretation and implementation might impact upon the
some CAs charge reduced fees for grouped applications, whereas others do not, and some CAs (e.g., hat
the Netherlands) charge an annual maintenance fee rather than charging for individual variation works
submissions. The key message is to recognise that fees may vary widely, depending upon where and -cubed is ideally positioned to translate this
how the submission is to be made. In many instances, the likely fee burden may also play a significant information into pragmatic, efficient and cost-effective variation submission strategies for our clients.
role in defining the overall submission structure (and possibly content). It is therefore particularly
important to undertake some planning and research into the fees charged by the relevant CA(s) in To ensure that variation applications are reviewed, assessed and approved with minimal
order to avoid prohibitive submission costs. delay, S-cubed can assist clients with the following tasks:
HOW SHOULD VARIATION DOCUMENTATION BE PRESENTED? Pre-submission: document review and gap analysis; definition of the most time- and cost-effective
submission strategy; preparation of the submission package (including ghost-authorship of expert
Many CAs now accept electronic (CD/DVD) only submissions, but it is still important to check each statements and arrangement of expert sign-off, if required).
file naming convention/submission structure (e.g., NeeS/eCTD/Special Mail 5) and numbers of Submission: S-cubed will either submit the variation package on behalf of the client or
submission copies, as these details may also vary between different Member States. The provide a submission-ready package for the client to submit themselves.
requirements of the individual CA(s) should be ascertained well in advance of any submission.
Post-submission: should any queries arise from CA review of the variation, S-cubed can formulate
HOW LONG DOES ASSESSMENT OF VARIATIONS TAKE? written responses to each of the queries within the specified response timeframes and liaise with
the CAs, as appropriate, to ensure that submissions avoid rejection and are ultimately approved.
In principle, the different types of variation (IA/IAIN/IB/II) follow the same assessment timescales
following successful validation, irrespective of the type of product licence held
(national/MRP/DCP/CP):
1. Type IA/IAIN 30 days

Page 251 of 270 Page 252 of 270
S QUESTION
R.
N ANSWER
SR. 66.0 CLINICAL TRIALS
QUESTION ANSWER
NO.
The following core documentation is required in a CTA application:
WHAT IS A CLINICAL TRIAL? Covering letter

Copy of EudraCT number
Clinical trials are required for new active substances or combinations of substances which are Clinical Trial Application and valid xml
intended to prevent or treat a human disease or illness. The purpose of a clinical development Protocol
program is to assess the pharmacological and pharmacodynamic effects along with the safety and
efficacy of an Investigational Medicinal Product (IMP). Investigational Medicinal Product Dossier (IMPD) or simplified IMPD
Non-IMP Dossier (if required), Scientific advice Meeting Minutes (if
Clinical trials are conducted so that sufficient data on the safety and efficacy of a new product can available) EMA Decision on the Paediatric Investigation Plan (if applicable)
be assessed before the product is granted by the regulatory authorities and supplied on the European Investigational Medicinal Product labelling (if applicable to the member
market. Depending on the type of product and its stage of development, the types of trials state) Proof of payment (if applicable to the member state)
conducted range from first-in-man studies for new compounds to studies with products which
already have marketing authorisations.
QP declaration
Additional national documents (varies depending on the member states)
Clinical trials are classified into the following phases:
Phase I trials: These studies enrol only a small number of people (20-80) and are designed to What is a Protocol?
evaluate the safety of a drug, determine a dosage range and identify side effects.
A clinical trial protocol is a document that outlines the key parameters and study plan for the
Phase II trials: These trials are given to larger groups of people (100-300) and are designed to proposed clinical trial. The protocol document outlines the objectives (primary and secondary),
evaluate how well the drug works and to test the safety of the drug. study design, dosing, inclusion/exclusion criteria and safety monitoring procedure for the study.
Phase III trials: These studies confirm the effectiveness of the drug, compare it to current
66 standards and collect sufficient data to illustrate that the drug can be used safely.
.1 investigational medicinal product(s) relevant to a clinical study. The IB provides the investigators and
Phase IV trials:
all other personnel involved in the trial with information to aid their understanding of the study
risks and benefits over a longer period of time and in a larger patient population.
design, rationale, dose frequency, administration and safety monitoring procedures.
What is an Investigational Medicinal Product Dossier?

