CTD Guidelines

MCAZ Registration Guidelines Published August 2012 Page 1 of 98
Medicines Control Authority of Zimbabwe

GUIDELINE ON SUBMISSION OF DOCUMENTATION FOR
REGISTRATION OF A MULTISOURCE (GENERIC) FINISHED
PHARMACEUTICAL PRODUCT (FPP): QUALITY PART IN
THE COMMON TECHNICAL DOCUMENT (CTD) FORMAT

APPROVED DATE: AUGUST 2012
EFFECTIVE DATE: MARCH 2013

106 Baines Avenue
P O Box 10559
Harare

Fax: +263 4 736980
E-mail: mcaz@mcaz.co.zw

NB: The guideline has been approved for use by the Authority as of August 2012. Applicants are
encouraged to use this guidance for submitting applications. Applications already submitted are
being evaluated using this guideline. Submission based on previous guideline and previous
format will be accepted until February 2012. From March 2013, the Common Technical
Document (CTD) format will be the only accepted format for submission of applications for
registration of finished pharmaceutical products.


Process and adoption of the guideline
Drafting of guideline February 2011
Discussion and review of comments within the Evaluations
and Registration Unit
December 2011
Approval for circulation of draft for comments by
Registration Committee
January 2012
Approval for circulation by DG January 2012
Circulation for comments January 2012
Collation and review of comments April 2012
Approval of the final draft by the Registration Committee June2012
Approval of the final draft by DG June 2012
Publication of final guideline August 2012
Requirements come into effect March 2013


CONTENTS
Process and adoption of the guideline ..........................................................................................2
CONTENTS ...............................................................................................................................3
ABBREVIATIONS ....................................................................................................................6
GLOSSARY ...............................................................................................................................7
INTRODUCTION .................................................................................................................... 10
Background ........................................................................................................................... 10
Objectives ............................................................................................................................. 11
Scope..................................................................................................................................... 11
General Principles ................................................................................................................. 11
GUIDANCE ON THE FORMAT AND PRESENTATION....................................................... 12
Guidance on format ............................................................................................................... 12
Guidance on presentation ....................................................................................................... 14
Additional guidance on sections to be included in Module 1 .................................................. 16
Cover letter ........................................................................................................................ 16
A completed and signed MC8 Form (see Annex I) ............................................................. 16
Declaration by the applicant ............................................................................................... 17
Screening Checklist............................................................................................................ 18
Proof of payment of appropriate fees .................................................................................. 18
Manufacturing and marketing authorisation(s)/international registration status ................... 18
Summary of product characteristics (SmPC) ...................................................................... 19
Labelling (Primary and secondary packaging) .................................................................... 19
Electronic Review Documents ............................................................................................... 21
Product Samples (e.g. FPP, device(s)) ................................................................................... 22
QUALITY SUMMARIES......................................................................................................... 23
MODULE 3: QUALITY ........................................................................................................... 24
4.1 Table of contents of Module 3 ......................................................................................... 24
4.2 Body of data .................................................................................................................... 24


3.2.S Drug substance (or active pharmaceutical ingredient (API)) .......................................... 24
3.2.S.1 General information (name, manufacturer) ............................................................. 25
3.2.S.2 Manufacture (name, manufacturer) ......................................................................... 28
3.2.S.3 Characterization (name, manufacturer) ................................................................... 32
3.2.S.4 Control of the API (name, manufacturer) ................................................................ 38
3.2.S.5 Reference standards or materials (name, manufacturer) .......................................... 42
3.2.S.6 Container closure system (name, manufacturer) ..................................................... 43
3.2.S.7 Stability (name, manufacturer) ............................................................................... 43
3.2.P Drug product (or finished pharmaceutical product (FPP)) (name, dosage form) ............ 48
3.2.P.1 Description and composition of the FPP (name, dosage form) ................................ 48
3.2.P.2 Pharmaceutical development (name, dosage form) ................................................. 49
3.2.P.3 Manufacture (name, dosage form) .......................................................................... 56
3.2.P.4 Control of excipients (name, dosage form) ............................................................. 62
3.2.P.5 Control of FPP (name, dosage form) ...................................................................... 65
3.2.P.6 Reference standards or materials (name, dosage form) ........................................... 70
3.2.P.7 Container closure system (name, dosage form) ....................................................... 70
3.2.P.8 Stability (name, dosage form) ................................................................................. 71
3.2.A Appendices .................................................................................................................. 75
3.2.R Regional information .................................................................................................... 75
3.2.R.1 Production documentation...................................................................................... 75
3.2.R.2 Analytical procedures and validation information .................................................. 77
3.3 Literature references ........................................................................................................ 78
MODULE 5 OF A PRODUCT DOSSIER FOR A MULTISOURCE PHARMACEUTICAL
PRODUCT................................................................................................................................ 78
Module 5: Clinical study reports ............................................................................................ 78


REFERENCES ......................................................................................................................... 79


ABBREVIATIONS

API Active Pharmaceutical Ingredient
ARV Antiretroviral
APIMF Active Pharmaceutical Ingredient Master File
BAN British Approved Name
BP British Pharmacopoeia
CAS Chemical Abstracts Service Registry Number
CEP European Certificate of Suitability
CoA Certificate of Analysis
CTD Common Technical Document
DRA Drug Regulatory Authority
EU European Union
FDA United States Food and Drug Administration
FDC Fixed Dose Combination
FPP Finished Pharmaceutical Product
ICH International Conference on Harmonisation
INN International Non-proprietary Name
GMP Good Manufacturing Practice
Int.Ph. International Pharmacopoeia
JP Japanese Pharmacopoeia
LOD Loss on drying
MCAZ Medicines Control Authority of Zimbabwe
SADC Southern African Development Community
SI 150 Statutory Instruments 150 of 1991
SmPC Summary of Product Characteristics
SMACS WHO pharmaceutical starting materials certification scheme
SRA Stringent Regulatory Authority
PDs Product Dossiers
PDE Permissible Daily Exposure
Ph. Eur European Pharmacopoeia
PQIT Product Quality Information Template
QA Quality Assurance
QIS Quality Information Summary
MCAZ-QOS MCAZ Quality Overall Summary
RH Relative Humidity
USAN United States Adopted Name
USP United States Pharmacopoeia
USD United States Dollars
WHO World Health Organisation
WHO TRS WHO Technical Report Series


GLOSSARY

The definitions provided below apply to the words and phrases used in these guidelines.
Although an effort has been made to use standard definitions as far as possible, they may have
different meanings in other contexts and documents. The following definitions are provided to
facilitate interpretation of the guidelines.

Active pharmaceutical ingredient (API)
Any substance or combination of substances used in a finished pharmaceutical product (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 a direct effect in restoring,
correcting or modifying physiological functions in human beings.

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 (ref. ICH Q7). See also starting
materials for synthesis.

Applicant
Means the person or entity by, or on whose behalf, an application for registration is made.

BCS highly soluble
An API for which the highest dose recommended by WHO (if the API appears on the WHO
Model List of Essential Medicines) or highest dose strength available on the market as an oral
solid dosage form (if the API does not appear on the WHO Model List of Essential Medicines) is
soluble in 250 ml or less of aqueous media over the pH range of 1.2 6.8 at 37C (ref. WHO
Technical Report Series, No. 937, Annex 7, 2006).

Commitment batches
Production batches of an API or FPP for which the stability studies are initiated or completed
post-approval through a commitment made in a regulatory application (ref. WHO Technical
Report Series, No. 953, Annex 2, 2009).

Comparator product
A pharmaceutical product with which the generic product is intended to be interchangeable in
clinical practice. The comparator product will normally be the innovator product for which
efficacy, safety and quality have been established (ref. MCAZ BE Guidelines). The selection of
the comparator product is based on the information presented under Guidance on Bioequivalence
Studies available on the Prequalification website.

Established multisource (generic) product


A multisource product that has been marketed by the applicant or manufacturer associated with
the dossier for at least five years and for which at least 10 production batches were produced
over the previous year, or, if less than 10 batches were produced in the previous year, not less
than 25 batches were produced in the previous three years.

Existing API
An API that is not considered a new active substance that has been previously approved through
a finished product by a stringent regulatory authority, MCAZ or WHO, but requires the filing of
a dossier. This would include, for example, new PDs and variations to multisource products.

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.

Innovator pharmaceutical product
Generally the pharmaceutical product that was first authorised for marketing (normally as a
patented product) on the basis of documentation of efficacy, safety and quality.

Manufacturer
A company that carries out operations such as production, packaging, repackaging, labelling and
re-labelling of pharmaceuticals.

Multisource (generic) pharmaceutical products
Pharmaceutically equivalent or pharmaceutically alternative products that may or may not be
therapeutically equivalent. Multisource pharmaceutical products that are therapeutically
equivalent are interchangeable (WHO Technical Report Series, No. 937, Annex 7, 2006).

Officially recognized pharmacopoeia (or compendium)
Those pharmacopoeias recognized by the MCAZ (i.e. The International Pharmacopoeia (Ph.Int.),
the European Pharmacopoeia (Ph.Eur.), the British Pharmacopoeia (BP) and the United States
Pharmacopeia (USP)).

Ongoing stability study
The study carried out by the manufacturer on production batches according to a predetermined
schedule in order to monitor, confirm and extend the projected retest period (or shelf-life) of the
API, or confirm or extend the shelf-life of the FPP.

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 that of a full production scale or 100 000 tablets
or capsules, whichever is the larger; unless otherwise adequately justified.

Primary batch


A batch of an API or FPP used in a stability study, from which stability data are submitted in a
registration application for the purpose of establishing a retest period or shelf-life. Primary batch
requirements are outlined in 3.2.S.7.1 and 3.2.P.8.1 for the API and FPP, respectively.

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,

Starting materials for synthesis
Materials that mark the beginning of the manufacturing process as described in an application or
in an APIMF. A starting material for a synthetic API is a chemical compound of defined
molecular structure that contributes to the structure of the API. See also API starting material


INTRODUCTION
Background

These guidelines are an update to the MCAZ Draft Registration Guidelines published in 2008,
which were based on SADC and WHO guidelines. Since 2008, several changes in regulatory
practice and policy were implemented. The improvements are based on the World Health
Organisation (WHO) Guideline on submission of documentation for a multisource (generic)
finished pharmaceutical product (FPP): quality part and on the International Conference on
Harmonisation guidelines.

Through the International Conference on Harmonisation (ICH) process, considerable
harmonisation has been achieved on the organisation of the registration documents with the
issuance of the common technical document (CTD) guideline. This recommended CTD format
for submitting registration applications has become widely accepted by regulatory authorities the
world over. This document provides recommendations on the format and presentation for these
types of product dossiers.

This document, Guideline on submission of documentation for a multisource (generic) finished
pharmaceutical product (FPP): quality part, provides recommendations on the quality
information for active pharmaceutical ingredients (APIs) and finished pharmaceutical products
(FPPs) that should be submitted to MCAZ to support applications for registration. Alternate
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
MCAZ may request information or material, or define conditions not specifically described in
this guidance, in order to adequately assess the quality of a pharmaceutical product.

The content of this guideline should be read in conjunction with relevant information described
in other existing MCAZ, WHO or ICH reference documents and guidelines. Scientific literature
may be appropriate to fulfill the requirements for some of the information or parameters outlined
in this guideline (e.g. qualification of specified identified impurities). Furthermore, the
requirements outlined in certain sections may not be applicable for the proposed API or FPP. In
these situations, a summary and the full reference to the scientific literature should be provided
or the non-applicability of the requested information should be clearly indicated as such with an
accompanying explanatory note.

Applicants interested in having their FPPs evaluated for registration in Zimbabwe should submit
a product dossier reflecting the data and information requested below. The current version of any
guideline or pharmacopoeia referred to in this guideline shall be applicable in all instances. Any
deviations must be highlighted, justified and require approval by the MCAZ.

When applicants are applying for registration of fixed dose combination (FDC) products they
should address all the requirements of the WHO TRS 929 Guideline for Registration of Fixed
Dose Combination Medicinal Products in addition to the guidelines below.



An application for registration of a medicine may be made by:
The prospective holder of the marketing authorisation/registration, hereinafter referred to
as the applicant
A nominee of the applicant who must submit evidence of power of attorney

Objectives

This guideline is intended to:

a) assist applicants on the preparation of applications for registration (product dossiers) for
multisource (generic) products by providing clear general guidance on the format of these
dossiers;

b) fully adopt the modular format of the Common Technical Document - Quality (M4Q) as
developed by ICH; and

c) provide guidance on the technical and other general data requirements.

These measures are intended to promote effective and efficient processes for the development of
the applications for registration by applicants and the subsequent assessment procedures by
MCAZ.

Scope

This guideline applies to applications for registration for multisource (generic) pharmaceutical
products containing APIs of synthetic or semi-synthetic origin. Fermentation, biological,
biotechnological and herbal APIs are covered by other guidelines.

General Principles

To facilitate the preparation of the application for registration (product dossier), this guideline is
organised in accordance with the structure of the Common Technical Document Quality (M4Q)
guideline, as developed by ICH.
The text of the M4Q (CTD-Q) guideline has been re-stated in this guideline, with minor
modifications to accommodate MCAZ terminology and include certain text that would be
appropriate for multisource pharmaceutical products, notably:

Drug substance is replaced with active pharmaceutical ingredient or API ;

Drug product is replaced with finished pharmaceutical product or FPP ;



Combination product is replaced with fixed-dose combination or FDC ;

clinical batches is replaced with comparative bioavailability or biowaiver batches .

GUIDANCE ON THE FORMAT AND PRESENTATION
Guidance on format

The CTD is organised into five modules. Module 1 is region/country-specific. Modules 2, 3, 4
and 5 are intended to be common for all regions. This section provides an overview of module
contents for a multisource (generic) finished pharmaceutical product in greater detail.

a) Module 1- Administrative information and prescribing information:
- This module should contain documents specific to Zimbabwe; for example, application
forms, screening forms, fees, package inserts and the proposed label for use in
Zimbabwe.
- A summary of the bioequivalence/bioavailability information should be provided
according to MCAZ Guidelines for the submission of documentation for the
demonstration of interchangeability between generic products (Bioequivalence).
- Quality information summary (QIS)

b) Module 2 - CTD summaries:
- This module should begin with a general introduction to the pharmaceutical product,
including its pharmacological class, mode of action and proposed clinical use. In general,
the Introduction should not exceed one page.
- A summary of the quality information should be provided according to the MCAZ
Quality overall summary (MCAZ QOS) template.
- The organization of these summaries is described in Guidelines for ICH M4Q, M4S and
M4E.

c) Module 3 - Quality:
- Information on quality should be presented in the structured format described in
Guidelines ICH M4Q and in this guidance

d) Module 4 - Non-clinical study reports:
- Generally not applicable for multisource products (some exceptions may apply).

e) Module 5 - Clinical study reports:
- The human study reports and related information should be presented in the order
described in Guidelines ICH M4E and the MCAZ guidelines on bioequivalence.



Table 1: Modular format of application for registration of multisource products in CTD
format
Module 1 Administrative information and prescribing information

1.0 Cover letter
1.1 Table of contents of the application including Module 1 (Modules 1-5
1.2 Application information:
1.2.1 Completed, signed and dated MC8 application form in duplicate (see Annex I)
1.2.2 Declaration by the applicant
1.2.3 A screening checklist (see Annex II) indicating that all the sections of the
application have been completed and the pages thereof.
1.2.4 Proof of Payment of the appropriate fees
1.2.5 Manufacturing and marketing authorisation(s)/international registration status and/or
the WHO certificate of pharmaceutical product (CPP)
1.2.6 Copy of certificate(s) of suitability of the European Pharmacopoeia (CEP) (including
any annexes)
1.2.7 Proof of compliance with current Good Manufacturing Practices (cGMP)
1.2.8 Biowaiver requests in relation to conducting a comparative bioavailability study
1.3 Product information:
1.3.1 Summary of product characteristics (SmPC)
1.3.2 Labelling (primary and secondary packaging)
1.3.3 Package insert and patient information leaflet
1.4 Regional summaries:
1.4.1 Bioequivalence application form (BAF)
1.4.2 Quality information summary (QIS)
1.5 Electronic review documents (e.g. product information, BAF, QIS, MCAZ-QOS)
1.6 Samples (e.g. FPP, device(s), certificates of analysis)

Module 2 Common technical document (CTD) summaries

2.1 CTD Table of contents (Modules 2-5)
2.2 CTD Introduction
2.3 Quality overall summary product dossier (QOS-PD)
2.4 Non-clinical overview generally not applicable for multisource products (some exceptions
may apply)
2.5 Clinical overview
2.6 Non-clinical written and tabulated summaries generally not applicable for multisource
products (some exceptions may apply)
2.7 Clinical summary generally not applicable for multisource products

Module 3 Quality



3.1 Table of contents of Module 3
3.2 Body of data
3.3 Literature references

Module 4 Non-clinical study reports generally not applicable for multisource products (some
exceptions may apply)

4.2 Study reports

Module 5 Clinical study reports

5.2 Tabular listing of all clinical studies
5.3 Clinical study reports
5.3.1 Reports of biopharmaceutical studies
5.3.7 Case report forms and individual patient listings

Text and tables should be prepared using margins that allow the document to be printed on A4
paper. The left-hand margin should be sufficiently large that information is not obscured by the
method of binding. Font sizes for text and tables should be of a style and size that are large
enough to be easily legible, even after photocopying. Times New Roman, 12-point font is
recommended for narrative text.

Acronyms and abbreviations should be defined the first time they are used in each module.

References should be cited in accordance with the current edition of the Uniform Requirements
for Manuscripts submitted to biomedical journals, International Committee of Medical Journal
Editors (ICMJE). Copies of relevant pages of references should be provided, with a copy of the
full article in the case of a publication. English translations should be provided as necessary.

All application forms must be completed in English.

Guidance on presentation

Applicants are required to submit two copies of the dossier (one hard copy and one electronic
copy). The paper copies of the application should be bound for easy access of information.

Each section of the dossier is to be marked by use of clearly annotated tabs and the
documentation should be filed in accessible files. Lever arch files are not acceptable. Each


binder should be labelled with the non-proprietary name and the proprietary name of the FPP
(e.g. Abacavir (as sulfate) Name ABC 300 mg Tablets) and the company name of the
applicant. For ease of reference, the following information could also be included on the label of
each binder (space permitting): the volume number for that binder (out of the total number of
volumes for that module), the section(s) contained within each volume and the date of the
application (month and year), e.g. FPP Nonproprietary name
Name ABC
Applicant XYZ
Module 3 - Quality
Volume 1 of 3
Module 3.1 - 3.2.S.3
Month/year

An application not submitted in the appropriate format, incomplete or illegible will be rejected.

There may be a number of instances where repeated sections can be considered appropriate.
Whenever a section is repeated, it should be made clear what the section refers to by creating a
distinguishing title in parentheses following the M4Q (CTD-Q) guideline heading, e.g. 3.2.S
Drug substance (or API) (name, Manufacturer A).

The following are recommendations for the presentation of the information in the Quality
Module for different scenarios that may be encountered:

a) the Open part (non-proprietary information) of each APIMF should always be included in
its entirety in the application for registration, as an annex to 3.2.S.
b) for an FPP containing more than one API: one complete 3.2.S section should be
provided for one API, followed by other complete 3.2.S sections for each other API.
c) for an API from multiple manufacturers: one complete 3.2.S section should be
provided for the API from one manufacturer, followed by other complete 3.2.S sections
for each other API manufacturer.
d) for an FPP with multiple strengths (e.g. 10, 50, 100 mg): one complete 3.2.P section
should be provided with the information for the different strengths provided within the
subsections. One complete copy of the application for registration should be provided for
each FPP strength.
e) for an FPP with multiple container closure systems (e.g. bottles and unit dose blisters):
one complete 3.2.P section should be provided with the information for the different
presentations provided within the subsections.
f) for multiple FPPs (e.g. tablets and a parenteral product): a separate dossier is required for
each FPP.
g) for an FPP supplied with reconstitution diluent(s), one complete 3.2.P section should
be provided for the FPP, followed by the information on the diluent(s) in a separate part
3.2.P , as appropriate.
h) for a co-blistered FPP, one complete 3.2.P section should be provided for each product.


Additional guidance on sections to be included in Module 1

Cover letter

The cover letter submitted with the application for registration should include a clear statement
from the responsible person submitting the dossier, indicating the contact details (telephone
number, e-mail, and fax) of the person to whom all correspondence should be addressed.

