Annex 3

WHO guidelines on variations to a prequalified product

Introduction 96
1. Background 97
1.1 Objectives 97
1.2 Scope and application 98
2. Guidance for implementation 99
2.1 Reporting types 99
2.1.1 Notifications 100
2.1.2 Minor variation (Vmin) 101
2.1.3 Major variation (Vmaj) 101
2.1.4 New applications and extension applications 101
2.1.5 Labelling information 101
2.2 Conditions to be fulfilled 101
2.3 Documentation required 102
3. Glossary 102
4. Administrative changes 104
1. Change in the name and/or corporate address of the supplier of the FPP 104
2. Change in the name or address of a manufacturer of an API that is not a supplier
of a prequalified API or that is not supported by a CEP 105
3. Change in the name and/or address of a manufacturer of the FPP 105
4. Deletion of a manufacturing site or manufacturer 105
5. Changes to a CEP or to a confirmation of API-prequalification
document 106
5. Submission of a new or updated CEP for an API or starting material or
intermediate used in the manufacturing process of the API 106
6. Submission of a new or updated confirmation of API-prequalification document 107
7. Submission of a new or updated transmissible spongiform encephalopathy
(TSE) CEP for an excipient or API (addition or replacement) 108
6. Quality changes 108
3.2. S Drug substance (or API) 108
3.2. S.2 Manufacture 108
8. Replacement or addition of a new manufacturing site or manufacturer of an API 108
9. Change or addition of a manufacturing block or unit at a currently accepted site
of API manufacture 112
10. Change in the manufacturing process of the API 112
11. Change in the in-process tests or limits applied during the manufacture of the API 114
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 WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-seventh report

12. Change in batch size of the API or intermediate 116

13. Change to the specifications or analytical procedures applied to materials used
in the manufacture of the API (e.g. raw materials, starting materials, reaction
intermediates, solvents, reagents, catalysts) 117
3.2. S.4 Control of the API by the API manufacturer 118
14. Changes to the test parameters, acceptance criteria, or analytical procedures
of the API manufacturer that do not require a change to the FPP manufacturer's
API specifications 118
3.2. S.4 Control of the API by the FPP manufacturer 119
15. Change to the test parameters or acceptance criteria of the API specifications
of the FPP manufacturer 119
16. Change to the analytical procedures used to control the API by the FPP
manufacturer 121
3.2. S.6 Container-closure system 123
17. Change in the immediate packaging (primary and functional secondary
components) for the storage and shipment of the API 123
18. Change in the specifications of the immediate packaging for the storage and
shipment of the API 124
19. Change to an analytical procedure on the immediate packaging of the API 125
3.2. S.7 Stability 126
20. Change in the retest period or shelf-life of the API 126
21. Change in the labelled storage conditions of the API 126
3.2. P Drug product (or FPP) 127
3.2. P.1 Description and composition of the FPP 127
22. Change in the composition of a solution dosage form 127
23. Change in the colouring system or the flavouring system currently used in
the FPP 128
24. Change in weight of tablet coatings or capsule shells 130
25. Change in the composition of an immediate-release solid oral dosage form 130
26. Change or addition of imprints, embossing or other markings, including
replacement or addition of inks used for product markings and change in
scoring configuration 132
27. Change in dimensions without change in qualitative or quantitative
WHO Technical Report Series No. 981, 2013

composition and mean mass 133

3.2. P.3 Manufacture 134
28. Addition or replacement of a manufacturing site for part or all of the
manufacturing process for an FPP 134
29. Replacement or addition of a site involving batch control testing 136
30. Change in the batch size of the FPP 136
31. Change in the manufacturing process of the FPP 138
32. Change to in-process tests or limits applied during the manufacture of the FPP
or intermediate 139
3.2. P.4 Control of excipients 140
33. Change in source of an excipient from a TSE risk to a material of vegetable or
synthetic origin 140
34. Change in the specifications or analytical procedures for an excipient 141
35. Change in specifications of an excipient to comply with an officially recognized
pharmacopoeia 141
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 Annex 3

3.2. P.5 Control of FPP 142

36. Change in the standard claimed for the FPP from an in-house to an officially
recognized pharmacopoeial standard 142
37. Change in the specifications of the FPP involving test parameters and
acceptance criteria 143
38. Change in the analytical procedures for the FPP 144
3.2. P.7 Container-closure system 145
39. Replacement or addition of a primary packaging type 145
40. Change in the package size 146
41. Change in the shape or dimensions of the container or closure 147
42. Change in qualitative and/or quantitative composition of the immediate
packaging material 147
43. Change in the specifications of the immediate packaging 148
44. Change to an analytical procedure on the immediate packaging 149
45. Change in any part of the (primary) packaging material not in contact with
the FPP formulation (e.g. colour of flip-off caps, colour code rings on ampoules,
or change of needle shield) 150
46. Change to an administration or measuring device that is not an integral part of
the primary packaging (excluding spacer devices for metered dose inhalers) 150
3.2. P.8 Stability 151
47. Change in the shelf-life of the FPP (as packaged for sale) 151
48. Change in the in-use period of the FPP (after first opening or after reconstitution
or dilution) 151
49. Change in the labelled storage conditions of the finished pharmaceutical product
(as packaged for sale), the product during the in-use period or the product after
reconstitution or dilution 152
Appendix 1. Examples of changes that make a new application or extension application
necessary 153

Appendix 2. Changes to excipients 154

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 WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-seventh report

Introduction
The variation guidelines have been completely updated and expanded, bringing
them into line with the principles of the new generic quality guidelines, WHO
Guidelines on submission of documentation for a multisource (generic) finished
pharmaceutical product for the WHO Prequalification of Medicines Programme:
quality part.
The guidelines1 retain the basic structure and function of the previous
variation guidelines, and have been expanded to include the classification of
additional post-approval/post-prequalification changes and to establish the level
of risk inherent to each change.2 Although the general requirements have not
significantly changed, the additional details help the reader to classify changes
that may occur related to all the major sections of a quality dossier, to understand
the considerations necessary to assess the risk of each change, and to determine
the documentation required to support the change.
In some cases, changes that previously were considered major changes
by default are now classified minor variations or notifications, and some minor
variations have been reclassified as notifications. In addition, for some categories
that previously required acceptance of the change prior to implementation, the
applicant can now implement the change immediately upon notification.
The change categories are organized according to the structure of the
common technical document (CTD). The specific CTD sections associated with
individual data requirements have been identified in order to assist in the filing of
documentation (reproduced with corresponding numbers in bold). Presentation
corresponds to section 1.4 in Annex 4 of WHO Technical Report Series, No. 970.3
Changes are classified as major only in those instances where the level
of risk is considered to be high and it is deemed necessary to provide the WHO
Prequalification of Medicines Programme (WHO/PQP) with adequate time
for an assessment of the supporting documentation. Particular circumstances
are identified where lower reporting requirements (annual notification (AN),
WHO Technical Report Series No. 981, 2013

immediate notification (IN) or minor variation (Vmin)) are possible. In all cases
where notification to WHO/PQP or acceptance by WHO/PQP is required prior

1
Guidance on variations to a prequalified product dossier. In: WHO Expert Committee on Specifications for
Pharmaceutical Preparations. Forty-first report. Geneva, World Health Organization, 2007 (WHO Technical
Report Series, No. 943), Annex 6.
2
WHO Guidelines on quality risk management. In: WHO Expert Committee on Specifications for
Pharmaceutical Preparations. Forty-seventh report. Geneva, World Health Organization, 2013 (WHO
Technical Report Series, No. 981), Annex 2.
3
Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product
for the WHO Prequalification of Medicines Programme: quality part. In: WHO Expert Committee on
Specifications for Pharmaceutical Preparations. Forty-sixth report. Geneva, World Health Organization, 2012
(WHO Technical Report Series, No. 970), Annex 4.
96
 Annex 3

to implementation, assessment timelines will be published in order to provide

predictable and reasonable timeframes.
In addition, the guidelines assist in understanding the possible
consequences of the listed changes, and may be useful as a risk management tool
to promote or enhance best practices within organizations.
A companion Question and Answer document is in preparation to assist
in interpretation of the guidelines. This document will address many of the
questions raised during the guidelines circulation process.

1. Background
This guidance document is technically and structurally inspired by the European
Union Institutions and Bodies Commission's Guideline on the details of the
various categories of variations to the terms of marketing authorizations for
medicinal products for human use and veterinary medicinal products. It is
intended to provide supportive information on how to present an application to
implement a change to a product.
This guidance supersedes the guidance published in 2007.4
An applicant is responsible for the safety, efficacy and quality of a product
throughout its life-cycle. Therefore, the applicant is required to make changes to the
details of the product in order to accommodate technical and scientific progress,
or to improve or introduce additional safeguards for the prequalified product.
Such changes, whether administrative or substantive, are referred to as variations
and may be subject to acceptance by WHO/PQP prior to implementation.
Technical requirements for the different types of variations are set out in
these guidelines in order to facilitate the submission of appropriate documentation
by applicants and their assessment by WHO/PQP and to ensure that variations to
the medicinal product do not result in health concerns.
The procedure for submitting variations is not within the scope of these
guidelines. Advice on the procedure for submitting a variation and current review
timelines are set out on the WHO/PQP web site which may be updated from time
to time. Applicants are advised to consult information on the web site whenever
they are considering the submission of a variation application.

1.1 Objectives
These guidelines are intended to:
■ assist applicants with the classification of changes made to the
quality part of a prequalified finished pharmaceutical product (FPP);

4
See footnote 1.
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 WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-seventh report

■ provide guidance on the technical and other general data

requirements to support changes to the quality attributes of the active
pharmaceutical ingredient (API) or FPP.

1.2 Scope and application

These guidelines apply to applicants intending to make changes to the quality
sections of product dossiers for an API or an FPP. This guidance should be read
in conjunction with the WHO Guidelines on submission of documentation for a
multisource (generic) finished pharmaceutical product for the WHO Prequalification
of Medicines Programme: quality part 5 as well as other related WHO guidelines.
This guidance document is applicable only to APIs and excipients
manufactured by chemical synthesis or semi-synthetic processes and FPPs
containing such APIs and excipients. APIs produced by fermentation and APIs
of biological, biotechnological or herbal origin are treated as special cases. The
applicant is requested to contact WHO/PQP regarding planned variations to
such products.
The notification requirements for API-related changes differ depending
on the manner in which information on the API was submitted in the FPP
application, namely, use of a prequalified API, use of a European Pharmacopoeia
Certificate of Suitability (CEP), use of the API master file (APIMF) procedure, or
as provided in full within the dossier.
The conditions and documentation stipulated in this guidance for API-
related variations focus primarily on those FPPs that relied upon the provision
of full API information within the FPP dossier. In general FPPs that rely upon
the APIMF procedure have reduced reporting requirements because the API
manufacturers themselves have notified the relevant API-related change directly
to WHO/PQP. Similarly, when an FPP relies upon a CEP or a prequalified API,
FPP applicants are required to notify WHO/PQP only when the associated CEP
or Confirmation of API Prequalification document has been revised.
WHO Technical Report Series No. 981, 2013

Guidance for API manufacturers on the technical and procedural

requirements for changes to prequalified APIs and to APIs supported by the
APIMF procedure is available on the Prequalification web site. Regardless of
whether the API-related change is notified primarily by the API manufacturer
(API prequalification (API-PQ) procedure, APIMF procedure or CEP), or the
FPP manufacturer (full API information in dossier) the technical requirements
are in principle the same as those stipulated in these guidelines.
Whenever FPPs have been prequalified on the basis of approval by a
stringent regulatory authority (SRA) (innovator products or generic products),
subsequent applications for variations should be approved by the same SRA and

5
See footnote 3.
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 Annex 3

WHO/PQP should be notified of the approval of the changes. Applicants are

advised to refer to the Letter of Prequalification.
When a variation leads to a revision of the summary of product
characteristics (SmPC), the patient information leaflet (PIL), labelling and
packaging leaflet and updated product information should be submitted as part
of the application.
For variations that require generation of stability data on the API or FPP,
the stability studies required, including commitment batches, should always be
continued to cover the currently accepted retest or shelf-life period. WHO/PQP
should be informed immediately if any problems with the stability of APIs or
FPPs occur during storage, e.g. if found to be outside specifications or potentially
outside specifications.
Applicants should be aware that some variations may require the
submission of additional consequential variations, including where the variation
states, “no variation is required, such changes are handled as amendments to
the APIMF by the APIMF holder”. Therefore, for any given change the applicant
should consider whether one or more variations may be required to be submitted.
If changes to the dossier only concern editorial changes, such changes
need not be submitted as a separate variation, but can be included as a notification
together with a subsequent variation concerning that part of the dossier. In
such a case, a declaration should be provided that the contents of the associated
sections of the dossier have not been changed by the editorial changes beyond the
substance of the variation submitted.

2. Guidance for implementation

2.1 Reporting types
The definitions outlined in the following reporting types are intended to provide
guidance with respect to the classification of quality-related changes. Specific
examples of changes are provided in these guidelines. However, it should be noted
that a change not covered by these guidelines, should be considered as a major
change by default. Whenever the applicant is unclear about the classification of a
particular change, WHO/PQP should be contacted. It remains the responsibility
of the applicant to submit relevant documentation to justify that the change will
not have a negative impact on the quality of the product.
Individual changes normally require the submission of separate variations.
Grouping of variations is acceptable only under the following circumstances:

■ when variations are consequential to each other, e.g. introduction of a

new impurity specification that requires a new analytical procedure;
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 WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-seventh report

■ when the same change affects multiple FPPs, e.g. addition of a new
API manufacturing site for multiple FPPs;
■ when all the changes are annual notification.
For the purposes of classification, an application involving two or more
types of variations will be considered as the highest risk type, e.g. a variation
grouping both a minor change and a major change will be classified as a major
change.
Applicants are also advised to exercise caution whenever several changes
to the same FPP are envisaged. Although each of the individual changes may
be classified as a particular reporting type, classification within a higher risk
category may be warranted as a result of the composite effect of these changes. In
all such cases, applicants are advised to contact WHO/PQP prior to submission
of the variation application to obtain guidance on classifying such changes.

2.1.1 Notifications
Notifications are changes that could have minimal or no adverse effects on
the overall safety, efficacy and quality of the FPP. Such notifications do not
require prior acceptance, but must be notified to WHO/PQP immediately after
implementation (immediate notification (IN)), or within 12 months following
implementation (annual notification (AN)) of the change.
It should be highlighted that an IN or AN may be rejected in specific
circumstances with the consequence that the applicant must cease to apply the
already implemented variation.

Annual notification (AN)

Applicants must satisfy themselves that they meet all of the prescribed conditions
for the change. The change should be summarized as part of the notification but
the indicated documentation is not required to be submitted. The documentation
WHO Technical Report Series No. 981, 2013

indicated for ANs should be available on request or at the time of inspection.

ANs should be submitted to WHO/PQP within 12 months of implementation
of the changes. For convenience applicants may group several AN changes as a
single submission.

Immediate notification (IN)

Applicants must satisfy themselves that they meet all of the prescribed conditions
for the change and submit all required documentation with the notification
application. Such changes can be implemented immediately at the time of
submission and they can be considered accepted if an objection is not issued by
WHO/PQP within 30 calendar days of the date of acknowledgement of receipt
of the application.
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 Annex 3

2.1.2 Minor variation (Vmin)

Minor variations are changes that may have minor effects on the overall safety,
efficacy and quality of the FPP. Applicants must satisfy themselves that they
meet all of the prescribed conditions for the change and submit all required
documentation with the variation application.
Such variations can be implemented if no objection letter has been issued
within a time period indicated on the WHO/PQP web site. Should questions
arise during the specified period, the change can only be implemented on receipt
of a letter of acceptance from WHO/PQP.

