April 2015 Botswana Medicines

Guidance Regulatory Authority

MODULE 2.3
QUALITY OVERALL SUMMARY – PRODUCT DOSSIER (QOS –PD)

INTRODUCTION
The introduction should include proprietary name, non-proprietary name or common
name of the drug substance, company name, dosage form(s), strength(s), route of
administration, and proposed indication(s).

a) Summary of product information:

Non-proprietary name of the finished

pharmaceutical product (FPP)
Proprietary name of the finished
pharmaceutical product (FPP)
International non-proprietary name(s) of
the active pharmaceutical ingredient(s)
(API(s)), including form (salt, hydrate,
polymorph)
Applicant name and address
Dosage form
Application Number(s)
Strength(s)
Route of administration
Proposed indication(s)
Contact information Name:
Phone:
Fax:
Email:

b) Other Introductory information:

Related dossiers (e.g. FPP(s) with the same API(s) submitted to the MRA by the
applicant):

Registration Registered API, strength, dosage API manufacturer

Number (e.g. (Y/N) form (Including address)
BOT14000XX) (e.g. Abacavir (as
sulphate) 300 mg
tablets)

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Identify available literature references for the API and FPP:

Most recent
Most recent
edition/volume
Publication(s) edition/volume
in which API/FPP
consulted
appears
API status in pharmacopoeia and forum:
Ph.Int.
<e.g. monograph under
Ph.Int. monographdevelopment
development or
(through www.who.int)
draft/final published>
USP
PharmacopeialForum
Ph.Eur.
Pharmeuropa
BP
Other (e.g. JP)
FPP status in pharmacopoeia and forum:
Ph.Int.
<e.g. monograph under
Ph.Intmonographdevelopment
development or
(through www.who.int)
draft/final published>
USP
PharmacopeialForum
BP
Other (e.g. JP)
Other reference texts (e.g. public access reports):

SUMMARY OF QUALITY ASSESSMENT OF LABELLING AND SAMPLES

(MRA Use Only)
Discussion/comments on the quality components of:
Summary of product characteristics
<insert assessment observations, comments, etc.>
Labelling (outer and inner labels)
<insert assessment observations, comments, etc.>

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Package leaflet (patient information leaflet)
<insert assessment observations, comments, etc.>
Samples (e.g. FPP, device)
<insert assessment observations, comments, etc.>

2.3.S DRUG SUBSTANCE (NAME, MANUFACTURER)

Complete the following table for the option that applies for the submission of API
information:

Name of API:
Name of API
manufacturer:
□ Confirmation of API Prequalification document
□ Certificate of suitability to the European Pharmacopoeia (CEP)
□ Full details in the PD

2.3.S.1 General Information (name, manufacturer)

Information from 3.2.S.1 should be included.

2.3.S.1.1 Nomenclature (name, manufacturer)

a) (Recommended) International Non-proprietary name (INN):

b) Compendial name, if relevant:

c) Chemical name(s):

d) Company or laboratory code:

e) Other non-proprietary name(s) (e.g. national name, USAN, BAN):

f) Chemical Abstracts Service (CAS) registry number:

2.3.S.1.2 Structure (name, manufacturer)

a) Structural formula, including relative and absolute stereochemistry:

b) Molecular formula:
c) Relative molecular mass:

2.3.S.1.3 General Properties (name, manufacturer)

a) Physical description (e.g. appearance, colour, physical state):

b) Solubilities:

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In common solvents:

Quantitative aqueous pH solubility profile (pH 1 to 6.8):

Medium (e.g. pH 4.5 buffer) Solubility (mg/ml)

Dose/solubility volume calculation:

c) Physical form (e.g. polymorphic form(s), solvate, hydrate):

Polymorphic form:

Solvate:

Hydrate:

d) Other:

Property
pH
pKa
Partition coefficients
Melting/boiling points
Specific optical rotation
(specify solvent)
Refractive index (liquids)
Hygroscopicity
UV absorptionmaxima/molar
absorptivity
Other

2.3.S.2 Manufacture (name, manufacturer)

Information from 3.2.S.2 should be included:
 Information on the manufacturer;

a) Name, address and responsibility (e.g. fabrication, packaging, labelling,

testing, storage) of each manufacturer, including contractors and each
proposed production site or facility involved in these activities:

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Name and address Responsibility CEP number (if
(includingblock(s)/unit(s)) applicable)

b) Manufacturing authorization for the production of API(s) and, where

available, certificate of GMP compliance (GMP information should be
provided in Module 1):

 A brief description of the manufacturing process (including, for example,

reference to starting materials, critical steps, and reprocessing) and the controls
that are intended to result in the routine and consistent production of material(s)
of appropriate quality;
 A flow diagram, as provided in 3.2.S.2.2;