A completed and signed MC8 Form (see Annex 1)

A completed, signed and dated MC8 form should be submitted for each FPP. A copy of the form
can be obtained from the MCAZ website: www.mcaz.co.zw. For clarity, the following
considerations apply in determining whether the FPP requires one or separate applications

a) Tablets/Capsules/Suppositories/Lozenges:
i) Different pack-sizes of the same strength and formulation will require one application
ii) Different strengths and/or formulations will require separate applications.
b) Syrups/Elixirs/Liquids/Solutions (non parenterals)/Creams/ointments
i) Different container sizes of the same strength and formulation will require one
application
ii) Same container size of different strengths and/or formulations will require separate
applications.
c) Ampoules, Vials and Large Volume Parenterals
i) Ampoules containing identical solutions of the same strength but of different volumes
will require separate applications;
ii) Ampoules containing solutions of different strengths will require separate applications;
iii) Ampoules and/or single dose vials containing dry powder, crystals etc., of different mass
will require separate applications;
iv) Dry powders or crystals etc. of the same respective mass, packaged in ampoules and
single dose vials will require separate applications;
v) Ampoules, single dose vials, as well as disposable syringes and cartridges containing
identical solutions of the same strength and same volume of liquid will require one
application;
vi) Dental cartridges containing fluids of different volumes will require one application;
vii) Ampoules containing "water for injection", but of different volumes will require one
application;
viii) Special ampoules of dry powder and "water for injections" contained in the same
unit, but intended for mixing at the time of injection, will require one application;
ix) Ampoules containing identical solutions of different volumes used only as a diluent in the
reconstitution of a preparation for parenteral use will require separate applications;
x) Multi-dose vials of the same strength and formulation in different volumes will require
separate applications;
xi) Multi-dose vials and a single dose ampoule of the same formulation will require separate
applications;


xii) Multi-dose vials containing dry powder of different masses and the same formulation,
and having the same concentration when reconstituted will require one application;
xiii) A container of diluent to be used with any preparation in (iii), (iv) or (xii) will
require one application provided that the diluent is also fully described in the dossier
together with the product;
xiv) An ampoule of diluent to be used with any biological preparation will require one
application;
xv) Infusion solutions of the same or different volumes and of the same formulation, which
are packed in containers of exactly the same type of material, will require one
application;
xvi) Infusion solutions of the same or different volumes and of the same formulation,
which are packed in containers made of different types of materials, will require separate
applications;
xvii) A preparation, packed in plastic containers and intended also to be marketed in
glass containers containing the same volume and the same formulation, will require one
application provided the following data are submitted: -
- Characteristics of the rubber stopper;
- Specifications for the glass;
- A comprehensive manufacturing process with particular reference to the washing
and sterilization cycles and apparatus used;
- Data on particulate matter (contamination);
- Stability data with reference to the effect of the pH of the solution.
xviii) Products with the same strength and formulation but with different colours and/or
flavours will require separate applications;
xix) Applications containing the same active ingredient(s), and where additional
indications are sought, where such new indications render the product in a different
category of distribution (scheduling status), or different pharmacological classification or
have any other restrictions imposed other than the original application, will require
separate registration.
d) Different applicants/proprietary names for the same formula;
i) Same formula applied under different proprietary names will require separate
applications.
ii) Same formula from different applicants will require separate applications.

Declaration by the applicant

A declaration should be made by the applicant or a responsible person nominated by the
applicant and who has the requisite skills and necessary qualifications. It is stressed that only a
person who can attest to the accuracy of the contents in the application should sign on behalf of
the applicant. False / misleading declarations will lead to prosecution.

Failure to make the declaration will lead to rejection of the application.


Screening Checklist

A screening checklist in Annex 2 should be completed by the applicant. The Authority will
assess the application for completeness upon submission before it is accepted for evaluation by
MCAZ. Incomplete applications will be rejected and the applicant requested to submit a
complete application. The Authority may charge a re-submission fee for products that fail
screening.

Proof of payment of appropriate fees

A copy of the invoice or proof of payment of registration fees should be attached to the
application for registration.

Applicants should consult the current fee schedule for the correct and appropriate fee. Note that
Registration fees can be split into three main tiers, depending on the site of manufacture of the
FPP. Fees for products wholly manufactured outside Zimbabwe attract a different fee from
products wholly or partly (e.g. re-labelled and re-packaged) manufactured in Zimbabwe. All fees
are payable according to the gazetted fee schedule

Unless the full application fee is received, the application will not be accepted. Applicants can
remit payment of fees in cash, bank draft, telegraphic transfers and direct deposit into the
Authority account. Please note that direct transfers usually attract a commission charged by the
banks leading to a shortfall in fees. Provision should, therefore, be made to cover such shortfalls.
Applicants are further advised to specify very clearly in their instructions to the bank that such
direct deposits are for application for registration of a medicine to avoid unnecessary delays.

Note that the application fee covers the cost of evaluating the initial submission and a single
laboratory analysis of the product sample. Samples that require repeat analysis after failure of the
first analysis, or as a result of modification or revalidation of the analytical method, attract an
additional re-analysis fee. Any amendments to the original submission will attract amendment
fees according to the gazetted fee schedule. The application fee excludes the GMP inspection
fees, for which a separate charge is applicable.
Fees once received are not refundable, including those for rejected applications or voluntary
withdrawals by the applicant.

Manufacturing and marketing authorisation(s)/international registration status

List the countries in which:
the FPP (or set of FPPs) has been granted a marketing authorisation;
the FPP (or one or more of the set of FPPs) has been withdrawn from the market; and
an application for the marketing of the FPP (or one or more of the set of FPPs) has been
rejected, deferred or withdrawn


The details of registration in the country of origin are required. Reasons for non-registration
should be stated if the medicine is not registered in the country of origin.
Registration status in the country of manufacture should be indicated including any withdrawal,
cancellations, suspension / revocations. The reasons for these should also be indicated.

For further guidance see Section 3.2.P.3.1.

Summary of Product Characteristics (SmPC)

The Summary of Product Characteristics format in Annex III should be used. Two types of
SmPC aimed at the following audiences should be submitted.
a) Product information for health professionals
b) Product information for the patient
Copies of all package inserts and any information intended for distribution with the product to
the patient should be submitted. These should be written in English, be legible and
comprehensible.

The presence of alcohol in the product must be declared, and the concentration stated on the
label, the package insert and in the patient information leaflet.

The Authority will determine the appropriate category for distribution of a medicine as set out in
the sixth schedule of the Medicines and Allied Substances Control Regulations (Statutory
Instrument 150 of 1991).
The categories are:
a) Narcotic Medicines or Dangerous Drug (abbreviated as N ) - products
containing ingredients stated as such in the legislation and which may be subject
to control by the International Narcotics Board.
b) Prescription Preparations (P.P.) medicines belonging to this category are
available on prescription only
c) Specially Restricted Preparations (S.R.) - Possession is restricted to pharmacies at
central hospitals and the prescription is to be certified by a Medical
Superintendent at such a hospital
d) Pharmacist Initiated Medicines (P.I.M) medicines that may be initiated and
dispensed by a pharmacist without a prescription
e) Pharmacy Drugs (P) - these products are available from licensed pharmacies only
f) Household Remedies (H.R.) - Medicines in this category are available in
pharmacies, dispensaries and all licensed trade supermarkets.
g) Veterinary Medicines (General Dealer) (V.M.G.D.) veterinary medicines in this
category are available in all licensed shops.

Labelling (Primary and secondary packaging)

The Primary Packaging Label should comply with the Medicines and Allied Substances Control
Regulations (S.I. 150 of 1991) with at least the following:


a) The name of the FPP
b) Route of administration
c) A list of API(s) (using INNs if applicable) with the amount of each present in
a dosage unit, and a statement of the net contents of the container, e.g. number
of dosage units, weight or volume
d) List of excipients known to be of safety concern for some patients, e.g.
lactose, gluten, metabisulfites, parabens, ethanol
e) Instruction on use
f) The batch number assigned by the manufacturer
g) The manufacturing AND expiry date in an un-coded form
h) Storage conditions or handling precautions that may be necessary. The
labelled storage conditions should be achievable in practice in the distribution
network
i) Directions for use, and any warnings or precautions that may be necessary
j) The name and physical address of the manufacturing site(s)
k) For containers of capacity less than or equal to 10 ml that are marketed in an
outer pack such as a carton, and the outer pack bears all the required
information, the immediate container need only contain items (a), (b), (c), (f)
and (g) or a logo that unambiguously identifies the company and the
name of the dosage form or the route of administration

For Blisters and strips, as a minimum, the following information should be stated:
a) Name, strength and pharmaceutical form of the FPP
b) Name of the manufacturer, company or person responsible for placing the
product on the market
c) The batch number assigned by the manufacturer
d) The expiry date in an un-coded form

The Secondary/Outer Packaging Label should also contain all the information in section 1.3.2.

Note: For all labelling, the generic name should be more prominent than the trade name.
Provision for Zimbabwean registration details i.e. category for distribution and registration
number, should be made on the label.

Package insert
The package insert should comply with the Medicines and Allied Substances Control
Regulations (S.I. 150 of 1991) with at least the following:

a) the name and address of the principal;
b) the name and address of the manufacturer;
c) the approved name of the active ingredient of the medicine which shall be of greater
size and prominence than the proprietary name (trade mark), if any, of the medicine;
d) the house-mark, if any, of the principal or manufacturer of the medicine;
e) the quantity and strength of the active ingredient of the medicine;


f) the name and percentage of any bacteriostatic or bactericidal agent which is added to
the medicine as a preservative;
g) the strength of the medicine where applicable;
h) the requirements for the method of storage or other necessary precautions for the
preservation of the medicine;
i) the category of distribution of the medicine which may be represented by words or
symbols as set out in the Sixth Schedule;
j) the pharmacological classification of the medicine determined in terms of section 34;
k) the dosage of the medicine and the directions for use;
l) the description of the pharmacological action of the medicine;
m) indications of the medicine;
n) contra indications of the medicine;
o) warnings relating to the use of the medicine and such warning shall be printed in a
colour as approved by the Authority;
p) the side-effects and special precautions of the medicine;
q) known symptoms of over dosage and particulars of its treatment;
r) the identification of the medicine;
s) the form in which the medicine is presented, whether tablet, capsule, liquid, etc., and
the colour thereof;
t) the date of publication of the package insert;
u) any necessary warning concerning the administration or use of the medicine by
children, old people, pregnant women or patients suffering from certain diseases, or
the use of the medicine in conjunction with the consumption of alcohol or any
particular food or any other medicine;
v) a summary of relevant information concerning the purpose and the beneficial,
detrimental, injurious or other effects of the medicine, and the possible dangers that
may arise from the prolonged use of the medicine;
w) relevant information, including particulars in regard to a specific medicine as an
antidote (if known), concerning the treatment of a patient in cases where an overdose
of the medicine has been administered or where a patient reacts adversely to the
medicine;
x) any other particulars or warning notices as may be directed by the Authority.

For multisource (generic) products, the applicant shall not include the proprietary name in the
body of text of the package insert unless clinical studies were conducted. Only the non-
proprietary name should be used. Provision for Zimbabwean registration details should be made
on the package insert.

Applicant is required to submit the actual package insert and A4 size copies in English.

Electronic Review Documents


Electronic submission of documentation on electronic storage media e.g. CD or DVD should be
submitted in Microsoft Word (required for templates/summaries, e.g. QOS PD, QIS, BTIF) or
text-selectable PDF format (other documentation).

Product Samples (e.g. FPP, device[s])

Samples and certificates of analysis of the FPP(s) and devices(s) should be provided to enable
visual inspection of the pharmaceutical product, the packaging materials and the label as well as
comparison of the data with that in the SmPC, labelling and the package insert.

Draft labelling may be submitted at the time of dossier submission when labelling for marketing
has not been finalised. Applicants should provide samples of the FPP in its final container and
labelling as intended for presentation to the Zimbabwean market or closest reference packs when
the labelling for marketing has not been finalised. Samples of the FPP in the market container
should be provided to allow examination by the evaluators (assessors). In addition to the above,
additional samples should be submitted for laboratory analysis by the MCAZ laboratory. The
quantities of samples that should be submitted to the Authority for laboratory analysis should, in
general, be twice the amount that is normally required for carrying out the full finished product
analytical tests by the applicant s own quality control laboratory. This amount will enable repeat
testing, if necessary. The precise quantities of samples required are indicated in Annexure IV.
The applicants may be required to submit reference analytical standards and their certificates of
analysis to allow the MCAZ laboratory to expedite the analysis. Note that the MCAZ laboratory
analyses a wide range of medicines and it is almost impossible to keep analytical reference
standards for all medicines.


QUALITY SUMMARIES

3.1 Module 2.3: Quality Overall Summary Product Dossiers (QOS-PD)

The Quality Overall Summary (QOS) is a summary that follows the scope and the outline of the
Body of Data in Module 3. The QOS should not include information, data or justification that
was not already included in Module 3 or in other parts of the CTD.

The QOS should include sufficient information from each section to provide the Quality assessor
with an overview of Module 3. The QOS should also emphasise critical key parameters of the
product and provide, for instance, justification in cases where guidelines were not followed. The
QOS should include a discussion of key issues that integrates information from sections in the
Quality Module and supporting information from other Modules (e.g., qualification of impurities
via toxicological studies), including cross-referencing to volume and page numbers in other
Modules.

The MCAZ Quality Overall Summary Product Dossiers (QOS-PD) template should be
completed for multisource pharmaceutical products containing APIs of synthetic or semi-
synthetic origin and their corresponding FPPs.

All sections and fields in the QOS-PD template that would be applicable should be completed.
It is understood that certain sections and fields may not apply and should be indicated as such by
reporting not applicable in the appropriate area with an accompanying explanatory note.

The use of tables to summarise the information is encouraged, where possible. The tables
included in the template may need to be expanded or duplicated (e.g. for multiple strengths), as
necessary. These tables are included as illustrative examples of how to summarise information.
Other approaches to summarise the information can be used if they fulfil the same purpose.

3.2 Module 1.4.2: Quality Information Summary (QIS)

The QIS template should be completed to provide a condensed summary of the key quality
information for the PD and constitutes part of the submission package. The QIS provides an
accurate record of technical data in the PD. The QIS is acondensed version of the QOS-PD and
represents the final agreed upon key API and FPP information from the PD assessment (inter alia
identification of the manufacturer[s]/siteaddresses API/FPP specifications, stability conclusions
and relevant commitments).

The QIS template is structured according to the numbering and section headings of the ICH
M4Q (CTD-Q) guideline to permit the rapid assembly of the QIS by copying requisite
information from the corresponding portions of the QOS-PD filed with the PD. It is
acknowledged that the numbering of the sections in the QIS may not be entirely sequential.
Those sections not considered necessary to be included in the QIS have been removed (e.g.


2.3.S.5 Reference standards or materials) and the remaining sections have retained their
numbering to be consistent with the original PD.

The QIS will serve as an official reference document in the course of GMP inspections, variation
assessments and re-registration assessments as performed by MCAZ.

MODULE 3: QUALITY


A Table of Contents for the filed product dossier should be provided.

4.2 Body of data

3.2. S Drug substance (or active pharmaceutical ingredient (API))

The API information can be submitted to MCAZ in one of the following two options:
Option 1: Certificate of Suitability of the European Pharmacopoeia (CEP), including
all its annexes;
Option2: Full details in the PD.

The applicant should clearly indicate at the beginning of the API section (in the PD and in the
MCAZ QOS) how the information on the API for each API manufacturer is being submitted.
The API information submitted by the applicant/FPP manufacturer should include the following
for each of the options used.

Option 1: Certificates of Suitability of the European Pharmacopoeia (CEP)

A complete copy of the CEP (including any annexes) should be provided in Module 1. The
declaration of access for the CEP should be duly filled out by the CEP holder on behalf of the
FPP manufacturer or applicant to the MCAZ.

In addition, a written commitment should be included that the applicant will inform MCAZ in
the event that the CEP is withdrawn. It should also be acknowledged by the applicant that
withdrawal of the CEP will require additional consideration of the API data requirements to
support the PD. The written commitment should accompany the copy of the CEP in Module 1.

Along with the CEP, the applicant should supply the following information in the dossier, with
data summarised in the MCAZ QOS.


- 3.2.S.1.3 General properties - discussions on any additional, applicable physicochemical
and other relevant API properties that are not controlled by the CEP and Ph.Eur.
monograph, e.g. solubility and polymorphs as per guidance in this section.
- 3.2.S.3.1 Elucidation of structure and other characteristics - studies to identify
polymorphs (exception: where the CEP specifies a polymorphic form) and particle size
distribution, where applicable, as per guidance in this section.
- 3.2.S.4.1 Specification - the specifications of the FPP manufacturer, including all tests
and limits of the CEP and Ph.Eur. monograph and any additional tests and acceptance
criteria that are not controlled in the CEP and Ph.Eur. monograph, such as polymorphs
and/or particle size distribution.
- 3.2. S.4.2 / 3.2.S.4.3 Analytical procedures and validation for any tests in addition to
those in the CEP and Ph.Eur. monograph.
- 3.2. S.4.4 Batch analysis - results from three batches of at least pilot scale, demonstrating
compliance with the FPP manufacturer s API specifications.
- 3.2. S.6 Container closure system - specifications including descriptions and
identification of primary packaging components. Exception: where the CEP specifies a
retest period.
- 3.2. S.7 Stability - exception: where the CEP specifies a retest period that is the same as
or of longer duration than the retest period proposed by the applicant.

In the case of sterile APIs, it should be noted that sterilization of the API is generally regarded by
the MCAZ as part of finished product manufacture. Therefore data on the sterilization process of
the API, including validation data, should be included in the application for registration.

Option 2: Full details in the PD

Information on the 3.2.S Active pharmaceutical ingredient sections, including full details of
chemistry, manufacturing process, quality controls during manufacturing and process validation
for the API, should be submitted in the application file as outlined in the subsequent sections of
this guideline. The MCAZ QOS should be completed as per Section 3.1 of this guideline.

3.2. S.1 General information (name, manufacturer)
3.2. S.1.1 Nomenclature (name, manufacturer)

(Recommended) International Non-proprietary Name (INN);
Compendial name, if relevant;
Chemical name(s);
Company or laboratory code;
Other non-proprietary name(s) (e.g., national name, United States Adopted Name
(USAN), British Approved Name [BAN]); and
Chemical Abstracts Service (CAS) registry number.

The listed chemical names should be consistent with those appearing in scientific literature and
those appearing on the product labelling information (e.g., summary of product characteristics,


package leaflet [also known as patient information leaflet or PIL], labelling). Where several
names exist, the preferred name should be indicated.

Where an API is formed in situ during FPP manufacture (e.g. by chemical reaction), both the
starting material(s) and the in situ formed API should be described (say for instance,
Ciprofloxacin Intravenous Infusion BP). Starting materials for in situ API preparation should be
treated as APIs in the Section 3.2.S of the application for registration. For example, in the case of
Ciprofloxacin Intravenous Infusion BP, ciprofloxacin and lactic acid would be treated as APIs in
the application for registration when they are used for the in situ preparation of ciprofloxacin
lactate.

3.2. S.1.2 Structure (name, manufacturer)
The structural formula, including relative and absolute stereochemistry, the molecular
formula, and the relative molecular mass should be provided.

This information should be consistent with that provided in Section 3.2.S.1.1. For APIs existing
as salts, the molecular mass of the free base or acid should also be provided.

3.2. S.1.3 General properties (name, manufacturer)
A list should be provided of physicochemical and other relevant properties of the API.

This information can be used in developing the specifications, in formulating FPPs and in the
testing for release and stability purposes.

The physical and chemical properties of the API should be discussed including the physical
description, solubility in common solvents (e.g. water, alcohols, dichloromethane, acetone);
quantitative aqueous pH solubility profile (e.g. pH 1 to 6.8, dose/solubility volume);
polymorphism; pH and pKa values; UV absorption maxima and molar absorptivity; melting
point; refractive index (for a liquid); hygroscopicity; partition coefficient, etc. (see table in the
QOS-PD). This list is not intended to be exhaustive, but provides an indication as to the type of
information that could be included.

Some of the more relevant properties to be considered for APIs are discussed below in greater
detail.

Physical description
The description should include appearance, colour and physical state. Solid forms should be
identified as being crystalline or amorphous (see 3.2.S.3.1 for further information on API solid
forms).

Solubility/quantitative aqueous pH solubility profile
The following should be provided for all options for the submission of API data.

