4-3 documentation quality

7/29/2019 4-3 Documentation Quality

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Jakarta, October 2009

Requirements on documentation of API and FPPquality and evaluation process

Presented byRutendo Kuwana

Prequalification of Medicines Programme

QSM / EMP / HSS


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WHO Reference text for Multisource

(Generic) products / Definitions

Active Pharmaceutical Ingredient (API)

A substance or compound that is intended to be used in the manufacture of a

pharmaceutical product as a therapeutically active compound (ingredient)

Pharmaceutical Product

Any preparation for human or veterinary use that is intended to modify or

explore physiological systems or pathological states for the benefit of therecipient.

Finished Pharmaceutical Product (FPP)

A product that has undergone all stages of production, including packaging in

its final container and labelling.


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Reference texts

Prequalification quality guidelines for dossier submission

Guideline on submission of documentation for prequalification of multi-

source (Generic) Finished Pharmaceutical Products (FPPs) used intreatment of HIV/AIDS, Malaria and Tuberculosis (Main Generic guide with8 annexes) [under revision]

Supplement 1 : Dissolution testing

Supplement 2 : Extension of the WHO list of stable APIs (not easilydegradable)

Guidelines for registration of fixed-dose combination medicinal products

Guideline on Active Pharmaceutical Ingredient Master File (APIMF)Procedure

Guidance on variations to a prequalified dossier

ICH notes for guidance (When WHO or PQ guidelines silent)

Prequalification of Generic products approved by Stringent RegulatoryAuthorities (SRAs) NEW

Requalification Draft not finalised and not yet adopted


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Guidelines for Product dossier /Quality

Main Generic guide

Guideline on Submission of Documentation for Prequalification of

Multisource (Generic) Finished Pharmaceutical Products (FPPs) Used inthe Treatment of HIV/AIDS, Malaria and Tuberculosis [under revision]

Annex 1 - Model Certificate of a Pharmaceutical Product

Annex 2 - Model Batch Certificate of Pharmaceutical Product

Annex 3 - Model Stability Report of Active Pharmaceutical Ingredient (API)

Annex 4 - Model Stability Report of Capsules/Tablets

Annex 5 - Suggested Structure of the Summary of Product Characteristics(SmPC)

Annex 6 - Suggested Structure of the Package Information Leaflet (PIL)

Annex 7 - Presentation of Bioequivalence Trial Information (BTIF)

