Draft Guidance Document of Biological Products

GUIDANCE DOCUMENT FOR SUBMISSION OF APPLICATION ON
FORM 5-F (CTD) FOR REGISTRATION OF BIOLOGICAL DRUG

PRODUCTS FOR HUMAN USE
Document No.: BE&R/GL/AF

Document History: 1st Edition
Effective Date: DD-MM-YYYY
This draft guideline is uploaded on the official website of DRAP dated on 9th May, 2023, for seeking
comments and suggestions from stakeholders on the draft document. Stakeholders can submit their comments
and suggestions within 15 days of uploading this document using prescribed format, (further information on
comments submission can access on this link. Comments and suggestions can be forwarded via email to a
ahmad.ansari@dra.gov.pk copying at ahsan.hafiz@dra.gov.pk , or can be posted at mailing address, Director,
Biological Drugs, Drug Regulatory Authority of Pakistan, 4th floor TF Complex, 7th Mauve Area, G-9/4,
Islamabad.
Drug Regulatory Authority of Pakistan

Islamabad - Pakistan.
Guidance Document for Submission of Application for Registration of Biological Products on Form 5-F (CTD) (Edition 1)
1. HISTORY
This is the first edition of these guidelines after the introduction of Form-5F (CTD).
2. APPLICATION 1 - Guidance for Industry.

This document is applicable to the Biological products (BP) manufacturer and importers who intend to
apply for registration / Marketing Authorization for import or local manufacture intended for human use.
3. SCOPE
The scope of this Guideline is limited to application on Form-5F (CTD) for registration of biological
drug products for human use.
4. BACKGROUND
Section 7 (c) (ii, viii, ix) of DRAP Act 2012, mandated the registration of therapeutic goods,
implementation of internationally recognized GLP, cGMP etc and systematic implementation of
internationally recognized standards of World Health Organization, International Conference on
Harmonization (ICH), and Food and Drug Administration guidelines etc.
These guidelines conform and shall be read in consistence to DRAP Act, 2012 and Drugs Act 1976 and
Rules framed there under.
1
The Guidance document is prepared by Drug Regulatory Authority of Pakistan for better illustration of data
requirements of the Form 5-F (CTD). However, content of guidance document only reflects the current thinking
perspective of the Authority on the subject and does not create or confer any rights for or on any person and does not
operate to bind the Authority or the public.
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Division of Biological Evaluation & Research Effective Date: DD-MM-YYYY
Contents
1. INTRODUCTION .................................................................................................................. 5
2. LEGAL PROVISIONS .......................................................................................................... 5
3. GENERAL GUIDANCE FOR APPLICANTS ................................................................... 5
MODULE 1: (ADMINISTRATIVE PART) ............................................................................... 6
1.1 Covering Letter and Fee Deposit Slip .......................................................................................... 6
1.2 Table of Contents (From Module 1 to Module 5) ........................................................................ 6
1.3 Applicant Information ................................................................................................................... 6
1.4 Type of Application ........................................................................................................................ 7
1.5 Detailed Information of Drug, Dosage From & Labeling Claims ............................................. 8
MODULE 2: (OVERVIEWS AND SUMMARIES) ................................................................. 12
MODULE 3: (QUALITY / CMC) .............................................................................................. 30
REFERENCES ............................................................................................................................ 41
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GLOSSARY
ACRONYMS
API Active Pharmaceutical Ingredient
BAN British Approved Name
BCS Biopharmaceutics Classification System
BP British Pharmacopoeia
BSE Bovine Spongiform Encephalopathy
CAS Chemical Abstract Service
CEP Certificate of Suitability
CoA Certificate of Analysis
CPP Critical Process Parameters
CQA Critical Quality Attribute
CTD Common Technical Document
DML Drug Manufacturing License
DRAP Drug Regulatory Authority of Pakistan
EPAR European Public Assessment Report
FDA Food & Drug Administration of United States
GCP Good Clinical Practices
GLP Good laboratory Practices
GMP Good Manufacturing Practices
ICH International Conference on Harmonization
INN International nonproprietary name
IR Infrared
JP Japanese Pharmacopoeia
LR&A Licensing, Registering & Advertising
MS Mass Spectrometry
NMR Nuclear Magnetic Resonance
OSD Oral Solid Dosage form
PAR Public Assessment Report
Ph.Eur European Pharmacopoeia
Ph.Int International Pharmacopoeia
PMDA Pharmaceuticals and Medical Devices Agency of Japan
RRA Reference Regulatory Authority
SAE Serious Adverse Events
TSE Transmissible Spongiform Encephalopathies
USAN United States Adopted Name
USP United States Pharmacopoeia
UV Ultraviolet-Visible
WHO World Health Organization
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1. INTRODUCTION
This guidance is developed to assist manufacturers and importers in developing their applications for
registration of human biological drug products. Drug Regulatory Authority of Pakistan (DRAP) has
adapted CTD format for registration of all such drugs vide SRO-713(l)/2018 dated 8th June 2018. The
detailed guidance regarding the data requirement for CTD format has been provided in ICH M-4
guidelines. Since the DRAP is introducing the CTD in a progressive manner, therefore, initial guidance
to applicants would be helpful for harmonization and appropriate data submission to achieve consistency
and uniformity of application.
This guidance document is developed on the basis of best available knowledge and scientific data /
evidence.
2. LEGAL PROVISIONS
Rule 26 of the Drugs (Licensing, Registering and Advertising) Rules, 1976, as amended vide S.R.O
713(I)/2018 dated 8th June, 2018, under 26(1) section provides the standard formats and requirements
for submission of registration application dossier on Form 5F (Common Technical Documents) for
registration of Human drugs.
3. GENERAL GUIDANCE FOR APPLICANTS

For submitting applications on CTD format, applicant needs to follow the following general
instructions/guidance to ensure proper submission.
1. Module 1 (Administrative part) shall be prepared as provided in Form-5F without deleting any
component. Applicant shall mention “Not applicable” with proper justification for those parts
which are not related to any particular application.
2. Quality Overall Summary (QOS) in module 2 shall be prepared using WHO QOS-PD template
or template provided hereinafter without deleting any component / table of the template.
Applicant shall mention “Not applicable” with proper justification for those parts which are not
related to any particular application.
3. The Quality overall Summary (QOS) prepared as per WHO QOS-PD template or template
provided hereinafter needs to be submitted as “MS Word document” in CD / USB as well.
4. Application shall be submitted along with complete data as per the module 3.
5. Each section / sub section of CTD application shall be properly segregated using page separators.
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MODULE 1: (ADMINISTRATIVE PART)

1.1 Covering Letter and Fee Deposit Slip
a) Covering letter on the Applicant company / manufacturer / importer letter head in context to the
application for the registration of the Pharmaceutical Drug Product shall be submitted, which
shall be dully signed by owner/ authorized person on behalf of company/ manufacturer/ importer
as per below mentioned format:
“I / We …………………............... of …………………………………hereby apply for
registration of the drug, namely …………………………………………details of which
are enclosed.”
b) An original cash deposit slip of prescribed fee as per Notification No. F. 7-11/2012-B&A/DRAP
dated 13-07-2021, for specified category shall be attached therewith.
1.2 Table of Contents (From Module 1 to Module 5)

a) A comprehensive Table of Contents shall contain Module and sub module heading with page
number on the pharmaceutical dossier. The contents of all the Module from 1 to 5 shall be
covered. Comprehensive Table of Contents is different form individual table of contents in the
beginning of each Module.
b) Also, a complete list of all documents provided in the registration dossier by Module, Section
and sub-section shall be included.
1.3 Applicant Information