WHAT IS A CLINICAL TRIAL AUTHORISATION (CTA) APPLICATION?
The IMPD provides information related to the quality of the IMP, its manufacture and control, along
In order to conduct a clinical trial in the EU, a Clinical Trial Authorisation must be obtained. A CTA with data from previous non-clinical and clinical studies, and an overall risk/benefit assessment. The
application is submitted to the National Competent Authorities involved in the study or to the IMPD should also include information on any reference products or any placebos that are intended to
Clinical Trials Facilitation Group (CTFG) when the Voluntary Harmonisation Procedure (VHP) is be used in a clinical trial.
being used. A trial can only start once the CTA has been approved and the Ethics Committee has
issued a favourable opinion. How do you manage a CTA once it has been approved?
Once a trial has been authorised, there are a number of activities that need to be conducted during the
management of the study, as summarised below.
Substantial and Non-Substantial Amendments
During the life-cycle of a clinical trial, a sponsor can change or update data and documents within
the original CTA application package approved by the regulatory authorities. Depending on the type
of
-
Page 253 of 270
Page 254 of 270
SR. QUESTION ANSWER
NO.
SR. QUESTION ANSWER
NO.
Information on what changes constitute a substantial amendment is available in guidance provided

by the European Commission.
CASE STUDY
All substantial amendments must be submitted to the Competent Authorities involved in the study
and the Ethics Committee, whereas non-substantial amendments can be made at any time. The At S-cubed we have recently assisted a US-based company (with no European presence or
following documentation is needed to support an amendment: regulatory capabilities), with their EU clinical programme. The client required regulatory support
for the preparation and compilation of a Clinical Trial Authorisation (CTA) Application for a
amendment form proposed First- In-Human study.
updated CTA Form and xml file
description of the amendment and Initially, we provided the client with a comprehensive list of CTA documentation requirements,
justification copy of the proposed together with a project plan outlining the timeline for the project deliverables and anticipated CTA
changes approval dates, based on our previous experience of making submissions to the particular
supporting data regulatory agency. We then conducted a gap analysis of the core supporting data and documents
against EU regulatory requirements, and highlighted areas of potential deficiency. Where possible
Safety Reporting we suggested remedial actions that would address the gaps and support a successful CTA
submission.
During the conduct of the trial, it is the responsibility of the sponsor to ensure all Suspected
Unexpected Serious Adverse Reactions (SUSARs) are reported to the Competent Authorities. S-cubed was tasked with writing the Investigational Medicinal Product Dossier (IMPD). We
Furthermore, sponsors are required to submit Development Safety Update Reports (DSUR), which ensured that the IMPD, through the inclusion of pharmaceutical development and manufacturing
take into account all new process data, demonstrated that the dosage form, formulation, manufacturing process, device and
container closure system were appropriate for the proposed study, and that the products performance
duration of the clinical trial. was acceptable. We confirmed that the analytical tests outlined in the drug product specification
were appropriate and ensured that the release specification acceptance criteria were based both on
End of Trial Notifications EU/ICH guidance and ranges seen in previous batch data, and would support the proposed Phase I
study. In addition, we conducted a thorough review of the nonclinical data package and provided
Upon completion of the trial, a form declaring the end of a clinical trial should be sent to National feedback on safety aspects which might impact the CTA assessment, along with recommendations
Competent Authorities within 90 days. for future studies.
Submission of Study Reports
Upon completion of the trial, the study report should be submitted to the competent authorities As the study involved the use of a medical device, our team ensured that the study and CTA
within one year of the end of the trial. application satisfied the Medical Devices Regulations governing the use of devices in clinical
investigations. We also advised the client on the documentation and importation requirements for
other concomitant medications used in the study.
WHAT ASSISTANCE CAN S-CUBED PROVIDE?
S-cubed can provide the following EU CTA regulatory support activities:
We reviewed the clinical protocol and provided input on the trial design, clinical endpoints and
Prepare, review and finalise the Investigational Medicinal Product Dossier
ure
As the client was based in the USA, the S-cubed team managed the CTA compilation and
Prepare and coordinate the preparation of all necessary CTA documents and ensure all submission process on their behalf, and ensured that the local submission requirements were
