Sanitation of manufacturing premises

• Sanitation means promoting health through prevention of human contact

with the hazards of wastes as well as proper disposal of sewage.
• Guidelines for the maintenance of sanitation
• As per GMP guidelines says, sanitation is “any building used in the
manufacture, processing, packing or holding of a drug product shall be
maintained in a clean and sanitary condition”
Sanitation control procedures:
• Sanitation SOP
•  Each processor should have and implement a written sanitation standard
operating procedure (herein referred to as SSOP) or similar document that is
specific to each location where Drug and drug products are produced. The
SSOP should specify how the processor will meet those sanitation
conditions and practices
• Sanitation monitoring
• Each processor shall monitor the conditions and practices during processing
with sufficient frequency to ensure, at a minimum, conformance with
required conditions as follows,
• The manufacturing premises shall be cleaned and maintained in an orderly
manner, so that it is free from accumulated waste, dust, debris and other
similar material
• A validated cleaning procedure shall be maintained. The manufacturing
areas shall not be used for storage of materials, except for the material being
processed.
• It shall not be used as a general through fare
• A routine sanitation program shall be drawn up and observed, which shall be
properly recorded and which shall indicate
• a) specific areas to be cleaned and cleaning intervals
• b) cleaning procedure to be followed, including equipment and materials
to be used for cleaning
• c) personnel assigned to and responsible for the cleaning operation.
• The adequacy of the working and in-process storage space shall permit the
orderly and logical positioning of equipment and materials so as to minimize
the risk of mix-up between different pharmaceutical products or their
components to avoid cross contamination, and to minimize the risk of
omission or wrong application of any of the manufacturing or control steps
• Production areas shall be well lit, particularly where visual on-line controls
are carried out
• Sanitation control records
• Each processor shall maintain sanitation control records that, at a minimum,
document the monitoring and corrections
• Relationship to HACCP plan
•  Sanitation controls may be included in the HACCP plan
• Hazard analysis critical control point
• Importance of sanitation :
• Prevents contamination of products
• Cross contamination is avoided
• Provides health and safety to workers
• Improves product quality
Other measures need to be taken to maintain sanitation are,
• Regular pest control programme should be drawn up for stores,
manufacturing and packaging areas. Services of a pest control agency may
be employed.
• Manufacturing areas should not be used for other than manufacturing
purposes
• Eating, chewing or smoking should not be allowed in manufacturing areas
• Manufacturing areas should not be used as general to store any personnel
materials except processing materials
Records of sanitation
• Records of sanitation should be maintained in the form of log- book
• A separate log book should be maintained for each section
Example of sanitation report

Mix – ups and Cross contamination

Mix –up
• Mix –up is defined as “the contamination at unsafe levels of one product
with another via inadequate plant and process design or human error”
• Most commonly occurs through labeling, receipting, line clearance type
problems, human error
Risks with mix -up
• Causes cross contamination
• Causes poor personnel hygiene
• Reasons for mix –up
• Improper cleaning and sanitation
• Time and temperature abuse
• Cartons of one product to another.
• Tablets of one product with another product which have different shape size
or color.
• Close proximity of two products i.e size , shape & color etc;
• Pack in same color container
• Multiple products/packs handled in same area.
• Same apparatus or instrument used for multiple products.
• Improper labeling
• No identification code
Precautions for mix-up
• Handle the drug materials and products by proper air handling system
• Processing of sensitive drugs like Beta-lactum antibiotics, cytotoxic
substances must be taken care
• Proper labeling system should be adopted to avoid mix-up during production
stages
Cross contamination
• Cross-contamination is the contamination of a starting material, intermediate
or finished product with another starting material or product.

It is presence of some material which is not desired. It may not always be

visibly seen.
Eg. Fine dust of one product into another product.
Fine black particles of dust into processing

Sources of contamination
TYPES OF HIGHLY CROSS CONTAMINATED PRODUCTS
The products are which are more likely to prone to cross contamination include:
 Highly sensitive materials.
 Biological preparations.
 Hormones
 Cytotoxics
MATERIALS:
 Improper handling of materials can lead to spillage on ground & cause
contamination.
 Broken materials can leak out and pose a contamination danger.
 Dusty uncontrolled activities can contaminate processing environment.

PEOPLE:
 People working in the processing area are a powerful source of
contamination.
They cause contamination from two sources:
 By their indiscipline activities in the processing area.
 Infectious nature of skin or other body parts.
MANUFACTURING AREAS:
 • Manufacturing areas are classified in categories based on expected
cleanliness such as aseptic filling area, other sterile operation areas, non-
sterile processing areas, corridors, change rooms etc;
• If proper pressure difference is not maintained between the areas then there
is chance for entry of air from unclean area to clean area which result in
contamination of materials.
• If packaging lines are not well segregated, it can lead to accidental mix-ups
of materials from two adjacent lines.
MACHINES AND OPERATIONS:
 Equipments which are not in use for long time, if not maintained clean cause
contamination.
 Discharge of exhausted dust, smoke fumes , gases from any equipment or
operation can cause contamination.
CONTROLLING OF CROSS CONTAMINATION AND MIX-UPS:
 Exhaust system with proper air filtration and dust collection should be
placed where heavy dust is generated.
 Separate air handling units should be provided for each work-station
activities.
 Depending upon nature of products being handled different rooms should be
maintained at different pressure.
 A pressure difference of 1.5 mm of water guage in the adjacent rooms is
recommended.
 Isolation between processes prevents cross contamination; separate rooms,
air showers, door interlocks
 “Onion” concept: cleanest areas are inside, have to pass through
successively cleaner areas to reach these areas.
 Packaging lines in the central packaging areas should be well segregated. A
partition of at least 1.2 to 1.5 meters is recommended in two adjacent
packaging lines.
Problems with cross contamination
• Affects product stability and Quality
• Deteriorates the product
 • Reduces safety and efficacy to patients
• Increases market recall
Reasons for cross contamination
• Poorly designed air handling system and dust extraction systems
• Poorly operated and maintained air handling system and dust extraction
systems
• Inadequate procedures and training for personnel and equipment
Reasons for cross contamination
• Poorly designed air handling system and dust extraction systems
• Poorly operated and maintained air handling system and dust extraction
systems
• Inadequate procedures and training for personnel and equipment
Control measures for cross contamination
• Dedicate the facility to the manufacture of a single formulation of product
• Utilize a closed manufacturing system where the product is not exposed to
the immediate room environment
• Perform area line clearance according to approved procedures
• Use cleaning status labeling on all equipment and materials used within the
manufacturing facility
Cont.,
• External contaminants can be removed by filtration of supply air to retain
the required cleanroom classification
• Internal contaminants can be removed by displacing airflow
• Personnel training and clothing
Prior to and during employment, all personnel should undergo the relevant GMP
and cleaning training, and be periodically assessed for competency
Cont.,
• The importance of gowning should be implicit and competency of
gowning/de-gowning procedures should be clearly documented and
 routinely monitored particularly in sterile situations via microbiological
testing.
• Personnel should wear appropriate clothing to the duties they perform and
the environment they work in. These include,
1. Personnel protective equipment (PPE)
2. Clean body coverings (refer to Basic GMP Gowning)
3. Cleanroom clothing (appropriate for each cleanroom classification), which
can withstand repeated wear and laundering with minimal deterioration
(refer to Cleanroom Gowning)
Cont.,
• Appropriate footwear (e.g. steel-capped shoes and shoe covers)must be
wored, which is provided by the company
• Street clothing and shoes must not be worn within GMP areas
• Direct contact should be avoided between the operator and starting
materials, primary packing materials and intermediate and finished products
PROCESSING OF INTERMEDIATE AND BULK PRODUCTS
 Intermediate product: Partly processed product that must undergo further
manufacturing
steps before it becomes a bulk product.
 Bulk product: Any product that has completed all processing stages up to,
but not including, final packaging.
 Starting from the receipt of raw materials till these materials are converted
into bulk goods ready for packaging into their primary and then finished
packs, certain points that are required to be kept in mind are
 Identity
 Strength
 Safety
 Purity
 Following are some of these points:
i) Before starting any processing, the materials received from the stores should
be checked for the identity and quantity.
 This verification can be done against the labels on their containers and by
actually weighing or measuring the quantity of materials.
 ii)Process area and equipment must be clean and no traces of previous
product be there.
 iii) Environmental conditions must meet the processing requirements e.g.
temperature, relative humidity, pressure gradient, class of air, lighting etc.,
such observations should be recorded in B.P.C.R and other relevant registers
etc.
 iv)All primary containers used for filling of finished products should be
clean to the acceptable level of cleanliness.
 Bulk containers used for storage of in-process materials should also
thoroughly cleaned before use.
V) Yield of materials at all critical stages of operations should be checked e.g.
• granulation,
• compression,
• filling operations of capsules,
• liquid bottles etc.
and compared against theoretical yields expected, any abnormal deviations
must be investigated and corrective actions taken.
vi) Checks should be carried out to ensure that pipelines and other pieces of
equipment used for the transportation of products from one area to another area
connected in a correct manner. All pathogenic microbes should always be
absent.
vii) All measuring, weighing, recording and controlling equipment and
instruments should be calibrated regularly so that they always remain in a state
of calibration. Records of such calibrations should be maintained
viii)Repairs and maintenance operations should not present any hazard to the
quality of the products.
ix) All I.P.Q.C checks should be carried out at pre-determined stages and
deviations should be recorded and investigated.
x) Access to production areas should be restricted only to authorised persons.
xi)Normally, non medicinal products should not be produced in areas and with
the equipment destined for the production of medicinal products.
PACKAGING OPERATIONS
Overview:
 Introduction
 Packaging of
 Solids
 Parenterals
 Semisolids
 Precautions
Introduction
What is packaging ?
 Packaging is defined as the collection of different components which
surround the pharmaceutical product from the time of production until its
use.
 PACKAGING MATERIAL
Materials of construction refer to the substances (e.g., glass, high density
polyethylene(HDPE) resin, metal) used to manufacture packaging
component
Packaging component
 A packaging component means any single part of a container closure
system.
 Typical components are
 Containers (e.g., ampoules, vials, bottles),
 Container liners (e.g., tube liners), closures (e.g., screw caps,
stoppers),
 Closure liners,
 Stopper over seals,
  Container inner seals,

