Transcript Guidelines - Pharmaceutical Export Promotion Council

WHO Prequalification and
API Requirements
Maryam MEHMANDOUST
Prequalification of Medicines Programme
QSM / EMP / HSS
Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
Glossary

API
Active Pharmaceutical Ingredient (interchangeable with drug substance or active substance)

APIMF
Active Pharmaceutical Ingredient Master File

ARV
Antiretroviral

CoS (CEP)
Certificate of Suitability

EDQM
European Directorate for Quality of Medicines and HealthCare

EoI
Expression of Interest

EMEA
European Medicines Agency

FPP
Finished Pharmaceutical Product

GMP
Good Manufacturing Practices

ICH
International Conference on Harmonization

Int. Ph.
International Pharmacopoeia

JP
Japanese Pharmacopoeia

Ph. Eur.
European Pharmacopoeia

PQ
Prequalification

PQIF
Pharmaceutical Quality Information form

RH
Reproductive Health

TB
Tuberculosis

USFDA
US Food and Drug Administration

USP
United States Pharmacopoeia
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WHO Prequalification and API Requirements – Maryam MEHMANDOUST
UN / WHO Prequalification Medicines
Programme
 Action plan of UN since 2001 aiming to facilitate access to priority medicinal
products
 Revision of the procedure in October 2008
– Categories: HIV/AIDS, Malaria, Tuberculosis, Reproductive Health, Influenza
– Potentially other categories of products possible, if there is the need
– To ensure quality, efficacy and safety of medicines procured using international funds
(e.g. GFTAM, UNITAID)
– Products meeting WHO recommended Quality Standards to be included in the list of
Prequalified products
– Inclusion in the list does imply any approval by WHO of the products and
manufacturing sites- this is the sole prerogative of National Authorities
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WHO Prequalification and API Requirements – Maryam MEHMANDOUST
Prequalification Medicines Programme
Principles of Quality assessment procedure
 General understanding of the production and quality control activities of
the manufacturer
 Assessment of product data and information on safety, efficacy and quality
 Assessment of manufacturing sites for consistency in production, quality
control of starting materials and FPPS through compliance with GMP
 Assessment of clinical testing units or CROs for compliance with GCP and
and GLP
 Reliance on the information supplied by national DRAs
 Random sampling and testing
 Handling of complaints and recalls
 Monitoring of complaints from agencies and countries
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WHO Prequalification and API Requirements – Maryam MEHMANDOUST
Prequalification Medicines Programme
How does it work?
Expression
of Interest
- Product dossier
- Site Master File
Assessment
Response to
questions
Inspections
Corrective
actions
Compliance
Compliance
Prequalification
Listing
Maintenance and monitoring
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WHO Prequalification and API Requirements – Maryam MEHMANDOUST
Prequalification Medicines Programme
TB drugs in the latest (9th) Expression of Interest

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

Levofloxacin
Draft USP

Moxifloxacin
Ph. Eur., USP, BP

Prothionamide
Ph. Int., JP

p-Aminosalicylic acid (and sodium salt)
Ph. Eur., USP
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WHO Prequalification and API Requirements – Maryam MEHMANDOUST
Prequalification Medicines Programme
Anti-malarials in the latest (8th) Expression of Interest
 Artemether
Ph. Int.
 Artesunate
Ph. Int.
 Artemotil (arte-ether)
Ph. Int.
 Amodiaquine
Ph. Int., USP
 Dihydroartemisinin
Ph. Int.
 Mefloquine
Ph. Int., Ph. Eur., USP
 Sulphadoxine
Ph. Int., Ph. Eur., USP
 Pyrimethamine
Ph. Int., Ph. Eur., USP
 Piperaquine
 Lumefantrine
Ph. Int. (July 2008)
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WHO Prequalification and API Requirements – Maryam MEHMANDOUST
Prequalification Medicines Programme
ARVs in the latest (9th) Expression of Interest

Abacavir
Ph. Int.

Didanosine
Ph. Int., Ph. Eur., USP

Efavirenz
Ph. Int.

Emtricitabine
Ph. Int. (February 2009)

Indinavir
Ph. Int., USP, Ph. Eur.

lamivudine
Ph. Eur., USP, BP, Ph. Int.

Nelfinavir mesilate
Ph. Int.

Nevirapine
Ph. Int., USP, Ph. Eur.

Stavudine
Ph. Eur., USP, BP, Ph. Int.