documentation is assembled according to the local requirements (from Phase I to IV) fulfilled.
Finalise and submit the CTA
Prepare and submit medical device notifications for non-CE marked devices (as The CTA application submission package was submitted on time (and within budget) and the CTA
required) Act as the legal representative for Non-EU sponsors was approved by the Competent Authority within the clients expected timeline with minimal
Support all CTA maintenance activities through to the completion of the study and questions. Our team is now assisting the client with the preparation of an application to obtain a CE-
submission of the End of Trial Notification mark for their medical device as well as providing advice for the next phase of their clinical
Organise meetings with EU regulatory authorities (as required) development program.
Provide ad hoc regulatory and strategic advice to assist the sponsor in managing their EU
activities
Page 255 of 270
Page 256 of 270
S QUESTI
R. ON
N ANSWER
O.
SR. QUESTION ANSWER must be considered and accounted for in preparation of the MAA dossier. In addition, for medicinal
NO. product quality, the general chapters and monographs of the European Pharmacopoeia or other
national pharmacopoeias should also be accounted for as appropriate.
WHAT IS A MARKETING AUTHORISATION NEEDED FOR?
Not all data requirements are mandatory or required for each and every application or product type.
In accordance with EU Directive 2001/83 and Regulation (EC) No. 726/2004 governing medicinal If an element is considered to be not relevant or not applicable, the absence of such should be fully
products, in order to legally place a medicinal product on the market in the European Economic Area justified.
proved. To obtain an MA, a
Marketing Authorisation Application (MAA) is submitted to the appropriate Competent Authority(s) There may also be regional differences that will need to be taken into account in dossier
(CAs), for assessment and MA approval.
preparation. The following is a summarised description of the information to be included in each
WHAT DOES AN MAA CONSIST OF?
Module.
An MAA is a comprehensive dossier of information and data describing all aspects
(Administrative/Quality/Safety/Efficacy) of a medicinal product demonstrating that it is appropriate for Module 1
use in patients. There is an internationally agreed standard for the overall content and format for this This Module includes all of the administrative information relating to the application and the concerned
dossier which is referred to as the Common Technical Document (CTD). medicinal product. Key items for inclusion are:
Cover letter
The CTD format is applicable for all MAA regulatory submission routes and all product types, although Application form and annexes (e.g. manufacturing licences, proof of payment of fees, letters
some modifications may be required for certain application/product types. CTD format is also of access)
applicable to other submission types including variations and renewals. Product Information including the Summary of Product Characteristics (SmPC), labelling,
patient leaflet, braille, results of readability testing
At the top level, a CTD dossier is split into five modules: Information about the experts
Specific requirements for different types of applications
67.1 Module 1: Administrative information and prescribing information (any additional region-specific Environmental Risk Assessment
information not specified in the CTD is also included in this module) Pharmacovigilance system
description Risk Management Plan
Module 2: CTD Summaries
Module 2
Module 3: Quality
This Module presents summary information for the quality, non-clinical and clinical Modules with
Module 4: Non-clinical Study Reports so- called expert review of the information and data in the context of the MAA and regulatory
framework.
Module 5: Clinical Study Reports
Module 3
The overall organisation of the CTD is fixed and should not be changed. Documents and data should be
assigned to the most appropriate sections in Modules 1 to 5. The only exceptions to this are the non- Module 3 is the Quality Module which presents all of the information regarding drug substance
clinical and clinical summaries, within which individual formats/tables can be modified as required to and drug product development, characterisation, manufacturing and testing to demonstrate that
best present the data for assessment. the medicinal product is of suitable quality.
WHAT INFORMATION AND DATA IS REQUIRED IN EACH CTD MODULE? Module 4
Guidance on the top level structure and content of the CTD dossier can be found in Eudralex Volume This is the Non-clinical Module which includes all of the non-clinical study reports and literature
Common Te addressing the complete battery of non-clinical testing required for the medicinal product and
application type.
CTD does not specify the detailed content in terms of what studies and data are required. There are
European Community guidelines regarding the quality, safety and efficacy of medicinal products which Module 5
Page 257 of 270 Page 258 of 270

