2nd & 3rd Floors, Clay Building

Sekou Toure Avenue, Mamba Point

Monrovia, Montserrado County
Republic of Liberia

P. O. Box 1994
Cell: +231 – 777140555/888140555
Email: [email protected] Website: www.lmhra.gov.lr

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 TABLE OF CONTENTS
ACKNOWLEDGEMENT ................................................................................................................................... 4
BACKGROUND ................................................................................................................................................. 5
INTRODUCTION ............................................................................................................................................... 6
LIST OF ABBREVIATIONS ............................................................................................................................. 7
GLOSSARY ........................................................................................................................................................ 8
PROCEDURE FOR SUBMISSION OF APPLICATIONS IN CTD FORMAT .............................................. 15
TYPE OF APPLICATIONS.............................................................................................................................. 16
1.1. Payment of Fees ......................................................................................................... 17
1.2. Criteria for rejection of application submission ........................................................ 18
1.3. General format and guidance for preparation of dossiers ......................................... 18
MODULE 1: ADMINISTRATIVE AND PRODUCT INFORMATION ......................................................... 21
Good Manufacturing Practice and Certificate of Pharmaceutical Product ................................................. 21
Registration status ......................................................................................................................................... 23
Manufacturing and Marketing authorization ..................................................................................................... 23
VARIATION PRINCIPLES ............................................................................................................................. 23
PRODUCT REGISTRATION APPLICATION FORM FOR VARIATION ........................................... 23
ANNEX I: APPLICATION FORM .................................................................................................................. 29
MODULE 2.3: QUALITY OVERALL SUMMARY: PRODUCT DOSSIER (QOS-PD)............................... 34
2.3.P DRUG PRODUCT (or FINISHED PHARMACEUTICAL PRODUCT (FPP)) ................................. 46
QUALITY INFORMATION SUMMARY (QIS) ............................................................................................. 63
PRESENTATION OF BIOEQUIVALENCE TRIAL INFORMATION .......................................................... 67
2 CLINICAL STUDY REPORT .................................................................................................................. 68
Comment from Assessors ............................................................................................................................ 72
3 TRIAL SUBJECTS ................................................................................................................................... 73
3.3 Comments from review of Section 3 – Assessors use only........................................ 73
4 PROTOCOL DEVIATIONS ..................................................................................................................... 73
4.2 Comments from review of Section 4 – Assessors use only........................................ 73
5 SAFETY EVALUATION ......................................................................................................................... 74
5.2 Comments from review of Section 5 – Assessors use only........................................ 74
6.5 Comments from review of Section 6 – Assessors use only........................................ 76
7 ANALYTICAL VALIDATION REPORT ............................................................................................... 77
7.12 Comments from review of Section 7 – Assessors use only........................................ 79
8 BIOANALYTICAL STUDY REPORT .................................................................................................... 79

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 8.8 Comments from review of Section 9 – Assessors use only........................................ 81
9 QUALITY ASSURANCE ......................................................................................................................... 81
9.3 Comments from review of Section 10 – Assessors use only...................................... 81
10.0 CONCLUSIONS AND RECOMMENDATIONS – Assessors use only ................... 82
ANNEX B1- MODEL COVER LETER ........................................................................................................... 82
ANNEX B2 MODEL LETTER OF ACCESS TO CEP .................................................................................... 84

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 ACKNOWLEDGEMENT

The writing of this guideline is an outcome of a five (5)-day retreat for senior staff of the Liberia
Medicines and Health Products Regulatory Authority (LMHRA). We herein acknowledge the
ingenuity, far-sightedness and leadership role of Pharm. Keturah C. Smith, Managing Director of
LMHRA, which led to the successful convening of the retreat.

We also acknowledge the organizational skills and guidance of the 2020 Retreat Committee led by Dr.
Thomas B.L. Kokulo who is the Deputy Director of the Inspectorate Department of LMHRA. We salute
the retreat participants for the useful comments during the deliberations of the retreat. Their
contributions during the deliberations and the resolution derived from the Retreat helped in the
crafting of this regulatory guidance document.

Much recognition is given to the Guideline Drafting Team which includes Pharm. Patricia Quaye-
Freeman, Director of Evaluation of Registration; Pharm. Mary G. Jalloh-Tozo, Deputy Director of
Evaluation of Registration; Pharm. Emmanuel Willie, Data & Research Manager; Pharm. Alexander
Momoh; Dr. Sumo Maiwo; and Pharm. Humphrey Taylor. Our heartfelt thanks also go to Dr. Flomoku
G. Miller, Technical Advisor to the Managing Director, for his encouragement, technical and moral
support to the Guideline Drafting Team.

We also acknowledge and give recognition to the World Health Organization (WHO) and the
International Committee on Harmonization (ICH) for making available documents which were used
as resource materials in the compilation of this guideline.

Most importantly and above all else, we sincerely give thanks and praises to the Almighty God for
endowing us with the insight, resourcefulness and strength to draft this guideline. The guideline, along
with other quality documents, shall constitute the legal basis for the evaluation and registration of
medicines and health products in Liberia.

The LMHRA Evaluation and Registration Department shall welcome comments/suggestions for
improvement of this guideline during its implementation.

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 BACKGROUND

ECOWAS recognizing that all the fifteen member states have different requirements for submission of
their dossiers for the granting of marketing authorization, initiated activities to harmonize medical
products registration in the region. This initiative resulted in the development of registration
requirements based on CTD format that were validated, and adopted by ECOWAS member states. A
Common Technical Document (CTD) is an internationally agreed upon format for the organization
and preparation of application dossiers for marketing authorization developed through the International
Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human use (ICH)
process, it is used by an increasing number of regulatory authorities, including the European Union,
the US Food and Drug Administration, Japan, and Canada among others. The WHO has adopted the
CTD as the format for applications submitted to its Prequalified Programme. The CTD is organized
into five modules (see the CTD triangle below). Module 1 is region specific and modules 2, 3, 4 and
5 are intended to be common for all regions. Applicants should not modify the overall organization of
the CTD.

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 INTRODUCTION

The regulation of medicines and related health products in Liberia is governed by the provisions and
requirements of the Liberia Medicines and Health Products Regulatory Authority (LMHRA) Act,
2010.

The law requires that all medicines manufactured, imported or exported, distributed, or sold in Liberia
should be of acceptable quality, safe and efficacious. The process of medicines registration forms an
important basis for evaluating and assuring that medicines and health products are of good quality and
safe. Mindful of the need to increase access to quality medicines and to promote and protect public
health by developing regulatory systems that satisfy minimum regulatory capacity, the Liberia
Medicines and Health Products Regulatory Authority has adopted the Common Technical Document
format for submission of documentation for registration of pharmaceuticals for human use in Liberia.

Objective

These guidelines are intended to provide guidance to applicants to prepare product dossiers in CTD
format for submission to LMHRA.

LEGAL BASIS

In pursuance of Part 1 Section 1 of the Act to Establish the Liberia Medicines and Health Products
Regulatory Authority (LMHRA) of 2010, these guidelines, which require use of the Common
Technical Document (CTD) format shall be followed by all applicants when preparing applications
for Marketing Authorization of Pharmaceutical Products for Human use intended for submission to
LMHRA. This guideline is hereby made to provide guidance to applicants on the procedure for
registering medicines and health products in Liberia. Applicants are required to familiarize themselves
with this document and the above law before completing the registration application form (Appendix
1)

Scope

These guidelines apply to all pharmaceutical products of synthetic or semi-synthetic origin other than
biological products, traditional medicinal products, diagnostic aids and medical appliances.

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 LIST OF ABBREVIATIONS

API Active pharmaceutical ingredient

APIMF Active pharmaceutical ingredient master file
BCS Biopharmaceutics Classification System
BP British Pharmacopoeia
CEPT Certificate of Suitability
CPP Certificate of Pharmaceutical Product
CTD Common Technical Document
DMF Drug Master File
DOS-PD Dossier Overall Summary of Product Dossier
FPP Finished Pharmaceutical Product
GMP Good Manufacturing Practice
ICH International Council for Harmonization
IVIVC in vitro-in vivo correlation
JP Japanese Pharmacopoeia
LMHRA Liberia Medicines & Health Products Regulatory Authority
OTC Over-the-counter
Ph.Eur. European Pharmacopoeia
Ph.Int. The International Pharmacopoeia
QIS Quality Information Summary
QOS Quality Overall Summary
SmPC Summary of Product Characteristics
SOP Standard operating procedure
USP United States Pharmacopeia
WHO World Health Organization

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 GLOSSARY

The definitions provided below apply to the words and phrases used in these guidelines to facilitate
interpretation of the guidelines:

Active pharmaceutical ingredient (API)

Any substance or mixture of substances intended to be used in the manufacture of a pharmaceutical

dosage form and that, when so used, becomes an active ingredient of that pharmaceutical dosage form.
Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis,
cure, mitigation, treatment, or prevention of disease or to affect the structure and function of the body.

Allopathic

A product or substance other than a medical device, which is to be administered to one or more human
beings on its own, or as an ingredient in the preparation of a substance, for a medicinal purpose.

