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22 February 2011
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
mehmandoustm@who.int

Slide 2 M. MEHMANDOUST- Cairo- June 2007
Glossary
API Active Pharmaceutical Ingredient
APIMF Active Pharmaceutical Ingredient Master File
ARV Antiretroviral
CoS Certificate of Suitability
EDQM European Directorate for Quality of Medicines and HealthCare
EoI Expression of Interest
FPP Finished Pharmaceutical Product
GMP Good Manufacturing Practices
ICH International Conference on Harmonization
Int. Ph. International Pharmacopoeia
JP Japanese Pharmacopoeia
Ph. Eur. European Pharmacopoeia
PIL Patient Information Leaflet
PQ Prequalification
PQIF Pharmaceutical Quality Information form
SPC Summary of Product Characteristics
TB Tuberculosis
USP United States Pharmacopoeia

Slide 3 M. MEHMANDOUST- Cairo- June 2007
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/

Slide 4 M. MEHMANDOUST- Cairo- June 2007
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.

Slide 5 M. MEHMANDOUST- Cairo- June 2007
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

Multisources which are therapeutically equivalent are interchangeable

Slide 6 M. MEHMANDOUST- Cairo- June 2007
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))

Same Safety – Equal quality with the
Same efficacy comparator or a quality shown and
assessed to be as acceptable

Demonstration of pharmaceutical equivalence of the
FPP including that of the API

Slide 7 M. MEHMANDOUST- Cairo- June 2007
Reference texts
Prequalification 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/

Slide 8 M. MEHMANDOUST- Cairo- June 2007
Documentation on Quality Part
to 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

Slide 9 M. MEHMANDOUST- Cairo- June 2007
Documentation on Quality Part
to be submitted to the WHO PQ team /PQIF

Slide 10 M. MEHMANDOUST- Cairo- June 2007
Documentation on Quality Part
to be submitted to the WHO PQ team /PQIF

Slide 11 M. MEHMANDOUST- Cairo- June 2007
Documentation on Quality Part
to be submitted to the WHO PQ team / PQIF

Slide 12 M. MEHMANDOUST- Cairo- June 2007
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

Slide 13 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 2

Active Pharmaceutical Ingredient
(API)

Slide 14 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 2
Active 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

Slide 15 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 2
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
** The requirements may differ depending on if the API is pharmacopoeial or
non-pharmacopoeial

Slide 16 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 2
Active Pharmaceutical Ingredient (API)
TB drugs / 6th EoI
 Rifampicin (rifampin) Ph. Eur., USP, BP, Ph. Int.
 Ethambutol 2HCl Ph. Eur., USP, BP, Ph. Int., JP
 Pyrazinamide Ph. Eur., USP, BP, Ph. Int., JP
 Isoniazid Ph. Eur., USP, BP, Ph. Int., JP
 Streptomycin sulfate Ph. Eur., USP, BP, Ph. Int.
 Amikacin Ph. Eur., USP, BP, Ph. Int., JP
 Kanamycin Ph. Eur., USP, BP
 Capreomycin USP, Ph. Int.
 Cycloserine USP, JP
 Ethionamide Ph. Eur., USP, BP, Ph. Int., JP
 Ofloxacin Ph. Eur., USP, BP
 Prothionamide Ph. Int., JP
 p-Aminosalicylic acid (and sodium salt) Ph. Eur., USP

Slide 17 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 2
Active Pharmaceutical Ingredient (API)
Artemisinin based antimalarial drugs / EoI May 2005
 Artesunate Ph. Int.
 Artemether Ph. Int.
 Artemotil (arte-ether) Ph. Int.
 Amodiaquine Ph. API
 mefloquine
 Sulphadoxine
 Pyrimethamine
 Lumefantrine Non-pharmacopoeial