1.3.1. Name, address and contact details of Applicant / Marketing Authorization Holder:
a) In this section, administrative information related to the applicant is required.
b) It is necessary to provide the complete particulars of the applicant, which shall contain:
i. Name of Licensed Pharmaceutical Manufacturer / Licensed Importer having Drug Sale
License by respective licensing authority.
ii. Manufacturing Site Address of Pharmaceutical unit or address of the godown / warehouse
in case the applicant is Drug Sale license Holder.
iii. Contact details, including postal address, telephone contact number, Fax number, website
and email address.
1.3.2. Name, address and contact details of manufacturing site

There could be following three situations:
a) The applicant is manufacturer
Provide the details including name, DML number and complete address of the manufacturing
site of the applicant (manufacturer).
b) Contract Manufacturing (The applicant is not manufacturer for the applied product)
Provide the details including name, DML number and complete address of the manufacturing
site of the manufacturer.
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c) Import (The applicant is importer for the applied product)

Provide the details including name and complete address of the manufacturing site and name
of marketing authorization Holder/ Product License Holder for the applied product. In case
multiple manufacturing sites are involved, provide details for each.
1.3.3. Specify whether the Applicant is:

a. Manufacturer
b. Importer
c. Is involved in none of the above (contract giver)
This point requires the status of applicant for the instant product. The applicant must select one of the
above-mentioned options.
• A manufacturer will provide all the requisite information as per Registration procedure of
Pakistan, subsequently mentioned in 1.3.4-1.3.5.
• An importer shall provide Certificate of Pharmaceutical Product (CoPP) / Free Sale
certificate and GMP certificate of the Manufacturer issued by relevant regulatory authority
in the country of origin and name of exporting country.
• “c” is for Contract Manufacturing as per Rule 20-A of Drugs (Licensing, Registering and
Advertising) Rules, 1976.
1.3.4. Valid Drug Manufacturing License (DML) of manufacturer / Applicant or Drug Sale
License, whichever is applicable.
a) For drug to be locally manufactured, copy of valid Drug Manufacturing License (DML) issued
by Licensing Division, DRAP.
b) For drugs to be imported, copy of valid Drug Sale License (DSL) issued by relevant licensing
authority. The address of applicant mentioned on Drug Sale License (DSL) shall match with
the information provided in sub-section 4.3.1 and sole agency agreement / letter of authorization
between applicant and marketing authorization holder (abroad).
1.3.5. Evidence of approval of manufacturing facility / Approved Section from Licensing

Authority
a) To be provided if option a or c is selected in sub-section 1.3.3
b) Approval letter of the section (Dosage form) in which manufacturing of the applied product is
to be carried out needs to be submitted or panel inspection report conducted for renewal of
DML or grant of GMP certificate. In case of contract manufacturing, the same documents from
the contract manufacturer shall be submitted.
c) GMP inspection report/ GMP certificate of the manufacturing unit issued within the last three
years shall be submitted.
1.3.6. List of already approved registered drugs in this section

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The submission against this point is optional
1.3.7. Identification of Signature(s) of authorized persons, Incharge Production, Quality Control

and Incharge Quality Assurance
The submission against this point is optional.
1.3.8. Manufacturer’s Site Master File and Credential (for importer)

1.4 Type of Application
1.4.1. Application is for the registration of:

New Drug Product (NDP)
Similar Biotherapeutic Product (SBP)
a) New Drug Product (Product not already registered in Pakistan) includes New Molecule/ New
strength / New Formulation.
b) It is important to specify here whether the applicant has submitted the CTD for a New Drug
Product Registration or a similar Biotherapeutic Product.
c) It is important to mention here if the Biological Product is a vaccine manufactured under
relevant WHO TRS or is a new vaccine for which WHO TRS is not yet developed.
d) It is to be noted that established vaccines are not Biosimilar Biologicals, each vaccine is unique
in its own right but are similar due to absence of difference in the parameter of interest.
1.4.1 Biological product is intended for:

Domestic sale
Export sale
Domestic and Export sales
a) Applicant needs to clarify whether the applied product (drug product) is intended for sale in
domestic market or both for domestic and export market.
b) For Export only registrations application on Form 5F (CTD) is already exempted by the
Authority vide its Circular No. F.1-21/2019-Add: Dir. (PE&R) dated 06-02-2019.
1.4.2. For imported products, please specify one of following:

 Finished Pharmaceutical Product Import
 Bulk Import and local repacking (specify status of bulk)
 Bulk Import Local Repacking for Export purpose only
This point only pertains to registration applications of drug products for import.
The applicant / importer needs to specify whether the import is of finished pharmaceutical product or of
bulk product. In case of bulk import local repack, the applicant also needs to provide following
documents:
a) Evidence and GMP status of packing facility for the bulk imported drug to be repacked and batch
release.
b) Agreement between the importer and the firm responsible for local repacking in Pakistan.
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1.4.3. Contract Manufacturing as per Rule 20-A of Drugs (Licensing, Registering and
Advertising) Rules, 1976.
 Domestic Manufacturing
 Export Purpose Only
a) Provide notarized copy of Contract manufacturing agreement.
b) Provide documents confirming number of approved sections of the applicant (DML holder).
c) Provide details of already registered drug products of contract giver on contract manufacturing.
1.5 Detailed Information of Drug, Dosage From & Labeling Claims
1.5.1. Generic name with chemical name & synonyms of the applied drug.
The following necessary information shall be provided in this sub-section:
a) (Recommended) International Non-proprietary name (INN):
b) Compendia name, if relevant:
c) Chemical name(s):
d) Chemical Abstracts Service (CAS) registry number: (where applicable)
The submission of following is optional
a) Company or laboratory code
b) Other non-proprietary name(s) (e.g. national name, USAN, BAN):
1.5.2. Strength / concentration of drug of Active Pharmaceutical ingredient (API) per unit
a) Strength of Active ingredient shall be stated clearly.
For example, each tablet contains, each ml contains in case of Injectable. However, description
like each ampoule / vial contains shall be avoided.
1.5.3 The proposed proprietary name / brand name under which the drug is intended to be sold
with trade mark certification / clearance.
a) The proposed brand name shall be justified keeping in view the LASA (Look alike and Sound
alike) with specific emphasis on prefix, mid-name and suffix.
b) An undertaking in this regard that the applicant shall be responsible to change the name in case
the name resembles with already approved / registered names.
1.5.4 Proposed Pack size and Proposed unit price of drug e.g., per tablet / capsule. Maximum Retail
Price (MRP) per pack shall also be mentioned.
a) The applicant needs to submit the proposed pack size as well as demanded price for each pack
size.
1.5.5 Pharmacotherapeutic Group of Active Pharmaceutical Ingredient (API)
a) Indicate Pharmacological class of the API (drug substance) with proper reference.
b) Also, state the WHO ATC code for each distinct therapeutic indication.
1.5.6 Pharmacopoeial reference / Status of applied formulation