2.1.3 Major variation (Vmaj)

Major variations are changes that could have major effects on the overall safety,
efficacy and quality of the FPP. The documentation required for the changes
included in this reporting type should be submitted. Prior acceptance by
WHO/PQP is required before the changes can be implemented. A letter of
acceptance will be issued for all major variations if and when the variation is
considered acceptable.

2.1.4 New applications and extension applications

Certain changes are so fundamental that they alter the terms of the accepted
dossier and consequently cannot be considered as changes. In these cases a new
dossier must be submitted. Examples of such changes are listed in Appendix 1.

2.1.5 Labelling information

For any change to labelling information (SmPC, PIL, labels) not covered by the
variation categories described in this document, WHO/PQP must be notified and
submission of the revised labelling information is expected as per the guidance
on the WHO/PQP web site.

2.2 Conditions to be fulfilled

For each variation, attempts have been made to identify particular circumstances
where lower reporting requirements (IN, AN or Vmin) are possible. A change
that does not meet all of the conditions stipulated for these specific circumstances
is considered to be a Vmaj.
In some circumstances Vmaj categories have been specifically stated for
a given variation. This has been done to indicate to applicants what documents
should be provided. This is for informational purposes only. The list of
documentation is not intended to be comprehensive and further documentation
may be required. For all changes it remains the responsibility of the applicant to
provide all necessary documents to demonstrate that the change does not have a
negative effect on the safety, efficacy or quality of the FPP.
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 WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-seventh report

2.3 Documentation required

Examples of variations are organized according to the structure of the CTD. For
each variation, certain documents have been identified as supporting data and are
organized according to CTD structure. Regardless of the documents specified,
applicants should ensure that they have provided all relevant information to
support the variation.
Where applicable, the following should be included in the application:
■ a variation application form (a template can be downloaded from
the web site). All sections of this form should be completed and the
document signed. Electronic versions of the application form, both as
a Word document and a scanned signed PDF, should be provided in
addition to the printed version;
■ an updated quality information summary (QIS) (if applicable);
■ replacement of the relevant sections of the dossier as per CTD format;
■ copies of SmPC, PIL and labels, if relevant.
It should be noted that WHO/PQP reserves the right to request further
information not explicitly described in these guidelines.
The QIS provides a summary of the key quality information from the
product dossier. For FPPs that have an agreed-upon QIS, the QIS should be
revised and submitted (in Word format only) with every variation application.
Any revised sections within the QIS should be highlighted. If there is no change
to the QIS as a result of the variation, a statement should be made in the covering
letter to this effect.
Alternative approaches to the principles and practices described in this
document may be acceptable provided they are supported by adequate scientific
justification. It is also important to note that WHO/PQP may request information
or material, or define conditions not specifically described in this guidance, in
WHO Technical Report Series No. 981, 2013

order to adequately assess the safety, efficacy and quality of an FPP.

3. Glossary
The definitions provided below apply to the terms used in this guidance. They
may have different meanings in other contexts and documents.
active pharmaceutical ingredient (API)
A substance used in the FPP, intended to furnish pharmacological activity or
to otherwise have direct effect in the diagnosis, cure, mitigation, treatment or
prevention of disease, or to have direct effect in restoring, correcting or modifying
physiological functions in human beings.
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 Annex 3

active pharmaceutical ingredient (API) starting material

A raw material, intermediate, or an API that is used in the production of an API
and that is incorporated as a significant structural fragment into the structure
of the API. An API starting material can be an article of commerce, a material
purchased from one or more suppliers under contract or commercial agreement,
or produced in-house.
applicant
For the purposes of this document, the term applicant refers to any person or
entity who has participated in the procedure for prequalification of FPPs by
submission of the required documentation on a product that has been listed after
evaluation as prequalified.
biobatch
The batch used to establish bioequivalence or similarity to the comparator
product as determined in bioequivalence or biowaiver studies, respectively.
final intermediate
The last reaction intermediate in the synthetic pathway that undergoes synthetic
transformation to the API or the crude API. Purification is not considered to be
a synthetic transformation.
finished pharmaceutical product (FPP)
A finished dosage form of a pharmaceutical product which has undergone all
stages of manufacture including packaging in its final container and labelling.
in-process control
Check performed during manufacture to monitor or to adjust the process in
order to ensure that the final product conforms to its specifications.
manufacturer
A company that carries out operations such as production, packaging, repackaging,
labelling and re-labelling of pharmaceuticals.
officially recognized pharmacopoeia (or compendium)
Those pharmacopoeias recognized in the WHO/PQP (i.e. The International
Pharmacopoeia (Ph. Int.), the European Pharmacopoeia (Ph. Eur.), the British
Pharmacopoeia (BP), the Japanese Pharmacopoeia (JP) and the United States
Pharmacopeia (USP)).
pilot-scale batch
A batch of an API or FPP manufactured by a procedure fully representative of
and simulating that to be applied to a full production-scale batch. For example,
for solid oral dosage forms, a pilot scale is generally, at a minimum, one-tenth
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 WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-seventh report

that of a full production scale or 100 000 tablets or capsules, whichever is the
larger, unless otherwise adequately justified.6
production batch
A batch of an API or FPP manufactured at production scale by using production
equipment in a production facility as specified in the application.
stringent regulatory authority (SRA)
A stringent regulatory authority is:
■ the medicines regulatory authority in a country which is: (a) a
member of the International Conference on Harmonisation (ICH)
(European Union (EU), Japan and the United States of America); or
(b) an ICH Observer, being the European Free Trade Association
(EFTA) as represented by SwissMedic and Health Canada (as may be
updated from time to time); or (c) a regulatory authority associated
with an ICH member through a legally-binding, mutual recognition
agreement including Australia, Iceland, Liechtenstein and Norway (as
may be updated from time to time);
■ only in relation to good manufacturing practices (GMP)
inspections: a medicines regulatory authority that is a member of the
Pharmaceutical Inspection Co-operation Scheme (PIC/S) as specified
at http://www.picscheme.org

4. Administrative changes

Description of change Conditions to Documentation Reporting

be fulfilled required type
1 Change in the name and/ 1 1 IN
WHO Technical Report Series No. 981, 2013

or corporate address of the

supplier of the FPP.

Conditions to be fulfilled
1. Confirmation that the supplier of the product remains the same legal entity.
Documentation required
1. A formal document from a relevant official body (e.g. the national medicines
regulatory authority (NMRA)) in which the new name and/or address is mentioned.
continues

6
Procedure for prequalification of pharmaceutical products. In: WHO Expert Committee on Specifications for
Pharmaceutical Preparations. Forty-third report. Geneva, World Health Organization, 2009 (WHO Technical
Report Series, No. 953), Annex 3.
104
 Annex 3

Table continued
Description of change Conditions to Documentation Reporting
be fulfilled required type
2 Change in the name or 1 1–2 IN
address of a manufacturer of
an API that is not a supplier
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2. An updated Letter of Access in case of change in the name of the holder of the APIMF.

Description of change Conditions to Documentation Reporting

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Description of change Conditions to Documentation Reporting

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105
 WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-seventh report

Table continued
Conditions to be fulfilled
1. At least one other site continues to perform the same function(s) as the site(s)
intended to be deleted.
2. The deletion of the site is not a result of critical deficiencies in manufacturing.
Documentation required
1. Clear identification of the manufacturing, packaging and/or testing site to be deleted,
in the letter accompanying the application.

5. Changes to a CEP or to a confirmation

of API-prequalification document

Description of change Conditions to Documentation Reporting

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1. No change in the FPP release and shelf-life specifications.
WHO Technical Report Series No. 981, 2013


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106
 Annex 3

Table continued
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"1*
EBUB
SFRVJSFNFOUT
UP
TVQQPSU
UIF
QSPEVDU

dossier.
3. Replacement of the relevant pages of the dossier with the revised information for
UIF
$&1
TVCNJTTJPO
PQUJPO
TUJQVMBUFE
VOEFS
TFDUJPO
4
PG
UIF
8)0
Guidelines
on submission of documentation for a multisource (generic) finished pharmaceutical
product for the WHO Prequalification of Medicines Programme: quality part.
4. (S.2.5) For sterile APIs, data on the sterilization process of the API, including
validation data.

1

*O
UIF
DBTF
PG
UIF
TVCNJTTJPO
PG
B
$&1
GPS
BO
"1*
JG
UIF
RVBMJUZ
DIBSBDUFSJTUJDT

of the API are changed in such a way that it may impact the stability of the FPP,
a commitment to put under stability one batch of the FPP of at least pilot-scale,
and to continue the study throughout the currently accepted shelf-life and to
immediately report any out-of-specification results to WHO/PQP.
6. (S.4.1) Copy of FPP manufacturer’s revised API specifications.

Description of change Conditions to Documentation Reporting

be fulfilled required type

6 4VCNJTTJPO
PG
B
OFX
PS
VQEBUFE
DPOmSNBUJPO
PG
"1*QSFRVBMJmDBUJPO

document
6a.1 from a currently accepted 1–3 1–3, 5 AN
manufacturer
6a.2 1–2 1–5 Vmin
6b.1 from a new manufacturer 1–3 1–3, 5 IN
6b.2 1–2 1–5 Vmin

Conditions to be fulfilled
1. No change in the FPP release and shelf-life specifications.
2. For low solubility APIs the API polymorph is the same, and whenever particle size is
DSJUJDBM
JODMVEJOH
MPX
TPMVCJMJUZ
"1*T

UIFSF
JT
OP
TJHOJmDBOU
EJõFSFODF
JO
QBSUJDMF
TJ[F

distribution, compared to the API lot used in the preparation of the biobatch.

5IFSF
JT
OP
EJõFSFODF
JO
JNQVSJUZ
QSPmMF
PG
UIF
QSPQPTFE
"1*
UP
CF
TVQQMJFE

including organic, inorganic, genotoxic impurities and residual solvents, compared
to that of the API currently supplied. The proposed API manufacturer's specifications
EP
OPU
SFRVJSF
UIF
SFWJTJPO
PG
UIF
'11
NBOVGBDUVSFShT
"1*
TQFDJmDBUJPOT
continues
107
 WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-seventh report

Table continued
Documentation required
1. Copy of the current (updated) confirmation of API-PQ document. The API
manufacturer should duly fill out the authorization box with the name of the
applicant or FPP manufacturer seeking to use the document.
2. Replacement of the relevant pages of the dossier with the revised information
for the API-PQ procedure submission option (Option 1: confirmation of API
Prequalification document) stipulated under section 3.2.S. of the WHO Guidelines
on submission of documentation for a multisource (generic) finished pharmaceutical
product for the WHO Prequalification of Medicines Programme: quality part.
3. (S.2.5) For sterile APIs, data on the sterilization process of the API, including validation.
4. (S.4.1) Copy of FPP manufacturer's revised API specifications.

1

*G
UIF
RVBMJUZ
DIBSBDUFSJTUJDT
PG
UIF
"1*
BSF
DIBOHFE
JO
TVDI
B
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UIBU
JU
NBZ

impact the stability of the FPP, a commitment to put under stability one batch of
at least pilot-scale of the FPP and to continue the study throughout the currently
accepted shelf-life and to immediately report any out-of-specification results to
WHO/PQP.

Description of change Conditions to Documentation Reporting

be fulfilled required type
7 Submission of a new or None 1 AN
updated transmissible
spongiform encephalopathy
54&

$&1
GPS
BO
FYDJQJFOU
PS

API (addition or replacement)
Conditions to be fulfilled
None
Documentation required

$PQZ
PG
UIF
DVSSFOU
VQEBUFE

54&
$&1
WHO Technical Report Series No. 981, 2013

6. Quality changes
3.2. S Drug substance (or API)
3.2. S.2 Manufacture

Description of change Conditions to Documentation Reporting

be fulfilled required type
8 Replacement or addition of a new manufacturing site or manufacturer of an
API involving:
continues
108
 Annex 3

Table continued
Description of change Conditions to Documentation Reporting
be fulfilled required type
8a.1 API testing only 1, 2, 4 1, 3–4 IN
8a.2 2, 4 1, 3–4 Vmin
8b.1 production of API starting 3–4 /P
WBSJBUJPO
JT
SFRVJSFE

material such changes are handled as
amendments to the APIMF by
the APIMF holder.
8b.2 4–5 1–2, 12 IN
8b.3 None 1,2,5, 7–8,12, 13 Vmaj
8c.1 production of API 3–4 /P
WBSJBUJPO
JT
SFRVJSFE

intermediate such changes are handled as
amendments to the APIMF by
the APIMF holder.
8c.2 4, 6 1–2, 12 IN
8c.3 None 1, 2, 5, 7–8, 12, 13 Vmaj
8d.1 production of API (APIMF 3, 7–9 1, 2, 6, 8 IN
procedure)
8d.2 3, 7, 9 1, 2, 6–8 Vmin
8e.1 production of API (full 1, 9–11 1–2, 4, 8–9 IN
dossier)
8e.2 None 1, 2, 4, 5, 7–8, Vmaj
10–11, 13
Conditions to be fulfilled
1. The API is non-sterile.
2. The transfer of analytical methods has been successfully undertaken.
3. The new site is supported by an APIMF that is currently accepted through the
APIMF procedure and the FPP manufacturer holds a valid Letter of Access.
4. No change in the FPP manufacturer's API specifications.
5. The impurity profile of the API starting material is essentially the same as other
BDDFQUFE
TPVSDFT
5IF
JOUSPEVDUJPO
PG
UIF
OFX
TVQQMJFS
EPFT
OPU
SFRVJSF
UIF

revision of the API manufacturer's API starting material specifications. The route of
synthesis is verified as identical to that already accepted.
6. Specifications (including in-process, methods of analysis of all materials), method
of manufacture and detailed route of synthesis are verified as identical to those
BMSFBEZ
BDDFQUFE
5IF
JOUSPEVDUJPO
PG
UIF
OFX
TVQQMJFS
EPFT
OPU
SFRVJSF
UIF

revision of the API manufacturer's API intermediate specifications.
continues
109
 WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-seventh report

Table continued
Conditions to be fulfilled
7. No change in the FPP release and end-of-shelf-life specifications.

/P
EJõFSFODF
JO
JNQVSJUZ
QSPmMF
PG
UIF
QSPQPTFE
"1*
UP
CF
TVQQMJFE
JODMVEJOH

organic, inorganic and genotoxic impurities and residual solvents. The proposed
"1*
NBOVGBDUVSFST
TQFDJmDBUJPOT
EP
OPU
SFRVJSF
UIF
SFWJTJPO
PG
UIF
'11

manufacturer’s API specifications.
9. For low-solubility APIs the API polymorph is the same, and whenever particle size
JT
DSJUJDBM
JODMVEJOH
MPXTPMVCJMJUZ
"1*T

UIFSF
JT
OP
TJHOJmDBOU
EJõFSFODF
JO
QBSUJDMF

size distribution, compared to the API lot used in the preparation of the biobatch.
10. Specifications (including in-process controls, methods of analysis of all
materials), method of manufacture (including batch size) and detailed route of
synthesis are verified as identical to those already accepted (such situations are
generally limited to additional sites by the same manufacturer or a new contract
NBOVGBDUVSJOH
TJUF
XJUI
FWJEFODF
PG
BO
BDDFQUBCMF
BOE
TJNJMBS
RVBMJUZ
TZTUFN
UP

that of the main manufacturer).
11. Where materials of human or animal origin are used in the process, the
NBOVGBDUVSFS
EPFT
OPU
VTF
BOZ
OFX
TVQQMJFS
GPS
XIJDI
BTTFTTNFOU
JT
SFRVJSFE

of viral safety or of compliance with the current WHO Guidelines on transmissible
spongiform encephalopathies in relation to biological and pharmaceutical products
XXXXIPJOUCJPMPHJDBMT

PS
&."hT
Note for guidance on minimizing the risk of
transmitting animal spongiform encephalopathy agents via human and veterinary
medicinal products (www.emea.europa.eu/ema) PS
FRVJWBMFOU
HVJEFMJOFT
PG
UIF
*$)

region and associated countries.
Documentation required
1. (S.2.1) Name, address, and responsibility of the proposed site or facility involved
in manufacture or testing (including block(s) and unit(s)). A valid testing
BVUIPSJ[BUJPO
PS
B
DFSUJmDBUF
PG
(.1
DPNQMJBODF
JG
BQQMJDBCMF

2. (S.2.2) A side-by-side comparison of the manufacturing flowcharts for production
of the API, intermediate, or API starting material (as applicable) at the parent and
QSPQPTFE
TJUFT
BOE
B
UBCVMBUFE
TVNNBSZ
PG
UIF
EJõFSFODFT
3. (S.4.3) Copies or summaries of validation reports or method transfer reports, which
WHO Technical Report Series No. 981, 2013

EFNPOTUSBUF
FRVJWBMFODF
PG
BOBMZUJDBM
QSPDFEVSFT
UP
CF
VTFE
BU
UIF
QSPQPTFE

testing site.