S
QUESTION
R.
N ANSWER
O.
ARE THERE SPECIFIED REQUIREMENTS FOR FORMATTING SUCH AS

FILENAMES, MARGINS, FONT TYPE AND SIZE, HYPERLINKING, ETC?
There is some general but limited guidance on formatting available, however the aim is obviously to
facilitate dossier navigation and review. Margins need to be large enough to ensure that bindings do
not obscure any data. The selected font and font size should be easily legible. Times New Roman
and 12- point font are recommended for narrative text, although variations to this are accepted, for
example for tabulated data where it might be necessary to reduce the font size slightly to ensure a
table fits on the page.
In terms of pagination and segregation, documentation should be prepared in line with

CHMP/ICH/2887/99 Revision 1 Organisation CTD recommendation.
National-only submissions must consider any Member State-specific requirements. For example in
the UK, the MHRA recommends file naming conventions through Special Mail 5. European
submissions would be in accordance with Non-eCTD electronic Submissions (NeeS) or fully
electronic (eCTD) format.
IS THERE A REQUIREMENT TO RE-FORMAT OLD DOSSIERS?
There is no obligation to reformat approved dossiers. However it is possible to re-format Quality

documentation into Module 3 format in order to facilitate ongoing life-cycle management of the
licence, as variations, renewals, etc., will need to be submitted in CTD format. Re-formatting is not
recommended for Modules 4 and 5 for Non-clinical and Clinical data.
When re-formatting into Module 3, all approved variations must be fully integrated into the re-
formatted Module. In terms of the regulatory procedure to be followed to submit the re-formatted
Module 3, this does not constitute a variation in itself. Therefore it is recommended that it is submitted
as part of another regulatory procedure (e.g. variation or licence renewal), subject to agreement from
the concerned CA.
If however, an old format licence is to be used as the basis for MAAs to be submitted via the
Mutual Recognition Procedure (MRP), the current approved documentation will need to be
reformatted into CTD format. It is recommended that Applicants discuss any MRP plans with the
proposed Reference Member State (RMS) in advance to determine the best means of doing this, as
different Member States may prefer different approaches.
S QUESTI
R. ON
N ANSWE
O. R
ARE THERE DIFFERENT NATIONAL ADMINISTRATIVE REQUIREMENTS (I.E.

DELIVERY ADDRESSES, NUMBER OF COPIES, PAPER/ELECTRONIC, ETC)?
There are likely to be a variety of Member State-specific administrative requirements, some of