API starting material

A raw material, intermediate, or an API that is used in the production of an API and that is incorporated
as a significant structural fragment into the structure of the API. An API starting material can be an
article of commerce, a material purchased from one or more suppliers under contract or commercial
agreement, or produced through in-house synthesis.

Applicant

The person or entity who submits an application for product registration to the Authority is responsible
for all the product information.

Authorized local agent (Representative)

Any pharmaceutical company or Pharmacist established within a country or jurisdiction who has
received a mandate from the manufacturer to act on his behalf for specified tasks with regard to the
manufacturer’s obligations under legislation of the medicine and other regulatory guidance’s issued
by the Authority.

Batch records

All documents associated with the manufacture of a batch of bulk product or finished product. They
provide a history of each batch of product and of all circumstances pertinent to the quality of the final
product.

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Batch (or lot)

A defined quantity of starting material, packaging material, or product processed in a single process
or series of processes so that it could be expected to be homogeneous. In the case of continuous
manufacture, the batch must correspond to a defined fraction of the production, characterized by its
intended homogeneity. It may sometimes be necessary to divide a batch into a number of sub-batches,
which are later brought together to form a final homogeneous batch.

Batch number (or lot number)

A distinctive combination of numbers and/or letters which specifically identifies a batch on the labels,
the batch records, the certificates of analysis, etc.

Bio-equivalence

Two pharmaceutical products are bioequivalent if they are pharmaceutically equivalent or

pharmaceutical alternatives, and their bioavailability, in terms of peak (Cmax and Tmax) and total
exposure (area under the curve (AUC)) after administration of the same molar dose under the same
conditions, are similar to such a degree that their effects can be expected to be essentially the same.

Bioavailability

The rate and relative amount of the administered drug which reaches the general circulation intact, or
the rate and extent to which the API is absorbed from a drug product and becomes available at the
site(s) of action.

Biological Products

Vaccines, immunizer, antigens, hormones, cytokines, enzymes, and other products.

BCS (Biopharmaceutics Classification System) highly soluble

An API for which the highest dose included in the List of Essential Medicines (if the API appear in
the List of Essential Medicines) or, the highest dose strength available on the market as an oral solid
dosage form is soluble in 250 ml or less of aqueous media over the pH range of 1.2–6.8 at 37ºC.

Bulk Product

Any product that has completed all processing and steps up to, but not including final packaging.

Clinical trial

Any systematic study on pharmaceutical products in human subjects whether in patients or non-patient
volunteers in order to discover or verify the effects of, and/or identifies any adverse reaction to
investigational products, and/or to study absorption, distribution, metabolism, and excretion of the
products with the object of ascertaining their efficacy and safety.

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Commitment batches

Production batches of an API or finished pharmaceutical product (FPP) for which the stability studies
are initiated or completed post-approval through a commitment provided with the application.

Comparator product

A pharmaceutical product with which the generic product is intended to be interchangeable in clinical
practice. The comparator product will normally be the innovator product for which efficacy, safety,
and quality have been established.

Container

That which holds the article and is or may be in direct contact with the drug.

Critical process

A process that may cause variation in the quality of the pharmaceutical product.

Cross-contamination

Contamination of a starting material, intermediate product, or finished product with another starting
material or product during production.

Counterfeit Medicine

Means a medicine that is deliberately and fraudulently mislabeled with respect to identity for source.
Counterfeit products may be branded or generic medicines, and may include products with the correct
ingredients, with the wrong ingredient, without ingredients, with insufficient active ingredient, or with
fake packaging material.

Dosage Form

Formulation of an active ingredient(s) so that it can be administered to a patient in specified

quantity/strength, e.g., tablets, capsules, injection solution, syrups, ointments, suppositories, etc.
"Pharmaceutical Form" and "Finished Product" are synonymous to "Dosage Form.

Drug Master File

A drug master file (DMF) is a master file that provides a full set of data on an API. In some countries,
the term may also comprise data on an excipient or a component of a product such as a container.

Drug Substance

Another term used for the Active Pharmaceutical Ingredient.

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Established multisource (generic) product

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

Excipient

Any component of a finished dosage form other than the claimed therapeutic ingredient or active
ingredients.

Finished Pharmaceutical Product (FPP)

A finished dosage form that has undergone all stages of manufacture, including packaging in its final
container and labelling. Related terms – Intermediate Product, Bulk Product.

Generic Products

The term generic product means a pharmaceutical product, usually intended to be interchangeable with
the innovator product, which is usually manufactured without a licence from the innovator company
and marketed after expiry of the patent or other exclusivity rights.

Intermediate product

Partly processed product that must undergo further manufacturing steps before it becomes a bulk
product.

Immediate Container

That part of a product container which is in direct contact with the drug at all times.

Innovator pharmaceutical product

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

Labeling

Includes any legend, word, or mark attached to, included in, belonging to, or accompanying any drug
including: 1) the immediate container label; 2) cartons, wrappers, and similar items; 3) information
materials, such as instructional brochures and package inserts.

Manufacturer

A company that carries out operations such as production, packaging, repackaging, labeling, and
relabeling of products.

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Manufacture

All operations of purchase of materials and products, production, packaging, quality control, release,
storage, shipment of finished products, and the related controls.

Manufacturing process

The transformation of starting materials into finished products (drug substances or pharmaceutical
dosage forms) through a single operation or a sequence of operations involving installations, personnel,
documentation and environment.

Marketing authorization

An official document issued for the purpose of marketing or free distribution of a product after
evaluation of safety, efficacy, and quality of the product.

Master formula (MF)

A document or a set of documents specifying the starting materials, with their quantities and packaging
materials, together with a description of the procedures and precautions required to produce a specified
quantity of a finished product as well as the processing instructions, including in-process controls.

Multisource (generic) pharmaceutical products

Pharmaceutically equivalent or pharmaceutical alternative products that may or may not be

therapeutically equivalent. Multisource pharmaceutical products that are therapeutically equivalent
are interchangeable.

Officially recognized pharmacopoeia (or compendium)

Those pharmacopoeias recognized by the Authority, i.e., The International Pharmacopoeia (Ph.Int.),
European Pharmacopoeia (Ph.Eur.), British Pharmacopoeia (BP), Japanese Pharmacopoeia (JP), and
the United States Pharmacopeia (USP).

Ongoing stability study

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

Pharmaceutical equivalents

Products are pharmaceutically equivalent if they contain the same amount of the same active
ingredient(s) in the same dosage form, if they meet the same or comparable standards, and if they are
intended to be administered by the same route.

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Pilot-scale batch

A batch of an API or FPP manufactured by a procedure fully representative of and simulating that to
be applied to a full production-scale batch; for example, for solid oral dosage forms, a pilot scale is
generally, at a minimum, one-tenth that of a full production scale or 100,000 tablets or capsules,
whichever is the larger; unless otherwise adequately justified.

Primary batch

A batch of an API or FPP used in a stability study from which stability data are submitted in a
registration application for the purpose of establishing a re-test period or shelf-life.

Production batch

A batch of an API or FPP manufactured at production scale by using production equipment in a

production facility as specified in the registration dossier.

Production

All operations involved in the preparation of a pharmaceutical product, from receipt of materials,
through processing and packaging, to completion of the finished product.

Packaging material

Any material, including printed material, employed in the packaging of a pharmaceutical product,
excluding any outer packaging used for transportation or shipment. Packaging materials are referred
to as primary or secondary according to whether or not they are intended to be in direct contact with
the product.

Packaging

All operations, including filling and labeling, that a bulk product has to undergo in order to become
a finished product. Sterile filling would not normally be regarded as part of packaging, the bulk product
being the filled, but not the finally packaged, primary container.

Standard operating procedure (SOP)

An authorized written procedure giving instructions for performing operations not necessarily specific
to a given product or material but of a more general nature (e.g., equipment operation, maintenance
and cleaning; validation; cleaning of premises and environmental control; sampling and inspection).
Certain SOPs may be used to supplement product-specific master and batch production documentation.

Specification

A document describing in detail the requirements with which the products or materials used or obtained
during manufacture have to conform. Specifications serve as a basis for quality evaluation.

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Stability

The ability of an active ingredient or a drug product to retain its properties within specified limits
throughout its shelf-life. The chemical, physical, microbiological, and biopharmaceutical aspects of
stability must be considered.

Validation protocol (or plan)

A document describing the activities to be performed in a validation, including the acceptance criteria
for the approval of a manufacturing process or a part thereof for routine use.

Validation

The demonstration, with documentary evidence, that any procedure, process, equipment, material,
activity, or system actually leads to the expected results.

Validation report

A document in which the records, results and evaluation of a completed validation program are
assembled. It may also contain proposals for the improvement of processes and/or equipment.

Variation

A change to any aspect of a pharmaceutical product including, but not limited to, a change to
formulation, method, and site of manufacture or specifications for the finished product, ingredients,
container and container labeling, product package (design, color, etc.) and product information.

ICH

The International Council for Harmonization of Technical Requirements for Pharmaceuticals for
Human use.

