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Dossier Requirements for Generics: Quality (Part I) EMRO 1st workshop on WHO Prequalification Programme of Priority Essential Medicines 6-7 June 2007, Cairo, EGYPT Maryam MEHMANDOUST, PhD Pre-qualification programme: Priority Essential Medicines WHO- HTP/ PSM/ QSM [email protected]

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16 september 2012

Dossier Requirements for Generics: Quality (Part I)

EMRO 1st workshop on WHO Prequalification Programme of Priority Essential Medicines6-7 June 2007, Cairo, EGYPT

Maryam MEHMANDOUST, PhDPre-qualification programme: Priority Essential MedicinesWHO- HTP/ PSM/ QSM [email protected]


Glossary

Glossary

  • APIActive Pharmaceutical Ingredient

  • APIMFActive Pharmaceutical Ingredient Master File

  • ARVAntiretroviral

  • CoSCertificate of Suitability

  • EDQMEuropean Directorate for Quality of Medicines and HealthCare

  • EoIExpression of Interest

  • FPPFinished Pharmaceutical Product

  • GMPGood Manufacturing Practices

  • ICHInternational Conference on Harmonization

  • Int. Ph. International Pharmacopoeia

  • JPJapanese Pharmacopoeia

  • Ph. Eur. European Pharmacopoeia

  • PILPatient Information Leaflet

  • PQPrequalification

  • PQIFPharmaceutical Quality Information form

  • SPC Summary of Product Characteristics

  • TBTuberculosis

  • USPUnited States Pharmacopoeia


Who reference text for multisource generic products

WHO Reference text for Multisource (Generic) products

WHO/DMP/RGS/98.5 - Marketing Authorisation of Pharmaceutical Products with Special Reference to Multisource (Generic) Products - A Manual for a Drug Regulatory Authority (Blue Book) (1999). [under revision]

available on WHO web-site: http://www.who.int/prequal/


Who reference text for multisource generic products definitions

WHO Reference text for Multisource (Generic) products / Definitions

Active Pharmaceutical Ingredient (API)

A substance or compound that is intended to be used in the manufactureof 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 the recipient.

Finished Pharmaceutical Product (FPP)

A product that has undergone all stages of production, including packaging in its final container and labelling.


Multisource generic product

Multisource (Generic) product

Multisources are Pharmaceutically equivalent (WHO definition)

  • same amount of the same API

  • same dosage form

  • meet the same or comparable standards

  • intended to be administered by the same route

    Multisourceswhich are therapeutically equivalent are interchangeable


Quality of a generic product

Quality of a Generic product

Multisource products must be of good quality and at least as safe and efficacious as existing products (WHO Manual, Blue Book, P. 29, chapter H., Interchangeability))

Equal quality with the

comparator ora quality shown and assessed to be as acceptable

Same Safety –

Same efficacy

Demonstration of pharmaceutical equivalenceof the FPP including that of the API


Reference texts prequalification quality guidelines for dossier submission

Reference textsPrequalification quality guidelines for dossier submission

  • Guideline on submission of documentation for prequalification of multi-source (Generic) Finished Pharmaceutical Products (FPPs) used in treatment of HIV/AIDS, Malaria and Tuberculosis (Main Generic guide with 8 annexes) [under revision]

  • Supplement 1 : Dissolution testing

  • Supplement 2 : Extension of the WHO list of stable APIs (not easily degradable)

  • Guidance on variations to a prequalified dossier

  • Guideline on Active Pharmaceutical Ingredient Master File (APIMF) Procedure

  • ICH notes for guidance (when applicable)

    These documents are available on WHO website:http://www.who.int/prequal/


Documentation on quality part to be submitted to the who pq team

Documentation on Quality Partto be submitted to the WHO PQ team

  • Covering letter

  • Product dossier on part Quality

  • PQIF (annex 8 to the main generic guide): properly filled out in WinWord format, See mock-up PQIF on www.who.int/prequal/ under training material and workshops, Hanoi, Vietnam, January 2006