4

%FTDSJQUJPO
PG
UIF
CBUDIFT
DPQJFT
PG
DFSUJmDBUFT
PG
BOBMZTJT
BOE
CBUDI

analysis data (in a comparative tabular format) for at least two (minimum pilot-
scale) batches of the API from the currently accepted and proposed manufacturers
and/or sites.

3FMFWBOU
TFDUJPOT
PG
4

EPDVNFOUBUJPO
JO
GVMmMNFOU
PG
SFRVJSFNFOUT
GPS
GVMM

information provided in the dossier under section 3.2.S of the WHO Guidelines on
submission of documentation for a multisource (generic) finished pharmaceutical
product for the WHO Prequalification of Medicines Programme: quality part.7
continues

7
See footnote 3.
110
 Annex 3

Table continued
Documentation required
6. The open part of the new APIMF (with a Letter of Access provided in Module 1)
BOE
EPDVNFOUBUJPO
JO
GVMmMNFOU
PG
SFRVJSFNFOUT
GPS
UIF
"1*.'
PQUJPO
VOEFS

section 3.2.S of the WHO Guidelines on submission of documentation for a
multisource (generic) finished pharmaceutical product for the WHO Prequalification of
Medicines Programme: quality part.8

1

*G
UIF
RVBMJUZ
DIBSBDUFSJTUJDT
PG
UIF
"1*
BSF
DIBOHFE
JO
TVDI
B
XBZ
UIBU
JU

may impact the stability of the FPP, a commitment to put under stability one
production-scale batch of the FPP and to continue the study throughout the
currently accepted shelf-life and to immediately report any out of specification
results to WHO/PQP.
8. (S.4.1) A copy of the FPP manufacturer's API specifications.

4

"
EFDMBSBUJPO
GSPN
UIF
TVQQMJFS
PG
UIF
QSFRVBMJmFE
'11
UIBU
UIF
SPVUF
PG

TZOUIFTJT
NBUFSJBMT
RVBMJUZ
DPOUSPM
QSPDFEVSFT
BOE
TQFDJmDBUJPOT
PG
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"1*
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key (ultimate) intermediate in the manufacturing process of the API (if applicable)
are the same as those already accepted.

"
EJTDVTTJPO
PG
UIF
JNQBDU
PG
UIF
OFX
"1*
PO
UIF
TBGFUZ
FöDBDZ
BOE
RVBMJUZ
PG
UIF

FPP.

'PS
MPX
TPMVCJMJUZ
"1*T
XIFSF
QPMZNPSQIJD
GPSN
JT
EJõFSFOU
PS
XIFOFWFS
QBSUJDMF

TJ[F
JT
DSJUJDBM
JODMVEJOH
MPXTPMVCJMJUZ
"1*T

XIFSF
UIFSF
JT
B
TJHOJmDBOU
EJõFSFODF

in particle size distribution compared to the lot used in the biobatch, evidence
UIBU
UIF
EJõFSFODFT
EP
OPU
JNQBDU
UIF
RVBMJUZ
BOE
CJPBWBJMBCJMJUZ
PG
UIF
'11
12. Certificates of analysis for at least one batch of API starting material or
intermediate (as applicable) issued by the new supplier and by the API
manufacturer. Comparative batch analysis of final API manufactured using API
starting material or intermediate (as applicable) from the new source and from
a previously accepted source. For an alternative source of plant-derived starting
material, control of pesticide residues must be established. This can either be in
the form of an attestation from the starting material supplier that no pesticides
are used during the growth of the plant material, or by providing the results of
pesticide screening from one batch of the starting material.
13. An analysis of the impact of the change in supplier with respect to the need for API
stability studies and a commitment to conduct such studies if necessary.
continues

8
See footnote 3.
111
 WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-seventh report

Table continued
Description of change Conditions to Documentation Reporting
be fulfilled required type
9a change or addition of a 1–5 /P
WBSJBUJPO
JT
SFRVJSFE

manufacturing block or unit such changes are handled as
at a currently accepted site amendments to the APIMF by
of API manufacture the APIMF holder.
9b 1, 3–5 1–4 IN
Conditions to be fulfilled
1. The API is non-sterile.
2. The API manufacturing block or unit is currently accepted through the APIMF
procedure.

5IF
TBNF
RVBMJUZ
TZTUFN
DPWFST
DVSSFOUMZ
BDDFQUFE
BOE
QSPQPTFE
VOJUT
PS
CMPDLT

4. For low-solubility APIs, there is no change in the polymorphic form and whenever
particle size is critical (including low solubility APIs) there is no significant change to
the particle size distribution compared to the API lot used in the preparation of the
biobatch.

/P
DIBOHF
JO
UIF
SPVUF
PG
TZOUIFTJT
RVBMJUZ
DPOUSPM
QSPDFEVSFT
BOE
TQFDJmDBUJPOT
PG

the API and key (ultimate) intermediate in the manufacturing process of the API (if
BQQMJDBCMF

.JOPS
DIBOHFT
JO
UIF
FRVJQNFOU
BSF
BDDFQUBCMF
Documentation required

4

"
EFDMBSBUJPO
GSPN
UIF
TVQQMJFS
PG
UIF
'11
UIBU
UIF
SPVUF
PG
TZOUIFTJT
RVBMJUZ

control procedures and specifications of the API and key (ultimate) intermediate in
the manufacturing process of the API (if applicable) are the same as those already
accepted.
2. (S.2.1) Name, address, and responsibility of the proposed production site or facility
involved in manufacturing and/or testing (including block(s) and unit(s)). A valid
NBOVGBDUVSJOH
BOEPS
UFTUJOH
BVUIPSJ[BUJPO
BOE
B
DFSUJmDBUF
PG
(.1
DPNQMJBODF
JG

available.
WHO Technical Report Series No. 981, 2013


4

%FTDSJQUJPO
PG
UIF
CBUDIFT
DPQJFT
PG
DFSUJmDBUFT
PG
BOBMZTJT
BOE
CBUDI
BOBMZTJT

data (in a comparative tabular format) for at least two (minimum pilot-scale)
batches of the API from the currently accepted and proposed units or blocks.

4

"
TVNNBSZ
PG
EJõFSFODFT
CFUXFFO
NBOVGBDUVSF
BOE
DPOUSPM
PG
UIF
"1*
BU
UIF

currently accepted and proposed units or blocks, if applicable.

Description of change Conditions to Documentation Reporting

be fulfilled required type
10a change in the 1–3, 9 1–2, 8 AN
manufacturing process
10b.1 of the API 1–2, 4, 6–9 3–4, 11–12 IN

continues
112
 Annex 3

Table continued
Description of change Conditions to Documentation Reporting
be fulfilled required type
10b.2 change in the 1–2, 4, 6–8, 10 3–4, 11–12 Vmin
manufacturing process
10c of the API 1–2, 4–7 3–4, 11–12 Vmin

10d None 2–14 Vmaj

Conditions to be fulfilled
1. No change in the physical state (e.g. crystalline, amorphous) of the API.
2. For low solubility APIs, there is no change in the polymorphic form and whenever
particle size is critical (including low solubility APIs) there is no significant change
in the particle size distribution compared to that of the API lot used in the
preparation of the biobatch.
3. The API manufacturing site is currently accepted through the APIMF procedure.
4. Where materials of human or animal origin are used in the process, the
manufacturer does not use any new process for which assessment of viral safety
EBUB
PS
54&
SJTL
BTTFTTNFOU
JT
SFRVJSFE

5. No change in the route of synthesis (i.e. intermediates remain the same) and there
are no new reagents, catalysts or solvents used in the process.

/P
DIBOHF
JO
RVBMJUBUJWF
BOE
RVBOUJUBUJWF
JNQVSJUZ
QSPmMF
PS
JO
QIZTJDPDIFNJDBM

properties of the API.

5IF
DIBOHF
EPFT
OPU
BõFDU
UIF
TUFSJMJ[BUJPO
QSPDFEVSFT
PG
B
TUFSJMF
"1*
8. The change involves only steps before the final intermediate.

5IF
DIBOHF
EPFT
OPU
SFRVJSF
SFWJTJPO
PG
UIF
TUBSUJOH
NBUFSJBM
JOUFSNFEJBUF
PS
"1*

specifications.

5IF
DIBOHF
EPFT
OPU
SFRVJSF
SFWJTJPO
PG
UIF
"1*
TQFDJmDBUJPOT
Documentation required
1. A copy of the APIMF amendment acceptance letter.

1

*G
UIF
RVBMJUZ
DIBSBDUFSJTUJDT
PG
UIF
"1*
BSF
DIBOHFE
JO
B
XBZ
UIBU
NBZ
JNQBDU

the stability of the FPP, a commitment to put under stability one production-scale
batch of the FPP and to continue the study throughout the currently accepted
shelf-life and to immediately report any out of specification results to WHO/PQP.
3. (S.2.2) A side-by-side comparison of the current process and the new process.
4. (S.2.2) A flow diagram of the proposed synthetic process(es) and a brief narrative
description of the proposed manufacturing process(es).

4

*OGPSNBUJPO
PO
UIF
RVBMJUZ
BOE
DPOUSPMT
PG
UIF
NBUFSJBMT
FH
SBX
NBUFSJBMT

starting materials, solvents, reagents, catalysts) used in the manufacture of the
proposed API, where applicable.
continues

113
 WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-seventh report

Table continued
Documentation required

4

&JUIFS
B
54&
$&1
GPS
BOZ
OFX
TPVSDF
PG
NBUFSJBM
PS
XIFSF
BQQMJDBCMF

documented evidence that the specific source of the material that carries a risk of
54&
IBT
QSFWJPVTMZ
CFFO
BTTFTTFE
CZ
UIF
DPNQFUFOU
BVUIPSJUZ
BOE
TIPXO
UP
DPNQMZ

with the current WHO guidelines on transmissible spongiform encephalopathies in
relation to biological and pharmaceutical products (www.who.int/biologicals) or
&."T
Note for guidance on minimizing the risk of transmitting animal spongiform
encephalopathy agents via human and veterinary medicinal products (www.
FNFBFVSPQBFVFNB

PS
FRVJWBMFOU
HVJEFMJOFT
PG
UIF
*$)
SFHJPO
BOE
BTTPDJBUFE

countries.
7. (S.2.4) Information on controls of critical steps and intermediates, where applicable.

4

&WJEFODF
PG
QSPDFTT
WBMJEBUJPO
BOEPS
FWBMVBUJPO
TUVEJFT
GPS
TUFSJMJ[BUJPO
JG

applicable.

4

&WJEFODF
GPS
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PG
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XIFSF
BQQMJDBCMF
10. (S.3.2) Information on impurities.
11. (S.4.1) A copy of currently accepted specifications of API (and starting material and
intermediate, if applicable).

4

%FTDSJQUJPO
PG
UIF
CBUDIFT
DFSUJmDBUFT
PG
BOBMZTJT
PS
CBUDI
BOBMZTJT
SFQPSU

and summary of results, in a comparative tabular format, for at least two batches
(minimum pilot-scale) manufactured according to the current and proposed
processes.
13. (S.7.1) Results of two batches of at least pilot-scale with a minimum of three months
of accelerated (and intermediate as appropriate) and three months of long-term
testing of the proposed API.
14. For low-solubility APIs where the polymorphic form has changed or whenever
particle size is critical (including low-solubility APIs) where there is dissimilar particle
size distribution compared to the lot used in the biobatch, evidence that the
EJõFSFODFT
EP
OPU
JNQBDU
UIF
RVBMJUZ
BOE
CJPBWBJMBCJMJUZ
PG
UIF
'11

Description of change Conditions to Documentation Reporting

be fulfilled required type
WHO Technical Report Series No. 981, 2013

11 Change in the in-process tests or limits applied during the manufacture of

the API:

11a any change in the 1 /P
WBSJBUJPO
JT
SFRVJSFE

manufacturing process such changes are handled as
controls amendments to the APIMF by
the APIMF holder

11b tightening of in-process 2–4 1 AN

limits

11c addition of a new in- 2, 5 1–5 AN

process test and limit

continues
114
 Annex 3

Table continued
Description of change Conditions to Documentation Reporting
be fulfilled required type
11d addition or replacement None 1–5, 7, 8–10 Vmin
of an in-process test as
a result of a safety or
RVBMJUZ
JTTVF
11e.1 deletion of an in-process 2, 6–7 1–3, 6 AN
test
11e.2 None 1–3, 7–10 Vmaj
11f relaxation of the None 1–3, 5, 7–10 Vmaj
in-process test limits
Conditions to be fulfilled
1. API manufacturing site is currently accepted through the APIMF procedure.
2. The change is not necessitated by unexpected events arising during manufacture
FH
B
OFX
VORVBMJmFE
JNQVSJUZ
PS
B
DIBOHF
JO
UPUBM
JNQVSJUZ
MJNJUT
3. The change is within the range of currently accepted limits.
4. The analytical procedure remains the same, or changes to the analytical procedure
are minor.

"OZ
OFX
BOBMZUJDBM
QSPDFEVSF
EPFT
OPU
DPODFSO
B
OPWFM
OPOTUBOEBSE
UFDIOJRVF

PS
B
TUBOEBSE
UFDIOJRVF
VTFE
JO
B
OPWFM
XBZ

5IF
BõFDUFE
QBSBNFUFS
JT
OPOTJHOJmDBOU

5IF
DIBOHF
EPFT
OPU
BõFDU
UIF
TUFSJMJ[BUJPO
QSPDFEVSFT
PG
B
TUFSJMF
"1*
Documentation required
1. A comparison of the currently accepted and the proposed in-process tests.
2. (S.2.2) Flow diagram of the proposed synthetic process(es) and a brief narrative
description of the proposed manufacturing process(es).
3. (S.2.4) Information on the controls performed at critical steps of the manufacturing
process and on intermediates of the proposed API.

%FUBJMT
PG
BOZ
OFX
OPOQIBSNBDPQPFJBM
BOBMZUJDBM
NFUIPE
BOE
WBMJEBUJPO
EBUB

where relevant.
5. Justification for the new in-process test and/or limits.
6. Justification and/or risk-assessment showing that the parameter is non-significant.

4

&WJEFODF
PG
QSPDFTT
WBMJEBUJPO
BOEPS
FWBMVBUJPO
TUVEJFT
GPS
TUFSJMJ[BUJPO

where applicable.
8. (S.3.2) Information on impurities, if applicable.
9. (S.4.1) Copy of currently accepted specifications of API (and intermediates, if
applicable).