which are documented in the available EU Guidances. However, there is still the possibility of
additional requirements or nuances not readily available in the standard sources of information. In
the absence of direct, recent experience of an MAA submission to the concerned Member States
(MSs), it is highly recommended that contact be made with the relevant CA to establish any specific
national requirements in advance of submission.
Requirements for final submission to the MSs again may vary and therefore needs to be checked in
advance. In terms of final publication and dispatch of the MAA, this aspect of MAA preparation is
often dismissed as minor, yet it requires the same level of care and attention as preparation of the
dossier itself. Timelines frequently do not allow much time for this part of the project.
Consequently any delays ahead of publication can mean publication and dispatch activities need to
be completed at speed, potentially compromising the quality of the final submission.
WHAT ASSISTANCE CAN S-CUBED PROVIDE?
The Regulatory Affairs team at S-cubed has significant experience of MAA preparation submission
across the EU.
In a recent project, S-cubed assisted the client by:
providing a comprehensive list of country-specific documentation and fees requirements

writing and reviewing the Module 3 Quality section (drug substance and drug product),
Modules
2.4 and 2.5 Nonclinical and Clinical Overviews
arranging for experts to review and approve the Overviews
reviewing the clinical- and nonclinical (Modules 4 and 5) MAA sections
compiling the NeeS submission, with creation of bookmarks and
hyperlinks validating the electronic submission with the appropriate
Agency checkers
liaising with the RMS and CMSs to ensure the successful validation of the submission
QRD and national templates
Page 259 of 270 Page 260 of 270

S QUESTI
R. ON
N ANSWE 68.0 EUDRALEX
O. R
POST-APPROVAL ACTIVITIES
S-cubed can provide the following post-approval regulatory support activities: TYPES OF VOLUME
Volume 1 - EU pharmaceutical legislation for medicinal products for human use

Licence Renewal Applications through national, mutual recognition, decentralised and
centralised procedures Volume 2 - Notice to applicants and regulatory guidelines for medicinal products for human use
Reclassification Applications
Article 61(3) applications changes to packaging artwork which do not constitute a variation Volume 3 - Scientific guidelines for medicinal products for human use
Management of sunset clause notifications and requests for waivers
Regulatory compliance reviews checking approved licence information against technical Volume 4 - Guidelines for good manufacturing practices for medicinal products for
documents used in manufacturing and testing of medicinal products human and veterinary use
Change of ownership applications and associated management of changeover of pack
artwork and rundown of old stock Volume 5 - EU pharmaceutical legislation for medicinal products for veterinary use
Change of Reference Member State (RMS) for licences approved via mutual recognition or
decentralised procedures The basic legislation is supported by a series of guidelines that are also published in the following
Assistance with management of site licences (Wholesale dealers and Manufacturers licences) volumes of "The rules governing medicinal products in the European Union":
Review and approval of pack artwork and advertising/promotional materials
Volume 6 - Notice to applicants and regulatory guidelines for medicinal products for veterinary use
details)
Volume 7 - Scientific guidelines for medicinal products for veterinary use
Liaison with Competent Authorities on behalf of Marketing Authorisation Holders
(MAHs) Drug Master File (DMF) reviews Volume 8 - Maximum residue limits
6 Volume 9 - Guidelines for pharmacovigilance for medicinal products for human and veterinary use
8.
1 Volume 10 - Guidelines for clinical trial.
EudraLex - Volume 4 Good manufacturing practice (GMP) Guidelines.

Volume 4 of "The rules governing medicinal products in the European Union" contains guidance
for the interpretation of the principles and guidelines of good manufacturing practices for
medicinal products for human and veterinary use laid down in Commission Directives
91/356/EEC, as amended by Directive 2003/94/EC, and 91/412/EEC respectively.
Part I - Basic Requirements for Medicinal
Products Chapter 1 : Pharmaceutical Quality System

Chapter 2: Personnel
Chapter 3 : Premises and
Equipment Chapter 4 :
Documentation Chapter 5 :
Production
S QUESTI
Chapter 6 : Quality Control
R ON
Chapter 7: Contract Manufacture and
. ANSWER
Analysis Chapter 8 : Complaints and
Product
Part II -Recall
Basic Chapter 9 : Selffor Active Substances used as Starting Materials
Requirements
Page 261 of 270 Basic requirements for active substances used as starting materials
Page 262 of 270