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 PROCEDURE FOR SUBMISSION OF APPLICATIONS IN CTD FORMAT

All applications should be submitted in:

 English
 Electronic submission of dossiers on a Flash disk in PDF
 Summaries in word format
 Confirm that the electronic submission has been checked with up-to-date and state-of-the-art
antivirus software along with duly sign commitment that the submission is free from any form of
virus

Applications shall be accompanied by:

 A duly signed covering letter

 Completed applications form in accordance with the sequence of appendices and shall be dated,
signed and stamped by the applicant/license holder.
 Samples of the product in the final packaging as specified in Samples Schedule (Sample of
Comparator Product should be submitted for all generic formulation)
 Reference or working standard for Active Pharmaceutical Ingredient and related impurities
where necessary.
 All supporting documents (Product Dossier) as specified in accordance with the CTD format
 A separate application is required for each product with the same pharmaceutical ingredient but
varies in strength and dosage form. The following products will be regarded as either being the
same product or separate product applications.
 The summaries (Quality Information Summary (QIS), Quality Overall Summary (QOS),
Bioequivalence Trial Information and Bio waiver Application Form) should be formatted as
word document and the body data in pdf format.

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TYPE OF APPLICATIONS
Applications
# Type of Application
Same Separate

1 Each individual dosage form of a particular medicine X

2 Variations of the active pharmaceutical ingredient (API) of a product X

3 Tablets/Capsules/Suppositories/Lozenges X

4 Different pack-sizes of exactly the same strength and Formulation X

5 Different strengths and formulations. X

6 Uncoated and coated tablets of the same strength and formulation.

X

7 Syrups/Liquids/Solutions (excluding parenteral) /Creams/ Ointments different X

container sizes of the same strength and formulation.

8 The same container size of different strengths and formulations. Ampoules and Vials X
and Large Volume Parenteral

9 Different strengths and formulations.

X

10 Uncoated and coated tablets of the same strength and formulation.

X

11 Syrups/Liquids/Solutions (excluding parenteral) /Creams/ Ointments different X

container sizes of the same strength and formulation.

12 The same container size of different strengths and formulations. Ampoules and Vials X
and Large Volume Parenteral

13 Ampoules or single dose vials containing identical solutions of the same strength but X
of different volumes (i.e. resulting in different total doses).

14 Ampoules containing solutions of different strengths.

X

15 Ampoules and single dose vials containing e.g. dry powder, crystals of different mass
X

16 Ampoules containing “water for injection”, but of different volumes.

X

17 Special ampoules of dry powder and “water for injections” contained in the same X
unit, but intended for mixing at the time of injection if water for injections is fully
described in dossier

18 Ampoules containing identical solutions of different volumes used only as diluents X

in the reconstitution of a preparation for parenteral use.

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 19 Multidose vials containing different volumes of the same strength and formulation X
with the same dosage schedule.

20 Multidose vials and a single dose ampoule or vial of the same formulation if the X
single-dose ampoule or vial corresponds to the dose indicated for the Multidose vial.

21 Multidose vials containing dry powder of different mass of the same formulation, X
and the same concentration when reconstituted.
22 An ampoule of diluents packed together with any preparation including biological X
medicines if diluent is fully described in dossier.
23 Infusion solutions of the different volumes and of the same formulation which are
packed in containers of exactly the same type of material depending on the relevant X

information submitted.
24 Infusion solutions of the same formulation and of the same or different volume which X
are packed in containers made of different types of materials.
25 A preparation, packed in plastic containers, intended to be marketed in glass X
containers containing the same volume and the same formulation.
26 Products with the same strength and formulation but with different colors and/or X
flavors.
27 Applications containing the same API(s) applying for additional indications which
render the product in a different scheduling status, or different pharmacological X
classification, or have any other restrictions imposed other than the original
application.
28 Removal of antimicrobial preservative from single dose presentation of registered X
vaccine that included a preservative in the original approved formulation
29 Same formulation with different proprietary names whether of the same or different X
applicants

Application for the registration of Pharmaceuticals Products shall be made only by:

 The manufacturer
 A distributor authorized by the manufacturer, license/patent holder
 An authorized Local Agent or Technical Representative (Registered Pharmacist) of the
manufacturer

The name, physical address, telephone number, fax number, and e-mail address of the applicant shall
be provided.

1.1. Payment of Fees

 All application shall be accompanied by non-refundable registration fee as specified in fee schedule

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  All registration shall be accompanied by non-refundable maintenance fee as specified in fee
schedule
 All registered/approved products shall be subjected to premarket analysis and applicants are
require to pay the applicable fee as specified in fee schedule
 All application submitted to LMHRA for registration of Pharmaceutical Products for human use
shall be accompanied by Pharmacovigilance Plan or Risk Management Plan prior to granting
Marketing authorization (no fees attached to this plan)

1.2. Criteria for rejection of application submission

Rejection at reception: All applications submitted to the Authority shall be subjected to the
provisions of these guidelines otherwise the application shall be rejected and applicant notified
immediately however the applicant shall have fifteen (15) working days to re-submit the application
in line with all submission requirements as specified in the guidelines. Nonconformity to the above
shall be given additional fifteen (15) working days, failure to comply, the application will be cancelled
and applicant will be required to re-apply and pay all necessary fees.

Rejection after screening and assessors review: Applicant will be notified on the status of their
application depending on the submission type either Fast Track or Regular. Assessors Queries will be
formulated in to questionnaires communicated to manufacturer of the medicinal product. The applicant
is given ninety (90) days to respond to all the queries. Failure to adequately provide answers to the
queries the Product will be rejected.

1.3. General format and guidance for preparation of dossiers

The CTD is organized into five modules; Module 1 is specific to the regulatory Authority of Liberia
which includes Administrative and Product information. Modules 2, 3, 4, and 5 are intended to be
common for all situations.

The following Modular format of PDs in the CTD content should always be considered during dossier
preparation for registration submission to the Authority:

Module 1 – Administrative information and prescribing information

1.1 Cover Letter
1.2. Table of Contents of the Application, including Module 1 (Modules 1-5)
1.3. Application Form
1.4 Correspondence

1.5 Administrative Information

1.6 Regional Summaries

1.6.1 Certificate of Suitability (CEP), if any

1.6.2 Good Manufacturing Practice Certificate and Certificate of Pharmaceutical Product

1.7 Product Information
1.7.1. Summary of Product Characteristics
1.7.2. Labeling Information (immediate and outer label)

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1.7.3. Patient Information Leaflet (PIL)
1.8. Evidence of LMHRA Application Fee (Payment Receipts)
Module 2 – Dossier Overall Summary of Product Dossier (DOS-PD)
2.1 PD Table of Contents (Modules 2-5)
2.2 CTD Introduction
2.3 Quality Overall Summary of Product Dossier (QOS-PD)
2.3.S Drug Substance
2.3.P Finished Pharmaceutical Product
2.3.A Appendices
2.3.R Regional Information

2.4 Nonclinical Overview – generally not applicable for multisource products (some exceptions may apply)
2.5 Clinical Overview
2.6 Nonclinical Written and Tabulated Summaries – generally not applicable for multisource products (some
exceptions may apply)
2.7 Clinical Summary – generally not applicable for multisource products
Module 3 – Quality
3.1 Table of Contents of Module 3
3.2.S Body of Data - Drug Substance
3.2.P Body of Data – Finished Drug Product (name, dosage form)
Module 4 – Nonclinical Study Reports – generally not applicable for multisource products (some exceptions
may apply)

4.1 Table of Contents of Module 4

4.2 Study Reports
4.3 Literature References
Module 5: Clinical Summaries
5.1 Table of Contents of Module 5
5.2 Tabular Listing of all Clinical Studies
5.3 Clinical Study Reports
5.3.1Reports of Biopharmaceutical Studies (mainly BE study reports for generic products )
5.3.7 Literature References
REFERENCES:
ANNEX A: PRODUCT LABELLING GUIDANCE
Module 1.3.1 Summary of Product Characteristics (SmPC)

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Module 1.3.2 Patient Information Leaflet

Module 1.3.3 Container Labeling (Inner and Outer Labels)

ANNEX B: FORMS

B.1 MODEL COVER LETTER LINK

B.2 MODEL APPLICATION FORM FOR DRUG MARKET AUTHORIZATION

B.3 MODEL LETTERS OF ACCESS

B.4 MODEL FEE FORM

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MODULE 1: ADMINISTRATIVE AND PRODUCT INFORMATION

1.1. Covering Letter

Dated and signed letter for submission of the dossier by mentioning the product included in the dossier
from the manufacturer and/or local agent responsible for registration.

1.2. Table Contents of Modules 1 to 5

Table of contents of Module 1 through Module 5 (of the PD) should be provided in Module 1.

1.3. Application Form

Completed and signed application form as provided in these Guidelines should be submitted. The date
of application should correspond to the date of submission of the registration dossier to the Authority.

Good Manufacturing Practice and Certificate of Pharmaceutical Product

A Good Manufacturing Practice (GMP) Certificate and Certificate of Pharmaceutical Product (CPP)
issued by a competent authority in the exporting country should be provided in Module 1.