Annex 8 - Presentation of Pharmaceutical Quality Information (PQIF)
http://healthtech.who.int/pq/info_applicants/Guidelines/GuideGenericSubmitDocFPPs_08_2005_ANNEX1.pdfhttp://healthtech.who.int/pq/info_applicants/Guidelines/GuideGenericSubmitDocFpps_08_2005_ANNEX2.pdfhttp://healthtech.who.int/pq/info_applicants/Guidelines/GuideGenericSubmitDocFPPs_08_2005_ANNEX3.pdfhttp://healthtech.who.int/pq/info_applicants/Guidelines/GuideGenericSubmitDocFPPs_08_2005_ANNEX4.pdfhttp://healthtech.who.int/pq/info_applicants/Guidelines/GuideGenericSubmitDocFPPs_08_2005_ANNEX5.pdfhttp://healthtech.who.int/pq/info_applicants/Guidelines/GuideGenericSubmitDocFPPs_08_2005_ANNEX6.pdfhttp://healthtech.who.int/pq/info_applicants/Guidelines/GuideGenericSubmitDocFPPs_08_2005_ANNEX7.dochttp://healthtech.who.int/pq/info_applicants/Guidelines/GuideGenericSubmitDocFPPs_08_2005_ANNEX8.dochttp://healthtech.who.int/pq/info_applicants/Guidelines/GuideGenericSubmitDocFPPs_08_2005_ANNEX8.dochttp://healthtech.who.int/pq/info_applicants/Guidelines/GuideGenericSubmitDocFPPs_08_2005_ANNEX8.dochttp://healthtech.who.int/pq/info_applicants/Guidelines/GuideGenericSubmitDocFPPs_08_2005_ANNEX7.dochttp://healthtech.who.int/pq/info_applicants/Guidelines/GuideGenericSubmitDocFPPs_08_2005_ANNEX7.dochttp://healthtech.who.int/pq/info_applicants/Guidelines/GuideGenericSubmitDocFPPs_08_2005_ANNEX6.pdfhttp://healthtech.who.int/pq/info_applicants/Guidelines/GuideGenericSubmitDocFPPs_08_2005_ANNEX6.pdfhttp://healthtech.who.int/pq/info_applicants/Guidelines/GuideGenericSubmitDocFPPs_08_2005_ANNEX5.pdfhttp://healthtech.who.int/pq/info_applicants/Guidelines/GuideGenericSubmitDocFPPs_08_2005_ANNEX5.pdfhttp://healthtech.who.int/pq/info_applicants/Guidelines/GuideGenericSubmitDocFPPs_08_2005_ANNEX4.pdfhttp://healthtech.who.int/pq/info_applicants/Guidelines/GuideGenericSubmitDocFPPs_08_2005_ANNEX4.pdfhttp://healthtech.who.int/pq/info_applicants/Guidelines/GuideGenericSubmitDocFPPs_08_2005_ANNEX3.pdfhttp://healthtech.who.int/pq/info_applicants/Guidelines/GuideGenericSubmitDocFPPs_08_2005_ANNEX3.pdfhttp://healthtech.who.int/pq/info_applicants/Guidelines/GuideGenericSubmitDocFpps_08_2005_ANNEX2.pdfhttp://healthtech.who.int/pq/info_applicants/Guidelines/GuideGenericSubmitDocFpps_08_2005_ANNEX2.pdfhttp://healthtech.who.int/pq/info_applicants/Guidelines/GuideGenericSubmitDocFPPs_08_2005_ANNEX1.pdf


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Assessment Process - Quality

Submission of application

PQIF, Dossier, BTIF

Screening (Internal)

Acceptance

Pre Assessment Screening

Assessment

Report

Additional data

Prequalification LoPQ

Requalification


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Quality dossier / Section 1

Information on the FPP

1.1. Details of the Product

- Name, dosage form and strength of the product

- Approved generic name (INN)

- Visual description of the FPP

- Visual description of the packaging

1.2. Samples to be provided (for visual examination of assessors and

comparison with the SPC and PIL)

1.3. Regulatory situation in Member States / list countries

- Countries where a MA has been issued

- Countries where a MA has been withdrawn

- Countries where a Marketing Application has been rejected, deferred


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Active Pharmaceutical Ingredient

(API)


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Scientific data on the API can be submitted using

following ways and order of preference

A valid Certificate of Suitability(CoS) or CEP, latest version, with

all its annexes issued by EDQM

AnAPIMF(Active Pharmaceutical Ingredient Master File) submittedby the API manufacturer, containing the whole information requested

in section 2 and presented in CTD format (see APIMF guideline)

Completesubmission ofdata requested in Section 2


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of PQIF - Active Pharmaceutical Ingredient (API)

2.1. Nomenclature

2.2. Properties of the API

2.3. Site(s) of manufacture

2.4. Route(s) of synthesis

2.5. Specifications

2.6. Container- closure system

2.7. Stability testing


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CTD Structure of API Sections

2.3.S DRUG SUBSTANCE

2.3.S.1 General Information

2.3.S.2 Manufacture

2.3.S.3 Characterisation

2.3.S.4 Control of Drug Substance

2.3.S.5 Reference Standards or Materials

2.3.S.6 Container Closure System

2.3.S.7 Stability


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2.3.S DRUG SUBSTANCE

2.3.S.1 General Information

2.3.S.1.1 Nomenclature

Include INN, compendial name, chemical name(s),company/laboratory code, other non-proprietary names eg USAN,JAN, BAN and Chemical Abstracts Service (CAS) registry number.

2.3.S.1.2 Structure

Include structural formula with relative and absolutestereochemistry, molecular formula, and the relative molecularmass.