NO. R. ON
N ANSWER
O.
Part III - GMP related documents
Site Master File
Annex 14
Q9 Quality Risk Management Manufacture of Products derived from Human Blood or Human Plasma
Q10 Note for Guidance on Pharmaceutical Quality
System MRA Batch Certificate
Annex 15
Template for the 'written confirmation' for active substances exported to the European Union for
Qualification and validation
medicinal products for human use
Annex 16
Annex 1
Certification by a Qualified person and Batch Release
Manufacture of Sterile Medicinal Products
Annex 17
Annex 2
Parametric Release
Manufacture of Biological active substances and Medicinal Products for Human Use
Annex 19
Annex 3
Reference and Retention Samples
Manufacture of Radiopharmaceuticals
Annex 4
Manufacture of Veterinary Medicinal Products other than Immunological Veterinary Medicinal Product
Annex 5
Manufacture of Immunological Veterinary Medicinal Products
Annex 6
Manufacture of Medicinal Gases
Annex 7
Manufacture of Herbal Medicinal Products
Annex 8
Sampling of Starting and Packaging Materials
Annex 9
Manufacture of Liquids, Creams and Ointmentspdf(13 KB)
Annex 10
Manufacture of Pressurised Metered Dose Aerosol Preparations for Inhalation
Annex 11
Computerised Systems (revision January 2011)
Annex 12
Use of Ionising Radiation in the Manufacture of Medicinal Products
Annex 13
Manufacture of Investigational Medicinal Products
Page 263 of 270 Page 264 of 270

S QUESTION
R.
N ANSWER
SR. 69.0SUPAC
QUESTION ANSWER
NO.
transdermals, parenteral solutions), as well as a related document(s) for bulk active
substances, are at various stages of development.
The FDA and industry have been working very closely to prepare these documents. Industry
The acronym "SUPAC" stands for "Scale-Up and Post-Approval Changes". supplies its input at meetings and workshops as well as through written comments.
It refers to the FDA-recommended testing and filing actions to be taken by a pharmaceutical firm Although these SUPAC documents are not regulations, the FDA is working to ensure that the
when it changes the manufacturing processes of a drug product that has been approved via a New Guidances are as consistently interpreted and applied by both the Agency and industry as possible. To
Drug Application (NDA), an Abbreviated New Drug Application (ANDA), or an Abbreviated this end, the Agency has undertaken a rather comprehensive training program, providing in-house
Antibiotic Drug Application (AADA). The Agency has provided its recommendations to industry in training for its personnel and public workshops for others. Furthermore, although the main thrust of
the form of Guidances. the training is provided at the time a Guidance is issued, the Agency has been diligent in ensuring that
subsequent, ongoing interpretation and application of the recommendations remain consistent. In fact,
As you may be aware, 21 CFR 314.70 already provides instructions for how changes to approved as recent as February 1997, the FDA issued two documents discussing how to properly utilize the
manufacturing process should be reported to the Agency. Specifically, depending on the magnitude SUPAC-IR Guidance for Industry (issued November 1995). These documents are:
of the change and the possibility that the change could negatively affect the product, the Code
provides that notification should be accomplished in one of three ways: Manufacturing Equipment Addendum to the Guidance for Industry for Scale-Up and
Post Approval Changes: Immediate Release Products (SUPAC-IR), Draft Guidance
1. Via a supplement that requires approval by the FDA prior to implementation of the change; for Industry. Released on February 3, 1997.
2. Via a supplement that does not require approval by the FDA prior to implementation of Letter to industry from Dr. Roger L. Williams, Deputy Center Director for Pharmaceutical
the change ("changes being effected"); Science, CDER, dated February 18, 1997. This letter discussed how industry should interpret
3. Via an annual report. stand alone packaging operation site changes and stand alone analytical site changes based
upon the Agency's re-assessment of these issues. In addition, it provided the answers to
significant questions frequently asked by industry.
69
.1 Unfortunately, the instructions indicating which type of changes fall into what notification category
can be broadly interpreted and are sometimes difficult to follow. Luckily, the regulations [21 CFR Finally, you asked how these Guidances affect you and your company, specifically. That depends
314.70(a)] also indicate that less burdensome routes of notification may be followed if those routes on what types of products you manufacture, and your job responsibilities in the company. If you
are published in the Federal Register (FR). That is the main purpose of the SUPAC Guidances - to are involved in regulatory affairs submission work, scale-up activities, process validation, or
provide industry with clear, streamlined (i.e., "less burdensome") ways to test and report analytical testing, you may be affected, assuming your company manufactures immediate release
manufacturing changes. (Note: As required by 21 CFR 314.70(a), the documents are issued via the oral dosage forms and nonsterile semisolid dosage forms. (As indicated above, only these two
FR.) types of products are currently covered by SUPAC Guidances.) If you manufacture another
product type, SUPAC won't affect you now; your company must still interpret and follow 21 CFR
Why do the SUPAC Guidances offer an advantage over the regulations?
314.70. But even if that is the case, keep an eye out for future SUPAC Guidances that could affect
The documents are specific for particular dosage forms. This approach was taken since your product -- they may be coming soon.
some product types are more complicated than others, and as such, will likely require more
complicated controls. To date, two Guidances have been finalized. They are:
Guidance for Industry: Immediate Release Solid Oral Dosage Forms---Scale-Up and
Post- Approval Changes: Chemistry, Manufacturing and Controls, In Vitro Dissolution
Testing, and In Vivo Bioequivalence Documentation (November 1995)
Guidance for Industry: Nonsterile Semisolid Dosage Forms---Scale-Up and Post-