Mention the reference specifications of the finished product (drug product) from the following list
• USP
• BP
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• Int. Ph.
• JP
• Pharmacopoeia of any Reference Regulatory Authority
• Manufacturer’s specifications.
• Specifications as per Innovator’s product
• Any other (specify exact reference)
• Any other pharmacopoeia as mentioned in Drug specification rules. (Specify the exact
reference).
1.5.7 Route of administration

The applicant needs to specify the exact route of administration for the applied drug product. In case of
multiple route of administration, specify all routes of administration.
1.5.8 For Biosimilar Drug Product, reference of other similar approved medicines with
information pertaining to Manufacturer name, brand name, strength, composition, registration
number & dosage form, Pack size and Price.
If the applicant has selected Biosimilar Drug Product (GDP) in sub-section 1.4.1, the reference of already
registered product including the following details needs to be submitted.
• Brand name
• Manufacturer/Registration holder
• Registration number
If the applicant has selected New Drug Product (NDP) in sub-section 1.4.1 “Not applicable since this is
a new drug” needs to be mentioned against this point.
1.5.9 The registration status of applied drug in same molecule and salt, strength, dosage form,
container closure system, indications and route of administration etc. in other countries. The status
in reference regulatory authorities is mandatory to mention.
Evidence of approval / registration / marketing status of the applied formulation in the same composition,
salt form and dosage form in one of the reference regulatory authority specified by Registration Board.
The name of the reference authority shall be mentioned as adopted by Board currently.
Mention the name of innovator product in case of non-pharmacopoeial product.
1.5.10 Dosage form of applied drug

• Dosage form of applied drug shall be mentioned clearly.
1.5.11 Proposed label [outer (secondary) & inner (primary)] & colour scheme in accordance with
Drug (Labelling & Packing) Rules, 1986 along with specimens
1.5.12 Description of Batch numbering system

1.5.13 Training evidence of technical staff with respect of manufacturing of applied drug
(mandatory in case of specially designed pharmaceutical product / Novel Dosage Form).
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1.5.14 Summary of Product Characteristics (SmPC) including Prescribing Information (PI) along
with Patient information Leaflet (PIL) of the Finished Pharmaceuticals Product (FPP).
1.5.15 – 1.5.20 Commitments

I/ we hereby undertake that:
1.5.15 After registration of applied drug, the Pharmacovigilance department of the applicant /
manufacture is liable to impose similar restrictions, addition of any clinical information (like
in Indications, Contra-indications, Side effects, Precautions, Dosage & Adverse Drug
Reactions etc. in Summary of Product Characteristics (SmPC), Labelling & Promotional
material) or withdraw the drug from market in Pakistan within fourteen days after knowing
that such information (which was not available or approved by the DRAP at the time of
registration) / actions taken (for safety reasons) by any reference / stringent drug regulatory
agency / authority & also inform the DRAP (Drug Regulatory Authority of Pakistan) for
further action in this regard.
1.5.16 We shall recall the defective Finished Pharmaceutical Products (FPP) and notify the
compliance to the authority along with detail of actions taken by him as soon as possible but
not more than ten days. The level of recall shall also be defined.
1.5.17 In case of any false claim / concealing of information, the DRAP has the right to reject the
application at any time, before and even after approval or registration of the product in case
if proved so.
1.5.18 We will follow the official pharmacopoeia specifications for product / substance as published
in the latest edition & shall update its specification as per latest editions of the same. In case,
the specifications of product / substance not present in any official pharmacopoeia the firm
shall establish the specifications. In both cases, the validation of specifications shall be done
by the applicant. (For drug products to be imported, this commitment must be submitted by
manufacturer abroad as well).
1.5.19 In case of any post approval change, the applicant shall ensure that the product with both
approvals shall not be available in the market at the same time. And the product with new
approvals shall be marketed only after consumption / withdrawal of stock with previous
approvals. The company shall be liable to inform the same regarding marketing status of
product to the DRAP after getting such post-registration approvals.
1.5.20 We will perform process validation and stability studies till the assigned shelf life for the first
three consecutive batches of commercial scale, stability study of at least one batch every year
in accordance with the protocols and continue real time stability study till assigned shelf life
of the applied product.
1.5.20 a) We will be responsible to change the brand name in case the name resembles with already
approved / registered names.
b) We will be responsible to change the label design if it resembles with any of the previously
registered drug.
I / We hereby undertake that the above given information is true and correct to the best of my / our
knowledge and belief.
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1.5.21 Protocols along with the commitment to follow Good Laboratory Practices (GLP) by the
Manufacturer.
1.5.22 Protocols to implement Good Pharmacovigilance Practice by the Pharmacovigilance

department/section of the Manufacturer / Company.
1.6 Miscellaneous Information

1.6.1 Information on Prior-related Applications
1.6.2 Appendix
1.6.3 Electronic Review Package

The applicant shall submit electronic review package in CD / USB including Quality Overall Summary.
1.6.4 QIS (Quality Information Summary)

The submission against this point is optional
1.6.5 Drug Substance related Document including following:

a. Name and address of API manufacturer.
b. Approval of manufacturing facility of API by regulatory body of country and validity.
For applications of locally manufactured drug product(s), the one of the following documents shall be
submitted.
i. Valid Drug Manufacturing License issued by the relevant regulatory authority of country of
origin.
ii. Valid Good Manufacturing Practice (GMP) certificate of the Drug Substance manufacturer
issued by relevant regulatory authority of country of origin.
For applications of imported drug product(s), the submission against this point is not required.
MODULE 2: (OVERVIEWS AND SUMMARIES)

2.3 Quality Overall Summary (QOS)
• The QOS as per ICH template for consideration by the Registration Board.
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).
2.3.S. DRUG SUBSTANCE (NAME, MANUFACTURER)
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2.3.S.1 General Information (name, manufacturer)

Information from 3.2.S.1 should be included. 2.3.S.2 Manufacture (name, manufacturer) Information
from 3.2.S.2 should be included:
• Information on the manufacturer
• 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;
• A description of the Source and Starting Material and raw materials of biological origin used in the
manufacture of the drug substance, as described in 3.2.S.2.3;
• 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;
• A description of process validation and/or evaluation, as described in 3.2.S.2.5.
• 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 1 The Common Technical
Document - Quality used batches affected by these manufacturing changes, as provided in the CTD-
S and CTD-E modules of the dossier.
2.3.S.3 Characterization (name, manufacturer)

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.
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.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.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

a) CoA of primary / secondary reference standard including source and lot number
<For testing of Pharmacopeial Drug Substance, the use of primary reference standard is recommended,
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however for non-pharmacopeial Drug Substance, a secondary reference standard provided by the Drug
Substance manufacturer is acceptable>
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.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.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.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.3 Manufacture (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.4 Control 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.5 Control 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.6 Reference Standards or Materials (name, dosage form)

Information from 3.2.P.6 (tabulated presentation, where appropriate) should be included.
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2.3.P.7 Container Closure System (name, dosage form)

A brief description and discussion of the information in 3.2.P.7 should be included.
2.3.P.8 Stability (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.A Appendices
2.3.A.1 Facilities and Equipment
<Provide a list of manufacturing and testing facilities / equipment available with reference to the applied
drug product>
2.3.A.2 Adventitious Agents Safety Evaluation