2.3.S.2.2 Description of Manufacturing Process and Process Controls (name,

manufacturer)

(a) Flow diagram of the synthesis process(es):

(b) Brief narrative description of the manufacturing process(es):

(c) Alternate processes and explanation of their use:

(d) Reprocessing steps and justification:

 A description of the Source and Starting Material and raw materials of

biologicalorigin used in the manufacture of the drug substance, as described in
3.2.S.2.3;

2.3.S.2.3 Control of Materials (name, manufacturer) – Option 3 only

(a) Summary of the quality and controls of the starting materials used in
the manufacture of the API:

Step/starting material Test(s)/method(s) Acceptance criteria

(b) Name and manufacturing site address of starting material

manufacturer(s):

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(c) Where the API(s) and the starting materials and reagents used to
manufacture the API(s) are without risk of transmitting agents of
animal spongiform encephalopathies, a letter of attestation confirming
this can be found in:

 A discussion of the selection and justification of critical manufacturing steps,

process controls, and acceptance criteria. Highlight critical process intermediates,
as described in 3.2.S.2.4;

2.3.S.2.4 Controls of Critical Steps and Intermediates (name, manufacturer)

(a) Summary of the controls performed at critical steps of the

manufacturing process and on intermediates:

Step/materials Test(s)/method(s) Acceptance criteria

 A description of process validation and/or evaluation, as described in 3.2.S.2.5.

2.3.S.2.5 Process Validation and/or Evaluation (name, manufacturer)

(a) Description of process validation and/or evaluation studies (e.g. for

aseptic processing and sterilization):

 A brief summary of major manufacturing changes made throughout development

and conclusions from the assessment used to evaluate product consistency, as
described in 3.2.S.2.6. The QOS should also cross-refer to the non-clinical and
clinical studies that used batches affected by these manufacturing changes, as
provided in the CTD-S and CTD-E modules of the dossier.

2.3.S.2.6 Manufacturing Process Development (name, manufacturer)

(a) Description and discussion of the significant changes made to the

manufacturing process and/or manufacturing site of the API used in
producing comparative bioavailability or biowaiver, stability, scale-
up, pilot and, if available, production scale batches:

2.3.S.3 Characterisation (name, manufacturer)

For NCE: A summary of the interpretation of evidence of structure and isomerism, as

described in 3.2.S.3.1, should be included.

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When a drug substance is chiral, it should be specified whether specific stereoisomers or
a mixture of stereoisomers have been used in the nonclinical and clinical studies, and
information should be given as to the stereoisomer of the drug substance that is to be used
in the final product intended for marketing.

For Biotech: A description of the desired product and product-related substances and a
summary of general properties, characteristic features and characterisation data (for
example, primary and higher order structure and biological activity), as described in
3.2.S.3.1, should be included.

For NCE and Biotech: The QOS should summarise the data on potential and actual
impurities arising from the synthesis, manufacture and/or degradation, and should
summarise the basis for setting the acceptance criteria for individual and total impurities.
The QOS should also summarise the impurity levels in batches of the drug substance
used in the non-clinical studies, in the clinical trials, and in typical batches manufactured
by the proposed commercial process. The QOS should state how the proposed impurity
limits are qualified. A tabulated summary of the data provided in 3.2.S.3.2, with
graphical representation, where appropriate should be included.

2.3.S.3 Characterisation (name, manufacturer)

2.3.S.3.1 Elucidation of Structure and other Characteristics (name, manufacturer)

(a) List of studies performed (e.g. IR, UV, NMR, MS, elemental analysis)
and conclusion from the studies (e.g. whether results support the
proposed structure):

(b) Discussion on the potential for isomerism and identification of

stereochemistry (e.g. geometric isomerism, number of chiral centres
and configurations) of the API batch(es) used in comparative
bioavailability or biowaiver studies:

(c) Summary of studies performed to identify potential polymorphic

forms (including solvates):

(d) Summary of studies performed to identify the particle size

distribution of the API:

(e) Other characteristics:

2.3.S.3.2 Impurities (name, manufacturer)

(a) Identification of potential and actual impurities arising from the

synthesis, manufacture and/or degradation:

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(i) List of API-related impurities (e.g. starting materials, by-
products, intermediates, chiral impurities, degradation
products), including chemical name, structure and origin:

API-related impurity Structure Origin

(chemical name or
descriptor)

(ii) List of process-related impurities (e.g. residual solvents,

reagents), including compound names and step used in
synthesis:

Process-related impurity (compound Step used in synthesis

name)

(b) Basis for setting the acceptance criteria for impurities:

(i) Maximum daily dose (i.e. the amount of API administered per
day) for the API, corresponding to ICH
Reporting/Identification/Qualification Thresholds for the API-
related impurities and the concentration limits (ppm) for the
process-related impurities (e.g. residual solvents):

Maximum daily dose for the API: <x mg/day>

Test Parameter ICH threshold or
concentration limit
API-related impurities Reporting Threshold
Identification
Threshold
Qualification

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Maximum daily dose for the API: <x mg/day>
Test Parameter ICH threshold or
concentration limit
Threshold
Process-related impurities <solvent 1>
<solvent 2>, etc.

