CDSCO Document

Post Approval Changes in
Biological Products:
Quality Safety and Efficacy
Documents
Document No. - PAC/2024

Version – 1.2
Published by
Central Drugs Standard Control Organization
Ministry of Health, Government of India
Date Revised 28.02.2024

Date Adopted 16.05.2024
Date Implementation 16.05.2024
Guidance for Industry
Central Drugs Standard Control Organization Page 1 of 138
Table of Contents
Abbreviations ........................................................................................................................................................ 4
1. INTRODUCTION ...................................................................................................................................... 6
1.1 Objectives .................................................................................................................................................. 6
1.2 Scope and Application ............................................................................................................................ 7
1.3 Background ............................................................................................................................................... 7
2. GUIDANCE FOR IMPLEMENTATION ................................................................................................ 8
2.1 Reporting Categories for Quality Changes.......................................................................................... 8
2.1.1 Level I – Supplements (Major Quality Changes)............................................................................. 8
2.1.2 LeveI II – Notifiable Changes (Moderate Quality Changes) ......................................................... 9
2.1.3 Level III – Annual Notification (Minor Quality Changes) ............................................................... 9
2.1.4 Level IV – Changes (Record of Changes) ............................................................................................ 9
2.2 Documentation – Quality Changes ...................................................................................................... 10
2.2.1 General Information ............................................................................................................................... 10
2.2.2 Supporting Data – Level I and Level II Changes: .............................................................................. 11
2.2.3 Supporting Data – Level III Changes ................................................................................................. 11
2.2.4 Supporting Data – Level IV Changes .................................................................................................. 12
2.3 Reporting Categories for Safety, Efficacy Changes ......................................................................... 12
2.3.1 Level I – Supplements (Safety and Efficacy) ..................................................................................... 13
2.3.2 Level II – Notifiable Change (Safety and Efficacy) that are risk/harm management
changes ................................................................................................................................................... 15
2.3.3 Level II – Notifiable Change (Safety and Efficacy) that are not risk/harm management
changes ................................................................................................................................................... 16
2.3.4 Level III (Safety and Efficacy) Changes – Annual Notification ........................................................ 17
2.3.5 Documentation – Safety and Efficacy Changes: ............................................................................... 18

3. SPECIAL CONSIDERATIONS ............................................................................................................. 19
3.1 Comparative Studies.............................................................................................................................. 19
3.2 Bridging Clinical Studies........................................................................................................................ 20
3.3 Stability Testing ...................................................................................................................................... 21
3.4 Pharmaceutical Development and Quality by Design ...................................................................... 22
3.5 Multiple Changes .................................................................................................................................... 23
3.6 Post-Approval Change Management Protocol-PACMP ................................................................... 24
3.7 Production Documents .......................................................................................................................... 25
3.8 Expedited Review Procedure (Reliance Pathway) ........................................................................... 25
3.9 Similar Biotherapeutic Products (SBP) / Similar Biologics ............................................................... 25
4. POST APPROVAL CHANGES (BIOLOGICALS) .............................................................................. 26
3.2.S DRUG SUBSTANCE ................................................................................................................ 27
3.2.S.1 General Information................................................................................................................ 27
3.2.S.2 Manufacture ............................................................................................................................ 28
3.2.S.3 Characterization ..................................................................................................................... 50
3.2.S.4 Control of the Drug Substance ............................................................................................. 50
3.2.S.5 Reference Standards or Materials ....................................................................................... 58
3.2.S.6 Container Closure System .................................................................................................... 60
3.2.S.7 Stability..................................................................................................................................... 63
3.2.P DRUG PRODUCT ...................................................................................................................... 68
3.2.P.1 Description and Composition of the Drug Product ........................................................ 68
3.2.P.2 Pharmaceutical Development .......................................................................................... 77
3.2.P.3 Manufacture ........................................................................................................................ 77
3.2.P.4 Control of Excipients .......................................................................................................... 88
3.2.P.5 Control of Drug Product ..................................................................................................... 96
3.2.P.6 Reference Standards or Materials ................................................................................. 104

3.2.P.7 Container Closure System .............................................................................................. 106
3.2.P.8 Stability............................................................................................................................... 110
5. POST-APPROVAL CHANGE MANAGEMENT PROTOCOL-PACMP ........................................ 115
6. EFFICACY POST APPROVAL CHANGES ..................................................................................... 116
7. ADMINISTRATIVE CHANGES .......................................................................................................... 119
8. PRODUCT LABELLING INFORMATION CHANGES .................................................................... 121
9. APPENDICES ....................................................................................................................................... 122
Appendix 1: Examples of Level IV Changes but not limited to ......................................................... 122
Appendix 2: ANNUAL REPORT FORM (Minor Changes) ................................................................. 123
Appendix 3: Glossary ............................................................................................................................... 125
10. REFERENCES ..................................................................................................................................... 138

Abbreviations
AEFI : Adverse Event Following Immunization
BAN : British Approved Names
BSE : Bovine Spongiform Encephalopathy
CDSCO : Central Drugs Standard Control Organization
CMC : Chemistry, Manufacturing and Control
CQA : Critical Quality Attribute
CTD : Common Technical Document
EDQM : European Directorate for the Quality of Medicines & HealthCare
GMP : Good Manufacturing Practices
HA : Haemagglutinin
HVAC : Heating, Ventilation, Air Conditioning
ICH : International Council for Harmonization
INN : International Non‐proprietary Name
MA : Marketing Authorization
MCB : Master Cell Bank
NA : Neuraminidase
NC : Notifiable Change
NCL : National Control Laboratory
NIBSC : National Institute for Biological Standards and Control
NRA : National Regulatory Authority
PAC : Post Approval Change
PACMP : Post-approval change management protocol
PI : Package Insert
PK/PD : Pharmacokinetic/pharmacodynamic
PPD : Product Permission Document
PSUR : Periodic Safety Update Report
QC : Quality Control
SBP : Similar Biotherapeutic Products
SPC : Summary of Product Characteristics
TAG : Technical Advisory Group
TSE : Transmissible Spongiform Encephalopathy

USAN : United States Adopted Name
WCB : Working Cell Bank
WFI : Water for Injection
WHO : World Health Organization
1. INTRODUCTION
This document is intended to provide guidance to manufacturers on regulating
changes to already licensed biological products in order to assure their continued
quality, safety and efficacy, as well as continuity in supply and access.
Changes are essential for the continual improvement of the manufacturing

process and for maintaining state-of-the-art control of biological products, and often
need to be implemented after the product has been approved (that is, when it has
been licensed or when marketing authorization has been received). Changes may be
made for a variety of reasons, including: (a) to maintain routine production (for
example, replenishment of reference standards, or change of raw materials); (b) to
improve product quality, or the efficiency and consistency of manufacture (for
example, changes in the manufacturing process, equipment or facility, or adding a
new manufacturing site); (c) to make safety or efficacy changes (for example, adding
a new indication, changing the dosage regimen, or adding information on co-
administration with other medicines); (d) to update product labelling information (for
example, improvement of the management of risk by addition of a warning statement
for a particular target population, or limiting the target population); or (e) to address
administrative changes (for example, change in the proper/nonproprietary or trade
name of a biological product).
Marketing authorization holders should recognize that:
 any change to a biological product has a potential impact on the quality,

safety and/or efficacy of that product;
 any change to the information associated with the product (that is, product
labelling information) may have an impact on its safe and effective use.
The regulation of changes to approved biological products is key to ensuring that

products of consistent quality, safety and efficacy are marketed after they receive
authorization or licensure. An attempt has been made to cover a range of possible
changes in manufacture, quality control, safety, efficacy and product labelling
information and to provide guidance on the data needed to support changes to
approved biological products in order to ensure comparability of the pre-change and

post-change products with respect to quality, safety and efficacy.
This document is intended to serve as a guide for post-approval changes to

biological products. The categories of changes and reporting procedures are
provided in the main body of the document and the data requirements to support the
proposed changes are provided in the subsequent sections.
Purpose and scope
This Guideline provides guidance for marketing authorization holders on the

regulation of changes to the original marketing authorization dossier or product
license for an approved biological product in terms of: (a) the procedures and criteria
for the appropriate categorization and reporting of changes; and (b) the data required
to enable NRAs to evaluate the potential impact of the change on the quality, safety
and efficacy of the product.
1.1 Objectives
a) To assist with the classification of changes made to biological products

approved by CDSCO for import / manufacturing and marketing in India.
b) To provide Marketing Authorization Holders (MA holders) with

recommendations on the data to support a change which would be
considered sufficient to allow a determination of the impact of the change on
the quality of the approved products as it relates to safety, efficacy and/or
effective use of the products.
1.2 Scope and Application
This guidance document applies to MA holders intending to make changes to

biological products that have received an approval to market the products.
1.3 Background
This would include an emphasis on applying a science-based and risk-based

approach to the quality, safety and efficacy assessment of the biological products.
As such, the guidance documents were needed to outline the information needed to
support quality, safety and efficacy changes to biological products which apply a
modernized, science-based, and risk-based approach to this area.
2. GUIDANCE FOR IMPLEMENTATION
2.1 Reporting Categories for Quality Changes

The following criteria are meant to provide guidance with respect to the classification
of a change. Specific change examples based on the application of these criteria are
provided in this guidance. For assistance in classifying a change, MA holders are
advised to contact CDSCO.
2.1.1 Level I – Supplements (Major Quality Changes)

Level I - Supplements (Major Quality Changes) are changes that have a
substantial potential to have an adverse effect on the identity, strength, quality,
purity, or potency of a biological product as these factors may relate to the safety
and/or efficacy of the product.
In general, a change that is supported by extensive documentation and/or requiring

extensive assessment of the supporting documentation would be considered a Level
I - Supplement (Major Quality Change) (e.g., a change supported by in-vivo studies).
This is to allow CDSCO the opportunity to apply the principles of risk management
by having the necessary time for an appropriate assessment of the documentation.
This assessment will take into consideration any potential impact upon market
availability as well as the adverse effects on the identity, strength, quality, purity, or
potency of the biological product.
The changes included in this reporting category shall not be implemented for
commercial purpose without prior approval from CDSCO.
The changes included in this reporting category shall be submitted along with the
recommended supporting data, to CDSCO. Appropriate fee, as applicable and in
accordance with rules shall be paid along with submission.
2.1.2 LeveI II – Notifiable Changes (Moderate Quality Changes)
Level II - Notifiable Changes (Moderate Quality Changes) are changes that have a
moderate potential to have an adverse effect on the identity, strength, quality,
purity, or potency of the biological product as these factors may relate to the safety
and/or efficacy of the product.
The changes included in this reporting category should be submitted along with the
recommended supporting data, to CDSCO as a Notifiable Change (NC).
2.1.3 Level III – Annual Notification (Minor Quality Changes)
Level III -Annual Notification (Minor Quality Changes) are changes that have minimal
potential to have an adverse effect on the identity, strength, quality, purity, or
potency of the biological product as these factors may relate to the safety and/or
efficacy of the product. The changes included in this reporting category may be
implemented by the MA holder without the prior review by CDSCO of the data
supporting such a change (except for cases of change in shelf life of DS and DP).
2.1.4 Level IV – Changes (Record of Changes)
Level IV (Quality only) changes are changes to a biological product that are not
Level I, Level II or Level III and are not expected to have an adverse effect on the
identity, strength, quality, purity, or potency of the drug product as these factors may
relate to the safety and/or efficacy of the drug product. The changes included in this
reporting category may be implemented by the MA holders without prior review by
CDSCO. The changes should be retained as part of the drug product’s record at
manufacturing site and should comply with the requirements of ‘Good Manufacturing
Practices’. For importers, the said data to be submitted once in three years during re
registration of RC.
A list of examples of Level IV changes is provided in Appendix 1.
2.2 Documentation – Quality Changes
2.2.1 General Information
The examples presented in Post Approval Changes (Biologics) are intended to assist
with the classification of changes made to the Quality, Safety, Efficacy and
Administrative information. The information summarized in the tables provides
recommendations for:
a) The conditions to be fulfilled for a given change are classified as a Level I, II,
III or IV change. If the conditions outlined for a given change are not fulfilled,
the particular change is automatically considered the next higher level of
change.; For example, if any of the conditions recommended for a Level II ‐
Notifiable Change are not fulfilled, the change is considered a Level I ‐
Supplement. Similarly, if any of the conditions recommended for a Level I ‐
Supplement are not fulfilled, the change would warrant the filing of a New
Drug.
b) The supporting data for a given change is either to be submitted to CDSCO

and/or maintained by the MA holders. Wherever applicable, the corresponding
sections of the application for the supporting data have been identified; if any
supporting data is not provided / not applicable, then a justification should be
provided.
c) The reporting categories (e.g., Supplement, Notifiable Change, Annual

Notification and Record of Changes).
2.2.2 Supporting Data – Level I and Level II Changes:
All data recommended to support the change should be provided with the
submission. Where applicable, these data should be provided in the format
defined b y CDSCO or i n the format of Common Technical Documents (CTD).
Supporting Data Common to Level I and Level II Changes:

The following should be included, where applicable, in the submission package for
Level I and Level II Quality changes:
a) a covering letter (including a list of changes describing each in sufficient detail
to allow for a quick assessment as to whether the appropriate reporting
category has been used);
b) where relevant, a side-by-side comparison of the previously approved and the
changed information;
In addition to the above common information, recommendations are included in

Post Approval Change (Biologics) categories outlining the specific information to
support the various changes of Quality, Safety, Efficacy and Administrative. It
should be noted that the common information is not repeated for the various
changes outlined in the sections.
When cross-references are made to previously submitted information, details on

the cross-referenced information should be indicated in the covering letter (e.g.,
brand name / generic name of the drug product, MA holders name, submission
type, File number, date approved).
2.2.3 Supporting Data – Level III Changes
Annual notifications shall be submitted to CDSCO by 1st quarter of every calendar

year. Any data for calendar year (January to December) that may have been
generated by the MA holders in support of a Level III change s h o u l d not b e
submitted with annual notification, however, should b e available t o CDSCO
within thirty (30) calendar days, if requested. For submission of each minor change,
Appendix 2: Annual Report Form (Minor Changes) of this guidance shall be referred
by MA holder.
Note: For extension of shelf life that is categorized as Level III as per this guidance,
MA holder should submit the PAC application along with applicable supporting
documents and should implement the change only after approval from CDSCO.
2.2.4 Supporting Data – Level IV Changes
The Quality changes included in this category should be retained as part of the drug
product’s record by MA holder and comply with the requirements of ‘Good
Manufacturing Practices’. These changes should be annotated / updated in the
affected documents (e.g., Package Insert, SPC or PPD) with the filing of the next
submission to CDSCO.
2.3 Reporting Categories for Safety, Efficacy Changes

After assessing the effect of a change related to clinical use or to product labelling
information on the safe and effective use of a biological product, MA holders should
classify this change in one of the following categories:
 Level I – Supplements (Safety and Efficacy);
 Level II – Notifiable Changes (Safety and Efficacy) i.e. risk/harm management
change
 Level II – Notifiable Changes (Safety and Efficacy) that are not risk/harm
management changes
 Level III – Annual Notifications (Safety and Efficacy)
Further information on each category is provided below.
Safety and efficacy changes are changes that have an impact on the clinical use of
the biological product in relation to safety, efficacy, dosage and administration and
that require data from clinical studies to support the change. Safety and efficacy
changes require approval prior to implementation of the change.
The type and scope of the required supporting non-clinical and/or clinical safety and
efficacy data are determined case-by-case on the basis of risk-benefit considerations
related to the impact of the changes. Additionally, non-clinical and/or clinical data
generated in other countries may be used for such risk benefit consideration.
Other considerations which may be applicable for vaccines, only:

 robustness of the immune response elicited by the vaccine and availability of

a correlate of protection (i.e. data establishing a threshold level of antibody
needed to protect against the development of disease following exposure);
 availability of animal models; and
 vaccine attributes (e.g. live vaccines as opposed to inactivated ones).
MA holders are encouraged to consult CDSCO on the adequacy of the clinical data
needed to support a safety and efficacy change if deemed necessary. Additionally,
some changes such as dosage form, content of excipients or residual components,
or delivery device may require clinical data as well as revision of the product labelling
information. CDSCO may also be consulted on the data required to support such
changes.
If the conditions / supporting data outlined for a given change are not fulfilled, then
appropriate scientific justification shall be provided by the MA holders.
2.3.1 Level I – Supplements (Safety and Efficacy)
A Level I change is defined as a change to the label of a drug that has the potential
to change the exposure levels of the drug, either by expanding the population that is
exposed (i.e. related to market expansion), or by increasing individual exposure.
Label changes that can result in increased exposure levels of the drug include:
 addition or expansion of a safety claim or efficacy claim, whether explicit or

implied;
 change in the strength, route of administration, recommended dose/dosing
range, dosage form, dosing schedule, including the addition of a booster
dose;
 co-administration with other vaccines or biological products; or
 deletion or reduction of existing risk management measures (e.g.
contraindications, adverse events, warnings or cautionary text/statements, in
the product labelling information).
Examples: Examples of Level I changes include but are not limited to the following:
 The addition of a new contraindication, a change in an existing

contraindication, the addition of a serious warning or precaution or the
tightening of clinical monitoring requiring a change to the labels of sections of
the Package Insert
 Changes to the existing text of the label that refers to any potential benefits of
the drug (implied or explicit), including claims regarding the safety profile or
efficacy. This includes changes in text with reference to sub-populations and
any reference to possible claims regarding side effects.
 Addition of a new indication or the revision to existing text of a current
indication.
 Addition of a new route of administration, dosage form, or strength.
 A change regarding the mechanism of action of the product as detailed in the
Action and Clinical Pharmacology section of the Product labelling that results
in an explicit or implicit claim.
 A change to the Clinical Trial section of the Product labelling which results in a
new claim, explicit or implied (e.g., listing of additional outcome measures, or
revision to the description of study design such that a new benefit is implied
for a specific subpopulation).
 Data has been added from an efficacy or safety (tolerability) study in a special
population
 A change in condition of use from prescription to non-prescription status.
 An existing contraindication, warning or cautionary text anywhere in the
Product
 Labelling, has been deleted in its entirety, has been modified to reflect a
reduction or diminishment in risk/harm management measure. These may
result from a range of supporting data (e.g., post-marketing data, safety
studies, pharmacokinetic data etc.).
 Existing text regarding an adverse event or set of events has been modified to
reflect, in any way, an apparent reduction in risk/harm. This includes changes
related only to animal data.
Note: The changes that are considered as “New Drugs” as per “The New Drugs and
Clinical Trials Rules, 2019, MA holder should submit the MA application in Form CT-
21/Form CT-18 in SUGAM with applicable fee along with supporting documentation
as described for the respective post approval change category, followed by
amendment / endorsement of current Form 28 D license, as applicable .
Note: A declaration to state that no change to other remaining section/s of the MA

dossier, including impact on safety/efficacy, shall be submitted, as applicable.
2.3.2 Level II – Notifiable Change (Safety and Efficacy) that are risk/harm
management changes
A Level II - Notifiable (Safety and Efficacy) change (i.e. risk/harm management

change) is defined as a change to the label that has the potential to improve the
management of risk/harm to the population currently indicated for use of the drug, or
in any other way exposed to the drug by:
 the identification or characterization of any adverse event following

immunization (AEFI) resulting in the addition or strengthening of risk
management measures for an adverse event which was identified to be
consistent with a causal association to immunization with the vaccine
concerned;
 the addition or strengthening of risk management measures, including
instructions on dosing or any other conditions of use.
 the identification of subgroups, or conditions of use, for which the benefit/risk
profile of biological product has the potential to be less favorable; and
Examples:
Examples of Level II – Notifiable (Safety and Efficacy) that are risk/harm

management changes include but are not limited to the following:
 An addition to, strengthening or clarification of text anywhere in these sections:

Contraindications, Warnings and Precautions and Adverse Events. These
changes may include the provision of recommended risk/harm management

actions (e.g., required testing prior to initiation of the drug, specific monitoring
during product use, ensuring patient awareness of certain risks, etc.), or the
identification of a specific sub-population as being at greater risk such as those
with a concomitant condition, those taking concomitant medicine, or a specific
age group.
 The instructions for use including dosage and administration, in the Product
labelling have been reworded and/or otherwise altered with respect to risk/harm
management to optimize the safe use of the drug.
 A new drug interaction has been added, or an existing drug interaction has
been better characterized that identifies a risk/harm.
 A change to the toxicology data, explicitly or implied, stating an increase in
risk/harm to the target population (other changes to the toxicology data, in
general, are submitted as Level II - Supplements (Safety and Efficacy) that are
not risk/harm management changes.
 An existing indication has been withdrawn in its entirety or the indication has
been modified for the purpose of risk/harm management including a reduction
in scope.
 A change to improve the clarity of the message to patients in Part III of the
Product labelling.
 Revisions to the existing text of the labels to add clarity to the safe use of the
drug, but without expanding, explicitly or implied, the claims of the drug.
2.3.3 Level II – Notifiable Change (Safety and Efficacy) that are not risk/harm
management changes
There are some Level II - Notifiable (Safety and Efficacy) changes that do not meet
the criteria of a Level I - Supplement or a risk/harm management change of a Level II
- Notifiable (Safety and Efficacy), but for which prior approval by CDSCO is required.
Examples include but are not limited to the following:
 Changes to the text related to the Overdose section (e.g., additional overdose
symptoms or treatments).
 Changes made to the text of the Pharmacology, Microbiology, Toxicology

sections of the Package Insert, except where criteria for Level II – Notifiable
(Safety and Efficacy) risk/harm management changes are met.
 A new drug interaction or pharmacokinetic study has been added, or has been
better characterized with no risk/harm identified and does not expand the claim
of the drug, explicitly or implied.
 The addition of data or modification of text, other than Level I - Supplements,
Level II – Notifiable (Safety and Efficacy) that are risk/harm management
changes or Level III changes, that does not result in any other changes to the
information provided to the Health Care Professional or patient/consumer. For
these changes, the applicant is not seeking a statement that may be interpreted
as a new claim.
2.3.4 Level III (Safety and Efficacy) Changes – Annual Notification
A Level III change is defined as any change to the label that is not expected to
impact the safety, efficacy, and/or effective use of the drug. The changes included in
this reporting category may be implemented by the applicant without prior review by
CDSCO of the data supporting such a change. Any data that may have been
generated by the MA holder in support of a Level III change should be submitted to
DCGI within 30 calendar days, upon request.
Examples of Level III related changes include but are not limited to the following:
 The existing text of the labels have been revised to add clarity and maintain
consistency with common label phrase standards (e.g., change from "Product
labelling information available on request" to "Product labelling information
available to health care professional on request",
 change from "Not recommended for children" to "Not for use in children".
 Revisions to Product labelling to standardize text in each of the following
sections: Overdose, Missed Dose, How to Store It or Reporting Suspected Side
Effects.
 Any change in spelling of the text of the label (e.g.,"adition" is replaced by
"addition").
 Updating bar codes and technical codes,

 Removing graphics,
 Removing non-regulatory label information,
 Changing colour of graphics where there is no text overlay or changing colour
of company logo,
 Updating contact information (e.g., customer service number, website
addresses, etc.).
2.3.5 Documentation – Safety and Efficacy Changes:
For a change under these categories (Safety and Efficacy), the MA holder should
submit an application to CDSCO that may include but is not limited to;
 a detailed description and rationale of the proposed change;
 a summary of the methods used and studies performed to evaluate the effect
of the change on the biological products safety or efficacy;
 amended product labelling information;
 clinical studies (protocol, statistical analysis plan, clinical study report and
Periodic Safety Update Report (PSUR) data or bioequivalence trials,
pharmacokinetic studies, pharmacodynamic studies, epidemiological data,
pharmacovigilance studies, review reports/analysis of specific safety
concerns, if applicable);
 the risk management plan/pharmacovigilance plan or patient registry data.
 Other data that may be relevant to the submission. Real world information
regarding drug use, declarations/attestations, opinion papers, conference
presentations, publications in peer-reviewed scientific journals and drug
utilization information.
 Pre-submission meeting minutes or other written feedback, if applicable.
2.4 Administrative Product Labelling Information Changes
Administrative product labelling information changes are changes that are not
expected to affect the safe and efficacious use of the biological product. In some
cases, these changes may require reporting to the CDSCO and receipt of approval
prior to implementation, while in other cases reporting may not be required, as

follows:
 Examples of product labelling information changes that require approval by the
CDSCO prior to implementation are changes in the name of the MA holder that
are due to a merger or changes in the proper name or trade name of the
biological product. The changes in this category are considered important for
reasons of liability and monitoring.
o Product labelling changes submitted along with the MA transfer or license
amendment application, to the CDSCO, may not require separate
reporting.
 Examples of product labelling information changes that do not require approval

by the CDSCO prior to implementation are changes to a distributor’s address or
minor changes in format. These changes should be reported to the CDSCO as
part of subsequent safety and efficacy changes or product labelling information
changes when updated product labelling information is included.
For an administrative product labelling information change that requires approval

prior to implementation, the MA holder should submit an application containing
background information on the change and annotated and clean drafts of the product
labelling information. The review and approval timeline for an administrative product
labelling information change shall be around 30 days from the date of submission.
3. SPECIAL CONSIDERATIONS
3.1 Comparative Studies
The need for – and extent of – a comparability exercise depends upon the potential
impact of the change(s) on the quality, safety and efficacy of the product.
Comparability exercises can range from analytical testing alone (for example, where
process changes have no impact on any quality attribute) to a comprehensive
exercise requiring nonclinical and clinical bridging studies. For example, a change in
the culture conditions or in the purification process may cause the alteration of the
glycosylation profile of the product, including site directed glycosylation. Alteration of
glycosylation profiles may cause a change in the pharmacokinetic/
pharmacodynamic (PK/PD) profile of the product (see also section 3.2 on Bridging
Clinical Studies). If comparability can be demonstrated through analytical studies
alone, then, nonclinical or clinical studies with the post change product are not
necessary. However, where the relationship between specific quality attributes and
safety and efficacy has not been established, and/ or differences are observed
between some critical quality attributes of the pre-change and post-change product,
it may be necessary to include a combination of quality, nonclinical and/or clinical
studies in the comparability exercise.
3.2 Bridging Clinical Studies
A number of changes outlined in this guidance document include

recommendations for supporting by bridging clinical studies.
Clinical bridging studies are trials in which a parameter of interest (e.g.

manufacturing process, formulation, dosing schedule) is directly compared with a
changed version of that parameter with respect to the effect of the change on the
product’s clinical performance. Comparison of immune responses and safety
outcomes (e.g. rates of common and serious AEFIs) are often the primary
objectives. If the immune response and safety profiles are similar, the safety and
efficacy of the vaccine can be inferred.
If the physicochemical properties, biological activity, purity and/or level of impurities

of the pre-change and post change product are comparable, the safety and efficacy
of the biotherapeutics product can be inferred. However, nonclinical and/or clinical
bridging studies may be required when analytical data alone either do not establish
comparability or are insufficient to do so. The comparison of efficacy responses and
safety outcomes (for example, PK/PD profile, or rates of common adverse events
and serious adverse events) is often the primary objective.
a) For ethical reasons, it is desirable to apply the 3R principles (Replacement,
Reduction, Refinement) to the use of animals where scientifically appropriate.
The following are examples of changes that are likely to require nonclinical
and/or clinical bridging studies: generation of a new MCB derived from a
different host cell line;
b) a new dosage form;

c) a new formulation (for example, a new excipient);
d) a new presentation (for example, addition of pre-filled pens to vials); (e) a new
route of administration; and
e) a new dosing schedule
For these and comparable changes, any proposed use of alternative approaches to
a bridging study must be justified and discussed with CDSCO
In some cases, safety and efficacy data comparing the approved vaccine to the
vaccine produced with the change (bridging studies) may be required. The following
are examples of manufacturing changes that may require clinical bridging studies:
 use of a new or re-derived antigen (i.e. re-derived virus seed or bacterial cell
bank) or host cell line (i.e. re-derived master cell bank);
 new agents used for inactivation or splitting of the antigen;
 a new dosage form (e.g., lyophilized powder to liquid, Intramuscular to
Subcutaneous, oral to injectable).
 a new formulation (e.g. amount of ingredients, adjuvants, preservatives,
reactogenic residual components from the manufacturing process).
MA holders should consult the applicable “The New Drugs and Clinical Trials
Rules, 2019”, ICH and WHO guidance documents when conducting clinical
bridging studies.
3.3 Stability Testing
If stability studies are recommended to support a change, these studies should be

conducted in accordance with applicable CDSCO, ICH and WHO guidance
documents,
a. The New Drugs and Clinical Trials Rules, 2019
b. Stability Testing of New Drug Substances and Products (Q1A)
c. Stability Testing: Photostability Testing of New Drug Substances and Products
(Q1B)
d. Stability Testing for New Dosage Forms (Q1C)
e. Bracketing and Matrixing Designs for Stability Testing of New Drug
Substances and Products (Q1D)

f. Evaluation of Stability Data (Q1E)
g. Stability Testing of Biotechnological/Biological Products (Q5C)
h. Guidelines on stability evaluation of vaccines. In: WHO Expert Committee on
Biological Standardization: Fifty-Seventh report. Geneva: World Health
Organization; 2011: Annex 3 (WHO Technical Report Series, No. 962).
3.4 Pharmaceutical Development and Quality by Design
The International Council for Harmonization (ICH) has developed two guidelines,
Q11 Development and Manufacture of Drug Substances (Chemical Entities and
Biotechnological/Biological Entities) and Q8: Pharmaceutical Development and Q8
Annex which describe respectively the suggested contents for the 3.2.S.2.2 to
3.2.S.2.6 sections and for the 3.2.P.2 Pharmaceutical Development section of a
regulatory submission in the Common Technical Document (CTD) format.
The Pharmaceutical Development section is intended to provide a comprehensive

understanding of the product and manufacturing process for reviewers and
inspectors.
The aim of pharmaceutical development is to design a quality product and its

manufacturing process to consistently deliver the intended performance of the
product. The information and knowledge gained from pharmaceutical development
studies and manufacturing experience provide scientific understanding to support the
establishment of the design space, specifications, and manufacturing controls.
Design space is proposed by the applicant, and is subject to regulatory assessment

and approval. Working within the design space is not considered as a change that
would require prior approval but should be documented with the requisite Change
Controls where necessary.
Movement outside of the design space is considered to be a change and would

normally initiate a regulatory post approval change process.
For example, some of the Post Approval Changes that are listed in Post-Approval
Changes (Biologics) of this guidance document as Level I ‐ Supplements (Major
Quality Changes) or Level II ‐ Notifiable Changes (Moderate Quality Changes) may

not require approval prior to implementation if they are within the approved design
space.
If desired, a MA holder may also establish a new design space for an existing
product. This would provide the advantage, once approved, of limiting the necessity
to file future submissions for changes within the ranges of the design space.
If proposed and approved, the details of the design space should be recorded in the
PPD. MA holders are encouraged to discuss with CDSCO when considering the
establishment of a design space.
3.5 Multiple Changes
Multiple related changes, involving various combinations of individual changes, may

be submitted in the same supplement. For example, a manufacturing site change
may also involve changes to the equipment and manufacturing process. For
submissions that include multiple changes, the marketing authorization holder should
clearly specify which data support each change. Multiple major or moderate quality
changes for the same product may be filed in a single submission provided that the
changes are related and/or supported by the same information. Minor quality
changes that were implemented previously and that are related and/or consequential
to a moderate or major quality change should be described in the Supplement
change for the moderate or major quality change. If the proposed changes are
related, the marketing authorization holder should indicate the association between
them. The marketing authorization holder should also clearly specify which
supporting data support which change. Such changes could affect both the drug
substance and the drug product. If too many changes are filed within the same
submission, or if major issues are identified with a change and extensive time would
be required to review them, the CDSCO may ask the marketing authorization holder
to divide the changes into separate submissions and to resubmit the file. If the
recommended reporting categories for the individual changes differ, the submission
should be in accordance with the most restrictive of the categories recommended for
the individual changes. In the case of numerous changes of the same category, the
CDSCO may reclassify the submission to the next higher level on the basis of the
potential impact of the totality of the changes on the quality, safety and efficacy of
the product. This reclassification should be communicated to the marketing
authorization holder at the start of the assessment.
In case where an identical change is applicable to multiple drugs, a single

submission may be submitted capturing the impacted products in the cover letter and
supported with appropriate data.
3.6 Post-Approval Change Management Protocol-PACMP
Post-approval change management protocol (PACMP) establishes a framework for a

well-defined plan for the future implementation of a quality change, including the
tests to be done and acceptable limits to be achieved to demonstrate the lack of
negative effect of specific manufacturing changes on the quality, safety or efficacy of
a biological product. A comparability protocol is a highly specific plan for the future
implementation of a quality change.
For some changes, the routine quality tests performed to release the drug substance
or drug product are not considered adequate for assessing the impact of the change,
and additional in-process tests and characterization tests may be needed (e.g.
addition of bioburden and endotoxin tests to support the removal of preservatives
from the manufacturing process). Comparability protocols are often used for routine
replenishment of WCBs and reference standards used in quality control tests when
the remaining aliquots of reference standards expire or diminish.
Comparability can be demonstrated for a particular step/stage of manufacture (eg.

Upstream manufacturing change could be evaluated within the drug substance
manufacturing stage). For such approach of comparability scientific justification
should be provided without generating drug product data for comparability.
The purpose of a comparability protocol is to allow for a more expedient distribution

of a product by permitting the MA holder to submit a protocol for a change which, if
approved, may justify a reduced reporting category for the change when the
comparability data are obtained and the change is implemented.
3.7 Production Documents
Production documents (i.e. executed lot records) or topics related to GMP are in
general not required to support changes to the MA dossier or product license.
However, such documents may be requested and should be available during site
GMP inspections.
3.8 Expedited Review Procedure (Reliance Pathway)
Expedited review/Reliance pathway can be considered in Biological products for

priority diseases to treat serious or life-threatening illness with unmet medical needs,
in public health emergencies or during shortages, and also for orphan products.
The CDSCO office could recognize the decision of recognized regulatory authorities
(Reference NRA) and may expedite the review of the change submission on case by
case basis, once the change is submitted through expedited review / reliance
pathway procedure.
The CDSCO office performs an assessment of the decision of the recognized

regulatory authority to determine if recognition of that recognized regulatory authority
decision is appropriate. The submission consists of:
 the cover letter from the MA holder informing the procuring NRA about the
change;
 a copy of the approval letter and assessment report issued by recognized
reference country;
 a detailed description of the change along with supporting data.
If accepted, the review and approval timeline shall be expedited.
3.9 Similar Biotherapeutic Products (SBP) / Similar Biologics
Following approval, an SBP is considered to be independent from the reference

product and has its own life-cycle. The manufacturer is not required to re‐establish
similarity to the reference product when comparability exercises are conducted.
A major change in clinical use for an SBP that relies on the previously demonstrated
similarity provided in the original approval of the SBP may be considered by CDSCO
on a case-by-case basis. For example, a new indication given to the reference

product after approval of an SBP should not automatically be given to the SBP.
However, when new safety information on the reference product is added after the
original approval of the SBP, the labelling information changes of the SBP should
follow the changes made for the reference product unless it can be demonstrated
that the new information on the reference product is not relevant to the SBP.
4. POST APPROVAL CHANGES (BIOLOGICALS)
The change examples presented below are intended to as sist wit h the
classification of changes made to the Quality, Safety, Efficacy and administrative
information of biological products. The information summarized in the tables provides
recommendations for:
a. The conditions to be fulfilled for a given change to be classified under reporting
category as a either a Level I - Supplement, a Level II - Notifiable Change, or a
Level III - Annual Notification.
b. The supporting data for a given change, either to be submitted to the CDSCO
and/or retained as part of the drug product’s record by MA holder. If any of the
supporting data outlined for a given change are not provided, are different or are
not considered applicable, adequate scientific justification should be provided.
The supporting data should be provided in the appropriate sections of the CTD
modules and in the separate documents, wherever required.
3.2.S DRUG SUBSTANCE
3.2.S.1 General Information

Conditions
Supporting Reporting
Description of Change to be
Data Category
Fulfilled
1. Change in the name of the
drug substance,
(e.g, change in name of drug
substance for seasonal influenza
Annual
vaccine, Covid-19 vaccine, change 1 1-3
Notification
in compendial name of drug
substance, or change from in-house
to compendial name of the drug
substance)
Conditions
1. Confirmation that information on the drug substance has not changed as a result
of the submission (e.g., cross reference(s) should be provided to the previously
approved drug submission, quoting the date approved and approval number(s)).
Supporting Data
1. Product Monograph [e.g. Title Page, Storage and Stability (Part I), Dosage Forms,
Composition, Packaging] and Revised product labelling information (Inner and
Outer Labels), as applicable.
2. Information on the changed nomenclature of the drug substance (e.g.,
Recommended INN, compendial name, chemical name(s)) (3.2.S.1.1).
3. Evidence that the changed name for the drug substance is recognized (e.g., proof
of acceptance by WHO, a copy of recommended INN, USAN, BAN).
3.2.S.2 Manufacture
Conditions
Data Category
Fulfilled
2. Change to a drug substance manufacturing facility / suite or site / premises
including DS testing sites (release, stability, etc.) involving:
a. Replacement or addition of
manufacturing facility / suite in a
new geographical site / premises 1-6, 8-12,
11 Supplement
and / or manufacturer of the drug 15, 16
substance, or any intermediate of
the drug substance
Note: MA holder shall submit MA application in Form CT-21/Form CT-18 in SUGAM
with applicable fees along with supporting documentation as described for the post
approval change category, for addition of manufacturer or for addition of
manufacturing facility/suite, for a drug substance, in a new geographical site/
premises. CDSCO will issue a No Objection Certificate for obtaining an amendment /
endorsement of the current Form 28 D license, as applicable.
A declaration to state that no change to other remaining section/s of the MA dossier,

including impact on safety/efficacy, shall be submitted, as applicable.
b. replacement or addition of
manufacturing facility / suite to
manufacture drug substance or 1-6, 8-12, Notifiable
1-6
any intermediate of the drug 15, 16 Change
substance in existing
manufacturing site / premises
c. conversion of a drug substance
Notifiable
manufacturing facility / suite from 4, 5 11, 12, 15
Change
single-product to multi-product
d. Conversion of production and 5, 7 13, 15 Notifiable
Conditions
Data Category
Fulfilled
related area(s) from campaign to Change
concurrent for a multiproduct
facility / suite
e. introduction of yeasts/bacterial
cell culture into a multi-product Notifiable
3-5 11-13, 15
microbial fermentation facility / Change
suite
f. Introduction of microbial hosts into
a multi‐product mammalian cell None 12, 14 Supplement
culture facility / suite or vice versa
g. introduction of a different
Annual
host/media-type into an approved 8 7, 15
Notification
multi-product facility / suite.
h. addition of product(s) to an
Annual
approved multi - product 4, 5, 8 12, 13
Notification
manufacturing suite / facility.
i. deletion of a manufacturing facility
/ suite or manufacturer for a Annual
9, 10 None
starting material, bulk Notification
intermediate, or drug substance.
Conditions
1. The proposed manufacturing facility/suite is a CDSCO approved drug substance
manufacturing site / premises for the same MA holder.
2. No changes have been made to the validated manufacturing process and
controls, and identical or equivalent equipment are used.
3. The production process and controls are the same as those used by the. MA
holder within the existing approved facility.
4. No changes have been made to the approved and validated cleaning and
change-over procedures.
5. The proposed change does not involve additional containment requirements.
6. The facility / suite or site / premises is under same Quality system oversight
7. The manufacturing process is a closed process for shared areas.
8. No changes to the cleaning protocol are necessary to support the introduction of
new products (no changes in acceptance criteria, and no new materials have
been introduced that need to be evaluated for clearance in a cleaning step
9. There should remain at least one site/manufacturer, as previously authorized,
performing the same function as the one(s) to be deleted.
10. The deletion should not be due to critical deficiencies in manufacturing (for
example, recurrent out-of-specification events, environmental monitoring failures,
etc.).
11. No changes have been made to the starting material and the expression system
Supporting Data
1. Updated or relevant DMF (CMC Module 3 Quality) data of drug substance.
(3.2.S)
2. Name, address, and responsibility of the changed production facility or facility
involved in manufacturing and testing. (3.2.S.2.1)
3. For drug substances obtained from or drug substances manufactured with
reagents obtained from sources that are at risk of transmitting BSE/TSE agents
(e.g., ruminant origin), information and evidence that the material does not pose a
potential BSE/TSE risk (e.g., name of manufacturer, species and tissues from
which the material is a derivative, country of origin of the source animals, its use
and previous acceptance). A TSE Certificate of Suitability (CEP) from a qualified
laboratory, if available, is acceptable for raw materials, auxiliary materials, and
reagents only. This is also applicable for substances used in conjugation or
linkages processes. (3.2.S.2.3)
4. Information on the controls performed at critical steps of the manufacturing
process and on the intermediate of the changed drug substance, if revised
(3.2.S.2.4).
5. Process validation and/or evaluation studies (e.g., for aseptic processing and
sterilization). (3.2.S.2.5).
6. Comparability of the approved and changed product with respect to physico–
chemical characterization, biological activity, impurity profile, comparability of the
equipment and operating principles for the manufacturing processes including
technology transfer documentation as applicable for the product at the existing vs
the proposed new facility/suite (3.2.S.2.6). (Occasionally, the manufacturer may
be required to undertake bridging non-clinical or clinical studies, to support the
quality data, when quality data is insufficient to establish comparability)
7. Information on the in-process control testing to demonstrate lack of carry-over or
cross-contamination (3.2.S.2.2).
8. Description of the batches, certificates of analyses, summary of in-process
control results and summary of results as quantitative data, in a comparative
tabular format, for at least three (3) commercial scale batches of the approved
and changed drug substance Matrixing, bracketing, use of smaller-scale batches,
use of fewer than three batches and/or leveraging data from scientifically justified
representative batches, or batches not necessarily manufactured consecutively,
may be acceptable where justified (refer ICH Q1D) (3.2.S.2.5 & 3.2.S.4.4)
9. Results of a) accelerated stability testing (usually a minimum of three (3) months)
and b) a minimum of three (3) months of real time/real temperature testing on
three (3) commercial scale batches of the proposed changed drug substance, as
well as commitment to submit the stability report when completed and to notify
CDSCO of any failures in the ongoing stability studies (3.2.S.7.3). Matrixing,
bracketing, the use of smaller scale batches and use of fewer than 3 batches for
stability testing of proposed changed drug substance may be acceptable if
scientifically justified (refer ICH Q1D) by the manufacturer /MA holder to CDSCO.
10. Updated post-approval stability protocol and stability commitment to place the
first production scale batch of the drug product manufactured using the changed
drug substance into the stability programme, as applicable (3.2.S.7.2).
11. Information on the changed production facility involved in manufacturer of Drug
substance, including the complete set of floor plans and flow charts (drawings,
room classification, water systems, HVAC systems), as well as the cleaning and
shipping validation, as appropriate. (3.2.A.1)