Certificate of Suitability (CEP), if applicable

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

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

Along with the CEP, the applicant should supply the following information in the dossier, with data
summarized in the DOS-PD and Module 3 of the dossier:

 3.2. S.1.3 General properties ‒ discussion of any additional applicable physicochemical and other
relevant API properties that are not controlled by the CEP and Ph.Eur. Monograph, e.g. solubility
and polymorphs.
 3.2. S.3.1 Elucidation of structure and other characteristics‒ studies to identify polymorphs
(exception: where the CEP specifies a polymorphic form) and particle size distribution, where
applicable.
 3.2.S.4.1 Specification ‒ the specifications of the FPP manufacturer, including all tests and limits
of the CEP and Ph. Eur. monograph, and any additional tests and acceptance criteria that are not
controlled in the CEP and Ph. Eur. monograph, such as polymorphs and/or particle size
distribution.
 3.2.S.4.2 / 3.2.S.4.3 Analytical procedures and validation ‒ for any tests in addition to those in the
CEP and Ph. Eur. monograph.
 3.2.S.4.4 Batch analysis‒ results from three batches of at least one pilot scale, demonstrating
compliance with the FPP manufacturer’s API specifications.

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 3.2.S.6 Container closure system‒ specifications including descriptions and identification of
primary packaging components (exception: where the CEP specifies a re-test period).
 3.2. S.7 Stability ‒ exception: where the CEP specifies a re-test period that is the same as or of
longer duration than the re-test period proposed by the applicant.

Product information

Product information including package insert, labeling, and Summary of Product Characteristics
(SmPC) should be provided in Module 1 of the dossier. All product information label statements are
required to be in English. Any information appearing in the product information (labels, PIL, and
SmPC) should be based on scientific justification.

Labeling (immediate and outer label)

Only original labels or computer-ready color-printed or indelible ink labels are accepted for final
approval. In the case where the text of the labels is printed directly on plastic bottles through a silk
screen process, photocopies of these labels will be accepted for approval.

The titles for batch number, manufacturing, and expiry dates should be part of the printing (typewritten
materials, stickers, etc., are not acceptable). If the labeling technology of the manufacturer is such that
this information is to be printed on the label during production, a written commitment to show all the
required information on the label of the finished product must be submitted. The contents of the label
should at least contain:

a) The name of the product‒ brand and generic/International Non-proprietary Name

b) Pharmaceutical form and route of administration;

c) Qualitative and quantitative composition of active ingredient(s), preservative(s), and

antioxidant (s);
d) The volume of the contents, and/or the number of doses, or quantity in container;
e) Directions to consult the package insert or the carton label for complete directions for use;
f) Handling and storage conditions;

g) Batch/Lot number;
h) Manufacturing date;

i) Expiry date; and,

j) Name and full address of manufacturer.

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Registration status

Registration status within ECOWAS countries and with Stringent Drug Regulatory Authorities

Evidence of API and/or FPP prequalified by WHO

If an evidence indicating that the active pharmaceutical ingredient and/or finished pharmaceutical
products are prequalified by WHO is available, it should be presented in Module 1.

Manufacturing and Marketing authorization

Submit a valid Certificate of Pharmaceutical Product in format recommended by the World Health
Organization together with a valid Manufacturing Authorization for pharmaceutical production.

VARIATION PRINCIPLES

Variations are changes that may have minor or major effects on the overall safety, efficacy and quality
of the product. Applicants must satisfy themselves that they meet all of the prescribed conditions for
the change and submit all required documentation with the variation application. Such variations can
be implemented if no objection letter has been issued within a time period. Should questions arise
during the specified period; the change can only be implemented on receipt of a letter of approval from
LMHRA.

Please note: patent rights are highly considered like package color, size, applicable pictorials (not more
than two), package presentation (size, color, labeling, etc.), administration variation, composition,
shelf life or storage and name.

NB// Refer to application form for more details.

PRODUCT REGISTRATION APPLICATION FORM FOR VARIATION

SE DETAIL: APPLICATION NUMBER: DATE RECEIVED:
C
1 Applicant

Name of Applicant: ___________________________________________________________

Premises/Business Address ____________________________________________________
___________________________________________________________________________

Telephone: _____________________________ Email: ______________________________

Website: _______________________________

Name of Local Agent _________________________________________________________

Premises/Business Address ____________________________________________________
___________________________________________________________________________

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 Telephone: _____________________________ Email: ______________________________

Website: _______________________________

Name of Manufacturer _______________________________________________________

Premises/Business Address ____________________________________________________
___________________________________________________________________________

Telephone: _____________________________ Email: ______________________________

Website: _______________________________

Country of Origin

2 STATUS OF APPLICANT (mark as X)

Manufacturer Importer

Government Agency Donor Agency

Hospital Local Agent

Other (Please Specify) _________________________________________________________

3 PRODUCT

Name of Product Promotional Category (mark X)

Proprietary Name Prescription Only Medicines (POM)

Generic Name Pharmacy Recommended Medicines (PM)

International Non-Proprietary Name (INN) Over The Counter Medicines (OTC)

Controlled Drug

Registration in Country of Origin Yes No

List of Countries in which product is 1.

registered or awaiting registration (attached
sheet where necessary) 2.

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 3.

4 PHARMACOLOGICAL
CLASSIFICATION

5 INDICATIONS

6 REASON(S) FOR VARIATION(S)

7 AREA(S) OF VARIATION(S)
8 PRESENTATIONS & PACKAGING

9 DOSAGE FORMS AND

SPECIFICATION
10 NAME & QUANTITY OF EACH INGREDIENT
No. Ingredient Specification Strength
1
2
3

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A Additional raw materials (if any) used
in the manufacturing process but NOT
present in the final product

B Give specification of packaging

materials (where no specifications for
packaging materials exist, this must be
mentioned).

C List any ingredient likely to cause

dependance or listed in the United
Nations list of psychotropic and
narcotic substances

Reference to the following publications will, where applicable be accepted:

i. British pharmacopoeia
ii. European pharmacopoeia
iii. United States pharmacopoeia
iv. International pharmacopoeia
v. British pharmacopoeia Codex
vi. Martindale’s Extra pharmacopoeia
vii. Any other works of reference as may be approved by the Authority from time to time

11 CHEMICAL NAME & STRUCTURAL FORMULAR OF EACH ACTIVE INGREDIENT

Chemical Name:

Empirical Formula:

Molecular Weight:

Structural Formula:

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12 - Requirements

- Batch processing

- In – Process Checks

- Packaging Operation

13 Route of Administration - Oral

- Intravenous

- Intramuscular

- Topical

- Inhalation

Others (specify) _____________________________

14 ADVERSE EFFECTS & CONTRA-INDICATION

Adverse Effects

Drug Interactions

Precautions & Warning

Use in Pregnancy and Nursing

Mothers

Contra-indications
15 TREATMENT/ANTIDOTE IN
THE EVENT OF OVERDOSE

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16 TERATOGENICITY
Pregnancy

Development Toxicity

17 ANALYTIC METHODS
Specification & Test Methods of
Active Ingredients

Specification & Test Methods of

Excipients

Specification & Test Methods of

Finished Products

18 DECLARATION
I the undersigned certify that the information in the accompanying documentation concerning
the application for registration of the Medicine or health product indicated hereinis correct and
true, and reflects the total information available.
I further certify that I have examined the statements made in this form and I attest to their
accuracy. I further confirm that the information referred to in my application file is available
for verification. I also agree that I am obliged to comply with the requirements of the Authority
related to the stated product at any time in the future.

Name: ______________________________________________________________

Signature: ___________________________________________________________

Position in Company: __________________________________________________

Date: _______________________________________________________________

STAMP/SEAL

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ANNEX I: APPLICATION FORM

LIBERIA MEDICINES AND HEALTH PRODUCTS REGULATORY AUTHORITY

A. Type of application (check the box applicable)

New Application
Periodic re-registration
Variation to existing marketing authorization
(If selected, complete the information
below.)
 Previous registration number

 Previous registration condition

 Brief description of change intended

 Reasons for variations

B. Details on the product

Proprietary name (trade name)

Approved generic name (s) (use INN if any)

Standard claimed (BP, Ph.In, Ph. Eur., USP,

IP, etc.)
Strength(s) per dosage unit

Dosage form

Route of administration

Shelf life (months)

Storage condition

Visual description

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Description of container closure

Packaging and pack size

Therapeutic category

Use category Scheduled Narcotic

Prescription only
Hospital use only
Pharmacy
Over-the-counter (OTC)

Composition Strength Specification

Complete qualitative and quantitative

composition (indicate per unit dosage form,
e.g., per tablet, per 5ml, etc.)**
** Add/delete as many rows and columns as
needed.

Complete qualitative and quantitative Composition Strength Specification

composition (indicate per batch in Kg, L,
etc.)

Statement of similarity and difference of clinical, bio-batch, stability, validation, and

commercial batch sizes

Regulatory situation in other country

(Provide a list of countries in which this

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 product has been granted a marketing
authorization and the restrictions on sale or
distribution, e.g., withdrawn from the
market, etc.)