4

%FTDSJQUJPO
PG
UIF
CBUDIFT
DFSUJmDBUFT
PG
BOBMZTJT
PS
CBUDI
BOBMZTJT
SFQPSU

and summary of results, in a comparative tabular format, for at least two batches
(minimum pilot-scale) for all specification parameters.
continues
115
 WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-seventh report

Table continued
Description of change Conditions to Documentation Reporting
be fulfilled required type
12 Change in batch size of the API or intermediate involving:

12a up to 10-fold compared 1–2, 4, 6 1, 3–4 AN

to the currently accepted
batch size

12b.1 downscaling 1–4 1, 3–4 AN

12b.2 1–3 1–4 IN

12c any change in scale 5 1–2, 4–5 AN

(APIMF procedure)

12d more than 10-fold 1–2, 4, 6 1, 3–4 Vmin

increase compared to the
currently accepted batch
size

Conditions to be fulfilled
1. No changes to the manufacturing process other than those necessitated by
DIBOHFT
JO
TDBMF
FH
VTF
PG
B
EJõFSFOU
TJ[F
PG
FRVJQNFOU



5IF
DIBOHF
EPFT
OPU
BõFDU
UIF
SFQSPEVDJCJMJUZ
PG
UIF
QSPDFTT

3. The change is not necessitated by unexpected events arising during manufacture or
due to stability concerns.
4. The change does not concern a sterile API.
5. The API manufacturing site and batch size is currently accepted through the APIMF
procedure.
6. The proposed batch size increase is relative to either the originally accepted batch
WHO Technical Report Series No. 981, 2013

TJ[F
PS
UIF
CBUDI
TJ[F
BDDFQUFE
UISPVHI
B
TVCTFRVFOU
NBKPS
PS
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Documentation required
1. (S2.2) A brief narrative description of the manufacturing process.
2. (S.2.5) Where applicable, evidence of process validation and/or evaluation studies
for sterilization.
3. (S.4.1) Copy of the currently accepted specifications of the API (and of the
intermediate, if applicable).
4. (S.4.4) Batch analysis data (in tabular format) issued by the FPP manufacturer for
a minimum of two batches each of the currently accepted batch size and the
proposed batch size.
5. A copy of the APIMF amendment acceptance letter.
continues
116
 Annex 3

Table continued
Description of change Conditions to Documentation Reporting
be fulfilled required type
13 Change to the specifications or analytical procedures applied to materials used
in the manufacture of the API (e.g. raw materials, starting materials, reaction
intermediates, solvents, reagents, catalysts) involving:

13a any change 1 /P
WBSJBUJPO
JT
SFRVJSFE

such changes are handled as
amendments to the APIMF by
the APIMF holder

13b tightening of the 2–4 1–3 AN

specification limits

13c minor change to an 5–7 2–3 AN

analytical procedure

13d addition of a new 2, 7–9 1–3 AN

specification parameter
and a corresponding
analytical procedure where
necessary

13e deletion of a specification 2, 10 1–4 AN

parameter or deletion of
an analytical procedure

13f addition or replacement of None 1–3, 5 Vmin

a specification parameter
as a result of a safety or
RVBMJUZ
JTTVF

13g relaxation of the currently 4, 7, 9–10 1, 3–4 IN

accepted specification
limits for solvents,
reagents, catalysts and raw
materials

13h relaxation of the None 1–3, 5 Vmaj

currently accepted
specification limits for
API starting materials and
intermediates

continues
117
 WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-seventh report

Table continued
Conditions to be fulfilled
1. API manufacturing site is currently accepted through the APIMF procedure.
2. The change is not necessitated by failure to meet specifications resulting from
unexpected events arising during manufacture, or because of stability concerns.
3. Any change is within the range of currently accepted limits.
4. The analytical procedure remains the same.

5IF
NFUIPE
PG
BOBMZTJT
JT
CBTFE
PO
UIF
TBNF
BOBMZUJDBM
UFDIOJRVF
PS
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FH

changes to the analytical procedure are within allowable adjustments, to column
length and other parameters, but do not include variations beyond the acceptable
SBOHFT
PS
B
EJõFSFOU
UZQF
PG
DPMVNO
BOE
NFUIPE

6. Appropriate validation studies have been performed in accordance with the
relevant guidelines and show that the updated analytical procedure is at least
FRVJWBMFOU
UP
UIF
GPSNFS
BOBMZUJDBM
QSPDFEVSF
7. No change to the total impurity limits; no new impurities are detected.

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OPWFM
OPOTUBOEBSE
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PS
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UFDIOJRVF
VTFE
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9. The change does not concern a genotoxic impurity.

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QBSBNFUFS
JT
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has been previously accepted.
Documentation required
1. Comparative table of currently accepted and proposed specifications.

4

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PO
UIF
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BOE
DPOUSPMT
PG
UIF
NBUFSJBMT
FH
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starting materials, solvents, reagents, catalysts) used in the manufacture of the
proposed API, where applicable.
3. (S.2.4) Information on intermediates, where applicable.
4. Justification and/or risk assessment showing that the parameter is non-significant.
5. (S.3.2) Information on impurities, where applicable.
WHO Technical Report Series No. 981, 2013

3.2. S.4 Control of the API by the API manufacturer

Description of change Conditions to Documentation Reporting

be fulfilled required type
14 Changes to the test parameters, acceptance criteria, or analytical procedures of
UIF
"1*
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API specifications involving:
14a a. API supported through 1–2 /P
WBSJBUJPO
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the APIMF procedure. such changes are handled as
amendments to the associated
APIMF

continues
118
 Annex 3

Table continued
Description of change Conditions to Documentation Reporting
be fulfilled required type
14b b. API not supported 2 1–4 IN
through the APIMF
procedure.
Conditions to be fulfilled
1. The revised test parameters, acceptance criteria, or analytical procedures have been
submitted as amendments to the associated APIMF and accepted.
2. The API manufacturer has provided the relevant documentation to the FPP
manufacturer. The FPP manufacturer has considered the API manufacturer's
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UIBU
OP
DPOTFRVFOUJBM
SFWJTJPOT
UP
UIF
'11
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"1*
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PS
BOBMZUJDBM
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UP

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PG
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Documentation required
1. (S.4.1) Copy of the current and proposed API specifications dated and signed by the
API manufacturer.
2. (S.4.2) Copies or summaries of analytical procedures, if new analytical procedures
are used.
3. (S.4.3) Copies or summaries of validation reports for new or revised analytical
procedures, if applicable.

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specifications.

3.2. S.4 Control of the API by the FPP manufacturer

Description of change Conditions to Documentation Reporting

be fulfilled required type
15 Change to the test parameters or acceptance criteria of the API specifications
of the FPP manufacturer involving:
15a updating a test 11 1–5 AN
parameter or acceptance
criterion controlled in
compliance with an
officially recognized
pharmacopoeial
monograph as a result
of an update to this
monograph to which the
API is controlled.
continues
119
 WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-seventh report

Table continued
Description of change Conditions to Documentation Reporting
be fulfilled required type
15b.1 deletion of a test 1–2 1, 6 AN
parameter
15b.2 10 1, 6, 8 IN
15b.3 None 1, 6 Vmaj
15c.1 addition of a test 1, 4–8 1–6 AN
parameter
15c.2 1, 5–6, 10 1–6, 8 IN
15c.3 1, 5–6 1–6 Vmin
15c.4 None 1–7 Vmaj
15d.1 replacement of a test 1, 5–8 1–6 IN
parameter
15d.2 5, 7, 10 1–6, 8 Vmin
15d.3 None 1–7 Vmaj
15e.1 tightening of an 1, 3, 9 1, 6 AN
acceptance criterion
15f.1 relaxation of an 1, 5–9 1, 6 IN
acceptance criterion
15f.2 5, 7, 10 1, 6, 8 Vmin
15f.3 None 1, 6–7 Vmaj
Conditions to be fulfilled
1. The change is not necessitated by failure to meet specifications resulting from
unexpected events arising during manufacture, or because of stability concerns.
2. The deleted test has been demonstrated to be redundant with respect to the
remaining tests.
3. The change is within the range of currently accepted acceptance criteria.
WHO Technical Report Series No. 981, 2013


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OFX
BOBMZUJDBM
QSPDFEVSF
EPFT
OPU
DPODFSO
B
OPWFM
OPOTUBOEBSE
UFDIOJRVF

PS
B
TUBOEBSE
UFDIOJRVF
VTFE
JO
B
OPWFM
XBZ
5. For insoluble APIs there is no change in the polymorphic form and whenever
particle size is critical (including low-solubility APIs) there is no change in particle
size distribution acceptance criteria.
6. No additional impurity found over the ICH identification threshold.
7. The change does not concern sterility testing.
8. The change does not involve the control of a genotoxic impurity.
9. The associated analytical procedure remains the same.
10. The change has resulted from a revision of the API manufacturer’s specifications
and is accepted as part of an APIMF amendment.

/P
DIBOHF
JT
SFRVJSFE
JO
'11
SFMFBTF
BOE
TIFMGMJGF
TQFDJmDBUJPOT
continues
120
 Annex 3

Table continued
Documentation required
1. (S.4.1) A copy of the proposed API specifications (of the FPP manufacturer) dated
and signed by authorized personnel and a comparative table of currently accepted
and proposed specifications. In addition, if the change has resulted from a revision
to the API manufacturer's specifications, a copy of the API specifications (of the API
manufacturer) dated and signed by authorized personnel and a comparative table
of currently accepted and proposed specifications.
2. (S.4.2) Copies or summaries of analytical procedures, if new analytical procedures
are used.
3. (S.4.3) Copies or summaries of validation or verification reports issued by the FPP
manufacturer, if new analytical procedures are used.
4. (S.4.3) Where an in-house analytical procedure is used and a pharmacopoeial
TUBOEBSE
JT
DMBJNFE
SFTVMUT
PG
BO
FRVJWBMFODF
TUVEZ
CFUXFFO
UIF
JOIPVTF
BOE

pharmacopoeial methods.

4

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PG
UIF
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PG
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PS
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and summary of results in tabular format, for at least one batch if new tests and/or
analytical methods are implemented.
6. (S.4.5) Justification of the proposed API specifications (e.g. test parameters,
acceptance criteria, or analytical procedures).
7. (P.2) Where changes have occurred to the particle size criteria of an insoluble API or
XIFSFWFS
QBSUJDMF
TJ[F
JT
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FWJEFODF
JT
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UIBU
UIF
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EP
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BõFDU

the in vitro release properties and bioavailability of the FPP. In general, it is sufficient
to provide multipoint comparative dissolution profiles (in three media covering the
physiological range (pH 1.2 or (0.1N HCl), 4.5 and 6.8) without surfactant) for one
batch of FPP manufactured using API that meets the proposed criteria; one batch of
FPP manufactured using API that meets the currently accepted criteria; and data on
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dissolution medium contains a surfactant, the applicant should contact WHO/PQP
for advice. For changes to the polymorph of an insoluble API the applicant should
contact WHO/PQP for advice before embarking upon any investigation.
8. Copy of the APIMF amendment acceptance letter.

Description of change Conditions to Documentation Reporting

be fulfilled required type
16 Change to the analytical procedures used to control the API by the FPP
manufacturer involving:
16a change in an analytical None 1–3 AN
procedure as a result
of a revision to the
officially recognized
pharmacopoeial
monograph to which the
API is controlled.
continues
121
 WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-seventh report

Table continued
16b change from a currently None 1–4 IN
accepted in-house
analytical procedure to
an analytical procedure
in an officially recognized
pharmacopoeia or from
the analytical procedure in
one officially recognized
pharmacopoeia to an
analytical procedure in
another official recognized
pharmacopoeia
16c.1 addition of an analytical 1–3 1–3 AN
procedure
16c.2 3, 8 1–3, 5 AN
16c.3 8 1–3, 5 Vmin
16c.4 None 1–3 Vmaj
16d.1 modification or 1–6 1–4 AN
replacement of an
16d.2 analytical procedure 2–3, 5–6, 8 1–5 AN
16d.3 1–3, 5–6 1–4 Vmin
16d.4 5–6, 8 1–5 Vmin
16d.5 None 1–4 Vmaj
16e.1 deletion of an analytical 6–7 1, 6 AN
procedure
16e.2 6, 8 1, 5, 6 IN
16e.3 None 1, 6 Vmaj
WHO Technical Report Series No. 981, 2013

Conditions to be fulfilled

"OZ
OFX
BOBMZUJDBM
QSPDFEVSF
EPFT
OPU
DPODFSO
B
OPWFM
OPOTUBOEBSE
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B
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VTFE
JO
B
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2. The change is not necessitated by failure to meet specifications resulting from
unexpected events arising during manufacture, or because of stability concerns.
3. No new impurities have been detected as a result of the use of the new analytical
method.

5IF
NFUIPE
PG
BOBMZTJT
JT
CBTFE
PO
UIF
TBNF
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UFDIOJRVF
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changes to the analytical procedure are within allowable adjustments to column
length and other parameters, but do not include variations beyond the acceptable
SBOHFT
PS
B
EJõFSFOU
UZQF
PG
DPMVNO
BOE
NFUIPE

BOE
OP
OFX
JNQVSJUJFT
BSF
EFUFDUFE
continues
122
 Annex 3

Table continued
Conditions to be fulfilled
5. Comparative studies are available demonstrating that the proposed analytical
QSPDFEVSF
JT
BU
MFBTU
FRVJWBMFOU
UP
UIF
DVSSFOUMZ
BDDFQUFE
BOBMZUJDBM
QSPDFEVSF

6. The change does not concern sterility testing.

5IF
EFMFUFE
BOBMZUJDBM
QSPDFEVSF
JT
BO
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NFUIPE
BOE
JT
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UP
B

currently accepted method.
8. The new or modified analytical method is identical to that used by the API
manufacturer and has been accepted as part of an amendment to the associated
APIMF.
Documentation required
1. (S.4.1) Copy of the proposed API specifications dated and signed by authorized
personnel and a comparative table of currently accepted and proposed specifications.
2. (S.4.2) Copies or summaries of analytical procedures if new or significantly modified
analytical procedures are used.
3. (S.4.3) Copies or summaries of validation or verification reports issued by the FPP
manufacturer if new or significantly modified analytical procedures are used.
4. (S.4.4) Comparative analytical results demonstrating that the proposed analytical
QSPDFEVSFT
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UP
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5. A copy of the APIMF acceptance letter.
6. (S.4.5) Justification for the deletion of the analytical procedure, with supporting data.

3.2. S.6 Container-closure system

Description of change Conditions to Documentation Reporting

be fulfilled required type
17a Change in the immediate 3, 4 1–2, 4 AN
packaging (primary and
17b functional secondary 1–2, 4 2–3 IN
17c components) for the storage 4 1–3 Vmin
and shipment of the API
Conditions to be fulfilled
1. Results demonstrate that the proposed primary packaging type is at least
FRVJWBMFOU
UP
UIF
DVSSFOUMZ
BDDFQUFE
QSJNBSZ
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relevant properties (e.g. including results of transportation or interaction studies,
and moisture permeability among others).
2. The change does not concern a sterile API.
3. The change has previously been accepted through the APIMF procedure.
4. The change is not the result of stability issues.
continues
123
 WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-seventh report

Table continued
Documentation required

4

&WJEFODF
PG
QSPDFTT
WBMJEBUJPO
BOEPS
FWBMVBUJPO
TUVEJFT
GPS
TUFSJMJ[BUJPO
JG

EJõFSFOU
GSPN
UIF
DVSSFOU
QSPDFTT
2. (S.6) Information on the proposed primary packaging (e.g. description and
specifications) and data in fulfillment of condition 1.

4

3FTVMUT
PG
PS
B
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UP
TUVEZ
JO
UIF
DBTF
PG
EFNPOTUSBUFE
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or more protective packaging) a minimum of 3 months of accelerated (and
intermediate, as appropriate) and 3 months of long-term testing of the API in the
proposed primary packaging type.
4. A copy of the APIMF amendment acceptance letter.