The solubility in a number of common solvents should be provided (e.g. water, alcohols,
dichloromethane, acetone).



The solubility over the physiological pH range (pH 1.2 to 6.8) in several buffered media should
be provided in mg/ml. If this information is not readily available (e.g. literature references), it
should be generated in-house.

For solid oral dosage forms, the dose/solubility volume should be provided as determined by:

(mg/ml*) drug the of ion concentrat minimum the
(mg) strength dose largest
me ility volu Dose/solub =

*Corresponding to the lowest solubility determined over the physiological pH range (pH1.2 to
6.8) and temperature (37 0.5C).

As per the Biopharmaceutics Classification System(BCS), highly soluble (or highly water
soluble) APIs are those with a dose/solubility volume less than or equal to 250 ml.

For example, compound A has as its lowest solubility at 37 0.5C, 1.0 mg/ml at pH 6.8 and is
available in 100 mg, 200 mg and 400 mg strengths. This API would not be considered a BCS
highly soluble API as its dose/solubility volume is greater than 250 ml (400 mg/1.0567 mg/ml =
400 ml).

Polymorphism

As recommended in ICH s CTD-Q Questions and answers/location issues document the
following refers to where specific data should be located in the PD:

the polymorphic form(s) present in the proposed API should be listed in Section
3.2.S.1.3;
the description of the manufacturing process and process controls (3.2.S.2.2) should
indicate which polymorphic form is manufactured, where relevant;
the literature references or studies performed to identify the potential polymorphic forms
of the API, including the study results, should be provided in Section 3.2.S.3.1;
if a polymorphic form is to be defined or limited (e.g. for APIs that are not BCS highly
soluble and/or where polymorphism has been identified as an issue), details should be
included in 3.2.S.4.1 through 3.2.S.4.5.

Additional information is included in the referenced sections of this guideline.

Particle size distribution

As recommended in ICH s CTD-Q Questions and Answers/Location Issues document, the
studies performed to identify the particle size distribution of the API should be provided in
Section 3.2.S.3.1 (refer to this section of this guideline for additional information).


Information from literature

Supportive data and results from specific studies or published literature can be included within or
attached to this section. Reference documents: ICH Q6A

3.2. S.2 Manufacture (name, manufacturer)
3.2. S.2.1 Manufacturer(s) (name, manufacturer)

The name, address, and responsibility of each manufacturer, including contractors, and each
proposed production site or facility involved in manufacturing and testing should be provided.

The facilities involved in the fabrication, packaging, labelling, testing and storage of the API
should be listed. It should be clearly indicated, if certain companies are responsible only for
specific steps (e.g. milling of the API).

The list of manufacturers/companies should specify the actual addresses of production or
manufacturing site(s) involved (including block(s) and units(s)), rather than the administrative
offices. Telephone number(s), fax number(s) and e-mail address (es) should be provided.

A valid manufacturing authorisation (license) should be provided for the production of APIs. A
certificate of GMP compliance in the format of a WHO-type GMP certificate from the competent
authority of the country of manufacture should be provided in the PD in Module 1.

3.2. S.2.2 Description of manufacturing process and process controls (name, manufacturer)

The description of the API manufacturing process represents the applicant s commitment to the
manufacture of the API. Information should be provided to adequately describe the
manufacturing process and process controls. For example:

A flow diagram of the synthetic process(es) should be provided that includes molecular
formulae, weights, yield ranges, chemical structures of starting materials, intermediates, reagents
and API reflecting stereochemistry. The flow diagram should also identify operating conditions,
purification steps, catalysts and solvents.

A sequential procedural narrative of the manufacturing process should be submitted. The
narrative should include, for example, quantities of raw materials, solvents, catalysts and
reagents reflecting the representative batch scale for commercial manufacture, identification of
critical steps, process controls, equipment and operating conditions (e.g. temperature, pressure,
pH, time).

Alternate processes should be explained and described with the same level of detail as the
primary process. Reprocessing steps should be identified and justified. Any data to support this
justification should be either referenced or filed in 3.2.S.2.5.


The following requirements apply to the second option for submission of API information, where
full details are provided in the dossier.

As discussed in ICH Q7 and WHO Technical Report Series, No. 957 Annex 2, the point at which
the API starting material is introduced into the manufacturing process is the starting point of the
application of GMP requirements. The API starting material itself needs to be proposed and
justified by the manufacturer and accepted as such by assessors. This justification should be
documented.

The API starting material should be fully characterised with respect to identity and purity. In
addition, the steps prior to the step where the API starting material appears, which may involve
starting materials for synthesis, should be available at least in the form of a flow chart. The
starting material for synthesis defines the starting point in the manufacturing process for an API
to be described in an application.

The applicant should propose and justify which substances should be considered as starting
materials for synthesis. See section 3.2.S.2.3 for further guidance.

In addition to the detailed description of the manufacturing process as per ICH M4Q, the
recovery of materials, if any, should be described in detail with the step in which they are
introduced into the process. Recovery operations should be adequately controlled such that
impurity levels do not increase over time. For recovery of solvents, any processing to improve
the quality of the recovered solvent should be described. Regarding recycling of filtrates (mother
liquors) to obtain second crops, information should be available on maximum holding times of
mother liquors and the maximum number of times that the material can be recycled. Data on
impurity levels should be provided to justify recycling of filtrates.

Where there are multiple manufacturing sites for one API manufacturer, a comprehensive list in
tabular form should be provided comparing the processes at each site and highlighting any
differences.

All solvents used in the manufacture (including purification and/or crystallisation step[s]) should
be clearly identified. Solvents used in the final steps should be of high purity. Use of recovered
solvents in the final steps of purification and/or crystallization is not recommended.

Where polymorphic/amorphous forms have been identified, the form resulting from the synthesis
should be stated.

Where particle size is considered a critical attribute (see 3.2.S.3.1 for details), the particle size
reduction method(s) (e.g., milling, micronization) should be described.

Justification should be provided for alternate manufacturing processes. Alternate processes
should be explained with the same level of detail as the primary process. It should be
demonstrated that batches obtained by the alternate processes have the same impurity profile as


the principal process. If the obtained impurity profile is different, it should be demonstrated to be
acceptable according to the requirements described under S.3.2.

It is acceptable to provide information on pilot scale manufacture, provided it is representative of
production scale and scale-up is reported immediately to MCAZ according to the requirements
of the MCAZ Guideline on Amendments.

3.2. S.2.3 Control of materials (name, manufacturer)

Materials used in the manufacture of the API (e.g. raw materials, starting materials, solvents,
reagents, catalysts) should be listed, identifying where each material is used in the process.
Information on the quality and control of these materials should be provided. Information
demonstrating that materials meet standards appropriate for their intended use should be
provided, as appropriate (details in 3.2. A .2).


In general, the starting material for synthesis described in the application for registration should:
be a synthetic precursor of one or more synthesis steps prior to the final API intermediate.
Acids, bases, salts, esters and similar derivatives of the API, as well as the racemate of a
single enantiomer API, are not considered final intermediates;
be a well characterised, isolated and purified substance with its structure fully elucidated,
including its stereochemistry (when applicable);
have well-defined specifications that include, among others, one or more specific identity
tests and limits for assay and specified, unspecified and total impurities; and
be incorporated as a significant structural fragment into the structure of the API.

For each starting material, the name and manufacturing site address of the manufacturer should
be indicated. If there are several manufacturers, it should be clarified whether the starting
material obtained from different sources is prepared by the same route of synthesis or if different
routes are used. Specifications proposed for the starting material should apply to the material
from each source.

Copies of the specifications for the materials used in the synthesis, extraction, isolation and
purification steps should be provided in the application file, including starting materials,
reagents, solvents, catalysts and recovered materials. Confirmation should be provided that the
specifications apply to materials used at each manufacturing site. A certificate of analysis of the
starting material for synthesis should be provided. A summary of the information on starting
materials should be provided in the MCAZ QOS.

The carry-over of impurities of the starting materials for synthesis into the final API should be
considered and discussed.


For excipients obtained from sources that are at risk of transmitting Bovine Spongiform
Encephalopathy (BSE)/Transmissible Spongiform Encephalopathy (TSE) agents (e.g., sources of
ruminant origin), a letter of attestation (with supporting documentation) should be provided
confirming that the API and the starting materials and reagents used to manufacture the API are
without risk of transmitting agents of animal spongiform encephalopathies.

When available, a CEP demonstrating TSE-compliance should be provided. A complete copy of
the CEP (including any annexes) should be provided in Module 1.

Reference documents: ICH Q6A

3.2. S.2.4 Controls of critical steps and intermediates (name, manufacturer)

Critical steps: Tests and acceptance criteria (with justification including experimental data)
performed at critical steps identified in 3.2.S.2.2 of the manufacturing process to ensure that the
process is controlled should be provided.
Intermediates: Information on the quality and control of intermediates isolated during the
process should be provided.


The critical steps should be identified. These can be among others: steps where significant
impurities are removed or introduced, steps introducing an essential molecular structural element
such as a chiral centre or resulting in a major chemical transformation, steps having an impact on
solid-state properties and homogeneity of the API that may be relevant for use in solid dosage
forms.

Specifications for isolated intermediates should be provided and should include tests and
acceptance criteria for identity, purity and assay, where applicable.


3.2. S.2.5 Process validation and/or evaluation (name, manufacturer)
Process validation and/or evaluation studies for aseptic processing and sterilization should
be included.


It is expected that the manufacturing processes for all APIs are properly controlled. If the API is
prepared as sterile, a complete description should be provided for aseptic processing and/or
sterilisation methods. The controls used to maintain the sterility of the API during storage and
transportation should also be provided. Alternate processes should be justified and described (see
guidance in 3.2.S.2.2 for the level of detail expected).



3.2. S.2.6 Manufacturing process development (name, manufacturer)
A description and discussion should be provided of the significant changes made to the
manufacturing process and/or manufacturing site of the API used in producing comparative
bioavailability or biowaiver, scale-up, pilot, and, if available, production scale batches.

Reference should be made to the API data provided in section 3.2.S.4.4.

3.2. S.3 Characterization (name, manufacturer)
3.2. S.3.1 Elucidation of structure and other characteristics (name, manufacturer)
Confirmation of structure based on, e.g. synthetic route and spectral analyses should be provided.
Information such as the potential for isomerism, the identification of stereochemistry, or the
potential for forming polymorphs should also be included.

Elucidation of structure
The PD should include quality assurance (QA) certified copies of the spectra, peak assignments
and a detailed interpretation of the data of the studies performed to elucidate and/or confirm the
structure of the API. The MCAZ QOS should include a list of the studies performed and a
conclusion from the studies (e.g. if the results support the proposed structure).

For APIs that are not described in an officially recognised pharmacopoeia, the studies carried out
to elucidate and/or confirm the chemical structure normally include elemental analysis, infrared
(IR), ultraviolet (UV), nuclear magnetic resonance (NMR) and mass spectra (MS) studies. Other
tests could include x-ray powder diffraction (XRPD) and differential scanning calorimetry
(DSC).

For APIs that are described in an officially recognised pharmacopoeia, it is generally sufficient
to provide copies of the IR spectra of the API from each of the proposed manufacturer(s), run
concomitantly with a pharmacopeial reference standard. See Section 3.2.S.5 for details on
acceptable reference standards or materials.

Isomerism/Stereochemistry
When an API is chiral, it should be specified whether specific stereoisomers or a mixture of
stereoisomers have been used in the comparative bio-studies, and information should be given as
to the stereoisomer of the API that is to be used in the FPP.

For non-pharmacopeial APIs, unequivocal proof of configuration of asymmetric centers such as
x-ray of a single crystal should be provided when a single enantiomer of the API is claimed.

A discussion should be included of the possible isomers that can result from the manufacturing
process, the steps where they were introduced or formed and a summary of the results of the
studies carried out to investigate the physical, chemical and biological properties of these
isomers. If there is a preferred isomer or isomeric mixture, a discussion of the material that was


used in the comparative bioavailability or biowaiver study should be included and the API
specification should include a test to ensure isomeric identity and purity.

If, based on the structure of the API, there is not a potential for isomerism, it is sufficient to
include a statement to this effect.

Polymorphism
Many APIs can exist in different physical forms in the solid state. Polymorphism is characterized
as the ability of an API to exist as two or more crystalline phases that have different
arrangements and/or conformations of the molecules in the crystal lattice. Amorphous solids
consist of disordered arrangements of molecules and do not possess a distinguishable crystal
lattice. Solvates are crystal forms containing either stoichiometric or nonstoichiometric amounts
of a solvent. If the incorporated solvent is water, the solvates are also commonly known as
hydrates.

Polymorphic forms of the same chemical compound differ in internal solid-state structure and,
therefore, may possess different chemical and physical properties, including packing,
thermodynamic, spectroscopic, kinetic, interfacial and mechanical properties. These properties
can have a direct impact on API processability, pharmaceutical product manufacturability and
product quality/performance, including stability, dissolution and bioavailability. Unexpected
appearance or disappearance of a polymorphic form may lead to serious pharmaceutical
consequences.

Applicants and API manufacturers are expected to have adequate knowledge about the
polymorphism of the APIs used and/or produced. Information on polymorphism can come from
the scientific literature, patents, compendia or other references to determine if polymorphism is a
concern, e.g. for APIs that are not BCS highly soluble. In the absence of published data for APIs
that are not BSC highly soluble, polymorphic screening will be necessary to determine if the API
can exist in more than one crystalline form. Polymorphic screening is generally accomplished via
crystallisation studies using different solvents and conditions.

There are a number of methods that can be used to characterise the polymorphic forms of an
API. Demonstration of a non-equivalent structure by single crystal x-ray diffraction is currently
regarded as the definitive evidence of polymorphism. XRPD can also be used to provide
unequivocal proof of polymorphism. Other methods, including microscopy, thermal analysis
(e.g. DSC, thermal gravimetric analysis and hot-stage microscopy) and spectroscopy (e.g. IR,
Raman, solid-state nuclear magnetic resonance [ssNMR]) are helpful to further characterise
polymorphic forms. Where polymorphism is a concern, the applicants/manufacturers of APIs
should demonstrate that a suitable method, capable of distinguishing different polymorphs, is
available to them.

Decision tree 4(1) of ICH Q6A can be used where screening is necessary and 4(2) can be used to
investigate if different polymorphic forms have different properties that may affect performance,
bioavailability and stability of the FPP and to decide whether a preferred polymorph should be
monitored at release and on storage of the API. Where there is a preferred polymorph,


acceptance criteria should be incorporated into the API specification to ensure polymorphic
equivalence of the commercial material and that of the API batches used in the comparative
bioavailability or biowaiver studies. The polymorphic characterisation of the API batches used in
comparative bioavailability or biowaiver studies by the above-mentioned methods should be
provided. The method used to control polymorphic form should be demonstrated to be specific
for the preferred form.

Polymorphism can also include solvation or hydration products (also known as pseudo
polymorphs). If the API is used in a solvated form, the following information should be
provided:

specifications for the solvent-free API in 3.2.S.2.4, if that compound is a synthetic
precursor;
specifications for the solvated API including appropriate limits on the weight ratio of API
to solvent (with data to support the proposed limits);
a description of the method used to prepare the solvate in 3.2.S.2.2.

Particle size distribution

For APIs that are not BCS highly soluble contained in solid FPPs, or liquid FPPs containing un-
dissolved API, the particle size distribution of the material can have an effect on the in vitro
and/or in vivo behaviour of the FPP. Particle size distribution can also be important in dosage
form performance (e.g. delivery of inhalation products), achieving uniformity of content in low-
dose tablets (e.g. 2 mg or less), desired smoothness in ophthalmic preparations and stability of
suspensions.

If particle size distribution is an important parameter (e.g. as in the above cases), results from an
investigation of several batches of the API should be provided, including characterisation of the
batch (es) used in the comparative bioavailability or biowaiver studies. API specifications should
include controls on the particle size distribution to ensure consistency with the material in the
batch (es) used in the comparative bioavailability and biowaiver studies (e.g. limits for d10, d50
and d90). The criteria should be established statistically based on the standard deviation of the
test results from the previously mentioned studies. The following is provided for illustrative
purposes as possible acceptance criteria for particle size distribution limits:

d10 not more than (NMT) 10% of total volume less than X Lm
d50 XX Lm - XXX Lm
d90 not less than (NLT) 90% of total volume less than XXXX Lm.

Other controls on particle size distribution can be considered acceptable, if scientifically
justified.



3.2. S.3.2 Impurities (name, manufacturer)

Information on impurities should be provided.

Details on the principles for the control of impurities (e.g. reporting, identification and
qualification) are outlined in the ICH Q3A, Q3B and Q3C impurity guidelines. Additional
information to provide further guidance on some of the elements discussed in the ICH guidelines
is outlined below.

Regardless of whether a pharmacopeial standard is claimed, a discussion should be provided of
the potential and actual impurities arising from the synthesis, manufacture, or degradation of the
API. This should cover starting materials, by-products, intermediates, chiral impurities and
degradation products and should include the chemical names, structures and origins. The
discussion of pharmacopeial APIs should not be limited to the impurities specified in the API
monograph.

The tables in the QOS-PD template should be used to summarise the information on the API-
related and process-related impurities. In the QOS-PD, the term origin refers to how and where
the impurity was introduced (e.g. Synthetic intermediate from Step 4 of the synthesis ,
Potential by-product due to rearrangement from Step 6 of the synthesis ). It should also be
indicated if the impurity is a metabolite of the API.

The ICH thresholds for reporting, identification (used to set the limit for individual unknown
impurities) and qualification are determined on the basis of potential exposure to the impurity,
e.g. by the maximum daily dose (MDD) of the API. For APIs available in multiple dosage forms
and strengths having different MDD values, it is imperative that the thresholds and
corresponding controls for each of the presentations be considered to ensure that the risks posed
by impurities have been addressed. This is normally achieved by using the highest potential daily
MDD, rather than the maintenance dose. For parenteral products, the maximum hourly dose of
the API should also be included.

It is acknowledged that APIs of semi-synthetic origin do not fall within the scope of the ICH
impurity guidelines. However, depending on the nature of the API and the extent of the chemical
modification steps, the principles on the control of impurities (e.g. reporting, identification and
qualification) could also be extended to APIs of semi-synthetic origin. As an illustrative
example, an API whose precursor molecule was derived from a fermentation process, or a
natural product of plant or animal origin that has subsequently undergone several chemical
modification reactions generally would fall within this scope, whereas an API whose sole
chemical step was the formation of a salt from a fermentation product generally would not fall
within this scope. It is understood that there is some latitude for these types of APIs.

Identification of impurities

It is recognised by the pharmacopoeias that APIs can be obtained from various sources and thus
can contain impurities not considered during the development of the monograph. Furthermore, a


change in the production or source may give rise to additional impurities that are not adequately
controlled by the official compendial monograph. As a result, each PD is assessed independently
to consider the potential impurities that may arise from the proposed route(s) of synthesis. For
these reasons, the ICH limits for unspecified impurities (e.g. NMT 0.10% or 1.0 mg per day
intake [whichever is lower] for APIs having a maximum daily dose 2 g/day) are generally
recommended, rather than the general limits for unspecified impurities that may appear in the
official compendial monograph that could potentially be higher than the applicable ICH limit.

Qualification of impurities

The ICH impurity guidelines should be consulted for options on the qualification of impurities.
The limit specified for an identified impurity in an officially recognised pharmacopoeia is
generally considered to be qualified. The following is an additional option for qualification of
impurities in existing APIs:

The limit for an impurity present in an existing API can be accepted by comparing the impurity
results found in the existing API with those observed in an innovator product using the same
validated, stability-indicating analytical procedure (e.g. comparative HPLC studies). If samples
of the innovator product are not available, the impurity profile may also be compared to a
different FPP, acceptable to MCAZ, with the same route of administration and similar
characteristics (e.g. tablet versus capsule). It is recommended that the studies be conducted on
comparable samples (e.g. age of samples) to obtain a meaningful comparison of the impurity
profiles.

Levels of impurities generated from studies under accelerated or stressed storage conditions of
the innovator or comparator are not considered acceptable/qualified.

A specified impurity present in the existing API is considered qualified if the amount of the
impurity in the existing API reflects the levels observed in the innovator/comparator.

Basis for setting the acceptance criteria
The basis for setting the acceptance criteria for the impurities should be provided. This is
established by considering the identification and qualification thresholds for API-related
impurities (e.g. starting materials, by-products, intermediates, chiral impurities or degradation
products) and the concentration limits for process-related impurities (e.g. residual solvents) as
per the applicable ICH guidelines (e.g. Q3A, Q3C).