(ii) Data on observed impurities for relevant batches (e.g.

comparative bioavailability or biowaiver, stability batches):

Impurity Acceptance Results (include batch number* and use**)

(API-related and Criteria
process-related)

* include strength, if reporting impurity levels found in the FPP (e.g. for
comparative studies)
** e.g. comparative bioavailability or biowaiver studies, stability

(iii) Justification of proposed acceptance criteria for impurities:

2.3.S.4 Control of Drug Substance (name, manufacturer)

A brief summary of the justification of the specification(s), the analytical procedures, and
validation should be included. Specification from 3.2.S.4.1 should be provided. A
tabulated summary of the batch analyses from 3.2.S.4.4, with graphical representation
where appropriate, should be provided.

2.3.S.4 Control of the API (name, manufacturer)

2.3.S.4.1 Specification (name, manufacturer)

(a) API specifications of the FPP manufacturer:

Standard (e.g. Ph.Int.,Ph.Eur., BP, USP, House)

Specification reference number and version
Test Acceptance criteria Analytical procedure
(Type/Source/Version)
Description

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Standard (e.g. Ph.Int.,Ph.Eur., BP, USP, House)
Specification reference number and version
Test Acceptance criteria Analytical procedure
(Type/Source/Version)
Identification
Impurities
Assay
etc.

2.3.S.4.2 Analytical Procedures (name, manufacturer)

(a) Summary of the analytical procedures (e.g. key method parameters,

conditions, system suitability testing):

See 2.3.R Regional Information for summaries of the analytical

procedures and validation information (i.e. 2.3.R.2 Analytical Procedures
and Validation Information).

2.3.S.4.3 Validation of Analytical Procedures (name, manufacturer)

(a) Summary of the validation information (e.g. validation parameters

and results):

See 2.3.R Regional Information for summaries of the analytical

procedures and validation information (i.e. 2.3.R.2 Analytical Procedures
and Validation Information).

2.3.S.4.4 Batch Analyses (name, manufacturer)

(a) Description of the batches:

Batch number Batch size Date and Use (e.g. comparative

site of production bioavailability or
biowaiver, stability)

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(b) Summary of batch analyses release results of the FPP manufacturer
for relevant batches (e.g. comparative bioavailability or biowaiver,
stability):

Test Acceptance Results

Criteria <batch x> <batch y> etc.
Description
Identification
Impurities
Assay
etc.

(c) Summary of analytical procedures and validation information for

those procedures not previously summarized in 2.3.S.4.2 and 2.3.S.4.3
(e.g. historical analytical procedures):

2.3.S.4.5 Justification of Specification (name, manufacturer)

(a) Justification of the API specification (e.g. evolution of tests, analytical

procedures and acceptance criteria, differences from officially
recognized compendial standard(s)):

2.3.S.5 Reference Standards or Materials (name, manufacturer)

Information from 3.2.S.5 (tabulated presentation, where appropriate) should be included.

2.3.S.5 Reference Standards or Materials (name, manufacturer)

(a) Source (including lot number) of primary reference standards or

reference materials (e.g. Ph.Int.,Ph.Eur., BP, USP, in-house):

(b) Characterization and evaluation of non-official (e.g. not from an

officially recognized pharmacopoeia) primary reference standards or
reference materials (e.g. elucidation of structure, certificate of
analysis):

(b) Description of the process controls of the secondary reference

standard (comparative certificate of analysis and IR spectra against
primary standard) :

2.3.S.6 Container Closure System (name, manufacturer)

A brief description and discussion of the information, from 3.2.S.6 should be included.

2.3.S.6 Container Closure System (name, manufacturer)

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(a) Description of the container closure system(s) for the shipment and
storage of the API (including the identity of materials of construction
of each primary packaging component and a brief summary of the
specifications):

Packaging Materials of Specifications (list parameters e.g.

component construction identification (IR))

(b) Other information on the container closure system(s) (e.g. suitability

studies):

2.3.S.7 Stability (name, manufacturer)

This section should include a summary of the studies undertaken (conditions, batches,
analytical procedures) and a brief discussion of the results and conclusions, the proposed
storage conditions, retest date or shelf-life, where relevant, as described in 3.2.S.7.1.
The post-approval stability protocol, as described in 3.2.S.7.2, should be included.
A tabulated summary of the stability results from 3.2.S.7.3, with graphical representation
where appropriate, should be provided.