Description of change Conditions to Documentation Reporting

be fulfilled required type
18 Change in the specifications of the immediate packaging for the storage and
shipment of the API involving:
18a tightening of specification 1–2 1 AN
limits
18b addition of a test 2–3 1–3 AN
parameter
18c deletion of a non-critical 2 1, 4 AN
parameter
18d any change (APIMF 4 /P
WBSJBUJPO
JT
SFRVJSFE

procedure) such changes are handled as
amendments to the associated
APIMF
Conditions to be fulfilled
1. The change is within the range of currently accepted limits.
WHO Technical Report Series No. 981, 2013

2. The change is not necessitated by failure to meet specifications resulting from

unexpected events arising during manufacture, or because of stability concerns.

"OZ
OFX
BOBMZUJDBM
QSPDFEVSF
EPFT
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DPODFSO
B
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OPOTUBOEBSE
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PS

B
TUBOEBSE
UFDIOJRVF
VTFE
JO
B
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4. The change has previously been accepted through the APIMF procedure.
Documentation required
1. (S.4.5) Comparative table of currently accepted and proposed specifications,
justification of the proposed specifications.

4

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PG
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BOE
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PG
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PG
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3. (S.6) Certificate of analysis for one batch.
4. Justification to demonstrate that the parameter is not critical.
continues
124
 Annex 3

Table continued
Description of change Conditions to Documentation Reporting
be fulfilled required type
19 Change to an analytical procedure on the immediate packaging of the API
involving:

19a minor change to an 1–3 1 AN

analytical procedure

19b other changes to an 2–4 1 AN

analytical procedure
including addition
or replacement of an
analytical procedure

19c deletion of an analytical 5 2 AN

procedure

19d any change (APIMF 6 /P
WBSJBUJPO
JT
SFRVJSFE

procedure) such changes are handled as
amendments to the associated
APIMF
Conditions to be fulfilled

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PG
BOBMZTJT
JT
CBTFE
PO
UIF
TBNF
BOBMZUJDBM
UFDIOJRVF
PS
QSJODJQMF
FH

changes to the analytical procedure are within allowable adjustments to column
length and other parameters, but do not include variations beyond the acceptable
SBOHFT
PS
B
EJõFSFOU
UZQF
PG
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BOE
NFUIPE

2. Appropriate (re)validation studies have been performed in accordance with the
relevant guidelines.

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to the currently accepted procedure.

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B
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B
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currently accepted method.
6. The change has previously been accepted through the APIMF procedure.
Documentation required
1. (S.6) Comparative validation results demonstrating that the currently accepted and
QSPQPTFE
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BSF
BU
MFBTU
FRVJWBMFOU
2. Justification for deletion of the analytical procedure.

125
 WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-seventh report

3.2. S.7 Stability

Description of change Conditions to Documentation Reporting

be fulfilled required type
20 Change in the retest period or shelf-life of the API involving:
20a any change (APIMF 4 4 IN
procedure)
20b reduction 3 1–2 IN
20c extension 1–2 1–3 Vmin
Conditions to be fulfilled
1. No change to the primary packaging in direct contact with the API or to the
recommended condition of storage.
2. Stability data were generated in accordance with the currently accepted stability
protocol.
3. The change is not necessitated by unexpected events arising during manufacture or
because of stability concerns.
4. The revised retest period has previously been accepted through the APIMF
procedure.
Documentation required
1. (S.7.1) Proposed retest period or shelf-life, summary of stability testing according to
currently accepted protocol and test results.
2. (S.7.2) Updated post-acceptance stability protocol and stability commitment and
justification of change, when applicable.
3. (S.7.3) Stability data to support the change.
4. A copy of the APIMF acceptance letter.

Description of change Conditions to Documentation Reporting

WHO Technical Report Series No. 981, 2013

be fulfilled required type

21 Change in the labelled storage conditions of the API involving:
21a any change in storage 1 1 IN
conditions (APIMF
procedure)
21b any change in storage 2 2 Vmin
conditions
Conditions to be fulfilled
1. The revised storage conditions have previously been accepted through the APIMF
procedure.
continues
126
 Annex 3

Table continued
Conditions to be fulfilled
2. The change is not necessitated by failure to meet specifications resulting from
unexpected events arising during manufacture, or because of stability concerns.
Documentation required
1. A copy of the APIMF acceptance letter.
2. (S.7.1) Stability and/or compatibility test results to support the change to the
storage conditions.

3.2. P Drug product (or FPP)

3.2. P.1 Description and composition of the FPP

Description of change Conditions to Documentation Reporting

be fulfilled required type
22a Change in the composition 1–6 2, 4, 7, 9–10 IN
of a solution dosage form
22b None 1–10 Vmaj
Conditions to be fulfilled

5IF
BõFDUFE
FYDJQJFOU T

EPFTEP
OPU
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UP
BõFDU
UIF
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BOEPS
UIF

absorption of the API.

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BõFDUFE
FYDJQJFOU T

EPFTEP
OPU
GVODUJPO
BT
B
QSFTFSWBUJWF
PS
QSFTFSWBUJWF

enhancer.

/P
DIBOHF
JO
UIF
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PG
UIF
BõFDUFE
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PS
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'11
4. No change in the physical characteristics of the FPP (e.g. viscosity, osmolality, pH).
5. The change does not concern a sterile FPP.

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BSF
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concentration) of each excipient is within ±10% of the amount (or concentration)
PG
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Documentation required
1. Supporting clinical or comparative bioavailability data or justification for not
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PO
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1

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1

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excipients, compatibility of API and excipients, suitability studies on the packaging
system for the changed product).
4. (P.3) Batch formula, description of manufacturing process and process controls,
controls of critical steps and intermediates, process validation protocol and/or
evaluation.
continues
127
 WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-seventh report

Table continued
5. (P.4) Control of excipients, if new excipients are proposed.

1

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region or associated countries and shown to comply with the scope of the current
guidelines in the countries of the ICH region or associated countries. The following
information should be included for each such material: name of manufacturer,
species and tissues from which the material is derived, country of origin of the
source animals, and use of the material.
7. (P.5) Copies of FPP release and shelf-life specifications and certificates of analysis
for a minimum of two pilot- or production-scale batches. If applicable, data
to demonstrate that the new excipient does not interfere with the analytical
procedures for the FPP.
8. (P.8.1) Results of stability testing generated on at least two pilot- or production-
scale batches with a minimum of 3 months of accelerated (and intermediate, as
appropriate) and 3 months of long-term testing.
9. (P.8.2) Updated post-acceptance stability protocol and stability commitment to
place the first production-scale batch of each strength of the proposed product
into the long-term stability programme (bracketing and matrixing for multiple
strengths and packaging components could be applied, if scientifically justified).
10. (R.1) Copies of relevant pages of blank master production documents with changes
highlighted, as well as relevant pages of the executed production document
for one batch and confirmation that there are no changes to the production
documents other than those highlighted.

Description of change Conditions to Documentation Reporting

be fulfilled required type
23 Change in the colouring system or the flavouring system currently used in the
FPP involving:
WHO Technical Report Series No. 981, 2013

23a reduction or increase of 1–3, 6 1, 4, 6–7 AN

one or more components
of the colouring or the
flavouring system
23b deletion, addition or 1–6 1–7 IN
replacement of one or more
components of the colouring
or the flavouring system
Conditions to be fulfilled
1. No change in the functional characteristics of the pharmaceutical form e.g.
disintegration time or dissolution profile.
continues
128
 Annex 3

Table continued
Conditions to be fulfilled
2. Any minor adjustment to the formulation to maintain the total weight is made using
an excipient which currently makes up a major part of the FPP formulation.
3. Specifications for the FPP are updated only with respect to appearance, odour and/
or taste or if relevant, deletion or addition of a test for identification.
4. Any new component must comply with section 3.2.P.4 of the WHO Guidelines on
submission of documentation for a multisource (generic) finished pharmaceutical
product for the WHO Prequalification of Medicines Programme: quality part.9
5. Any new component does not include the use of materials of human or animal
PSJHJO
GPS
XIJDI
BTTFTTNFOU
PG
WJSBM
TBGFUZ
EBUB
JT
SFRVJSFE
PS
JT
JO
DPNQMJBODF
XJUI

the current WHO Guidelines on transmissible spongiform encephalopathies in relation
to biological and pharmaceutical products
XXXXIPJOUCJPMPHJDBMT

PS
&."hT
Note
for guidance on minimizing the risk of transmitting animal spongiform encephalopathy
agents via human and veterinary medicinal products (www.emea.europa.eu/ema) or an
FRVJWBMFOU
HVJEF
GSPN
UIF
*$)
SFHJPO
BOE
BTTPDJBUFE
DPVOUSJFT

8IFSF
BQQMJDBCMF
UIF
DIBOHF
EPFT
OPU
BõFDU
UIF
EJõFSFOUJBUJPO
CFUXFFO
TUSFOHUIT

BOE
GPS
QBFEJBUSJD
GPSNVMBUJPOT
JU
EPFT
OPU
SFRVJSF
TVCNJTTJPO
PG
SFTVMUT
PG
UBTUF

acceptability studies.
Documentation required
1. Sample of the FPP.

1

%JTDVTTJPO
PO
UIF
DPNQPOFOUT
PG
UIF
'11
FH
DPNQBUJCJMJUZ
PG
"1*
BOE

RVBMJUBUJWF
DPNQPTJUJPO
PG
UIF
DPMPVSJOH
PS
nBWPVSJOH
TZTUFN
JG
QVSDIBTFE
BT
B

mixture, with specifications, if relevant).

1

&JUIFS
B
$&1
GPS
BOZ
OFX
DPNQPOFOU
PG
BOJNBM
PSJHJO
TVTDFQUJCMF
UP
54&
SJTL
PS

XIFSF
BQQMJDBCMF
EPDVNFOUFE
FWJEFODF
UIBU
UIF
TQFDJmD
TPVSDF
PG
UIF
54&
SJTL
NBUFSJBM

has been previously assessed by an NMRA in the ICH region or associated countries and
shown to comply with the scope of the current guidelines in the countries of the ICH
region or associated countries. The following information should be included for each
such material: name of manufacturer, species and tissues from which the material is
derived, country of origin of the source animals, and use of the material.
4. (P.5) Copies of revised FPP release and shelf-life specifications and certificates of
analysis for a minimum of two pilot- or production-scale batches.
5. (P.5.3) If applicable, data to demonstrate that the new excipient does not interfere
with the analytical procedures for the FPP.
6. (P.8.1) Results of stability testing generated on at least two pilot- or production-
scale batches with a minimum of 3 months of accelerated (and intermediate, as
appropriate) and 3 months of long-term testing.
7. (R.1) Copies of relevant sections of blank master production documents with changes
highlighted as well as relevant pages of the executed production documents for
one batch and confirmation that there are no changes to the production documents
other than those highlighted.
continues

9
See footnote 3.
129
 WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-seventh report

Table continued
Description of change Conditions to Documentation Reporting
be fulfilled required type
24 Change in weight of tablet coatings or capsule shells involving:
24a immediate-release oral FPPs 1–3 2–5 AN
24b gastro-resistant, modified None 1–5 Vmaj
or prolonged release FPPs
Conditions to be fulfilled
1. Multipoint in vitro dissolution profiles of the proposed version of the product
(determined in the routine release medium on at least two batches of pilot- or
production-scale), are similar to the dissolution profiles of the biobatch.
2. Coating is not a critical factor for the release mechanism.
3. Specifications for the FPP are updated only with respect to weight and dimensions,
if applicable.
Documentation required

+VTUJmDBUJPO
GPS
OPU
TVCNJUUJOH
B
OFX
CJPFRVJWBMFODF
TUVEZ
BDDPSEJOH
UP
UIF

DVSSFOU
8)0
HVJEFMJOFT
PO
CJPFRVJWBMFODF
Proposal to waive in vivo bioequivalence
requirements for WHO Model List of Essential Medicines immediate-release, solid oral
dosage forms, WHO Technical Report Series, No. 937, 2006, Annex 8).
2. (P.2) Comparative multipoint in vitro dissolution profiles in the routine release
medium (or media), on at least two batches of pilot- or production-scale of the
proposed product versus the biobatch.
3. (P.5) Copies of revised FPP release and shelf-life specifications and certificates of
analysis for a minimum of one pilot- or production-scale batch.
4. (P.8.1) Results of stability testing generated on at least one pilot- or production-
scale batch with a minimum of 3 months of accelerated (and intermediate, as
appropriate) and 3 months of long-term testing.
5. (R.1) Copies of relevant sections of blank master production documents with
changes highlighted as well as relevant pages of the executed production
WHO Technical Report Series No. 981, 2013

documents for one batch and confirmation that there are no changes to the
production documents other than those highlighted.

Description of change Conditions to Documentation Reporting

be fulfilled required type
25 Change in the composition of an immediate-release solid oral dosage form
including:
25a.1 replacement of a 1–5 1–10 Vmin
single excipient with a
25a.2 comparable excipient at None 1–10 Vmaj
a similar concentration
continues
130
 Annex 3

Table continued
Description of change Conditions to Documentation Reporting
be fulfilled required type
25b.1 RVBOUJUBUJWF
DIBOHFT
JO
1–4 1–4, 7–10 Vmin
excipients
25b.2 None 1–4, 7–10 Vmaj
Conditions to be fulfilled
1. No change in functional characteristics of the pharmaceutical form.

0OMZ
NJOPS
BEKVTUNFOUT
TFF
"QQFOEJY


BSF
NBEF
UP
UIF
RVBOUJUBUJWF

composition of the FPP; any minor adjustment to the formulation to maintain the
total weight is made using an excipient which currently makes up a major part of
the FPP formulation.
3. Stability studies have been started under conditions according to WHO Guidelines
on submission of documentation for a multisource (generic) finished pharmaceutical
product for the WHO Prequalification of Medicines Programme: quality part 10 (with
indication of batch numbers) and relevant stability parameters have been assessed
in at least two pilot- or production-scale batches, satisfactory stability data
covering at least 3 months are at the disposal of the applicant, and the stability
profile is similar to that of the currently accepted product.
4. The dissolution profile of the proposed product determined on a minimum of two
pilot-scale batches is similar to the dissolution profile of the biobatch.
5. The change is not the result of stability issues and/or does not result in potential
TBGFUZ
DPODFSOT
JF
EJõFSFOUJBUJPO
CFUXFFO
TUSFOHUIT
Documentation required
1. Supporting clinical or comparative bioavailability data or justification for not
TVCNJUUJOH
B
OFX
CJPFRVJWBMFODF
TUVEZ
BDDPSEJOH
UP
UIF
DVSSFOU
8)0
HVJEFMJOFT

PO
CJPFRVJWBMFODF

1

%FTDSJQUJPO
BOE
DPNQPTJUJPO
PG
UIF
'11

1

%JTDVTTJPO
PO
UIF
DPNQPOFOUT
PG
UIF
QSPQPTFE
QSPEVDU
FH
DIPJDF
PG

excipients, compatibility of API and excipients), comparative multipoint in vitro
dissolution profiles obtained on at least two batches of pilot- or production-scale
of the proposed product and the biobatch (depending on the solubility and
permeability of the drug, dissolution in the routine release medium or in multiple
media covering the physiological pH range).
4. (P.3) Batch formula, description of manufacturing process and process controls,
controls of critical steps and intermediates, process validation protocol and/or
evaluation.
5. (P.4) Control of excipients, if new excipients are proposed.
continues

10
See footnote 3.
131
 WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-seventh report

Table continued
Documentation required

1

*G
BQQMJDBCMF
FJUIFS
B
$&1
GPS
BOZ
OFX
DPNQPOFOU
PG
BOJNBM
PSJHJO

TVTDFQUJCMF
UP
54&
SJTL
PS
XIFSF
BQQMJDBCMF
EPDVNFOUFE
FWJEFODF
UIBU
UIF
TQFDJmD

TPVSDF
PG
UIF
54&
SJTL
NBUFSJBM
IBT
CFFO
QSFWJPVTMZ
BTTFTTFE
CZ
BO
/.3"
JO
UIF
*$)

region or associated countries and shown to comply with the scope of the current
guidelines in the countries of the ICH region or associated countries. The following
information should be included for each such material: name of manufacturer,
species and tissues from which the material is derived, country of origin of the
source animals and its use.
7. (P.5) Copies of FPP release and shelf-life specifications and certificates of analysis
for a minimum of two pilot- or production-scale batches. If applicable, data
to demonstrate that the new excipient does not interfere with the analytical
procedures for the FPP.
8. (P.8.1) Results of stability testing generated on at least two pilot- or production-
scale batches with a minimum of 3 months of accelerated (and intermediate, as
appropriate) and 3 months of long-term testing.
9. (P.8.2) Updated post-acceptance stability protocol and stability commitment to
place the first production-scale batch of each strength of the proposed product
into the long-term stability programme (bracketing and matrixing for multiple
strengths and packaging components could be applied, if scientifically justified).
10. (R.1) Copies of relevant sections of blank master production documents with
changes highlighted as well as relevant pages of the executed production
documents for one batch, and confirmation that there are no changes to the
production documents other than those highlighted.