The qualified level should be considered as the maximum allowable limit. However, limits
which are considerably wider than the actual manufacturing process capability are generally
discouraged. For this reason, the acceptance criteria are also set taking into consideration the
actual levels of impurities found in several batches of the API from each manufacturer, including
the levels found in the batches used for the comparative bioavailability or biowaiver studies.
When reporting the results of quantitative tests, the actual numerical results should be provided
rather than vague statements such as within limits or conforms . In the cases where a large


number of batches have been tested it is acceptable to summarise the results of the total number
of batches tested with a range of analytical results.

If there are identified impurities specified in an official compendial monograph that are not
controlled by the proposed routine in-house analytical procedure, a justification for their
exclusion from routine analyses should be provided (e.g. Impurities D, E and F listed in the Ph.
Int. monograph are not potential impurities from the proposed route of synthesis used by
manufacturer X ). If acceptable justification cannot be provided it should be demonstrated that
the routine in-house method is capable of separating and detecting the impurities specified in the
official compendial monograph at an acceptable level (e.g. 0.10%). If such a demonstration
cannot be performed, a one-time study should be conducted applying the pharmacopeial method
to several recent batches to demonstrate the absence of the pharmacopoeia listed impurities.

ICH Class 2 solvent(s) used prior to the last step of the manufacturing process may be exempted
from routine control in API specifications if suitable justification is provided.

Submission of results demonstrating less than 10% of the ICH Q3C limit (option I) of the
solvent(s) in three consecutive production-scale batches or six consecutive pilot-scale batches of
the API or a suitable intermediate would be considered acceptable justification. The last step
solvents used in the process should always be routinely controlled in the final API.

For guidance on acceptable residual solvent limits, refer to ICH Q3C. The limit for residues of
triethylamine (TEA) is either 320 ppm on the basis of ICH Q3C option I or 3.2 mg/day on the
basis of permitted daily exposure (PDE).

The absence of known established highly toxic impurities (genotoxic) used in the process or
formed as a by-product should be discussed and suitable limits should be proposed. The limits
should be justified by appropriate reference to available guidances (e.g.
MEA/CHMP/QWP/251344/2006 or USFDA Guidance for Industry: Genotoxic and
carcinogenic impurities in drug substances and products, recommended approaches, December
2008) or by providing experimental safety data or published data in peer-reviewed journals.

Residues of metal catalysts used in the manufacturing process and determined to be present in
batches of API are to be controlled in specifications. This requirement does not apply to metals
that are deliberate components of the pharmaceutical substance (such as a counter ion of a salt)
or metals that are used as a pharmaceutical excipient in the FPP (e.g. an iron oxide pigment). The
guideline on the specification limits for residues of metal catalysts or metal reagents
EMEA/CHMP/SWP/4446/2000 or any equivalent approaches can be used to address this issue.
The requirement normally does not apply to extraneous metal contaminants that are more
appropriately addressed by GMP, GDP or any other relevant quality provision such as the heavy
metal test in monographs of recognised pharmacopoeias that cover metal contamination
originating from manufacturing equipment and the environment.

Reference documents: ICH Q3A, Q3C, Q6A


3.2. S.4 Control of the API (name, manufacturer)
3.2. S.4.1 Specification (name, manufacturer)

The specification for the API should be provided.
As defined in ICH s Q6A guideline, a specification is:

a list of tests, references to analytical procedures and appropriate acceptance criteria, which
are numerical limits, ranges, or other criteria for the tests described. It establishes the set of
criteria to which an API or FPP should conform to be considered acceptable for its intended
use. Conformance to specifications means that the API and / or FPP, when tested according
to the listed analytical procedures, will meet the listed acceptance criteria. Specifications are
critical quality standards that are proposed and justified by the manufacturer and approved by
regulatory authorities.

Copies of the API specifications, dated and signed by authorised personnel (e.g. the person in
charge of the quality control or quality assurance department) should be provided in the PD,
including specifications from each API manufacturer as well as those of the FPP manufacturer.

The FPP manufacturer s API specification should be summarised according to the table in the
MCAZ-QOS template under the headings tests, acceptance criteria and analytical procedures
(including types, sources and versions for the methods).

The standard declared by the applicant could be an officially recognised compendial
standard (e.g. Ph. Int. Ph. Eur., BP, USP) or a House (manufacturer s) standard.
The specification reference number and version (e.g. revision number and/or date)
should be provided for version control purposes.
For the analytical procedures, the type should indicate the kind of analytical procedure
used (e.g. visual, IR, UV, HPLC, laser diffraction), the source refers to the origin of the
analytical procedure (e.g. Ph. Int., Ph. Eur., BP, USP, in-house) and the version (e.g. code
number/version/date) should be provided for version control purposes.

In cases where there is more than one API manufacturer, the FPP manufacturer s API
specifications should be one single compiled set of specifications that is identical for each
manufacturer. It is acceptable to lay down in the specification more than one acceptance criterion
and/or analytical method for a single parameter with the statement for API from manufacturer
A (e.g. in the case of residual solvents).

Any non-routine testing should be clearly identified as such and justified along with the proposal
on the frequency of non-routine testing.

The ICH Q6A guideline outlines recommendations for a number of universal and specific tests
and criteria for APIs.


Reference documents: ICH Q3A, Q3C, Q6A, officially recognized pharmacopoeia (Ph. Int, BP,
USP, Ph. Eur.)

3.2. S.4.2 Analytical procedures (name, manufacturer)

The analytical procedures used for testing the API should be provided.

Copies of the in-house analytical procedures used to generate testing results provided in the PD,
as well as those proposed for routine testing of the API by the FPP manufacturer should be
provided. Unless modified, it is not necessary to provide copies of officially recognized
compendia analytical procedures.

Tables for summarizing a number of the different analytical procedures and validation
information (e.g. HPLC assay/impurity methods, GC methods) can be found in the 2.3.R
Regional information section of the MCAZ-QOS (i.e. 2.3.R.2). These tables should be used to
summarize the in-house analytical procedures of the FPP manufacturer for determination of the
residual solvents, assay and purity of the API, in section 2.3.S.4.2 of the MCAZ-QOS. Other
methods used to generate assay and purity data in the PD can be summarised in 2.3.S.4.4 (c) or
2.3.S.7.3 (b) of the MCAZ-QOS. Officially recognised compendia methods need not be
summarised unless modifications have been made.

Although, HPLC is normally considered the method of choice for determining API-related
impurities, other chromatographic methods such as GC and TLC can also be used, if
appropriately validated. For determination of related substances, reference standards should
normally be available for each of the identified impurities, particularly those known to be toxic
and the concentration of the impurities should be quantitated against their own reference
standards. Impurity standards may be obtained from pharmacopoeias (individual impurities or
resolution mixtures), from commercial sources or prepared in-house. It is considered acceptable
to use the API as an external standard to estimate the levels of impurities, provided the response
factors of those impurities are sufficiently close to that of the API, i.e. between 80 and 120%. In
cases where the response factor is outside this range, it may still be acceptable to use the API,
provided a correction factor is applied. Data to support calculation of the correction factor should
be provided for an in-house method. Unspecified impurities may be quantitated using a solution
of the API as the reference standard at a concentration corresponding to the limit established for
individual unspecified impurities (e.g. 0.10%). The test for related substances in the Ph. Int.
monograph for Lamivudine serves as a typical example.

The system suitability tests (SSTs) represent an integral part of the method and are used to
ensure the adequate performance of the chosen chromatographic system. As a minimum, HPLC
and GC purity methods should include SSTs for resolution and repeatability. For HPLC methods
to control API-related impurities, this is typically done using a solution of the API with a
concentration corresponding to the limit for unspecified impurities. Resolution of the two closest
eluting peaks is generally recommended. However, the choice of alternate peaks can be used if
justified (e.g. choice of a toxic impurity). In accordance with the Ph. Int, section on Methods of
Analysis, the repeatability test should include an acceptable number of replicate injections.


HPLC assay methods should include SSTs for repeatability and in addition either peak
asymmetry, theoretical plates or resolution. For TLC methods, the SSTs should verify the ability
of the system to separate and detect the analyte(s) (e.g. by applying a spot corresponding to the
API at a concentration corresponding to the limit of unspecified impurities).

Reference documents: ICH Q2, WHO Technical Report Series, No. 943, Annex 3

3.2. S.4.3 Validation of analytical procedures (name, manufacturer)

Analytical validation information, including experimental data for the analytical procedures used
for testing the API, should be provided.

Copies of the validation reports for the analytical procedures used to generate testing results
provided in the application file, as well as those proposed for routine testing of the API by the
FPP manufacturer, should be provided.

Tables for summarizing a number of the different analytical procedures and validation
Regional information section of the MCAZ QOS (i.e. 2.3.R.2). These tables should be used to
summarize the validation information of the analytical procedures of the FPP manufacturer for
determination of residual solvents, assay and purity of the API, in section 2.3.S.4.3 of the QOS-
PD. The validation data for other methods used to generate assay and purity data in the PD can
be summarized in 2.3.S.4.4 (c) or 2.3.S.7.3 (b) of the MCAZ QOS.

As recognised by regulatory authorities and pharmacopoeias themselves, verification of
compendial methods can be necessary. The compendial methods as published are typically
validated based on an API or an FPP originating from a specific manufacturer. Different sources
of the same API or FPP can contain impurities and/or degradation products that were not
considered during the development of the monograph. Therefore the monograph and compendial
method should be demonstrated suitable to control the impurity profile of the API from the
intended source(s).

In general verification is not necessary for compendial API assay methods. However, specificity
of a specific compendial assay method should be demonstrated if there are any potential
impurities that are not specified in the compendial monograph. If an officially recognised
compendial method is used to control API-related impurities that are not specified in the
monograph, full validation of the method is expected with respect to those impurities.

If an officially recognised compendial standard is claimed and an in-house method is used in lieu
of the compendial method (e.g. for assay or for specified impurities), equivalency of the in-house
and compendial methods should be demonstrated. This could be accomplished by performing
duplicate analyses of one sample by both methods and providing the results from the study. For
impurity methods, the sample analysed should be the API spiked with impurities at
concentrations equivalent to their specification limits.


Reference documents: ICH Q2

3.2. S.4.4 Batch analyses (name, manufacturer)

Description of batches and results of batch analyses should be provided.
The information provided should include batch number, batch size, date and production site of
relevant API batches used in comparative bioavailability or biowaiver studies, stability, pilot,
scale-up and, if available, production-scale batches. This data is used to establish the
specifications and evaluate consistency in API quality.

Analytical results should be provided from at least two batches of at least pilot scale from each
proposed manufacturing site of the API and should include the batch(es) used in the comparative
bioavailability or biowaiver studies. A pilot-scale batch should be manufactured by a procedure
fully representative of and simulating that to be applied to a full production scale batch.

Copies of the certificates of analysis, both from the API manufacturer(s) and the FPP
manufacturer, should be provided for the profiled batches and any company responsible for
generating the test results should be identified. The FPP manufacturer s test results should be
summarised in the MCAZ-QOS.

The discussion of results should focus on observations noted for the various tests, rather than
reporting comments such as all tests meet specifications . For quantitative tests (e.g. individual
and total impurity tests and assay tests), it should be ensured that actual numerical results are
provided rather than vague statements such as within limits or conforms .

A discussion and justification should be provided for any incomplete analyses (e.g. results not
tested according to the proposed specification).

Reference documents: ICH Q3A, Q3C, Q6A

3.2. S.4.5 Justification of specification (name, manufacturer)
Justification for the API specification should be provided.

A discussion should be provided on the inclusion of certain tests, evolution of tests, analytical
procedures and acceptance criteria, differences from the officially recognised compendial
standard(s), etc. If the officially recognised compendial methods have been modified or replaced,
a discussion should be included.

The justification for certain tests, analytical procedures and acceptance criteria may have been
discussed in other sections of the application file (e.g. impurities, particle size distribution) and
does not need to be repeated here, although a cross-reference to their location should be
provided.

Reference documents: ICH Q3A, Q3C, Q6A, officially recognised pharmacopoeia


3.2. S.5 Reference standards or materials (name, manufacturer)

Information on the reference standards or reference materials used for testing of the
API should be provided.

Information should be provided on the reference standard(s) used to generate data in the PD, as
well as those to be used by the FPP manufacturer in routine API and FPP testing.

The source(s) of the reference standards or materials used in the testing of the API should be
provided (e.g. those used for the identification, purity, assay tests). These could be classified as
primary or secondary reference standards.

A suitable primary reference standard should be obtained from an officially recognised
pharmacopeial source (e.g. Ph. Int, Ph. Eur, BP, and USP) where one exists and the lot number
should be provided. Where a pharmacopoeial standard is claimed for the API and/or the FPP, the
primary reference standard should be obtained from that pharmacopoeia when available. Primary
reference standards from officially recognised pharmacopeial sources do not need further
structural elucidation.

Otherwise, a primary standard may be a batch of the API that has been fully characterised (e.g.
by IR, UV, NMR, MS analyses). Further purification techniques may be needed to render the
material acceptable for use as a chemical reference standard. The purity requirements for a
chemical reference substance depend upon its intended use. A chemical reference substance
proposed for an identification test does not require meticulous purification, since the presence of
a small percentage of impurities in the substance often has no noticeable effect on the test. On
the other hand, chemical reference substances that are to be used in assays should possess a high
degree of purity (such as 99.5% on the dried or water/solvent free basis). Absolute content of the
primary reference standard must be declared and should follow the scheme: 100% minus organic
impurities (quantitated by an assay procedure, e.g. HPLC, DSC, etc.) minus inorganic impurities
minus volatile impurities by loss on drying (or water content minus residual solvents).

A secondary (or in-house) reference standard can be used by establishing it against a suitable
primary reference standard, e.g. by providing legible copies of the IR of the primary and
secondary reference standards run concomitantly and by providing its certificate of analysis,
including assay determined against the primary reference standard. A secondary reference
standard is often characterised and evaluated for its intended purpose with additional procedures
other than those used in routine testing (e.g. if additional solvents are used during the additional
purification process that are not used for routine purposes).

Reference standards should normally be established for specified impurities. Refer to
3.2. S.4.2 for additional guidance.

Reference documents: ICH Q6A, WHO Technical Report Series, No. 943, Annex 3


3.2. S.6 Container closure system (name, manufacturer)

A description of the container closure system(s) should be provided, including the identity of
materials of construction of each primary packaging component, and their specifications. The
specifications should include description and identification (and critical dimensions with
drawings, where appropriate). Non-compendial methods (with validation) should be included,
where appropriate.

For non-functional secondary packaging components (e.g. those that do not provide additional
protection), only a brief description should be provided. For functional secondary packaging
components, additional information should be provided.

The suitability should be discussed with respect to, for example, choice of materials, protection
from moisture and light, compatibility of the materials of construction with the API, including
sorption to container and leaching, and/or safety of materials of construction.

The WHO Guidelines on packaging for pharmaceutical products (WHO Technical Report
Series, No. 902, Annex 9, 2002) and the officially recognised pharmacopoeias should be
consulted for recommendations on the packaging information for APIs.

Primary packaging components are those that are in direct contact with the API or FPP. The
specifications for the primary packaging components should be provided and should include a
specific test for identification (e.g. IR).

Copies of the labels applied on the secondary packaging of the API should be provided and
should include the conditions of storage. In addition, the name and address of the manufacturer
of the API should be stated on the container, regardless of whether relabelling is conducted at
any stage during the API distribution process.

3.2. S.7 Stability (name, manufacturer)

3.2. S.7.1 Stability summary and conclusions (name, manufacturer)

The types of studies conducted, protocols used, and the results of the studies should be
summarised. The summary should include results, for example, from forced degradation studies
and stress conditions, as well as conclusions with respect to storage conditions and retest date or
shelflife, as appropriate.

The purpose of stability testing is to:

provide evidence of how the quality of an API or FPP varies with time under the influence of a
variety of environmental factors such as temperature, humidity and light.


The tables in the MCAZ-QOS template should be used to summarise the results from the
stability studies and related information (e.g. conditions, testing parameters, conclusions,
commitments).

Stress testing

As outlined in the ICH Q1A guidance document, stress testing of the API can help identify the
likely degradation products, which can in turn help establish the degradation pathways and the
intrinsic stability of the molecule and validate the stability indicating power of the analytical
procedures used. The nature of the stress testing will depend on the individual API and the type
of FPP involved.

Stress testing may be carried out on a single batch of the API. For examples of typical stress
conditions refer to WHO Technical Report Series, No. 953, Annex 2, Section 2.1.2, as well as,
A typical set of studies of the degradation 1379 paths of an active pharmaceutical ingredient
1380 in WHO Technical Report Series, No. 929, Annex 5, Table A.1.

The objective of stress testing is not to completely degrade the API, but to cause degradation to
occur to a small extent, typically 10-30% loss of active by assay when compared with non-
degraded API. This target is chosen so that some degradation occurs, but not enough to generate
secondary products. For this reason, the conditions and duration may need to be varied when the
API is especially susceptible to a particular stress factor. In the total absence of degradation
products after 10 days, the API is considered stable under the particular stress condition.

The tables in the MCAZ QOS template should be used to summarise the results of the stress
testing and should include the treatment conditions (e.g. temperatures, relative humidities,
concentrations of solutions, durations) and the observations for the various test parameters (e.g.
assay, degradation products). The discussion of results should highlight whether mass balance
was observed.

Photostability testing should be an integral part of stress testing. The standard conditions are
described in ICH Q1B. If protect from light is stated in one of the officially recognised
pharmacopoeia for the API, it is sufficient to state protect from light on labelling, in lieu of
photostability studies, when the container closure system is shown to be light protective.

When available, it is acceptable to provide the relevant data published in the scientific literature
(inter alia WHOPARs, EPARs) to support the identified degradation products and pathways.

Accelerated and long-term testing

Available information on the stability of the API under accelerated and long-term conditions
should be provided, including information in the public domain or obtained from scientific
literature. The source of the information should be identified.


The required long-term storage conditions for APIs by MCAZ is either 30C2C/65%5%RH
or 30C2C/75%5%RH. Studies covering the proposed retest period at the above-mentioned
long-term storage conditions will provide better assurance of the stability of APIs at the
conditions of the supply chain corresponding to the Zimbabwean environment. Alternative
conditions should be supported with appropriate evidence, which may include literature
references or in-house studies, demonstrating that storage at 30C is inappropriate for the API.
For APIs intended for storage in a refrigerator and those intended for storage in a freezer refer to
the WHO stability guideline WHO Technical Report Series, No. 953 Annex 2. APIs intended for
storage below -20C should be treated on a case-by-case basis.

To establish the retest period, data should be provided on not less than three batches of at least
pilot scale. The batches should be manufactured by the same synthesis route as production
batches and using a method of manufacture and procedure that simulates the final process to be
used for production batches. The stability testing programme should be summarized and the
results of stability testing should be summarized in the dossier and in the tables in the QOS-PD.

The information on the stability studies should include details such as storage conditions, batch
number, batch size, container closure system and completed (and proposed) test intervals. The
discussion of results should focus on observations noted for the various tests, rather than
reporting comments such as all tests meet specifications . Ranges of analytical results where
relevant and any trends that were observed should be included. For quantitative tests (e.g.
individual and total degradation product tests and assay tests), it should be ensured that actual
numerical results are provided rather than vague statements such as within limits or
conforms . Where different from the methods described in S.4.2, descriptions and validation of
the methodology used in stability studies should be provided.

The minimum data required at the time of submitting the dossier (in the general case) are as
follows:

Storage
temperature(C)
Relative humidity
(%)
Minimum time
period (months)
1. Accelerated 402 755 6
2. Intermediate * - - -
3. Long-term 302 655 or 755 6

*Where long-term conditions are 30C2C/65%5%RH or 30C2C/75%5%RH, there is no
intermediate condition.

Refer to WHO Technical Report Series, No. 953, Annex 2 for further information regarding the
storage conditions, container closure system, test specifications and testing frequency.

Proposed storage statement and retest period


A storage statement should be established for display on the label based on the stability
evaluation of the API. The WHO stability guideline includes a number of recommended storage
statements that should be used, when supported by the stability studies.

A retest period should be derived from the stability information and should be displayed on the
container label.