2.3.S.7 Stability (name, manufacturer)

2.3.S.7.1 Stability Summary and Conclusions (name, manufacturer)

(a) Summary of stress testing (e.g. heat, humidity, oxidation, photolysis,

acid/base): and results:

Stress condition Treatment Results (e.g. including discussion whether

mass balance is observed)
Heat
Humidity
Oxidation
Photolysis
Acid
Base
Other

(b) Summary of accelerated and long-term testing parameters (e.g.

studies conducted):

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Storage Batch Batch Container Completed (and
condition number size closure system proposed) testing
(◦C, % RH) intervals

Summary of the stability results observed for the above accelerated

and long-term studies:

Test Results
Description
Moisture
Impurities
Assay
etc.

(c) Proposed storage statement and re-test period (or shelf-life, as

appropriate):

Container closure system Storage statement Re-test period*

* indicate if a shelf-life is proposed in lieu of a re-test period (e.g. in the case of

labile APIs)

2.3.S.7.2 Post-approval Stability Protocol and Stability Commitment (name,

manufacturer)

(a) Stability protocol for Primary stability batches (e.g. storage conditions
(including tolerances), batch numbers and batch sizes, tests and
acceptance criteria, testing frequency, container closure system(s)):

Parameter Details
Storage condition(s) (◦C, % RH)
Batch number(s) / batch size(s)
Tests and acceptance criteria Description
Moisture
Impurities
Assay
etc.

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Parameter Details
Testing frequency
Container closure system(s)

(b) Stability protocol for Commitment batches (e.g. storage conditions

(including tolerances), batch numbers (if known) and batch sizes, tests
and acceptance criteria, testing frequency, container closure
system(s)):

Parameter Details
Storage condition(s) (◦C, % RH)
Batch number(s) / batch size(s) <not less than three production batches>
Tests and acceptance criteria Description
Moisture
Impurities
Assay
etc.

Testing frequency
Container closure system(s)

(c) Stability protocol for Ongoing batches (e.g. storage conditions

(including tolerances), batch sizes and annual allocation, tests and
acceptance criteria, testing frequency, container closure system(s)):

Parameter Details
Storage condition(s) (◦C, % RH)
Annual allocation <at least one production batch per year (unless none
is produced that year)in each container closure
system >
Tests and acceptance criteria Description
Moisture
Impurities
Assay
etc.

Testing frequency
Container closure system(s)

2.3.S.7.3 Stability Data (name, manufacturer)

(a) The actual stability results should be provided in Module 3.

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(b) Summary of analytical procedures and validation information for

those procedures not previously summarized in 2.3.S.4 (e.g. analytical
procedures used only for stability studies):

2.3.P DRUG PRODUCT (NAME, DOSAGE FORM)

2.3.P.1 Description and Composition of the Drug Product (name, dosage form)
Information from 3.2.P.1 should be provided. Composition from 3.2.P.1 should be
provided.

2.3.P.1 Description and Composition of the FPP

(a) Description of the FPP:

(b) Composition of the FPP:

(i) Composition, i.e. list of all components of the FPP and their
amounts on a per unit basis and percentage basis (including
individual components of mixtures prepared in-house (e.g.
coatings) and overages, if any):

Component and Function Strength (label claim)

quality standard
(and grade, if
applicable) Quant. % Quant. % Quantit %
per per y per
unit unit unit
<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

(ii) Composition of all components purchased as mixtures (e.g.

colourants, coatings, capsule shells, imprinting inks):

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(c) Description of accompanying reconstitution diluent(s), if applicable:

(d) Type of container closure system used for the FPP and accompanying
reconstitution diluent, if applicable:

2.3.P.2 Pharmaceutical Development (name, dosage form)

A discussion of the information and data from 3.2.P.2 should be presented.
A tabulated summary of the composition of the formulations used in clinical trials and a
presentation of dissolution profiles should be provided, where relevant.

2.3.P.2 Pharmaceutical Development

2.3.P.2.1 Components of the FPP

2.3.P.2.1.1 Active Pharmaceutical Ingredient

(a) Discussion of the:

(i) compatibility of the API(s) with excipients listed in

2.3.P.1:

(ii) key physicochemical characteristics (e.g. water content,

solubility, particle size distribution, polymorphic or
solid state form) of the API(s) that can influence the
performance of the FPP:

(iii) for fixed-dose combinations, compatibility of APIs with

each other:

2.3.P.2.1.2 Excipients

(a) Discussion of the choice of excipients listed in 2.3.P.1 (e.g. their

concentrations, their characteristics that can influence the FPP
performance):

2.3.P.2.2 Finished Pharmaceutical Product

2.3.P.2.2.1 Formulation Development

(a) Summary describing the development of the FPP (e.g. route of

administration, usage, optimization of the formulation, etc.):