C. Details on the applicant

Name

Business address

Street number and postal address

Telephone number

Fax number

E-mail and website address

Contact person in a company Name:

Position:
Postal address:
Telephone number:
Fax number:
E-mail:
Details of Manufacturer, if different from <<Insert the required information as
above indicated above>>>

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D. Details on active pharmaceutical(s) ingredient(s) manufacturer
Name of manufacturer

Street and postal address

Telephone/Fax number

E-mail

Retest period/Shelf life

E. Details on local agent (representative) in LIBERIA

Name of local agent

Sub-city and postal address

Telephone/Fax number

E-mail

Contact person in company

Address of company

F. Details on dossiers submitted with the application

Section of dossier Annex, page number, etc.
Module 1

Module 2

Module 3

Module 4

Module 5

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 CERTIFICATION BY A RESPONSIBLE PERSON IN THE APPLICANT COMPANY

I, the undersigned, certify that all the information in the accompanying documentation
concerning an application for a marketing authorization for:

Proprietary name (trade name)

Approved generic name(s) (INN)

Strength(s) per dosage unit

Dosage form

Applicant

Manufacturer

… is correct and true, and reflects the total information available.

I further certify that I have examined the following statements and I attest to their accuracy.

1. The current edition of the WHO Guideline, ―Good manufacturing practices for pharmaceutical
products, is applied in full in all premises involved in the manufacture of this product.
2. The formulation per dosage form correlates with the master formula and with the batch
manufacturing record forms.
3. The manufacturing procedure is exactly as specified in the master formula and batch manufacturing
record forms.
4. Each batch of all starting materials is either tested or certified against the full specifications in the
accompanying documentation and comply fully with those specifications before it is released for
manufacturing purposes.
5. All batches of active pharmaceutical ingredient(s) are obtained from the source(s) specified in the
accompanying documentation.
6. No batch of active pharmaceutical ingredient will be used unless a copy of the batch certificate
established by the active ingredient manufacturer is available.
7. Each batch of the container/closure system is tested or certified against the full specifications in the
accompanying documentation and complies fully with those specifications before it is released for
manufacturing purposes.
8. Each batch of the finished product is either tested or certified against the full specifications in the
accompanying documentation and complies fully with the release specifications before it is released
for sale.

9. The person releasing the product for sale is an authorized person as defined by the WHO guideline
―Good manufacturing practices: Authorized person - the role, functions and training.
10. The procedures for control of the finished product have been validated for this formulation.
11. The market authorization holder has a standard operating procedure for handling adverse reaction
reports on its products.
12. The market authorization holder has a standard operating procedure for handling batch recalls of
its products.

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13. All the documentation referred to in this Certificate is available for review during a GMP
inspection.
14. Any clinical trials including bioequivalence study were conducted according to WHO’s
―Guidelines for good clinical practice (GCP) for trials on pharmaceutical products.

Signature _____________________________________________________________________
Name _____________________________________________________________________
Position in company (print or type) ________________________________________________
Date: _________________________________________________________________________

MODULE 2.3: QUALITY OVERALL SUMMARY: PRODUCT DOSSIER (QOS-PD)

See sections 1.5, 3 and 4 of “Guideline on submission of documentation for a multisource
(generic) finished pharmaceutical product (FPP): quality part” for general and detailed
instructions on the completion of this template.

INTRODUCTION
Summary of product information:
Non-proprietary name(s) of the finished pharmaceutical product(s)
(FPP)

Proprietary name(s) of the finished pharmaceutical product(s) (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

Reference Number(s)

Strength(s)

Route of administration

Proposed indication(s)

Title:
Name:
Contact person responsible for this application Phone:
Fax:
Email:

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 If there are other contacts who should be routinely copied into correspondence for this
application, they should also be listed below.

2.3.S DRUG SUBSTANCE (or ACTIVE PHARMACEUTICAL INGREDIENT (API)) (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:

 a copy of the confirmation of API Prequalification document should be provided

in Module 1, and
□
 summaries of the relevant information should be provided under the appropriate
sections (e.g. S.1.3, S.2, S.3.1, S.4.1 through S.4.4, S.5 and S.7; see Quality
guideline).

Certificate of suitability to the European Pharmacopoeia (CEP):

 is a written commitment provided that the applicant will inform WHO in the event
that the CEP is withdrawn and acknowledged that withdrawal of the CEP will
require additional consideration of the API data requirements to support the dossier:

□ yes, □ no;
□
 a copy of the most current CEP (with annexes) and written commitment should be
provided in Module 1;
 the declaration of access should be filled out by the CEP holder on behalf of the
FPP manufacturer or applicant to PQTm who refers to the CEP; and
 summaries of the relevant information should be provided under the appropriate
sections (e.g. S.1.3, S.3.1, S.4.1 through S.4.4, S.5, S.6 and S.7; see Quality
guideline).

Active pharmaceutical ingredient master file (APIMF):

 a copy of the letter of access should be provided in Module 1; and

□
 summaries of the relevant information from the Open part should be provided under
the appropriate sections; see Section 3.2.S in the Quality guideline.

Active pharmaceutical ingredient pre-qualified by WHO

□
Provide evidence from WHO
Full details in the PD:

□  Summaries of the full information should be provided under the appropriate

sections; see Section 3.2.S in the quality guideline.

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

2.3.S.1.1 Nomenclature (name, manufacturer)

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

(b) Compendia 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, color, physical state):

(b) Solubility:

In common solvents:
Quantitative aqueous pH solubility profile (pH 1.2 to 6.8) at 37°C:

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:

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 Property

pH

pK

Partition coefficients

Melting/boiling points

Specific optical rotation (specify solvent)

Refractive index (liquids)

Hygroscopicity

UV absorption maxima/molar absorptivity

Other

2.3.S.2 Manufacture (name, manufacturer)

2.3.S.2.1 Manufacturer(s) (name, 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:
API-PQ
Name and address
Responsibility number/APIMF/CEP
(including block(s)/unit(s))
number (if 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):

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:

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2.3.S.2.3 Control of Materials (name, manufacturer)

(a) Name of starting material:

(c) Name and manufacturing site address of starting material manufacturer(s):
(d) 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

(e) 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:

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

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):

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 bio-waiver, stability, scale-up, pilot and, if available, production scale
batches:

2.3.S.3 Characterization (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):

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 (b) Discussion on the potential for isomerism and identification of stereochemistry (e.g.
geometric isomerism, number of chiral centers and configurations) of the API batch(es)
used in comparative bioavailability or bio-waiver studies:

(c) Summary of studies performed to identify potential polymorphic forms (including

solvates): <including identification of and data on the API lot used in bioavailability
studies>

(d) Summary of studies performed to identify the particle size distribution of the API:
<including identification of and data on the API lot used in bioavailability studies>

(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:
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

(chemical name and Structure Origin

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):

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

Test Parameter ICH threshold or

concentration limit

API-related impurities 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, 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 the API (name, manufacturer)

2.3.S.4.1 Specification (name, manufacturer)

(a) API specifications of the FPP manufacturer:

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 Standard (e.g. Ph.Int., Ph.Eur., BP, USP, in-house)

Specification reference number and version

Analytical procedure
Test Acceptance criteria
(Type/Source/Version)

Description

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):

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

Summarized tabulated methods and validation may be provided in a separate file

<provide reference>.

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

(a) Description of the batches:

Use (e.g. comparative

Date and
Batch number Batch size bioavailability or
site of production
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 compendia standard(s)):

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):

(c) 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) 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):

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 Specifications (list parameters e.g.
Packaging component Materials of construction
identification (IR))

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

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:

Results (e.g. including discussion whether

Stress condition Treatment
mass balance and peak purity are observed)
Heat
Humidity
Oxidation
Photolysis
Acid
Base
Others

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

Storage Completed (and

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

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Summary of the stability results observed for the above accelerated and long-term studies:

Test (limits) 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) <primary batches>
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>
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.

(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):

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 2.3.P DRUG PRODUCT (or FINISHED PHARMACEUTICAL PRODUCT (FPP))

2.3.P.1 Description and Composition of the FPP

(a) Description of the FPP (in signed specifications):

(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 Quant. % Quant. % Quantity %
applicable) per unit per unit per unit
or per or per or per
mL mL mL
<complete with appropriate titles e.g. Core tablet (Layer 1, Layer 2, etc. as applicable), 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. colorants, coatings,

capsule shells, imprinting inks):
(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

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:

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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 bio-waiver, stability, commercial:

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 i. Summary of batch numbers:

Batch number(s) of the FPPs used in

<e.g. bioequivalence batch A12345> <e.g.

Bioequivalence or bio-waiver
bio-waiver batch X12345>

For proportional strength bio-waiver: the

bioequivalence batch of the reference
strength

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)

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 ii. Summary of formulations and discussion of any differences:

Component and Relevant batches

quality standard
Comparative Stability Process validation Commercial
(e.g. NF, BP,
bioavailability or (2.3.P.1)
Ph.Eur, in-
bio-waiver
house)
<Batch nos. and <Batch nos. and <Batch nos. and <Batch nos. and
sizes> sizes> sizes> sizes>

Theoretical % Theoretical % Theoretical % Theoretical %

quantity per quantity per quantity per quantity per

batch 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 >

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 bio-waiver), 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):

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 Summary of the multi-point dissolution profiles for the bio-batch (es) in three BCS
media across the physiological pH range and the proposed medium if different from the
BCS media:

(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

(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 bio-waiver 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 for the lowest intended dose):

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):

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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:

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

Largest intended commercial batch size:

Other intended commercial batch sizes:

<information on all intended commercial batch sizes should be in the QOS-PD>

(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):

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 Strength (label claim)
Master production document
reference number and version
Proposed commercial batch size(s) (e.g.
number of dosage units)
Quantity per Quantity per Quantity per
Component and quality standard
batch (e.g. batch (e.g. batch (e.g.
(and grade, if applicable)
kg/batch) kg/batch) kg/batch)
<complete with appropriate titles e.g. Core tablet (Layer 1, Layer 2, etc. as applicable), 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:

(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 (parameters/limits/frequency of

(e.g. granulation, compression, coating) testing)

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 Proposed/validated holding periods for intermediates (including bulk product):

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):

Document code(s) for the process validation protocol(s) and/or report(s) (including
reference number/version/date):

2.3.P.4 Control of Excipients

2.3.P.4.1 Specifications

(a) Summary of the specifications for in-house standard specifications:

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):

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
compendia 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 scientific discussion (PQTm). See quality guideline for
definition.