After this retest period, a batch of API destined for use in the manufacture of an FPP could be
retested and then, if in compliance with the specification, could be used immediately (e.g. within
30 days). If retested and found compliant, the batch does not receive an additional period
corresponding to the time established for the retest period. However, an API batch can be
retested multiple times and a different portion of the batch used after each retest, as long as it
continues to comply with the specification. For APIs known to be labile (e.g. certain antibiotics),
it is more appropriate to establish a shelflife rather than a retest period (reference: ICH Q1A).

Limited extrapolation of the real time data from the long-term storage condition beyond the
observed range to extend the retest period can be undertaken at the time of assessment of the PD,
if justified. Applicants should consult the ICH Q1E guideline for further details on the evaluation
and extrapolation of results from stability data (e.g. if significant change was not observed within
6 months at accelerated condition and the data show little or no variability, the proposed retest
period could be up to two times the period covered by the long-term data, but should not exceed
the long-term data by 12 months).

Reference documents: ICH Q1A, Q1B, Q1D, Q1E, WHO Technical Report Series, No. 953,
Annex 2

3.2. S.7.2 Post-approval stability protocol and stability commitment (name, manufacturer)

The post-approval stability protocol and stability commitment should be provided.

Primary stability study commitment

When available long-term stability data on primary batches do not cover the proposed retest
period granted at the time of assessment of the application file, a commitment should be made to
continue the stability studies in order to firmly establish the retest period. A written commitment
(signed and dated) to continue long-term testing over the retest period should be included in the
dossier when relevant.

Commitment stability studies

The long-term stability studies for the commitment batches should be conducted through the
proposed retest period on at least three production batches. Where stability data was not provided
for three production batches, a written commitment (signed and dated) should be included in the
dossier.


The stability protocol for the commitment batches should be provided and should include, but not
be limited to, the following parameters:

a) number of batch(es) and different batch sizes, if applicable;
b) relevant physical, chemical, microbiological and biological test methods;
c) acceptance criteria;
d) reference to test methods;
e) description of the container closure system(s);
f) testing frequency;
g) description of the conditions of storage (standardised conditions for long-term
testing as described in these guidelines and consistent with the API labelling,
should be used); and
h) other applicable parameters specific to the API.

Ongoing stability studies

The stability of the API should be monitored according to a continuous and appropriate
programme that will permit the detection of any stability issue (e.g. changes in levels of
degradation products). The purpose of the ongoing stability programme is to monitor the API
and to determine that the API remains and can be expected to remain within the retest period in
all future batches.

At least one production batch per year of API (unless none is produced during that year) should
be added to the stability monitoring programme and tested at least annually to confirm the
stability. In certain situations, additional batches should be included. A written commitment
(signed and dated) for ongoing stability studies should be included in the dossier.

Refer to WHO Technical Report Series, No. 953, Annex 2, Section 2.1.11 for further information
on ongoing stability studies.

Any differences in the stability protocols used for the primary batches and those proposed for the
commitment batches or ongoing batches should be scientifically justified.

Reference documents: ICH Q1A, Q1B, Q1D, Q1E, WHO Technical Report Series, No. 953,
Annex 2

3.2. S.7.3 Stability data (name, manufacturer)

Results of the stability studies (e.g. forced degradation studies and stress conditions) should be
presented in an appropriate format such as tabular, graphical, or narrative. Information on the
analytical procedures used to generate the data and validation of these procedures should be
included.

The actual stability results used to support the proposed retest period should be included in the
dossier. For quantitative tests (e.g. individual and total degradation product tests and assay tests),


it should be ensured that actual numerical results are provided rather than vague statements such
as within limits or conforms .

Reference documents: ICH Q1A, Q1B, Q1D, Q1E, Q2, WHO Technical Report Series, No. 953,
Annex 2.

3.2. P Drug product (or finished pharmaceutical product (FPP)) (name, dosage form)

3.2. P.1 Description and composition of the FPP (name, dosage form)

A description of the FPP and its composition should be provided. The information provided
should include, for example:

Description of the dosage form

The description of the FPP should include the physical description, available strengths, release
mechanism (e.g. immediate, modified [delayed or extended]), as well as any other
distinguishable characteristics, e.g.:

The proposed XYZ 50mg Tablets are available as white, oval, film-coated tablets,
debossed with 50 on one side and a break-line on the other side.

The proposed XYZ 100mg Tablets are available as yellow, round, film-coated tablets,
debossed with 100 on one side and plain on the other side.

Composition, i.e. list of all components of the dosage form, and their amount on a per unit
basis (including overages, if any), the function of the components, and a reference to their
quality standards (e.g. compendial monographs or manufacturers specifications)

The tables in the QOS template should be used to summarise the composition of the FPP and
express the quantity of each component on a per unit basis (e.g. mg per tablet, mg per ml, mg per
vial) and percentage basis, including a statement of the total weight or measure of the dosage
unit. The individual components for mixtures prepared in-house (e.g. coatings) should be
included in the tables, where applicable.

All components used in the manufacturing process should be included, including those that may
not be added to every batch (e.g. acid and alkali), those that may be removed during processing
(e.g. solvents) and any others (e.g. nitrogen, silicon for stoppers). If the FPP is formulated using
an active moiety, then the composition for the active ingredient should be clearly indicated (e.g.
1 mg of active ingredient base =1.075 mg active ingredient hydrochloride ). All overages
should be clearly indicated (e.g. contains 2% overage of the API to compensate for
manufacturing losses ).


The components should be declared by their proper or common names, quality standards (e.g.
Ph. Int., Ph. Eur., BP, USP, House) and, if applicable, their grades (e.g. Microcrystalline
Cellulose NF [PH 102] ) and special technical characteristics (e.g. lyophilised, micronised,
solubilised, emulsified).

The function of each component (e.g. diluent/filler, binder, disintegrant, lubricant, glidant,
granulating solvent, coating agent, antimicrobial preservative) should be stated. If an excipient
performs multiple functions, the predominant function should be indicated.

The qualitative composition, including solvents, should be provided for all proprietary
components or blends (e.g. capsule shells, colouring blends, imprinting inks). This information
(excluding the solvents) is to be listed in the product information (e.g. summary of product
characteristics, labelling, package leaflet).

Description of accompanying reconstitution diluent(s)

For FPPs supplied with reconstitution diluent(s) that are commercially available or have been
assessed and considered acceptable for this purpose, a brief description of the reconstitution
diluents(s) should be provided.

For FPPs supplied with reconstitution diluent(s) that are not commercially available or have not
been assessed and considered acceptable by MCAZ, information on the diluent(s) should be
provided in a separate FPP portion ( 3.2.P ), as appropriate.

Type of container and closure used for the dosage form and accompanying reconstitution
diluent, if applicable

The container closure used for the FPP (and accompanying reconstitution diluent, if applicable)
should be briefly described, with further details provided under 3.2.P.7 Container closure system,
e.g.

The product is available in HDPE bottles with polypropylene caps (in sizes of 100 s,
500s and 1000 s) and in PVC/Aluminum foils unit dose blisters (in packages of 100 s
(cards of 5 x 2, 10 cards per package).


3.2. P.2 Pharmaceutical development (name, dosage form)

The Pharmaceutical Development section should contain information on the development studies
conducted to establish that the dosage form, the formulation, manufacturing process, container
closure system, microbiological attributes and usage instructions are appropriate for the purpose
specified in the product dossier. The studies described here are distinguished from routine
control tests conducted according to specifications. Additionally, this section should identify and


describe the formulation and process attributes (critical parameters) that can influence batch
reproducibility, product performance and FPP quality. Supportive data and results from specific
studies or published literature can be included within or attached to the Pharmaceutical
Development section. Additional supportive data can be referenced to the relevant non-clinical
or clinical sections of the product dossier.

Pharmaceutical development information should include, at a minimum:

a) the definition of the quality target product profile (QTPP) as it relates to quality, safety
and efficacy, considering for example the route of administration, dosage form,
bioavailability, strength and stability;

b) identification of the potential critical quality attributes (CQAs) of the FPP so as to
adequately control the product characteristics that could have an impact on quality;

c) discussion of the potential CQAs of the API(s), excipients and container closure
system(s) including the selection of the type, grade and amount to deliver drug product of
the desired quality;

d) discussion of the selection criteria for the manufacturing process and the control strategy
required.

These features should be discussed as part of the product development using the principles of
risk management over the entire lifecycle of the product (ref: ICH Q8).

In case of fixed-dose combination FPPs, the development strategy should take into account the
formulae of the individual component comparator FPPs. The compatibility of APIs with each
other should be studied and the results documented. For a discussion of additional
pharmaceutical development issues specific to the development of FDCs, reference should be
made to WHO Technical Report Series, No. 929, Annex 5, Section 6.3.2.

Reference documents: ICH Q6A, Q8, Q9 and Q10.

3.2. P.2.1 Components of the FPP (name, dosage form)

3.2. P.2.1.1 Active pharmaceutical ingredient (name, dosage form)

The compatibility of the API with excipients listed in 3.2.P.1 should be discussed.
Additionally, key physicochemical characteristics (e.g. water content, solubility, particle size
distribution, polymorphic or solid state form) of the API that can influence the performance of
the FPP should be discussed. For fixed-dose combinations, the compatibility of APIs with each
other should be discussed.

Physicochemical characteristics of the API may influence both the manufacturing capability and
the performance of the FPP.



Guidance on compatibility studies is provided in Appendix 3 of the WHO Guidelines for
registration of fixed-dose combination medicinal products (WHO Technical Report Series, No.
929, Annex 5, 2005). In addition to visual examination, chromatographic results (assay, purity)
are required to demonstrate API-API and API-excipient compatibility. In general, API-excipient
compatibility is not required to be established for specific excipients when evidence is provided
(e.g. SmPC or product leaflet) that the excipients are present in the comparator product.

3.2. P.2.1.2 Excipients (name, dosage form)

The choice of excipients listed in 3.2.P.1, their concentration, and their characteristics that can
influence the FPP performance should be discussed relative to their respective functions.

Ranges or alternates for excipients are normally not accepted, unless supported by appropriate
process validation data. Where relevant, compatibility study results (e.g. compatibility of a
primary or secondary amine API with lactose) should be included to justify the choice of
excipients. Specific details should be provided where necessary (e.g. use of potato or corn
starch).

Where antioxidants are included in the formulation, the effectiveness of the proposed
concentration of the antioxidant should be justified and verified by appropriate studies.

Antimicrobial preservatives are discussed in 3.2.P.2.5.

3.2. P.2.2 Finished pharmaceutical product (name, dosage form)

3.2. P.2.2.1 Formulation development (name, dosage form)

A brief summary describing the development of the FPP should be provided, taking into
consideration the proposed route of administration and usage. The differences between the
comparative bioavailability or biowaiver formulations and the formulation (i.e. composition)
described in 3.2.P.1 should be discussed. Results from comparative in vitro studies (e.g.
dissolution) or comparative in vivo studies (e.g. bioequivalence) should be discussed, when
appropriate.

MCAZ defines an established multisource product as one that has been marketed by the
applicant or manufacturer associated with the dossier for at least five years and for which at least
10 production batches were produced over the previous year, or, if less than 10 batches were
produced in the previous year, not less than 25 batches were produced in the previous three
years. For products that meet the criteria of an established multisource product, all sections of
P.2.2.1 of the dossier and QOS-PD should be completed with the exception of P.2.2.1 (a). In
addition, a product quality review should be provided as outlined in Annex V.


Break-marks (score lines) are justified in the tablets only when the tablet can be divided into
fractional doses according to approved posology or is specified for the FPP in the listing of
recommended comparator products.

If the proposed FPP is a scored tablet, it should comply with the requirements of the Ph. Eur.
(Subdivision of tablets test) and the results of the study of the uniformity of dosage units of the
tablet halves should be provided. The data provided in the PD should include a description of the
test method, individual values, mean and relative standard deviation (RSD) of the results.
Uniformity testing (i.e. content uniformity or weight variation, depending on the requirement for
the whole tablet) should be performed on each split portion from a minimum of 10 randomly
selected whole tablets. As an illustrative example, the number of units (i.e. the splits) would be
10 halves for bisected tablets (one-half of each tablet is retained for the test) or 10 quarters for
quadrisected tablets (one-quarter of each tablet is retained for the test). At least one batch of
eachstrength should be tested. Ideally, the study should cover a range of the hardness values. The
splitting of the tablets should be performed in a manner that would be representative of that used
by the consumer (e.g. manually split by hand).

The uniformity test on split portions can be demonstrated on a one-time basis and does not need
to be added to the FPP specification(s). The tablet description in the FPP specification and in the
product information (e.g. summary of product characteristics, labelling, package insert) should
reflect the presence of a score.

In vitro dissolution or drug release

A discussion should be included as to how the development of the formulation relates to
development of the dissolution method(s) and the generation of the dissolution profile.

The results of studies justifying the choice of in vitro dissolution or drug release conditions (e.g.
apparatus, rotation speed, medium) should be provided. Data should also be submitted to
demonstrate whether the method is sensitive to changes in manufacturing processes and/or
changes in grades and/or amounts of critical excipients and particle size where relevant. The
dissolution method should be sensitive to any changes in the product that would result in a
change in one or more of the pharmacokinetic parameters. Use of a single point test or a
dissolution range should be justified based on the solubility and/or biopharmaceutical
classification of the API.

For slower dissolving immediate-release products (e.g. Q=80% in 90 minutes), a second time
point may be warranted (e.g. Q=60% in 45 minutes).

Modified-release FPPs should have a meaningful in vitro release rate (dissolution) test that is
used for routine quality control. Preferably this test should possess in vitro-in vivo correlation.
Results demonstrating the effect of pH on the dissolution profile should be submitted if
appropriate for the type of dosage form.


For extended-release FPPs, the testing conditions should be set to cover the entire time period of
expected release (e.g. at least three test intervals chosen for a 12-hour release and additional test
intervals for longer duration of release). One of the test points should be at the early stage of
drug release (e.g. within the first hour) to demonstrate absence of dose dumping. At each test
period, upper and lower limits should be set for individual units. Generally, the acceptance range
at each intermediate test point should not exceed 25% or 12.5% of the targeted value.
Dissolution results should be submitted for several lots, including those lots used for
pharmacokinetic and bioavailability or biowaiver studies.

Recommendations for conducting and assessing comparative dissolution profiles can be found in
Annexure VI.

3.2. P.2.2.2 Overages (name, dosage form)

Any overages in the formulation(s) described in 3.2.P.1 should be justified.

Justification of an overage to compensate for loss during manufacture should be provided,
including the step(s) where the loss occurs, the reasons for the loss and batch analysis release
data (assay results).

Overages for the sole purpose of extending the shelf life of the FPP are generally not acceptable.

3.2. P.2.2.3 Physicochemical and biological properties (name, dosage form)

Parameters relevant to the performance of the FPP, such as pH, ionic strength, dissolution, re-
dispersion, reconstitution, particle size distribution, aggregation, polymorphism, rheological
properties, biological activity or potency, and/or immunological activity, should be addressed.

In addition to the above considerations, refractive index may be a relevant parameter for some
FPPs.

3.2. P.2.3 Manufacturing process development (name, dosage form)

The selection and optimisation of the manufacturing process described in 3.2.P.3.3, in particular
its critical aspects, should be explained. Where relevant, the method of sterilisation should be
explained and justified.

Where relevant, justification for the selection of aseptic processing or other sterilisation methods
over terminal sterilisation should be provided.

Differences between the manufacturing process (es) used to produce comparative bioavailability
or biowaiver batches and the process described in 3.2.P.3.3 that can influence the performance of
the product should be discussed.


For products that meet the criteria of an established multisource product, in order to fulfill the
requirements of section P.2.3, section P.2.3 (b) of the dossier and QOS-PD should be completed
and a product quality review should be submitted as outlined in Annexure V. The guidance that
follows applies to all other products, for which section P.2.3 should be completed in its entirety.

The rationale for choosing the particular pharmaceutical product should be provided. The
scientific rationale for the choice of the manufacturing, filling and packaging processes that can
influence FPP quality and performance should be explained (e.g. wet granulation using high
shear granulator). API stress study results may be included in the rationale. Any developmental
work undertaken to protect the FPP from deterioration should also be included (e.g. protection
from light or moisture).

The scientific rationale for the selection, optimisation and scale-up of the manufacturing process
described in 3.2.P.3.3 should be explained; in particular the critical aspects (e.g. rate of addition
of granulating fluid, mixing time, granulation end-point). The equipment should be identified by
type and working capacity.

3.2. P.2.4 Container closure system (name, dosage form)

The suitability of the container closure system (described in 3.2.P.7) used for the storage,
transportation (shipping) and use of the FPP should be discussed. This discussion should
consider, e.g. choice of materials, protection from moisture and light, compatibility of the
materials of construction with the dosage form (including sorption to container and leaching)
safety of materials of construction, and performance (such as reproducibility of the dose delivery
from the device when presented as part of the FPP).

Testing requirements to verify the suitability of the container closure system contact material(s)
depend on the dosage form and route of administration. The pharmacopoeias provide standards
that are required for packaging materials, including for example the following:
Glass containers: USP <660>
Ph. Eur. 3.2.1
Plastic containers: Ph. Eur. 3.2.2, 3.2.2.1
USP <661>
Rubber/Elastomeric closures: USP <381>
Ph. Eur. 3.2.9
The following table outlines the general recommendations for the various dosage forms for one-
time studies to establish the suitability of the container closure system.

Table 2: Demonstration of suitability of container closure system
Solid oral products Oral liquid and
topical products
Sterile products
(including
Ophthalmics)
Description of any
additional treatments*
X X
X (sterilization and
depyrogenation of the


components)
Extraction studies --- X X
interaction studies
(migration / sorption)
---

X X
Moisture permeability X (uptake) X (usually loss) X (usually loss)
Light transmission X ** X X
*e.g. coating of tubes, siliconisation of rubber stoppers, sulfur treatment of ampoules/vials
X =information should be submitted
--- =information does not need to be submitted
** Not required if product has been shown to be photostable

For solid oral dosage forms and solid APIs, compliance with regulations on food-contact plastic
materials, (for example [EU] No. 10/2011)can be considered acceptable.

The suitability of the container closure system used for the storage, transportation (shipping) and
use of any intermediate/in-process products (e.g. premixes, bulk FPP) should also be discussed.

A device is required to be included with the container closure system for oral liquids or solids
(e.g. solutions, emulsions, suspensions and powders/granules for such), any time the package
provides for multiple doses.

In accordance with the Ph. Int., general chapter Liquid Preparations for Oral Use:

Each dose from a multi-dose container is administered by means of a device suitable for
measuring the prescribed volume. The device is usually a spoon or a cup for volumes of 5
ml or multiples thereof, or an oral syringe for other volumes or, for oral drops, a suitable
dropper.

For a device accompanying a multi-dose container, the results of a study should be provided
demonstrating the reproducibility of the device (e.g. consistent delivery of the intended volume),
generally at the lowest intended dose.

A sample of the device should be provided in Module 1.

3.2. P.2.5 Microbiological attributes (name, dosage form)

Where appropriate, the microbiological attributes of the dosage form should be discussed,
including, for example, the rationale for not performing microbial limits testing for non-sterile
products and the selection and effectiveness of preservative systems in products containing
antimicrobial preservatives. For sterile products, the integrity of the container closure system to
prevent microbial contamination should be addressed.

Where an antimicrobial preservative is included in the formulation, the amount used should be
justified by submission of results of the product formulated with different concentrations of the


preservative(s) to demonstrate the least necessary but still effective concentration. The
effectiveness of the agent should be justified and verified by appropriate studies (e.g. USP or Ph.
Eur. general chapters on antimicrobial preservatives using a batch of the FPP. If the lower limit
for the proposed acceptance criterion for the assay of the preservative is less than 90.0%, the
effectiveness of the agent should be established with a batch of the FPP containing a
concentration of the antimicrobial preservative corresponding to the lower proposed acceptance
criteria.

As outlined in the WHO stability guideline (WHO Technical Report Series, No. 953, Annex 2,
2009), a single primary stability batch of the FPP should be tested for effectiveness of the
antimicrobial preservative (in addition to preservative content) at the proposed shelf-life for
verification purposes, regardless of whether there is a difference between the release and shelf-
life acceptance criteria for preservative content.

3.2. P.2.6 Compatibility (name, dosage form)

The compatibility of the FPP with reconstitution diluent(s) or dosage devices (e.g. precipitation
of API in solution, sorption on injection vessels, stability) should be addressed to provide
appropriate and supportive information for the labelling.

Where a device is required for oral liquids or solids (e.g. solutions, emulsions, suspensions and
powders/granules for such) that are intended to be administered immediately after being added to
the device, the studies mentioned in the following paragraphs are not required.