Description of change Conditions to Documentation Reporting

be fulfilled required type
26 Change or addition of imprints, embossing or other markings, including
WHO Technical Report Series No. 981, 2013

replacement or addition of inks used for product markings and change in

scoring configuration involving:
26a changes in imprints, 1–3 1–2, 5–6 IN
embossing or other
markings
26b deletion of a scoreline 2–5 1, 5–6 IN
26c.1 addition of a scoreline 2–4 1, 3, 5–6 Vmin
26c.2 None 1, 3–6 Vmaj
continues

132
 Annex 3

Table continued
Conditions to be fulfilled
1. Any ink complies with section 3.2.P.4 of the WHO Guidelines on submission of
documentation for a multisource (generic) finished pharmaceutical product for the
WHO Prequalification of Medicines Programme: quality part.11

5IF
DIBOHF
EPFT
OPU
BõFDU
UIF
TUBCJMJUZ
PS
QFSGPSNBODF
DIBSBDUFSJTUJDT
FH
SFMFBTF

rate) of the FPP.
3. Changes to the FPP specifications are those necessitated only by the change to the
appearance or to the scoring.
4. Addition or deletion of a score line from a generic product is consistent with a
TJNJMBS
DIBOHF
JO
UIF
DPNQBSBUPS
QSPEVDU
PS
XBT
SFRVFTUFE
CZ
8)0121

5IF
TDPSJOH
JT
OPU
JOUFOEFE
UP
EJWJEF
UIF
'11
JOUP
FRVBM
EPTFT
Documentation required
1. Sample of the FPP.
2. (P.1.) Qualitative composition of the ink, if purchased as a mixture.

1

%FNPOTUSBUJPO
PG
UIF
VOJGPSNJUZ
PG
UIF
EPTBHF
VOJUT
PG
UIF
UBCMFU
QPSUJPOT

XIFSF
UIF
TDPSJOH
JT
JOUFOEFE
UP
EJWJEF
UIF
'11
JOUP
FRVBM
EPTFT

1

%FNPOTUSBUJPO
PG
UIF
TJNJMBSJUZ
PG
UIF
SFMFBTF
SBUF
PG
UIF
UBCMFU
QPSUJPOT
GPS

gastro-resistant, modified or prolonged release products.
5. (P.5) Copies of revised FPP release and shelf-life specifications.
6. (R.1) Copies of relevant sections of blank master production documents with
changes highlighted as well as relevant pages of the executed production
documentation for one batch and confirmation that there are no changes to the
production documents other than those highlighted.

Description of change Conditions to Documentation Reporting

be fulfilled required type
27 $IBOHF
JO
EJNFOTJPOT
XJUIPVU
DIBOHF
JO
RVBMJUBUJWF
PS
RVBOUJUBUJWF

composition and mean mass of:

27a tablets, capsules, 1–2 2–6 IN

suppositories and
pessaries other than those
stated in change no. 27b

27b gastro-resistant, modified 1–2 1–6 Vmin

or prolonged-release FPPs
and scored tablets
continues

11
See footnote 3.
133
 WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-seventh report

Table continued
Conditions to be fulfilled
1. Specifications for the FPP are updated only with respect to dimensions of the FPP.
2. Multipoint in vitro dissolution profiles of the current and proposed versions of the
product (determined in the routine release medium, on at least one batch of pilot-
or production-scale), are comparable.
Documentation required
1. For gastro-resistant, modified or prolonged release FPPs, justification for not
TVCNJUUJOH
B
OFX
CJPFRVJWBMFODF
TUVEZ
BDDPSEJOH
UP
UIF
DVSSFOU
8)0
HVJEFMJOFT

PO
CJPFRVJWBMFODF
'PS
TDPSFE
UBCMFUT
XIFSF
UIF
TDPSJOH
JT
JOUFOEFE
UP
EJWJEF
UIF

'11
JOUP
FRVBM
EPTFT
EFNPOTUSBUJPO
PG
UIF
VOJGPSNJUZ
PG
UIF
UBCMFU
QPSUJPOT
2. Sample of the FPP.

1

%JTDVTTJPO
PO
UIF
EJõFSFODFT
JO
NBOVGBDUVSJOH
QSPDFTT FT

CFUXFFO
UIF

currently accepted and proposed products and the potential impact on product
performance.
4. (P.2) Comparative multipoint in vitro dissolution profiles in the routine release
medium, on at least one batch of pilot- or production-scale of the current and
proposed products.
5. (P.5) Copies of revised FPP release and shelf-life specifications.
6. (R.1) Copies of relevant sections of blank master production documents
with changes highlighted as well as relevant pages of executed production
documentation for one batch and confirmation that there are no changes to the
production documents other than those highlighted.

3.2. P.3 Manufacture

Description of change Conditions to Documentation Reporting

be fulfilled required type
28 Addition or replacement of a manufacturing site for part or all of the
WHO Technical Report Series No. 981, 2013

manufacturing process for an FPP involving:

28a secondary packaging of 2–3 1 IN
all types of FPPs
28b primary packaging site of:
28b.1 solid FPPs (e.g. tablets, 2–4 1, 8 IN
capsules), semi-solid FPPs
(e.g. ointments, creams)
BOE
TPMVUJPO
MJRVJE
'11T

28b.2 PUIFS
MJRVJE
'11T
2–5 1, 5, 8 IN
(suspensions, emulsions)
continues
134
 Annex 3

Table continued
Description of change Conditions to Documentation Reporting
be fulfilled required type
28c all other manufacturing 1–3, 5 1–9 Vmin
operations except batch
control and/or release
testing
Conditions to be fulfilled
1. No change in the batch formula, description of manufacturing process and process
DPOUSPMT
FRVJQNFOU
DMBTT
BOE
QSPDFTT
DPOUSPMT
DPOUSPMT
PG
DSJUJDBM
TUFQT
BOE

intermediates, or FPP specifications.
2. Satisfactory inspection in the last three years either by WHO or an SRA.
3. Site appropriately authorized by an NMRA (to manufacture the pharmaceutical form
and the product concerned).
4. The change does not concern a sterile FPP.
5. Validation protocol is available or validation of the manufacturing process at
the new site has been successfully carried out on at least three production-scale
batches in accordance with the current protocol.
Documentation required

&WJEFODF
UIBU
UIF
QSPQPTFE
TJUF
IBT
CFFO
BQQSPQSJBUFMZ
BVUIPSJ[FE
JO
UIF
MBTU
UISFF

years, for the pharmaceutical form and the product concerned:
t
B
DPQZ
PG
UIF
DVSSFOU
NBOVGBDUVSJOH
BVUIPSJ[BUJPO
B
(.1
DFSUJmDBUF
PS

FRVJWBMFOU
EPDVNFOU
JTTVFE
CZ
UIF
/.3"
t
B
(.1
TUBUFNFOU
PS
FRVJWBMFOU
JTTVFE
CZ
8)0
PS
BO
43"
t
date of the last satisfactory inspection concerning the packaging facilities by
WHO or an SRA in the last three years.

%BUF
BOE
TDPQF
XJUI
JOEJDBUJPO
BT
UP
XIFUIFS
TDPQF
XBT
FH
QSPEVDUTQFDJmD
PS

related to a specific pharmaceutical form) of the last satisfactory inspection.
3. (P.2) Where applicable, GPS
TFNJTPMJE
BOE
MJRVJE
GPSNVMBUJPOT
JO
XIJDI
UIF
"1*
JT

present in non-dissolved form, appropriate validation data including microscopic
imaging of particle size distribution and morphology.
4. (P.2) For solid dosage forms, data on comparative dissolution tests in the routine
release medium, with demonstration of similarity of dissolution profiles with those
of the biobatch, performed on one production-scale batch each from current and
proposed manufacturing sites and comparison with the biobatch results, with
commitment to generate dissolution profiles on two more production-scale batches.
5. (P.3.5) Process validation reports or validation protocol (scheme) for three batches
of the proposed batch size, which includes comparative dissolution against the
biobatch results with f2 calculation as necessary.
6. (P.5.1) Copies of release and shelf-life specifications.
7. (P.5.4) Batch analysis data on one production-scale batch from the proposed site
and comparative data on the last three batches from the previous site.
continues
135
 WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-seventh report

Table continued
Documentation required
8. (P.8.2) Updated post-acceptance stability protocol and stability commitment to
place the first production-scale batch of the FPP produced at the new site into the
long-term stability programme (bracketing and matrixing for multiple strengths and
packaging components could be applied, if scientifically justified).

3

&YFDVUFE
QSPEVDUJPO
EPDVNFOUT
GPS
POF
CBUDI
PG
UIF
'11
NBOVGBDUVSFE
BU
UIF

new site.

Description of change Conditions to Documentation Reporting

be fulfilled required type
29 Replacement or addition 1–2 1–3 AN
of a site involving batch
control testing
Conditions to be fulfilled
1. Site is appropriately authorized by the NMRA and satisfactorily inspected either by
WHO or an SRA.
2. Transfer of methods from the current testing site to the proposed testing site has
been successfully completed.
Documentation required

$MFBS
JEFOUJmDBUJPO
PG
UIF
DVSSFOUMZ
BDDFQUFE
BOE
QSPQPTFE
RVBMJUZ
DPOUSPM
TJUFT
PO

the letter accompanying the application.

%PDVNFOUFE
FWJEFODF
UIBU
UIF
TJUF
JT
BQQSPQSJBUFMZ
BVUIPSJ[FE
CZ
UIF
/.3"
BOE

satisfactorily inspected either by WHO or an SRA.

1

%PDVNFOUFE
FWJEFODF
PG
TVDDFTTGVM
USBOTGFS
PG
BOBMZUJDBM
QSPDFEVSFT
GSPN
UIF

current to the proposed site.
WHO Technical Report Series No. 981, 2013

Description of change Conditions to Documentation Reporting

be fulfilled required type
30 Change in the batch size of the FPP involving:
30a up to and including a 1–7 2, 5–6 IN
factor of 10 compared to
the biobatch
30b downscaling 1–5 2, 6 AN
30c other situations 1–7 1–7 Vmin
Conditions to be fulfilled

5IF
DIBOHF
EPFT
OPU
BõFDU
UIF
SFQSPEVDJCJMJUZ
BOEPS
DPOTJTUFODZ
PG
UIF
QSPEVDU
continues
136
 Annex 3

Table continued
Conditions to be fulfilled
2. The change pertains only to immediate-release oral pharmaceutical forms and to
OPOTUFSJMF
MJRVJE
GPSNT
3. Changes to the manufacturing method and/or to the in-process controls are only
UIPTF
OFDFTTJUBUFE
CZ
UIF
DIBOHF
JO
CBUDI
TJ[F
FH
VTF
PG
EJõFSFOUTJ[FE
FRVJQNFOU
4. A validation protocol is available or validation of the manufacture of three
production-scale batches has been successfully undertaken in accordance with the
current validation protocol.
5. The change is not necessitated by unexpected events arising during manufacture or
because of stability concerns.

5IF
DIBOHF
EPFT
OPU
SFRVJSF
TVQQPSUJOH
JO
WJWP
EBUB
7. The biobatch size was at least 100 000 units in the case of solid oral dosage forms.
Documentation required
1. (P.2) For solid dosage forms: dissolution profile data, in the routine release medium,
on a minimum of one representative production-scale batch and comparison of the
data with the biobatch results and one production-scale batch of the previous batch
TJ[F
%BUB
PO
UIF
OFYU
UXP
GVMM
QSPEVDUJPOTDBMF
CBUDIFT
TIPVME
CF
BWBJMBCMF
PO

SFRVFTU
BOE
TIPVME
CF
SFQPSUFE
JG
UIFZ
EP
OPU
NFFU
EJTTPMVUJPO
QSPmMF
TJNJMBSJUZ
G


SFRVJSFNFOUT
'PS
TFNJTPMJE
EPTBHF
GPSNT
FH
MPUJPOT
HFMT
DSFBNT
BOE
PJOUNFOUT


containing the API in the dissolved or non-dissolved form, comparative in vitro data
PO
NFNCSBOF
EJõVTJPO
NFNCSBOF
SFMFBTF
UFTUJOH

TIPVME
CF
TVCNJUUFE
PS
CF

BWBJMBCMF
PO
SFRVFTU
2. (P.3.5) Process validation reports for three batches of the proposed batch size or
validation protocol (scheme).
3. (P.5.1) Copies of release and shelf-life specifications.
4. (P.5.4) Batch analysis data (in a comparative tabular format) on a minimum of one
production-scale batch manufactured to both the currently accepted and the
proposed batch sizes. Batch data on the next two full production-scale batches
TIPVME
CF
BWBJMBCMF
PO
SFRVFTU
BOE
TIPVME
CF
SFQPSUFE
JNNFEJBUFMZ
CZ
UIF
TVQQMJFS

of the product, if outside specifications (with proposed remedial action).
5. (P.8.2) Updated post-acceptance stability protocol (approved by authorized
personnel) and stability commitment to place the first production-scale batch
of each strength at the proposed scale into the long-term stability programme
(bracketing and matrixing for multiple strengths and packaging components could
be applied, if scientifically justified).
6. (R.1) Copies of relevant sections of blank master production documents with
changes highlighted as well as relevant pages of the executed production
EPDVNFOUBUJPO
GPS
POF
CBUDI
JG
NBOVGBDUVSFE
BT
SFRVJSFE
CZ
EPDVNFOUBUJPO



(above) and confirmation that there are no changes to the production documents
other than those highlighted.
7. Supporting clinical or comparative bioavailability data or justification for not
TVCNJUUJOH
B
OFX
CJPFRVJWBMFODF
TUVEZ
BDDPSEJOH
UP
UIF
DVSSFOU
8)0
HVJEFMJOFT

PO
CJPFRVJWBMFODF
continues
137
 WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-seventh report

Table continued
Description of change Conditions to Documentation Reporting
be fulfilled required type
31a Change in the 1–9 1–4, 6–7 AN
manufacturing process of
31b the FPP 1–3, 5–9 1–7 Vmin

Conditions to be fulfilled

5IF
DIBOHF
EPFT
OPU
SFRVJSF
TVQQPSUJOH
JO
WJWP
EBUB


/P
DIBOHF
JO
RVBMJUBUJWF
BOE
RVBOUJUBUJWF
JNQVSJUZ
QSPmMF
PS
JO
QIZTJDPDIFNJDBM

properties; dissolution profiles are similar to those of the biobatch.
3. The manufacturing processes for the currently accepted and proposed products
use the same principles (e.g. a change from wet to dry granulation, from direct
compression to wet or dry granulation or vice versa would be considered a change
in manufacturing principle), the same processing intermediates and there are no
changes to any manufacturing solvent used in the process.