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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, in-house)

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

2.3.P.5.2 Analytical Procedures

(a) Summary of the analytical procedures (e.g. key method parameters, conditions, system
suitability testing):

2.3.P.5.3 Validation of Analytical Procedures

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

2.3.P.5.4 Batch Analyses

(a) Description of the batches:

Use (e.g. comparative

Strength and Date and
Batch size bioavailability or bio-waiver,
batch number site of production
stability)

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

Acceptance Results
Test
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.P.5.2 and 2.3.P.5.3 (e.g. historical analytical procedures):

2.3.P.5.5 Characterization of Impurities

(a) Identification of potential and actual impurities:

Degradation product
(code name, chemical
name and compendia Structure Origin
name (e.g. USP RC A) if
relevant)

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):

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 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
bio-waiver):

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 compendia standard(s)):

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:

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2.3.P.7 Container Closure System

(a) Description of the container closure systems, including unit count or fill size, container
size or volume:

Description Strength Unit count or fill size Container size

(including materials (e.g. 60s, 100s etc.) (e.g. 5 ml, 100 ml etc.)
of construction)

(b) Summary of specifications of each primary and functional secondary (e.g. foil pouches)
packaging components:

Specifications
Packaging component
(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.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, demonstration of stability-indication of purity/assay method(s)):

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

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

Summary of additional stability studies, if applicable (with reference to data location)

<e.g. studies at intermediate conditions, holding period studies for intermediates and bulk
product, transport studies, in-use studies>:

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)):

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

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 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)

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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):

(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)

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

provided in other sections of the submission: If applicable.

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

(a) Summary of the information assessing the risk with respect to potential contamination
with adventitious agents: If applicable.

2.3.A.3 Excipients

(a) Summary of the details of manufacture, characterization and controls, with cross
references to supporting safety data (nonclinical and/or clinical) for the novel
excipients: Not applicable. Novel excipients are not accepted in PQTm. See quality
guideline for definition.

2.3.R REGIONAL INFORMATION

2.3.R.1 Production Documentation

2.3.R.1.1 Executed Production Documents

(a) List of batches (including strengths) for which executed production documents have
been provided (e.g. comparative bioavailability or bio-waiver 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.

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2.3.R.2 Analytical Procedures and Validation Information

ANALYTICAL PROCEDURES AND VALIDATION INFORMATION SUMMARIES

ATTACHMENT NUMBER:

HPLC Method Summary Volume/Page:

Method name:
Version and/or
Method code:
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 preparation and concentration
(expressed as mg/ml, let this be termed “A”):
Reference solution preparation and 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):

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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:
Number of
concentrations:
Range (expressed as %
“A”):
Linearity / Range:
Slope:
Y-intercept:
Correlation coefficient
2
(r ) :
Conc.(s) (expressed as %
“A”):
Accuracy:
Number of replicates:
Percent recovery
(avg/RSD):
Conc.(s) (expressed as %
Precision /
“A”):
Repeatability:
Number of replicates:
(intra-assay precision)
Result (avg/RSD):
Precision /
Intermediate Precision: Parameter(s) altered:
(days/analysts/equipment Result (avg/RSD):
)
Limit of Detection (LOD): (expressed as % “A”)
Limit of Quantitation (LOQ): (expressed as % “A”)
Stability of solutions:
Robustness:

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

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QUALITY INFORMATION SUMMARY (QIS)
INTRODUCTION

(a) Summary of product information:

Non-proprietary name(s) of the finished

pharmaceutical product(s) (FPP)
Proprietary name(s) of the finished
pharmaceutical product(s) (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
Reference Number(s)
Strength(s)
Route of administration
Proposed indication(s)

Title:
Primary contact person responsible for
First name:
this application1
Family Name:
Contact person's job title
Contact person's postal address
Unit
Building/PO Box number
Road/Street
Plant/Zone
Village/suburb
Town/City
District and Mandal
Province/State
Postal code
Country
Contact person's email address
Contact person's phone number

1 Please note that the contact listed in this form will be the primary contact for email and mail communication for this specific application.

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 (b) Administrative Summary:

Applicant’s date of preparation or revision

of the QIS
Internal version and/or date of acceptance (WHO use only)

Related dossiers (e.g. FPP(s) with the same API(s) submitted to the Prequalification Team:
medicines (PQTm) by the applicant):

Reference
API, strength, dosage form API manufacturer
number Prequalified
(eg. Abacavir (as sulphate) (including address if same
(e.g. (Y/N)
300 mg tablets) supplier as current dossier)
HA998)

2.3.S DRUG SUBSTANCE (or ACTIVE PHARMACEUTICAL INGREDIENT (API)) (NAME,

MANUFACTURER)

Indicate which option applies for the submission of API information: <check one only>

Name of API:
Name of API
manufacturer:
□ Confirmation of API prequalification document
□ Certificate of suitability to the European Pharmacopoeia (CEP)
Active pharmaceutical ingredient master file (APIMF) procedure:
APIMF number assigned by WHO (if known): _______ ; version number(s) including
□
amendments (and/or date(s)) of the open part: _______ ; version number(s) including
amendments (and/or date(s)) of the restricted part: : _______.
Full details in the PD
□
Document version number/identifier of current module 3.2.S: _______________
2.3.S.2 Manufacture (name, manufacturer)

2.3.S.2.1 Manufacturer(s) (name, 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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 API-PQ number
Name and address
/APIMF/CEP Letter of access
(including Responsibility
number (if provided?
block(s)/unit(s))
applicable)

2.3.S.2.3 Control of Materials (name, manufacturer) – for API option 4 only

(a) Name of starting material:

(b) Name and manufacturing site address of starting material manufacturer(s):

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, in-house)

Specification reference number and version
Analytical procedure
Test Acceptance criteria
(Type/Source/Version)
Description
Identification
Impurities
Assay
etc.

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

(a) Description of the container closure system(s) for the storage and shipment of the API:

2.3.S.7 Stability (name, manufacturer)

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

(c) Proposed storage conditions 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)

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2.3.P DRUG PRODUCT (or FINISHED PHARMACEUTICAL PRODUCT (FPP))

2.3.P.1 Description and Composition of the FPP

(a) Description of the FPP (in signed specifications):

(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
Quant. % Quant. % Quantity %
applicable)
per unit per unit per unit
or per or per or per
mL mL mL

<complete with appropriate titles e.g. Core tablet (Layer 1, Layer 2, etc. as applicable),
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):
(c) Description of accompanying reconstitution diluent(s), if applicable:

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2.3.P.2.2.1 Formulation Development

(b) Information on primary (submission, registration, and exhibit) batches including

comparative bioavailability or bio-waiver, stability, commercial:
(i) Summary of batch numbers:

PRESENTATION OF BIOEQUIVALENCE TRIAL INFORMATION

BIOEQUIVALENCE TRIAL INFORMATION

1 SUMMARY
1.1 Summary of bioequivalence studies performed
(Provide a brief description of each comparative bioavailability study included in the submission)

1.2 Tabulation of the composition of the formulation(s) proposed for marketing and those used for
bioequivalence studies
(State the location of the master formulae in the quality part of the submission)
(Tabulate the composition of the biobatch using the table below. For solid oral dosage forms the table
should contain only the ingredients in tablet core /contents of a capsule. A copy of the table should be
filled in for the film coating / hard capsule, if any.
Important: If the formulation proposed for marketing and those used for bioequivalence studies are
not identical, copies of this table should be filled in for each formulation with clear identification in
which bioequivalence study the respective formulation was used.)

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 Composition of the batches used for bioequivalence studies
Batch number
Batch size (number of unit doses)2
Comments, if any

Comparison of unit dose compositions and of clinical FPP batches

(duplicate this table for each strength, if compositions are different)
Unit
Ingredients (and quality Unit dose Biobatch Biobatch
Function dose
standard) (%) (kg) (%)
(mg)

Total
Equivalence of the compositions or justified
differences
Maximum intended commercial batch size

2 CLINICAL STUDY REPORT

a) Study number:
b) Study title:
c) Location of study protocol:
d) Start and stop dates for each phase of the clinical study:
e) Dates of product administration:

2.1 ETHICS

a) State the name of review committee, date of approval of protocol and consent form and the
location of approval letter in the submission

2
Bioequivalence batches should be at least of pilot scale (10% of production scale or 100,000 capsules/tablets
whichever is the greater) and manufacturing method should be the same as for production scale.