Where sterile, reconstituted products are to be further diluted, compatibility should be
demonstrated with all diluents over the range of dilution proposed in the labelling. These studies
should preferably be conducted on aged samples. Where the labelling does not specify the type
of containers, compatibility (with respect to parameters such as appearance, pH, assay, levels of
individual and total degradation products, sub visible particulate matter and extractables from the
packaging components) should be demonstrated in glass, PVC and polyolefin containers.
However, if one or more containers are identified in the labelling, compatibility of admixtures
needs to be demonstrated only in the specified containers.

Studies should cover the duration of storage reported in the labelling (e.g. 24 hours under
controlled room temperature and 72 hours under refrigeration). Where the labelling specifies co-
administration with other FPPs, compatibility should be demonstrated with respect to the
principal FPP as well as the co-administered FPP (i.e. in addition to other aforementioned
parameters for the mixture, the assay and degradation levels of each co-administered FPP should
be reported).

3.2. P.3 Manufacture (name, dosage form)

3.2. P.3.1 Manufacturer(s) (name, dosage form)


The name, address, and responsibility of each manufacturer, including contractors, and each
proposed production site or facility involved in manufacturing and testing should be provided.

The facilities involved in the fabrication, packaging, labelling and testing should be listed. It
should be clearly indicated if certain companies are responsible only for specific steps (e.g.
manufacturing of an intermediate). (Ref: WHO good distribution practices for pharmaceutical
products, WHO Technical Report Series, No. 957, Annex 5.)

The list of manufacturers/companies should specify the actual addresses of production or
manufacturing site(s) involved (including block[s] and unit[s]), rather than the administrative
offices.

For a mixture of an API with an excipient, the blending of the API with the excipient is
considered to be the first step in the manufacture of the final product and therefore the mixture
does not fall under the definition of an API. The only exceptions are in the cases where the API
cannot exist on its own. Similarly, for a mixture of APIs, the blending of the APIs is considered
to be the first step in the manufacture of the final product. Sites for such manufacturing steps
should be included in this section.

A valid manufacturing authorisation for pharmaceutical production, as well as a marketing
authorisation, should be submitted to demonstrate that the product is registered or licensed in
accordance with national requirements in the country of origin or country of manufacture
(Module 1, 1.2.2).

For each site where the major production step(s) are carried out, when applicable, attach a WHO-
type certificate of GMP issued by the competent authority in terms of the WHO Certification
Scheme on the Quality of Pharmaceutical Products Moving in International Commerce (Module
1, 1.2.2).

Justification for any differences to the product in the country or countries issuing the WHO type
certificate(s)

When there are differences between the product for which this application is submitted and that
marketed in the country/countries which provided the WHO-type certificate(s), provide data to
support the applicability of the certificate(s) despite the differences. Depending on the case, it
may be necessary to provide validation data for differences in site of manufacture, specifications,
formulation, etc. Note that only minor differences are likely to be acceptable. Differences in
container labelling need not normally be justified.

Regulatory situation in other countries

The countries should be listed in which this product has been granted a marketing authorisation,
this product has been withdrawn from the market and/or this application for marketing has been
rejected, deferred or withdrawn. (Module 1, 1.2.2)


Reference documents: WHO Technical Report Series, No. 908, Annex 4 and No. 957, Annex 5

3.2. P.3.2 Batch formula (name, dosage form)

A batch formula should be provided that includes a list of all components of the dosage form to
be used in the manufacturing process, their amounts on a per-batch basis, including overages,
and a reference to their quality standards.

Table 3 below should be used to summarise the batch formula of the FPP for each proposed
commercial batch size and express the quantity of each component on a per batch basis,
including a statement of the total weight or measure of the batch.

Table 3: Batch formula
Strength (label claim)
Master production document
reference number and/or version

Proposed commercial batch size(s) (e.g.
number of dosage units)

Component and quality standard
(and grade, if applicable)
Quantity per
batch (e.g.
kg/batch)
Quantity per
batch (e.g.
kg/batch)
Quantity per
batch (e.g.
kg/batch)
<complete with appropriate title e.g. Core tablet, Contents of capsule, Powder for injection>

Subtotal 1
<complete with appropriate title e.g. Film-coating >

Subtotal 2
Total

All components used in the manufacturing process should be included, including those that may
not be added to every batch (e.g. acid and alkali), those that may be removed during processing
(e.g. solvents) and any others (e.g. nitrogen, silicon for stoppers). If the FPP is formulated using
an active moiety, then the composition for the active ingredient should be clearly indicated (e.g.
1 kg of active ingredient base =1.075 kg active ingredient hydrochloride ). All overages should
be clearly indicated (e.g. Contains 5 kg [corresponding to 2%] overage of the API to
compensate for manufacturing losses ).

The components should be declared by their proper or common names, quality standards (e.g.
Ph. Int., Ph. Eur., BP, USP, House) and, if applicable, their grades (e.g. Microcrystalline
Cellulose NF [PH 102] ) and special technical characteristics (e.g. lyophilised, micronized,
solubilised, emulsified).



3.2. P.3.3 Description of manufacturing process and process controls (name, dosage form)

A flow diagram should be presented giving the steps of the process and showing where materials
enter the process. The critical steps and points at which process controls, intermediate tests or
final product controls are conducted should be identified.

A narrative description of the manufacturing process, including packaging that presents the
sequence of steps undertaken and the scale of production should also be provided. Novel
processes or technologies and packaging operations that directly affect product quality should be
described with a greater level of detail. Equipment should, at least, be identified by type (e.g.
tumble blender, in-line homogeniser) and working capacity, where relevant.

Steps in the process should have the appropriate process parameters identified, such as time,
temperature, or pH. Associated numeric values can be presented as an expected range. Numeric
ranges for critical steps should be justified in section 3.2.P.3.4. In certain cases, environmental
conditions (e.g. low humidity for an effervescent product) should be stated.

The maximum holding time for bulk FPP prior to final packaging should be stated. The holding
time should be supported by the submission of stability data, if longer than 30 days. For an
aseptically processed FPP, sterile filtration of the bulk and filling into final containers should
preferably be continuous; any holding time should be justified.

Proposals for the reprocessing of materials should be justified. Any data to support this
justification should be either referenced or filed in this section (3.2.P.3.3).

The information above should be summarised in the QOS-PD template and should reflect the
production of the proposed commercial batches. See Section 2. Glossary for definitions of pilot-
scale and production-scale batches.

For the manufacture of sterile products, the class (e.g. A, B, C etc.) of the areas should be stated
for each activity (e.g. compounding, filling, sealing etc.), as well as the sterilisation parameters
for equipment, container/closure, terminal sterilisation etc.

Reference documents: ICH Q8, Q9, Q10

3.2. P.3.4 Controls of Critical Steps and Intermediates (name, dosage form)

Critical Steps: Tests and acceptance criteria should be provided (with justification, including
experimental data) performed at the critical steps identified in 3.2.P.3.3 of the manufacturing
process, to ensure that the process is controlled.

Intermediates: Information on the quality and control of intermediates isolated during the process
should be provided.


Examples of applicable in-process controls include:

- granulations: moisture (limits expressed as a range), blend uniformity, bulk and tapped
- densities, particle size distribution;
- solid oral products: average weight, weight variation, hardness, thickness, friability,
- disintegration, weight gain during coating;
- fixed-dose combinations (FDCs): uniformity of content of each active prior to compression
(tablets) or filling (e.g. capsules, sachets and suspension dosage forms);
- semi-solids: viscosity, homogeneity, pH;
- transdermal dosage forms: assay of API-adhesive mixture, weight per area of coated patch
without backing;
- metered dose inhalers: fill weight/volume, leak testing, valve delivery;
- dry powder inhalers: assay of API-excipient blend, moisture, weight variation of individually
contained doses such as capsules or blisters;
- liquids: pH, specific gravity, clarity of solutions; and
- parenterals: appearance, clarity, fill volume/weight, pH, filter integrity tests, particulate
matter, leak testing of ampoules.

Reference documents: ICH Q2, Q6A, Q8, Q9, Q10, WHO Technical Report Series, No. 929,
Annex 5

3.2. P.3.5 Process validation and/or evaluation (name, dosage form)

Description, documentation, and results of the validation and/or evaluation studies should be
provided for critical steps or critical assays used in the manufacturing process (e.g. validation of
the sterilisation process or aseptic processing or filling). Viral safety evaluation should be
provided in 3.2A.2, if necessary.

For products that meet the criteria of an established multisource product, a product quality
review as outlined in Annexure V may be submitted in lieu of the information below.

The following information should be provided for all other products:

a) a copy of the process validation protocol, specific to this FPP, that identifies the critical
equipment and process parameters that can affect the quality of the FPP and defines
testing parameters, sampling plans, analytical procedures and acceptance criteria;
b) a commitment that three consecutive, production-scale batches of this FPP will be
subjected to prospective validation in accordance with the above protocol;
c) The applicant should submit a written commitment that information from these studies
will be available for verification after the FPP is registered by MCAZ and,
d) if the process validation studies have already been conducted (e.g. for sterile products), a
copy of the process validation report should be provided in the PD in lieu of (a) and (b)
above.


One of the most practical forms of process validation, mainly for non-sterile products, is the final
testing of the product to an extent greater than that required in routine quality control. It may
involve extensive sampling, far beyond that called for in routine quality control and testing to
normal quality control specifications and often for certain parameters only. Thus, for instance,
several hundred tablets per batch may be weighed to determine unit dose uniformity. The results
are then treated statistically to verify the "normality" of the distribution and to determine the
standard deviation from the average weight. Confidence limits for individual results and for
batch homogeneity are also estimated. Strong assurance is provided that samples taken at random
will meet regulatory requirements if the confidence limits are well within compendial
specifications.

Similarly, extensive sampling and testing may be performed with regard to any quality
requirements. In addition, intermediate stages may be validated in the same way, e.g. dozens of
samples may be assayed individually to validate mixing or granulation stages of low-dose tablet
production by using the content uniformity test. Products (intermediate or final) may
occasionally be tested for non-routine characteristics. Thus, sub visual particulate matter in
parenteral preparations may be determined by means of electronic devices, or tablets/capsules
tested for dissolution profile if such tests are not performed on every batch.

Where ranges of batch sizes are proposed, it should be shown that variations in batch size would
not adversely alter the characteristics of the finished product. It is envisaged that those
parameters listed in the following validation scheme will need to be re-validated once further
scale-up is proposed after registration.

The process validation protocol should include inter alia the following:

- a reference to the current master production document;
- a discussion of the critical equipment;
- the process parameters that can affect the quality of the FPP (critical process parameters
[CPPs]) including challenge experiments and failure mode operation;
- details of the sampling: sampling points, stages of sampling, methods of sampling and the
sampling plans (including schematics of blender/storage bins for testing of the final blend);
- the testing parameters/acceptance criteria including in-process and release specifications;
- the analytical procedures or a reference to appropriate section(s) of the dossier;
- the methods for recording/evaluating results; and
- the proposed timeframe for completion of the protocol.

The manufacture of sterile FPPs needs a well-controlled manufacturing area (e.g. a strictly
controlled environment, highly reliable procedures and appropriate in-process controls). A
detailed description of these conditions, procedures and controls should be provided, together
with actual copies of the following standard operating procedures:

a) washing, treatment, sterilising and depyrogenating of containers, closures and equipment;
b) filtration of solutions;
c) lyophilisation process;


d) leaker test of filled and sealed ampoules;
e) final inspection of the product; and
f) sterilisation cycle.

The sterilisation process used to destroy or remove microorganisms is probably the single most
important process in the manufacture of parenteral FPPs. The process can make use of moist heat
(e.g. steam), dry heat, filtration, gaseous sterilisation (e.g. ethylene oxide), or radiation. It should
be noted that terminal steam sterilisation, when practical, is considered to be the method of
choice to ensure sterility of the final FPP. Therefore, scientific justification for selecting any
other method of sterilisation should be provided.

The sterilisation process should be described in detail and evidence should be provided to
confirm that it will produce a sterile product with a high degree of reliability and that the
physical and chemical properties as well as the safety of the FPP will not be affected. Details
such as Fo range, temperature range and peak dwell time for an FPP and the container closure
should be provided. Although standard autoclaving cycles of 121C for 15 minutes or more
would not need a detailed rationale, such justifications should be provided for reduced
temperature cycles or elevated temperature cycles with shortened exposure times. If ethylene
oxide is used, studies and acceptance criteria should control the levels of residual ethylene oxide
and related compounds.

Filters used should be validated with respect to pore size, compatibility with the product, absence
of extractables and lack of adsorption of the API or any of the components.

For the validation of aseptic filling of parenteral products that cannot be terminally sterilised,
simulation process trials should be conducted. This involves filling ampoules with culture media
under normal conditions, followed by incubation and control of microbial growth. A level of
contamination of less than 0.1% is considered to be acceptable.

Reference documents: ICH Q8, Q9, Q10, WHO Technical Report Series, Nos. 902 and 908

3.2. P.4 Control of excipients (name, dosage form)

3.2. P.4.1 Specifications (name, dosage form)

The specifications for excipients should be provided.

The specifications from the applicant or the FPP manufacturer should be provided for all
excipients, including those that may not be added to every batch (e.g. acid and alkali), those that
do not appear in the final FPP (e.g. solvents) and any others used in the manufacturing process
(e.g. nitrogen, silicon for stoppers).


If the standard claimed for an excipient is an officially recognised compendial standard, it is
sufficient to state that the excipient is tested according to the requirements of that standard, rather
than reproducing the specifications found in the officially recognised compendial monograph.

If the standard claimed for an excipient is a non-compendial standard (e.g. House standard) or
includes tests that are supplementary to those appearing in the officially recognised compendial
monograph, a copy of the specification for the excipient should be provided.
For products submitted for registration, only excipients with an officially recognised
pharmacopeial monograph should be used. Exceptions should be justified.

For excipients of natural origin, microbial limit testing should be included in the specifications.
Skip testing is acceptable if justified (submission of acceptable results of five production
batches).

For oils of plant origin (e.g. soy bean oil, peanut oil) the absence of aflatoxins or biocides should
be demonstrated.

The colours permitted for use are limited to those listed in the Japanese pharmaceutical
excipients
1
, the EU List of permitted food colours
2
, and the FDA Inactive ingredient guide
3
.
For proprietary mixtures, the supplier s product sheet with the qualitative formulation should be
submitted, in addition to the FPP manufacturer s specifications for the product including
identification testing.

For flavours the qualitative composition should be submitted, as well as a declaration that the
excipients comply with foodstuff regulations (e.g. USA or EU).

Information that is considered confidential may be submitted directly to the MCAZ by the
supplier with reference to the specific related product.

Annexure VII contains ingredients which MCAZ has gazetted as undesirable in pharmaceutical
preparations. Any applications containing such ingredients will be rejected.

1
Japanese pharmaceutical excipients. Tokyo, Pharmaceutical and Cosmetics Division,
Pharmaceutical Affairs Bureau, Ministry of Health and Welfare (updated annually or biennially).

2
List of permitted food colors, Official journal of the European Communities, 1994. L237.
(European Commission Directive 94/36/EC).

3
Inactive ingredient guide. Rockville, MD, United States Food and Drug Administration,
Division of Drug Information and Research, 1996.


The use of alcohol in oral pharmaceutical formulation is generally discouraged. The Authority
has set the limits of alcohol content oral pharmaceutical products at NMT 10% for adult
preparations and NMT 5% in paediatric preparations.

Other certifications of at-risk components may be required on a case-by-case basis. If additional
purification is undertaken on commercially available excipients details of the process of
purification and modified specifications should be submitted.


3.2. P.4.2 Analytical procedures (name, dosage form)

The analytical procedures used for testing the excipients should be provided, where
appropriate.

Copies of analytical procedures from officially recognised compendial monographs do not need
to be submitted. Non-compendial analytical procedures used for testing the excipients should be
provided, where appropriate.


3.2. P.4.3 Validation of analytical procedures (name, dosage form)

Analytical validation information, including experimental data, for the analytical procedures
used for testing the excipients should be provided, where appropriate.

Copies of analytical validation information are normally not submitted for the testing of
excipients, with the exception of the validation of in-house methods where appropriate.


3.2. P.4.4 Justification of specifications (name, dosage form)

Justification for the proposed excipient specifications should be provided, where appropriate.

A discussion of the tests that are supplementary to those appearing in the officially recognised
compendial monograph should be provided.

3.2. P.4.5 Excipients of human or animal origin (name, dosage form)

For excipients of human or animal origin, information should be provided regarding adventitious
agents (e.g. sources, specifications, description of the testing performed, and viral safety data)
(details in 3.2.A.2).


The following excipients should be addressed in this section: gelatin, phosphates, stearic acid,
magnesium stearate and other stearates. If from plant origin a declaration to this effect will
suffice.

For these excipients from animal origin, a letter of attestation should be provided confirming that
the excipients used to manufacture the FPP are without risk of transmitting agents of animal
spongiform encephalopathies.

Materials of animal origin should be avoided whenever possible.

A CEP demonstrating TSE-compliance should be provided. A complete copy of the CEP
(including any annexes) should be provided in Module 1.

Reference documents: ICH Q5A, Q5D, Q6B, WHO Technical Report Series, No. 908, Annex 1

3.2. P.4.6 Novel excipients (name, dosage form)

For excipient(s) used for the first time in an FPP or by a new route of administration, full details
of manufacture, characterisation, and controls, with cross references to supporting safety data
(non-clinical and/or clinical) should be provided according to the API and/or FPP format (details
in 3.2.A.3).
Novel excipients are generally not recommended in products submitted for registration unless
adequate justification is provided. For the purpose of this guideline, a novel excipient is one that
has not been used (at a similar level and by the same route of administration) in a product
approved by an SRA or WHO.

3.2. P.5 Control of FPP (name, dosage form)

3.2. P.5.1 Specification(s) (name, dosage form)

The specification(s) for the FPP should be provided.

As defined in ICH s Q6A guideline, a specification is:

a list of tests, references to analytical procedures and appropriate acceptance criteria, which
are numerical limits, ranges, or other criteria for the tests described. It establishes the set of
criteria to which an API or FPP should conform to be considered acceptable for its intended
use. Conformance to specifications means that the API and / or FPP, when tested according
to the listed analytical procedures, will meet the listed acceptance criteria. Specifications are
critical quality standards that are proposed and justified by the manufacturer and approved by
regulatory authorities.

A copy of the FPP specification(s) from the applicant (as well as the company responsible for the
batch release of the FPP, if different from the applicant), dated and signed by authorised


personnel (i.e. the person in charge of the quality control or quality assurance department) should
be provided in the PD. Two separate sets of specifications may be set out: after packaging of the
FPP (release) and at the end of shelf-life.

The specifications should be summarised according to the tables in the QOS-PD template
including the tests, acceptance criteria and analytical procedures (including types, sources and
versions for the methods):

- the standard declared by the applicant could be an officially recognised compendial
standard (e.g. Ph. Int., BP, USP) or a House (manufacturer s) standard;
- the specification reference number and version (e.g. revision number and/or date) should
be provided for version control purposes;
- for the analytical procedures, the type should indicate the kind of analytical procedure
- used (e.g. visual, IR, UV, HPLC), the source refers to the origin of the analytical
procedure (e.g. Ph. Int., Ph. Eur., BP, USP, in-house) and the version (e.g. code
number/version/date) should be provided for version control purposes.

ICH s Q6A guideline outlines recommendations for a number of universal and specific tests and
criteria for FPPs. Specifications should include, at minimum, tests for appearance, identification,
assay, purity, pharmaceutical tests (e.g. dissolution), physical tests (e.g. loss on drying, hardness,
friability, particle size, apparent density), uniformity of dosage units, identification of colouring
materials, identification and assay of antimicrobial or chemical preservatives (e.g. antioxidants)
and microbial limit tests.