2.3.S.1.3 General Properties

Physicochemical and other relevant properties of the API.


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2.3.S.2 Manufacture

Information on the manufacturer;

A brief description of the manufacturing process

(including, for example, starting materials, reagents,

solvents, critical steps, and reprocessing) and the

controls intended to result in the routine and consistentproduction of API.

A flow diagram;

A description of the Source and Starting Material and rawmaterials used in the manufacture of the API;


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2.3.S.2 Manufacture Contd

A discussion of the selection and justification of criticalmanufacturing steps, process controls, and acceptancecriteria. Discuss critical process intermediates;

A description of process validation and/or evaluation.

A brief summary of major manufacturing changes madethroughout development and conclusions from theassessment used to evaluate product consistency. TheQOS should cross-refer to the non-clinical and clinical

studies that used batches affected by thesemanufacturing changes.


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2.3.S.3 Characterisation

A summary of the interpretation of evidence of structureand isomerism.

When an API is chiral, it should be specified whether

specific stereoisomers or a mixture of stereoisomers have

been used in the nonclinical and clinical studies, and

information should be given as to the stereoisomer of the

API that is to be used in the final product intended for

marketing.


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2.3.S.3 Characterisation Contd:

Impurities

Summary of the data on potential and actual impurities arising fromthe synthesis, manufacture and/or degradation, and should

summarise the basis for setting the acceptance criteria for

individual and total impurities.

Summary of the impurity levels in batches of the API used in the

non-clinical studies, in the clinical trials, and in typical batches

manufactured by the proposed commercial process. The QOS

should state how the proposed impurity limits are qualified.

A tabulated summary, with graphical representation, where

appropriate should be included.


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2.3.S.4 Control of Drug Substance

A summary of the specification(s), the analyticalprocedures, and validation should be included.

A tabulated summary of the batch analyses.


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2.3.S.5 Reference Standards or Materials

Information on primary and working standards of the APIand specified impurities.


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2.3.S.6 Container Closure System

A brief description and discussion of the primary andsecondary packaging components.


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2.3.S.7 Stability

This section should include a summary of the studiesundertaken (conditions, batches, analytical procedures)

and a brief discussion of the results and conclusions, the

proposed storage conditions, retest date or shelf-life.

The post-approval stability protocol should be included.


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PQ dossier section 2CTD2.1 Nomenclature

2.2 Properties of API (s)

S.1 General Information- Nomenclature

- Structure

- General Properties

2.3 Site(s) of Manufacture

2.4 Route(s) of synthesis- API not described in pharmacopoeia

- Specifications of raw materials and intermediates used in

synthesis

- API described in a pharmacopoeia

S.2 Manufacture- Manufacturer- Description of manufacturing process

- Control of materials- Control of critical steps and intermediates

- Process validation

- Manufacturing process development

S.3 Characterisation- Elucidation of structure

- Impurities

2.5 SpecificationsS.4 Control of Drug Substance

S.5 Reference Standards or Materials

2.6 Container Closure System

2.7 Stability testing

S.6 Container Closure System

S.7 Stability testing


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Finished Pharmaceutical Product

(FPP)


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Finished Pharmaceutical Product (FPP)3.1. Manufacturing and marketing authorization

3.2. Pharmaceutical development

3.3. Formulation

3.4. Sites of manufacture

3.5. Manufacturing process

3.6. Manufacturing process controls of Critical steps and intermediates

3.7. Process validation and Evaluation

3.8. Specifications for excipients

3.9. Control of the FPP

3.10. Container/closure system (s) and other packaging



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3.12. Container labelling

3.13. Product information for health professionals

3.14. Patient information and package leaflet

3.15. Justification for any differences to the product in the country

ORcountries issuing the submitted WHO-type certificate(s)


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3.1. Manufacturing and Marketing Authorization

- Valid manufacturing authorization for pharmaceuticalproduction including the pharmaceutical form applied for

- Marketing authorization to demonstrate the product isregistered / licensed in accordance with national requirements


The aim is to build a quality product by design.