Saquinavir mesilate
Ph. Int., USP

Ritonavir
Ph. Int., USP, Ph. Eur.

Zidovudine
Ph.Int., USP, Ph. Eur., BP

Tenofovir, Lopinavir, Atazanavir
Non-pharmacopoeial
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WHO Prequalification and API Requirements – Maryam MEHMANDOUST
Reproductive Health in the latest (4th) EOI
Antivirals 2nd EOI
Reproductive Health

Ethinylestradiol
Ph. Int., Ph. Eur., USP, BP

Estradiol derivatives
USP (cypronate), Ph. Eur., USP (valerate)

Etonogestrel
Non pharmacopoeial

Desogestrel
Ph. Eur., USP

Levonorgestrel
Ph. Int., Ph. Eur., USP, BP

Medroxyprogesterone acetate
Ph. Int., Ph. Eur., USP, BP

Lynestrenol
Ph. Eur.

Norethisterone
Ph. Int., Ph. Eur.

Norgestrel
USP, Ph. Eur.

Oxytocin

Mifepristone

Misoprostol
Ph. Int., USP, draft Ph. Eur.
Ph. Eur.
Influenza-specific antiviral drugs

Oseltamivir
Ph. Int. (December 2008), draft Ph. Eur., draft USP

Zanamivir
Non pharmacopoeial
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WHO Prequalification and API Requirements – Maryam MEHMANDOUST
Prequalification Medicines Programme
Guidelines for the assessment of product dossiers/quality API
 Guideline on Submission of Documentation for Prequalification of
Multisource (Generic) Finished Pharmaceutical Products (FPPs) Used in
the Treatment of HIV/AIDS, Malaria and Tuberculosis [Main Generic Guide,
under revision], Section 2 on APIs
 Supplement 2- Extension of the WHO list of stable (not easily degradable
APIs)
 Guideline on Active Pharmaceutical Ingredient Master File (APIMF)
Procedure (DMF type procedure)
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WHO Prequalification and API Requirements – Maryam MEHMANDOUST
Prequalification Medicines Programme
Guidelines for the assessment of product dossiers/quality
ICH guidelines are used when a quality aspect cannot
be (fully) assessed by the WHO guidelines,
for instance:
– Q3A(R2)
Impurities in new drug substances
– Q3C(R3)
Impurities: Guideline for residual solvents
– Q6A
Specifications: Test procedures and
acceptance criteria for new drug substances and new drug
products: chemical substances (with decision trees)
– Q7
GMP for active pharmaceutical ingredients
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WHO Prequalification and API Requirements – Maryam MEHMANDOUST
How to submit data on APIs in PQ product
dossier- Section 2
Scientific data on the API can be submitted using
following ways and order of preference
 A valid Certificate of Suitability (CoS) or CEP, issued by EDQM
 An APIMF (Active Pharmaceutical Ingredient Master File)
submitted by the API manufacturer, containing the whole
information requested in section 2 and presented in CTD format
(see APIMF guideline and separate presentation)
 Complete submission of data requested in Section 2 of PQ product
dossier
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WHO Prequalification and API Requirements – Maryam MEHMANDOUST
CEP Option
What to provide in the PQ dossier?
 A copy of the latest version of CEP with all appendices + access
box duly filled out
 Information which may not be covered by the CEP
– Physicochemical characteristics and any relevant testing
– Container closure system (if not mentioned on the CEP)
– Stability data (if no re-test period on the CEP)
 Results of batch analysis (for attributes listed in the monograph +
any additional tests listed on the CEP + sterility if applicable)
 In case of sterile substances (e.g. Medroxyprogesterone acetate)
When there is no subsequent sterilization for the FPP
– Sterilization process as specified on the CEP
– Validation data
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WHO Prequalification and API Requirements – Maryam MEHMANDOUST
APIMF Option / Procedural aspects
 Procedure implemented in PQ since January 2007, www.who.int/Prequal/
 Adopted by the WHO Expert Committee on Specifications for
Pharmaceutical Preparations in October 2007 and recently published in
WHO Technical Report Series (TRS) 948 as Annex 4.
 Inspired from the Active Substance Master File (ASMF)/DMF procedure in
use in EU, CPMP/QWP/227/02 Rev 2.
 Scope only open to APIs # US and Canada DMFs (Drug Master File)
– Applicable to all types of chemical APIs: pharmacopoeial and nonpharmacopoeial
– Biological APIs out of scope of the APIMF procedure (like in EU)
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WHO Prequalification and API Requirements – Maryam MEHMANDOUST
APIMF Option / Procedural aspects
 Mainly used when the API manufacturer is different from the FPP
manufacturer but possible when API and FPP manufacturers are the same
 Allows to protect valuable confidential "know-how" of the API manufacturer
 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/
FPP manufacturer
 The APIMF procedure is not mandatory
 For Prequalification,
– Permits to avoid multiplication of assessments of one API from one
source /centralised handling
– Lightens the workload of manufacturers (reduces number of
deficiencies sent to manufacturers)
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WHO Prequalification and API Requirements – Maryam MEHMANDOUST
APIMF Option / Procedural aspects