 administration ports (e.g., on large-volume parenterals (LVPs)),

 overwraps,
 administration accessories,
 container labels.
 Types:
 A primary packaging component means
 a packaging component that is or may be in direct contact with the dosage
form
 A secondary packaging component means a packaging component that is
not and will not be in direct contact with the dosage form.
 A container closure system refers to the sum of packaging components that
together contain and protect the dosage form.
 This includes
 primary packaging components and
 secondary packaging components,
 The latter are intended to provide additional protection to the drug product.
A packaging system is equivalent to a container closure system
 A package or market package refers to the
 Container closure system and
 Labelling,
 Associated components (e.g., dosing cups, droppers, spoons), and
 External packaging (e.g., cartons or shrink wrap).
 Quality refers to the
 physical,
 chemical,
 microbiological,
  biological,
 bioavailability, and
 stability attributes that a drug product should maintain if it is to be
deemed suitable for therapeutic or diagnostic use. (21 CFR 211.94(a)).
 Importance of packaging
 • Protect against all adverse external influences that can alter the properties
of the product.
 • Protect against biological contamination.
 • Protect against physical damage.
 • Carry the correct information and identification of the product.
 • Tamper evident / Child resistance
 / Anti counterfeiting.
 Packaging
 For
 Solids-Blister Packaging
 Liquids-Vials packaging
 Semi-solids-Ointments packaging
Blister packaging
 Two basic types of pharmaceutical blister packages exist.
 In one variety the cavity is constructed of clear, thermoformed plastic, and
the lid is formed of clear plastic or a combination of plastic, paper, and/or
foil.
 The other type of package contains foil as an essential component of both
webs, and its cavity is created by cold stretching. Figure 1 shows the basic
configuration of a blister pack.
 Blister packaging components

Steps involved:
Blister packaging machinery: Modern thermoform–fill–seal machines can
operate at speeds <800 packages/min.
General assembly: The sequence involves
 Heating the plastic,
 Thermoforming it into blister cavities,
 Loading the blister with the
product,
 Placing lidding material over the blister, and
 Heat-sealing the package.
The essential parts and functions of an intermittently operating packaging
machine include the following.
 The unwinding station.
 The heating station.
 The forming station.
 The cooling station.
 The feeding machine.
 The sealing station.
 The cooling station.
 Labelling through packaging.

Vials & Ampoule Packaging

Components of vials and ampoules:
Containers for parenterals products are produced from one of 3 types of
glass or from one of a variety of plastic materials.
Types of glass:
Type I:
Type II (sulphated glass)
Type III (soda glass)
Types of containers
 Glass ampoules-Commonly used
 For aqueous solutions- neutral glass is used.
 Amber glass ampoules-light sensitive products.
 Clear ampoules -packaged in a light-resistant box.
 Glass vials sealed -rubber closures
 The rubber closure is held in place by an aluminium sealing ring.
 The rubber closure permits the penetration of a syringe needle to allow the
withdrawal of a dose of injection.
Precautions
 Similar to manufacturing operations, packaging operations should also have
to follow certain precautions to get a good quality product at the end.
 Following are some of the certain points, which should be remembered
while carrying out the packaging operations.
 Avoid risk of contamination and mix-ups
 Each packaging equipment and lines must be cleaned before starting of fresh
packaging activity. “Line-clearance” SOP should be followed and records
maintained.
 Each packaging equipment and line should be identified by a conspicuously
fixed board, indicating following information eg.
 Name of the equipment.
 Batch numbers.
 Pack size.
 Date of packing.
 Normally, filling and sealing should be followed as quickly as possible by
labelling and final packing.
 If labelling is delayed, appropriate steps should be taken to prevent mix-ups.
 To avoid this no batch should be taken for packing unless all packaging
materials are available in full quantities.
 Otherwise at same time you are likely to have situation in which, for a given
batch of product you have different materials of packaging departments e.g.
Bulk Tablets (For want of foils).
 Strips or blisters (For want of cartons). Filled cartons (For want of shippers).
◦ E.g. such situations must be strictly avoided.
 The Packaging and Labelling Sections of the batch record should contain
◦ Complete records for the packaging and
◦ Labelling operations, including drug product and label reconciliation.
IN PROCESS QUALITY CONTROL IN MANUFACTURING (IPQC)
Overview
o What is IPQC
o Scope of IPQC
o Objectives
o Responsibility
o Location
o Sampling
o Testing
o Documentation
o Summary
What is IPQC
 Manufacturing a formulation involves many processes with some critical
steps in it.
 Monitoring of all the critical steps for their good performance is essential to
get a quality product.

So, there should be a written procedures for performing the quality

checks during and after manufacturing, and these procedures include IPQC.
INSPECTION TESTING:
 IPQC is concerned with providing

• Accurate
• Specific procedures to be employed from the receipt of raw
• Definite materials to the release of finished dosage form.
Scope of IPQC in manufacturing
 Receipt of material
 Sampling and testing
 Dispensing
 Manufacturing
 Packing
 Final testing and release of the finished product
Objectives
1. Quality control
This function is performed by documenting production parameters.
• Measured values obtained from process equipment, e.g. Temperatures
• Measured values obtained by persons, e.g. Times
• Product attributes, e.g. Weight, hardness, friability
• Measured values obtained from the room environment, e.g. Particle counts
• Tests following completion of intermediate products
• Process control
• During manufacturing and packaging a lot of data are recorded which
represent control factors of the manufacturing process. These data may be
process parameters (e.g. outlet air temperature of a fluid bed dryer) or
product attributes (e.g. hardness of tablet cores).
Process control by means of in-process controls
Organization and responsibilities
 Location
• In-process controls may be carried out within the production area provided
they do not carry any risk for the production.
• Central in-process control laboratories are occasionally set up to carry out
tests relevant to all areas.
Sampling
It should be done accordance with approved written procedures that
describe:
 Method of sampling
 Amount of sample to be taken
 Type and condition of the sample container to be used
 Identification of containers sampled
 Storage conditions
Testing
• Samples are tested to verify conformance with specifications
 Identity
 Component conformity to written specifications
 Container/Closure conformity to written
specifications
 Examination for contamination
• Documentation and evaluation of data
 Information required for documentation of in-process controls
How IPQC is carried out
1. Identifying the parameters for IPQC
• critical steps of manufacturing
o Mixing
o Compression
o Coating
o Filling of containers
o Labeling
o Packing