The following information provides guidance for specific tests that are not addressed by ICH s
Q6A guideline:

For fixed-dose combination FPPs (FDC-FPPs):
- analytical methods that can distinguish each API in the presence of the other API(s)
should be developed and validated,
- acceptance criteria for degradation products should be established with reference to
the API they are derived from. If an impurity results from a chemical reaction
between two or more APIs, its acceptance limits should be calculated with reference
to the worst case (the API with the smaller area under the curve). Alternatively the
content of such impurities could be calculated in relation to their reference standards,
- when any one API is present at less than 25 mg or less than 25% of the weight of the
dosage unit, a test and limit for content uniformity is required for each API in the
FPP,
- when all APIs are present at greater than 25 mg and greater than 25% of the weight
of the dosage unit, a test and limit for weight variation may be established for each
API in the FPP, in lieu of content uniformity testing;
modified-release products: a meaningful API release method;
- inhalation and nasal products: consistency of delivered dose (throughout the use of
the product), particle or droplet size distribution profiles (comparable to the product


used in in-vivo studies, where applicable) and; if applicable for the dosageform,
moisture content, leak rate, microbial limits, preservative assay, sterility and weight
loss;
suppositories: uniformity of dosage units, melting point; and
transdermal dosage forms: peal or shear force, mean weight per unit area, dissolution.

Unless there is appropriate justification, the acceptable limit for the API content of the FPP in the
release specifications is 5% of the label claim (i.e. 95.0-105.0%).

For products such as tablets, capsules and suppositories where a test for uniformity of single dose
preparations is required, a test and limit for content uniformity is required when the API is
present in the FPP at less than 5 mg or less than 5% of the weight of the dosage unit. Otherwise,
the test for mass uniformity may be applied.

Skip testing is acceptable for parameters such as identification of colouring materials and
microbial limits, when justified by the submission of acceptable supportive results for five
production batches. When skip testing justification has been accepted, the specifications should
include a footnote, stating at minimum the following skip testing requirements: NLT every tenth
batch and at least one batch annually is tested. In addition, for stability-indicating parameters
such as microbial limits, assay and degradants, testing will be performed at release and shelf-life
during stability studies.

Any differences between release and shelf-life tests and acceptance criteria should be clearly
indicated and justified. Note that such differences for parameters such as dissolution are
normally not accepted.

Reference documents: ICH Q3B, Q3C, Q6A

3.2.P.5.2 Analytical procedures (name, dosage form)

The analytical procedures used for testing the FPP should be provided.
Copies of the in-house analytical procedures used during pharmaceutical development (if used to
generate testing results provided in the PD) as well as those proposed for routine testing should
be provided. Unless modified, it is not necessary to provide copies of officially recognised
compendial analytical procedures.

Tables for summarising a number of the different analytical procedures and validation
information (e.g. HPLC assay/impurity methods) can be found in the 2.3.R Regional information
section of the MCAZ QOS (i.e. 2.3.R.2). These tables should be used to summarise the analytical
procedures used for determination of the assay, related substances and dissolution of the FPP.

Refer to section 3.2.S.4.2 of this guideline for additional guidance on analytical procedures.



3.2. P.5.3 Validation of analytical procedures (name, dosage form)

Analytical validation information, including experimental data, for the analytical procedures
used for testing the FPP, should be provided.

Copies of the validation reports for the in-house analytical procedures used during
pharmaceutical development (if used to support testing results provided in the PD) as well as
those proposed for routine testing should be provided.

Tables for summarising a number of the different analytical procedures and validation
Regional information section of the QOS-PD (i.e. 2.3.R.2). These tables should be used to
summarise the validation information of the analytical procedures used for determination of the
assay, related substances and dissolution of the FPP.

As recognised by regulatory authorities and pharmacopoeias themselves, verification of
compendial methods can be necessary. The compendial methods, as published, are typically
validated based on an API or an FPP originating from a specific manufacturer. Different sources
of the same API or FPP can contain impurities and/or degradation products or excipients that
were not considered during the development of the monograph. Therefore the monograph and
compendial method(s) should be demonstrated suitable for the control of the proposed FPP.

For officially recognised compendial FPP assay methods, verification should include a
demonstration of specificity, accuracy and repeatability (method precision). If an officially
recognised compendial method is used to control related substances that are not specified in the
monograph, full validation of the method is expected with respect to those related substances.

If an officially recognised compendial standard is claimed and an in-house method is used in lieu
of the compendial method (e.g. for assay or for related compounds), equivalency of the in-house
and compendial methods should be demonstrated. This could be accomplished by performing
duplicate analyses of one sample by both methods and providing the results from the study. For
related compound methods, the sample analysed should be the FPP spiked with related
compounds at concentrations equivalent to their specification limits.


3.2. P.5.4 Batch analyses (name, dosage form)

A description of batches and results of batch analyses should be provided.

Information should include strength and batch number, batch size, date and site of production
and use (e.g. used in comparative bioavailability or biowaiver studies, stability, pilot, scale-up
and, if available, production-scale batches) on relevant FPP batches used to establish the
specification(s) and evaluate consistency in manufacturing.


Analytical results tested by the company responsible for the batch release of the FPP (generally,
the applicant or the FPP manufacturer, if different from the applicant) should be provided for not
less than two batches of at least pilot scale, or in the case of an uncomplicated FPP
4
(e.g.
immediate-release solid FPPs [with noted exceptions], non-sterile solutions), not less than one
batch of at least pilot scale and a second batch which may be smaller (e.g. for solid oral dosage
forms, 25 000 or 50 000 tablets or capsules) of each proposed strength of the FPP. These batches
should be manufactured by a procedure fully representative of and simulating that to be applied
to a full production-scale batch.

The testing results should include the batch (es) used in the comparative bioavailability or
biowaiver studies. Copies of the certificates of analysis for these batches should be provided in
the PD and the company responsible for generating the testing results should be identified.

reporting comments such as all tests meet specifications . This should include ranges of
analytical results, where relevant. For quantitative tests (e.g. individual and total impurity tests
and assay tests), it should be ensured that actual numerical results are provided rather than vague
statements such as within limits or conforms (e.g. levels of degradation product A ranged
from 0.2 to 0.4 % ). Dissolution results should be expressed at minimum as both the average and
range of individual results. Recommendations for conducting and assessing comparative
dissolution profiles can be found in Appendix 1.

A discussion and justification should be provided for any incomplete analyses (e.g. results not
tested according to the proposed specification).


3.2. P.5.5 Characterization of impurities (name, dosage form)

Information on the characterization of impurities should be provided, if not previously provided
in 3.2.S.3.2 Impurities .

A discussion should be provided of all impurities that are potential degradation products
(including those among the impurities identified in 3.2.S.3.2 as well as potential degradation
products resulting from interaction of the API with other APIs (FDCs), excipients or the
container closure system) and FPP process-related impurities (e.g. residual solvents in the
manufacturing process for the FPP).

4
The term "complicated FPP" includes sterile products, metered dose inhaler products, dry
powder inhaler products and transdermal delivery systems. Other specific products under
"complicated FPP" include ritonavir/lopinavir FDC tablets and FDCs containing rifampicin or an
artemisinin. Due to the rolling nature of the products listed in the invitations for EOI, the listing
of individual "complicated" FPPs is not meaningful and applicants should contact MCAZ in case
of doubt.




3.2. P.5.6 Justification of specification(s) (name, dosage form)

Justification for the proposed FPP specification(s) should be provided.

A discussion should be provided on the omission or inclusion of certain tests, evolution of tests,
analytical procedures and acceptance criteria, differences from the officially recognised
compendial standard(s), etc. If the officially recognised compendial methods have been modified
or replaced, a discussion should be included.

The justification for certain tests, analytical procedures and acceptance criteria (e.g. degradation
products, dissolution method development) may have been discussed in other sections of the PD
and does not need to be repeated here, although a cross-reference to their location should be
provided.

ICH Q6A should be consulted for the development of specifications for FPPs.

3.2. P.6 Reference standards or materials (name, dosage form)

Information on the reference standards or reference materials used for testing of the FPP should
be provided, if not previously provided in 3.2.S.5 Reference standards or materials .

See Section 3.2.S.5 for information that should be provided on reference standards or materials.
Information should be provided on reference materials of FPP degradation products, where not
included in 3.2.S.5.

Reference documents: ICH Q6A, WHO Technical Report Series, No. 943, Annex 3

3.2. P.7 Container closure system (name, dosage form)

A description of the container closure systems should be provided, including the identity of
materials of construction of each primary packaging component and its specification. The
specifications should include description and identification (and critical dimensions, with
drawings where appropriate). Non-compendial methods (with validation) should be included,
where appropriate.

For non-functional secondary packaging components (e.g. those that neither provide additional
protection nor serve to deliver the product), only a brief description should be provided. For
functional secondary packaging components, additional information should be provided.

Suitability information should be located in 3.2.P.2.


The WHO Guidelines on packaging for pharmaceutical products (WHO Technical Report
Series, No. 902, Annex 9, 2002) and the officially recognised pharmacopoeias should be
consulted for recommendations on the packaging information for FPPs.

Descriptions, materials of construction and specifications (of the company responsible for
packaging the FPP, generally the FPP manufacturer) should be provided for the packaging
components that are:

in direct contact with the dosage form (e.g. container, closure, liner, desiccant,
filler);
used for drug delivery (including the device(s) for multi-dose solutions,
emulsions, suspensions and powders/granules for such);
used as a protective barrier to help ensure stability or sterility; and
necessary to ensure FPP quality during storage and shipping.

Primary packaging components are those that are in direct contact with the API or FPP.

The specifications for the primary packaging components should include a specific test for
identification (e.g. IR). Specifications for film and foil materials should include limits for
thickness or area weight.

Information to establish the suitability (e.g. qualification) of the container closure system should
be discussed in Section 3.2.P.2. Comparative studies may be warranted for certain changes in
packaging components (e.g. comparative delivery study (droplet size) for a change in
manufacturer of dropper tips).

3.2. P.8 Stability (name, dosage form)

3.2. P.8.1 Stability summary and conclusions (name, dosage form)

The types of studies conducted, protocols used, and the results of the studies should be
summarised. The summary should include, for example, conclusions with respect to storage
conditions and shelf-life, and, if applicable, in-use storage conditions and shelf-life.

The WHO stability guideline Stability testing of active pharmaceutical ingredients and finished
pharmaceutical products (WHO Technical Report Series, No. 953, Annex 2, 2009) should be
consulted for recommendations on the core stability data package required for the registration of
products.

As outlined in the WHO stability guideline, the purpose of stability testing is to provide evidence
of how the quality of an API or FPP varies with time under the influence of a variety of
environmental factors such as temperature, humidity and light. The stability program also
includes the study of product-related factors that influence its quality, for example, interaction of
API with excipients, container closure systems and packaging materials.



Stress testing
As outlined in the WHO stability guideline, photostability testing should be conducted on at least
one primary batch of the FPP if appropriate. If protect from light is stated in one of the
officially recognised pharmacopoeia for the API or FPP, it is sufficient to state protect from
light on labelling, in lieu of photostability studies, when the container closure system is shown
to be light protective. Additional stress testing of specific types of dosage forms may be
appropriate (e.g. cyclic studies for semi-solid products, freeze-thaw studies for liquid products).

Accelerated, intermediate (if necessary) and long-term testing

Stability data must demonstrate stability of the medicinal product throughout its intended shelf-
life under the climatic conditions for Climatic Zone IV.

The minimum data required at the time of submitting the dossier (in the general case):

Storage temperature
(C)
Relative humidity (%) Minimum time
period (months)

Accelerated 402 755 6
Intermediate * N/A N/A
Long-term 302 655** 12
*Where long-term conditions are 30C2C/75%5%RH, there is no intermediate condition.
** Stability studies conducted at 75% relative humidity are also acceptable

Other storage conditions are outlined in the WHO stability guideline for FPPs packaged in
impermeable and semi-permeable containers and those intended for storage in a refrigerator and
in a freezer. FPPs intended for storage below -20C should be treated on a case-by-case basis.

To establish the shelf-life, data should be provided on not less than two batches of at least pilot
scale, or in the case of an uncomplicated FPP (e.g. immediate-release solid FPPs (with noted
exceptions), non-sterile solutions), not less than one batch of at least pilot scale and a second
batch which may be smaller (e.g. for solid oral dosage forms, 25 000 or 50 000 tablets or
capsules) of each proposed strength of the FPP. These batches should be manufactured by a
procedure fully representative of and simulating that to be applied to a full production-scale
batch.

The stability testing programme should be summarised and the results of stability testing should
be reported in the dossier and summarised using the tables below. Bracketing and matrixing of
proportional strengths can be applied, if scientifically justified.


Table 4: Summary of accelerated and long-term testing parameters (e.g. studies conducted
Storage conditions
(C, % RH)
Strength and
batch number
Batch size Container
closure system
Completed (and
proposed) test
intervals

Table 5: Summary of the accelerated and long term stability results
Test Results
Description
Moisture
Impurities
Assay
etc.

Copies of certificates of analysis at the start of stability studies should be submitted.

For sterile products sterility should be reported at the beginning and end of shelf-life. For
parenteral products, subvisible particulate matter should be reported frequently, but not
necessarily at every test interval. Bacterial endotoxins need only be reported at the initial test
interval. Weight loss from plastic containers should be reported over the shelf-life. In-use periods
for parenteral and ophthalmic products should be justified with experimental data.

The information on the stability studies should include details such as

storage conditions;
strength;
batch number, including the API batch number(s) and manufacturer(s);
batch size;
container closure system including orientation (e.g. erect, inverted, on-side) where
applicable; and
completed (and proposed) test intervals.

reporting comments such as all tests meet specifications . This should include ranges of
analytical results and any trends that were observed. For quantitative tests (e.g. individual and
total degradation product tests and assay tests), it should be ensured that actual numerical results
are provided rather than vague statements such as within limits or conforms . Dissolution
results should be expressed at minimum as both the average and range of individual results.


Applicants should consult ICH s Q1E guideline for details on the evaluation and extrapolation of
results from stability data (e.g. if significant change was not observed within 6 months at
accelerated condition and the data show little or no variability, the proposed shelf-life could be
up to two times the period covered by the long-term data, but should not exceed the long term
data by 12 months).

Proposed storage statement and shelf-life

The proposed storage statement and shelf-life (and in-use storage conditions and in-use period, if
applicable) for the FPP should be provided.

Table 6: Proposed shelf life and storage conditions
Container closure system Storage statement Shelf-life

The recommended labelling statements for use, based on the stability studies, are provided in the
WHO stability guideline.

Reference documents: WHO Technical Report Series, No. 953, Annex 2, ICH Q1A, Q1B, Q1C,
Q1D, Q1E, Q3B, Q6A

3.2. P.8.2 Post-approval stability protocol and stability commitment (name, dosage form)

The post-approval stability protocol and stability commitment should be provided.

Primary stability study commitment

When available long-term stability data on primary batches do not cover the proposed shelf life
granted at the time of assessment of the product dossier, a commitment should be made to
continue the stability studies in order to firmly establish the shelf-life. A written commitment
(signed and dated) to continue long-term testing over the shelf-life period should be included in
the dossier.

Commitment stability studies

The long-term stability studies for the Commitment batches should be conducted through the
proposed shelf-life on at least three production batches of each strength in each container closure
system. Where stability data was not provided for three production batches of each strength, a
written commitment (signed and dated) should be included in the dossier.

Ongoing stability studies


As described in the WHO stability guideline, an ongoing stability programme is established to
monitor the product over its shelf-life and to determine that the product remains and can be
expected to remain within specifications under the storage conditions on the label. Unless
otherwise justified, at least one batch per year of product manufactured for each strength and
every container closure system, if relevant, should be included in the stability programme (unless
none is produced during that year). Bracketing and matrixing may be applicable. A written
commitment (signed and dated) to this effect should be included in the dossier.

Any differences in the stability protocols used for the primary batches and those proposed for the
commitment batches or ongoing batches should be scientifically justified.


3.2. P.8.3 Stability data (name, dosage form)

Results of the stability studies should be presented in an appropriate format (e.g. tabular,
graphical, and narrative). Information on the analytical procedures used to generate the data and
validation of these procedures should be included.
Information on characterisation of impurities is located in 3.2.P.5.5.

The actual stability results/reports used to support the proposed shelf-life should be provided in
the product dossier. For quantitative tests (e.g. individual and total degradation product tests and
assay tests), it should be ensured that actual numerical results are provided rather than vague
statements such as within limits or conforms . Dissolution results should be expressed at
minimum as both the average and range of individual results.

Reference documents: ICH Q1A, Q1B, Q1C, Q1D, Q1E, Q2

3.2. A Appendices

3.2. A.1 Facilities and equipment

Not applicable (i.e. not a biotech product).

3.2. A.2 Adventitious agents safety evaluation

3.2. A.3 Novel excipients

3.2. R Regional information

3.2. R.1 Production documentation


3.2. R.1.1 Executed production documents

A minimum of two batches of at least pilot scale, or in the case of an uncomplicated FPP (e.g.
immediate-release solid FPPs (with noted exceptions), non-sterile solutions), not less than one
batch of at least pilot scale (the batch used in comparative bioavailability or biowaiver studies)
and a second batch which may be smaller (e.g. for solid oral dosage forms, 25 000 or 50 000
tablets or capsules), should be manufactured for each strength. These batches should be
manufactured by a procedure fully representative of and simulating that to be applied to a full
production-scale batch.

For solid oral dosage forms, pilot scale is generally, at a minimum, one-tenth that of full
production scale or 100 000 tablets or capsules, whichever is the larger.

Copies of the executed production documents should be provided for the batches used in the
comparative bioavailability or biowaiver studies. Any notations made by operators on the
executed production documents should be clearly legible.

If not included in the executed batch records through sufficient in-process testing, data should be
provided for the batch used in comparative bioavailability or biowaiver studies that demonstrates
the uniformity of this batch. The data to establish the uniformity of the biobatch should involve
testing to an extent greater than that required in routine quality control.

English translations of executed records should be provided, where relevant.

Alternatively in cases where BMR cannot be submitted i.e. for innovator products, the following
should be submitted:
A formal communication (written correspondence) from the applicant of the innovator
company seeking exemption from submission of batch records giving reasons thereof
A WHO-type Certificate of Pharmaceutical product (CPP) issued by one of the regulatory
authorities of the ICH region or associated countries
A summary of product characteristics (SmPC) approved by the respective regulatory
authority
A copy of the quality assessment report issued by a competent regulatory authority. This
may be send directly from the drug regulatory authority in the country of origin of the
product to the MCAZ
A WHO-type batch certificate from the manufacturer
An undertaking that the packaging of the product is the same as that approved by the drug
regulatory authorities of the ICH region and associated countries
The product information to be the same as on the WHO-type CPP for at least unit and
batch composition, strength and specifications

3.2. R.1.2 Master production documents


Copies of the FPP master production documents should be provided for each proposed strength,
commercial batch size and manufacturing site.

The details in the master production documents should include, but not be limited to, the
following:

a) master formula;
b) dispensing, processing and packaging sections with relevant material and
operational details;
c) relevant calculations (e.g. if the amount of API is adjusted based on the assay
results or on the anhydrous basis);
d) identification of all equipment by, at minimum, type and working capacity
(including make, model and equipment number, where possible);
e) process parameters (e.g. mixing time, mixing speed, milling screen size,
processing temperature range, granulation end-point, tablet machine speed
(expressed as target and range));
f) list of in-process tests (e.g. appearance, pH, assay, blend uniformity, viscosity,
particle size distribution, LOD, weight variation, hardness, disintegration
time, weight gain during coating, leaker test, minimum fill, clarity, filter
integrity checks) and specifications;
g) sampling plan with regard to the:
i. steps where sampling should be done (e.g. drying, lubrication,
compression),
ii. number of samples that should be tested (e.g. for blend uniformity
testing of low dose FPPs, blend drawn using a sampling thief from x
positions in the blender),
iii. frequency of testing (e.g. weight variation every x minutes during
compression or capsule filling);
h) precautions necessary to ensure product quality (e.g. temperature and
humidity control, maximum holding times);
i) for sterile products, reference to SOPs in appropriate sections and a list of all
relevant SOPs at the end of the document;
j) theoretical and actual yield;
k) compliance with the GMP requirements.

Reference documents: WHO Technical Report Series, Nos. 902 and No. 908

3.2. R.2 Analytical procedures and validation information

The tables presented in section 2.3.R.2 in the MCAZ-QOS template should be used to summarise
the analytical procedures and validation information from sections 3.2.S.4.2, 3.2.S.4.3, 2.3.S.4.4
(c), 2.3.S.7.3 (b), 3.2.P.5.2 and 3.2.P.5.3, where relevant.



References to the scientific literature relating to both the API and FPP should be included in this
section of the dossier when appropriate.

MODULE 5 OF A PRODUCT DOSSIER FOR A MULTISOURCE
PHARMACEUTICAL PRODUCT

The majority of product dossiers for multisource products are supported by one or more pivotal
comparative bioavailability studies. When filing a product dossier in the CTD format, it is
anticipated that only the following relevant sections of Module 5 will normally be required.