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The section should contain information on the development studiesconducted to establish that

the dosage form,

the formulation, the manufacturing process,

the container closure system,

microbiological attributes and

storage and usage instructions

are appropriate for the purpose specified in the dossier.


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3.2. Pharmaceutical development (pre-formulation)

Physico-chemical characteristics of the APIs

solubility (composition)

water content (stability)

hygroscopicity (stability)

particle size (solubility, bioavailability, suspension properties,

stability )

polymorphism (solubility, bioavailability, stability)

Data obtained from literature : Books, Journals, International Pharmaceutical

Abstracts, Chemical Abstracts, Analytical Abstracts, Internet

Experimental data (if necessary)


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3.2. Pharmaceutical development (choice of excipients)

Intended function of each excipient

Criteria compatibility of excipients with API(s),

characteristics of the excipients (water content, particle size, flowability,density, rheological behavior)

Particularly : other non active constituents (lowest acceptableconcentration to be chosen e.g. concentration of parabens aspreservatives)

Experimental data needed.


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3.2. Pharmaceutical development (choice of the manufacturing

process)

Parameters : characteristics of the APIs, dosage form, composition. .

Rational behind the choice (e.g. why a non over kill process as a sterilisationprocess instead of terminal sterilisation in final container)

Justification of the overage (if any)

Identification of the critical steps

In Process Control (IPC)

Selection and optimisation of manufacturing process

Q li d i / S i 3


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3.2. Pharmaceutical development (dissolution testing)

To study dissolution operating conditions (media, pH, rotation, )

To develop a discriminatory dissolution method

Comparative dissolution testing is a tool, mandatory in developmentpharmaceutics section of the dossier in PQ, See Supplement 1

Help in selection of the formulation

- compare formulation(s) with innovator product,

- a basic strategy in development to maximize thechances of bioequivalence

Comparison of pivotal batches to commercial batches/ post-approval changes

Setting of dissolution specifications

Q li d i / S i 3


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Finished Pharmaceutical Product (FPP)3.2. Pharmaceutical development (comparative dissolution testing)

1. Three media - 900 ml or less - all at 37C Buffer pH 1.2 or0.1M HCl

Buffer pH 4.5

Buffer pH 6.8

Water may be usedadditionally (not instead of)

2. Paddle at 50 orbasket at 100 rpm

3. Twelve units of each product in all 3 media

4. Dissolution samples collected at short intervals, e.g. 10, 15, 20, 30, 45 and 60 minutes Analyse samples for all APIs, when applicable

5. Calculate similarity factor f2


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3.2. Pharmaceutical development (details of batches

studied)

Provide a summary of development of the FPP from pre-

formulation to production scale.

Provide a comparison of formulas (tabulated form) of: bio-batche(s) (clinical / bioequivalence),

development batches,

stability batches,

batches for validation/production


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3.2. Pharmaceutical development (choice of formulation

and compatibility)

Compatibility of APIs with the excipients

Compatibility of APIs between each other in case of fixed dose

combinations


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3.3. Formulation

Formula in tabulated form for :

Administration unit (e.g. one tablet),

Typical batch

- Precise any overage,

- Precise quantity adjustment of the API,

- Precise q.s. for excipient.

Excipients :

State function (e.g. lubricant, disintegrant),

Precise technical grade (e.g. micronised, purified water),

describe also those removed during process (e.g. water),

Describe also those not always added (e.g. acid & alkali for pH adjustment,

Capsule shells, inked imprints on dosage form, Also gas (inert atmosphere).

Q / S 3


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3.4. Manufacturing sites

Name and street address of each facility where any aspect ofmanufacture occurs including production, sterilisation,packaging and quality control include Units and/or Blocks

Include any alternative manufacturers

Certificate issued by the Competent DRA according to WHOCertification scheme for each site where a major step ofmanufacturing is performed

Submit a valid GMP certificate

Q lit d i / S ti 3


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3.5. Manufacturing process (cont.)