2. Defining the specifications for parameters

• Inprocess specifications for each parameter shall be consistent
with the final formulation specifications.
• These specifications can be derived by applying suitable
statistical procedures to the previous acceptable limits of the
particular parameter.
3. Establishing the procedures for IPQC
4. Summary
5. In-process control not only provides a means of controlling production, it
also performs a quality assurance function.
6. The in-process control group personnel may be assigned to production or
quality control depending on the relevant company structure.
7. The in-process control methods that are part of the manufacturing formula
are compiled and validated under the supervision of quality control.
8. Rejected Inprocess materials shall be identified and controlled under a
quarantine system designed to prevent their use in manufacturing.
9. Statistical evaluation and periodic review of in-process data contributes to
the general assessment of process performance and product quality
Release of Finished Product
Overview
 What is a product ?
 What is a finished product ?
 WHO guidelines for finished products
 Release of finished products
 SOP on releasing of finished products
 Sampling
 Testing
 Quality Review & Quality Audit
 Documents related to release of finished product
 Conclusion
What is a product ? ? ?
 A product is anything that can be offered to a market that might satisfy a
want or need
 Eg., Pharmaceutical Products Viz.,
 Paracetamol, Asprin etc.
What is a finished product ? ? ?
 A Product in the marketable pack is classified as finished product.
 Practically its a transportable pack, i.e. a shipper containing the salable pack
(in retail) is considered the finished product.
WHO Guidelines for finished products
 Finished product should be held in quarantine until their final release, after
which they should be stored as usable stock under conditions established by
the manufacturer.
 For each batch of drug product, there should be an appropriate laboratory
determinations of satisfactory conformity to its finished product
specifications prior to release.
What happens when its not followed ? ? ?
 Product failing to meet the established specifications or any other relevant
quality criteria should be rejected
 Reprocessing may be performed if feasible, but the reprocessed product
should meet all specifications and other quality criteria to its acceptance and
release
Release of Finished Product
 Qualitative and Quantitative characteristic analysis are carried with test
procedure and checked if they are within the acceptance limit or not, which
the finished product must comply at the time of the manufacture (at its
release)
 The specification limits of the finished product at the time of batch release
are set by the marketing authorization applicant w.r.t pharmacopoeias, such
that the specifications proposed at the end of shelf life are guaranteed.
Who guarantees it ? ? ?
 The compliance of each batch of finished product with its specification at
manufacture should be guaranteed by GMP
SOP on releasing product should address the following points
 1.Who is the authority to release a batch?
He may be:
• a. “Authorised person” as per regulatory requirements
• b. QA head, or
• c. Any other person suitably Authorised for this purpose

2. Before releasing the finished product at least following points should be

considered
a. Completed B. P. C. R. (Batch Production & Control Rec)
 b. Test reports of I. P. Q. C.

• c. Test reports of finished product / analysis.

 • d. Deviations reports if any.
• e. Sterility reports along with environmental conditions reports
(In case of sterile products)
• f. Any other reports related to the manufacturing and packaging
of the batch.
• 3. Part batch release is generally not acceptable practice. It can
be done only under justified exceptional conditions, under
deviation control system.
• 4. A formal report / certificate of release may be prepared and
should become the part of the B.P.C.R.
Sampling
 Its a procedure for collecting a ‘sample’ and ‘sample’ means a small part or
quantity intended to show what the ‘whole’ (or entire lot) is like
 Majorly performed by QC persons
Acceptance Sampling
 It may be defined as the process of evaluating a portion of the product
in a lot for the purpose of accepting or rejecting the entire lot as either
conforming or not conforming to a quality specifications.
 100% inspection concept cannot always possible to apply in all the
pharmaceutical operations. Therefore its based on the statistical process
Sampling Labels
 Sampling labels should be attached to collected samples
 After sampling, materials should be tested by standard testing methods
using reference materials which were approved (this is the reason y we
keep few more approved sample before release)
Sampling plans
 Attributer Plans: A random sample is taken from the lot and each unit is
classified as acceptable or defective
 The number of defectives is then compared with the allowable number stated
in the plan, and a decision is made to accept or reject the lot
  Variable Plans: A sample is taken and a measurement of a specified quality
characteristics is made on each unit
 This measurement are then summarized in sample statistics, and the
observed value is compared with an allowable value defined in the plan and
a decision is made to accept or reject the lot
Testing
 Test the material using ‘ Standard test Method ’ against the approval
material specification.
 Testing activity
 Pre Testing Part - Setting the parameters
 Testing Part - Perform the parameters
 Post Testing Part - Check the parameters for
acceptance
The two important things concerned with Release of finished product
 Quality Review
 Quality Audit
Quality Review
(Reviewing of records)
 Before a finished product is released for sale or distribution, the complete
production and control records must be reviewed and assured satisfaction
about the entire process of production and control.
 This is considered to be the last stage in the control process before the
product moves out of the manufacturing premises.
How the quality review can be done?
 By setting up investigation Planning
 Investigation planning should be done and training to the investigator should
be given
 List of Witness of investigation should be prepared
Auditing ? ? ?
  A systematic and independent examination to determine whether quality
activities and related results comply with planned arrangements and whether
these arrangements are implemented effectively and are suitable to achieve
objectives
 “Audit" means checking of the auditee’s quality system to determine
compliance with the relevant regulatory requirements
 Quality audit is basic control procedures to see a particular activity is going
on as desired
 If any deviations are observed then necessary corrective actions can be taken
to bring the process to normal
 Quality audit is basic control procedures to see a particular activity is going
on as desired
 If any deviations are observed then necessary corrective actions can be taken
to bring the process to normal
How frequent can an audit be performed ? ? ?
 Should be performed routinely.
 Normal frequency may be 4 to 6 months.
 It may also be performed on special occasions, e.g. in case of product recall
or repeated rejection or when an inspection by the health authority is
announced
 Should be performed routinely.
 Normal frequency may be 4 to 6 months.
 It may also be performed on special occasions, e.g. in case of product recall
or repeated rejection or when an inspection by the health authority is
announced
Why auditing is so important ? ?
 Play an imp role in evaluating conformity with procedures specified by
cGMP
8
 Provide independent assessment of the compliance, relevance of system and
give direction to QA for future 
 Also to obtain unbiased management information
  To know factually if the company is at risk
 To assess individuals performance based on facts
 How good is the compliance with GMP
 Identifies Deficiencies and faults and make quality improvement
 Investigate root cause of problem ; Helps to educate and train people
 Helps to reduce cost ; Helps to control external activities
 Help to make supplier aware of your problem 
Overview of Audit Activities
 Preparing, approving and distributing the audit report
 Completing the audit
 Conducting the audit follow up
Who can do Auditing ? ? ?
  Quality audit team may be formulated with people from various operational
areas like Production QA / QC Validation, Engineering, Warehousing.
 Personnel Audit members are selected on the basis of understanding the
concept of GMP and GLP
Documents related to Release of Finished Product
 Laboratory investigation and report form
 Stability Data ; Finished good cards ; finished pdt shipping form
 Master document Change control form
 Test sample log book ; Retention sample log book
 QA inspection Sheet ; Laboratory Work Book
 Finished Product specification & test report
 Calibration policies and related reports
 Reference substance specification report
 Managing Analytical reagent ; Laboratory Waste management
 Stability & Trail Testing Procedure
  Laboratory Results- Out of specification investigation reports
Finished Product Register