An APIMF is always submitted ONLY in support of a FPP dossier.

Scientific information in an APIMF should be presented according to CTD (mandatory).

Information divided in 2 parts Restricted part + Applicant's part to fulfil the objectives of the
procedure (similar to EU and Canada DMF)

Restricted part (Closed part)
– Confidential information to be submitted only to WHO PQ

Applicant's part (Open part)
– Information regarded as to be non-confidential and to be given to the applicant
– Information to be given also to WHO PQ as part of APIMF

Letter of Access (LoA) to be given to WHO PQ with copy to the applicant
Changes and updates

In case of changes introduced in the APIMF
- Those requiring filing a variation by the applicant to be notified to each applicant.
- Those not requiring filing a variation are to be submitted to WHO PQ only and this before
implementation.

Tabular list summarizing changes
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WHO Prequalification and API Requirements – Maryam MEHMANDOUST
Requirements and format for the API/CTD
APIMF or data in the dossier
CTD
PQ dossier section 2
S.1 General Information
2.1 Nomenclature
- Nomenclature
- Structure
2.2 Properties of API (s)
- General Properties
S.2 Manufacture
2.3 Site(s) of Manufacture
- Manufacturer
- Description of manufacturing process
- Control of materials
- Control of critical steps and intermediates
- Process validation
- Manufacturing process development
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.3 Characterisation
- Elucidation of structure
- Impurities
S.4 Control of Drug Substance
2.5 Specifications
S.5 Reference Standards or Materials
S.6 Container Closure System
2.6 Container Closure System
S.7 Stability testing
2.7 Stability testing
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WHO Prequalification and API Requirements – Maryam MEHMANDOUST
Requirements and format
API Section/ CTD
 S.1. General information
 S.2. Manufacture
– Manufacturer(s), description of the manufacturing process, control of
materials, control of critical steps and intermediates, process validation,
manufacturing process development)
 S.3. Characterisation
 S.4. Control of API
 S.5. Reference standards or Materials
 S.6. Container closure system
 S.7. Stability testing
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WHO Prequalification and API Requirements – Maryam MEHMANDOUST
3.2.S.2. Manufacture
Manufacturer(s)
- Name, address and responsibility of each manufacturer, including contractors,
and each proposed manufacturing site or facility involved in the manufacturing
chain including specific steps such as milling or micronisation
- Actual manufacturing sites with indication of unit, plot, block (if any)
- Same information as above for alternative sites
GMP compliance certificate for each site of production of API (if available), A valid
manufacturing authorization for the production of APIs
Manufacturing process should be performed according to the GMP for APIs
ICH Q7: Good manufacturing practice for active pharmaceutical ingredients
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WHO Prequalification and API Requirements – Maryam MEHMANDOUST
3.2.S.2. Manufacture
Description of manufacturing process and process controls

A flow diagram of the process and a scheme of synthesis

Detailed description of the synthesis step-by-step indicating materials, reagents and solvents
used and critical steps identified by the manufacturer

Description of the synthesis should go sufficiently back to well-characterized starting
materials (see under control of materials)

Scale of manufacture: typical batch size and the maximum batch size (the range)

Last solvent of purification and crystallisation always to be controlled

Attention to concordance between the flow sheet of the synthesis and description of the
process

Alternate processes (if any) can be accepted ONLY if there is no change in the final
specifications of the API and in its impurity profile

In such case, description of the alternate process should be with the same level of details
than the main process

If alternate process may lead to different specifications / impurity profile, then separate APIMF
should be filed
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WHO Prequalification and API Requirements – Maryam MEHMANDOUST
3.2.S.2. Manufacture
Description of manufacturing process and process controls

Mention clearly if reprocessing and reworking steps are performed or not. If performed, they
should be clearly described with justification.

Attention to different impurity profile which may result from reworking.