Flow chart with indication of each step showing where materials

enter the process. Indication of critical steps and in-process

controls

Description of manufacturing/packaging including

Scale

Equipment by type (e.g. tumble blender) & working capacity

Process parameters for steps, (e.g. time, temperature, pH)

Environmental conditions, e.g. relative humidity for hygroscopic

FPPs., area class for sterile FPPs

Steps of the process

Alternative methods

Q lit d i / S ti 3


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3.5. Manufacturing process (cont.)

Proposal for reprocessing justified with data.

Copy of master formula.

Batch manufacturing record real batch.

Sterile products sterilisation steps and/or aseptic procedures.

Description of in-process tests including plan of sampling and acceptance

limits.

Data for 3 full scale batches to support achievement of predetermined

specifications.

Q lit d i / S ti 3


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3.6. Manufacturing Process Controls of Critical steps and

Intermediates

Identification of critical steps with test methods and justified

acceptance criteria

Information on quality of isolated intermediates, test methods

and justified acceptance criteria to control them

Q lit d i / S ti 3


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3.7. Process Validation and Evaluation

Validation mandatory for processes including a critical step

The aim is to show that critical steps are under control and lead continuously tothe desirable quality

Examples of critical steps (list non exhaustive) mixing,

coating,

granulation,

emulsification,

non-standard sterilisation

Q lit d i / S ti 3


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3.7. Process Validation and Evaluation (details on 3 first production batches)

Batches. batch number

. batch size

. place and date of manufacture

. batch number of API(s)

. yield

. batch purpose (validation, stability, clinical trial )

Process. equipment

. process parameters

. validation protocol.

Results

. critical steps

. in process control

. finished product



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Concurrent validation carried out during normal production on

the first 3 production batches

OR

For well-established processes

process data, in-process controls and quality controls on a total

of 10- 25 batches to present a statistically significant picture

Q lit d i / S ti 3


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If validation data (on production scale batches) are not

available submit

validation protocol,

commitment that validation report will be submitted later for

evaluation,

commitment that data will be available in case of inspection,

commitment that WHO will be informed of any significant

deviation.

Q lit d i / S ti 3


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Validation protocol should include

brief description of the process with summary of critical steps and parameters to befollowed during validation,

specifications of the FPP at release,

details of analytical procedures and limits,

sampling plan,

unifromity of dosage units essential for FDCs,

proposed timeframe

Validation report when submitted should includeresults for each batch, certificates of analysis, batch production records,report on unusual findings, modifications, observations and conclusions



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Finished Pharmaceutical Product (FPP)3.8. Specifications for excipients

- Non pharmacopoeial substances- Details for manufacturing process,- Specifications (description of procedures and acceptance criteria)- Stability data- Cross-reference to non-clinical (toxicological)- clinical data for safety aspects- Certificates of analyses

- Pharmacopoeial excipients

Copy of the pharmacopoeial monograph used for control + certificates of analysis

- For excipients of animal, human, microbial origin

- TSE (Transmissible Spongiform Encephalopathy) risks and viral safety should beaddressed- TSE CEP preferred

Permitted colorantsare those allowed in UE, USA and Japan



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3.9. Control of the FPP

2 sets of specifications are possible: at release and at the end of shelf-life(list of attributes non exhaustive)

Description of the FPP /appearance

Identification of API

Assay of API: 5% of the label claim at release and 10% at the end of shelf-life

Degradation products

Pharmaceutical tests e.g. dissolution, disintegration (where applicable)

Uniformity of dosage units (mass or content)

Identification of colorants, identification and assay of anti-oxidants, chemical

preservatives

Microbial contamination, Sterility, bacterial endotoxins

Q lit d i / S ti 3


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3.9. Control of the FPP (cont.)