12. Information describing the change-over procedures for shared product contact
equipment’s and the segregation procedures, as applicable. If no revisions, a
statement from the manufacturer that no changes were made to the change-over
procedures.
13. Data demonstrating lack of carry-over or cross-contamination
14. Results of the environmental monitoring studies in critical classified areas.
15. Information on the cleaning procedures (including data in a summary validation
report and the master cleaning protocol for the introduction of new products, as
applicable) demonstrating lack of carry over or cross contamination
16. Evidence of GMP compliance of the facility
Conditions
Data Category
Fulfilled
3. Change/Modification in a facility/ premises involved in the manufacture of a
drug substance, such as:
a. for an active ingredient
manufactured in an open system,
Notifiable
any changes which affect the None 1, 2, 5
Change
trends or action limits of the
environmental monitoring program
b. relocation of equipment to another
room in the same facility/suite/
premises or another approved
Annual
facility / suite/ premises, 1-3 3-5
Notification
Qualification of a new room or
change in classification of an
existing room
c. Modification to a manufacturing Annual
1, 2 3-5
area or to an existing service / Notification
Conditions
Data Category
Fulfilled
system (e.g., change to WFI
systems or HVAC systems,
moving a wall).
d. change in the location of steps in
Annual
the production process within the 1 1, 4, 5
Notification
same facility
Conditions
1. The change in the location of steps has no impact on the risk of contamination or
cross-contamination and is supported by validated cleaning procedures.
2. The modification has no direct product impact.
3. Re-qualification of the equipment follows the original qualification protocol, if
applicable.
Supporting Data
1. Information on the in-process control testing (3.2.S.2.2).
2. Process validation and/or evaluation studies or the proposed validation protocol
of the changed drug substance, including technology transfer validation,
equipment qualification, as appropriate (3.2.S.2.5).
3. Information demonstrating re-qualification of the equipment or re- qualification of
the change (operational qualification, performance qualification), as appropriate.
(3.2.A.1)
4. Information on the modified production facility/area involved in manufacturing,
including the floor plans and flow charts (drawings, room classification, water
systems, HVAC systems). (3.2.A.1)
5. Results of the environmental monitoring studies in critical classified areas.
Conditions to Supporting Reporting

Description of change
be fulfilled data category
4. Change to the drug substance fermentation, viral propagation or
Conditions
Data Category
Fulfilled
cellular propagation process, involving:
a. a critical change with high
potential to have an impact on the
quality of the antigen / drug
None 1-5, 7-11 Supplement
substance or final product (e.g.
incorporation of disposable
bioreactor technology)
b. a change with moderate potential
to have an impact on the quality of
the drug substance or final 1-5, 7, 8, 12, Notifiable
2, 4
product (e.g. extension of the in- 13 Change
vitro cell age beyond validated
parameters)
c. a non-critical change with minimal
quality of the drug substance or
drug product, such as
(e.g., change in harvesting and/or
pooling procedures which does
not affect the method of
Annual
manufacture, recovery, storage 1-5, 7-10, 12 1-6, 8, 12
Notification
conditions, sensitivity of detection
of adventitious agents, or
production scale; or duplication of
a fermentation train; or addition of
identical or similar / comparable
bioreactors).
Conditions
Data Category
Fulfilled
5. Change to the drug substance purification process involving:
a. a critical change (a change with
high potential to have an impact
on the quality of the drug
substance or final product)
(e.g. a change that could None 1-3, 5, 7-11 Supplement
potentially have an impact on the
viral clearance capacity of the
process or the impurity profile of
the drug substance)
b. a change with moderate potential
to have an impact on the quality of
the drug substance or final
product 1-3, 5, 7-9, Notifiable
2, 4
(e.g. a change in the chemical 11, 13 Change
separation method, such as ion-
exchange HPLC to reverse-phase
HPLC)
c. a noncritical change with minimal
quality of the drug substance or Annual
1-5 1-3, 6, 8, 12
final product (e.g. addition of an Notification
in-line filtration step equivalent to
the approved filtration step)
6. Change in scale of the manufacturing process:
a. at the fermentation, viral
3-5, 8, 9, 11, Notifiable
propagation or cellular 2, 4, 7-10
12 Change
propagation stage
Conditions
Data Category
Fulfilled
Notifiable
b. at the purification stage 1-3, 5, 9 2, 7-10
Change
7. Change in the parameters of an
Notifiable
approved holding step or none 7, 14
Change
addition of a new holding step
Conditions
1. The change does not concern the method of sterilization of a sterile drug
substance.
2. The change does not impact the viral clearance data or the source of a chemical
nature of an inactivating agent.
3. No change in the drug substance specifications outside of the approved limits.
4. No change in the impurity profile of the drug substance outside of the approved
limits.
5. The change is not necessitated by unexpected events arising during manufacture
or because of stability concerns.
6. The change does not result in a change to the drug substance specification.
7. The scale-up consists in the addition of identical bioreactors/fermenter or new
fermentation train is identical to the to the approved fermentation train(s)
8. The change does not affect the purification process.
9. The scale-up is linear with respect to proportionality of production parameters
and raw materials.
10. No change in the approved in-vitro cell age
11. The change is not expected to have an impact on the quality, safety or efficacy of
the final product
12. The change in scale involves the use of the same bioreactor (i.e., does not
involve the use of a larger bioreactor)
Supporting Data
1. Justification for the classification of the change(s) as critical, moderate or non-

critical as it relates to the impact on the quality of the antigen/drug substance.
2. Flow diagram (including process and in-process controls) of the changed

manufacturing process(es) and a brief narrative description of the changed
manufacturing process(es) (3.2.S.2.2).
3. Information on the quality and controls of the materials (e.g., raw materials,
starting materials, solvents, reagents, catalysts) used in the manufacture of the
changed drug substance when there is change in the raw material (3.2.S.2.3)
4. If the change results in an increase in the number of population doublings or

subcultivations, information on the characterization and testing of the post-
production cell bank for recombinant product, or of the drug substance for non-
recombinant product. (3.2.S.2.3)
5. For drug substances obtained from or manufactured with reagents obtained from
sources that are at risk of transmitting BSE/TSE agents (e.g., ruminant origin),
information assessing the risk with respect to potential contamination with
adventitious agents and evidence that the material does not pose a potential
BSE/TSE risk, and there is no impact on the viral clearance studies(e.g., name of
manufacturer, species and tissues from which the material is a derivative, country
of origin of the source animals, its use and previous acceptance) (3.2.S.2.3).

process and on intermediates of the changed drug substance (3.2.S.2.4).
sterilization, new reprocessing step, new or revised holding step) (3.2.S.2.5).
8. Comparability of the approved and changed product with respect to physico-

chemical characterization, biological activity, and impurity profile. Occasionally,
bridging non-clinical and/or clinical studies may be required when quality data are
insufficient to establish comparability. The extent and nature of nonclinical and/or
clinical studies should be determined on a case-by-case basis taking into
consideration the quality comparability findings, the nature and level of the
knowledge of the biological, existing relevant nonclinical and clinical data, and
aspects of biological use (3.2.S.2.6).
9. Description of the batches, certificates of analyses, and summary of in-process

and release testing results as quantitative data, in a comparative tabular format,
for at least three (3) commercial scale batches of the approved and changed drug
substance (3.2.S.2.5 & 3.2.S.4.4). Matrixing, bracketing, the use of smaller scale
batches, and/or the use of less than 3 batches may be acceptable where justified
(refer ICH Q1D)
10. Results of accelerated (usually a minimum of three (3) months) and a minimum of
three (3) months of real time/real temperature testing on three (3) commercial
scale batches of the changed drug substance as well as commitment to submit
the stability report when completed and to notify CDSCO of any failures in the
ongoing stability studies (3.2.S.7.3). Matrixing, bracketing, the use of smaller
scale batches and use of fewer than 3 batches for stability testing of proposed
changed drug substance may be acceptable if scientifically justified (refer ICH
Q1D).
first production scale batch of the drug product manufactured using the changed
drug substance into the stability programme, as applicable (3.2.S.7.2).
12. Description of the batches and summary of in-process and release testing results
as quantitative data, in a comparative tabular format, for one (1) commercial
batch of the approved and proposed drug substance (3.2.S.2.5 & 3.2.S.4.4)
13. Comparative pre and post-change test results for the manufacturer’s
characterised key stability indicating attributes with at least one (1) commercial
scale batch produced with the proposed changes under real time/real
temperature testing conditions. Comparative pre-change test results do not need
to be generated concurrently; relevant historical results for lots on the stability
programme are acceptable. The data should cover a minimum of 3 months
testing unless otherwise justified (3.2.S.7.3)
14. Demonstration that the new or revised holding step has no negative impact on
the quality of the drug substance (data from one scientifically justified
representative drug substance batch should be provided). (3.2.S.2.5)
Conditions
Data Category
Fulfilled
8. Changes to the cell bank:
a. generation of new Master Cell
Bank (MCB) from the same Notifiable
1 1, 5-8
expression construct with same or Change
closely related cell line; or
generation of a new MCB from a

different expression construct with
the same coding sequence and
None 1-8 Supplement
the same cell line, or
adaptation of a MCB into a new

fermentation medium.
b. generation of a new MCB for a
Notifiable
recombinant product or a viral 1 1-3, 5-7
Change
vaccine
c. generation of a new Working Cell Annual
2-4 1, 2
Bank (WCB) Notification
d. Extension of Shelf-life of the MCB Annual
7 1, 2
or WCB Notification
9. Changes to the Seed Bank/Lot:
a. new Master Seed Bank/Lot
None 1, 3-8 Supplement
(MSB/MSL).
b. Working Seed Bank/Lot
Notifiable
(WSB/WSL) extended beyond an None 3-8
Change
approved passage level.
Annual
c. Generation of a new WSB/WSL. 2-4 3, 4
Notification
Conditions
Data Category
Fulfilled
10. Change in cell bank / seed Notifiable

None 1, 2, 9
bank/lot manufacturing site Change
11. Changes in cell bank / seed Annual
5, 6 9
bank/lot testing / Storage site Notification
Notifiable
None 10, 11
12. Change in cell bank / seed Change
bank/lot qualification protocol Annual
6, 8 11
Notification
Conditions
1. The new MCB is generated from the original clone or a pre-approved Master or
Working Cell Bank or the new MSL is generated from a pre-approved MSL or
WSL.
2. The new cell/seed bank is generated from a pre-approved MCB/MSB/pre-master
bank/parent strain.
3. The new cell/seed bank is at the pre-approved passage level.
4. The new cell/seed bank is released according to a pre-approved protocol.
5. No changes have been made to the test or acceptance criteria used for the
release of cell bank/ seed lot.
6. No changes have been made to the storage conditions used for the cell
bank/seed lot and transport conditions of the cell bank/ seed lot has been
validated.
7. The testing to support the extension of shelf‐life is performed according to the
pre‐approved protocol.
8. The protocol is considered more stringent (that is, addition of new tests or
narrowing of acceptance criteria).
Supporting Data
1. Qualification of the cell bank or seed lot. (3.2.S.2.3)
2. Information on the characterization and testing of the post-production cell bank

for recombinant product, or of the product for non-recombinant product.
(3.2.S.2.3)
3. Comparability of the approved and changed product with respect to physico-
chemical characterization, biological activity, and impurity profile
4. Description of the batches, certificates of analyses, and summary of results as
quantitative data, in a comparative tabular format, for the new seed lot
(3.2.S.2.3).
and release testing results as quantitative data, in a comparative tabular format,
for at least three (3) commercial scale batches of the drug substance derived
from the new cell/seed bank (. Matrixing, bracketing, the use of smaller-scale
batches, and/or the use of fewer than 3 batches may be acceptable where
justified (refer ICH Q1D) (3.2.S.2.5 & 3.2.S.4.4).
6. Results of accelerated (usually a minimum of three (3) months) and a minimum of
three (3) months of real time/real temperature testing on three (3) commercial
scale batches of the proposed changed drug substance as well as commitment to
submit the stability report when completed and to notify CDSCO of any failures in
the ongoing stability studies (3.2.S.7.3). Matrixing, bracketing, the use of smaller-
scale batches, the use of fewer than 3 batches and/or use of accelerated
temperature conditions for stability testing may be acceptable where justified
(refer ICH Q1D).
first production scale batch of the drug product using the changed drug
substance into the real time/real temperature stability programme (3.2.S.7.2).
8. Supporting non-clinical and clinical data or a request for a waiver of in-vivo
studies.
9. Evidence that the new company or facility is GMP compliant.
10. Justification of the change to the cell bank/seed lot qualification protocol
(3.2.S.2.3)
11. Updated cell bank/seed lot qualification protocol (3.2.S.2.3)

Description of Change
be Fulfilled Data Category
13. Change in product-contact equipment / material used in drug substance
manufacturing process, such as:
a. Introduction of equipment having Notifiable
None 1-3, 5-7
different operating principles / Change
properties and different product Annual
1-3 1-3, 7
contact material Notification
b. Introduction of new equipment Notifiable
None 1, 5-7
having same operating principles / Change
properties but different product Annual
1-3 1, 3, 6, 7
contact material Notification
c. Introduction of new equipment Notifiable
None 1, 2, 5, 7
having different operating Change
principles/ properties but same Annual
3 1-3, 5, 7
product contact material Notification
d. Replacement of product contact
Annual
equipment for an identical/ 6 1, 3, 5, 7, 8
Notification
equivalent equipment.
e. product‐contact equipment change Annual
4, 5 1, 4
from dedicated to shared Notification
Conditions
1. The change does not affect equipment used in the Fermentation process.
2. The manufacturing process is not impacted by the change in the product contact
equipment.
3. The change has no impact on product quality.
4. The site is approved as multi‐product facility by CDSCO.
5. The change has no impact on the risk of cross‐contamination and is supported by
validated cleaning procedures.
6. The change is considered “like for like” (e.g., change in supplier of the same
filter).
Supporting Data
1. Information on the in-process control testing. (3.2.S.2.2)
2. Process validation and/or evaluation studies or the proposed validation protocol
of the changed drug substance, including technology transfer validation, as
appropriate. (3.2.S.2.5)
3. Information on qualification or demonstrating re-qualification of the equipment or
re- qualification of the change
4. Information describing the change‐over procedures for the shared product‐
contact equipment.
5. Description of the batches and summary of results as quantitative data, in a
comparative tabular format, for one commercial scale batch of the drug
substance produced with the approved and proposed product contact
equipment/material. Batch data on the next two full-production batches should be
made available on request and reported by the MA holder if outside specification
(with proposed action). (3.2.S.4.4)
6. Information on leachables and extractables as applicable.
7. Information on the new equipment and comparison of similarities and differences
regarding operating principles and specifications between the new and the
replaced equipment
8. Demonstration that performance of the proposed equipment is equivalent to the
approved equipment (i.e. data from one batch)

14. Change in the specifications of materials, involving:
a. Change in supplier of auxiliary Notifiable
None 11, 12-15
materials / reagents of biological Change
origin (e.g., fetal calf serum,
Annual
insulin, human serum albumin, 16 11, 12
Notification
trypsin)
b. Change in source of auxiliary Notifiable
None 6, 11, 13-15
materials / reagents of biological Change
origin (e.g., fetal calf serum,
Annual
insulin, human serum albumin, 16 6, 11
Notification
trypsin)
c. raw materials/intermediates: Notifiable
None 1, 3, 4, 6, 7
widening of the approved Change
specifications limits for starting
materials, which may have a
Annual
significant effect on the overall 1-3, 12, 13 1, 3-7, 11
Notification
quality of the drug substance
and/or final product.
d. raw materials/intermediates:
Narrowing of the approved Annual
1, 2, 6, 7 1, 3-5, 7, 12
specification limits for starting Notification
materials/ intermediates
Annual
e. solvents, reagents, catalysts 1, 2, 7 1, 3-5
Notification
f. Change in raw materials testing Annual
6 10
site Notification
15. Change to the in-process tests and/or acceptance criteria applied during
the drug substance manufacturing process or on Intermediates, involving:
a. narrowing of in-process limits None 2, 12, 13 Notifiable

Change
Annual
1, 3, 8, 9 2, 7
Notification
b. replacement or addition of new Annual
2-5, 8-11 2-5, 7,8, 12, 13
in-process test Notification
c. deletion of a non-significant in- 1-3, 5, 8, 12, Annual
2, 7, 9, 12
process test 14, 15 Notification
d. widening of the approved in- Notifiable
None 2-8, 12, 13
process limits, which may have Change
a significant effect on the overall Annual
1-3, 12 2, 6-8
quality of the drug substance Notification
e. deletion of an in-process test
which may have a significant Annual
None 2, 6, 7, 8
effect on the overall quality of Notification
the antigen/drug substance
f. addition or replacement of an in-
Notifiable
process test as a result of a None 2-7, 8
Change
safety or quality issue
g. revision as per updated Annual
1, 2 2
pharmacopoeia Notification
16. Change in in-process control
testing site
Note: Transfer of in-process control
testing to a different facility within a
Annual
GMP-compliant site is not considered 1-3, 8, 11 10
Notification
to be a reportable change but is
treated as a minor GMP change (Level
IV) and is reviewed during inspections
Conditions
1. No change in the drug substance specifications outside of approved ranges,
except for revision as per updated pharmacopoeia.
2. No change in the impurity profile of the drug substance outside the approved
limits.
4. Any new analytical procedure does not concern a novel non-standard technique
or a standard technique used in a novel way.
5. The change does not affect the principle of sterilization of a sterile drug
substance.
6. The change in specification for the materials is within the approved limit except
for revision as per updated pharmacopoeia.
7. The grade of the materials is same or is of higher quality, where appropriate.
8. No change in the in-process controls outside the approved limits.
9. The test procedure remains the same, or changes in the test procedure are
minor.
10. The test method is not a biological/immunological/immunochemical or
physicochemical method or a method using a biological reagent (does not include
standard pharmacopoeial microbiological methods).
11. The replaced analytical procedure maintains or tightens precision, accuracy,
specificity and sensitivity, if applicable.
12. The test does not concern the critical attribute (e.g. content, impurity, any
physical characteristics or microbial purity.)
13. The change has no significant effect on the overall quality of the drug substance
and/or drug product and there are no changes to the cell banks
14. The deleted test has been demonstrated to be redundant with respect to the
remaining tests
15. The deleted test is not for a viral clearance/removal step
16. The change is for compendial auxiliary materials/reagents of biological origin

(excluding human plasma derived materials).
Supporting Data
1. Revised information on the quality and controls of the materials (e.g., raw
materials, starting materials, solvents, reagents, catalysts) used in the
manufacture of the changed drug substance (3.2.S.2.3).
2. Revised information on the controls performed at critical steps of the
manufacturing process and on intermediates of the changed drug substance
(3.2.S.2.4).
3. Updated specifications of the drug substance, if affected by the change
(3.2.S.4.1).
4. Copies or summaries of analytical procedures, if new analytical procedures are
used (3.2.S.4.2).
5. Copies or summaries of validation reports, if new analytical procedures are used
(3.2.S.4.3).
and release testing results (as quantitative data), in a comparative tabular format,
for at least three (3) commercial scale batches of the approved and changed drug
substance. (3.2.S.2.5 & 3.2.S.4.4). Matrixing, bracketing, the use of smaller-scale
batches, the use of fewer than three batches and/or leveraging data from
scientifically justified representative batches, or batches not necessarily
manufactured consecutively, may be acceptable where justified (refer ICH Q1D)
7. Comparative table or description, where applicable, of pre- and post-change in-
process tests/limits.
Results of accelerated and a minimum of three (3) months of real time/real
temperature testing on three (3) commercial scale batches of the proposed
changed drug substance are available as well as commitment to submit the
stability report when completed and to notify CDSCO of any failures in the
ongoing stability studies (3.2.S.7.3). Matrixing, bracketing, the use of smaller
changed drug substance may be acceptable if scientifically justified (refer ICH
Q1D) by the manufacturer /MA holder and agreed by CDSCO.
8. Justification for the new in-process test and limits.
9. Justification/risk assessment showing that the attribute is non-significant.