(b) Information on primary (submission, registration, exhibit)

batches including comparative bioavailability or biowaiver,
stability, commercial:

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(i) Summary of batch numbers:

Batch number(s) of the FPPs used in

Bioequivalence or biowaiver
Dissolution profile studies
Stability studies (primary batches)
‹packaging configuration I›
‹ packaging configuration II›
‹Add/delete as many rows as necessary›
Stability studies (production batches)
‹ packaging configuration I›
‹ packaging configuration II›
(Add/delete as many rows as necessary)
Validation studies (primary batches) if available
‹ packaging configuration I›
‹ packaging configuration II›
(Add/delete as many rows as necessary)
Validation studies (at least the first three
consecutive production batches)
or code(s)/version(s) for process validation
protocol(s)

(ii) Summary of formulations and discussion of any

differences:

Component and Relevant batches

quality Comparative Stability Process Commercial
standard (e.g. bioavailability or validation (2.3.P.1)
NF, BP, biowaiver
Ph.Eur, in-
house) <Batch nos. and <Batch nos. and <Batch nos. and <Batch nos. and
sizes> sizes> sizes> sizes>
Theor. % Theor. % Theor. % Theor. %
quantity quantit quantit quantit
per batch y per y per y per
batch batch 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>

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Component and Relevant batches
quality Comparative Stability Process Commercial
standard (e.g. bioavailability or validation (2.3.P.1)
NF, BP, biowaiver
Ph.Eur, in-
house) <Batch nos. and <Batch nos. and <Batch nos. and <Batch nos. and
sizes> sizes> sizes> sizes>
Theor. % Theor. % Theor. % Theor. %
quantity quantit quantit quantit
per batch y per y per y per
batch batch batch
Subtotal 2
Total

(c) Description of batches used in the comparative in vitro studies

(e.g. dissolution) and in the in vivo studies (e.g. comparative
bioavailability or biowaiver), including strength, batch
number, type of study and reference to the data (volume,
page):

(d) Summary of results for comparative in vitro studies (e.g.

dissolution):

(e) Summary of any information on in vitro-in vivo correlation

(IVIVC) studies (with cross-reference to the studies in Module
5):

(f) For scored tablets, provide the rationale/justification for

scoring:

2.3.P.2.2.2 Overages

(a) Justification of overages in the formulation(s) described in

2.3.P.1:

2.3.P.2.2.3 Physicochemical and Biological Properties

(a) Discussion of the parameters relevant to the performance of

the FPP (e.g. pH, ionic strength, dissolution, particle size
distribution, polymorphism, rheological properties):

2.3.P.2.3 Manufacturing Process Development

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(a) Discussion of the development of the manufacturing process of the
FPP (e.g. optimization of the process, selection of the method of
sterilization):

(b) Discussion of the differences in the manufacturing process (es) for the
batches used in the comparative bioavailability or biowaiver studies
and the process described in 2.3.P.3.3:

2.3.P.2.4 Container Closure System

(a) Discussion of the suitability of the container closure system (described

in 2.3.P.7) used for the storage, transportation (shipping) and use of
the FPP (e.g. choice of materials, protection from moisture and light,
compatibility of the materials with the FPP):

(b) For a device accompanying a multi-dose container, a summary of the

study results demonstrating the reproducibility of the device (e.g.
consistent delivery of the intended volume):

2.3.P.2.5 Microbiological Attributes

(a) Discussion of microbiological attributes of the FPP (e.g. preservative

effectiveness studies):

2.3.P.2.6 Compatibility

(a) Discussion of the compatibility of the FPP (e.g. with reconstitution

diluent(s) or dosage devices, co-administered FPPs):

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

Information from 3.2.P.3 should include:
 Information on the manufacturer. •
 A brief description of the manufacturing process and the controls that are intended
to result in the routine and consistent production of product of appropriate quality.
 A flow diagram, as provided under 3.2.P.3.3.
 A brief description of the process validation and/or evaluation, as described in
3.2.P.3.5.

2.3.P.3 Manufacture

2.3.P.3.1 Manufacturer(s)

(a) Name, address and responsibility (e.g. fabrication, packaging,

labelling, testing) of each manufacturer, including contractors and
each proposed production site or facility involved in manufacturing
and testing:

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Name and address Responsibility

(include block(s)/unit(s))

(b) Manufacturing authorization, marketing authorization and, where

available, WHO-type certificate of GMP (GMP information should be
provided in Module 1):

2.3.P.3.2 Batch Formula

(a) List of all components of the FPP to be used in the manufacturing

process and their amounts on a per batch basis (including individual
components of mixtures prepared in-house (e.g. coatings) and
overages, if any):