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.
2.3.A.3 Excipients
<For excipient(s) used for the first time in a drug product or by a new route of administration, full details
of manufacture, characterization, and controls, with cross references to supporting safety (nonclinical
and/or clinical) data shall be provided>
2.3.R Regional Information
2.3.R.1 Production Documentation
2.3.R.1.1 Executed Production Documents
<Provide copy of Batch Manufacturing Record (BMR) for all the batches of drug product for which
stability studies data is provided in Module 3 section 3.2.P.8.3>
2.3.R.1.2 Comparability Protocols
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This point is only for Biosimilar Drugs. The applicant shall submit summary of quality comparison of
their product with Innovator product.
2.4 NONCLINICAL OVERVIEW

The Nonclinical Overview should provide an integrated overall analysis of the information in the
Common Technical Document. In general, the Nonclinical Overview should not exceed about 30 pages.
The Nonclinical Overview should present an integrated and critical assessment of the pharmacologic,
pharmacokinetic, and toxicologic evaluation of the pharmaceutical. There should be comment on the
GLP status of the studies submitted. Any association between nonclinical findings and the quality
characteristics of the human pharmaceutical, the results of clinical trials, or effects seen with related
products should be indicated, as appropriate. Except for biotechnology-derived products, an assessment
of the impurities and degradants present in the drug substance and product should be included along with
what is known of their potential pharmacologic and toxicologic effects. This assessment should form
part of the justification for proposed impurity limits in the drug substance and product, and be
appropriately cross-referenced to the quality documentation.
Content and Structural Format

The Nonclinical Overview should be presented in the following sequence:
• Overview of the nonclinical testing strategy
• Pharmacology
• Pharmacokinetics
• Toxicology
• Integrated overview and conclusions
• List of literature references
2.5 CLINICAL OVERVIEW

The Clinical Overview should present the strengths and limitations of the development program and
study results, analyze the benefits and risks of the medicinal product in its intended use, and describe how
the study results support critical parts of the prescribing information.
In order to achieve these objectives, the Clinical Overview should:
• describe and explain the overall approach to the clinical development of a medicinal product, including
critical study design decisions.
• assess the quality of the design and performance of the studies, and include a statement regarding GCP
compliance.
• provide a brief overview of the clinical findings, including important limitations (e.g., lack of
comparisons with an especially relevant active comparator, or absence of information on some patient
populations, on pertinent endpoints, or on use in combination therapy).
• provide an evaluation of benefits and risks based upon the conclusions of the relevant clinical studies,
including interpretation of how the efficacy and safety findings support the proposed dose and target
indication and an evaluation of how prescribing information and other approaches will optimize benefits
and manage risks.
• address particular efficacy or safety issues encountered in development, and how they have been
evaluated and resolved.
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• explore unresolved issues, explain why they should not be considered as barriers to approval, and
describe plans to resolve them.
• explain the basis for important or unusual aspects of the prescribing information.
The Clinical Overview should generally be a relatively short document (about 30 pages). It is not intended
that material presented fully elsewhere be repeated in the Clinical Overview; cross-referencing to more
detailed presentations provided in the Clinical Summary or in Module 5 is encouraged.
2.5.1 Product Development Rationale

2.5.2 Overview of Biopharmaceutics
2.5.3 Overview of Clinical Pharmacology
2.5.4 Overview of Efficacy
2.5.5 Overview of Safety
2.5.6 Benefits and Risks Conclusions
2.5.6.1 Therapeutic Context
2.5.6.1.1 Disease or Condition
2.5.6.1.2 Current Therapies
2.5.6.2 Benefits
2.5.6.3 Risks
2.5.6.4 Benefit-Risk Assessment
2.5.6.5 Appendix
2.5.7 Literature References
2.6 NONCLINICAL WRITTEN AND TABULATED SUMMARIES
Order of Presentation of Information within Sections

When available, in vitro studies should precede in vivo studies.
Where multiple studies of the same type need to be summarized within the Pharmacokinetics and
Toxicology sections, studies should be ordered by species, by route, and then by duration (shortest
duration first).
Species should be ordered as follows:

• Mouse
• Rat
• Hamster
• Other rodent
• Rabbit
• Dog
• Non-human primate
• Other non-rodent mammal
• Non-mammals
Routes of administration should be ordered as follows:

• The intended route for human use
• Oral
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• Intravenous
• Intramuscular
• Intraperitoneal
• Subcutaneous
• Inhalation
• Topical
Sequence of Written Summaries and Tabulated Summaries

The following order is recommended:
• Introduction
• Written Summary of Pharmacology
• Tabulated Summary of Pharmacology
• Written Summary of Pharmacokinetics
• Tabulated Summary of Pharmacokinetcs
• Written Summary of Toxicology
• Tabulated Summary of Toxicology
2.7 Clinical Summary

The Clinical Summary includes information provided in ICH E3 clinical study reports; information
obtained from any meta-analyses or other cross-study analyses for which full reports have been included in
Module 5; and post-marketing data for products that have been marketed in other regions. The comparisons
and analyses of results across studies provided in this document should focus on factual observations.
In contrast, the CTD Clinical Overview document should provide critical analysis of the clinical
study program and its results, including discussion and interpretation of the clinical findings and discussion
of the place of the test drug in the armamentarium. The length of the Clinical Summary will vary
substantially according to the information to be conveyed, but it is anticipated that (excluding attached
tables) the Clinical Summary will usually be in the range of 50 to 400 pages.
Table of Contents:
2.7.1 Summary of Biopharmaceutic Studies and Associated Analytical Methods

2.7.1.1 Background and Overview
2.7.1.2 Summary of Results of Individual Studies
2.7.1.3 Comparison and Analyses of Results Across Studies
2.7.1.4 Appendix
2.7.2 Summary of Clinical Pharmacology Studies
2.7.2.1 Background and Overview
2.7.2.4 Special Studies
2.7.2.5 Appendix
2.7.3 Summary of Clinical Efficacy
2.7.3.1 Background and Overview of Clinical Efficacy
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2.7.3.4 Analysis of Clinical Information Relevant to Dosing Recommendations
2.7.3.5 Persistence of Efficacy and/or Tolerance Effects
2.7.3.6 Appendix
2.7.4 Summary of Clinical Safety
2.7.4.1 Exposure to the Drug
2.7.4.2 Adverse Events
2.7.4.3 Clinical Laboratory Evaluations
2.7.4.4 Vital Signs, Physical Findings, and Other Observations Related to Safety
2.7.4.5 Safety in Special Groups and Situations
2.7.4.6 Post-marketing Data
2.7.4.7 Appendix
2.7.5 Literature References
2.7.6 Synopses of Individual Studies
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5. MODULE 3: (QUALITY / CMC)
3.1. TABLE OF CONTENTS OF MODULE 3

A Table of Contents for the filed application should be provided.
3.2. BODY OF DATA
3.2.S DRUG SUBSTANCE* (NAME, MANUFACTURER)
3.2.S.1 General Information (name, manufacturer)
3.2.S.1.1 Nomenclature (name, manufacturer)
Information on the nomenclature of the drug substance should be provided. For example:
• Recommended International Nonproprietary 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),
Japanese Accepted Name (JAN); British Approved Name (BAN), and
• Chemical Abstracts Service (CAS) registry number.
*For a drug product containing more than one drug substance, the information requested for part “S”
should be provided in its entirety for each drug substance.
3.2.S.1.2 Structure (name, manufacturer)