10. Evidence that new company/facility is GMP-compliant.
11. For drug substance obtained from, or manufactured with, reagents obtained from
sources that are at risk of transmitting bovine spongiform encephalopathy/
transmissible spongiform encephalopathy (BSE/TSE) agents (for example,
ruminant origin), information and evidence that the material does not pose a
potential BSE/TSE risk (for example, name of manufacturer, species and tissues
from which the material is a derivative, country of origin of the source animals,
use and previous acceptance of the material) (3.2.S.2.3)
and release testing results (as quantitative data), in a comparative tabular format,
for at least one (1) commercial batch of the approved and changed drug
substance. Batch data on the next two full-production batches should be made
available on request and reported by the MA holder if outside specification (with
proposed action). The use of a smaller-scale batch may be acceptable where
justified. (3.2.S.2.5 & 3.2.S.4.4)
13. Rationale for the change supported by data.
14. Information demonstrating comparability of the auxiliary materials/reagents or

starting materials of both sources
15. Information assessing the risk with respect to potential contamination with
adventitious agents (eg. Impact on the viral clearance studies, BSE/TSE risks)

17. Change in the approved design space, involving:
a. establishment of a new design
None 1 Supplement
space
b. expansion of the approved design
None 1 Supplement
space

c. reduction in the approved design
space (any change that reduces Annual
1 1
or limits the range of parameters Notification
used to define the design space
Conditions
1. The reduction in design space is not necessitated by recurring problems having
arisen during manufacture.
Supporting Data
1. Manufacturing development data to support the establishment or changes to the
design space (including changes to process parametric release for sterile
products) (3.2.S.2.6)
3.2.S.3 Characterization
There are not any quality change examples for this section at the present time that
have not
been addressed in other sections.
3.2.S.4 Control of the Drug Substance
Conditions
Data Category
Fulfilled
18. Change in the standard / monograph (i.e., specifications) claimed for the
drug substance, involving:
a. change from the Pharmacopoeial
Notifiable
standard or a monograph to an in- None 1-3, 5, 7
Change
house standard
b. change in the standard claimed for Notifiable
None 1-6
the drug substance (e.g., from in- Change
Conditions
Data Category
Fulfilled
house to pharmacopoeial standard)
or from one pharmacopoeial
Annual
standard/monograph to a 1-3 1-3
Notification
different/pharmacopoeial
standard/monograph
c. change in the specifications for the
drug substance to comply with an
updated pharmacopoeial
monograph
Note: Change in specifications and
Annual
analytical procedures for the drug 1, 2 1-3
Notification
substance to comply with an updated
pharmacopoeial monograph within 6
months of pharmacopoeia update
should be captured under Level IV
changes
Conditions
1. The change is made exclusively to comply with the (applicable) pharmacopoeia /
standard.
2. No change to the specifications for functional properties of the drug substance,
outside the approved ranges.
3. No deletion or relaxation to any of the tests, analytical procedures, or acceptance
criteria of the approved specifications except to comply with pharmacopoeial
standard / monograph.
Supporting Data
1. Revised product labelling information (Package Insert, Inner and Outer Labels),
as applicable.
2. Updated, copy of changed/proposed drug substance specifications (3.2.S.4.1).
3. Where an in-house analytical procedure is used and a standard is claimed,

results of an equivalency study between the In-house and compendial methods.
4. Description of the batches, certificates of analyses, and summary of results, in a
tabular format, for at least three (3) commercial scale batches of the changed
drug substance (3.2.S.4.4).
5. Justification of the changed drug substance specifications (e.g., demonstration of
the suitability of the monograph to control the drug substance, including
impurities) (3.2.S.4.5).
6. Demonstration that consistency of quality and of the production process is
maintained.
(3.2.S.4.3).

19. Changes in the control strategy of the drug substance, involving:
a. Change from end‐product testing
to upstream controls for some
test(s) (e.g., Real‐Time Release None 1-5 Supplement
Testing, process analytical
technology)
b. Addition of a new Critical Quality
Notifiable
Attribute (CQA) in the control None 1-5
Change
strategy
c. Deletion of a Critical Quality
Notifiable
Attribute (CQA) from the control None 1, 5
Change
strategy
Conditions:
None
Supporting Data
process and on intermediates of the proposed drug substance (3.2.S.2.4)

2. Updated, copy of the changed/proposed drug substance specifications (or where
applicable, the final version of the specifications to be signed by QC after
CDSCO approval), if changed (3.2.S.4.1)
used. (3.2.S.4.2)
4. Copies or summaries of validation reports, if new analytical procedures are used.
(3.2.S.4.3)
5. Justification and supporting data for each proposed change to the control
strategy.
Conditions
Data Category
Fulfilled
20. Changes affecting the quality control (QC) testing of the drug substance
(release and stability), involving:
a. transfer of the QC testing Notifiable
None 1, 2
activities for a non- Change
pharmacopoeial assay (in‐house)
to a new company/premises, to a
different facility within the same
company/premises or to a Annual
1-4 1, 2
different laboratory within the Notification
same facility not approved in the
current market authorization or
license.
b. transfer of the QC testing Notifiable
None 1, 2
activities for a pharmacopoeial Change
assay to a new Annual
2 1, 2
company/premises not approved Notification
Conditions
Data Category
Fulfilled
in the current market
authorization or license.
Conditions
1. The transfer involves the relocation of the equipment and laboratory staff to the
new laboratory or facility.
2. The transferred QC test is not a potency assay or a bioassay.
3. No changes are made to the test method.
4. The transfer is within a facility approved in the current marketing authorization for
the performance of other tests
Supporting Data
1. Information demonstrating technology transfer qualification for the non‐
pharmacopoeial assays or verification for the pharmacopoeial assays (3.2.S.2.5).
2. Evidence that the new company/facility is GMP compliant.
Conditions
Data Category
Fulfilled
21. Change in the test for Drug Substance at Release / Shelf life involving:
Notifiable
None 1, 6, 7
Change
a. deletion of a test
Annual
1, 7 1, 6
Notification
Notifiable
None 1-6
Change
b. replacement or addition of a test
Annual
1, 2, 8 1-3, 6
Notification
c. relaxation of an acceptance Notifiable
None 1, 6, 7
criterion Change
Conditions
Data Category
Fulfilled
d. tightening of an acceptance Annual
1, 2, 4, 9 1
criterion Notification
Conditions
2. The change is within the range of approved acceptance criteria.
3. Any new analytical procedure does not concern a novel, non-standard technique
4. Acceptance criterion for residuals are within recognized or approved acceptance
limits, e.g., within ICH limits for Class 3 residual solvent or pharmacopoeial
requirements.
5. The deleted analytical procedure has been demonstrated to be redundant with
respect to the remaining analytical procedures.
6. The change does not concern sterility testing.
7. The analytical procedure/test is deleted in-line with the updated pharmacopoeia /
Standard; or there is no change in the compliance status of applicable
pharmacopoeia / Standard (e.g. The deleted test is the Abnormal Toxicity
Test/General Safety Test).
8. The addition of test is not to monitor new impurity species.
9. The analytical procedures remain the same or changes to analytical procedure
are minor.
Supporting Data
1. Updated drug substance specifications (3.2.S.4.1).
used (3.2.S.4.2).
(3.2.S.4.3).
4. Where an in -house analytical procedure is used and a Pharmacopoeial standard
is claimed, results of an equivalency study between the In-house and compendial

methods.
tabular format, for at least three (3) commercial scale batches of the changed
drug substance (3.2.S.4.4).
6. Justification of the changed drug substance specifications (e.g., test parameters,
acceptance criteria, or analytical procedures) (3.2.S.4.5).
7. Documented evidence that consistency of quality and of the production process
is maintained.
Conditions
Data Category
Fulfilled
22. Change in the analytical procedures for the drug substance, involving
Notifiable
1 1, 5
Change
a. deletion of an analytical procedure.
Annual
1, 6 1, 5
Notification
Notifiable
None 1-5
b. replacement or addition of an Change
analytical procedure. Annual
5, 7, 8 1-5
Notification
c. minor changes to an approved Annual
1-3, 5, 8 1, 4, 5
analytical procedure. Notification
d. a change from an in-house
analytical procedure to a Annual
1, 5 1-3
Pharmacopoeial analytical Notification
procedure.
e. change in animal species/strains
Notifiable
for a test (e.g., new None 6, 7
Change
species/strains, animals of different
Conditions
Data Category
Fulfilled
age, new supplier where genotype
of the animal cannot be confirmed)
Conditions
1. No change in the acceptance criteria outside of the approved ranges.
2. The method of analysis is the same and is based on the same analytical
technique or principle (e.g., a change in column length or temperature, but not a
different type of column or method) and no new impurities are detected.
3. Results of method validation demonstrate that the proposed analytical procedure
is at least equivalent to the approved analytical procedure.
5. The change does not concern potency testing.
6. The analytical procedure is deleted in-line with the updated pharmacopoeia /
pharmacopoeia / Standard.
7. The change is from a pharmacopoeial assay to another pharmacopoeial assay.
8. The modified analytical procedure maintains or improves performance
parameters of the method.
Supporting Data
1. Updated drug substance specifications (3.2.S.4.1).
used (3.2.S.4.2).
(3.2.S.4.3).
4. Comparative results demonstrating that the approved and changed analytical
procedures are equivalent.
5. Justification of the changed drug substance specifications (e.g., test parameters,
acceptance criteria, or analytical procedures) (3.2.S.4.5).
6. Data demonstrating that the change in animals/strains give comparable results

with those obtained using the approved animals/strains.
7. Copies of relevant certificate of fitness for use (e.g., veterinary certificate).
3.2.S.5 Reference Standards or Materials

23. Change in reference standards or materials used to release the drug
substance, involving
a. qualification of a new reference Notifiable
None 1
standard Change
b. update the reference standards
from pharmacopoeial / Notifiable
None 1, 5
international standard to an in- Change
house
c. update the reference standards
from an in-house to Annual
2 1, 5
pharmacopoeial / international Notification
standard
d. Qualification of a new lot of
reference standard (except for a Annual
2 1, 5
bacterial or viral vaccine, Notification
bacterial toxin)
24. Qualification of a new lot of reference standard against the approved
reference standard for a bacterial or viral vaccine, bacterial toxin, involving:
a. reference standard used in a
qualitative test, physicochemical Annual
2 1
test, semi‐quantitative or Notification
quantitative biological assay
b. Change to reference standard Notifiable
None 3, 4
qualification protocol (except for Change

a bacterial or viral vaccine, Annual
4 3, 4
bacterial toxin) Notification
25. Change to reference standard qualification protocol for a bacterial or viral
vaccine, bacterial toxin, involving:
a. a reference standard used in a Annual
None 3, 4
qualitative test Notification
b. a reference standard used in a
physicochemical test, semi‐ Annual
4 3, 4
quantitative or quantitative Notification
biological assay.
26. Extension of reference
Annual
standard shelf-life / Re-test 3 2
Notification
period
Conditions
1. The in -house reference standard is calibrated against an official (e.g.,
pharmacopoeial/ NIBSC/WHO/EDQM/NCL) reference standard.
2. Qualification of the reference standard is performed according to the approved
protocol (i.e. no deviation from the approved protocol).
3. The extension of the shelf-life / re-test is according to an approved protocol.
4. The protocol is considered more stringent (i.e., addition of new tests or tightening
of acceptance criteria). If deletion of tests is proposed, the tests proposed to be
deleted were not implemented to monitor the quality of the reference standard
(e.g., was implemented for research or validation work).
Supporting Data
1. Information demonstrating qualification of the changed reference standards or

materials (e.g., source, characterization, certificate of analysis). (3.2.S.5)
2. Summary of stability testing and results to support the extension of reference
standard shelf-life. (3.2.S.5)
3. Justification of change to the reference standard qualification protocol.
4. Updated reference standard qualification protocol.
5. Justification for change in the reference standard.
3.2.S.6 Container Closure System

27. Change in the primary container Notifiable
None 1-3, 5
closure system(s) for the storage Change
and shipment of the drug Annual
1 1, 4, 5
substance Notification
Conditions
1. Proposed container closure system is at least equivalent to the approved
container closure system with respect to its relevant properties (including results
of transportation or compatibility studies, if appropriate).
Supporting Data
1. Information on the changed container closure system (e.g., description,
specifications) (3.2.S.6).
2. Results of accelerated and a minimum of three (3) months of real time/real
temperature testing of the 3 commercial scale batches of changed drug
substance (3.2.S.7.3), as well as commitment to submit the stability report when
completed and to notify CDSCO of any failures in the ongoing stability studies.
3. Data demonstrating the suitability of the container closure system (for example,
extractable/leachable testing) and compliance with pharmacopoeial standards, if
applicable.
4. Results demonstrating that the proposed container closure system is at least

equivalent to the approved container closure system with respect to its relevant
properties (e.g. results of transportation or interaction studies,
extractable/leachable studies).
5. Comparative table of pre and post-change specifications.

28. Change in the supplier for a primary container involving:
Notifiable
None 1-3
a. replacement or addition of Change
supplier. Annual
1, 2 None
Notification
Annual
b. deletion of supplier. None None
Notification
Conditions
1. No change in the type of container closure, materials of construction or in the
sterilization process for a sterile container closure component.
2. No change in the specifications of the container closure component outside of the
approved ranges.
Supporting Data
1. Data demonstrating the suitability of the container closure system (e.g.,
extractable/leachable testing).
2. Information on the proposed container closure system (e.g., description,
materials of construction of primary packaging components, specifications).
3. Stability test results from: a) accelerated testing and b) a minimum of three (3)
months of real time/real temperature testing on three (3) commercial scale
batches of the proposed drug substance are available, as well as commitment to
notify CDSCO of any failures in the ongoing long term stability studies.
(3.2.S.7.3).

29. Change in the specification/analytical procedure of the primary container
system for the Drug Substance, involving:
Annual
a. deletion of test 1, 2 1, 2
Notification
Annual
b. addition of test 3 1-3
Notification
c. replacement of an analytical Annual
6, 7 1-3
procedure Notification
d. minor changes to an analytical Annual
4-7 1-3
procedure Notification
e. widening of an acceptance Notifiable
None 1, 2
criteria Change
f. narrowing of an acceptance Annual
8 1
criteria Notification
Conditions
1. The deleted test has been demonstrated to be redundant compared to the
remaining tests or is no longer a pharmacopoeial requirement.
2. The change to the specification does not affect the functional properties of the
container closure component nor result in a potential impact on the performance
of the antigen/drug substance.
3. The change is not necessitated by unexpected recurring events arising during
manufacture or because of stability concerns.
4. There is no change in the acceptance criteria outside the approved limits.
5. The new analytical procedure is of the same type.
6. Results of method validation demonstrate that the new or modified analytical
procedure is at least equivalent to the approved analytical procedure.
7. The new or modified analytical procedure maintains or tightens precision,
accuracy, specificity and sensitivity.
8. The change is within the range of approved acceptance criteria or has been
made to reflect a new pharmacopoeial monograph specification for the container

closure component.
Supporting Data
1. Updated copy of the proposed specification for the primary container closure
system. (3.2.S.6)
2. Rationale for the change in specification for a primary container closure system.
3. Description of the analytical procedure and, if applicable, validation data.

(3.2.S.6)
3.2.S.7 Stability
30. Change in the shelf life of drug substance or for a stored intermediate of
the drug substance, involving:
Notifiable
None 1-4, 6
Change
a. Extension
Annual
1-5 1, 2, 5
Notification
Notifiable
None 1-5
Change
b. Reduction
Annual
6 2-4
Notification
Conditions
1. No change to the container closure system in direct contact with the drug
substance or to the recommended storage conditions of the drug substance.
2. The approved shelf life is at least 24 months.
3. Full long term stability data are available covering the changed shelf life and are
based on stability data generated on at least three production scale batches.
4. Stability data were generated in accordance with the approved stability protocol.
5. Significant changes (as defined in ICH’s Q1A guideline) were not observed in the
stability data.
6. The reduction in the shelf-life is not necessitated by recurring events arising
during manufacture or because of stability concerns.
Supporting Data
1. Summary of stability testing and results (e.g., studies conducted, protocols used,
results obtained). (3.2.S.7.3)
2. Proposed storage conditions and shelf life as appropriate.
3. Updated post-approval stability protocol and stability commitment. (3.2.S.7.2)
4. Justification of the change to the post-approval stability protocol or stability
commitment.
5. Results of stability testing (i.e. full real time/real temperature stability data
covering the changed shelf life generated on at least three (3) production scale
batches). (3.2.S.7.3). For intermediates, data to show that the extension of shelf‐
life has no negative impact on the quality of the drug substance
6. Interim stability testing results and a commitment to notify CDSCO of any failures
in the ongoing long term stability studies. Extrapolation of shelf‐life should be
made in accordance with ICH Q1E guideline. For intermediates, data to show
that the extension of shelf‐life has no negative impact on the quality of the drug
substance (i.e., batch analysis on three (3) commercial scale batches).
(3.2.S.7.3).