Few other documents

 Finished product shipping form
 Finished product specification and test report
 QA Inspection Sheet
Conclusion
 Release of the finished product should be done with atmost care. So this
forms an important aspect for a pharmaceutical company to enter the market
with a good name and surviving in the market inspite of great competition
and lesser will be the product recalls.
PROCESS DEVIATION
 A deviation is an event from which there is non-compliance of
recommended practice or a standard operating procedure.
 Deviations are also known as variations and/or non-conformances
What is Process Deviation?
 Process deviation is defined as variation in the production or any other
processes from the pre defined procedure.
 Production Deviation
 Quality Improvement Deviation
 Audit Deviation
 Customer Service Deviation
 Technical Deviation
 Material Complaint
 System Routing Deviation
 There are two types of deviations
 Planned Deviation.
 Unplanned Deviation.
• Planned deviation:
• Planned deviations, which are described, and pre-approved deviation
from the current operational document/system, covering a specified
period of time or number of batches.
 • Planned deviation shall be approved before execution
Unplanned deviation
• Unplanned deviations also called as incident.
• Incident can be defined as unplanned or uncontrolled event in the form of
non-compliance from the designed systems or procedures at any stage of
manufacturing, packaging, testing, holding and storage of drug product due
to system failure or equipment breakdown or manual error.
• Incidents are again of two type:
• i) Quality Impacting Incident:
• Quality impacting incidents are errors or occurrences during execution of an
activity which will affect the Quality, Purity, Strength of the drug product.
• ii) Quality Non- impacting Incident:-
• Quality Non-impacting incidents are errors or occurrences during execution
of an activity which may have no impact on the quality, purity and strength
of a drug product.
• When to Report Deviation?
• A Deviation should be raised when there is a deviation from:
• methods or controls specified in manufacturing documents,
• material control documents,
• standard operating procedure for products and
• confirmed out of specification results and
 • the occurrence of an event and observation suggesting the existence of a real
or potential quality related problem.
• A deviation should be reported if a trend is noticed that requires further
investigation.
• Reporting deviation is required regardless of final batch disposition. If a
batch is rejected a deviation reporting is still required.
• How to Manage Reported Deviation?
• Regulatory requirement to capture all sorts of deviations evolves in order to
maintain the continuous improvement of processes and systems.
• All batch production deviations (planned or unintended) covering all
manufacturing facilities, equipments, operations, distribution, procedures,
systems and record keeping should be reported and investigated for
corrective and preventative action (CAPA).
• Deviation should be documented when there is a deviation from methods or
controls in manufacturing documents, material control documents, and/or
standard operating procedures.
• What To Check During The Deviation Assessment?
• QA delegate has to conduct a primary Investigation on the deviation
reported and evaluate the following information:
• Scope of the deviation - batch affected
• Trends relating to similar products, materials, equipment and testing
processes, product complaints, previous deviations, annual product reviews,
and /or returned goods etc where appropriate.
• Are view of similar causes.
• Potential quality impact.
• Regulatory commitment impact.
•
Other batches potentially affected.
•
Market actions (i.e. recall etc)
Procedure for Raising deviation Report
 • Request for deviation shall be raised by manager of respective department.
• The location head Technical director shall comment on the deviation.
• Comments by Regulatory & product development dept. Stability study for
change control required or not.
• 4.Decision regarding approval / non approval of the deviation shall be taken
by Q.A. Manager.
• 5.Closer remark shall be made mentioning B.No. & date of completion.
Flow chart for handling deviation

Charge in of components
Introduction:
CFR> Title 21 > Chapter I > Part 211 >
Sec 211.101. Charge-in of components.
 Title 21- Food and drugs
 Chapter1- Food and drugs administration, department of health and human
services
 Part 211- Current good manufacturing practices for finished pharmaceuticals
 Subpart f- production and process controls
211.101 - Charge-in of components
A written procedure used to formulate a batch and followed
  Written production and control procedures
 designed to assure that the drug products
produced have the identity, strength, quality,
and purity they purport or are represented
to possess
(b)Components for drug product manufacturing shall be weighed, measured, or
subdivided as appropriate. If a component is removed from the original container
to another, the new container shall be identified with the following information.
1. Component name or item code
2. Receiving or control number;
3. Weight or measure in new container;
4. Batch for which component was dispensed,
including its product name, strength, and lot
number
(c) Weighing, measuring, or subdividing operations for components shall be
adequately supervised. Each container of component dispensed to
manufacturing shall be examined by a second person(preferably a Q.A
person) to assure that:

(1) The component was released by the quality control unit;

(2) The weight or measure is correct as stated in the batch Production
records (3) The containers are properly identified.
If the weighing, measuring, or subdividing operations are performed by
automated equipment under 211.68, only one person is needed to assure
paragraphs (c)(1), (c)(2), and (c)(3) of this section.
(d) Each component shall either be added to the batch by one person and verified
by a second person or, if the components are added by automated equipment under
211.68, only verified by one person.
 Generally, addition is done by an operator or worker and verified by a
production pharmacist. It may be advisable that the addition of the active
substance is done in the presence of a I.P.Q.C. person, to enhance the level
of confidence in manufacturing.
The IPQC person should check following things during addition.
 Name of the product and B.No
 Name of the active component and its analytical reference No and quantity.
Documents Required
B.P.C.R.(showing who has added and who has checked the addition of the active
component. Also the quantity added satisfies the condition of addition of 100% of
the active component in batch).
Drug product inspection:
DRUG PRODUCT: It is the dosage form in the final primary packaging intended
for marketing.
DRUG INSPECTION: Drug inspection is the act of examining or looking
closely at all the drug attributes and the condition of all the facilities that deal with
drugs.
The overall objectives of drug inspection are to ensure that drugs and related
supplies, either locally manufactured or imported from outside the country, meet
set standards of quality.
WHAT NEEDS TO BE INSPECTED:
To ensure the quality of drugs entering or circulating in the market, the
following establishments associated with drug supply should be inspected
regularly:
 Pharmacies shops (established and new ones, before they are licensed).
 Wholesalers (both established and new ones, before they are licensed).
 Manufacturing facilities (both established and new ones, before they are
licensed).
WHY DRUG PRODUCT INSPECTION IS IMPORTANT?
 It is a concept which suggests that the samples should be collected randomly
by the I.P.Q.C/I.P.Q.A department from the finished product.
This system suggests three things:
1. Packaged and labeled product shall be examined during finishing operations
to provide assurance that containers and packages in the lot have correct
label.
 2. A representative samples shall be collected at the completion of visually
examined for correct labeling.
3. Results of these examination shall be recorded in B.P.C.R.
METHODS OF INSPECTION:
The inspector uses different methods to check compliance with the national or
international drug laws and regulations. Among these methods are:
 Comprehensive/routine inspection
 Concise inspection
 Follow up inspection
 Special inspection
COMPREHENSIVE/ROUTINE INSPECTION:
This is a full inspection of all applicable components of GMP and licensing
provisions. It may be indicated when the manufacturer:
 Is newly established.
 Requests renewal of a license to operate.
 Has not been inspected during the last 3-5 years.
CONCISE INSPECTION:
The focus of concise inspection is on a limited number of GMP
requirements selected as indicators of overall GMP performance, plus the
identification of any significant changes that could have been introduced since the
last inspection.
 FOLLOW UP INSPECTION:
Follow up results are made to monitor the result of corrective
actions. They are normally carried out from 6 weeks to 6 months after the initial
inspection.
• SPECIAL INSPECTION:
Special visits may be necessary to undertake spot checks
following complaints or recalls related to suspected quality defects in products.
Inspection of drug manufactures:
 Inspection and licensing of pharmaceutical manufacturing facilities on
the basis of compliance with GMP are a vital element of drug control.
The objectives are to control and enforce general standards of
production and to provide authorization for the manufacture of specific
pharmaceutical products:
 The first objective involves a sequential examination of production and
control activities on the basis of the GMP guidelines.
 The second requires verification that production and quality control
procedures employed in the manufacture of specific products are performed
correctly.
Inspection will of course, depend on national legislation and regulations.
Guides to inspect dosage form drug manufactures:
Prescription vs. non-prescription:
 Records relating to prescription drugs must be readily available for review in
accordance with Sec. 704(a) (1)(B) of the FD&C Act.
 If the product is an OTC drug which is covered by an NDA or ANDA, FDA
may review, copy and verify the records under Sec. 505(k) (2) of the FD&C
Act.
Organization and personnel(21CFR 211 Subpart-B)
 In drug industry, an employee’s education and training for their position has
a significant impact on the production of a quality product.
 The type of the training program received should be described.
 The training received by an employee should be documented.
Guides to inspect dosage form drug manufactures-c GMPR’S:
Buildings and facilities (21CFR 211-Subpart C):
 The firm must provide adequate space for the placement of equipment and
materials to prevent mix-ups in the following operations:
 Receiving, sampling, and storage of raw materials.
 Manufacturing or processing.
 Packaging and labeling.
  Storage for containers, packaging materials, labeling and finished products.
 Production and control laboratories.
Equipment(21 CFR211 Subpart-D):
 The cleaning and maintenance of the equipment are usually documented in
a log book maintained in the immediate area.
 Equipment of suitable capacity and accuracy for use in measuring, weighing,
or mixing operations is determined.
 Equipment must have written calibration procedure for calibrating the
equipment and calibration should be documented.
Components and product containers(21CFR211 Subpart E):
 Inspect the ware house and determine how components, drug containers, and
closures are received, identified, stored, handled, sampled, tested , and
approved or rejected.
 Sanitary conditions in the storage area, stock rotation practices, retest dates,
and special storage conditions are to be checked.
Production and process controls (21CFR Subpart F):
Critical manufacturing steps( 21 CFR 211.101):
 Each critical step in the manufacturing process shall be inspected.
 Critical manufacturing steps includes:
 Selection.
 Weighing.
 Measuring.
 Identifying of components.
 Addition of components during processing.
 The manufactured steps documented should be inspected.
Production and process control(21CFR Subpart F):
Equipment identification(21CFR 211.105):
 Labels of all the equipments and containers should be inspected.
 Batch should be handled and stored to prevent the mix-ups or contamination.
Inline and bulk testing(21CFR211.110):
 To ensure the uniformity and integrity of products, there shall be adequate
in-process controls such as :
o Checking the weight and disintegration time of tablets.
o Fill of liquids
o Adequacy of mixing
o The homogeneity of suspensions
o Clarity of solutions.
Production and process controls(21CFR subpart F):
Actual yield(21CFR211.103):
Personnel habits:
During inspection the work habits of plant personnel should be observed and
determined:
 Their attitudes and actions involving the jobs they perform.
 Their dresses.
 If proper equipment is used for a given job or whether shortcuts are taken.
Production record review:
Review of raw materials should include checks for:

Utilization of correct
components
Weighing of correct
Correct labelling of
amounts
All components “in date” for
components
quality and potency
Production control records which must be reviewed include:
Review of laboratory records must be made in order to ensure:
1.Proper analytical methods utilized for the drug substance assay
2.All test results meet compendial, in house, or NDA specifications
3.Retention samples for future needs retained
4.Assay results included in both departmental records and batch production records
Need of production records:
 A full and comprehensive review of every aspect of the manufacturing,
packaging, and control documentation is very time consuming and namely
identifies more than the absence of signatures or the misplacement of a
document.
 Consequently, the emphasis must be on the operations themselves.
 Ensuring that all employees understand the importance of the procedures
and the need to follow them or document atypical non complying situations,
and that supervisors and managers pay enough attention to this during there
routine activities.
 When production deviations occur they must be documented, investigated
and appropriate levels of management must be involved in the review of the
data and in any decision making.
 It is particularly important to decide what actions are required to minimise
the potential or recurrence –retraining, process improvement, revalidation.
CHANGE CONTROL:
 Change control may be defined as a system of procedures through which
changes are reviewed, justified, documented, approved and implemented in
conformances with regulatory and corporate requirements.
 Change control is a system that controls change by:
1. Identifying the ownership of the change.
2. Allowing for review and approval of the change.
3. Preventing changes that could adversely affect product quality or conflict
with the registration or regulatory requirements.
4. Providing an assessment of change and monitor the impact of change.
purpose of managing change within the quality system is for evaluating the
potential impact on:
 Validated conditions, processes or systems maintained in a state of control.
 Regulatory commitments.
 Product quality and safety.
Anticipate changes in the quality organization :
 An inordinate number of rejects means the process has shifted and the cause
must be found.
 Product complaints are another indication that need changes to be
implemented with appropriate review and approval.
The evaluation of the changes, which must be documented, will include:
 Clear definition of the proposed change with the reason for the change
 Identification of potential impact and evaluation to be performed, such as
accelerated stability, revalidation, retraining
 Regulatory impact(all countries involved) and approvals required
 Schedule for implementation
 Definition of who needs to approved the change and a record of their
concurrence.
Changes are classified into 3 types:
 Major changes
 Minor changes
 Non-notifiable changes
MAJOR CHANGES:
  These types of changes generally affect the form, fit, or function of the
product, or are associated with the transfer of manufacturing to another
location.
 Changes in materials of construction, suppliers, manufacturing methods, test
methods, or product specifications are considered major changes.
MINOR CHANGES:
 Minor changes do not have the potential to affect the customer’s product.
 Minor changes are generally associated
with packaging, labeling, or documentation.
NON NOTIFIABLE CHANGES:
 Non-notifiable changes are defined as changes that require management
oversight and control, but create no real or apparent change in the product or
any of its aspects or properties.
Manufacturing Process Changes:
The following elements of change control may be considered standard
requirements for major changes in the pharmaceutical industry:
1. documented justification for the change
2. impact assessment of the change
3. management approval of the proposed change
4. management approval of the implementation and validation
5. regulatory and customer notification
Product Changes
 Product and packaging changes on the part of a pharmaceutical supplier can
represent significant changes in the product configuration or design.
 The original product may be discontinued after customers are given
adequate time to validate the new product
 Product specification changes generally fall into one of two categories:
 1. major changes that either shift the specification range or widen the range
to allow the acceptance of product that was previously out of specification.
  2. minor changes that reflect a narrower specification range that falls
entirely within the original specification range.
 Packaging Changes
 All packaging changes that do not affect the pharmaceutical supplier’s
product configuration or the materials that are in contact with the product are
considered to be minor changes
 Labeling Changes:
 Labeling changes that do not affect a supplier’s product claims or
specifications are considered minor changes
Conclusion
 
 Change is inevitable, and because continuous improvement is impossible
without change, progress is built on change.
 The key to making successful change in the pharmaceutical world is to
manage it, both from internal and external perspectives.
PRODUCTION CONTROL - STERILE PRODUCTS:
PRODUCTION CONTROL:
Definition:
Production control is defined as the  systematic planning, coordinating,
and directing of all manufacturing activities and influences to ensure having goods
made on time, of adequate quality, and at reasonable cost .
 The manufacturing objective of medicinal drug, pharmaceutical or other
health care products lies in ensuring the safety, well-being and protection of
the patient.
 Sterility is defined as the state of complete absence of the living organisms
 Sterile drugs must be prepared and sterilised under conditions which aim at
such a result that in one million units there will be no more than one living
micro-organism
 Sterile pharmaceutical products includes parenteral products ex: IV and IM
injectables ophthalmic preparations ex: eye drops, eye ointments and Non-
injectable preparations such as catguts, dusting powders, surgical
dressings......etc.
Sterile Products Manufacturing Requires:
 Qualified personnel with appropriate training
 Adequate premises
 Suitable production equipment, designed for easy cleaning and sterilization.
 Validated procedures for all critical production steps.
 Adequate precautions to minimize the bioburden prior to sterilization
 Environmental monitoring and in-process testing procedures
Objectives:
 To review basic GMP requirements in the manufacture of sterile
pharmaceutical products
 To review air classifications for activities related to the manufacture of
sterile products
 To review the different types of sterilization methods
 To review quality assurance aspects in the manufacture and control of sterile
products
GMP requirements for Sterile Products Manufacture includes:
 Specific points relating to minimizing risks of contamination by
 microbes
 particulate matter
 Pyrogens
 Production in clean areas
 Appropriate standard of cleanliness
 Supply of filtered air
 Airlocks for entry
 Personnel and/or equipment
 Materials
 Separate areas for operations
  component preparation (containers and closures)
 product preparation, filling, sterilization, etc.
Premises:
Clean Rooms:
 A clean room may be defined as follows
 Clean room is an enclosed space with quantitatively specified control of:
 Particles
 Temperature
 Pressure
 Humidity
A clean room should be constructed with non porous surfaces which are easy
to clean and maintain the controlled access via air-locks, and operated in
accordance with procedures designed to keep contamination below a defined low
level.
 There are three classes of US Federal Standard 209 Cleanroom, which are
particularly relevant to sterile products manufacture:


 In clean areas, all exposed surfaces:
 Smooth, impervious, unbroken.
 Minimize shedding and accumulation of particles, microorganisms.
 Permit cleaning and disinfection.
 No un cleanable recesses, ledges, shelves, cupboards, equipment
 False ceilings sealed
 Proper installation of pipes and ducts, no recesses, no unsealed openings
 Sinks and drains avoided, and excluded in Grade A and B areas
 Changing rooms
 Designed as airlocks
 Effective flushing with filtered air
 Separate rooms for entry and exit desirable
 Hand washing facilities
 Interlocking system for doors
 Visual and/or audible warning system
 Use filtered air supply to maintain pressure cascade
 Pressure differential approximately 10 to 15 Pascals.
 In addition premises of sterile products manufacturing should consist of...
 An air supply filtered through high-efficacy particulate air filters under
positive pressure, regardless of whether flow is laminar or non-laminar.
 A system for monitoring environmental conditions.
 A system for cleaning and disinfecting the room and equipment to produce
aseptic conditions.
 A system for maintaining any equipment used to control aseptic conditions.
 Equipment for adequate control over air pressure, microorganisms, dust,
humidity and temperature shall be used when appropriate.
 Air filtration systems, including pre-filters and particulate matter air filters,
shall be used when appropriate on air supplies to production areas.
 EQUIPMENT:
 Conveyer belts should be used.
 Sterilization of equipment should be carried out.
 Maintenance and repairs from outside the clean area
 -if taken apart, resterilised before use
 -Clean instruments and tools should be used.
 Planned maintenance, validation and monitoring
 Equipment, air filtration systems, sterilizers water treatment systems.
 SANITATION:
 Frequent, thorough cleaning of areas is necessary
 Regular monitoring to detect resistant strains of microorganisms
 Chemical disinfection should be carried out periodically
 Monitoring of disinfectants and detergents
 Dilutions
 Clean containers, stored for defined periods of time
 Sterilized before use, when used in Grade A or B areas
 Monitoring of clean areas
 Monitoring of personnel and surfaces after critical operations
 Frequent monitoring in areas where aseptic operations are carried out
 Settle plates, volumetric air samples, surface sampling (swabs and contact
plates)
 Sampling methods should not contaminate the area
 Microbial levels in a clean surfaces may be determined by the use of
 Settle plates
 Air samplers
 Surface sampling
 Finger dabs
 PERSONNEL:
 Minimum number of personnel in clean areas especially during aseptic
processing.
 Inspections and controls from outside.
 Training to all including cleaning and maintenance staff regarding.
 Manufacturing, hygiene, microbiology
 high standards of hygiene and cleanliness.
 Periodic health checks.
 No shedding of particles
 No introduction of microbiological hazards
 No outdoor clothing
 Changing and washing procedure
 No watches, jewellery and cosmetics
 Always move gently or steadily
 Avoid talking unless absolutely necessary
 Do not touch other operators
 Keep garments fully fastened up. Do not unfasten or loosen them
 Unless there is a special hazard involved, do not pick up dropped items
 Outdoor clothing not in change rooms leading to grade B and C rooms
 Change at every working session, or once a day (if supportive data)
 Change gloves and masks at every working session
 Disinfect gloves during operations
 Washing of garments – separate laundry facility
 No damage, and according to validated procedures
 MANUFACTURING OPERATIONS:
 There are two distinct approaches for making a sterile product
 Terminal sterilisation: filling and sealing the product into its final
container and then sterilising it
 Aseptic preparation: Sterilising a product at some earlier stage, before it is
filled or packed, and then carrying out further processing and filling into
sterile containers, using aseptic techniques and taking aseptic precautions
 The European community GMP guidelines refers to Grade A, B, C and D for
the manufacture of sterile products.
 Grade A:
 Local zone, high risk operations, e.g. filling, aseptic connections
 Usually UDAF systems used
 Grade B:
 Background environment to grade A (in case of aseptic preparation and
filling)
 Grade C and Grade D:
 Clean areas for less critical operations


 To reach Grade B, C and D, the number of air changes should be appropriate

to the size of the area, number of personnel, equipment present.
 Minimum of 20 air changes per hour should be carried out
 Clean up time should be maintained at about 15-20 minutes
 Maintainance of good airflow pattern in the area
 HEPA-filtered air should be used
 Processing:
 Precautions to minimize contamination should be taken during all
processing stages including the stages before sterilisation.
 Care should be taken that any validation does not compromise the processes
  Starting materials – microbiological contamination should be minimal
 Containers and materials liable to generate fibres should be minimised in
clean areas.
 Appropriate, measures should be taken to minimize the particulate
contamination of
 the end product.
 Components, containers and equipment should be handled after the final
cleaning process in such a way that they are not recontaminated.
 Sterilization:
 Control of sterilisation process:
 Properly validated sterilisation process must be employed
 For effective sterilization:
 Whole of the material subjected to the treatment
 Biological indicators are used
 Additional methods of monitoring should be adopted
 Autoclave tapes are used.
 Risk of contamination should be known
Methods of sterilization:
 Moist or dry heat
 Irradiation (ionizing radiation)
 Sterilizing by gaseous agents (e.g. ethylene oxide)
 Filtration with subsequent aseptic filling
 Whenever possible: Terminal sterilization by heat in their final container
should be made the method of choice
 Terminal Sterilization:
 Sterilization by moist heat
 Sterilization by dry heat
  Sterilization by radiation
 Sterilization by gases and fumigants
 Aseptic preparation:
 Sterilisation by filtration
Steam sterilisation:
 It is important to ensure that the steam used is of suitable quality and does
not contain additives, or other substances which could cause chemical
contamination of the product, material or equipment being sterilised
 Both temperature and pressure should be used to moniter the process
 System and cycle faults should be registered and observed by the operator
 The reading from an independent temperature indicator should be routinely
checked against the chart recorder during the sterilisation period.
 Items to be sterilised other than products in scaled containers, should be
wrapped in a material that allows removal of air and penetration of steam but
that prevents re-contamination after sterilisation.
 
Sterilization by dry heat:
 Used for non-aqueous liquids, dry powders
 Air circulation in the chamber is maintained
 Positive pressure is maintained in chamber to prevent entry of non-sterile air
 HEPA filtered air is supplied
 When removing pyrogens, challenge tests
using endotoxins should be used as a part of the validation.
Sterilisation Times:
 171o C, 60 minutes, dry heat
 160o C, 120 minutes, dry heat
 149o C, 150 minutes, dry heat
 141o C, 180 minutes, dry heat
  121o C, 12 hours, dry heat
 121o C, 15 minutes, moist heat (but don’t start the clock until entire item is
up to temp—e.g., large volumes fluid)
Sterilization by radiation:
 Suitable for heat-sensitive materials and products
◦ confirm suitability of method for material
◦ ultraviolet irradiation not acceptable
 Contracting service – ensure validation status, responsibilities
 Measurement of dose during procedure
 Dosimeters independent of dose rate
◦ quantitative measurement
◦ number, location and calibration time-limit
 Biological indicators only as additional control
 Radiation sensitive colour discs are used.
 Information forms part of the batch record.
 Validation to cover effects of variation in density of packages.
 Handling procedures to prevent misidentification of irradiated and non-
irradiated materials.
 Each package to have a radiation-sensitive indicator
 Total radiation dose administered within a predetermined period of time.
Sterilization by gases and fumigants;
 Only when no other method is suitable
 e.g. ethylene oxide, hydrogen peroxide vapour
 Validation: should prove that gas has no damaging effect on product.
 Time and conditions for degassing (specified limits) – residue
 Direct contact with microbial cells essential
 Nature and quantity of packaging materials
  Humidity and temperature equilibrium
 Monitoring of each cycle with biological indicators
 time, pressure
 temperature, humidity and gas concentration
Sterilization by filtration;
 Through a sterile filter of 0.22 µm or less, into previously sterilized
containers to
◦ remove bacteria and moulds
◦ But not all viruses or mycoplasms are removed in this step.
 Consider complementing with some degree of heat treatment.
 Double filter layer or second filtration is advisable, just before filling - no
fibre shedding or asbestos filters.
 Filter integrity testing immediately after use
◦ also before use if possible
 Validation should include
◦ Time taken to filter a known volume
◦ Pressure difference to be used across the filter
 Significant differences to be noted and investigated, recorded in batch
records.
 Integrity of gas and air vent filters checked after use, other filters at
appropriate intervals.
 Same filter should not used for more than one working day, unless validated.
 Filter used should not interact with product, e.g.
◦ removal of ingredients
◦ releasing substances into product
AFTER STERILISATION:
There is a need to avoid re-contamination of a sterilised product or material, and
the mix up of sterilised with non-sterilised items.
 This includes:
 Examination for particles
 Sterility testing
 Leak detection testing
 Pyrogen testing
Quality control:
 Samples for sterility testing should be representative of whole batch.
 From parts of the batch, most at risk
◦ Aseptic filling – at beginning and end of batch filling, and after
interruptions
◦ Heat sterilized – coolest part of the load
◦ Sterility test procedure is followed as per pharmacopoeia, and
validated for each product
◦ Endotoxin testing for injectable products
◦ Water for injection, intermediate and finished product.
◦ Batch processing records, sterility testing records, environmental
records should be reviewed.
Finishing of products:
 Containers closed by means of validated methods
 Samples checked for integrity
 Maintenance of vacuum (where applicable) checked.
 Parenteral products inspected individually.
 Visual inspection under suitable and controlled conditions:
 illumination and background
 eyesight checks of operators
 allowed frequent breaks
 Other methods:
  validated, and equipment performance checked at intervals
 results recorded