Documentation on quality part to be submitted to the who pq team pqif

Documentation on Quality Partto be submitted to the WHO PQ team /PQIF


Documentation on quality part to be submitted to the who pq team pqif1

Documentation on Quality Partto be submitted to the WHO PQ team /PQIF


Documentation on quality part to be submitted to the who pq team pqif2

Documentation on Quality Partto be submitted to the WHO PQ team / PQIF


Quality dossier section 1

Quality dossier / Section 1

Information on the Finished Pharmaceutical Product (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 (visual examination 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


16 september 2012

Quality dossier / Section 2Active Pharmaceutical Ingredient (API)


Quality dossier section 2 active pharmaceutical ingredient api

Quality dossier / Section 2Active Pharmaceutical Ingredient (API)

Scientific data on the API can be submitted in the following order of preference

  • A valid Certificate of Suitability (CoS) or CEP, latest version, with all its annexes issued by EDQM

  • An APIMF (Active Pharmaceutical Ingredient Master File) submitted by the API manufacturer, containing the whole information requested in section 2

  • Complete submission of data requested in Section 2


Quality dossier section 2 active pharmaceutical ingredient api1

Quality dossier / Section 2Active 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

** The requirements may differ depending on if the API is pharmacopoeial or non-pharmacopoeial


Quality dossier section 2 active pharmaceutical ingredient api2

Quality dossier / Section 2Active Pharmaceutical Ingredient (API)

TB drugs / 6th EoI

  • Rifampicin (rifampin)Ph. Eur., USP, BP, Ph. Int.

  • Ethambutol 2HClPh. Eur., USP, BP, Ph. Int., JP

  • PyrazinamidePh. Eur., USP, BP, Ph. Int., JP

  • IsoniazidPh. Eur., USP, BP, Ph. Int., JP

  • Streptomycin sulfate Ph. Eur., USP, BP, Ph. Int.

  • AmikacinPh. Eur., USP, BP, Ph. Int., JP

  • KanamycinPh. Eur., USP, BP

  • CapreomycinUSP, Ph. Int.

  • CycloserineUSP, JP

  • EthionamidePh. Eur., USP, BP, Ph. Int., JP

  • OfloxacinPh. Eur., USP, BP

  • ProthionamidePh. Int., JP

  • p-Aminosalicylic acid (and sodium salt)Ph. Eur., USP


Quality dossier section 2 active pharmaceutical ingredient api3

Quality dossier / Section 2Active Pharmaceutical Ingredient (API)

Artemisinin based antimalarial drugs / EoI May 2005

  • ArtesunatePh. Int.

  • ArtemetherPh. Int.

  • Artemotil (arte-ether)Ph. Int.

  • AmodiaquinePh. API

  • mefloquine

  • Sulphadoxine

  • Pyrimethamine

  • LumefantrineNon-pharmacopoeial


Quality dossier section 2 active pharmaceutical ingredient api4

Quality dossier / Section 2Active Pharmaceutical Ingredient (API)

Antiretrovirals

  • AbacavirPh. Int.

  • DidanosinePh. Int.

  • EfavirenzPh. Int.

  • IndinavirPh. Int., USP

  • lamivudinePh. Eur., USP, BP, Ph. Int.

  • NelfinavirPh. Int.

  • Nevirapine Ph. Int., USP, Ph. Int.

  • StavudinePh. Eur., USP, BP, Ph. Int.

  • SaquinavirPh. Int., USP

  • RitonavirPh. Int., USP

  • ZidovudinePh.Int., USP, Ph. Eur., BP

  • Tenofovir and EmtricitabineNon-pharmacopoeial


Quality dossier section 2 active pharmaceutical ingredient api5

Quality dossier / Section 2Active Pharmaceutical Ingredient (API)

2.1. Nomenclature (INN, chemical name, CAS No.)

2.2. Properties of the API (pharmacopoeial substances)- Properties which are not described in a monograph such as solubilities in water and different buffer solutions, existence/absence of polymorphs, Particle size

- Verification of structure by Infra-red (IR) comparison to an official Reference standard