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 Quantity per Quantity per Quantity per
(and grade, if applicable) batch (e.g. batch (e.g. batch (e.g.
kg/batch) kg/batch) 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

2.3.P.3.3 Description of Manufacturing Process and Process Controls

(a) Flow diagram of the manufacturing process:

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(b) Narrative description of the manufacturing process, including

equipment type and working capacity, process parameters:

(c) Justification of reprocessing of materials:

2.3.P.3.4 Controls of Critical Steps and Intermediates

(a) Summary of controls performed at the critical steps of the

manufacturing process and on isolated intermediates:

Step Controls
(e.g. granulation, compression,
coating)

2.3.P.3.5 Process Validation and/or Evaluation

(a) Summary of the process validation and/or evaluation studies

conducted (including product quality review(s) where relevant)
and/or a summary of the proposed process validation protocol for the
critical steps or critical assays used in the manufacturing process (e.g.
protocol number, parameters, results):

2.3.P.4Control of Excipients (name, dosage form)

A brief summary on the quality of excipients, as described in 3.2.P.4, should be included.

2.3.P.4 Control of Excipients

2.3.P.4.1 Specifications

(a) Summary of the specifications for officially recognized

compendialexcipients which include supplementary tests not included
in the officially recognized compendial monograph(s):

2.3.P.4.2 Analytical Procedures

(a) Summary of the analytical procedures for supplementary tests:

2.3.P.4.3 Validation of Analytical Procedures

(a) Summary of the validation information for the analytical procedures

for supplementary tests (where applicable):

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2.3.P.4.4 Justification of Specifications

(a) Justification of the specifications (e.g. evolution of tests, analytical

procedures and acceptance criteria, exclusion of certain tests,
differences from officially recognized compendial standard(s)):

2.3.P.4.5 Excipients of Human or Animal Origin

(a) For FPPs using excipients without risk of transmitting agents of

animal spongiform encephalopathies, a letter of attestation confirming
this can be found in:

(b) CEP(s) demonstrating TSE-compliance can be found in:

2.3.P.4.6 Novel Excipients

Novel excipients are not accepted in the Prequalification Programme.

2.3.P.5Control of Drug Product (name, dosage form)

A brief summary of the justification of the specification(s), a summary of the analytical
procedures and validation, and characterisation of impurities should be provided.
Specification(s) from 3.2.P.5.1 should be provided. A tabulated summary of the batch
analyses provided under 3.2.P.5.4, with graphical representation where appropriate
should be included.

2.3.P.5 Control of FPP

2.3.P.5.1 Specification(s)

(a) Specification(s) for the FPP:

Standard (e.g. Ph.Int., BP, USP, House)

Specification reference number and version
Test Acceptance criteria Acceptance criteria Analytical procedure
(release) (shelf-life) (type/source/version)
Description
Identification
Impurities
Assay
etc.

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2.3.P.5.2 Analytical Procedures

(a) Summary of the analytical procedures (e.g. key method parameters,

conditions, system suitability testing):

See 2.3.R Regional Information for summaries of the analytical

procedures and validation information (i.e. 2.3.R.2 Analytical Procedures
and Validation Information).

2.3.P.5.3 Validation of Analytical Procedures

(a) Summary of the validation information (e.g. validation parameters

and results):

See 2.3.R Regional Information for summaries of the analytical

procedures and validation information (i.e. 2.3.R.2 Analytical Procedures
and Validation Information).

2.3.P.5.4 Batch Analyses

(a) Description of the batches:

Strength and Batch size Date and Use (e.g. comparative

batch number site of production bioavailability or biowaiver,
stability)

(b) Summary of batch analyses release results for relevant batches (e.g.
comparative bioavailability or biowaiver, stability):

Test Acceptance Results

Criteria <Batch x> <Batch y> Etc.
Description
Identification
Impurities
Assay
etc.

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(c) Summary of analytical procedures and validation information for

those procedures not previously summarized in 2.3.P.5.2 and 2.3.P.5.3
(e.g. historical analytical procedures):

2.3.P.5.5 Characterisation of Impurities

(a) Identification of potential and actual impurities:

Degradation product Structure Origin

(chemical name or
descriptor)

Process-related impurity (compound Step used in the FPP manufacturing process

name)

(b) Basis for setting the acceptance criteria for impurities:

(i) Maximum daily dose (i.e. the amount of API administered per
day) for the API, corresponding ICH
Reporting/Identification/Qualification Thresholds for the
degradation products in the FPP and the concentration limits
(ppm) for the process-related impurities (e.g. residual
solvents):

Maximum daily dose for the API: <x mg/day>

Test Parameter ICH threshold or
concentration limit
Degradation product Reporting Threshold
Identification
Threshold
Qualification
Threshold
Process-related impurities <Solvent 1>
<Solvent 2>, etc.