Monographs of Ph. Int., USP, BP are acceptable for the FPP +

complementary tests

If non-pharmacopoeial FPP, note for guidance Q6A applicable

Description of all analytical procedures in details if not described in a

pharmacopoeial monograph

Validation of analytical methods and/or demonstration of applicability for

pharmacopoeial methods

Batch analyses for 3 lots with details of each lot (batch no, size, date of

manufacture, use of batch)



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3.10. Container-closure system

Discussion on the choice of container

Choice of the materialProtection against light and humiditycompatibility/interaction of materials in contact with dosage formSafety of materials used

Detailed description of the container

Specifications of the container with dimensions and drawingsSpecifications of materials in contact with FPPComposition of these materials, compliance with pharmacopoeiaIdentification of components e.g. IR for plastic materials

Description of the secondary packaging



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The purpose of stability testing is to provide evidence on how the

quality of a FPP varies with time under the influence of a variety

of environmental conditions such as temperature, humidity

and light and to establish a shelf-life for the FPP, to determine

the storage conditions and the in-use stability.



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Lots included in the study: 1 production batch and 2 of pilot scalemanufactured according to the process described in the dossier3 Pilotscale batches are acceptable(exception for 2nd line TB products: 2 pilot batches)

Pilot scale batch for solid dosage forms is 10% of production scale or100 000 whichever is greater

Parameters susceptible to change over storage should be followed:

. Organoleptic properties

. Assay of each API: 10% of the label claim possible at the end of shelf-life

. Assay of degradation products

. Assay of antioxidants and chemical preservatives, check also for their efficacy

. Dissolution testing (limits should remain unchanged to release)

. Microbial contamination, sterility, bacterial endotoxins

In-use stability data (if applicable)



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Study should be performed in the claimed commercial packaging (container-closure)

Storage conditions and frequency of testing according to WHO stability guideline inTRS 953

Minimum stability data to be submitted at time of submission:

Long term 12 months or 6 months or 3 months (as appropriate according toSupplement 2 to the Main Generic guide and exception for TB 2nd line

products) 6 months intermediate 30C/65% RH

6 months accelerated 40C/75% RH

Unless otherwise justified, 30C / 75% RH is the recommended storage condition forPrequalification

Definition of "significant change" in WHO stability guide is the same as ICH Q1A (R2)



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Case of products packed in semi-permeable containers foreseen (liquiddosage forms susceptible to loss of solvent or water loss in low relativehumidity condition). The storage condition will be long term ICH 25C / 40%RHOR30C/35% RH and accelerated 40C/25% RH

Extrapolation of data to accord a longer shelf-life possible according to ICHQ1E + Supplement 2 in condition of commitments

Supplement 2: tentative 2 year re-test period and /or shelf-life may beaccorded to APIs and corresponding solid forms (tablets and capsules)listed in Supplement 2 based only on 6 months accelerated data and 6months long term data

Long term stability should anyhow be followed to cover the whole shelf-life

accorded



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3.12. Container labellingOuter packaging : Where no outer packaging, on immediatepackaging, e.g. HDPE bottle.

Labelling should include at least the following :

The name of the FPP.

Method of administration.

A list of API(s) (using INNs if applicable) showing the amount of each present in adosage unit, and a statement of the container, e.g. number of dosage units, weight or

volume. List of excipients known to be a safety concern for some patients, e.g. lactose, gluten,

metabisulfites, parabens, ethanol, or tartrazine.

Instruction on use.

The batch number assigned by the manufacturer.

The expiry date in an uncoded form.

Storage conditions or handling precautions that may be necessary.

Directions for use, and any warnings or precautions that may be necessary.

The name and address of the manufacturer, company or person responsible for placingthe product on the market.



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3.12. Container labelling

Blisters and stripsshould include, as a minimum, the following

information

Name, strength and pharmaceutical form of the FPP

Name of the manufacturer, company or person

responsible for placing the product on the market

The batch number assigned by the manufacturer

The expiry date in an un-coded form



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3.13. Product information for Health Professionals

Summary of product characteristics (SmPC)

Aimed at medical practitioners and health professionals Changes to SmPC to be approved by WHO

See Annex 5 of the main generic guide



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3.14. Patient information and package leaflet

Copy of the patient information leaflet (PIL)

In conformance with SmPC

See Annex 6 of the main Generic guide


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Thank youfor your attention

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