ASEPTIC PROCESS CONTROL
 The term aseptic indicates a controlled condition in which the microbial
contamination is reduced to a degree that micro organism can be excluded
from the product during processing.
 Sterile products are free from micro organisms, pyrogens and have
extremely high standards of quality and purity.
 Significance should be given to design and process control involved in
producing the final product.
Air flow and uniformity test:
 OBJECTIVE:
To verify air velocity when new filters are installed and to determine, air system
is capable of delivering sufficient air volume.
 PROCEDURE:
• A hot wire anemometer (thermo anemometer) is used for the measurement.
• Measurements should be taken for a minimum period of 15 secs at different
locations in the room.

 The probe should be placed at a specified distance from the filter face.
 The air velocity should be read directly and recorded in m/sec.
Calculation of air changes per hour:
= V×S×3600/C
 V= avg velocity
 S= surface area of HEPA filter.
 C= volume of the room.
 The number of air changes per hour should be atleast 20.
Temperature control test:
 Procedure:
 A calibrated dry bulb thermometer is used for the measurement of
temperature.
 Air conditioning system and lights must be in operation for 24 hours.
 Temperature at different predetermined areas of the rooms is measured for
every 15 mins for 2 hours.
Humidity control test:
Objective:
To evaluate the ability of the air handling system to control the relative
humidity at the specified test.
Procedure:
 A wet bulb and dry bulb thermometer or an automatic humidity recorder is
used for the measurement.
 The system must be in operation for 6 hours before the measurement.
 Humidity at different places is measured.
 The relative humidity must be between 45% to 55%.
Pressure control test:-
Objective:
To demonstrate the ability of the system to control pressure levels within the
specified limits.
Procedure:
o Equipment used in a pressure gauge or a manometer.
o The pressure differential is measured in the upstream duct of the HEPA
filter.
o The procedure is replaced to measure the pressure in the down stream duct
of HEPA filter.
o Manometer readings must be recorded twice a day.
o The pressure differential should be maintained within specified limits.
 o Aseptic area pressure must be higher than the pressure in surrounding non-
aseptic areas.
Test for air flow pattern:
Objective:-
To determine an air flow pattern that generates minimum turbulence.
Procedure:-
 A white visible or yellow smoke generator or pencils of titanium chloride
are used to generate smoke.
 Smoke is generated in critical locations of the room.
 The flow is considered acceptable only if it shows flow in proper direction.
 If the smoke flows back due to turbulence, the changes should be done.
• The flow pattern is termed acceptable when there is no back flow of smoke
due to turbulence.
• Readjustments should be done if necessary.
DECONTAMINATION TIME:-
 To determine the capabilities of a system to recover from an internally
generated contamination.
 The normal particle count of the room is determined.
 The particle count is artificially increased by using a smoke generator.
 The particle counts should be taken continuously and the time taken for the
count to come back to the normal levels is determined.
 Recovery time should be within the limits.
Gowning area:
• The gowning area must be adjacent to the sterile area.
• Air pressure must be maintained to prevent the flow of air between the
gowning area and the external environment and the gowning area and
aseptic area.
• It must be easy to disinfect and must be flushed with filtered air.
 • It must have appropriate mechanism to prevent the opening of more than
one door at a time.
• Entry to the area must be restricted to operating personnel only.
• The area must have adequate facilities for washing, cleaning and drying of
hands, for the storage of clean, sterile garments and for the disposal of used
garments.
• The room should have provision for the separation of different stages of
changing thereby minimising microbial and particulate contamination of
protective garments.
General requirements:-
 Access to clean and aseptic areas should be only through changing rooms
where normal factory clothing is exchanged for special protective garments,
commonly referred as GOWNS.
 Donning of sterile garments is called as gowning procedure.
 It is mainly done to minimize the microbial contamination.
 The following general rules must be followed while entering the sterile
area:-
 The clean area is normally reached after passing through 3 change rooms.
 Change over from street clothes and shoes to factory uniform and footwear
in the common change room facility provided at the entrance of the plant.
 Hands and feet should be thoroughly washed with soap and water before
putting on uniform.
 Both the doors of the change rooms should not be opened simultaneously
during the entry/exit to the sterile area.
 The entries of personnel should be restricted and the number of persons in
the change room at one point of time should be predetermined.
 Operators working in clean and aseptic rooms open and shut the doors
gently, do not rush or run in the rooms and, avoid talking.
FUMIGATION :-
 The environment in the aseptic area should be controlled to keep the bio-
burden at such a low level so that the micro organisms can be excluded
during the processing and packaging the sterile product.
  Formaldehyde is often used to fumigate rooms.
 Vapour form of hydrogen peroxide can also be used to sterilize rooms .
• The major advantage of using hydrogen peroxide is that the vapour get
converted to water vapour and oxygen, thus leaving no harmful products.
Procedure :-
 Formaldehyde is irritating to the eyes and skin.
 Therefore rubber gloves and goggles must be worn by the person fumigating
the room.
 The person must leave the room as soon as possible after placing the
formalin solution at the predetermined location.
 Prior to fumigation, the area must be cleaned and sanitized.
 Air supply and exhaust system must be shut off during fumigation.
 UV lights must be put off.
 Monitoring of temperature and humidity is essential during fumigation.
 Formaldehyde vapours are effective at a relative humidity of NLT 50% at
25°c.
 Here formaldehyde solution is placed in stainless steel container equipped
with a perforated lid.
 This container is placed on a hot plate.
 During fumigation, the blower must be put off.
 Potassium permanganate can also be used as an alternative.
 The entrances to this area are sealed and the area is left undisturbed for
sufficient period of time to ensure the proper sterilization
 After a certain period of time, the exhaust system should be put on.
 The room should be flushed with clean, filtered air.
 Then the operator can enter the area and remove the formalin container.
 The surfaces are then wiped with a suitable disinfectant.
 The ultra violet lamps are cleaned and then switched on.
  Nutrient agar plates are exposed at various critical locations to ensure that
fumigation has brought down the microbial load within acceptable limits.
PACKAGING;
LINE CLEARANCE:
 What is Line clearance?
 The term line clearance is used for the documented act of conducting any
necessary removal of products and materials from a manufacturing line to
prepare the line for the next production (packaging).
 An important requirement of GMP is that the packaging and labelling
facilities are inspected before use.
 Inspection is done to assure that all drug products are removed from
previous operations and that packaging and labelling materials not suitable
for subsequent operations have been removed.