Approval Changes: Chemistry, Manufacturing and Controls; In Vitro Dissolution
Testing and In Vivo Bioequivalence Documentation (May 1997)
In addition, SUPAC documents covering other dosage forms (e.g., extended-release
Page 265 of 270 Page 266 of 270

S QUESTION
R.
N
S ANSWER
70.0 EDQM
QUESTI
R. ON 71.0 ORANGE GUIDELINE (MHRA)
N ANSWER
The European Directorate for the Quality of Medicines & HealthCare (EDQM) is a directorate of the
Council of Europe that traces its origins and statutes to an international treaty enabling an international Orange Guideline is a MHRA (U.K) Guideline
cooperation for the elaboration of a common pharmacopoeia in Europe (Convention on the Elaboration
of a European Pharmacopoeia, CETS 50, Council of Europe in 1964,[1] Protocol [2])
In the following you can read on the Certificate of suitability of Monographs of the European
Pharmacopoeia (CEP).
70
.1 A manufacturer of a substance can provide proof that the quality of the substance is suitably
controlled by the relevant monographs of the European Pharmacopoeia by a CEP granted by the
Certification Secretariat of the European Directorate for the Quality of Medicines (EDQM). The
CEP confirms that pharmaceutical substances or active pharmaceutical ingredients (API) are
produced according to the monographs of the EP. The CEP bridges between European
Pharmacopoeia monographs and the need to prepare a file for licensing and thus it also bridges
between industry and health authorities.
There are 7 sections
Section I : Medicines and Healthcare products Regulatory Agency (MHRA)

Section II : Guidance on Good Manufacturing Practice (GMP)
Section III : Legislation on Manufacture
Section IV : Guidance on Wholesale Distribution
Practice Section V : Legislation on Wholesale
Distribution Section VI : Glossary of Legislation
Section VII : Index
There are 9 Chapters
1. MHRA: Licensing, Inspection and Enforcement for Human Medicines