5IF
TBNF
DMBTTFT
PG
FRVJQNFOU
PQFSBUJOH
QSPDFEVSFT
JOQSPDFTT
DPOUSPMT
XJUI
OP

widening or deleting of limits) are used for the currently accepted and proposed
products; no change in critical process parameters.
5. No change in the specifications of the intermediates or the FPP.
6. The change is not necessitated by failure to meet specifications resulting from
unexpected events arising during manufacture, or because of stability concerns.
7. The change does not involve packaging or labelling where the primary packaging
provides a metering and/or delivery function.
8. The change does not concern a gastro-resistant, modified or prolonged-release FPP.

5IF
DIBOHF
EPFT
OPU
BõFDU
UIF
TUFSJMJ[BUJPO
QBSBNFUFST
PG
B
TUFSJMF
'11

Documentation required
1. Supporting clinical or comparative bioavailability data or justification for not
TVCNJUUJOH
B
OFX
CJPFRVJWBMFODF
TUVEZ
BDDPSEJOH
UP
UIF
DVSSFOU
8)0
HVJEFMJOFT

PO
CJPFRVJWBMFODF
WHO Technical Report Series No. 981, 2013


1

%JTDVTTJPO
PO
UIF
EFWFMPQNFOU
PG
UIF
NBOVGBDUVSJOH
QSPDFTT
XIFSF

applicable:
t comparative in vitro testing, e.g. multipoint dissolution profiles in the routine
release medium for solid dosage units (one production batch and comparative
data on one batch from the previous process and the biobatch results; data on
UIF
OFYU
UXP
QSPEVDUJPO
CBUDIFT
TIPVME
CF
BWBJMBCMF
PO
SFRVFTU
PS
SFQPSUFE
JG

outside specification);
t
DPNQBSBUJWF
JO
WJUSP
NFNCSBOF
EJõVTJPO
NFNCSBOF
SFMFBTF
UFTUJOH

GPS

non-sterile semisolid dosage forms containing the API in the dissolved or non-
dissolved form (one production batch and comparative data on one batch
from the previous process and the biobatch results; data on the next two
QSPEVDUJPO
CBUDIFT
TIPVME
CF
TVCNJUUFE
PS
CF
BWBJMBCMF
PO
SFRVFTU
;
continues
138
 Annex 3

Table continued
Documentation required
t microscopic imaging of particles to check for visible changes in morphology
BOE
DPNQBSBUJWF
TJ[F
EJTUSJCVUJPO
EBUB
GPS
MJRVJE
QSPEVDUT
JO
XIJDI
UIF
"1*
JT

present in non-dissolved form.
3. (P.3) Batch formula, description of manufacturing process and process controls,
controls of critical steps and intermediates, process validation protocol and/or
evaluation.
4. (P.5) Specification(s) and certificate of analysis for one production-scale batch
manufactured according to the currently accepted process and for a batch
manufactured according to the proposed process.
5. (P.8.1) Results of stability testing generated on at least two pilot batches (for
uncomplicated products, one pilot batch; the other one can be smaller) with a
minimum of 3 months of accelerated (and intermediate, as appropriate) and 3
months of long-term testing.
6. (P.8.2) Updated post-acceptance stability protocol and stability commitment to
place the first production-scale batch of the proposed product into the long-term
stability programme.
7. (R.1) Copies of relevant sections of blank master production documents with
changes highlighted as well as executed production documentation for one batch
and confirmation that there are no changes to the currently accepted production
documents other than those highlighted.

Description of change Conditions to Documentation Reporting

be fulfilled required type
32 Change to in-process tests or limits applied during the manufacture of the FPP
or intermediate involving:

32a tightening of in-process 1–2, 5 1 AN

limits

32b deletion of a test 2, 4 1, 6 AN

32c addition of new tests and 2–3 1–6 AN

limits

32d revision or replacement of 2–3 1–6 IN

a test
Conditions to be fulfilled
1. The change is within the range of acceptance limits.
2. The change is not necessitated by failure to meet specifications resulting from
unexpected events arising during manufacture, or because of stability concerns.
continues
139
 WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-seventh report

Table continued
Conditions to be fulfilled

"OZ
OFX
UFTU
EPFT
OPU
DPODFSO
B
OPWFM
OPOTUBOEBSE
UFDIOJRVF
PS
B
TUBOEBSE

UFDIOJRVF
VTFE
JO
B
OPWFM
XBZ
4. The deleted test has been demonstrated to be redundant with respect to the
SFNBJOJOH
BOBMZUJDBM
QSPDFEVSFT
FH
DPMPVS

BOE
EPFT
OPU
BõFDU
UIF
DSJUJDBM
RVBMJUZ

attributes of the product (e.g. blend uniformity, weight variation).
5. No change in the analytical procedure.
Documentation required
1. (P.5.1) Copy of the proposed in-process specifications dated and signed by
authorized personnel and a comparative table of currently accepted and proposed
specifications.
2. (P.5.2) Copies or summaries of analytical procedures, if new analytical procedures
are used.
3. (P.5.3) Copies or summaries of validation reports, if new analytical procedures are
used.
4. (P.5.3) Where an in-house analytical procedure is used and a pharmacopoeial
TUBOEBSE
JT
DMBJNFE
SFTVMUT
PG
BO
FRVJWBMFODF
TUVEZ
CFUXFFO
UIF
JOIPVTF
BOE

pharmacopoeial methods.

1

%FTDSJQUJPO
PG
UIF
CBUDIFT
DFSUJmDBUFT
PG
BOBMZTJT
GPS
BU
MFBTU
POF
CBUDI

(minimum pilot-scale) and comparative summary of results, in tabular format, for
one batch using current and proposed methods, if new analytical procedures are
implemented.
6. (P.5.6) Justification for the addition or deletion of the tests and limits.

3.2. P.4 Control of excipients

Description of change Conditions to Documentation Reporting

WHO Technical Report Series No. 981, 2013

be fulfilled required type

33 Change in source of an 1 1 AN
FYDJQJFOU
GSPN
B
54&
SJTL
UP

a material of vegetable or
synthetic origin.
Conditions to be fulfilled
1. No change in the excipient and FPP release and shelf-life specifications.
Documentation required

%FDMBSBUJPO
GSPN
UIF
NBOVGBDUVSFS
PG
UIF
FYDJQJFOU
UIBU
JU
JT
FOUJSFMZ
PG
WFHFUBCMF
PS

synthetic origin.
continues
140
 Annex 3

Table continued
Description of change Conditions to Documentation Reporting
be fulfilled required type
34 Change in the specifications or analytical procedures for an excipient involving:
34a deletion of a non-significant 2 1–3 AN
in-house parameter
34b addition of a new test 2–3 1–2 AN
parameter or analytical
procedure
34c tightening of specification 1–2, 4 1–2 AN
limits
34d change or replacement of 2–3 1–2 Vmin
an analytical procedure
Conditions to be fulfilled
1. The change is within the range of currently accepted limits.
2. The change is not necessitated by failure to meet specifications resulting from
unexpected events arising during manufacture, or because of stability concerns.

"OZ
OFX
BOBMZUJDBM
QSPDFEVSF
EPFT
OPU
DPODFSO
B
OPWFM
OPOTUBOEBSE
UFDIOJRVF
PS

B
TUBOEBSE
UFDIOJRVF
VTFE
JO
B
OPWFM
XBZ
4. No change in the analytical procedure.
Documentation required
1. Justification for the change.
2. (P.5) Comparative table of currently accepted and proposed specifications,
justification of the proposed specifications and details of procedure and summary
of validation of any new analytical procedure (if applicable).
3. Justification to demonstrate that the parameter is not critical.

Description of change Conditions to Documentation Reporting

be fulfilled required type
35 Change in specifications 1 1 AN
of an excipient to comply
with an officially recognized
pharmacopoeia
Conditions to be fulfilled

/P
DIBOHF
UP
UIF
TQFDJmDBUJPOT
PUIFS
UIBO
UIPTF
SFRVJSFE
UP
DPNQMZ
XJUI
UIF

pharmacopoeia (e.g. no change in particle size distribution).
Documentation required
1. Comparative table of currently accepted and proposed specifications for the excipient.

141
 WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-seventh report

3.2. P.5 Control of FPP

Description of change Conditions to Documentation Reporting

be fulfilled required type
36a Change in the standard 1–3 1–5 AN
claimed for the FPP
from an in-house to an
officially recognized
pharmacopoeial standard

36b Update to the None 1, 3, 5 AN

specifications to comply
with an officially recognized
pharmacopoeial
monograph as a result of an
update to this monograph
to which the FPP is
controlled

Conditions to be fulfilled
1. The change is made exclusively to comply with the officially recognized
pharmacopoeia.
2. No change to the specifications that results in a potential impact on the
performance of the FPP (e.g. dissolution test).
3. No deletion of or relaxation of any of the tests, analytical procedures or acceptance
criteria of the specifications. Any deletion or relaxation of the tests should meet the
conditions of 37a or 37d and should follow the corresponding reporting types.

Documentation required
1. (P.5.1) Copy of the proposed FPP specifications dated and signed by authorized
personnel and a comparative table of currently accepted and proposed
WHO Technical Report Series No. 981, 2013

specifications.
2. (P.5.3) Where an in-house analytical procedure is used and a pharmacopoeial
TUBOEBSE
JT
DMBJNFE
SFTVMUT
PG
BO
FRVJWBMFODF
TUVEZ
CFUXFFO
UIF
JOIPVTF
BOE

pharmacopoeial methods.

1

%FTDSJQUJPO
PG
UIF
CBUDIFT
DFSUJmDBUFT
PG
BOBMZTJT
GPS
BU
MFBTU
POF
CBUDI

(minimum pilot-scale) and comparative summary of results, in tabular format, for
one batch using current and proposed procedures, if new analytical procedures are
implemented.
4. (P.5.6) Justification for the proposed FPP specifications.

1

%FNPOTUSBUJPO
PG
UIF
TVJUBCJMJUZ
PG
UIF
NPOPHSBQI
UP
DPOUSPM
UIF
'11
continues

142
 Annex 3

Table continued
Description of change Conditions to Documentation Reporting
be fulfilled required type
37 Change in the specifications of the FPP involving test parameters and
acceptance criteria:
37a deletion of a test 5 1, 6 AN
parameter
37b addition of a test 2–4, 7 1–6 AN
parameter
37c tightening of an 1–2 1, 6 AN
acceptance criterion
37d relaxation of an 2, 4, 6–7 1, 5–6 IN
acceptance criterion
37e replacement of a test 2–4, 6-7 1–6 IN
parameter
Conditions to be fulfilled
1. The change is within the range of currently accepted limits.
2. The change is not necessitated by failure to meet specifications resulting from
unexpected events arising during manufacture, or because of stability concerns.

"OZ
OFX
BOBMZUJDBM
QSPDFEVSF
EPFT
OPU
DPODFSO
B
OPWFM
OPOTUBOEBSE
UFDIOJRVF
PS

B
TUBOEBSE
UFDIOJRVF
VTFE
JO
B
OPWFM
XBZ
4. No additional impurity found over the ICH identification threshold.
5. The deleted test has been demonstrated to be redundant with respect to the
remaining tests.

5IF
DIBOHF
UP
UIF
TQFDJmDBUJPOT
EPFT
OPU
BõFDU
UIF
TUBCJMJUZ
BOE the performance
of the product.
7. The change does not concern sterility testing.
Documentation required
1. (P.5.1) Copy of the proposed FPP specifications dated and signed by authorized
personnel and a comparative table of currently accepted and proposed
specifications.
2. (P.5.2) Copies or summaries of analytical procedures, if new analytical procedures
are used.
3. (P.5.3) Copies or summaries of validation reports, if new analytical procedures are
used.
4. (P.5.3) Where an in-house analytical procedure is used and a pharmacopoeial
TUBOEBSE
JT
DMBJNFE
SFTVMUT
PG
BO
FRVJWBMFODF
TUVEZ
CFUXFFO
UIF
JOIPVTF
BOE

pharmacopoeial methods.
continues
143
 WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-seventh report

Table continued
Documentation required

1

%FTDSJQUJPO
PG
UIF
CBUDIFT
DFSUJmDBUFT
PG
BOBMZTJT
GPS
BU
MFBTU
POF
CBUDI

(minimum pilot-scale) and comparative summary of results, in tabular format, for
one batch using currently accepted and proposed procedures, if new analytical
procedures are implemented.
6. (P.5.6) Justification for the proposed FPP specifications.

Description of change Conditions to Documentation Reporting

be fulfilled required type
38 Change in the analytical procedures for the FPP involving:
38a deletion of an analytical 5 1, 6 AN
procedure
38b addition of an analytical 3–4, 6–7 1–5 AN
proceduref
38c.1 modification or 1–4, 6–7 1–5 AN
replacement of an
38c.2 analytical procedure 2–4, 6–7 1–5 Vmin

38d updating the analytical None 1–5 AN

procedure with an
officially recognized
pharmacopoeial
monograph as a result
of an update to that
monograph
38e change from an in-house 2, 7 1–3, 5 IN
analytical procedure to
WHO Technical Report Series No. 981, 2013

an analytical procedure
in an officially recognized
pharmacopoeial
monograph or from the
analytical procedure in
one officially recognized
pharmacopoeial
monograph to an
analytical procedure
in another officially
recognized
pharmacopoeial
monograph
continues
144
 Annex 3

Table continued
Conditions to be fulfilled

5IF
NFUIPE
PG
BOBMZTJT
JT
CBTFE
PO
UIF
TBNF
BOBMZUJDBM
UFDIOJRVF
PS
QSJODJQMF
FH

changes to the analytical procedure are within allowable adjustments to column
length and other parameters, but do not include variations beyond the acceptable
SBOHFT
PS
B
EJõFSFOU
UZQF
PG
DPMVNO
BOE
NFUIPE

BOE
OP
OFX
JNQVSJUJFT
BSF

detected.
2. Comparative studies demonstrate that the proposed analytical procedure is at least
FRVJWBMFOU
UP
UIF
DVSSFOUMZ
BDDFQUFE
BOBMZUJDBM
QSPDFEVSF

"OZ
OFX
BOBMZUJDBM
QSPDFEVSF
EPFT
OPU
DPODFSO
B
OPWFM
OPOTUBOEBSE
UFDIOJRVF
PS

B
TUBOEBSE
UFDIOJRVF
VTFE
JO
B
OPWFM
XBZ
4. The change does not concern sterility testing.

5IF
EFMFUFE
BOBMZUJDBM
QSPDFEVSF
JT
BO
BMUFSOBUJWF
NFUIPE
BOE
JT
FRVJWBMFOU
UP
B

currently accepted analytical procedure.
6. The change is not necessitated by failure to meet specifications resulting from
unexpected events arising during manufacture, or because of stability concerns.
7. No new impurities have been detected.
Documentation required
1. (P.5.1) A copy of the proposed FPP specifications dated and signed by authorized
personnel and a comparative table of currently accepted and proposed
specifications.
2. (P.5.2) Copies or summaries of analytical procedures, if new analytical procedures
are used.
3. (P.5.3) Copies or summaries of validation reports, including verification data for
assay or purity methods, if new analytical procedures are used.
4. (P.5.3) Where an in-house analytical procedure is used and a pharmacopoeial
TUBOEBSE
JT
DMBJNFE
SFTVMUT
PG
BO
FRVJWBMFODF
TUVEZ
CFUXFFO
UIF
JOIPVTF
BOE

pharmacopoeial methods.