Quality dossier section 2 active pharmaceutical ingredient api6

Quality dossier / Section 2Active Pharmaceutical Ingredient (API)

2.2. Properties of the API (non-pharmacopoeial substances)- Chemical structure, stereochemistry, molecular mass- Isomeric nature including stereo-chemical configuration

- Proof of the structure: interpreted spectra such as IR, NMR, UV, RX, thermograms…- Physico-chemical properties such as solubilities in water and different buffer solutions, existence/absence of polymorphs,…


Quality dossier section 2 active pharmaceutical ingredient api7

Quality dossier / Section 2Active Pharmaceutical Ingredient (API)

2.3. Site(s) of manufactureName and address of each facility /alternative facility + valid manufacturing authorization for production of API

2.4. Route(s) of synthesis (Pharmacopoeial substance)Brief outline of the manufacturing process i.e.- flow chart and brief description of the manufacturing of API- name of solvents, reagents and catalysts used in the process- emphasis on final steps specifically those of purification and crystallization


Quality dossier section 2 active pharmaceutical ingredient api8

Quality dossier / Section 2Active Pharmaceutical Ingredient (API)

2.4. Route(s) of synthesis (non-pharmacopoeial substance)- flow chart and detailed description of the manufacturing of API, operating conditions and materials used, typical batch size- list of materials used: solvents, reagents and catalysts used in the process and their specifications- specifications of starting key raw material and intermediates - emphasis on final steps specifically those of purification and crystallization- in-process controls, identification of critical steps and their validation- description of alternative processes while showing that the final impurity profile remains the same as that of the main process- Reprocessing- Declaration on use/non use of TSE risk materials


Quality dossier section 2 active pharmaceutical ingredient api9

Quality dossier / Section 2Active Pharmaceutical Ingredient (API)

2.5. Specifications (Pharmacopoeial substance)-Copy of the pharmacopoeial monograph used + additional tests not mentioned in the monograph- Specifications of the API (analytical procedures and associated limits) should comply with the requirements of a specific monograph + those of the general monograph (if applicable) + controls on residual solventse.g. Ph. Eur. General monograph on substances for pharmaceutical use (2034)- If the API is prepared by a different method of synthesis liable to leave impurities other than those mentioned in the monograh- impurities to be characterized- demonstrate that the pharmacopoeial analytical procedure is suitable to control these new impurities- if not, develop and propose a new validated method with an acceptable limit for that impurity


Quality dossier section 2 active pharmaceutical ingredient api10

Quality dossier / Section 2Active Pharmaceutical Ingredient (API)

2.5. Specifications (Pharmacopoeial substance) (cont.)

  • If existence of polymorphs, discuss the need for having or not a specification for polymorphs

  • if substance insoluble in water, discuss the need for a particle size specifications these aspects are not covered by the pharmacopoeial monograph

    - Batch analyses for at least 2 batches manufactured on each site and from each route of synthesis


Quality dossier section 2 active pharmaceutical ingredient api11

Quality dossier / Section 2Active Pharmaceutical Ingredient (API)

2.5. Specifications (non-pharmacopoeial substance)- Requirements of the note for guidance ICH Q6A apply

- Characterize organic impurities, inorganic impurities, residual solvents, catalysts residues which may be potentially present in the final substance

- Propose acceptable limits according to ICH Q3A (impurities) and ICH Q3C (residual solvents)

- Propose appropriate analytical procedures suitable for the intended use, correctly validated + full detailed description of the method in order to be replicated by a control laboratories

- Batch analyses for at least 2 batches manufactured on each site and from each route of synthesis

- Description on how the reference standard used in analytical procedures is prepared, how its identity, its purity and its assay have been set + 1 certificate of analysis


Quality dossier section 2 active pharmaceutical ingredient api12

Quality dossier / Section 2Active Pharmaceutical Ingredient (API)

2.6. Container-closure system

  • Description of the packaging

  • Identification of materials and components of the packaging

  • Specifications of these materials

  • Justification for choice of these materials, e.g.