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b) State location of a reference copy of the informed consent form

2.2 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE

a) Name of principal investigator(s) (State location of c.v. in the submission)

b) Clinical Facility (Name and full mailing address)

c) Clinical Laboratories (Name and full mailing address)

d) Analytical Laboratories (Name and full mailing address)

e) Company performing pharmacokinetic/statistical analysis (Name and full mailing address)

2.3 STUDY OBJECTIVES

Briefly state the study objectives.

2.4 INVESTIGATIONAL PLAN

2.4.1 Overall study design and plan — description

(Describe the type of study design employed in 1-2 sentences)

2.4.2 Selection of study population

2.4.2.1 Inclusion Criteria

(List the inclusion criteria applied to subjects)

2.4.2.2 Exclusion Criteria

(List the exclusion criteria applied to subjects)

2.4.2.3 Health Verification

(State location of the individual data included in the submission)

a) List criteria used and all tests performed in order to judge health status

b) Indicate when tests were performed

c) Study site normal values

(State location in submission of study site normal values for blood clinical chemistry,
haematology, and urinalysis clinical screen)

d) Report any results that were outside of study site normal values
(State location in submission of the summary of anomalous values)

2.4.2.4 Removal of Trial subjects from Trial or Assessment

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a) Number of subjects enrolled in the study
(All subjects including alternates, withdrawals, and dropouts)

b) Alternates
(Please note: Generally all subjects enrolled in the study should be included in the data set i.e.,
alternate subjects are strongly discouraged. However, in cases where there are alternate
subjects, describe the procedure of including/excluding the alternates and whether alternates
have been included in the study)

c) Withdrawals/dropouts
(Identify each withdrawal/dropout by subject and provide the reason for withdrawal/dropout
and at what point in the study the withdrawal/dropout occurred)

2.4.3 Products Administered

2.4.3.1 Test Product

a) Batch number, size, date of manufacture and expiry date for the test product

b) Potency (measured content) of test product as a percentage of label claim as per validated assay
method
(This information should be cross-referenced to the location of the certificate of analysis in the
submission)

2.4.3.2 Comparator (Reference) Product

(Append to this template a copy of product labelling (snap shot of the box, on which the name
of the product, name and address of the manufacturer, batch number, and expiry date are
clearly visible on the labelling)

a) Name and manufacturer of the comparator product and market where the comparator product
was purchased

b) Batch number and expiry date for the comparator product

c) Purchase, shipment, storage of the comparator product

(Indicate from which company/pharmaceutical distributor the comparator product has been
obtained. Clearly indicate in chronological order the steps and dates of shipment/transport
from company of purchase to the study site. In addition, the storage conditions should be given.
This information should be cross-referenced to location in submission of documents (e.g.
receipts) proving conditions)

d) Potency (measured content) of the comparator product as a percentage of label claim, as

measured by the same laboratory and under the same conditions as the test product
(This information should be cross-referenced to the location of the certificate of analysis in the
submission)

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e) Justification of choice of comparator product
(Provide short summary here and cross-reference to location of comprehensive justification in
study protocol)

2.4.4 Selection of doses in the study

a) State dose administered

(Indicate the number of dosage units comprising a single dose, e.g., 400 mg as 1 x 400 mg or 2
x 200 mg tablets)

2.4.5 Selection and Timing of Dose for Each Subject

a) State volume and type of fluid consumed with dose

b) Interval between doses (i.e., length of washout)

c) Protocol for the administration of food and fluid

d) Restrictions on posture and physical activity during the study

2.4.6 Blinding

2.4.6.1 Identify which of the following were blinded. If any of the groups were not blinded, provide a
justification for not doing so

a) study monitors: Yes  / No  If No, justify:

b) subjects: Yes  / No  If No, justify:
c) analysts: Yes  / No  If No, justify:

2.4.6.2 Identify who held the study code and when the code was broken

2.4.7 Drug Concentration Measurements

2.4.7.1 Biological fluid(s) sampled

2.4.7.2 Sampling protocol

a) Number of samples collected per subject

b) Volume of fluid collected per sample
c) Total volume of fluid collected per subject per phase of the study
d) List the study sampling times

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e) Identify any deviations from the sampling protocol
(State location of summary in the submission)
(Describe and explain reasons for deviations from sampling protocol. Comment on impact on
study. Indicate whether the deviations were accounted for in the pharmacokinetic analysis)

2.4.7.3 Sample Handling

a) Describe the method of sample collection

b) Describe sample handling and storage procedures

Comment from Assessors

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3 TRIAL SUBJECTS

3.1 Demographic and other baseline characteristics

a) Identify study population (i.e., normal, healthy adult volunteers or patients)

b) Summary of ethnic origin and gender of subjects
c) Identify subjects noted to have special characteristics and state notable characteristics
(e.g. fast acetylators of debrisoquine)
d) Range and mean age  SD of subjects
e) Range and mean height and weight  SD of subjects
f) Identify subjects whose ratio is not within 15% of the values given on a standard height/weight
table

3.2 Subjects who smoke

a) Number of smokers included in the study

b) Indicate how many cigarettes smoked per day per subject
c) Comment on the impact on study

3.3 Comments from review of Section 3 – Assessors use only

4 PROTOCOL DEVIATIONS

4.1 Protocol deviations during the clinical study

(Describe any such deviations and discuss their implications with respect to bioequivalence)

4.2 Comments from review of Section 4 – Assessors use only

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5 SAFETY EVALUATION

5.1 Identify adverse events observed

(List any adverse events by subject number. State whether a reaction occurred following
administration of the test or reference product, identify any causal relationships, and note any
treatments required. State location of this summary in the submission.)
(Discuss the implications of the observed adverse events with respect to bioequivalence.)

5.2 Comments from review of Section 5 – Assessors use only

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6 EFFICACY EVALUATION

Efficacy results and tabulations of individual trial subjects data

6.1 Presentation of data

a) State location in submission of tables of mean and individual subject concentrations

b) State location in submission of (mean and individual) linear and semi-logarithmic subject drug
concentration vs. time plots

6.2 Pharmacokinetic (PK) parameters

a) State how the pharmacokinetic parameters where calculated/obtained for AUC0-inf, AUC0-t, Cmax,
tmax, the elimination rate constant, and t½ (indicate location of description in protocol)

b) State whether actual sampling time points were used for estimation of the pharmacokinetic
parameters

c) Complete the table below

Test Reference

Interindividual Arithm Interindividua

Arithmeti Standard Standard
Parameter coefficient of etic l coefficient of
c mean deviation deviation
variation (%) mean variation (%)

AUC0-t
(units)

AUC0-inf
(units)

Cmax (units)

tmax (units)

t½ (units)

d) Ratio of AUC0-t to AUC0-inf

(State mean ratio for both test and reference, state location in submission where individual ratios
can be found)

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6.3 Statistical analysis

(State the method of calculation of the 90% confidence intervals for the ratio of test formulation
over the reference formulation and indicate how treatment, period, sequence and subjects within
sequence were included as factors in the ANOVA. Provide the following results from the ANOVA
(parametric) on the logarithmically transformed AUC0-t and CMAX and other relevant
parameters. State software used for computing ANOVA.)

a) Geometric means, results from ANOVA, Degrees of Freedom (DF) and derived CV (intra-
subject)

% Ratio of 90 %
Referenc
Parameter Test geometric Confidence DF CV (%)
e
means interval
AUC0-t (units)
AUC0-inf
(units)
Cmax (units)

b) Comparison of the results

(Compare the results, including mean values, inter- and intra-individual variability, of this study
with published results (literature, product information of reference product (innovator),
WHOPARs), and copies of the references used should be appended to this document)

6.4 Discussion of results

(State location of the discussion of the results in the submission)

6.5 Comments from review of Section 6 – Assessors use only

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7 ANALYTICAL VALIDATION REPORT

7.1 Analytical technique

7.1.1 Validation protocol

(State the location of the validation protocol)

7.1.2 Identify analyte(s) monitored

7.1.3 Comment on source and validity of reference standard

7.1.4 Identify internal standard

7.1.5 Comment on source and validity of internal standard

7.1.6 Identify method of extraction

7.1.7 Identify analytical technique or method of separation employed

7.1.8 Identify method of detection

7.1.9 Identify anticoagulant used (if applicable)

7.1.10 If based on a published procedure, state reference citation

7.1.11 Identify any deviations from protocol

7.2 Selectivity

(Address the methods to verify selectivity against endogenous/exogenous compounds & results)

7.3 Sensitivity

(Address the methods to verify sensitivity & results)

7.4 Carry-over

(Summarize the method to verify carry-over & results)

7.5 Standard curves

(State location in submission of tabulated raw data and back calculated data with descriptive
statistics)

a) List number and concentration of calibration standards used

b) Describe the regression model used including any weighting

c) List the back-calculated concentrations of the calibration standards of the validation runs
(highlight the values outside of the acceptance range, e.g., 15%, except 20% for LLOQ)

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7.6 Quality control samples

a) Identify the concentrations of the QC samples and the storage conditions employed prior to their
analysis