31. Change in the labelled storage conditions for the drug substance,
involving:
Notifiable
None 1-5
Change
a. addition of a cautionary statement.
Annual
1 1-5
Notification
Annual
b. deletion of a cautionary statement. None 2-4, 6
Notification

c. addition or change of storage Notifiable
None 1-5
condition for the drug substance Change
(e.g. widening or narrowing of a Annual
1, 2 2-5
temperature criterion). Notification
Conditions
1. The change is not necessitated by recurring events arising during manufacture or
because of stability concerns.
2. The change consists in the narrowing of a temperature criterion within the
approved ranges.
Supporting Data
1. Results of stability testing (i.e., full real time/real temperature stability data
covering the proposed shelf life generated on one (1) commercial scale batch)
(3.2.S.7.3).
as applicable.
3. Proposed storage conditions and shelf life.
4. Justification of the change in the labelled storage conditions/cautionary
statement.
5. Updated post-approval stability protocol and stability commitment (3.2.S.7.2).
6. Results of stability testing (i.e., full real time/real temperature stability data
covering the proposed shelf‐life generated on at least three (3) commercial scale
batches). (3.2.S.7.3)
Conditions
Data Category
Fulfilled
32. Change to the post-approval stability protocol of the drug substance,
involving:
a. Major / significant change to the None 1-6 Notifiable
Conditions
Data Category
Fulfilled
post-approval stability protocol or Change
stability commitment such as
deletion of a test, replacement of an Annual
1, 4 2-6
analytical procedure, change in Notification
storage temperature.
b. addition of time point(s) into the Annual
None 2, 3
post-approval stability protocol. Notification
c. addition of test(s) into the post- Annual
2 2-6
approval stability protocol. Notification
d. deletion of time point(s) from the
Annual
post-approval stability protocol None 2, 3
Notification
beyond the approved shelf life.
e. deletion of time point(s) from the
Annual
post-approval stability protocol 3 2-4
Notification
within the approved shelf life.
Conditions
1. For the replacement of an analytical procedure, the new analytical procedure
maintains or tightens precision, accuracy, specificity and sensitivity.
2. The addition of test(s) is not due to stability concerns or to the identification of
new impurities.
3. Deletion of time point(s) is made according to ICH Q5C.
4. For the replacement of an analytical procedure, the results of method validation
demonstrate that the new analytical procedure is at least equivalent to the
approved analytical procedure
Supporting Data
1. Proposed storage conditions and shelf life as appropriate.
2. Updated post-approval stability protocol and stability commitment (3.2.S.7.2).
commitment.
4. If applicable, stability testing results to support the change to the post- approval
stability protocol or stability commitment (e.g., data to show greater reliability of
the alternate test). (3.2.S.7.3)
used (3.2.S.4.2).
6. Validation study reports, if new analytical procedures are used (3.2.S.4.3).
3.2.P DRUG PRODUCT
3.2.P.1 Description and Composition of the Drug Product
Conditions
Data Category
Fulfilled
33. Change in the description or composition of the drug product, involving:
a. addition of a dosage form or
change in the formulation (e.g.
lyophilized powder to liquid,
None 1-12, 16 Supplement
change in the amount of
excipient, new diluent for
lyophilized product)
b. addition of a new strength (e.g. 1, 2-6, 8, 10,
None Supplement
50 mg dose vs 100 mg dose) or 11, 16
change in the concentration of
Notifiable
the active ingredient (e.g. 20 1-3, 5 1, 2, 6, 8, 16
Change
unit/mL vs 20 unit/2 mL)
Note: For these changes that are considered as “New Drugs” as per “The New
Drugs and Clinical Trials Rules, 2019, MA holder should submit MA application in
Form CT-21/Form CT-18 in SUGAM, with applicable fee, along with supporting
documentation as described for the respective post approval change category
followed by an amendment / endorsement of current Form 28 D license, as
applicable.
A declaration to state that no change to other remaining section/s of the MA dossier

shall be submitted, as applicable.
c. addition of a new presentation

2, 3, 6, 8-10, Notifiable
(e.g. addition of syringes to vial/ None
13-15 Change
prefilled syringe/cartridge/pre-
Conditions
Data Category
Fulfilled
filled pen/autoinjector where the
approved presentation in a vial or
vice a versa, addition of single
dose or multi-dose vial)
2, 6, 8, 10,
None Supplement
11
d. change in fill volume (same Notifiable
1, 4 2, 6, 8, 10
concentration, different volume) Change
Annual
1, 4, 5 6, 8, 10
Notification
Conditions
1. No change in dose is recommended
2. New concentration is bracketed by existing approved concentrations
3. More than 2 concentration are already approved (i.e. linear PK/PD profile of the
product from at least three different concentration over the bracketed range has
been demonstrated and two extreme concentration of the bracketed range have
been shown to be bio-equivalent or therapeutically equivalent
4. No changes are classified as major in the manufacturing process to
accommodate the new fill volume
5. The change involves narrowing the fill volume while maintaining the lower limit of
extractable volume
Supporting Data
1. Updated or new relevant CMC (Module 3 Quality) data of drug product. (3.2.P)
2. Revised Drug Product Labelling information i.e. Package Insert, Inner and Outer
Labels, as applicable.
3. Confirmation that information on the drug substance has not changed as a result
of the submission (e.g., cross reference(s) should be provided to the previously
approved drug submission, quoting the date approved and file Number(s)) or
revised information on the drug substance, if any of the attributes have changed.
4. Description and composition of the dosage form, if there are changes to the
composition or dose (3.2.P.1).
5. Discussion of the components of the drug product, as appropriate (e.g., choice of
excipients, compatibility of drug substance and excipients, leachates,
compatibility with new container closure system)
6. Batch Formula, Description of Manufacturing Process and Process Controls,
Controls of Critical Steps and Intermediates, Process Validation and/or
Evaluation in appropriate CTD sections. (3.2.P.3.2, 3.2.P.3.3. 3.2.P.3.4 &
3.2.P.3.5)
7. Control of Excipients, if new excipients are proposed (e.g., specifications,
confirmation that none of the excipients are prohibited by the Regulations)
(3.2.P.4).
8. Information on Specification(s), Analytical Procedures (if new analytical methods
are used), Validation of Analytical Procedures (if new analytical methods are
used) (3.2.P.5.1, 3.2.P.5.2, 3.2.P.5.3), Batch Analyses (certificate of analysis for
three commercial-scale batches should be provided). (3.2.P.5.4). Bracketing for
multiple strength products, container sizes and / or fill volumes may be
acceptable if scientifically justified (refer ICH Q1D).
9. Information (including description, materials of construction, summary of
specifications) on the container closure system, if any of the components have
changed (3.2.P.7).
10. Stability test results from: a) accelerated testing (usually a minimum of three (3)
months) or, preferably, forced degradation studies under appropriate time and
temperature conditions for the product; and b) three (3) months of real time/real
temperature testing on three (3) commercial scale batches of the proposed drug
product, or longer if less than three (3) time points are available (including the
zero time point), as well as commitment to notify CDSCO of any failures in the
ongoing long term stability studies Bracketing and matrixing for multiple strength
products, container sizes and/or fills may be acceptable if scientifically justified
(refer to ICH Q1D).

Comparative pre change and post change test results of three (3) months
accelerated and real time/real temperature testing on three (3) commercial scale
batches of the changed drug product, as well as commitment to submit the
stability report when completed and to notify CDSCO of any failures in the
ongoing stability studies (3.2.P.8.3). Matrixing, bracketing, the use of smaller
changed drug product may be acceptable if scientifically justified (refer ICH Q1D)
by the manufacturer /MA holder to CDSCO.
11. Supporting clinical data or scientific/ clinical justification for not performing
additional clinical study
12. Data demonstrating comparability of the new dosage form and/or formulation.
13. Supporting clinical data (usually PK/PD only) or scientific/clinical justification for
not performing additional clinical study.
14. The new device (e.g., pre-filled syringes, cartridge or pens), approval letter from
the CDSCO, as applicable.
15. Information on container closure system and extractables /leachable if any of
components have changed.
16. Duly Signed Form CT-18/Form CT-21 with applicable fee.
3.2.P.1 Description and Composition of the Drug Product: Change to an

adjuvant
Conditions
Data Category
Fulfilled
34. Change involving a chemical / synthetic adjuvant
Notifiable
None 3-6
a. change in supplier of a chemical / Change
synthetic adjuvant Annual
2, 3 4
Notification
b. change in manufacture of a None 2-6 Notifiable
Conditions
Data Category
Fulfilled
chemical / synthetic adjuvant Change
Annual
2, 3 8-10
Notification
c. change in release specifications of a Notifiable
None 5, 6, 8-10
chemical/ synthetic adjuvant Change
(including the tests and/or the Annual
2, 4 8-10
analytical procedures Notification
35. Change involving a biological adjuvant
a. change in supplier of a biological
adjuvant.
1-6, 8, 11,
None Supplement
b. change in manufacture of a 12
biological adjuvant Notifiable
1 1-4, 8, 11
Change
c. change in the release specifications 5, 6, 8-10, Notifiable
None
of a biological adjuvant (including 12 Change
the tests and/or the analytical Annual
2, 4 8-10
procedure). Notification
Conditions
1. The change does not concern the source of the adjuvant.
2. The specification of the adjuvant is equal to or narrow than the approved limits
(i.e. narrowing of acceptance criterion).
3. The adjuvant is an aluminium salt.
4. The change in specification consists in the addition of a new test or in a minor
change to an analytical procedure.
Supporting Data
1. Information on the quality and controls of the materials (e.g., raw materials,
starting materials, solvents, reagents, catalysts) used in the manufacture of the
changed adjuvant.
2. Flow diagram of the proposed manufacturing process (es), a brief narrative
description of the proposed manufacturing process (es), and information on the
controls performed at critical steps of the manufacturing process and on
intermediates of the changed adjuvant.
3. Process validation and/or evaluation studies (e.g., for manufacturing of the
adjuvant).
4. Description of the general properties, characteristic features and characterization
data of the product
comparative tabular format, for at least three (3) commercial scale batches of the
drug product with the approved and changed adjuvant, as applicable. (3.2.P.5.4).
temperature testing on three (3) batches of the changed adjuvant as well as
commitment to submit the stability report when completed and to notify CDSCO
of any failures in the ongoing stability studies (3.2.P.8.3). Matrixing, bracketing,
the use of smaller scale batches and use of fewer than 3 batches for stability
testing of proposed changed drug product may be acceptable if scientifically
justified (refer ICH Q1D) by the manufacturer /MA holder to CDSCO.
7. Supporting non-clinical and clinical data or scientific/clinical justification for not
performing additional clinical studies if in vitro tests are sufficient to prove
comparability.
8. Updated copy of the proposed specification for the adjuvant (3.2.P.4.1).
used (3.2.P.4.2).
10. Validation study reports, if new analytical procedures are used (3.2.P.4.3).
adventitious agents (e.g. impact on the viral clearance studies, BSE/TSE risk).
12. Comparability of the pre- and post-change adjuvant with respect to
physicochemical properties, biological activity, purity, impurities and
contaminants, as appropriate. Nonclinical and/or clinical bridging studies may
occasionally be required when quality data are insufficient to establish

comparability. The extent and nature of nonclinical and clinical studies should be
determined on a case-by-case basis, taking into consideration the quality
comparability findings, the nature and level of knowledge of the adjuvant, existing
relevant nonclinical and clinical data, and aspects of vaccine use.
13. Evidence of facility GMP compliance.
3.2.P.1 Description and Composition of the Drug Product: Change to a diluent
Conditions
Data Category
Fulfilled
36. Change to the diluent, involving:
Notifiable
None 1-6, 12
a. replacement or addition of a source Change
of a diluent Annual
1-3 2, 4, 5
Notification
Notifiable
None 2-6
b. change in manufacturing process of Change
a diluent Annual
1, 3 2-5
Notification
Notifiable
c. change in specification of a diluent None 2, 5, 7-11
Change
(Eg. deletion or replacement or
Annual
addition of test) 5-10 2, 5, 7-11
Notification
Annual
d. tightening of an acceptance criteria 5, 6 2, 5, 7-11
Notification
Notifiable
e. relaxation of an acceptance criteria 5, 7-10 2, 5, 7-11
Notification
f. change in facility used to Annual
1, 2 2, 4, 6
manufacture a diluent (same Notification
Conditions
Data Category
Fulfilled
company)
Annual
g. addition of a diluent filling line 1, 2, 4 2, 4, 6
Notification
h. addition of a diluent into an Annual
1, 2 2-5, 13
approved filling line Notification
Annual
i. deletion of a diluent None None
Notification
Conditions
1. The diluent is water for injection or a salt solution (including buffered salt
solutions) (i.e. it does not include an ingredient with a functional activity, such as
a preservative) and there is no change to its composition.
2. After reconstitution, there is no change in the final product specification outside
the approved limits.
3. The proposed diluent is commercially available in the NRA country.
4. The addition of the diluent filling line is in an approved filling facility.
8. Acceptance criterion for any Class 3 residual solvent is within the ICH limits.
9. The change to the specifications does not result in a potential impact on the
performance of the drug product.
Supporting Data
1. Demonstration that the changed diluent results in the same properties of the
product as with the approved diluent.

approved and changed diluent.
temperature testing (3.2.P.8.3) of the changed diluent and updated stability of the
product reconstituted with the new diluent (3.2.P.8.3). Matrixing, bracketing, the
use of smaller scale batches and use of fewer than 3 batches for stability testing
of proposed changed diluent may be acceptable if scientifically justified (refer ICH
Q1D) by the manufacturer /MA holder to CDSCO.
4. Flow diagram including process and in-process controls of the proposed
manufacturing process(es) and a brief narrative description of the proposed
manufacturing process(es).
5. Updated copy of the proposed specification for the diluent (3.2.P.5.1).
6. Evidence that the facility is GMP-compliant.
used (3.2.P.5.2).
(3.2.P.5.3).
9. Where a house analytical procedure is used and a Pharmacopoeial standard is
claimed, results of an equivalency study between the house and compendial
method.
10. Justification of the changed diluent specifications (e.g. demonstration of the
suitability of the monograph to control the diluent, including degradation products.
maintained.
as applicable.
13. Cleaning procedures (including data in a summary validation report)
demonstrating lack of carryover / cross contamination.
3.2.P.2 Pharmaceutical Development

37. Change in the approved design space, involving :
a. establishment of a new design
None 1 Supplement
space
b. expansion of the approved
None 1 Supplement
design space
c. reduction in the approved
design space (any change that
Annual
reduces or limits the range of 1 1
Notification
parameters used to define the
design space
Conditions
1. The reduction in design space is not necessitated by recurring problems having
arisen during manufacture.
Supporting Data
1. Pharmaceutical development data to support the establishment or changes to the
design space (3.2.P.2)
3.2.P.3 Manufacture

38. Changes involving a drug product manufacturing facility / premise (site):
a. replacement or addition of a None 1-10 Supplement
drug product manufacturing
facility / suite in new
Notifiable
geographical site / premises. 1-6 1, 3, 4, 6, 7-10
Change
(including formulation / filling
and primary packaging)

Note: For these changes, MA holder shall submit MA application in Form CT-
21/Form CT-18 in SUGAM with applicable fees along with supporting documentation
as described for the post approval change category, for addition of manufacturing
facility/suite, for a drug product, in a new geographical site/ premises. CDSCO will
issue a No Objection Certificate for obtaining an amendment / endorsement of the
current Form 28 D license, as applicable.
A declaration to state that no change to other remaining section/s of the MA dossier,

including impact on safety/efficacy, shall be submitted, as applicable.

b. replacement of a formulation /
3, 4, 6-10, 12- Notifiable
filling suite. 1, 7
13 Change
c. addition of an equivalent Notifiable
1 3, 4, 6, 8-10
formulation / filling suite Change
d. replacement or addition of a
secondary packaging
Annual
including secondary functional 2, 3 1-4
Notification
packaging / labelling / storage
and distribution facility
e. qualification of a new room or
Annual
change in classification of an 8, 9 11-13
Notification
existing room.
f. deletion of a drug product Annual
10 None
manufacturing facility Notification
g. modification to a
manufacturing area or
Annual
modification to an existing 8, 9 11-13
Notification
service/system (e.g., change
to WFI systems or HVAC

systems, moving a wall)
Conditions
1. The formulation/filling facility is approved facility or site (premises) is approved by
licensing authority.
2. No change in the composition, manufacturing process or drug product
specifications.
3. No change in the container/closure system and storage conditions.
4. The same validated manufacturing process is used.
5. The newly introduced product is in the same family of product(s) or therapeutic
classification as the one of those already approved at the site and uses the
similar/ comparable filling process/equipment.
6. The Site / Premise are under same Quality system oversight and owned by same
legal entity.
7. The new formulation/filling suite is equivalent to the approved formulation/filling
suite.
8. The change has no impact on the risk of contamination or cross‐contamination.

9. The modification has no product impact.
10. The deletion should not be due to critical deficiencies in manufacturing (for
example, recurrent out-of-specification events, environmental failures, etc.).
Supporting Data
1. Evidence that the facility is GMP-compliant.
2. Updated relevant drug product CMC (3.2.P) Sections.
3. Confirmation that information on the drug product has not changed as a result of
the submission (e.g., other than change in facility) or revised information on the
drug product, if any of the attributes have changed.
4. Name, address, and responsibility of the changed production facility involved in
manufacturing and testing.
5. Description of the manufacturing process if different from the approved process
and information on the controls performed at critical steps of the manufacturing
process and on the intermediate of the changed drug product.

6. Process validation and/or evaluation studies (3.2.P.3.5) or the proposed
validation protocol of the changed drug product is acceptable, but data could be
requested, including technology transfer validation, equipment qualification,
media fills, as appropriate, bracketing for multiple strength products, container
sizes and /or fills may be acceptable if scientifically justified (refer ICH Q1D).
approved and changed drug product (3.2.P.5.4), Bracketing for multiple strength
products, container sizes and /or fills may be acceptable if scientifically justified
(refer ICH Q1D).
8. Results of a minimum of three (3) months of accelerated and three (3) months of
real time/real temperature testing on three (3) commercial scale batches of the
changed drug product as well as commitment to submit the stability report when
completed and to notify CDSCO of any failures in the ongoing stability studies
(3.2.P.8.3). Bracketing for multiple strength products, container sizes and /or fills
may be acceptable if scientifically justified (refer to ICH Q1D).
9. Rationale for considering the proposed formulation/filling suite as equivalent.
10. Commitment to place the first batch of the drug product manufactured using the
proposed formulation/filling suite into the stability programme, and to notify
CDSCO of any failures in ongoing long-term stability studies.
11. Information demonstrating re‐qualification of the equipment or re‐qualification of
the change (e.g. operational qualification, performance qualification), as
appropriate.
12. Information on the proposed production facility involved in the manufacture of the
drug product, including the complete set of floor plans and flow charts (drawings,
room classification, water systems, HVAC systems), as well as the cleaning and
shipping validation, as appropriate.
13. Results of the environmental monitoring studies in classified areas.
14. Information describing the change‐over procedures for shared product‐contact
equipment or the segregation procedures, as applicable. If no revisions, a signed
attestation that no changes were made to the change‐over procedures.
Conditions
Data Category
Fulfilled
39. Change in a facility involved in the manufacture of a drug product, such as:
a. conversion of a drug product
Notifiable
manufacturing facility from single- None 1-3
Change
product to multiproduct
b. conversion of production and
related area(s) from campaign to Notifiable
1 1, 2, 4
concurrent for multiple product Change
manufacturing areas
c. introduction of new product into
Annual
an approved multiproduct 2-4 1-4
Notification
formulation / filling suite
Conditions
1. The manufacturing process is a closed process.
2. The newly introduced product does not introduce significantly different risk issues
(i.e., cytotoxic drugs to cytokine manufacturing area).
3. The newly introduced product is not of significantly different strength (i.e., mg vs
µg).
4. The maximum allowable carry-over is not affected by the introduction of the new
product.
Supporting Data
1. Information on the cleaning procedures (including validation) demonstrating lack
of carry-over or cross-contamination.
2. Information describing the change-over procedures for shared product- contact
equipment or the segregation procedures, as appropriate. If there are no
revisions, the manufacturer should state that no changes were made to the
changeover procedures.
3. Information on the product(s) which share the same equipment (e.g., therapeutic
classification).
4. Risk assessment summary.