    - protection against light, humidity

    - compatibility of the used materials with the API, interactions between the API and the closure such as sorption, leaching (mainly in case of a liquid API)


Quality dossier section 2 active pharmaceutical ingredient api13

Quality dossier / Section 2Active Pharmaceutical Ingredient (API)

2.6. Stability of the API

  • Stress study

    • to know different degradation pathways of an API and degradation products formed

    • to demonstrate the intrinsic stability of the API

      The above information is useful further for development pharmaceutics of the FPP

    • To demonstrate the stability indicating power of the analytical procedure used

      Reference can be done to the literature or to pharmacopoeiae, if the above information is there available


Quality dossier section 2 active pharmaceutical ingredient api14

Quality dossier / Section 2Active Pharmaceutical Ingredient (API)

2.6. Stability of the API

  • Formal stability study

    necessary to establish a re-test period and a precaution for storage / labelling statement

    Definition of the re-test period

    Period of time during which the API is expected to remain within its specifications and can be used in the manufacture of a given product (without control prior to manufacture of Drug Product) in condition that the API has been stored under defined storage conditions


Quality dossier section 2 active pharmaceutical ingredient api15

Quality dossier / Section 2Active Pharmaceutical Ingredient (API)

2.6. Stability of the API

  • Formal stability study

    • 3 lots of API: 1 production scale and 2 of pilot size

    • Parameters susceptible to change during storage should be followed: assay, related substances and degradation products, isomeric nature,…

    • Minimum of data at submission of the dossier

      • 12 months long term ICH condition 25°C/60% RH,

      • 12 months intermediate ICH condition 30°C/65% RH,

      • 6 months accelerated ICH 40°C/75% RH

        Unless otherwise justified, the long term storage condition for Prequalification is 30°C/ 65% RH


Submission of data on api section 2 certification of suitability cos cep option

Submission of data on API – section 2Certification of Suitability (CoS) / CEP Option

  • Issued by EDQM for substances described in the Ph. Eur. www.edqm.eu

  • 2 types of CEPs: quality CEP and TSE CEP

  • Information which can be found on a quality CEPCEP reference, CEP holder, site of manufacture of the substance, monograph according to which the dossier is evaluated, additional impurities and residual solvents not mentioned in the monograph, additional methods to those of the monograph are appended, re-test period with packaging system and storage condition (if applicable), date of validity of the CEP

    A quality CEP certifies that the quality of the substance can be checked according to the Ph. Eur. by applying the analytical methods described in the Ph. Eur. monograph supplemented by those appended to the CEP.


Submission of data on api section 2 apimf option

Submission of data on API – section 2APIMF Option

  • Procedure implemented since January 2007, www.who.int/prequal

  • To protect the "know-how" of the manufacturer of the API

  • While giving the whole information on manufacture of the API to the WHO PQ team of assessors

  • While giving a part of the information to the applicant to Prequalification/ manufacturer of the finished product

  • An APIMF is composed of: Applicant's /Open part + Restricted / Closed part

  • Manufacturer of the API should make available to the applicant to Prequalification the Applicant's part + Letter of access


Submission of data on api section 2 apimf option1

Submission of data on API – section 2APIMF Option

  • Manufacturer of the API should submit on the other hand the Applicant's part + Restricted + Letter of access to WHO team An APIMF is to be submitted only in support of a FPP dossier

  • An APIMF is not an independent dossier of API

  • Scope open to pharmacopoeial and non-pharmacopoeial APIs

  • Scope of APIMF only open to APIs≠ US and Canadian master file procedures

  • See annex 1 of the APIMF guide for the content of an APIMF

  • Content of APIMF corresponds to data required in section 2 of the prequalification quality dossier without difference between pharmacopoeial and non-pharmacopoeial APIs


16 september 2012

Quality dossier / Section 3

Finished Pharmaceutical Product

(FPP)


Quality dossier section 3 finished pharmaceutical product fpp

Quality dossier / Section 3Finished 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

3.11. Stability testing


Quality dossier section 3 finished pharmaceutical product fpp1

Quality dossier / Section 3Finished Pharmaceutical Product (FPP)

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 or countries issuing the submitted WHO-type certificate(s)


Quality dossier section 3 finished pharmaceutical product fpp2

Quality dossier / Section 3Finished Pharmaceutical Product (FPP)

3.1. Manufacturing and Marketing Authorization

  • Valid manufacturing authorization for pharmaceutical production including the pharmaceutical form applied for

  • Marketing authorization to demonstrate the product is registered / licensed in accordance with national requirements

    3.2. Pharmaceutical development

    The aim is to build a quality product by design.