2. EU Guidance on Good Manufacturing Practice
3. UK Guidance on Manufacture
4. EU Legislation on Manufacture
5. UK Legislation on Manufacture
6. EU Guidance on Wholesale Distribution Practice
7. UK Guidance on Wholesale Distribution Practice
8. EU Legislation on Wholesale Distribution
9. UK Legislation on Wholesale Distribution
Page 267 of 270 Page 268 of 270

PHARMA BOOK
S QUESTI
R. ON
N ANSWE
O. R
There are II Parts in EU Guidance on Good Manufacturing Practice
PART I - Basic Requirements for Medicinal Products
PART II- Basic Requirements for Active Substances Used as Starting Materials
In Part I there are 9 contents
1) Quality Management
2) Personnel
3) Premises and Equipment
4) Documentation
5) Production
6) Quality Control
7) Contract Manufacture and Analysis
8) Complaints and Product Recall
9) Self Inspection
Page 270 of 270
Page 269 of 270

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INDEX

VALIDATION MASTER PLAN (VMP) 7

QUALITY MANUAL (QM) 8

PLANT QUALITY REVIEW MEETING 37

PRODUCT QUALITY REVIEW (PQR) 51

QUALITY RISK MANAGEMENT 57

ANALYTICAL METHOD VALIDATION 70

2 HEALTH 90 48. PASS BOX 170

3 WATER SYSTEM 109 55. MVTR 221

Site Master File shall be store by QA department for 10 years.

Page 5 of 270 Page 6 of 270

SR.QUESTION SR. QUESTION ANSWER

Page 9 of 270 Page 10 of 270

Change in systems Training, Change in relevant documents, and/or

Change in expiry Stability studies, Change in relevant documents,

Page 13 of 270 Page 14 of 270

Activity / Document Examples of Deviations

Page 15 of 270 Page 16 of 270

A complaint is any expression of dissatisfaction with a product or service marketed.

In case of quality/efficacy related complaint, Head-CQA/Designee shall request the

If the required information provided by marketing department/complainant, Head - CQA shall

shall be forwarded to Head-QA/Designee at site.

Head-QA/Designee shall enter the complaint details in market complaint log

Page 17 of 270 Page 18 of 270

Sr. No.Example of Complaint

Sr. No. Example of Complaint Suggested investigation Critical Complaint:

Handling of Counterfeit Samples:

REVIEW AND TRENDING OF COMPLAINTS:

Page 27 of 270 Page 28 of 270

Page 29 of 270 Page 30 of 270

Root Cause Analysis :

Page 31 of 270 Page 32 of 270

Page 33 of 270 Page 34 of 270

FLOW CHART OF NPI 11

6 Health Canada (Canada) www.hc-sc.gc.ca

7 MHRA (Europe) www.mhra.gov.uk

11 1 MCC (South Africa) www.mccza.com

Page 35 of 270 Page 36 of 270

12. PLANT QUALITY REVIEW MEETING

metrics. the actions of KPIs.

Manager QA/Head QA shall nominate the Self Inspection team.

Internal auditor shall be trained with Auditor certification Training program.

Educational Qualification: Graduate in Science, Pharmacy, Engineering and other respective

Experience: Preferably 5 years of experience in pharmaceutical industry, GMP knowledge,

year The frequencies for audit shall be scheduled as twice in a year

Page 37 of 270 Page 38 of 270

Page 39 of 270 Page 40 of 270

PERIODIC EVALUATION OF APPROVED VENDORS

nd primary packing materials shall be audited once in three years.

Page 41 of 270 Page 42 of 270

cleanable Freely soluble From 1 to 10

Soluble From 10 to 30 parts (10 : 30) Easily cleanable

LD50 of API shall be mentioned as per following Table: product

Page 43 of 270 Page 44 of 270

Swab Sampling for Chemical analysis:

Swab sampling for Microbial analysis:

Microbial swab sample shall be collected before chemical swab.

Page 45 of 270 Page 46 of 270

FOR WORST CASE APPROACH;

MACO = [Mac10] x [Swab Area]