40. Changes involving a drug product manufacturing process:
a. critical change with high potential

Notifiable
to have an impact on the quality None 1-6
Change
of final product
b. non critical change with low
Annual
potential to have impact on the 1-4 1-5
Notification
quality of the of final product
c. addition of a new step (e.g. Notifiable
4 1-7
filtration step) Change
d. scale-up of the manufacturing
process at the formulation / filling
Notifiable
stage (e.g. Increase in Blend size 2, 4-6 1, 3-5, 8, 10
Change
or increase of batch size loaded in
the lyophilizer)
e. addition of a new scale bracketed
by the approved scales or Scale-
Annual
down of the manufacturing 2, 4-7 1, 3-5, 8, 9
Notification
process at the formulation / filling
stage
Conditions
1. No change in the drug product specifications.
2. The change does not affect the method of sterilization of the drug product.
3. No change in the excipients / preservative.
4. The change is not necessitated by unexpected events arising during

5. The scale-up or scale down uses the similar/ comparable approved equipment
(Note: Change in equipment size is not considered as using similar/comparable
equipment).
6. Any changes to the manufacturing process and/or to the in-process controls are
only those necessitated by the change in batch-size (e.g., the same formulation,
controls, standard operating procedures (SOPs) are utilized).
7. Change does not affect the lyophilization step. If the proposed change affects
the lyophilization cycle, then lower and upper cycle should be validated.
Supporting Data
1. Flow diagram of the changed manufacturing process (es) and a brief narrative
description of the changed manufacturing process (es) (3.2.P.3.3).
2. Information on the quality and controls of the materials (e.g., excipients) used in
the manufacture of the changed drug product (3.2.P.4).
process and on intermediates of the changed drug product (3.2.P.3.4).
sterilization) (3.2.P.3.5).
approved and changed drug product (3.2.P.5.4).
6. Results of accelerated and three (3) months of real time/real temperature testing
on three (3) commercial scale batches of the changed drug product as well as
justified (refer ICH Q1D) by the manufacturer /MA holder to CDSCO.
7. Information on leachable and extractables, as applicable.
8. Rationale for regarding the equipment as similar or comparable, as applicable.
9. Commitment to place the first production batch of the final product manufactured
using the proposed scale into the stability programme, and to notify the CDSCO
if any failure in the ongoing stability studies.
10. The results of stability studies that have been carried out under ICH conditions,
on the relevant stability parameters, on at least one pilot or industrial scale
batch, covering a minimum period of 3 months, and an assurance is given that
these studies will be finalised, and that data will be provided immediately to the
competent authorities if outside specifications or potentially outside
specifications at the end of the approved shelf life (with proposed action).

41. Change in equipment used in drug product manufacturing process, such
as:
a. replacement or addition of new Notifiable
None 1-3, 5, 7-9
equipment used in a critical step Change
(e.g., lyophilizer, formulation Annual
1 1, 3, 5, 6
tank, filling line and head) Notification
b. product contact equipment Notifiable
None 1, 3, 4
change from dedicated to shared Change
(e.g., formulation tank, Annual
2, 3 1, 3, 4, 10
lyophilizer) Notification
Conditions
1. Replacement of equipment with equivalent equipment; the change is considered
“Like to Like” (i.e. in terms of product contact material, equipment size, operating
principle).
2. The site is approved as multi‐product facility by CDSCO.
3. The change has no impact on the risk of cross‐contamination and is supported by
validated cleaning procedures.
Supporting Data
1. Information on the in-process control testing, as applicable.
validation protocol of the changed drug product, including technology transfer

validation, equipment qualification, media fills, as appropriate.
3. Information demonstrating qualification of the equipment or qualification of the
change.
4. Information on the cleaning procedures (including validation) demonstrating lack
of carry-over or cross-contamination.
5. Information on new equipment and comparison of similarities and differences
regarding operating principles and specifications between the new and the
replaced equipment.
6. Rationale to support the equipment as similar/ comparable, as applicable.
7. Description of manufacturing process, if different from the approved process,
and information on the controls performed at critical steps of the manufacturing
process and on the intermediate of the proposed drug product. (3.2.P.3.3)
8. Description of the batches and the summary of in-process controls and release
testing results as quantitative data in a comparative tabular format for at least
three commercial scale batches of the pre-change and post change drug
product. (3.2.P.3.3)
9. Results of accelerated and three (3) months of real time/real temperature testing
on three (3) commercial scale batches of the changed drug product as well as
justified (refer ICH Q1D) by the manufacturer /MA holder to CDSCO
10. Information describing the change‐over procedures for the shared product‐
contact equipment
Description of Change Conditions to Supporting Reporting

Conditions be Fulfilled Data Category
42. Change in the controls (in-process tests and/or acceptance criteria) applied
during the manufacturing process or on intermediates
a. Deletion of an in-process test
which may have a significant 1, 2, 4-6, 8, Notifiable
None
effect on the overall quality of 11 Change
the drug product
b. deletion of a non-significant in 1, 4, 5, 7, 10, Annual
2, 11, 12
process test 13 Notification
c. replacement or addition of an Annual
1-4, 6-8 1, 2, 4, 6, 8
in- process test Notification
1, 2, 4, 6, 7, Notifiable
None
d. relaxation of an acceptance 10, 11 Change
criterion Annual
1, 7, 8 2, 6, 8, 11
Notification
e. tightening of an acceptance Annual
1, 2, 7, 12 1, 12
f. addition or replacement of an
1-4, 6, 8, Notifiable
in-process test as a result of a None
10,11 Change
quality and safety issue
g. change in in-process control
testing site.
Note: Transfer of in-process control
testing to a different facility within a
Annual
GMP compliant site is not considered 1, 6-9, 11 9
Notification
to be a reportable change but it is
treated as a minor GMP change
(Level IV) and reviewed during
inspections.
Conditions

4. The changed test does not affect the sterility of a sterile drug product. or no
change in the principle of the sterilization procedures of the drug product.
remaining tests.
6. The replaced or added analytical procedure maintains or tightens precision,
accuracy, specificity, sensitivity.
7. No change in the impurity profile of the final product outside the approved limits.
8. No change in final product specification outside the approved limits.
9. No change in the in-process control limits outside the approved limits.
10. The deleted test is not for a viral clearance/removal step.
11. No Level II changes are made to the approved in‐process tests and/or
acceptance criteria.
12. Test procedure remains the same, or changing in test procedures are minor.
13. The test does not concern a critical attribute (for example, content, impurities,
any critical physical characteristics or microbial purity).
Supporting Data
1. Description of the changed process controls or acceptance criteria (comparative
table of current and proposed change).
2. Description of the changed process controls or acceptance criteria of the critical
steps and intermediates (3.2.P.3.4).
3. Method validation for any new analytical procedure. (3.2.P.5.3)
used. (3.2.P.5.2)
tabular format, for at least one production scale batch (3.2.P.5.4).
6. Rationale/justification for change in process test and limits supported by data.
7. Data to show that the relaxation has not a negative impact on the quality of the
batch. Results for at least one (1) batch are required.
comparative tabular format, for at least three (3) commercial scale batches of
the approved and changed drug product (3.2.P.5.4). Batch data on next two full
production batches should be made available on request and reported by the
MA holder if out-side specification (with proposed actions). Use of smaller scale
batch may be acceptable, where justified.
9. Evidence that the new company/facility is GMP-compliant.
10. Updated Drug Product specification if changed (3.2.P.5.1)
11. Description of the batches and summary of in-process control and release
testing results as quantitative data, in a comparative tabular format for three
commercial scale batches of the pre-change and post change drug product
(CoA should be provided) (3.2.P.3.5 and 3.2.P.5.4).
12. Justification/risk assessment showing that the attributes is non-significant.
3.2.P.4 Control of Excipients

43. Change in the standards / monograph for Excipients
a. change in the standard / Notifiable
None 1-4
monograph claimed for the Change
excipient (e.g., from an in-house to Annual
1-3 1-4
pharmacopoeial standard) Notification
b. change in the standard claimed for
the excipient (e.g., from Notifiable
None 1-4
pharmacopoeial standard to in- Change
house)
Conditions
1. The change is made exclusively to comply with the (applicable) Pharmacopoeia/
Standard.
2. No change to the specification for the functional properties of the excipient (e.g.,
particle size distribution) outside the approved range, or that results in a potential
impact on the performance of the drug product.
3. No deletion of or relaxation to any of the tests, analytical procedures, or
acceptance criteria of the approved specification except to comply with
pharmacopoeial standard/ monograph.
Supporting Data
1. Updated excipient specifications (3.2.P.4.1).
2. Where a In-house analytical procedure is used and a Pharmacopoeial standard
is claimed, results of an equivalency study between the In-house and
compendial methods.
3. Justification of the changed excipient specifications (e.g., demonstration of the
suitability of the monograph to control the excipient and potential impact on the
performance of the drug product) (3.2.P.4.4). Comparative table/description
wherever applicable of current and proposed specifications
maintained.
Conditions
Data Category
Fulfilled
44. Change in the specifications used for release of the excipient, involving:
Note: This change excludes adjuvants
Notifiable
None 1-4
Change
a. deletion of a test
Annual
5, 7 1-4
Notification
Notifiable
None 1-4
Change
b. replacement of a test
Annual
1-4, 6, 8, 9 1-4
Notification
Conditions
Data Category
Fulfilled
Notifiable
None 1-4
Change
c. addition of a test
Annual
4 1-3
Notification
Notifiable
None 1-4
d. relaxation of an acceptance Change
criterion Annual
1, 3, 4, 6 1-4
Notification
e. tightening of an acceptance Annual
1-4, 6, 10 1-4
Conditions
made to reflect the new pharmacopoeial monograph specification for the
excipient
4. Acceptance criterion for residual solvents are within the recognized or approved
acceptance limits (for example, within ICH limits for class 3 residual solvent or
pharmacopoeial requirements).
6. The change to the specifications does not affect the functional controls of the
excipient (e.g., particle size distribution) nor result in a potential impact on the
7. An alternative test analytical procedure is already authorized for this
specification attributes/test.
8. Results of method validation demonstrate that the proposed analytical

procedures are at least equivalent to the approved analytical procedure.
9. The replaced analytical procedures maintain or improves precision, accuracy,
specificity and sensitivity.
10. The analytical procedures remain the same, or changes in the test procedure
are minor.
Supporting Data
2. Where an In-house analytical procedure is used and a Pharmacopoeial standard
is claimed, results of an equivalency study between the In-house and compendial
methods.
performance of the drug product) (3.2.P.4.4).
maintained.
Conditions
Data Category
Fulfilled
45. Change in the analytical procedures used for the excipient, involving:
Note: This change excludes adjuvants
Notifiable
None 1, 3, 4
Change
a. deletion of an analytical procedure
Annual
6 1
Notification
Notifiable
None 1-4
analytical procedure Annual
3-5 1-4
Notification
c. minor changes to an approved 1, 2 1-4 Annual
Conditions
Data Category
Fulfilled
analytical procedure Notification
d. a change from an In-house
None 1, 2
procedure
Conditions
1. No change in the approved acceptance criteria.
2. The method of analysis is the same (e.g., a change in column length or
temperature, but not a different type of column or method) and no new impurities
are detected.
4. The replaced analytical procedure maintains or improves precision, accuracy,
specificity and sensitivity.
made to reflect the new pharmacopoeial monograph specification for the
excipient.
6. An alternative analytical procedure is already authorized for the specification
parameter/ test and this procedure has not been added through a minor change
submission.
Supporting Data
compendial methods.
performance of the drug product) (3.2.P.4.4).

maintained.
Conditions
Data Category
Fulfilled
46. Change in the source or manufacture of the excipient,
a. change in the source of an
excipient from a vegetable or
synthetic source to a TSE risk or None 2-7 Supplement
viral risk (e.g. human / animal
source)
b. change in the source of an
excipient from a TSE risk (e.g., Notifiable
None 1, 3, 5, 6
animal) source to a vegetable or Change
synthetic source
c. replacement in the source of an
excipient from a TSE risk source
Annual
to a different TSE risk source 6, 7 2-7
Notification
(e.g., different country of origin,
different animal species)
d. change in manufacture of a None 3-7, 9 Supplement

biological excipient
Notifiable
Note: excludes biological 2, 3 2, 3, 5-7
Change
adjuvants, refer to adjuvant
Annual
specific changes for details. 1-3 2, 3, 5
Notification
e. change in the supplier for a None 3, 8 Supplement
plasma-derived excipient (e.g.
Notifiable
human serum albumin) 4, 5 5, 6, 9
Change
Conditions
Data Category
Fulfilled
f. change in supplier for an excipient Notifiable
None 2, 3, 5-7
of non-biological origin or of Change
biological origin (excluding Annual
1, 5, 6 3
plasma-derived excipient) Notification
g. change in excipient testing site
Note: Transfer of testing to a
different facility within GMP
compliant site is not considered to Annual
1 10
be reportable change but it is Notification
treated as a minor GMP change
(Level IV) and is reviewed during
inspection
Conditions
1. No change in the specifications of the excipient or drug product outside the
approved limit.
2. The change does not concern a human plasma-derived excipient.
3. Properties of the changed excipient are not different from those of the approved
excipient.
4. The human plasma-derived excipient from the new supplier is an approved
medicinal product and no manufacturing changes were made by the supplier of
the new excipient since its last approval by CDSCO.
5. The excipient does not influence the structure / conformation of the active
ingredient.
6. The TSE risk source is covered by TSE certificate/declaration of suitability and is
of the same or lower TSE risk as the previously approved material.
7. Any new excipient does not require the assessment of viral safety data.
Supporting Data
1. Declaration from the manufacturer of the excipient that it is entirely of vegetable
or synthetic origin.
2. Details of the source or the excipient (animal species, country of origin) and the
steps undertaken in processing to minimize the risk of TSE exposure.
3. Information demonstrating comparability in term of physico-chemical
characterization and impurity profile of the changed excipient with the approved
excipient.
4. Information on the manufacturing process and on the controls performed at
critical steps of the manufacturing process and on the intermediate of the
changed excipient ( 3.2.P.3.3)
drug product without changed excipient and of the drug product with the changed
excipient (3.2.P.5.4).
6. Results from the stability testing (3 months accelerated testing and 3 months
real time/temperature) on three batches of the drug product with the changed
Excipient (3.2.P.8.3). Matrixing, bracketing, the use of smaller scale batches and
use of fewer than 3 batches for stability testing of proposed changed drug
product may be acceptable if scientifically justified (refer ICH Q1D) by the
manufacturer /MA holder to CDSCO.
adventitious agents (e.g., impact on the viral clearance studies, BSE/TSE risk).
(3.2.A.2)
8. Complete manufacturing and clinical safety data to support the use of the
proposed human plasma derived excipient.
9. Letter from supplier certifying that no changes were made to the plasma-derived
excipient compared to the currently approved corresponding medicinal product.
3.2.P.5 Control of Drug Product
Conditions Reportin
Supportin
Description of Change to be g
g Data
Fulfilled Category
47. Changes in standard / monograph (specifications) claimed for the drug
product, involving
a. a change from a pharmacopoeial
Notifiable
standard/ monograph to in-house None 1-3, 5-7
Change
standard
b. change in the standard claimed for the Notifiable
None 1-6
drug product (e.g., from an in-house Change
standard to pharmacopoeial
standard/monograph or from one Annual
pharmacopoeial standard / monograph 1, 3 1-3, 6, 7 Notificatio
to a different pharmacopoeial n
standard/monograph)
c. change in the specification for the drug
product to comply with an updated
pharmacopoeial monograph.
Note: Change in specifications and an Annual
analytical procedure for the Drug Product to 1, 2 1-3, 6, 7 Notificatio
comply with an updated pharmacopoeial n
monograph within 6 months of Pharmacopoeia
update should be captured under Level IV
changes
Conditions
1. The change is made exclusively to comply with the pharmacopoeia.
2. No change to the specification that results in a potential impact on the
3. No deletion of or relaxation to any of the tests, analytical procedures, or
acceptance criteria of the approved specification except to comply with
pharmacopoeial standard/ monograph.
Supporting Data
1. Revised Drug Product Labelling information, i.e. Package Insert and Inner and
Outer Labels, as applicable.
2. Updated, drug product specifications (3.2.P.5.1).
compendial methods.
tabular format, for at least two batches (minimum pilot scale) of the drug product
tested according to the changed specification (3.2.P.5.4).
5. Justification of the changed drug product specifications (e.g., demonstration of
the suitability of the monograph to control the drug product, including
degradation products) (3.2.P.5.6).
maintained.
(3.2.P.5.3).
Conditions
Data Category
Fulfilled
48. Change in the drug product release / shelf life specification, involving:
a. for sterile products, replacing the
sterility test with process None 1, 2, 5, 8-10 Supplement
parametric release
Notifiable
None 2, 9, 10
Change
b. deletion of a test
Annual
7 2, 9, 10
Notification
Notifiable
c. replacement or addition of a test None 2-7, 9, 10
Change
Annual
1, 2, 8 2-4, 9
Notification
d. change in animal species/strains
for a test (e.g., new species/
Notifiable
strains, animals of different age, None 11, 12
Change
new supplier where genotype of
the animal cannot be confirmed)
Notifiable
None 2, 9, 10
e. relaxation of an acceptance Change
criterion Annual
1, 3-6 2, 9, 10
Notification
f. tightening of an acceptance Annual
1, 2, 4, 9 2
Conditions
4. Acceptance criterion for any Class 3 residual solvent is within the ICH limits.
5. The change to the specifications does not result in a potential impact on the
6. The change does not concern sterility or potency testing.
7. The test is deleted in-line with the updated Pharmacopoeia/ Standard; or there is
no change in the compliance status of applicable Pharmacopoeia/ Standard
(E.g. The deleted test is the abnormal toxicity test / general safety test).
8. The addition of test is not to monitor new impurity species.
9. The method of analysis is the same (i.e. a change in column length, temperature,
but not a different type of column or method) and no new impurities are
detected.
Supporting Data
validation protocol of the changed drug product.
2. Updated drug product specifications (3.2.P.5.1).
used (3.2.P.5.2).
(3.2.P.5.3).
compendial methods.
6. Information demonstrating qualification of the method and comparability with the
approved method.
tested according to the changed specifications (3.2.P.5.4).
8. Description of the batches, certificates of analyses, and summary of results, of a
sufficient number of batches to support the process parametric release
(3.2.P.5.4).
9. Justification of the changed drug product specifications (e.g., demonstration of
the suitability of the monograph to control the drug product, including
degradation products) (3.2.P.5.6).
maintained.
11. Copies of relevant certificate of fitness for use (e.g., veterinary certificate).
12. Data demonstrating that the change in animals gives comparable results with
those obtained using the approved animals.

49. Change in the analytical procedures of drug product, involving:
Notifiable
a. deletion of an analytical None 1, 2-4
Change
procedure and/or an acceptance
Annual
criteria 5 1, 2-4
Notification
Notifiable
None 1, 3, 5-7
analytical procedure Annual
1, 3, 4, 6-8 1, 3, 5-7
Notification
c. minor changes to an approved Annual

1-4, 8 3, 5-7
d. change from an In-house

1-4, 8 1, 5, 6
procedure
Conditions
1. No change in the approved acceptance criteria.
2. The method of analysis is the same (e.g., a change in column length or
temperature, but not a different type of column or method) and no new impurities
are detected.
5. The analytical procedure is deleted in-line with the updated Pharmacopoeia/
Pharmacopoeia/ Standard.
7. The change is from a pharmacopoeial assay to another pharmacopoeial assay

or marketing authorization holder has demonstrated an increase understanding
of the relationship between method parameters and method performance define
by a systematic development approach including robustness studies.
8. The change does not concern the potency testing.
Supporting Data
1. Updated drug product specifications (3.2.P.5.1)
tested according to the changed specification (3.2.P.5.4).
3. Justification for the change to the analytical procedure (e.g. demonstration of
suitability of the analytical procedure to monitor the drug product).
maintained.
5. Copies of summaries of analytical procedures, if new analytical procedures are
used (3.2.P.5.2).
6. Copies of summaries of validation/qualification reports, if new analytical
procedures are used (3.2.P.5.3).
7. Comparative results demonstrating that the approved and proposed analytical
procedures are equivalent.