Quality dossier section 3 finished pharmaceutical product fpp3

Quality dossier / Section 3Finished Pharmaceutical Product (FPP)

3.2. Pharmaceutical development

The section should contain information on the development studies conducted 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.


Quality dossier section 3 finished pharmaceutical product fpp4

Quality dossier / Section 3Finished Pharmaceutical Product (FPP)

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)


Quality dossier section 3 finished pharmaceutical product fpp5

Quality dossier / Section 3Finished Pharmaceutical Product (FPP)

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 acceptable concentration to be chosen e.g. concentration of parabens as preservatives)

  • Experimental data needed.


Quality dossier section 3 finished pharmaceutical product fpp6

Quality dossier / Section 3Finished Pharmaceutical Product (FPP)

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 sterilisation process?)

  • Justification of the overage (if any)

  • Identification of the critical steps

  • In Process Control (IPC)

  • Selection and optimisation of manufacturing process


Quality dossier section 3 finished pharmaceutical product fpp7

Quality dossier / Section 3Finished Pharmaceutical Product (FPP)

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 development pharmaceutics 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 the chances of bioequivalence

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

    • Setting of dissolution specifications


Quality dossier section 3 finished pharmaceutical product fpp8

Quality dossier / Section 3Finished Pharmaceutical Product (FPP)

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


Quality dossier section 3 finished pharmaceutical product fpp9

Quality dossier / Section 3Finished Pharmaceutical Product (FPP)

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

    See example of 4FDC for TB products


Quality dossier section 3 finished pharmaceutical product fpp10

Quality dossier / Section 3Finished Pharmaceutical Product (FPP)

3.2. Pharmaceutical development (choice of formulation and compatibility)

  • Each tablet contains 4 APIs

    . Rifampicin ………………. 150 mg

    . Isoniazid …………………. 75 mg

    . Pyrazinamid …………….. 400 mg

    . Ethambutol 2HCl…………275 mg

    . Excipients ………………..


Quality dossier section 3 finished pharmaceutical product fpp11

Quality dossier / Section 3Finished Pharmaceutical Product (FPP)

3.2. Pharmaceutical development (choice of formulation and compatibility)

  • Rifampicin

    Oxidation (quinone & N-oxide)

    • Protect from air exposure

      Hydrolysis (3-formylrifamycin & 25-desacetyl)

    • Wet granulation/drying a potential problem ?

      Reaction with Isoniazid

    • Produces 3-(isonicotinylhydrazinomethyl) rifamycin or more commonly known as isonicotinyl hydrazone.

      Light sensitive

    • Product to be protected from light exposure


Quality dossier section 3 finished pharmaceutical product fpp12

Quality dossier / Section 3Finished Pharmaceutical Product (FPP)

3.2. Pharmaceutical development (choice of formulation and compatibility)

  • Isoniazid

    Reacts with aldehydes/reducing sugars

    • Sugar & lactose to be avoided in formulation !!

    • 3-formylrifamycin (from rifampicin)

  • Ethambutol hydrochloride (2HCl)

    Hygroscopic

    • Absorbs water reactions in tablets.

      Creates slightly acidic conditions

    • The acidic conditions enhance reaction between rifampicin and isoniazid (isonicotinyl hydrazone formation)


Quality dossier section 3 finished pharmaceutical product fpp13

Quality dossier / Section 3Finished Pharmaceutical Product (FPP)

3.2. Pharmaceutical development (preventive/protective measures)

  • Formulation – no sugar/lactose (isoniazid)

  • Separate granulation of rifampicin & isoniazid (limit contact)

  • Rifampicin as powder (not granulate) ?