7.7 Precision and accuracy during validation

a) Summarize inter-day/inter-run accuracy and precision of the calibration standards during

assay validation

b) Summarize inter-day/inter-run accuracy and precision of the calibration standards during

assay re-validation
(If applicable)

c) Summarize inter-day/inter-run and intra-day/intra-run accuracy and precision of the QC

samples during assay validation

d) Summarize inter-day/inter-run and intra-day/intra-run accuracy and precision of the QC

samples during assay re-validation
(If applicable)

7.8 Dilution integrity

(Summarize the method to verify dilution integrity & results)

7.9 Matrix effect (in case of MS detection)

(Summarize methods to verify the matrix effect & results)

7.10 Stability

(For each section provide the location of the raw data, a description of the methodology
employed and a summary of the data.)

a) Summarize data on long-term storage stability

b) Summarize data on freeze-thaw stability
c) Summarize data on bench top stability
d) Summarize data on auto-sampler storage stability
(e) Summarize data from any other stability studies conducted
(e.g. long-term stock solution and working solution stability, short-term stock solution and
working solution stability, dry-extract stability, wet-extract stability, stability in blood before
sample processing)

7.11 Re-injection reproducibility

(Summarize the method to verify re-injection reproducibility & results)

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7.12 Comments from review of Section 7 – Assessors use only

8 BIOANALYTICAL STUDY REPORT

(State the location of the bioanalytical report for the analysis of the study subject samples)

8.1 Analytical technique

(Confirm whether the method is the same as the validated method and whether the same
equipment was employed. Identify any differences between the validated method described above
in Section 7 and the method employed for subject sample analyses)

8.1.1 Analytical protocol

(State the location of the analytical protocol)

8.1.2 Identify any deviations from protocol

8.1.3 Dates of subject sample analysis

8.1.4 Longest period of subject sample storage

(Identify the time elapsed between the first day of sample collection and the last day of subject
sample analysis)

8.1.5 State whether all samples for a given subject were analyzed together in a single analysis
run

8.2 Standard curves

(State location in submission of tabulated raw data and back calculated data with descriptive
statistics)

a) List number and concentration of calibration standards used

b) State number of curves run during the study (valid and failed runs, including reasons of
failure).

c) Summarize descriptive data including slope, intercept, correlation coefficients

d) List the back-calculated concentrations of the calibration standards of the study runs
(highlight the values outside of the acceptance range, e.g., 15%, except 20% for LLOQ)

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8.3 Quality control samples

a) Identify the concentrations of the QC samples, their date of preparation and the storage
conditions employed prior to their analysis

b) State the number of QC samples in each analytical run per concentration

c) List the back-calculated concentrations of the QC samples of the study runs (highlight the
values outside of the acceptance range, e.g., 15%)

d) Discuss whether the concentrations of the QC sample concentrations are similar to the
concentrations observed in the study samples

e) State the percentage of QC samples per run with respect to the total number samples
assayed in each run

8.4 Precision and accuracy

a) Summarize inter-day precision of back-calculated standards and inter-day and intra-day

precision and accuracy of QC samples analysed during subject sample analysis

8.5 Repeat analysis (re-analysis, re-injection and re-integration)

a) List re-analysed samples by sample identification and include the following information
for each re-analysis: initial value; reason for re-analysis; re-analysed value(s); accepted
value; and reason for acceptance

b) Report the number of re-analysis as a percentage of the total number samples assayed

c) List re-injected samples by sample identification and include the following information for
each re-injection: initial value; reason for re-injection; re-injected value; accepted value;
and reason for acceptance

d) Report the number of re-injections as a percentage of the total number samples assayed

e) List re-integrated chromatograms by sample identification and include the following

information for each re-integration: initial value; reason for re-integration; re-integrated
value(s); accepted value; and reason for acceptance

f) Report the number of re-integrated chromatograms as a percentage of the total number of

samples assayed

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8.6 Incurred sample reanalysis

(State location in the submission and summarize the results of incurred sample reanalysis,
including the number of subject samples included in ISR and the total number of samples
analysed in the study)

8.7 Chromatograms

(State the location in the submission where the sample chromatograms can be found. The
chromatograms should be obtained from a minimum of two analytical batches and include at
least 20% of the subjects, up to a maximum of five. A complete set includes standards, QC
samples, pre-dose and post-dose subject samples for both phases. Each chromatogram should
be clearly labelled with respect to the following: date of analysis; subject ID number; study
period; sampling time; analyte; standard or QC, with concentration; analyte and internal
standard peaks; peak heights and/or areas)

8.8 Comments from review of Section 9 – Assessors use only

9 QUALITY ASSURANCE

9.1 Internal quality assurance methods

(State locations in the submission where internal quality assurance methods and results are
described for each of study sites (see 3.2 b-d.)

9.2 Monitoring, auditing, inspections

(Provide a list of all monitoring and auditing reports of the study, and of recent inspections of
study sites by regulatory agencies. State locations in the submission of the respective reports for
each study site (see 3.2 b-d.)

9.3 Comments from review of Section 10 – Assessors use only

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 10.0 CONCLUSIONS AND RECOMMENDATIONS – Assessors use only

ANNEX B1- MODEL COVER LETER

<Applicant>
<Address>
<Address>
<Post code> <Town>
<Country

<Applicant’s reference> <Date>

Liberia Medicines and Health Products Regulatory Authority

2nd & 3rd Floors Clay Building, Sekou Toure Avenue, Mamba Point, Monrovia, Liberia

Dear Sir:

Subject: Submission of Application Dossier(s) for Marketing Authorization of <Product

Name(s), [strength(s) of active pharmaceutical ingredient(s) and dosage form(s)

We are pleased to submit our Application Dossier(s) for the registration of human medicines in Liberia
for the following product(s):

Name of the medicinal product(s): ………………………………….……………………..

Pharmaceutical form(s) and strength(s): …………………………………………….…..
INN/active Pharmaceutical ingredient(s): ……………………................................
ATC Code(s): ………….…………………………………………………………………………..

<The application seeks market authorization for a new product not previously marketed in the
ECOWAS or any member country.>

<The application seeks to renew the following marketing authorization(s) …..>

<The application seeks a market authorization for a variation of <indicate the product and market
authorization # or previous application identifiers, e.g., LMHRA Registration numbers>>

<This submission responds to correspondence from <name of regulatory authority, (e.g., ECOWAS
or member country), dated <DAY, MONTH, YEAR>, related to application number <#####>. The
regulator’s correspondence is provided in module 1.1.2. The response to the correspondence is
provided in module 1.1.3.>

You will find enclosed the submission dossier as specified hereafter:

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 CTD format, 2 copies (following the regulator requirements):

 Soft copy
 Hard copy
 Both

CD ROM; Summaries in word format and body data in PDF format

We confirm that all future submissions for this specific product will be submitted in this same
format

We confirm that the electronic submission has been checked with up-to-date and state-of-the-art
antivirus software.

The electronic submission contains the following modules:

<- Module 1: Administrative information and product information
- Module 2: Overview and summaries
- Module 3: Quality
- Module 4: Non clinical study reports
- Module 5: Clinical study reports>

<The relevant fees have been paid.>

<xxx samples of the drug product have been submitted with this application.>

Yours sincerely,

…………………………………
<Signature>
<Name>
<Title>
<Phone number(s)>
<Email address>

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ANNEX B2 MODEL LETTER OF ACCESS TO CEP

Include the letter in Module 1 – Administration and Product Information, sub module 1.2.6 of the application
in CTD format

<Applicant>
<Address>
<Post code> <Town>
<Country

<Applicant’s reference> <Date>

Liberia Medicines and Health Products Regulatory Authority

2nd & 3rd Floors, Clay Building, Sekou Toure Avenue, Mamba Point, Monrovia, Liberia

Dear Sir:

Subject: Authorization to access Certificate of Suitability (CEP)

Reference is made to the above subject matter.

Consent is hereby granted to <LMRRA> to make reference to this company's Certificate(s) of Suitability (CEPs)
<number(s)> for <API(s) name(s)> in the evaluation of applications relating to the registration of <medicine
name(s)> submitted to <name of NMRA> by <applicant’s name>.

This consent <includes / does not include> authorization to supply information or extracts from or the whole
of the data to:

(Name of company or individual)

The API is manufactured by:

<Names and addresses of all manufacturing sites and manufacturing steps carried out at site>

A formal agreement exists between the applicant of the medicine and the manufacturer of the API, which
ensures that information will be communicated between them and to the <NMRA> before any significant
change is made to the site of manufacture, manufacturing procedure or quality control specifications of the API.
Except as permitted by the WAHO guidelines relating to changes to medicines, such changes will not be made
to the API to be used in manufacture of the medicine destined to be distributed in Liberia an ECOWAS member
country before written approval is granted by the Liberia Medicines and Health Products Regulatory Authority.

I understand that the consequences of failure to obtain approval for changes where approval is necessary may
include de-registration and recall of batches of medicines.

Any questions arising from the Liberia Medicines and Health Products Regulatory Authority.

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 evaluation of this CEP should be forwarded to:
(Name and address)

Yours faithfully

{Signature of Company Representative}

{Name}
{Position in Company}
{Date}

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