50. Changes affecting the quality control (QC) testing of the final product
(release and stability), involving :
a. transfer of the QC testing Notifiable
None 1, 2
responsibilities for a non - Change
pharmacopoeial assay (in-house) Annual
2-4 1, 2
to a new company Notification
b. transfer of the QC testing Annual
None 1, 2
responsibilities for a Notification

pharmacopoeial assay to a new
company
c. transfer of the QC testing
responsibilities for a
pharmacopoeial assay or a
nonpharmacopoeial assay to a
different site
Note #1: Change in specifications and
an analytical procedure for the Drug
Product to comply with an updated Annual
1 1, 2
pharmacopoeial monograph within 6 Notification
months of Pharmacopoeia update
requires no reporting.
Note #2: Transfer of testing to a different

facility within GMP compliant site is not
considered to be reportable change but it
treated as a minor GMP change (Level
IV) and is reviewed during inspection.
d. introduction of additional
Annual
laboratory in a facility to perform None 2
Notification
drug product testing
Conditions
1. The new QC testing site/facility is under the central quality assurance .
2. The transfer is within a facility approved in the current MA for the performance of
other test
3. The transferred quality control test is not a potency assay or bioassay.
4. There is no change in the test methods.
Supporting Data
2. Information demonstrating technology transfer validation and equipment

qualification, as appropriate.
Conditions
Data Category
Fulfilled
51. Changes in the control strategy of the drug product, involving:
a. Change from end‐product testing

to upstream controls for some
test(s) (e.g., Real‐Time Release None 1-5 Supplement
Testing, Process Analytical
Technology)
b. Addition of a new Critical Quality
Notifiable
Attribute (CQA) in the control None 1-5
Change
strategy
c. Deletion of a Critical Quality
Notifiable
Attribute (CQA) from the control None 1, 5
Change
strategy
Conditions
None
Supporting Data
process and on intermediates of the proposed product (3.2.P.3.4).
2. Updated, QC approved copy of the proposed drug product specifications (or
where applicable, the final version of the specifications to be signed by QC after
CDSCO approval), if changed (3.2.P.5.1).
used (3.2.P.5.2).
(3.2.P.5.3).
5. Justification and supporting data for each proposed change to the control
strategy.
3.2.P.6 Reference Standards or Materials
Condition to Supporting Reporting

52. Change in reference standards or materials used to release the drug
product, involving
a. qualification of a Reference Notifiable
None 1
Standard Change
b. update the reference standards Notifiable
1 1, 5
from pharmacopoeial to in-house Change
c. update the reference standards Annual
2, 3 1, 5
from in -house to pharmacopoeial Notification
d. qualification of a new lot of
reference standard (except for a Annual
2 1, 5
bacterial or viral vaccine, bacterial Notification
toxin)
53. Qualification of a new lot of reference standard against the approved
reference standard for a bacterial or viral vaccine, bacterial toxin, involving.
a. reference standard used in a
qualitative test, physicochemical Annual
2 1
test, semi‐quantitative or Notification
quantitative biological assay
54. Change to the reference Notifiable
None 2, 3
standard qualification protocol1 Change
(except for a bacterial or viral Annual
5 2, 3
vaccine, bacterial toxin) Notification
55. Change to reference standard qualification protocol for a bacterial or viral
vaccine, bacterial toxin involving:
Condition to Supporting Reporting

a. a reference standard used in a Annual
None 3, 5
qualitative test Notification
b. a reference standard used in a
physicochemical test, a semi‐ Annual
5 3, 5
quantitative or quantitative Notification
biological assay.
56. Extension of the shelf-life / re-
Annual
test period of the reference 4 4
Notification
standard
Conditions
1. The In-house reference standard is validated against an official (e.g.,
pharmacopoeial/ NIBSC/WHO/EDQM/NCL) reference standard.
2. Qualification of the reference standard is performed according to the approved
protocol (i.e. no deviation from the approved protocol).
3. The change is necessitated due to Pharmacopoeial requirement to meet with the
regulatory requirements.
4. The extension of the shelf-life of the reference standard is carried out in
accordance with an approved protocol.
5. The protocol is considered more stringent (i.e., addition of new tests or tightening
of acceptance criteria). If deletion of test is proposed, the tests proposed to be
deleted were not implemented to monitor the quality of the reference standard
(e.g., was implemented for research or validation work.).
Supporting Data
1. Information demonstrating qualification of the changed reference standards or
materials (e.g., source, characterization, certificate of analysis).
2. Justification of the change to the reference standard qualification protocol.
3. Updated reference standard qualification protocol.
4. Summary of stability testing and results or retest data to support the extension of
the reference standard shelf-life.
5. Justification for change in the reference standard.
3.2.P.7 Container Closure System

57. Change in primary container closure component, involving
a. modification of a container
closure system (e.g., new Notifiable
None 1-7
coating, adhesive, stopper, Change
prefilled syringe with attached
needle, prefilled syringe with Annual
1-3 3
separate needle). Notification
Note: The addition of a new container
closure system (e.g., addition of a pre‐
Annual
filled syringe where the currently 4 3, 6
Notification
approved presentation is only a vial) is
considered a change in presentation.
b. deletion of a container closure Annual
None 1
system Notification
c. change from a reusable container
to a disposable container with no
Notifiable
changes in product contact None 1, 3-4, 6
Change
material (e.g. change from
reusable pen to disposable pen)
Conditions
1. No change in the type of container closure or materials of construction.
2. The container closure shape dimensions or specifications are equivalent.
3. The change is made only to improve quality of the container and does not modify
the product contact material (e.g., increase thickness of the glass vial without
changing interior dimensions).
4. The modified part is not in contact with the Drug Product
Supporting Data
1. Revised Product Labelling information i.e. Package Insert and Inner and Outer
Labels, as appropriate.
2. For sterile products, process validation and/or evaluation studies (3.2.P.3.5).
3. Information on the proposed changed container closure system, as appropriate
(e.g., description, materials of construction of primary/secondary packaging
components, specifications) (3.2.P.7).
4. Summary of stability testing and results of minimum three months of accelerated
and a minimum of three (3) months of real time/real temperature testing on three
(3) commercial scale batches of the changed drug product stored in the
proposed container as well as commitment to submit the stability report when
completed and to notify CDSCO of any failures in the ongoing stability studies
(3.2.P.8.3). Matrixing, bracketing, the use of smaller scale batches and use of
fewer than 3 batches for stability testing of proposed changed drug product may
be acceptable if scientifically justified (refer ICH Q1D) by the manufacturer /MA
holder to CDSCO.
5. Summary of release testing results as quantitative data, in a comparative tabular
format, for at least three consecutive commercial-scale batches of the pre-
change and post-change drug product. Comparative pre-change test results do
not need to be generated concurrently; relevant historical testing results are
acceptable. Bracketing for multiple-strength products, container sizes and/or fills
may be acceptable if scientifically justified.
6. Information demonstrating suitability of the changed container/closure system
(e.g., results from last media fills, preservation of protein integrity, and
maintenance of the sterility in multi-dose container).
7. Results demonstrating protection against leakage, no leaching of undesirable
substance, compatibility with the product, and results from the toxicity and the
biological reactivity test.
Conditions
Description of Change Supporting Reporting
to be
Conditions Data Category
Fulfilled
58. Change in the supplier for a primary container closure component,
involving:
Notifiable
None 1-3
a. replacement or addition of a Change
supplier Annual
1, 2 3, 4
Notification
Annual
b. deletion of a supplier None None
Notification
Conditions
1. There is no change in the type of container closure, materials of construction;
and container closure shape, dimensions, specifications (or are equivalent) or in
the sterilization process for a sterile container closure component.
2. No change in the specifications of the container closure component outside of
the approved ranges.
Supporting Data
1. Data demonstrating the suitability of the container closure system (e.g.,
extractable/ leachable testing).
2. For sterile products, process validation and/or evaluation studies (3.2.P.3.5).
3. Information on the changed container closure system (e.g., description,
materials of construction of primary packaging components, specifications)
(3.2.P.7).
4. Certificate of analysis, or equivalent, for the container provided by the new
supplier and comparison with certificate of analysis, or equivalent, for the
approved container.

59. Change in the specifications for a primary container closure component or
functional secondary container closure component, involving:
Annual
a. deletion of a test 4, 5 1, 2
Notification
Notifiable
None 1
b. replacement or addition of a Change
test Annual
1-3 1, 2
Notification
c. relaxation of an acceptance Notifiable
None 1, 2
criterion Change
d. tightening of an acceptance Annual
1, 2 1
Conditions
2. The change is within the range of previously approved acceptance criteria.
5. The change to the specifications does not affect the functional properties of the
container closure component nor result in a potential impact on the performance
of the final product.
Supporting Data
1. Updated changed specifications, for the primary or functional secondary
container closure component (3.2.P.7).
2. Rationale for the change in specification for a primary container closure
component.

60. Change in the analytical procedures for a primary container closure
component or functional secondary container closure component
Notifiable
a. deletion, replacement or 3 1-3
Change
addition of an analytical
Annual
procedure 3, 4 1-3
Notification
b. minor changes to an Annual
1-4 1-3
Conditions
1. No change in the approved acceptance criteria outside the approved limits.
2. The analytical procedure is of the same type.
3. Results of method validation demonstrate that the proposed new or modified
analytical procedure is at least equivalent to the approved analytical procedure.
4. The new or modified analytical procedure maintains or tightens precision,
accuracy, specificity and sensitivity.
Supporting Data
1. Updated changed specifications. (3.2.P.7)
2. Description of the analytical procedure and, if applicable, validation data.
3. Rationale for the change in specification for a primary container closure
component.
3.2.P.8 Stability

61. Change in the shelf life for the drug product, involving:
a. extension (includes extension of Notifiable
None 1-4, 6, 7
shelf-life of the Drug Product as Change
packaged for sale, and hold 1-3, 4, 5 1, 2, 5, 7 Annual

time after opening and after Notification
dilution or reconstitution)
b. reduction (includes reduction as Notifiable
None 1-4, 5, 7
packaged for sale, after Change
opening, after dilution or Annual
6 2-4, 7
reconstitution) Notification
Conditions
1. No change to the container closure system in direct contact with the drug product
or to the recommended storage conditions of the drug product.
2. The approved re-test period (or shelf life) is at least 24 months.
3. Full long term stability data are available covering the changed re-test period (or
shelf life) and are based on stability data generated on at least three production
scale batches.
4. Stability data were generated in accordance with the approved stability protocol.
5. Significant changes (as defined in ICH's Q1A guideline) were not observed in the
stability data.
6. The reduction in the shelf life is not necessitated by recurring events arising
during manufacture or because of stability concerns.
Supporting Data
1. Summary of stability testing and results (e.g., studies conducted, protocols used,
results obtained) (3.2.P.8.3).
2. Proposed storage conditions and re-test period (or shelf life, as appropriate).
3. Updated post-approval stability protocol and stability commitment (3.2.P.8.2).
commitment.
5. Results of stability testing on both upright and inverted samples, except for
lyophilized products (i.e., full real time/real temperature stability data covering the
changed re-test period (or shelf life) generated on at least three (3) production
scale batches) (3.2.P.8.3).
6. Results of stability testing (i.e., less than full real time/real temperature stability
data covering the changed re-test period (or shelf life) and/or generated on less
than three (3) production scale batches), (3.2.P.8.3) and a commitment to submit
the stability report when completed and to notify CDSCO of any failures in the
ongoing stability studies. Full long term stability data are not available covering
the changed shelf life or are not based on stability data generated on at least
three batches, the extrapolation is in accordance with ICH's Q1E guideline.
7. Updated product labeling information, as applicable

62. Change in the labelled storage conditions for the drug product or the
diluted or reconstituted product, involving:
Notifiable
a. addition of a cautionary None 1, 2, 4, 5
Change
statement
Annual
(e.g. DO NOT FREEZE) 1 1, 2, 4, 5
Notification
b. deletion of a cautionary
Notifiable
statement None 1, 2, 4, 6
Change
(e.g. DO NOT FREEZE)
c. addition or change of Notifiable
None 1-5
storage condition for the Change
drug product, diluent or
reconstituted drug product Annual
1, 2 1-4
(e.g. relaxation or tightening Notification
of temperature criterion)
Conditions
2. The change consists in the tightening of a temperature criterion within the
approved ranges.
Supporting Data
as applicable.
2. Proposed storage conditions and shelf-life.
4. Justification of the change in the labelled storage conditions/cautionary
statement.
5. Results of stability testing under appropriate stability conditions covering the
proposed shelf-life, generated on one (1) commercial scale batch unless
otherwise justified (3.2.P.8.3).
6. Results of stability testing under appropriate conditions covering the proposed
shelf-life, generated on at least three (3) commercial scale batches unless
otherwise justified (3.2.P.8.3).

63. Change to the post-approval stability protocol or stability commitment of final
product, involving
a. major change to the post-approval
Notifiable
stability protocol or stability None 1-7
Change
commitment, such a deletion of a
test, replacement of an analytical
Annual
procedure, or change in storage 1, 4 2, 3, 5, 6
Notification
temperature
b. addition of time point (s) into the Annual

None 2, 3
post-approval stability protocol Notification
c. addition of test (s) into the post- Annual

1 2, 3, 5, 6
approval stability protocol Notification
d. deletion of time point (s) from the Annual
5 2, 3, 7
post-approval stability protocol Notification

beyond the approved shelf life
e. deletion of the time(s) from the
Annual
post-approval stability protocol 2 2, 3, 7
Notification
within the approved shelf-life
Notifiable
f. replacement of the sterility testing None 2, 3, 5-7
Change
by the container closure system
Annual
integrity testing 3 2, 3, 7
Notification
Condition
1. The addition of the test(s) is not due to stability concerns or to the identification of new
impurities.
2. The approved shelf–life of the final product is at least 24 months.
3. The method used to demonstrate the integrity of the container/closure system has
already been approved as part of a previous application.
4. For the replacement of an analytical procedure, the results of method validation
demonstrate that the new analytical procedure is at least equivalent to the approved
analytical procedure.
5. Deletion of the time-points is done according to relevant guideline (i.e. ICH Q5C).
Supporting Data
1. Proposed storage conditions and shelf life.
commitment.
4. If applicable, stability testing results to support the change to the post-approval stability
protocol or stability commitment. (3.2.P.8.3)
5. Copies or summaries of analytical procedures, if new analytical procedures are used
(3.2.P.5.2).
6. Validation study reports, if new analytical procedures are used (3.2.P.5.3).
7. Comparative results demonstrating that the approved and proposed analytical
procedure are equivalent.
5. POST-APPROVAL CHANGE MANAGEMENT PROTOCOL-PACMP
Conditions
Data Category
Fulfilled
a. Introduction of a post-approval
Notifiable
change management protocol None 1-3
Change
related to DS and/or DP
b. Deletion of an approved post-
Annual
approval change management 1 3, 4
Notification
protocol related to DS and/or DP
c. Minor changes to an approved Notifiable

None 3, 4
change management protocol Change
Conditions
1. The deletion of the approved change management protocol related to the active
substance is not a result of unexpected events or out of specification results
during the implementation of the change(s) described in the protocol and does
not have any effect on the already approved information in the dossier.
Supporting Data
1. Description of the proposed change
2. Change management protocol
3. Amendment of the relevant CTD CMC sections
4. Justification for the proposed change
6. EFFICACY POST APPROVAL CHANGES
Conditions
Data Category
Fulfilled
1. Change in the efficacy parameter
a. Addition of a new therapeutic

indication and/or modification of an 1 1-5 Supplement
approved one
amendment / endorsement of current Form 28 D license, as applicable.

dossier, shall be submitted, as applicable.
Notifiable
b. Deletion of a therapeutic indication None 3
Change
c. modification of an approved safety
claim, indication or efficacy claim
whether explicit or implicit (e.g.
expansion of the age of use or 1 1-5 Supplement
restriction of an indication based on
clinical studies demonstrating lack of
efficacy)
Conditions
1. No change in strength, dosage form and route of administration.
Supporting Data
1. Clinical data along with applicable preclinical data.
2. Copy of approval with new indication or any other regulatory certificate issued by
other recognized NRA or NRA of country of origin with new indication.

3. Copy of current Package Insert (PI) with proposed change,
4. Published data or relevant literature supporting the proposed change, if any.
5. Duly signed Form CT-18 or Form CT-21, with applicable fees (challan)
Conditions
Data Category
Fulfilled
2. Change / modification in the approved claim
a. new route of administration, new
strength (potency), or increase in
1 1-5 Supplement
the recommended dose / dosage
range
amendment / endorsement of current Form 28 D license, as applicable.

dossier, shall be submitted, as applicable.
Conditions
1. No change in, dosage form and indication.
Supporting Data
1. Clinical data along with applicable preclinical data
2. Copy of approval with new route of administration or any other regulatory
certificate issued by other recognized NRA or NRA of country of origin with new
route of administration.
3. Copy of current PI with the proposed change.
5. Duly signed Form CT-18 or Form CT-21, with applicable fees (challan)
Conditions
Data Category
Fulfilled
3. Other changes related to safety and efficacy, involving
a. change to add information on Notifiable
1 1-4
shedding and transmission Change
b. change in the recommended dose
and/ or dosing schedule (addition
None 1-4 Supplement
or modification new vaccination
regimen)
c. change to use in specific risk
groups (e.g. use in pregnant Notifiable
1 1-4
women or immunocompromised Change
patients)
d. change to add information on co-
Notifiable
administration with other vaccines 1 1-4
Change
or medicines
e. change to add a new delivery
1 1-4 Supplement
device
f. Change in existing risk-
management measures:
(i) deletion of an existing route of
administration, dosage form
and/or strength due to safety
Notifiable
reasons; 1 1-4
Change
(ii) deletion of a contraindication
(for example, use in pregnant
women);
(iii) changing a contraindication to
a precaution.
Conditions
1. No change in strength, dosage form and indication.
Supporting Data
1. Published clinical data along with applicable non-clinical data.
2. Copy of approval for proposed change or any other regulatory certificate issued
by other recognized NRA or NRA of country of origin with proposed change
3. Copy of current PI with proposed change.

a. Changes or replacement to the
active substance of a seasonal,
Notifiable
pre-pandemic or pandemic vaccine None 1-3
Change
against human influenza or
COVID-19
Conditions
None
Supporting Data
1. Revised CMC sections and labelling.
2. Pre-clinical data (Module 4) as applicable.
3. Clinical data (Module 5) as applicable.
7. ADMINISTRATIVE CHANGES

Description of the change
1. Change in the name and/or
address of the marketing Notifiable
authorization holder that was 1 1, 2
Change
granted the Marketing
Authorization for DS and / or

DP.
Conditions
1. The marketing authorization holder shall remain the same legal entity.
Supporting data
1. Approval for change of name as per statutory requirements.
2. Notification of new name in the form of a MA holder signed letter if the
manufacturer is sold or merged with another company. Note that if address
changes due to manufacturing facility change then MA application needs to be
resubmitted with fresh quality; safety and efficacy data according to the
manufacturing facility change requirements

2. Company sale, purchase, Notifiable
1 1-3
merger Change
Conditions
1. The marketing authorization holder shall remain the same legal entity.
Supporting data
1. Approval for sale/purchase as per statutory requirements.
2. Notification of new name if the manufacturer is sold or merged with another
company.
3. Revised labeling information.