The schematic amino acid sequence indicating glycosylation sites or other post-translational
modifications and relative molecular mass should be provided, as appropriate.
3.2.S.1.3 General Properties (name, manufacturer)
A list should be provided of physicochemical and other relevant properties of the drug substance, including
biological activity for Biotech.
Reference ICH Guidelines: Q6A and Q6B
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.
3.2.S.2.2 Description of Manufacturing Process and Process Controls (name, manufacturer)

The description of the drug substance manufacturing process represents the applicant’s commitment
for the manufacture of the drug substance. Information should be provided to adequately describe the
manufacturing process and process controls. For example:
Information should be provided on the manufacturing process, which typically starts with a vial(s)
of the cell bank, and includes cell culture, harvest(s), purification and modification reactions, filling, storage
and shipping conditions.
Batch(es) and scale definition
An explanation of the batch numbering system, including information regarding any pooling of
harvests or intermediates and batch size or scale should be provided.
Cell culture and harvest
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A flow diagram should be provided that illustrates the manufacturing route from the original
inoculum (e.g. cells contained in one or more vials(s) of the Working Cell Bank up to the last harvesting
operation. The diagram should include all steps (i.e., unit operations) and intermediates. Relevant
information for each stage, such as population doubling levels, cell concentration, volumes, pH, cultivation
times, holding times, and temperature, should be included. Critical steps and critical intermediates for which
specifications are established (as mentioned in 3.2.S.2.4) should be identified.
A description of each process step in the flow diagram should be provided. Information should be
included on, for example, scale; culture media and other additives (details provided in 3.2.S.2.3); major
equipment (details provided in 3.2.A.1); and process controls, including in-process tests and operational
parameters, process steps, equipment and intermediates with acceptance criteria (details provided in
3.2.S.2.4). Information on procedures used to transfer material between steps, equipment, areas, and
buildings, as appropriate, and shipping and storage conditions should be provided. (Details on shipping and
storage provided in 3.2.S.2.4.)
Purification and modification reactions
A flow diagram should be provided that illustrates the purification steps (i.e., unit operations) from
the crude harvest(s) up to the step preceding filling of the drug substance. All steps and intermediates and
relevant information for each stage (e.g., volumes, pH, critical processing time, holding times, temperatures
and elution profiles and selection of fraction, storage of intermediate, if applicable) should be included.
Critical steps for which specifications are established as mentioned in 3.2.S.2.4 should be identified.
A description of each process step (as identified in the flow diagram) should be provided. The
description should include information on, for example, scale, buffers and other reagents (details provided
in 3.2.S.2.3, major equipment (details provided in 3.2.A.1), and materials. For materials such as membranes
and chromatography resins, information for conditions of use and reuse also should be provided. (Equipment
details in 3.2.A.1; validation studies for the reuse and regeneration of columns and membranes in 3.2.S.2.5.)
The description should include process controls (including inprocess tests and operational parameters) with
acceptance criteria for process steps, equipment and intermediates. (Details in 3.2.S.2.4.)
Reprocessing procedures with criteria for reprocessing of any intermediate or the drug substance
should be described. (Details should be given in 3.2.S.2.5.)
Information on procedures used to transfer material between steps, equipment, areas, and buildings,
as appropriate, and shipping and storage conditions should be provided (details on shipping and storage
provided in 3.2.S.2.4.).
Filling, storage and transportation (shipping)
A description of the filling procedure for the drug substance, process controls (including in-process
tests and operational parameters), and acceptance criteria should be provided. (Details in 3.2.S.2.4.) The
container closure system(s) used for storage of the drug substance (details in 3.2.S.6.) and storage and
shipping conditions for the drug substance should be described.
Reference ICH Guidelines: Q5A, Q5B, and Q6B
3.2.S.2.3 Control of Materials (name, manufacturer)

Materials used in the manufacture of the drug substance (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 (e.g., media components, monoclonal antibodies, enzymes etc.) meet standards appropriate
for their intended use (including the clearance or control of adventitious agents) should be provided, as
appropriate.
Page 21 of 35
Control of Source and Starting Materials of Biological Origin
Summaries of viral safety information should be provided. (Details in 3.2.A.2.)
Source, history, and generation of the cell substrate
Information on the source of the cell substrate and analysis of the expression construct used to
genetically modify cells and incorporated in the initial cell clone used to develop the Master Cell Bank
should be provided as described in Q5B and Q5D.
Cell banking system, characterization, and testing
Information on the cell banking system, quality control activities, and cell line stability during
production and storage (including procedures used to generate the Master and Working Cell Bank(s)) should
be provided as described in Q5B and Q5D.
Reference ICH Guidelines: Q5A, Q5B, Q5C and Q5D
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.
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.
Sufficient information should be provided on validation and evaluation studies to demonstrate that
the manufacturing process (including reprocessing steps) is suitable for its intended purpose and to
substantiate selection of critical process controls (operational parameters and in-process tests) and their
limits for critical manufacturing steps (e.g., cell culture, harvesting, purification, and modification).
The plan for conducting the study should be described and the results, analysis and conclusions from
the executed study(ies) should be provided. The analytical procedures and corresponding validation should
be cross-referenced (e.g., 3.2.S.2.4, 3.2.S.4.3) or provided as part of justifying the selection of critical
process controls and acceptance criteria.
3.2.S.2.6 Manufacturing Process Development (name, manufacturer)

The developmental history of the manufacturing process, as described in 3.2.S.2.2, should be
provided. The description of change(s) made to the manufacture of drug substance batches used in support
of the marketing application (e.g., nonclinical or clinical studies) should include, for example, changes to
the process or to critical equipment. The reason for the change should be explained. Relevant information
on drug substance batches manufactured during development, such as the batch number, manufacturing
scale, and use (e.g., stability, nonclinical, reference material) in relation to the change, should be provided.
The significance of the change should be assessed by evaluating its potential to impact the quality of
the drug substance (and/or intermediate, if appropriate). For manufacturing changes that are considered
significant, data from comparative analytical testing on relevant drug substance batches should be provided
to determine the impact on quality of the drug substance (see Q6B for additional guidance). A discussion of
the data, including a justification for selection of the tests and assessment of results, should be included.
Page 22 of 35
Testing used to assess the impact of manufacturing changes on the drug substance(s) and the
corresponding drug product(s) can also include nonclinical and clinical studies. Cross-reference to the
location of these studies in other modules of the submission should be included.
Reference should be made to the drug substance data provided in section 3.2.S.4.4.
Reference ICH Guideline: Q6B
3.2.S.3 Characterization (name, manufacturer)

3.2.S.3.1 Elucidation of Structure and other Characteristics (name, manufacturer)
For desired product and product-related substances, details should be provided on primary,
secondary and higher-order structure, post-translational forms (e.g., glycoforms), biological activity, purity,
and immunochemical properties, when relevant.
3.2.S.3.2 Impurities (name, manufacturer)

Information on impurities should be provided.
Reference ICH Guidelines: Q3A, Q3C, Q5C, Q6A, and Q6B
3.2.S.4 Control of Drug Substance (name, manufacturer)

3.2.S.4.1 Specification (name, manufacturer)
The specification for the drug substance should be provided.
3.2.S.4.2 Analytical Procedures (name, manufacturer)

The analytical procedures used for testing the drug substance should be provided.
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 drug substance, should be provided.
Reference ICH Guidelines: Q2A, Q2B, and Q6B
3.2.S.4.4 Batch Analyses (name, manufacturer)