Slide 18 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 2
Active Pharmaceutical Ingredient (API)
Antiretrovirals
 Abacavir Ph. Int.
 Didanosine Ph. Int.
 Efavirenz Ph. Int.
 Indinavir Ph. Int., USP
 lamivudine Ph. Eur., USP, BP, Ph. Int.
 Nelfinavir Ph. Int.
 Nevirapine Ph. Int., USP, Ph. Int.
 Stavudine Ph. Eur., USP, BP, Ph. Int.
 Saquinavir Ph. Int., USP
 Ritonavir Ph. Int., USP
 Zidovudine Ph.Int., USP, Ph. Eur., BP
 Tenofovir and Emtricitabine Non-pharmacopoeial

Slide 19 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 2
Active 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

Slide 20 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 2
Active 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,…

Slide 21 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 2
Active Pharmaceutical Ingredient (API)
2.3. Site(s) of manufacture
Name 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

Slide 22 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 2
Active 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

Slide 23 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 2
Active 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 solvents
e.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

Slide 24 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 2
Active 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

Slide 25 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 2
Active 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

Slide 26 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 2
Active 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)

Slide 27 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 2
Active 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

Slide 28 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 2
Active 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

Slide 29 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 2
Active 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

Slide 30 M. MEHMANDOUST- Cairo- June 2007
Submission of data on API – section 2
Certification 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 CEP
CEP 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.

Slide 31 M. MEHMANDOUST- Cairo- June 2007
Submission of data on API – section 2
APIMF 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

Slide 32 M. MEHMANDOUST- Cairo- June 2007
Submission of data on API – section 2
APIMF 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
Slide 33 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 3

Finished Pharmaceutical Product

(FPP)

Slide 34 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 3
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
3.11. Stability testing

Slide 35 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 3
Finished 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)

Slide 36 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 3
Finished 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.

Slide 37 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 3
Finished 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.

Slide 38 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 3
Finished 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)

Slide 39 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 3
Finished 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.

Slide 40 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 3
Finished 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

Slide 41 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 3
Finished 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

Slide 42 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 3
Finished 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

Slide 43 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 3
Finished 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

Slide 44 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 3
Finished 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 ………………..

Slide 45 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 3
Finished 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

Slide 46 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 3
Finished 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)

Slide 47 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 3
Finished 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

Slide 48 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 3
Finished 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).

Slide 49 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 3
Finished 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

Slide 50 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 3
Finished 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

Slide 51 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 3
Finished 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.

Slide 52 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 3
Finished 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

Slide 53 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 3
Finished 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.

Slide 54 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 3
Finished 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”

Slide 55 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 3
Finished 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

Slide 56 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 3
Finished 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

Slide 57 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 3
Finished 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

Slide 58 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 3
Finished Pharmaceutical Product (FPP)
3.7. Process Validation and Evaluation

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

 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

Slide 59 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 3
Finished 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.

Slide 60 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 3
Finished 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 include
results for each batch, certificates of analysis, batch production records, report on
usual findings, modifications, observations and conclusions

Slide 61 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 3
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 be
addressed
- TSE CEP preferred
Permitted colorants are those allowed in UE, USA and Japan

Slide 62 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 3
Finished Pharmaceutical Product (FPP)
3.9. Control of the FPP
2 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

Slide 63 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 3
Finished 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)

Slide 64 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 3
Finished Pharmaceutical Product (FPP)
3.10. Container-closure system
 Discussion on the choice of container
Choice of the material
Protection against light and humidity
compatibility/interaction of materials in contact with dosage form
Safety of materials used

 Detailed description of the container
Specifications of the container with dimensions and drawings
Specifications of materials in contact with FPP
Composition of these materials, compliance with pharmacopoeia
Identification of components e.g. IR for plastic materials

 Description of the secondary packaging

Slide 65 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 3
Finished 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

Slide 66 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 3
Finished 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 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)

Slide 67 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 3
Finished 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

Slide 68 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 3
Finished 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

Slide 69 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 3
Finished Pharmaceutical Product (FPP)
3.12. Container labelling
Outer 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.

Slide 70 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 3
Finished 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

Slide 71 M. MEHMANDOUST- Cairo- June 2007
Quality dossier / Section 3
Finished 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

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Quality dossier / Section 3
Finished 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

Slide 73 M. MEHMANDOUST- Cairo- June 2007
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.

Slide 74 M. MEHMANDOUST- Cairo- June 2007