    • Prevent oxidation & hydrolysis

  • Low water content of tablet

  • Protect product from moisture and oxygen

    • Film coating,

    • Non-permeable packaging

  • Light protection


Quality dossier section 3 finished pharmaceutical product fpp14

Quality dossier / Section 3Finished Pharmaceutical Product (FPP)

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),

    • Also those removed during process (e.g. water),

    • Also those not always added (e.g. acid & alkali) : pH adjustment,

    • Capsule shells, inked imprints on dosage form,

    • Also gas (inert atmosphere).


Quality dossier section 3 finished pharmaceutical product fpp15

Quality dossier / Section 3Finished Pharmaceutical Product (FPP)

3.4. Manufacturing sites

  • Name and street address of each facility where any aspect of manufacture occurs including production, sterilisation, packaging and quality control

  • Include any alternative manufacturers

  • Certificate issued by the Competent DRA according to WHO Certification scheme for each site where a major step of manufacturing is performed

  • Submit a valid GMP certificate


Quality dossier section 3 finished pharmaceutical product fpp16

Quality dossier / Section 3Finished Pharmaceutical Product (FPP)

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


Quality dossier section 3 finished pharmaceutical product fpp17

Quality dossier / Section 3Finished Pharmaceutical Product (FPP)

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.


Quality dossier section 3 finished pharmaceutical product fpp18

Quality dossier / Section 3Finished Pharmaceutical Product (FPP)

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


Quality dossier section 3 finished pharmaceutical product fpp19

Quality dossier / Section 3Finished Pharmaceutical Product (FPP)

3.7. Process Validation and Evaluation

WHO validation definition

The documented act of proving that any procedure, process, equipment, material, activity, or system actually leads to the expected results.


Quality dossier section 3 finished pharmaceutical product fpp20

Quality dossier / Section 3Finished Pharmaceutical Product (FPP)

3.7. Process Validation and Evaluation

What should be validated ?

“Any aspect of operation, including significant changes to the premises, facilities, equipment or processes, which may affect the quality of the product, directly or indirectly, should be qualified and validated”


Quality dossier section 3 finished pharmaceutical product fpp21

Quality dossier / Section 3Finished Pharmaceutical Product (FPP)

3.7. Process Validation and Evaluation

Purpose of validation

Process validation is intended to establish that the proposed manufacturing process is a suitable one and yields consistently a product of the desired quality.i.e. that the process is suitable and under control


Quality dossier section 3 finished pharmaceutical product fpp22

Quality dossier / Section 3Finished Pharmaceutical Product (FPP)

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 to the desirable quality

Examples of critical steps (list non exhaustive)

  • mixing,

  • coating,

  • granulation,

  • emulsification,

  • non-standard sterilisation


Quality dossier section 3 finished pharmaceutical product fpp23

Quality dossier / Section 3Finished Pharmaceutical Product (FPP)

3.7. Process Validation and Evaluation (details on first 3 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


Quality dossier section 3 finished pharmaceutical product fpp24

Quality dossier / Section 3Finished Pharmaceutical Product (FPP)

3.7. Process Validation and Evaluation

  • Concurrent validation carried out during normal production on the first 3 production batches

    OR

  • For well-established processesprocess data, in-process controls and quality controls on a total of 10- 25 batches to present a statistically significant picture


Quality dossier section 3 finished pharmaceutical product fpp25

Quality dossier / Section 3Finished Pharmaceutical Product (FPP)

3.7. Process Validation and Evaluation

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.