 It is also stipulated that the results of inspection are documented in the batch
production records.
 The filling/packaging line and the areas immediately close to it should be
free from all filled/ packaged products as well as all the packaging and
labelling materials from the previous filling/ packaging operations.
 Rejects on the line such inadequately filled bottles , broken or damaged
packs , strips with empty pouches and so on should also be removed.
 Spillage on the line and the immediately areas should be mopped up or
cleared.
 Particular attention should be paid to left-over labels and cartons from the
previous run especially when a new batch of the same product is to be
packed on the line.
 It should be certified that the packaging equipment has been properly
cleaned and a tag marked ‘CLEANED’ indicating the status is attached to it.
The tag should also indicate:
 the date of cleaning
 the name of the product which the equipment was last used
  signed by the supervisor.
 If the equipment has been idle for an extended period of time before use, it
should be re inspected for cleanliness and re-cleaned before use, if required.
 Information regarding cleaning of major packing equipment should be
recorded in the ‘Equipment Cleaning and Use Log’ of the packaging
department.
 Filling or packaging of a batch should not commence until the line clearance
has been initialled by the supervisor on the filling order.
PACKAGING INSTRUCTIONS;
 Clearly defined packaging instructions must be available to the packaging
line supervisor and engineering staff who are setting up the line.
 The line supervisor will require the packaging specifications, specific batch
details and the customer requirements if any. The engineering staff will
require the line set-up instructions.

 It is necessary to have formally authorized packaging instructions for each

product, pack size and type.
 These should normally include the following:
 Name of the product
 Description of its dosage form and strength where applicable
 The pack size expressed in terms of the number, weight or volume of the
product in the final container.
  A complete list of packaging materials required for a standard batch , size ,
including quantities , sizes and types with the code or sequence number
relating to the specifications of each packaging materials.
 Special precautions to be observed including carefull examination of the
area and equipment in order to ascertain the line clearance before operation
begins.
 A description of the packaging operation , including any significant
subsidiary operations and equipment to be used.
 Details of in process controls with instructions for sampling and acceptance
limits.
 The number of person required to complete the packing or labeling
operation.
 Details of outer packaging includes the relevant labeling requirements.
 Personnel on an assembly line should be adequate to ensure that each and
every unit of the finished products is inspected for defects. No single person
should be made responsible for more than he is capable of handling or
controlling.
 Packaging orders are specific for a packing cycle involving one batch or one
product. They normally include the following.
 The name of the product.
 The code number of the product.
 The dosage form and strength of the products.
 The batch number of the bulk product being packaged.
 The packaging lot or the control number assigned to the packaging
operation, where a batch of a product is part-filled or filled in more than one
lot.
 The quantity of final packs required and the amounts of packaging material
required according to the relevant pack specifications.
 Any special instructions applicable for a particular operation including
specific labeling requirements on the outer shipment packages.
INTRODUCTION TO AUDITING:
A quality audit is a systematic, independent and documented process for obtaining
audit evidence and evaluating it objective to determine the extent to which agreed
criteria are fulfilled
(ISO 9000:2005 clause 3.9.1)
Why Audit?
• To determine whether the quality system conforms to specified requirements
• To determine the effectiveness of the implemented system
• To initiate improvements in the system
• To compare practice with procedure
• To provide objective evidence that the system is in compliance with the
standard (i.e for certification purpose) intake per set criteria
3 types of audits
• Process audits
• Product audits
• System audits
PROCESS AUDITS:
Evaluation of the contents and effectiveness of specific processes & work
activities:
• To confirm process parameters and improve capability of the process
• To ensure the realization the process quality characteristics.
• To ensure improvement of process control during service provision
Product Audits:
Investigation of product conformance to specified characteristics:
• To obtain additional neutral assessment of product’s level of quality
• To obtain additional assurance that specified quality requirements are met
Product audits:
• To identify opportunities for improvement.
• To establish the quality level of units before final inspection and testing
 • To establish the capability of the inspection function
• To determine the usefulness of inspections tests
System audits:
Evaluation of all the elements of the quality system in order to:
• Verify usefulness, suitability and effectiveness
• Verify adequate documentation
• Verify compliance with requirements.
• Determine weak points
Distinction of system audits by parties:
1st party audits (Internal Audits) – Organization audits its own QMS according
to a quality standard
2nd party audits (Supplier Audits) – Customer audits the supplier’s quality system
3rd party audits External certification audits by an independent institution in
order to .certify the QMS.
Who is an auditor?
A person who has the qualification to perform quality audits
Criteria for quality auditors
• Education
• Training
• Experience
• Personal Attributes
Attributes of an auditor:
A – Analytical
U – Unassuming/unbiased
D – Diplomatic
I – Inquisitive/independent
T – Thorough
O – Objective
 R – Reliable
The Audit Process:
• Plan and prepare the audit 50%
• Carry out the audit 30%
• Reporting and follow-up 20%
1. AUDIT PREPARATION:
Establish audit type and scope
2. Establish audit basis – it is the standard, manual, procedures or combination
thereof?
3. Establish audit personnel – size is dependent on the type, purpose and scope
of audit. Audit team may include specialists, trainee auditors, observers
acceptable to auditee and audit team
4. Read basis documentation as well as previous audit reports and determine
what records shall be pulled in advance
5. Prepare process model – identifying the expected results of the process to be
audited
6. Prepare an audit plan
7. Notify the auditee in advance of: time, date, the scope, the basis, timetable of
the audit
8. Prepare checklists – use open ended questions what? Why? Who? How?
Which?
PERFORMING THE AUDIT:
Before the start of audit:
• Auditee's management informs personnel in the involved departments about
expected audit
• Lead auditor and rest of the team must be acceptable to auditee management
FOUR PHASES OF AN AUDIT:
• Opening meeting
• Execution of audit
• Auditors’ meeting
 • Closing meeting
Typical opening meeting agenda:
• Introduction of members and observers and recording of those present
• Confirm objectives, scope, basis, reasons and benefits of the audit
• Review of audit plan
• Explanation of the audit method and documentation to be used
• Explain the tasks of the accompanying auditee’s representatives (i.e guide)
• Confirm method of communication
• Confirm availability of facilities
• Explain closing meeting/format
• Assure auditee of confidentiality
• Invite questions
Execution of audit:
• Must be done according to timetable
• Only ask open, factual questions
• Verify answer through observation
• Follow an audit trail
• Do more listening than talking
2 ear 1 month; therefore listen 2/3 of the time
• Keep calm and relaxed
• Look at the other person-eye contact
• Keep discussion factual
• Ask one question at a time
• Do not lecture
• Let the other person finish talking
• Keep the right distance from the person
• Be friendly without being too familiar
 • If your question causes uneasiness or uncertainty, formulate it differently
• Involve all participants
• Use the right gestures/expressions
• Keep personal opinions to yourself
AUDITOR SINS:

An auditor should never

• Compare the auditee with others
• Be sarcastic
• Swear
• Criticize
• Be side tracked
• Argue
• Discuss personalities
• Discuss religion or politics
• Discuss company policy
• Drink beer before an interview
• Be late
AUDITORS’ MEETING:
• Compilation of findings/observations
• Recording of non-conformities
• Preparation of summary report
• Formation of opinion to be presented at closing meeting
Typical closing meeting agenda
• Introductions and recording of attendance
• Thank the auditee
• Mention the principles of sampling followed during the audit
 • Summarize audit observations
(positive, general observations and nonconformities)
• Give non – conformities in details
• Present overall summary and conclusions
• Allow for discussion
• Request corrective actions and corrective action dates
• Agree on follow-up date
• Close meeting
Corrective Action Follow-up:
It is important to ensure that the auditee implements: -
1. Effective correction
2. Effective corrective actions
• REPORTING OF AUDITS: A standard proforma for the reporting of audit
should be used.
• Using the standard audit report sheets prepare a narrative summary of the
audit
• Ensure the positive as well as the negative findings are summarized
Report should cover the following headings: -
1. Title
2. Scope
3. Basis
4. Audit team
5. Introduction (opening meeting)
6. Findings
7. Debriefing (closing meeting)
8. Summary
The audit report including any non-conformity report,
Corrective action notices are issued to the auditee & MR
• ISO 19011:2002 includes recommendations for report contents
• Audit reports should be kept confidential lest
– Auditors lose respect
– Auditees are less willing to identify areas for improvement
• ANALYSIS OF AUDITS:
Management Representative will analyze audit reports to identify areas of
common deficiency within QMS
• This will initiate changes to the audit schedule
• A full analysis of audit reports is presented to management review meeting
Records & Administration of Audits:
• The MR should enter the audits in the audit log.
• Following documents be retained in departmental QMS files as records: -
• Original checklists
• Audit reports
• Related documents