Description of batches and results of batch analyses should be provided.
Reference ICH Guidelines: Q3A, Q3C, Q6A, and Q6B
3.2.S.4.5 Justification of Specification (name, manufacturer)

Justification for the drug substance specification should be provided.
Reference ICH Guidelines: Q3A, Q3C, Q6A and Q6B
3.2.S.5 Reference Standards or Materials (name, manufacturer)

Information on the reference standards or reference materials used for testing of the drug substance should
be provided.
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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.
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 drug substance, including sorption
to container and leaching, and/or safety of materials of construction.
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 summarized.
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 shelf-life, as appropriate.
Reference ICH Guidelines: Q1A, Q1B, and Q5C
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.
Reference ICH Guidelines: Q1A and Q5C
3.2.S.7.3 Stability Data (name, manufacturer)

Results of the stability studies (Real time & Accelerated) should be presented in an appropriate
format.
3.2.P Drug Product
3.2.P.1 Description and Composition of the Drug Product
a) Description of the dosage form

The description of the Drug product shall include the physical description, available strengths, release
mechanism (e.g. immediate or modified (delayed or extended)), as well as any other distinguishable
characteristics.
b) Composition
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 manufacturer’s specifications). * Overages are not acceptable unless fully justified
If the Drug product is formulated using an active moiety, then the composition for the active ingredient
shall be clearly indicated.
c) Description of accompanying reconstitution diluent(s)
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Provide information including type of diluent, its composition, quantity or volume, specifications (as
applicable) and regulatory status in Pakistan (as applicable) for the diluent which is to be provided along
with the applied drug.
d) Type of Container Closure:

The container-closure used for the Drug Product (and accompanying reconstitution diluent, if applicable)
shall be briefly described, with further details provided under 3.2.P.7 Container-closure system
3.2.P.2 Pharmaceutical Development

A brief information on the pharmaceutical development shall be included. This information specifies the
justification of formulation and method of manufacturing. It is also important that critical quality
attributes (CQAs) and Critical Process Parameters (CPP) shall be discussed.
3.2.P.2.1 Components of the Drug Product
Drug substance
The compatibility of the drug substance 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 drug substance that can influence the performance
of the drug product should be discussed. For combination products, the compatibility of drug substances
with each other should be discussed.
Excipients
The choice of excipients listed in 3.2.P.1, their concentration, their characteristics that can influence the
drug product performance should be discussed relative to their respective functions.
3.2.P.2.2 Formulation Development

A brief summary describing the development of the drug product should be provided, taking into
consideration the proposed route of administration and usage. The differences between clinical
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.
Any overages in the formulation(s) described in 3.2.P.1 should be justified.
Parameters relevant to the performance of the drug product, such as pH, reconstitution, particle size
biological activity or potency, and/or immunological activity, should be addressed.
3.2.P.2.3 Manufacturing Process Development

The selection and optimization of the manufacturing process described in 3.2.P.3.3, in particular its
critical aspects, should be explained. Where relevant, the method of sterilization should be explained
and justified.
Differences between the manufacturing process(es) used to produce pivotal clinical batches and the
process described in 3.2.P.3.3 that can influence the performance of the product should be discussed.
Page 25 of 35
3.2.P.2.4 Container Closure System
3.2.P.2.5 Microbiological Attributes

3.2.P.2.6 Compatibility
The compatibility of the drug product with reconstitution diluent(s) or dosage devices (e.g., precipitation
of drug substance in solution, sorption on injection vessels, stability) should be addressed to provide
appropriate and supportive information for the labeling.
3.2.P.3 Manufacture
3.2.P.3.1 Manufacturer
The name, address, and responsibility of each manufacturer, including contractors, and each proposed
production site or facility involved in manufacturing and testing shall be provided.
3.2.P.3.2 Batch formula

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.
3.2.P.3.3 Description of manufacturing process and process controls

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 represents 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 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.
3.2.P.3.4 Controls of critical steps and intermediates

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.
Reference ICH Guidelines: Q2A, Q2B, Q6A, and Q6B
3.2.P.3.5 Process validation and/or evaluation

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 sterilization
process or aseptic processing or filling).
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3.2.P.4 Control of Excipients Specifications

3.2.P.4.1 Specifications
3.2.P.4.2 Analytical procedures
3.2.P.4.3 Validation of analytical procedures
Validation information for the analytical procedures for in-house standard excipients shall be submitted.
<Copies of analytical procedures of non-compendial excipient shall be submitted>
3.2.P.4.4 Justification of specifications

Justification of the specifications for the analytical procedures for in-house standard excipients shall be
provided.
3.2.P.4.5 Excipients of Human or Animal Origin

For excipients of human or animal origin, a certificate shall be provided, confirming that the excipient(s)
are free from BSE and TSE.
3.2.P.4.6 Novel Excipients

For excipient(s) used for the first time in a drug product or by a new route of administration, full details
of specification and testing method shall be provided.
3.2.P.5 Control of Drug Product
3.2.P.5.1 Specification(s)
A copy of the drug product specification(s) including tests, acceptance criteria and reference to analytical
procedure shall be provided. Specifications shall also include the details of impurities (as applicable).
3.2.P.5.2 Analytical procedures

Detailed analytical procedures used for testing the drug product shall be provided.
3.2.P.5.3 Validation of analytical procedures

For in-house methods, analytical method validation shall be performed.
All the officially recognized compendial methods for assay, impurities etc. (as applicable) are required
to be verified and verification shall include a demonstration of specificity, repeatability (method
precision) and accuracy.
3.2.P.5.4 Batch analysis

The copies of complete analysis of at least two batches shall be provided.
3.2.P.5.5 Characterization of impurities

Information on the characterization of impurities should be provided, if not previously provided in
"3.2.S.3.2 Impurities".
3.2.P.5.6 Justification of specifications
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The justification of specification(s) for non-pharmacopeial products must be provided. Justification of
specification of non-pharmacopeial product shall be based on batch analysis results.
3.2.P.6 Reference Standards or Materials

For testing of Pharmacopeial Drug Product(s), the use of primary reference standard is recommended,
however for non-pharmacopeial Drug Product(s), a secondary reference standard is acceptable. COA of
primary / secondary reference standard including source and lot number shall be provided.
3.2.P.7 Container Closure System

A detail of the container closure systems, description of the primary container closure systems, including
materials of construction, unit count or fill size, container size or volume shall be provided.
3.2.P.8 Stability
For the pre-market authorization stability studies for a period of 6 months accelerated and real time in
proposed container closure system is required in accordance with the Zone IVa conditions. Based on the
satisfactory results, a two years shelf life will be granted. For selection of number and size of batches
applicant may follow, any of the following options:
a) ICH/WHO guidelines.
b) At least 2 batches having the following minimum batch size considering the scientific reliability
• OSDs: 5000 Units
• Oral Liquids: 2000
• Injectable: 2000
c) At least 3 batches having scientifically rational batch size, sufficient enough to perform complete
testing till the claimed shelf life.
3.2.P.8.1 Stability summary and conclusion (Finished Product):

Summary of stability batches with details of storage conditions, batch numbers, batch size, testing
intervals and container closure system along with proposed storage statement and shelf-life shall be
provided.
Summary of additional stability studies (if applicable) e.g. in-use studies for drug products which are to
be reconstituted before use, along with proposed in-use storage statement and in-use shelf-life shall be
provided.
3.2.P.8.2 Post-approval Stability Protocol and Stability Commitment:

For applications of locally manufactured drug product(s), stability protocol for commitment batches (e.g.
storage conditions, batch numbers and batch sizes, tests and acceptance criteria, testing frequency,
container closure system(s) shall be provided. A written commitment (signed and dated) to continue
long-term testing over the shelf-life shall be included in Module-1.
For applications of imported drug product(s) where stability study data till complete shelf life is
submitted, post-approval stability protocols and commitment is not required.
3.2.P.8.3 Stability Data:

Results of the stability studies shall be presented in an appropriate format (provided below).
The actual stability results and reports used to support the proposed shelf-life shall be provided. For
quantitative tests (e.g. individual and total degradation product tests and assay tests), actual numerical
Page 28 of 35
results shall be provided rather than vague statements such as “within limits” or “conforms”. Conduction
of stability study data shall be scientifically justified.
Storage Conditions: a)
General case
The general case applies if the drug product is not specifically covered by any other storage condition in
the subsequent sections.
Study Storage condition
Accelerated 40°C ± 2°C / 75% RH ± 5% RH
Long term 30°C ± 2°C / 65% RH ± 5% RH
b) Drug products packaged in semi-permeable containers

Aqueous-based products packaged in semi-permeable containers shall be evaluated for potential water
loss in addition to physical, chemical, biological, and microbiological stability.
Other comparable approaches can be developed and reported for non-aqueous, solvent-based products.

Accelerated 40°C ± 2°C / NMT 25% RH
Long term 30°C ± 2°C / 35% RH ± 5% RH
c) Drug products intended for storage in a refrigerator

Accelerated 25°C ± 2°C / 60% RH ± 5% RH
Long term 5°C ± 3°C
d) Drug products intended for storage in a freezer

Accelerated 5°C ± 3°C or 25°C ± 2°C
Long term - 20°C ± 5°C
Stability data submission:

• For applications of imported drug product(s), real time and accelerated stability data (summary
sheets) as per ICH guidelines or till claimed shelf life as per the storage conditions mentioned
above shall be provided.
• For applications of locally manufactured drug product(s), the stability study data shall be
provided as per the below mentioned format.
Stability study data submission locally manufactured products for CTD:
Stability Study Data Sheet
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Product details:
Product name ABCD Injection Batch No.
Description of pack Type I Glass Vial

(container closure Batch Size.
system)
Parameters and tests As per Product Specifications Mfg. Date
mentioned
Recommended storage Accelerated Exp Date
conditions conditions
Real time
conditions
Date of initiation of (API) lot no.
stability studies
Accelerated Stability study data:

Storage conditions
Assessment frequency (Months) Initial 3 6

Date of Testing
Tests (as per Acceptance Criteria
specifications)
Real time stability study data:

Storage conditions
Assessment frequency (Months) Initial 3 6

Date of Testing
Tests (as per Acceptance Criteria
specifications)
Documents / Data to be provided along with stability study data:
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1. Approval of API/ DML/GMP certificate of API manufacturer issued by concerned regulatory
authority of country of origin.
3. Data of stability batches will be supported by attested respective documents like chromatograms,
Raw data sheets, COA, summary data sheets etc.
4. Record of Digital data logger for temperature and humidity monitoring of stability chambers (real
time and accelerated)
3.2.A Appendices
3.2.A.1 Facilities and equipment

A list of manufacturing and testing facilities / equipment available with reference to the applied drug
product shall be provided.
3.2.A.2 Adventitious agent safety evaluation

For non-viral adventitious agents:
Detailed information should be provided on the avoidance and control of non-viral adventitious
agents (e.g., transmissible spongiform encephalopathy agents, bacteria, mycoplasma, fungi). This
information can include, for example, certification and/or testing of raw materials and excipients, and
control of the production process, as appropriate for the material, process and agent.
Reference ICH Guidelines: Q5A, Q5D, and Q6B
For viral adventitious agents:
Detailed information from viral safety evaluation studies should be provided in this section. Viral
evaluation studies should demonstrate that the materials used in production are considered safe, and that
the approaches used to test, evaluate, and eliminate the potential risks during manufacturing are suitable.
The applicant should refer to Q5A, Q5D, and Q6B for further guidance.
Materials of Biological Origin
Information essential to evaluate the virological safety of materials of animal or human origin (e.g.
biological fluids, tissue, organ, cell lines) should be provided. (See related information in 3.2.S.2.3, and
3.2.P.4.5). For cell lines, information on the selection, testing, and safety assessment for potential viral
contamination of the cells and viral qualification of cell banks should also be provided. (See related
information in 3.2.S.2.3).
Testing at appropriate stages of production
The selection of virological tests that are conducted during manufacturing (e.g., cell substrate,
unprocessed bulk or post viral clearance testing) should be justified. The type of test, sensitivity and
specificity of the test, if applicable, and frequency of testing should be included. Test results to confirm,
at an appropriate stage of manufacture, that the product is free from viral contamination should be
provided. (See related information in 3.2.S.2.4 and 3.2.P.3.4 ).
Viral Testing of Unprocessed Bulk
In accordance with Q5A and Q6B, results for viral testing of unprocessed bulk should be included.
Viral Clearance Studies
In accordance with Q5A, the rationale and action plan for assessing viral clearance and the results and
evaluation of the viral clearance studies should be provided. Data can include those that demonstrate the
validity of the scaled-down model compared to the commercial scale process; the adequacy of viral
inactivation or removal procedures for manufacturing equipment and materials; and manufacturing steps
Page 31 of 35
that are capable of removing or inactivating viruses. (See related information in 3.2.S.2.5 and 3.2.P.3.5).
Reference ICH Guidelines: Q5A, Q5D, and Q6B
Excipients
For excipient(s) used for the first time in a drug product or by a new route of administration, full details
of manufacture, characterization, and controls, with cross references to supporting safety (non-clinical
and/or clinical) data shall be provided.
3.2.R Regional Information
Comparability Protocols
For Biosimilar Drugs, the applicant shall submit complete quality comparison of their product with
Innovator product in light of guidelines approved by Registration Board in its 297th meeting.
Module 4: (Non-clinical / Safety)