Module 5: Clinical study reports

5.1 Table of contents for Module 5
5.2 Tabular listing of all clinical studies
5.3 Clinical study reports
5.3.1 Reports of biopharmaceutical studies
5.3.1.2 Comparative bioavailability and bioequivalence study reports
5.3.1.3 In vitro-in vivo correlation study reports
5.3.1.4 Reports of bioanalytical and analytical method for human studies
5.3.7 Case report forms and individual patient listings

For guidance regarding biowaivers, refer to the biowaiver implementation documents available
on the MCAZ website. For guidance regarding comparator products, refer to the information
available under Guidance on Bioequivalence Studies on the MCAZ website.


REFERENCES
1. Guidelines on packaging for pharmaceutical products. In: WHO Expert Committee on
Specifications for Pharmaceutical Preparations. Thirty-sixth report. Geneva, World Health
Organization, 2002, Annex 9 (WHO Technical Report Series, No. 902)

2. Good manufacturing practices for sterile pharmaceutical products. In: WHO Expert Committee
on Specifications for Pharmaceutical Preparations. Thirty-sixth report. Geneva, World Health

3. Good manufacturing practices for pharmaceutical products: main principles. In: WHO Expert
Committee on Specifications for Pharmaceutical Preparations. Thirty-seventh report. Geneva,
World Health Organization, 2003, Annex 4 (WHO Technical Report Series, No. 908)

4. Recommendations on risk of transmitting animal spongiform encephalopathy agents via
medicinal products. In: WHO Expert Committee on Specifications for Pharmaceutical
Preparations. Thirty-seventh report. Geneva, World Health Organization, 2003, Annex 1 (WHO
Technical Report Series, No. 908)

5. Guidelines for registration of fixed-dose combination medicinal products. Appendix 3:
Pharmaceutical development (or preformulation) studies. Table A1: Typical stress conditions in
preformulation stability studies. In: WHO Expert Committee on Specifications for
Pharmaceutical Preparations. Thirty-ninth report. Geneva, World Health Organization, 2005,
Annex 5 (WHO Technical Report Series, No. 929).

6. Multisource (generic) pharmaceutical products: guidelines on registration requirements to
establish interchangeability. In: WHO Expert Committee on Specifications for Pharmaceutical
Preparations. Fortieth report. Geneva, World Health Organization, 2006, Annex 7 (WHO
Technical Report Series, No. 937)

7. General guidelines for the establishment, maintenance and distribution of chemical reference
substances. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations.
Forty-first report. Geneva, World Health Organization, 2007, Annex 3 (WHO Technical Report
Series, No. 943).

8. Guidelines on active pharmaceutical ingredient master file procedure. In: WHO Expert
Committee on Specifications for Pharmaceutical Preparations. Forty-second report. Geneva,
World Health Organization, 2008, Annex 4 (WHO Technical Report Series, No. 948).

9. Stability testing of active pharmaceutical ingredients and finished pharmaceutical products. In:
WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-third report.
Geneva, World Health Organization, 2009, Annex 2 (WHO Technical Report Series, No. 953)


10. Procedure for prequalification of pharmaceutical products. In: WHO Expert Committee on
Specifications for Pharmaceutical Preparations. Forty-third report. Geneva, World Health

11. WHO good distribution practices for pharmaceutical products. In: WHO Expert Committee
on Specifications for Pharmaceutical Preparations. Forty-fourth report. Geneva, World Health


ANNEX I: MC8 FORM

The current MC8 form should be used. A new form based on these guidelines is under
development


ANNEX II: SCREENING CHECKLIST
SECTION
DOCUMENTS Submitted?
Yes No Location
(Page
numbers)
1. ADMINISTRATIVE INFORMATION
1.1 Comprehensive Table of Contents
~Include a complete list of all documents provided
in
the product dossier by module
~The location of each document should be located
by
the module number

1.2 Completed, signed and dated MC8 form
1.3 Introduction
~Quality Information Summary
~Justification for the lack of certain documents and
deviation(s) from guidelines

1.4 Labelling
1.4.1 Copies of Outer carton Labels
1.4.2 Copies of Inner/Blister Labels
1.4.3 Copies of Package Insert (PI)
1.4.4 Copies of Patient Information Leaflet (PIL)


1.5 SmPC for Innovator Product

1.6 GMP certification/proof of GMP compliance for each
FPP manufacturer {inclusive of secondary packer(s)}
from a competent authority

GMP certification/proof of GMP compliance for each
active pharmaceutical ingredient (API) manufacturer

2. COMMON TECHNICAL DOCUMENT
SUMMARIES

2.1
Overall CTD Table of Contents of Modules 2, 3, 4
and 5

2.2 Introduction
2.3 Quality Overall Summary (QOS)
2.4 Non-clinical Overview
2.5 Clinical Overview
2.6 Non-clinical Summary
2.6.1 Introduction
2.6.2 Pharmacology Written Summary
2.6.3 Pharmacology Tabulated Summary
2.6.4 Pharmacokinetics Written Summary
2.6.5 Pharmacokinetics Tabulated Summary
2.6.6 Toxicology Written Summary
2.6.7 Toxicology Tabulated Summary


2.7 Clinical Summary

2.7.1
Summary of Biopharmaceutics and Associated
Analytical Methods

2.7.2 Summary of Clinical Pharmacology Studies
2.7.3 Summary of Clinical Efficacy
2.7.4 Summary of Clinical Safety

2.7.5 Synopses of Individual Studies
3. QUALITY
3.1 Module 3 Table of Contents
3.2 Body of Data
3.2.S ACTIVE PHARMACEUTICAL INGREDIENTS
~If CEP (Certificate of Suitability) is submitted,
waiver of documents for this section can be
granted
except for S4.1, S4.2 & S4.4.
~Please note that information not included in the
CEP
would have to be supported by substantial data
(e.g.
S6 & S7 is required if no retest period and/or
packaging is stated in the CoA).

Certificate of suitability (CEP)
3.2.S.2.1 Manufacturer(s) name and address
3.2.S.2.2 Description of Manufacturing Process and Process
Controls


3.2.S.2.3 Control of Materials *
3.2.S.2.4 Controls of Critical Steps and Intermediates *
3.2.S.2.5 Process Validation and/or Evaluation
~ Must be submitted for sterile APIs and NCEs
*
3.2.S.2.6 Manufacturing Process Development *
*: For applications with DMF, sections S2.3, S2.4, S2.5 and
S2.6
are included in the closed part of DMF

3.2.S.3 CHARACTERISATION
3.2.S.3.1 Elucidation of Structure and other Characteristics
3.2.S.3.2 Impurities
3.2.S.4 CONTROL OF API
3.2.S.4.1 Specifications of API
3.2.S.4.2 Analytical Procedures
3.2.S.4.3 Validation of Analytical Procedures
*: Can be waived for methods that reference
compendial methods
*
3.2.S.4.4 Batch Analyses for three batches
3.2.S.4.5 Justification of Specification
*: Justification is not required if compendial
requirements are met
*
3.2.S.5 REFERENCE STANDARDS
3.2.S.6 CONTAINER CLOSURE SYSTEM
Specifications


Test Methods
3.2.S.7 STABILITY
3.2.S.7.1
Stability Summary and Conclusions
3.2.S.7.2
Post-approval Stability Protocol and Stability
Commitment

3.2.S.7.3
Stability Data
~ At point of submission, at least 12 months of real
time data and 6 months of accelerated data on at
least 3 primary batches of the API should be
provided

Forced Degradation studies
Accelerated Stability Studies
Real-Time Stability Studies
NOTE: S6 & S7 would have to be submitted if the
retest period is not stated in the CEP

3.2.P FINISHED PHARMACEUTICAL PRODUCT (FPP)
3.2.P.1 Description and Composition of the FPP
3.2.P.2 Pharmaceutical Development
3.2.P.3 Manufacture
3.1 Manufactuer(s) name(s) and physical address(es)
3.2 Batch Formula
~For multiple batch sizes, batch formula for each
batch sizes are to be provided

3.3 Description of manufacturing process and process
controls


3.4 Control of critical steps and intermediates
3.5 Process validation
~For three consecutive batches

3.2.P.4 Control of Excipients
4.1 Specifications
4.2 Analytical Procedures
4.3 Validation of Analytical Procedures
4.4 Justification of Specifications

4.5
Excipients of Human or Animal Origin
*: BSE / TSE free certification
*
4.6 Novel excipients
*: Provide information provided as per full API
Section
*
3.2.P.5 Control of FPP

5.1
Specification(s) of Finished Pharmaceutical Product
(FPP)

5.2 Analytical Procedures
5.3 Validation of Analytical Procedures
5.4 Batch Analyses for two batches
5.5 Characterisation of Impurities
5.6 Justification of Specification(s)
3.2.P.6 Reference Standards
3.2.P.7 Container- Closure System
Test Methods


Specifications
3.2.P.8 Stability
8.1 Stability Summary and Conclusions

8.2
Post-approval Stability Protocol and Stability
Commitment
*

8.3
Stability Data
~accelerated for 6 months for two batches
~real time for at least 6 months for two batches
*: (at time of approval at least 12 months real time
stability data should have been provided)

Photostability Data
Accelerated Stability Data
Real-time Stability Data
3.2.R REGIONAL INFORMATION/ REQUIREMENTS
3.2.R.1 Production documentation
Executed production documents
Master production documents
*

3.2.R.2 Analytical procedures and validation information *
3.3 LITERATURE REFERENCES *
4 NON-CLINICAL STUDY REPORTS
4.1 Table of Contents
4.2 Study Reports
4.2.1 Pharmacology



4.2.2 Pharmacokinetics
4.2.3 Toxicology
4.3 List of Literature References
5 CLINICAL STUDY REPORTS
5.1 Module 5 Table of Contents
5.2 Tabular Listing
5.3 Clinical Study Reports
5.3.1 Reports of Biopharmaceutical Studies

5.3.2
Reports of Studies Pertinent to Pharmacokinetics using
Human Biomaterials

5.3.3 Reports of Pharmacokinetic (PK) Studies
5.3.4 Reports of Pharmacodynamic (PD) Studies
5.3.5 Reports of Efficacy and Safety Studies
~ Study reports of ALL clinical trials, including the
appendices & tables
~ Study reports of pivotal or relevant clinical trials

5.3.6 Reports of Post-marketing Experience
5.3.7 Case Report Forms and Individual Patient Listings
5.4 List of Key Literature References

5.5 Other Supporting Documents


ANNEX III: SMPC/ Package Insert

Structure of the package insert
(with proposed sentence patterns and illustrative examples)

1. NAME OF THE FINISHED PHARMACEUTICAL PRODUCT

{(Trade/Invented) name of product <strength><pharmaceutical form>}

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

For excipients, see 6.1.

3. PHARMACEUTICAL FORM

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

<xxx is indicated for use in uncomplicated malaria. >

4.2 Posology and method of administration

Adults (for example)
Children and adolescents (4 to 17 years of age) (for example)
General administration recommendations (for example)
Special dosing considerations in adults (for example)

4.3 Contraindications

<Hypersensitivity to the API(s) or to any of the excipients <or {residues }>.

4.4 Special warnings and special precautions for use

Drug interactions (for example)
Acute haemolytic anaemia (for example)
Hyperglycaemia (for example)
Patients with coexisting conditions (for example)
Other

4.5 Interaction with other FPPs and other forms of interaction

Rifabutin (for example)
Ketoconazole (for example)
Itraconazole (for example)
Nevirapine (for example)
HMG -CoA reductase inhibitors (for example)
Rifampicin (for example)
Other


4.6 Pregnancy and lactation

Use during pregnancy (for example)
Use during lactation (for example)

4.7 Effects on ability to drive and use machines

<{INN name} has <no or negligible influence><minor or moderate influence><major
influence>on the ability to drive and use machines.>[describe effects where applicable]
<No studies on the effects on the ability to drive and use machines have been performed.>
<Not relevant.>

4.8 Undesirable effects

Laboratory test findings (for example)
Post-marketing experience (for example)

4.9 Overdose

<No case of overdose has been reported.>

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacological Classification: {see SI 150 of 1991}
Mechanism of action
Microbiology (when applicable)
Drug resistance (when applicable)
Cross resistance (when applicable)

Pharmacodynamic effects

Adults
Paediatric patients

5.2 Pharmacokinetic properties

Absorption
Distribution
Biotransformation
Elimination
Characteristics in patients

5.3 Preclinical safety data

<Preclinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to
reproduction.><Preclinical effects were observed only at exposures considered sufficiently in
excess of the maximum human exposure indicating little relevance to clinical use.>



<Adverse reactions not observed in clinical studies, but seen in animals at exposure
levels similar to clinical exposure levels and with possible relevance to clinical use
were as follows.>

Mutagenicity
Carcinogenicity
Developmental Toxicity

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule content (for example)
Capsule shell (for example)
Printing ink (for example)

6.2 Incompatibilities

<Not applicable.>
<In the absence of compatibility studies, this pharmaceutical product must not be mixed with
other pharmaceutical products.>
<This pharmaceutical product must not be mixed with other pharmaceutical products except
those mentioned in 6.6.>

6.3 Shelf life

<... ><6 months><... ><1 year><18 months><2 years><30 months><3 years><... >

6.4 Special precautions for storage

<Do not store above <25C>30C
<Store at 2C - 8C (in a refrigerator <Store in a freezer>
<Do not <refrigerate><or><freeze
<Store in the original <package><container <Keep the container tightly closed>
<Keep the container in the outer carton>
<No special precautions for storage>
<in order to protect from <light><moisture

6.5 Nature and contents of container

<Not all pack sizes may be marketed.>

6.6 Instructions for use and handling <and disposal>

<No special requirements.>

<Any unused product or waste material should be disposed of in accordance with local
requirements.>


7.1 NAME AND ADDRESS OF MANUFACTURER

7.2 NAME AND ADDRESS OF PRINCIPAL

8. REGISTRATION NUMBER

9. CATEGORY FOR DISTRIBUTION

10. DATE OF PUBLICATION OF THIS PACKAGE INSERT


ANNEX IV: QUANTITIES OF SAMPLES REQUIRED FOR
LABORATORY ANALYSIS

The following is the minimum sample size required for analysis. However as a guiding principle
the applicant should provide adequate sample for a full spectrum of analysis based on the
proposed finished product specifications and repeat if required.

Nature of Product Pack Size Number of Containers
Tablets and Capsules 24
30
60
90
100
120
500
1000
4
3
2
1
1
1
1
1
Oral Suspensions 60 ml
100 ml
240 ml
5
5
4
Powders for Oral Suspensions Market pack size 5
Sterile Solutions or Infusions
e.g Sodium Chloride 0.9%w/v
Intravenous Infusion
500 ml or less
1000 ml
3
3
Sterile Powders for Injections
e.g. Penicillin G Sodium
powder for injection
Powder in 2 ml vials
50
50
30
Injections 1 ml
2 ml
3 ml
5 ml
10 ml
100
50
30
20
15
Creams and Ointments 15 g
25 g
30 g
100 g
10
5
4
3

NB: Samples MUST be submitted in their original containers intended for marketing.
APPLICANTS please note:
1. Ensure that you have attached Copy of the certificate of analysis CoA.
2. Ensure that you have attached Finished Product Specifications & Method of Analysis
3. Ensure that you have provided all Chemical Reference Standards, Decomposition
products and Related substances required for a full monograph analysis when
submitting Registration samples.


ANNEX V: PRODUCT QUALITY REVIEW REQUIREMENTS FOR
ESTABLISHED GENERIC PRODUCTS

For an established generic product, a product quality review may satisfy the requirements of
Sections 3.2.P.2.2.1 (Formulation Development), 3.2.P.2.3 (Manufacturing Process
Development) and 3.2.P.3.5 (Process Validation and/or Evaluation) of the PD and QOS-PD.

A product quality review should be submitted with the objective of verifying the consistency of
the quality of the FPP and its manufacturing process. Rejected batches should not be included in
the analysis but must be reported separately together with the reports of failure investigations, as
indicated below. Reviews should be conducted with not less than 10 consecutive batches
manufactured over the period of the last 12 months, or, where 10 batches were not manufactured
in the last 12 months, not less than 25 consecutive batches manufactured over the period of the
last 36 months and should include at least:

1. A review of starting and primary packaging materials used in the FPP, especially those
from new sources.
2. A tabulated review and statistical analysis of quality control and in-process control
results.
3. A review of all batches that failed to meet established specification(s).
4. A review of all critical deviations or non-conformances and related investigations.
5. A review of all changes carried out to the processes or analytical methods.
6. A review of the results of the stability-monitoring programme.
7. A review of all quality-related returns, complaints and recalls, including export- only
medicinal products.
8. A review of the adequacy of previous corrective actions.
9. A list of validated analytical and manufacturing procedures and their revalidation dates.

Notes
Reviews must include data from all batches manufactured during the review period. Data should
be presented in tabular or graphical form (i.e. charts or graphs), when applicable.
The above is specific to the dossier assessment process requirements and does not relieve the
applicant of related GMP requirements.


ANNEX VI - RECOMMENDATIONS FOR CONDUCTING AND
ASSESSING COMPARATIVE DISSOLUTION PROFILES

The dissolution measurements of the two FPPs (e.g. test and reference (comparator), or two
different strengths) should be made under the same test conditions. A minimum of three time
points (zero excluded) should be included, the time points for both reference (comparator) and
test product being the same. The sampling intervals should be short for a scientifically sound
comparison of the profiles (e.g. 5, 10, 15, 20, 30, 45 (60, 90, 120) minutes). Inclusion of the 15
minute time point in the schedule is of strategic importance for profile similarity determinations
(very rapidly dissolving scenario). For extended-release FPPs, the time points should be set to
cover the entire time period of expected release, e.g. 1, 2, 3, 5 and 8 hours for a 12-hour release
and additional test intervals for longer duration of release.

Studies should be performed in at least three (3) media covering the physiological range,
including pH 1.2 hydrochloric acid, pH 4.5 buffer and pH 6.8 buffer. Compendia buffers are
recommended. The Authority recognises the International Pharmacopeia, British Pharmacopeia,
United Stated Pharmacopeia, and the European Pharmacopeia. Water may be considered as an
additional medium, especially when the API is unstable in the buffered media to the extent that
the data is unusable.
If both the test and reference (comparator) products show more than 85% dissolution in 15
minutes, the profiles are considered similar (no calculations required). Otherwise:
Similarity of the resulting comparative dissolution profiles should be calculated using the
following equation that defines a similarity factor (f2):

where Rt and Tt are the mean percent API dissolved in reference (comparator) and test
product, respectively, at each time point. An f2 value between 50 and 100 suggests the
two dissolution profiles are similar;

a maximum of one time-point should be considered after 85% dissolution of the reference
(comparator) product has been reached. In the case where 85% dissolution cannot be
reached due to poor solubility of the API, the dissolution should be conducted until an
asymptote (plateau) has been reached;

at least 12 units should be used for each profile determination. Mean dissolution values can be
used to estimate the similarity factor, f2. To use mean data, the % coefficient of variation at the
first time point should be not more than 20% and at other time points should not be more than
10%;

when delayed-release products (e.g. enteric coated) are being compared, the
recommended conditions are acid medium (pH 1.2) for 2 hours and buffer pH 6.8
medium;



when comparing extended-release beaded capsules, where different strengths have been
achieved solely by means of adjusting the number of beads containing the API, one
condition (normally the release condition) will suffice; and

surfactants should be avoided in comparative dissolution testing. A statement that the
API is not soluble in any of the media is not sufficient and profiles in absence of
surfactants should be provided. The rationale for the choice and concentration of
surfactant should be provided. The concentration of the surfactant should be such that the
discriminatory power of the test will not be compromised.


ANNEX VII: INGREDIENTS GAZETTED AS UNDESIRABLE IN
PHARMACEUTICAL PREPARATIONS BY THE MCAZ

CURRENT LIST

Astemizole
Benoxaprofen
Chlormezanone
Clioquinol (in medicines for oral administration)
Dipyrone
Lead and lead salts
Nimesulide
Oxyphenbutazone
Phenacetin
Phenformin
Phenolphthalein
Ponceau 4r
Practolol
Rofecoxib
Zomiperac
Chloroform (in liquid oral medicines or preparations)
Tartrazine (in medicines intended for oral use).
Chlorofluorocarbons (CFC )/halocarbons as propellants in aerosol inhalation products

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MCAZ Registration Guidelines Published August 2012 Page 1 of 98

Medicines Control Authority of Zimbabwe

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