3. Change in the (invented) name Notifiable
1 1, 2
of the product. Change
Conditions
1. The name is as per the updated Pharmacopeia.
Supporting data
1. Copy of the updated Pharmacopeia monograph.
as applicable.
8. PRODUCT LABELLING INFORMATION CHANGES
Product labelling information changes, which do not require clinical efficacy, safety
data or extensive pharmacovigilance (safety surveillance) data should be submitted.
Product labelling information changes require approval prior to implementation of
the change.
The following are examples of product labelling information changes that are
associated with changes that have an impact on clinical use:
1. Addition of an adverse event that is identified to be consistent with a causal

association to biological product concerned.
2. Change in the frequency of occurrence of a given adverse reaction.
3. Addition of a contraindication or a warning (e.g. identification of a specific

subpopulation as being at greater risk, such as persons with a concomitant
condition or taking concomitant medicines, or a specific age group). These
changes may include the provision of recommended risk-management actions
(e.g. required testing prior to vaccination, specific monitoring following
vaccination, ensuring patient awareness of certain risks).
In some cases, the safety-related changes listed above may be urgent and may
require rapid implementation (e.g. addition of a contraindication or a warning). To
allow for speedy processing of such requests, the submission for these changes
should be labelled as “Urgent Product Labelling Information Changes”.
9. APPENDICES
Appendix 1: Examples of Level IV Changes but not limited to
 Non-critical changes to the licensed application including spelling mistakes,

editorial changes and remediations made to documents such as Validation
Summaries and/or Reports, Analytical Procedures, SOPs, Production
Documentation Summaries, QOS, for added clarity that have no impact to affect
the safety, efficacy and quality of the product.
 Replacement of the membrane (filter) used during the UF/DF step.
 Replacement or addition of filter housing.
 Change in stopper cap colour for an injectable product.
 Modification to pretreatment stages of a WFI system, including purified water
systems used solely for pretreatment in WFI production.
 Change in the floor plan that does not affect production process or
contamination precautions.
 Addition of vial reject chute.
 Change in the in-process controls performed at non-critical manufacturing steps
or change to a non-critical manufacturing area (see Glossary).
 Transfer of in-process control testing to a different facility within a GMP-
compliant site
 Transfer of raw material / packaging material testing to a different facility within
GMP compliant site.
 Transfer of Pharmacopoeial testing of drug substance / drug product to a
different facility within GMP compliant site.
 Rooms upgrades, such as installation of improved finishes on floors/walls.
 Addition of a new GMP storage warehouse for raw materials, master and
working cell banks and drug substance.
 Installation of non-process-related equipment or rooms to improve the facility,
such as warehousing refrigerators or freezers.
 Replacement of equipment with identical equipment (non-product contact

equipment).
 Introduction of additional laboratory in a facility to perform drug substance
testing.
 Change in supplier for non-critical excipients.
 Change in tertiary packaging components of drug substance or drug product that
do not affect stability.
 Minor changes to the layout of the product labelling information items or revision
of typographical errors without changing the content of the label.
Appendix 2: ANNUAL REPORT FORM (Minor Changes)
January ________________ to December________________
Manufacturing site(s) or Area(s)

1.
involved
2. Product(s) involved
3. Description of change
4. Rationale of change
5. Reference to CDSCO guidelines Conditions:

6. Implementation date
Cross reference to validation protocols

7. and/ or SOP’s/STP’s/ Spec’s (If
relevant)
Relevant data from studies and tests

8. performed (Impact of change
assessed)
Submitted by: Date:

Appendix 3: Glossary
Adjuvant:
Component that potentiates the immune responses to an antigen/drug substance

and/or modulates it towards the desired immune responses. Adjuvant may be of
pharmaceutical origin (chemical/synthetic adjuvant) or of biological origin (biological
adjuvant).
Batch:
A quantity of drug in dosage form, a raw material, or a packaging material,

homogeneous within specified limits, produced according to a single production
order and as attested by the signatories to the order. In the case of continuous
manufacture, a batch corresponds to a defined fraction of the production that is
characterized by its intended homogeneity. It may sometimes be necessary to divide
a batch into a number of sub‐batches, which are later brought together to form a final
homogeneous batch.
Biological auxiliary material:
Raw material from a biological source which is intended to be used as a processing

aid in the fabrication of the drug. It may be absent from the drug or may remain as an
impurity in the drug at the end of the manufacturing process (e.g., biological
additives used to supplement cell culture medium in production fermenter, human
antithrombin III used to complex and remove human thrombin).
Biological starting material:
Raw material from a biological source which is intended to be used in the fabrication
of a drug and from which the active ingredient is derived either directly (e.g., plasma
derivatives, ascetic fluid, bovine lung, etc.) or indirectly (e.g., cell substrate,
host/vector production cells, eggs, viral strains, etc.).
Biotherapeutic product:
A biological medicinal product with the indication of treating human disease include
all biologically active protein products (including plasma-fractionated products) which
are used in the treatment of human diseases, and those intentionally modified by, for
example, fusion proteins, PEGylation, conjugation with a cytotoxic drug or
modification of rDNA sequences. They also include protein products used for in vivo
diagnosis (for example, monoclonal antibody products used for imaging).
Certificate of suitability (CEP):
A certificate of compliance of a substance with the relevant requirements of the

European Pharmacopoeia monographs for use in medicinal products issued by the
European Directorate for the Quality of Medicine of the Council of Europe (EDQM).
Change:
Refers to a change that includes, but is not limited to; the product composition,
manufacturing process, quality controls, equipment, facilities or product labelling
information made to an approved marketing authorization or license by the marketing
authorization holder. Also referred to as variation.
Change‐over procedure:
A logical series of validated steps that ensures the proper cleaning of suites and
equipment before the processing of a different product begins.
Closed process/closed system:
Process equipment or process step in which the product is not exposed to the
external environment. A closed system requires that the quality of materials entering
or leaving the system and the manner in which these materials are added/removed
from the system is carefully controlled.
Comparability study:
The activities, including study design, conduct of studies and evaluation of data that
are designed to investigate whether the pre- and post-change products are
comparable. In addition to routine analysis performed during production and control
of the antigen/drug substance or final product, these evaluations typically include a
comparison of manufacturing process steps and parameters impacted by the
change, characterization studies and an evaluation of product stability following the
change. In some cases, non-clinical or clinical data might contribute to the
conclusion.
Comparability protocol:
Establishes the tests to be done and acceptable limits to be achieved to demonstrate

the lack of a negative effect for specific manufacturing changes on the safety or
e f f i c a c y of the product. A comparability protocol is a highly specific, well defined
plan for the future implementation of a quality (i.e. manufacturing) change. Also
referred to as post-approval change management protocol.
Container closure system: refers to the following components:
 A primary container closure system is a packaging component that is in, or

may come into, direct contact with the drug product dosage form (for example,
vial or pre-filled syringe) or components that contribute to the
container/closure integrity of the primary packaging material for a sterile
product.
 A secondary container closure system is a packaging component that is not,
and will not be, in direct contact with the dosage form (for example, carton or
tray).
 A functional secondary container closure system is a packaging material that
is not in direct contact with the product and that provides additional protection
or serves to deliver the product.
Control Strategy:
A planned set of controls, derived from current product and process understanding
that ensures process performance and product quality. The controls can include
parameters and attributes related to drug substance and drug product materials and
components, facility and equipment operating conditions, in‐process controls,
finished product specifications, and the associated methods and frequency of
monitoring and control.
Critical manufacturing step:
A manufacturing process/step that may results in a potential change in the

purity/impurity profile or due to the nature of the starting materials or resulting
product/intermediate, requires containment within a specially designed
manufacturing area or production facility, for example, the development and
preparation of cell banks and seed lots, initial propagation, scale-up, blood and
plasma pooling and fractionation, fermentation, harvesting, inactivation, purification,
addition of adjuvants or preservatives, the conjugation and pooling of bulk
concentrates and the final preparation of drug product including concentration/
diafiltration, formulation, sterile filtration, filling and lyophilization.
Critical process parameter:
A process parameter whose variability has an impact on a critical quality attribute

and therefore should be monitored or controlled to ensure the process produces the
desired quality.
Critical Quality Attribute:
a physical, chemical, biological or microbiological property or characteristic that is

selected for its ability to indicate the consistent quality of the product within an
appropriate limit, range or distribution to ensure the desired product quality.
Design space:
The multidimensional combination and interaction of input variables (e.g., material

attributes) and process parameters that have been demonstrated to provide
assurance of quality. Working within the design space is not considered as a
change. Movement out of the design space is considered to be a change and would
normally initiate a regulatory post approval change process. Design space is
proposed by the applicant and is subject to regulatory assessment and approval.
Different host/media‐type:
Mammalian cells or any micro‐organisms involved in the manufacture of a drug

substance which are different from the existing hosts in the facility or use a cell
culture or fermentation medium with significantly differing composition.
Dosage form:
A drug product that has been processed to the point where it is now in a form in
which it may be administered in individual doses.
Drug product:
The dosage form in the final immediate packaging intended for marketing.
Drug substance:
The active pharmaceutical ingredient and associated molecules that may be

subsequently formulated to produce the drug product.
Equivalent equipment:
Equipment with the same technical parameters and fabricated with product- contact
material of same or higher grade quality. Equivalent equipment should give a product
of same quality as the one processed by the previous equipment.
Excipient:
Any component of the drug product, other than the active component/drug substance
and the packaging material, generally added during formulation. Also referred to as
“inactive ingredient” in other documents.
Facility/ Suite/Building:
A Facility/ Suite / building in which a specific manufacturing operation or multiple

operations take place, and for the purposes of this guidance only, the product-contact
equipment housed within the aforementioned Facility/ Suite / building.
Fermentation train:
Equipment and conditions involved in the stepwise expansion of the cell culture
process.
Final batch:
A collection of sealed final containers that is homogeneous with respect to the

composition of the product. A final batch must have been filled in one continuous
working session.
Formulated bulk:
An intermediate in the drug product manufacturing process, consisting of the final

formulation of drug substance and excipients at the concentration to be filled into
primary containers.
HVAC (Heating, Ventilation, and Air Conditioning):
Industry term for the systems and technology responsible for the heating, ventilation,
and air conditioning in buildings. HVAC systems regulate comfort (temperature and
humidity), energy efficiency, and air quality.
In-process control:
Check performed during production in order to monitor and, if necessary, to adjust

the process to ensure that the finished product conforms to its specifications. The
control of the production environment or equipment may also be regarded as part of
in-process control.
Intermediate:
A material produced during steps in the manufacture of a biotherapeutic product that
undergoes further processing before it becomes the drug product.
Manufacturer:
Any person or legal entity engaged in the manufacture of a product subject to
marketing authorization or licensure.
Marketing authorization:
A formal authorization for a medicine to be marketed. Once an NRA approves a

marketing authorization application for a new medicine, the medicine may be
marketed and may be available to be prescribed by physicians.
Marketing authorization application:
A formal application to the NRA for approval to market a new medicine. The purpose
of the marketing authorization application is to determine whether the medicine
meets the statutory standards for safety, efficacy, product labelling information and
manufacturing.
Marketing Authorization holder (MA holder):
Any person or legal entity or sponsor, or manufacturer or importer / license

manufacturer to manufacture / market a medicinal product that has received
marketing authorization or licensure to manufacture and/or distribute a medicine. It
also refers to a person or legal entity allowed to apply for a change to the marketing
authorization or license and is referred to as the manufacturer or applicant in this or
other documents.
Master cell bank (MCB):
An aliquot of a single pool of cells which generally has been prepared from the
selected cell clone under defined conditions, dispensed into multiple containers and
stored under defined conditions.
Mock-Up (i.e. Label, Carton, PI):
A full colour, actual size copy of the labels and a colour representation of the
packages intended to be used for the sale of the drug, including all
presentation/design elements, proposed graphics, fonts, colours and text
Multi-product facility/Suite:
A facility where more than one product of the same type or products from different
classes are fabricated (e.g., pharmaceutical and biological products).
Non‐critical area:
Area that does not encompass process steps.
Non‐critical excipient:
Excipient with no active function, e.g., solution used to adjust pH.
Non-critical manufacturing step:
A manufacturing process/step that has no impact upon purity and impurity profile or
requires no specific facility considerations, for example, buffer and media
preparation, storage of intermediates, and packaging (note that some biological
products may require critical temperature and/or light control during packaging).
Open system:
Any steps in a manufacturing process where in‐process materials or components are

exposed to the external environment.
Pilot scale:
A batch of a drug substance or drug product manufactured by a procedure fully

representative of and simulating that to be applied to a full production scale batch.
The methods of cell expansion, harvest, and product purification should be identical
except for the scale of production.
Presentation:
Container that contains the drug product. The container may be used directly or
indirectly in the administration of the drug (e.g., vials, pre-filled syringes, pre-filled
pens).
Primary container closure component:
Packaging material in direct contact with the product.
Primary packaging site:
Site involved in the activity of putting a drug in its primary container which is, or may
be, in direct contact with the dosage form.
Process validation:
Documented evidence which provides a high degree of assurance that a specific

process will consistently result in a product that meets its predetermined
specifications and quality characteristics.
Product labelling information:
Refers to printed materials that accompany a prescription medicine and all labelling
items, namely:
 prescribing information (an instruction circular that provides product

information on indication, dosage and administration, safety and efficacy,
contraindications, warnings and a description of the product for health-care
providers (also referred to as “summary of product characteristics” or
“package insert” in various countries);
 patient labelling or consumer information;
 inner label or container label;
 outer label or carton.
Quality attribute:
A physical, chemical, biological or microbiological property or characteristic.
Quality change:
A change in the manufacturing process, product composition, quality control testing,

equipment or facility. Also referred to as “chemistry manufacturing and control (CMC)
change” in other documents.
Raw materials:
A general term used to denote the culture media components, reagents or solvents
intended for use in the production of starting material, drug substance, intermediates
or drug products.
Real-time release testing:
Testing that provides the ability to evaluate and ensure the quality of in-process
and/or final product based on process data, which typically include a valid
combination of measured material attributes and process controls.
Reference standards/materials:
Well-characterized materials used as references against which batches of biological

products are assessed. These materials remain fundamental to ensuring the quality
of biological products as well as the consistency of production, and are essential for
the establishment of appropriate clinical dosing.
Reprocessing:
Subjecting all or part of a batch or lot of an in-process drug, a bulk process

intermediate (final biological bulk intermediate) or a bulk drug of a single batch/lot to
a previous step in the validated manufacturing process due to failure to meet
predetermined specifications.
r-DNA products:
Recombinant DNA (rDNA) molecules are DNA molecules formed by laboratory

methods of genetic recombination (such as molecular cloning) that bring together
genetic material from multiple sources, creating sequences.
Re-test period:
For biologics, also sometimes known as shelf life.
Safety and efficacy change:
A change that has an impact on the clinical use of the biotherapeutic product in
relation to safety, efficacy, dosage and administration, and that requires data from
clinical or post-marketing studies, and in some instances clinically relevant
nonclinical studies, to support the change
Secondary packaging facility:
Site involved in packaging activities using a packaging component that is not, and
will not be, in direct contact with the dosage form (for example, putting the primary
container in the outer container or affixing labels).
Shelf life (also referred to as expiration period):
The period of time during which a drug substance or drug product, if stored under the
conditions defined on the container label, is expected to comply with the
specification, as determined by stability studies on a number of batches of the
product. The expiry date is assigned to each batch by adding the shelf-life period to
the date of manufacture.
Similar Biologics:
“Similar biologic” means a biological product which is similar in terms of quality,

safety and efficacy to reference biological product licenced or approved in India, or
any innovator product approved in International Council of Harmonisation (ICH)
member countries.
Site/Premises:
The land occupied legally by company, which contains one or more manufacturing
facilities/suites/buildings cumulatively shall be called as premises, which will have its
own manufacturing license number issued by licensing authority.
Specification:
A list of tests, references to analytical procedures and appropriate acceptance

criteria which are numerical limits, ranges or other criteria for the tests described.
Specifications are critical quality standards that are proposed and justified by the
manufacturer and approved by the regulatory authorities.
Starting materials:
Materials that mark the beginning of the manufacturing process, as described in a
marketing authorization or product license. Generally, starting material refers to a
substance of defined chemical properties and structure that contributes an important
and/or significant structural element(s) to the active substance (examples for
vaccines: synthetic peptides, synthetic glycans, and starting materials for adjuvants).
The starting material for an antigen (drug substance) obtained from a biological
source is considered to consist of the 1) cells; 2) microorganisms; 3) plants, plant
parts, macroscopic fungi or algae; or 4) animal tissues, organs or body fluid from
which the antigen (drug substance) is derived.
Strength:
Quantity of medicinal ingredient in a particular dosage form. For solution,
concentration of the active pharmaceutical ingredient multiplied by the fill volume.
Vaccine:
A biological preparation that is used to stimulate the body’s immune response

against diseases.
Validation:
The demonstration, with documentary evidence, that any procedure, process,
equipment, material, activity or system will consistently produce a result meeting
predetermined acceptance criteria. Working cell bank (WCB): the working cell bank
is prepared from aliquots of a homogeneous suspension of cells obtained from
culturing the master cell bank under defined culture conditions.
Working cell bank (WCB):

The working cell bank is prepared from aliquots of a homogeneous suspension of
cells obtained from culturing the master cell bank under defined culture conditions.
10. REFERENCES
1. Drugs and Cosmetics Act 1940.

2. New Drugs and Clinical Trial Rules, 2019
3. Guidelines on Similar Biologics published by Department of Biotechnology
and CDSCO
4. Guidelines on procedures and data requirements for changes to approved
biotherapeutic products, Annex 3, WHO Technical Report Series 1011, 2018
5. Guidelines on procedures and data requirements for changes to approved
vaccines, Annex 4, WHO Technical Report Series 993, 2015
6. Post‐Notice of Compliance (NOC) Changes: Quality Document, Health
Canada, 2019
7. Stability Testing of New Drug Substances and Products (Q1A)
8. Stability Testing: Photostability Testing of New Drug Substances and Products
(Q1B)
9. Stability Testing for New Dosage Forms (Q1C)
10. Bracketing and Matrixing Designs for Stability Testing of New Drug
Substances and Products (Q1D)
11. Evaluation of Stability Data (Q1E)
12. Stability Testing of Biotechnological/Biological Products (Q5C)
13. Guidelines on stability evaluation of vaccines. In: WHO Expert Committee on
Biological Standardization: Fifty-Seventh report. Geneva: World Health
Organization; 2011: Annex 3 (WHO Technical Report Series, No. 962).

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Post Approval Changes in

Document No. - PAC/2024

Date Revised 28.02.2024

1.1 Objectives .................................................................................................................................................. 6

1.2 Scope and Application ............................................................................................................................ 7

1.3 Background ............................................................................................................................................... 7

2. GUIDANCE FOR IMPLEMENTATION ................................................................................................ 8

2.1 Reporting Categories for Quality Changes.......................................................................................... 8

2.1.1 Level I – Supplements (Major Quality Changes)............................................................................. 8

2.1.2 LeveI II – Notifiable Changes (Moderate Quality Changes) ......................................................... 9

2.1.3 Level III – Annual Notification (Minor Quality Changes) ............................................................... 9

2.1.4 Level IV – Changes (Record of Changes) ............................................................................................ 9

2.2 Documentation – Quality Changes ...................................................................................................... 10

2.2.1 General Information ............................................................................................................................... 10

2.2.2 Supporting Data – Level I and Level II Changes: .............................................................................. 11

2.2.3 Supporting Data – Level III Changes ................................................................................................. 11

2.2.4 Supporting Data – Level IV Changes .................................................................................................. 12

2.3 Reporting Categories for Safety, Efficacy Changes ......................................................................... 12

2.3.1 Level I – Supplements (Safety and Efficacy) ..................................................................................... 13

2.3.5 Documentation – Safety and Efficacy Changes: ............................................................................... 18

3. SPECIAL CONSIDERATIONS ............................................................................................................. 19

3.1 Comparative Studies.............................................................................................................................. 19

3.2 Bridging Clinical Studies........................................................................................................................ 20

3.3 Stability Testing ...................................................................................................................................... 21

3.4 Pharmaceutical Development and Quality by Design ...................................................................... 22

3.5 Multiple Changes .................................................................................................................................... 23

3.6 Post-Approval Change Management Protocol-PACMP ................................................................... 24

3.7 Production Documents .......................................................................................................................... 25

3.8 Expedited Review Procedure (Reliance Pathway) ........................................................................... 25

3.9 Similar Biotherapeutic Products (SBP) / Similar Biologics ............................................................... 25

4. POST APPROVAL CHANGES (BIOLOGICALS) .............................................................................. 26

3.2.S DRUG SUBSTANCE ................................................................................................................ 27

3.2.S.1 General Information................................................................................................................ 27

3.2.S.2 Manufacture ............................................................................................................................ 28

3.2.S.3 Characterization ..................................................................................................................... 50

3.2.S.4 Control of the Drug Substance ............................................................................................. 50

3.2.S.5 Reference Standards or Materials ....................................................................................... 58

3.2.S.6 Container Closure System .................................................................................................... 60

3.2.P DRUG PRODUCT ...................................................................................................................... 68

3.2.P.1 Description and Composition of the Drug Product ........................................................ 68

3.2.P.2 Pharmaceutical Development .......................................................................................... 77

3.2.P.3 Manufacture ........................................................................................................................ 77

3.2.P.4 Control of Excipients .......................................................................................................... 88

3.2.P.5 Control of Drug Product ..................................................................................................... 96

3.2.P.6 Reference Standards or Materials ................................................................................. 104

3.2.P.7 Container Closure System .............................................................................................. 106

3.2.P.8 Stability............................................................................................................................... 110

5. POST-APPROVAL CHANGE MANAGEMENT PROTOCOL-PACMP ........................................ 115

6. EFFICACY POST APPROVAL CHANGES ..................................................................................... 116

7. ADMINISTRATIVE CHANGES .......................................................................................................... 119

8. PRODUCT LABELLING INFORMATION CHANGES .................................................................... 121

9. APPENDICES ....................................................................................................................................... 122

Appendix 1: Examples of Level IV Changes but not limited to ......................................................... 122

Appendix 2: ANNUAL REPORT FORM (Minor Changes) ................................................................. 123

Appendix 3: Glossary ............................................................................................................................... 125

10. REFERENCES ..................................................................................................................................... 138

TSE : Transmissible Spongiform Encephalopathy

Changes are essential for the continual improvement of the manufacturing

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