(ii) Data on observed impurities for relevant batches (e.g.

comparative bioavailability or biowaiver):

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Impurity Acceptance Results

(degradation criteria
product and <batch no.,
process-related) strength, use>

(iii) Justification of proposed acceptance criteria for impurities:

2.3.P.5.6 Justification of Specification(s)

(a) Justification of the FPP specification(s) (e.g. evolution of tests,

analytical procedures and acceptance criteria, differences from
officially recognized compendial standard(s)):

2.3.P.6Reference Standards or Materials (name, dosage form)

Information from 3.2.P.6 (tabulated presentation, where appropriate) should be included.

2.3.P.6 Reference Standards or Materials

(a) Source (including lot number) of primary reference standards or

reference materials (e.g. Ph.Int.,Ph.Eur., BP, USP, in-house) not
discussed in 3.2.S.5:

(b) Characterization and evaluation of non-official (e.g. not from

an officially recognized pharmacopoeia) primary reference standards
or reference materials (e.g. elucidation of structure, certificate of
analysis) not discussed in 3.2.S.5:

(c) Description of the process controls of the secondary reference

standard (comparative certificate of analysis and IR spectra against
primary standard) not discussed in 3.2.S.5:

2.3.P.7Container Closure System (name, dosage form)

A brief description and discussion of the information in 3.2.P.7 should be included.

2.3.P.7 Container Closure System

(a) Description of the container closure systems, including unit count or

fill size, container size or volume:

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Description Strength Unit count or fill size Container size

(including
materials of
construction)

(b) Summary of specifications of each primary and functional secondary

(e.g. foil pouches) packaging components:

Packaging component Specifications

(list parameters e.g. identification (IR))
HDPE bottle
PP cap
Induction sealed liners
Blister films (PVC, etc)
Aluminum foil backing
etc.

(c) Other information on the container closure system(s):

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

A summary of the studies undertaken (conditions, batches, analytical procedures) and a
brief discussion of the results and conclusions of the stability studies and analysis of data
should be included. Conclusions with respect to storage conditions and shelf-life and, if
applicable, in- use storage conditions and shelf-life should be given.
A tabulated summary of the stability results from 3.2.P.8.3, with graphical representation
where appropriate, should be included. The post-approval stability protocol, as described
in 3.2.P.8.2, should be provided.

2.3.P.8 Stability

2.3.P.8.1 Stability Summary and Conclusions

(a) Summary of stress testing and results (e.g. photostability studies,

cyclic studies, freeze-thaw studies):

(b) Summary of accelerated and long-term testing parameters (e.g.

studies conducted):

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Storage conditions Strength and Batch size Container Completed (and
(◦C, % RH) batch number closure system proposed) test
intervals

Summary of the stability results observed for the above accelerated

and long-term studies:

Test Results
Description
Moisture
Impurities
Assay
etc.

(c) Proposed storage statement and shelf-life (and in-use storage

conditions and in-use period, if applicable):

Container closure system Storage statement Shelf-life

2.3.P.8.2 Post-approval Stability Protocol and Stability Commitment

(a) Stability protocol for Primary stability batches (e.g. storage conditions
(including tolerances), batch numbers and batch sizes, tests and
acceptance criteria, testing frequency, container closure system(s)):

Parameter Details
Storage condition(s) (◦C, % RH)
Batch number(s) / batch size(s)
Tests and acceptance criteria Description
Moisture
Impurities
Assay
etc.

Testing frequency
Container closure system(s)

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(b) Stability protocol for Commitment batches (e.g. storage conditions
(including tolerances), batch numbers (if known) and batch sizes, tests
and acceptance criteria, testing frequency, container closure
system(s)):

Parameter Details
Storage condition(s) (◦C, % RH)
Batch number(s) / batch size(s) <not less than three production batches in each
container closure system>
Tests and acceptance criteria Description
Moisture
Impurities
Assay
etc.
Testing Frequency
Container Closure System(s)

(c) Stability protocol for Ongoing batches (e.g. storage conditions

(including tolerances), number of batches per strength and batch
sizes, tests and acceptance criteria, testing frequency, container
closure system(s)):

Parameter Details
Storage condition(s) (◦C, % RH)
Batch size(s), annual allocation <at least one production batch per year (unless none
is produced that year)in each container closure
system >
Tests and acceptance criteria Description
Moisture
Impurities
Assay
etc.
Testing frequency
Container closure system(s)

2.3.P.8.3 Stability Data

(a) The actual stability results should be provided in Module 3.

(b) Summary of analytical procedures and validation information for

those procedures not previously summarized in 2.3.P.5 (e.g. analytical
procedures used only for stability studies):

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(c) Bracketing and matrixing design and justification for Commitment
and/or Ongoing stability batches, if applicable:

2.3.A APPENDICES
2.3.A.1 Facilities and Equipment (name, manufacturer)
Biotech: A summary of facility information described under 3.2.A.1 should be included.