The table of contents for Module 4 should include all of the numerical items listed in the CTD
guidance in order to identify all of the important components of the application and should continue
down to at least the level of the study report. Thus, each study report should be identified in the table of
contents.
The study reports should be presented in following order:
4.2.1 Pharmacology
4.2.1.1 Primary Pharmacodynamics
4.2.1.2 Secondary Pharmacodynamics
4.2.1.3 Safety Pharmacology
4.2.1.4 Pharmacodynamic Drug Interactions
4.2.2 Pharmacokinetics
4.2.2.1 Analytical Methods and Validation Reports (if separate reports are available)
4.2.2.2 Absorption
4.2.2.3 Distribution
4.2.2.4 Metabolism
4 2.2.5 Excretion
4.2.2.6 Pharmacokinetic Drug Interactions (nonclinical)
4.2.2.7 Other Pharmacokinetic Studies
4.2.3 Toxicology
4.2.3.1 Single-Dose Toxicity (in order by species, by route)
4.2.3.2 Repeat-Dose Toxicity (in order by species, by route, by duration; including
supportive toxicokinetics evaluations)
4.2.3.3 Genotoxicity
4.2.3.3.1 In vitro
4.2.3.3.2 In vivo (including supportive toxicokinetics evaluations)
4.2.3.4 Carcinogenicity (including supportive toxicokinetics evaluations)
4.2.3.4.1 Long-term studies (in order by species; including range-finding studies that cannot
appropriately be included under repeat-dose toxicity or pharmacokinetics)
Page 32 of 35
4.2.3.4.2 Short- or medium-term studies (including range-finding studies that cannot
appropriately be included under repeat-dose toxicity or pharmacokinetics)
4.2.3.4.3 Other studies
4.2.3.5 Reproductive and Developmental Toxicity (including range-finding studies and
supportive toxicokinetics evaluations) (If modified study designs are used, the following
sub-headings should be modified accordingly.)
4.2.3.5.1 Fertility and early embryonic development
4.2.3.5.2 Embryo-fetal development
4.2.3.5.3 Prenatal and postnatal development, including maternal function
4.2.3.5.4 Studies in which the offspring (juvenile animals) are dosed and/or further
evaluated.
4.2.3.6 Local Tolerance
4.2.3.7 Other Toxicity Studies (if available)
4.2.3.7.1 Antigenicity
4.2.3.7.2 Immunotoxicity
4.2.3.7.3 Mechanistic studies (if not included elsewhere)
4.2.3.7.4 Dependence
4.2.3.7.5 Metabolites
4.2.3.7.6 Impurities
4.2.3.7.7 Other
Module 5: (Clinical / Efficacy)
The table of contents for Module 5 should include all of the numerical items listed in the CTD
guidance in order to identify all of the important components of the application and should continue
down to at least the level of the clinical study report. Thus, each clinical study report should be identified
in the table of contents. The sections of a clinical study report (E3) could be identified in the Module 5
Table of Contents of the dossier or only in the table of contents of the individual clinical study report.
The study reports should be presented in following order:
Clinical Study Reports
5.3.1 Reports of Biopharmaceutic Studies
5.3.1.1 Bioavailability (BA) Study Reports
5.3.1.2 Comparative BA and Bioequivalence (BE) Study Reports
5.3.1.3 In vitro-In vivo Correlation Study Reports
5.3.1.4 Reports of Bioanalytical and Analytical Methods for Human Studies
5.3.2 Reports of Studies Pertinent to Pharmacokinetics using Human Biomaterials
5.3.2.1 Plasma Protein Binding Study Reports
5.3.2.2 Reports of Hepatic Metabolism and Drug Interaction Studies
5.3.2.3 Reports of Studies Using Other Human Biomaterials
5.3.3 Reports of Human Pharmacokinetic (PK) Studies
5.3.3.1 Healthy Subject PK and Initial Tolerability Study Reports
5.3.3.2 Patient PK and Initial Tolerability Study Reports
5.3.3.3 Intrinsic Factor PK Study Reports
5.3.3.4 Extrinsic Factor PK Study Reports
5.3.3.5 Population PK Study Reports
5.3.4 Reports of Human Pharmacodynamic (PD) Studies
Page 33 of 35
5.3.4.1 Healthy Subject PD and PK/PD Study Reports
5.3.4.2 Patient PD and PK/PD Study Reports
5.3.5 Reports of Efficacy and Safety Studies
5.3.5.1 Study Reports of Controlled Clinical Studies Pertinent to the Claimed Indication
5.3.5.2 Study Reports of Uncontrolled Clinical Studies
5.3.5.3 Reports of Analyses of Data from More Than One Study
5.3.5.4 Other Clinical Study Reports
REFERENCES
1. The DRAP Act, 2012.

2. The Drugs Act 1976.
3. The Drugs (Licensing, Registering and Advertising) Rules, 1976.
4. ICH -M4Q (R1) Guidelines.
5. ICH -SAFETY – M4S(R2)
6. ICH -EFFICACY - M4E(R2)
7. WHO GUIDELINES ON EVALUATION OF SIMILAR BIOTHERAPEUTIC PRODUCTS (SBPs)
8. WHO QUALITY OVERALL SUMMARY: PRODUCT DOSSIER (QOS-PD) TEMPLATE
Page 34 of 35
DRUG REGULATORY AUTHORITY OF PAKISTAN
Telecom Foundation Complex, G-9/4, Islamabad, Pakistan
Email: addl-dir.pe.reg@dra.gov.pk Phone:92-51-9107416 www.dra.gov.pk
www.dra.gov.pk

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GUIDANCE DOCUMENT FOR SUBMISSION OF APPLICATION ON

FORM 5-F (CTD) FOR REGISTRATION OF BIOLOGICAL DRUG

Document No.: BE&R/GL/AF

Drug Regulatory Authority of Pakistan

2. APPLICATION 1 - Guidance for Industry.

2. LEGAL PROVISIONS .......................................................................................................... 5

3. GENERAL GUIDANCE FOR APPLICANTS ................................................................... 5

MODULE 1: (ADMINISTRATIVE PART) ............................................................................... 6

1.1 Covering Letter and Fee Deposit Slip .......................................................................................... 6

1.2 Table of Contents (From Module 1 to Module 5) ........................................................................ 6

1.3 Applicant Information ................................................................................................................... 6

1.4 Type of Application ........................................................................................................................ 7

MODULE 2: (OVERVIEWS AND SUMMARIES) ................................................................. 12

MODULE 3: (QUALITY / CMC) .............................................................................................. 30

3. GENERAL GUIDANCE FOR APPLICANTS

MODULE 1: (ADMINISTRATIVE PART)

1.2 Table of Contents (From Module 1 to Module 5)

1.3 Applicant Information

1.3.2. Name, address and contact details of manufacturing site

c) Import (The applicant is importer for the applied product)

1.3.3. Specify whether the Applicant is:

1.3.5. Evidence of approval of manufacturing facility / Approved Section from Licensing

1.3.6. List of already approved registered drugs in this section

1.3.7. Identification of Signature(s) of authorized persons, Incharge Production, Quality Control

1.3.8. Manufacturer’s Site Master File and Credential (for importer)

1.4 Type of Application

1.4.1. Application is for the registration of:

1.4.1 Biological product is intended for:

1.4.2. For imported products, please specify one of following:

1.5 Detailed Information of Drug, Dosage From & Labeling Claims

1.5.6 Pharmacopoeial reference / Status of applied formulation

1.5.7 Route of administration

1.5.10 Dosage form of applied drug

1.5.12 Description of Batch numbering system

1.5.15 – 1.5.20 Commitments

1.5.22 Protocols to implement Good Pharmacovigilance Practice by the Pharmacovigilance

1.6 Miscellaneous Information

1.6.3 Electronic Review Package

1.6.4 QIS (Quality Information Summary)

1.6.5 Drug Substance related Document including following:

MODULE 2: (OVERVIEWS AND SUMMARIES)

2.3.S. DRUG SUBSTANCE (NAME, MANUFACTURER)

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

2.3.S.3 Characterization (name, manufacturer)

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

2.3.S.5 Reference Standards or Materials

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

2.3.P DRUG PRODUCT (NAME, DOSAGE FORM)

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

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

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

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

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

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

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

2.3.A.1 Facilities and Equipment

2.3.A.2 Adventitious Agents Safety Evaluation

2.3.R Regional Information

2.3.R.1 Production Documentation