1

%FTDSJQUJPO
PG
UIF
CBUDIFT
DFSUJmDBUFT
PG
BOBMZTJT
GPS
BU
MFBTU
POF
CBUDI

(minimum pilot-scale) and comparative summary of results, in tabular format, for
one batch using currently accepted and proposed analytical procedures.
6. Justification for the deletion of the analytical procedure, with supporting data.

3.2. P.7 Container-closure system

Description of change Conditions to Documentation Reporting

be fulfilled required type
39a Replacement or addition of 1 1–2, 4–6 Vmin
a primary packaging type
39b None 1–6 Vmaj
continues
145
 WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-seventh report

Table continued
Conditions to be fulfilled
1. The change does not concern a sterile FPP.
Documentation required
1. Samples of the product as packaged in the new container-closure system.

1

%BUB
PO
UIF
TVJUBCJMJUZ
PG
UIF
DPOUBJOFSDMPTVSF
TZTUFN
FH
FYUSBDUBCMF
MFBDIBCMF
UFTUJOH
QFSNFBUJPO
UFTUJOH
MJHIU
USBOTNJTTJPO

EFNPOTUSBUJOH
FRVJWBMFOU

or superior protection compared to the current packaging system. For changes to
functional packaging, data to demonstrate the functioning of the new packaging.
3. (P.3.5) For sterile FPPs, process validation and/or evaluation studies.
4. (P.7) Information on the proposed primary packaging type (e.g. description,
materials of construction of primary packaging components, specifications, and
results of transportation studies, if appropriate).
5. (P.8.1) Stability summary and conclusions, results for a minimum of two batches
of pilot- or production-scale, of 3 months of accelerated (and intermediate, as
appropriate) and 3 months of long-term testing and where applicable, results of
photostability studies.
6. (P.8.2) Updated post-acceptance stability protocol and stability commitment to
place the first production-scale batch of the proposed product into the long-term
stability programme, unless data were provided in documentation 5.

Description of change Conditions to Documentation Reporting

be fulfilled required type
40 Change in the package size involving:
40a change in the number 1–2 1–2 IN
of units (e.g. tablets,
ampoules, etc.) in a package
40b.1 change in the fill weight 1–3 1–2 IN
WHO Technical Report Series No. 981, 2013

or fill volume of non-

40b.2 parenteral multidose 1–2 1–2 Vmin
products
Conditions to be fulfilled
1. The change is consistent with the posology and treatment duration accepted in the
SmPC.
2. No change in the primary packaging material.
3. No increase in the headspace or surface/volume ratio.
Documentation required
1. Justification for the new pack-size, indicating that the new size is consistent with the
dosage regimen and duration of use as accepted in the SmPC.
continues
146
 Annex 3

Table continued
Documentation required
2. (P.8.2) A written commitment that stability studies will be conducted in accordance
XJUI
UIF
8)0
HVJEFMJOFT
GPS
QSPEVDUT
XIFSF
TUBCJMJUZ
QBSBNFUFST
DPVME
CF
BõFDUFE

Description of change Conditions to Documentation Reporting

be fulfilled required type
41 Change in the shape or dimensions of the container or closure for:

41a non-sterile FPPs 1–2 1–3 AN

41b sterile FPPs 1–2 1–4 Vmin

Conditions to be fulfilled

/P
DIBOHF
JO
UIF
RVBMJUBUJWF
PS
RVBOUJUBUJWF
DPNQPTJUJPO
PG
UIF
DPOUBJOFS
BOEPS

closure.
2. The change does not concern a fundamental part of the packaging material, which
DPVME
BõFDU
UIF
EFMJWFSZ
VTF
TBGFUZ
PS
TUBCJMJUZ
PG
UIF
'11

Documentation required
1. Samples of the product packaged in the new container-closure system.
2. (P.7) Information on the proposed container-closure system (e.g. description,
materials of construction, and specifications).
3. (P.8.1) In the case of changes to the thickness of a packaging component or for
sterile FPPs: stability summary and conclusions, results for a minimum of two
batches of pilot- or production-scale, of 3 months of accelerated (and intermediate,
as appropriate) and 3 months of long-term testing and, where applicable, results of
photostability studies. In the case of a change in the headspace or a change in the
surface/volume ratio for non-sterile FPPs, a commitment for the above studies.

1

&WJEFODF
PG
SFWBMJEBUJPO
TUVEJFT
JO
UIF
DBTF
PG
UFSNJOBMMZ
TUFSJMJ[FE
QSPEVDUT

The batch numbers of the batches used in the revalidation studies should be
indicated, where applicable.

Description of change Conditions to Documentation Reporting

be fulfilled required type
42 $IBOHF
JO
RVBMJUBUJWF
BOEPS
RVBOUJUBUJWF
DPNQPTJUJPO
PG
UIF
JNNFEJBUF

packaging material for:

42a solid FPPs 1–3 1–3 IN

42b TFNJTPMJE
BOE
MJRVJE
'11T 1–3 1–3 Vmin

continues
147
 WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-seventh report

Table continued
Conditions to be fulfilled
1. The change does not concern a sterile FPP.
2. No change in the packaging type and material (an example of an allowable change
is blister to blister).

5IF
SFMFWBOU
QSPQFSUJFT
PG
UIF
QSPQPTFE
QBDLBHJOH
BSF
BU
MFBTU
FRVJWBMFOU
UP
UIPTF

of the currently accepted material.

Documentation required

1

%BUB
EFNPOTUSBUJOH
UIF
TVJUBCJMJUZ
PG
UIF
QSPQPTFE
QBDLBHJOH
NBUFSJBM
FH

extractable/leachable testing, light transmission, permeation testing for oxygen,
carbon dioxide, and moisture).
2. (P.7) Information on the proposed packaging material (e.g. description, materials of
construction, and specifications).
3. (P.8.1) Stability summary and conclusions, results of (or a commitment to study in
UIF
DBTF
PG
EFNPOTUSBUFE
FRVJWBMFOU
PS
NPSF
QSPUFDUJWF
QBDLBHJOH

B
NJOJNVN

of two batches of pilot- or production-scale, of 3 months of accelerated (and
intermediate, as appropriate) and 3 months of long-term testing and, where
applicable, results of photostability studies.

Description of change Conditions to Documentation Reporting

be fulfilled required type
43 Change in the specifications of the immediate packaging involving:

43a tightening of specification 1–2 1 AN

limits

43b addition of a test parameter 2–3 1–2 AN

43c deletion of a non-critical 2 1, 3 AN

WHO Technical Report Series No. 981, 2013

parameter

Conditions to be fulfilled
1. The change is within the range of currently accepted limits.
2. The change is not necessitated by failure to meet specifications resulting from
unexpected events arising during manufacture, or because of stability concerns.

"OZ
OFX
BOBMZUJDBM
QSPDFEVSF
EPFT
OPU
DPODFSO
B
OPWFM
OPOTUBOEBSE
UFDIOJRVF
PS

B
TUBOEBSE
UFDIOJRVF
VTFE
JO
B
OPWFM
XBZ

Documentation required
1. (P.7) Comparative table of currently accepted and proposed specifications,
justification of the proposed specifications.
continues
148
 Annex 3

Table continued
Documentation required

1

%FTDSJQUJPO
PG
UIF
BOBMZUJDBM
QSPDFEVSF
BOE
TVNNBSZ
PG
WBMJEBUJPO
PG
UIF
OFX

analytical procedure.

%PDVNFOUBUJPO
UP
EFNPOTUSBUF
UIBU
UIF
QBSBNFUFS
JT
OPU
DSJUJDBM

Description of change Conditions to Documentation Reporting

be fulfilled required type
44 Change to an analytical procedure on the immediate packaging involving:

44a minor change to an 1–3 1 AN

analytical procedure

44b other changes to an 2–4 1 AN

analytical procedure
including addition
or replacement of an
analytical procedure

44c deletion of an analytical 5 2 AN

procedure
Conditions to be fulfilled

5IF
NFUIPE
PG
BOBMZTJT
JT
CBTFE
PO
UIF
TBNF
BOBMZUJDBM
UFDIOJRVF
PS
QSJODJQMF
FH

changes to the analytical procedure are within allowable adjustments to column
length and other parameters, but do not include variations beyond the acceptable
SBOHFT
PS
B
EJõFSFOU
UZQF
PG
DPMVNO
BOE
NFUIPE

2. Appropriate (re)validation studies have been performed in accordance with the
relevant guidelines.

$PNQBSBUJWF
TUVEJFT
JOEJDBUF
UIF
OFX
BOBMZUJDBM
QSPDFEVSF
UP
CF
BU
MFBTU
FRVJWBMFOU

to the former procedure.

"OZ
OFX
BOBMZUJDBM
QSPDFEVSF
EPFT
OPU
DPODFSO
B
OPWFM
OPOTUBOEBSE
UFDIOJRVF
PS

B
TUBOEBSE
UFDIOJRVF
VTFE
JO
B
OPWFM
XBZ

5IF
EFMFUFE
BOBMZUJDBM
QSPDFEVSF
JT
BO
BMUFSOBUJWF
NFUIPE
BOE
JT
FRVJWBMFOU
UP
B

currently accepted method.
Documentation required

1

%FTDSJQUJPO
PG
UIF
NFUIPE
BOE
DPNQBSBUJWF
WBMJEBUJPO
SFTVMUT
EFNPOTUSBUJOH

UIBU
UIF
DVSSFOUMZ
BDDFQUFE
BOE
QSPQPTFE
NFUIPET
BSF
BU
MFBTU
FRVJWBMFOU

%PDVNFOUBUJPO
UP
EFNPOTUSBUF
UIF
FRVJWBMFODF
PG
UIF
EFMFUFE
NFUIPE
BOE
B

currently accepted method.
continues

149
 WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-seventh report

Table continued
Description of change Conditions to Documentation Reporting
be fulfilled required type
45 Change in any part of 1 1–2 IN
the (primary) packaging
material not in contact with
the FPP formulation (e.g.
DPMPVS
PG
nJQPõ
DBQT
DPMPVS

code rings on ampoules, or
change of needle shield).
Conditions to be fulfilled
1. The change does not concern a fundamental part of the packaging material, which
BõFDUT
UIF
EFMJWFSZ
VTF
TBGFUZ
PS
TUBCJMJUZ
PG
UIF
'11

Documentation required
1. (P.7) Information on the proposed packaging material (e.g. description, materials of
construction, and specifications).
2. Sample of the FPP.

Description of change Conditions to Documentation Reporting

be fulfilled required type
46 Change to an administration or measuring device that is not an integral part
of the primary packaging (excluding spacer devices for metered dose inhalers)
involving:
46a addition or replacement 1, 2 1–2 IN
46b deletion 3 3 IN
Conditions to be fulfilled
WHO Technical Report Series No. 981, 2013


5IF
QSPQPTFE
NFBTVSJOH
EFWJDF
JT
EFTJHOFE
UP
BDDVSBUFMZ
EFMJWFS
UIF
SFRVJSFE
EPTF

for the product concerned in line with the posology, and results of such studies are
available.
2. The proposed device is compatible with the FPP.
3. The FPP can be accurately delivered in the absence of the device.
Documentation required

1

%BUB
UP
EFNPOTUSBUF
BDDVSBDZ
QSFDJTJPO
BOE
DPNQBUJCJMJUZ
PG
UIF
EFWJDF

2. Sample of the device.
3. Justification for the deletion of the device.

150
 Annex 3

3.2. P.8 Stability

Description of change Conditions to Documentation Reporting

be fulfilled required type
47 Change in the shelf-life of the FPP (as packaged for sale) involving:

47a reduction 3 1–3 IN

47b extension 1–2 1–3 Vmin

Conditions to be fulfilled
1. No change to the primary packaging type in direct contact with the FPP and to the
recommended conditions of storage.
2. Stability data were generated in accordance with the currently accepted stability
protocol.
3. The change is not necessitated by unexpected events arising during manufacture or
because of stability concerns.
Documentation required
1. (P.5.1) Copy of the currently accepted shelf-life specifications.
2. (P 8.1) Proposed shelf-life, summary of long-term stability testing according
to currently accepted protocol and test results for a minimum of two pilot- or
production-scale batches for a period sufficient to support the proposed shelf-life.
3. (P.8.2) Updated post-acceptance stability protocol and stability commitment and
justification of change.

Description of change Conditions to Documentation Reporting

be fulfilled required type

48 Change in the in-use period of the FPP (after first opening or after
reconstitution or dilution):

48a reduction 1 1 IN

48b extension None 1–2 Vmin

Conditions to be fulfilled
1. The change is not necessitated by unexpected events arising during manufacture or
because of stability concerns.
Documentation required
1. (P 8) Proposed in-use period, test results and justification of change.
2. (P 5.1) Copy of currently accepted end of shelf-life FPP specifications and, where
applicable, specifications after dilution or reconstitution.

continues
151
 WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-seventh report

Table continued
Description of change Conditions to Documentation Reporting
be fulfilled required type
49 Change in the labelled 1 1–2 Vmin
storage conditions of the
FPP (as packaged for sale),
the product during the in-
use period or the product
after reconstitution or
dilution
Conditions to be fulfilled
1. The change is not necessitated by failure to meet specifications resulting from
unexpected events arising during manufacture, or because of stability concerns.
Documentation required
1. (P.8.1) If applicable, stability and/or compatibility test results to support the change
to the storage conditions.
2. (P.8.2) Updated post-acceptance stability protocol and stability commitment and
justification of change.
WHO Technical Report Series No. 981, 2013

152
 Annex 3

Appendix 1
Examples of changes that make a new application or
extension application necessary
Description of change Conditions to Documentation Reporting
be fulfilled required type
1. Change of the API to a None 1 New
EJõFSFOU
"1* application/
2. Inclusion of an additional API extension
in a multicomponent product application
3. Removal of one API from a
multicomponent product
4. Change in the dose and/or
strength of one or more APIs
5. Change from an immediate-
release product to an
extended or delayed-release
dosage form or vice versa

$IBOHF
GSPN
B
MJRVJE
UP
B

powder for reconstitution or
vice versa
7. Changes in the route of
administration
Conditions to be fulfilled
None
Documentation required

%PDVNFOUT
JO
GVMmMNFOU
PG
UIF
SFRVJSFNFOUT
PVUMJOFE
JO
UIF
WHO Guidelines on
submission of documentation for a multisource (generic) finished pharmaceutical
product for the WHO Prequalification of Medicines Programme: quality part.12

12
See footnote 3.
153
 WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-seventh report

Appendix 2
Changes to excipients
Excipient Percentage excipient (w/w) out of total
target dosage form core weight
Filler ± 5.0
%JTJOUFHSBOU
t starch ± 3.0
t other ± 1.0
Binder ± 0.5
Lubricant
t Ca or Mg Stearate ± 0.25
t other ± 1.0
(MJEBOU
t talc ± 1.0
t other ± 0.1

■ These percentages are based on the assumption that the active

pharmaceutical ingredient (API) in the finished pharmaceutical
product (FPP) is formulated to 100.0% of label/potency declaration.
The total additive effect of all changes to excipients should be not more
than 5.0% relative to the target dosage form weight (e.g. in a product
consisting of API, lactose, microcrystalline cellulose and magnesium
stearate, the lactose increases by 2.5% and microcrystalline cellulose
WHO Technical Report Series No. 981, 2013

decreases by 2.5%).
■ If an excipient serves multiple functions (e.g. microcrystalline
cellulose as a filler and as a disintegrant), then the most
conservative recommended range should be applied (e.g. ± 1.0% for
microcrystalline cellulose should be applied in this example). If a
wider range is proposed, scientific justification and supporting data
should be provided to demonstrate that the wider range will not
affect the other function of the excipient.

154