(a) Summary of information on facilities and equipment, in addition to

the information provided in other sections of the submission: Not
applicable.

2.3.A.2 Adventitious Agents Safety Evaluation (name, dosage form and

manufacturer)
A discussion on measures implemented to control endogenous and adventitious agents in
production should be included.
A tabulated summary of the reduction factors for viral clearance from 3.2.A.2, should be
provided.

Summary of the information assessing the risk with respect to potential

contamination with adventitious agents:
2.3.A.3 Excipients
Summary of the details of manufacture, characterization and controls, with cross
references to supporting safety data (nonclinical and/or clinical) for the novel
excipients:

2.3.R REGIONAL INFORMATION

A brief description of the information specific for the region, as provided under “3.2.R”
should be included, where appropriate.

2.3.R.1 Production Documentation

2.3.R.1.1Executed Production Documents

(a) List of batches (including strengths) for which executed production

documents have been provided (e.g. comparative bioavailability or
biowaiver batches):

2.3.R.1.2 Master Production Documents

(a) The blank master production documents for each strength, proposed
commercial batch size and manufacturing facility should be provided
in Module 3.

2.3.R.2 Analytical Procedures and Validation Information

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ANALYTICAL PROCEDURES AND VALIDATION INFORMATION SUMMARIES

ATTACHMENT NUMBER:
HPLC Method Summary Volume/Page:
Method name:
Method code: Version and/or
Date:
Column(s) / temperature (if other than ambient):
Mobile phase (specify gradient program, if
applicable):
Detector (and wavelength, if applicable):
Flow rate:
Injection volume:
Sample solution concentration
(expressed as mg/ml, let this be termed “A”):
Reference solution concentration
(expressed as mg/ml and as % of “A”):
System suitability solution concentration
(expressed as mg/ml and as % of “A”):
System suitability tests (tests and acceptance criteria):
Method of quantification (e.g. against API or impurity
reference standard(s)):
Other information (specify):

ATTACHMENT NUMBER:
Validation Summary Volume/Page:
Analytes:
Typical retention times (RT)
Relative retention times (RTImp./RTAPI or Int. Std.):
Relative response factor (RFImp./RFAPI):
Specificity:
Linearity / Range: Number of concentrations:
Range (expressed as %
“A”):

Slope:
Y-intercept:
Correlation coefficient (r2)
:

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ATTACHMENT NUMBER:
Accuracy: Conc.(s) (expressed as %
“A”):

Number of replicates:
Percent recovery
(avg/RSD):
Precision / Conc.(s) (expressed as %
Repeatability: “A”):
(intra-assay precision) Number of replicates:
Result (avg/RSD):
Precision / Parameter(s) altered:
Intermediate Precision: Result (avg/RSD):
(days/analysts/equipment)
Limit of Detection (LOD): (expressed as % “A”)
Limit of Quantitation (LOQ): (expressed as % “A”)
Robustness: Stability of solutions:

Other variables/effects:
Typical chromatograms or spectra may be found
in:
Company(s) responsible for method validation:
Other information (specify):

3.2.R.3 Bioequivalence trial information form (BTIF)

3.2.R.3.1 A completed BTIF should be submitted both in hard copy and electronic
(word format)
3.2.R.3.2 Biowaiver requests in relation to conducting comparative bioavailability
study
A completed Biowaiver Application Form should be submitted both in hard copy and
electronic (word format)
Requirements for biopharmaceutic studies are described in the Botswana
Bioavailability/Bioequivalence Guideline. [3]

Notes to the Assessor

BIOEQUIVALENCE ASSESSMENT

Copy filled BTIF / Biowaiver-BCS Application Form / Biowaiver-Additional Strength

Form here and assess it here

POINTS TO BE COMMUNICATED TO THE MANUFACTURER

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Please copy all relevant observation and information to be communicated to the
manufacturer in the corresponding letter and save it accordingly

ACTIVE PHARMACEUTICAL INGREDIENT(s) (INN)

FINISHED PHARMACEUTICAL PRODUCT (INN .mg PHARMACEUTICAL FORM)

BIOEQUIVALENCE / BIOWAIVER-BCS / BIOWAIVER-ADDITIONAL STRENGTH

Overall recommendation
Please fill in the relevant recommendation (registration/rejection), based on the
review of the data on quality and bioequivalence.
The dossier can be proposed for registration only, if minor issues are pending.

Outstanding commitments
Please list the outstanding commitments, which should be answered before the
product can be listed on the registration list.

RECOMMENDATIONS FOR INSPECTION

Evaluator: Date:

Reviewer: Date:

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