Quality dossier section 3 finished pharmaceutical product fpp26

Quality dossier / Section 3Finished Pharmaceutical Product (FPP)

3.7. Process Validation and Evaluation

Validation protocol should include

  • brief description of the process with summary of critical steps and parameters to be followed 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 usual findings, modifications, observations and conclusions


Quality dossier section 3 finished pharmaceutical product fpp27

Quality dossier / Section 3Finished 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 excipientsCopy 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 be addressed- TSE CEP preferred

Permitted colorants are those allowed in UE, USA and Japan


Quality dossier section 3 finished pharmaceutical product fpp28

Quality dossier / Section 3Finished Pharmaceutical Product (FPP)

3.9. Control of the FPP2 sets of specifications are possible: at release and at the end of shelf-life(list 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


Quality dossier section 3 finished pharmaceutical product fpp29

Quality dossier / Section 3Finished Pharmaceutical Product (FPP)

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)


Quality dossier section 3 finished pharmaceutical product fpp30

Quality dossier / Section 3Finished Pharmaceutical Product (FPP)

3.10. Container-closure system

  • Discussion on the choice of containerChoice of the materialProtection against light and humiditycompatibility/interaction of materials in contact with dosage formSafety of materials used

  • Detailed description of the containerSpecifications 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


Quality dossier section 3 finished pharmaceutical product fpp31

Quality dossier / Section 3Finished Pharmaceutical Product (FPP)

3.11. Stability testing

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.

To know about length of the time and conditions where efficacy, safety and quality of the FPP are maintained


Quality dossier section 3 finished pharmaceutical product fpp32

Quality dossier / Section 3Finished Pharmaceutical Product (FPP)

3.11. Stability testing

  • Lots included in the study: 1 production batch and 2 of pilot scale manufactured according to the process described in the dossier

  • Pilot scale batch for solid dosage forms is 10% of production scale or 100 000 whichever is greater

  • Parameters susceptible to change over storage should be followed:

    Organoleptic propertiesAssay of each API: ±10% of the label claim possible at the end of shelf-lifeAssay of degradation productsAssay of antioxidants and chemical preservatives, check also for their efficacyDissolution testing (limits should remain unchanged to release)Microbial contamination, sterility, bacterial endotoxins

  • In-use stability data (if applicable)


Quality dossier section 3 finished pharmaceutical product fpp33

Quality dossier / Section 3Finished Pharmaceutical Product (FPP)

3.11. Stability testing

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

  • Storage conditions and frequency of testing according to ICH Q1A(R2)

  • Minimum stability data to be submitted at time of submission: 12 months long term ICH 25°C/60% RH, 12 months intermediate ICH 30°C/65% RH and 6 months accelerated ICH 40°C/75% RH with exception according to Supplement 2 to the Main Generic guide

  • Unless otherwise justified, 30°C / 65% RH is the recommended storage condition for Prequalification

  • Definition of "significant change" is the same as ICH Q1A (R2) see next presentation


Quality dossier section 3 finished pharmaceutical product fpp34

Quality dossier / Section 3Finished Pharmaceutical Product (FPP)

3.11. Stability testing

  • Case of products packed in semi-permeable containers foreseen (liquid dosage forms susceptible to loss of solvent or water loss in low relative humidity condition). The storage condition will be long term ICH 25°C / 40% RH and accelerated 40°C/25% RH

  • Extrapolation of data to accord a longer shelf-life possible according to ICH Q1E + Supplement 2 in condition of commitments

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

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


Quality dossier section 3 finished pharmaceutical product fpp35

Quality dossier / Section 3Finished Pharmaceutical Product (FPP)

3.12. Container labellingOuter packaging : Where no outer packaging, on immediate packaging, 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 a dosage 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 placing the product on the market.


Quality dossier section 3 finished pharmaceutical product fpp36

Quality dossier / Section 3Finished Pharmaceutical Product (FPP)

3.12. Container labelling

Blisters and strips should 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 uncoded form


Quality dossier section 3 finished pharmaceutical product fpp37

Quality dossier / Section 3Finished Pharmaceutical Product (FPP)

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


Quality dossier section 3 finished pharmaceutical product fpp38

Quality dossier / Section 3Finished Pharmaceutical Product (FPP)

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


16 september 2012

Data in the dossier should enable us to conclude

  • What is the product?

  • Is the quality presented is acceptable on grounds of safety and efficacy?

  • Is the quality presented is reproducible?

  • How long is it maintained?

    Quality must ensure consistency of safety and efficacy during the shelf life of all batches produced.


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