Recovery of materials, if any, should be described in details with the step they are introduced
in the process.

Recovery operations should be adequately controlled so impurity levels do not increase over
time.

For recovery of solvents, it is important to know if there is any processing to improve the
quality of the recovered solvent and if recovered solvents comes from manufacturing process
of the specific API or can come from other processes.

Regarding recycling of filtrates ( mother liquors), information should be available on
maximum holding times of mother liquors and maximum number of times the material can be
recycled. Data on impurity levels should be provided to justify recycling of filtrates.

If there is no recovery of materials, this should be clarified in the dossier.

Blending of batches of API to obtain batches of lager size is acceptable only if batches are
individually tested against specifications and found to meet specifications of the final API.
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WHO Prequalification and API Requirements – Maryam MEHMANDOUST
3.2.S.2. Manufacture
Control of Materials
Starting material of the API
Most of manufacturers justify the choice of their starting material as per ICH
Q7 definition, i.e.:
a raw material, intermediate, or an API that is used in production of an API and
that is incorporated as a significant structural fragment into the structure of
the API. It can be an article of commerce, purchased from another supplier
or manufactured in-house.
This definition is not sufficient from an assessment point of view
- Significant structural fragment incorporated into the structure of the API can be
a very complex molecule
- Commercial availability is not sufficient justification in itself
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WHO Prequalification and API Requirements – Maryam MEHMANDOUST
3.2.S.2. Manufacture
Control of Materials
Starting material of the API
Starting material for synthesis in the dossier may precede the ICH Q7 "API starting material" by
several steps in the synthetic process (Pharmaceutical sciences- Questions and answers,
Therapeutic Products Directorate, Health Canada, May 2007)

If the structure of the starting material is too complex and synthesis too short, the proposed
starting material should be rather considered as the "key intermediate". The real starting
material as a synthetic precursor- one or more synthetic steps prior to the final API
intermediate should be asked for.

Exception to the above, when the API starting material is covered by a CEP,

Acids, bases, salts, esters and similar derivatives of the API are not considered final
intermediates,

The starting material should be incorporated as a significant structural fragment into the
structure of the final API,

The starting material should be well characterized, its structure fully elucidated,

The starting material should have well defined specifications including one or more specific
identity tests, tests and limits for the assay, specified and unspecified impurities and total
impurities.
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WHO Prequalification and API Requirements – Maryam MEHMANDOUST
3.2.S.2. Manufacture
Control of Materials
Starting material of the API
 In order to assess the presence of all potential impurities, a brief outline of the preparation
of the starting material of the API beginning from simpler molecules should be presented
including solvents and reagents in order to enable assessors to judge of the
appropriateness of specifications of the starting material of the API.
 If the APIMF holder is not in possession of the above information which may be
considered confidential, then the starting material manufacturer/supplier can directly
submit it to WHO PQ by referencing the APIMF number.
 Indicate the name and address (preferably manufacturing site) of the starting material
manufacturer.
 If there are several starting material manufacturers, then clarify if the material obtained
from different sources is prepared by the same route or different routes and if the
specifications for the starting material can apply to the material sourced from all of them.
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WHO Prequalification and API Requirements – Maryam MEHMANDOUST
3.2.S.2. Manufacture
Control of Materials
Specifications of materials
 Specifications for solvents and reagents
- Solvents used in final stages require greater purity and control
- Control of residual benzene in solvents such as toluene, etc
 Recovered solvents: specifications
 Quantitative and qualitative composition of denatured solvents
 Recovered materials: specifications
 Any material used in the process which may be of biological origin, viral and/or TSE
safety aspects should be addressed. Declaration on use/non use of material of
biological origin.
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WHO Prequalification and API Requirements – Maryam MEHMANDOUST
3.2.S.2. Manufacture
Controls of critical steps and Intermediates

Specifications for isolated intermediates

In-process controls
 Identification of critical steps (examples)
• Steps where significant impurities are removed or introduced,
• Steps where an essential molecular structural element such as chiral
centres are introduced
• Steps where a major chemical transformation is performed
• Steps having an impact on solid-state properties and homogeneity
of the API (relevant for solid dosage forms)
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WHO Prequalification and API Requirements – Maryam MEHMANDOUST
3.2.S.3. Characterization
Elucidation of structure and other characteristics

Confirmation of structure based on synthetic route and spectral analyses

Pharmacopoeial APIs: comparison of spectral data between the pharmacopoeial
reference standard and the test product

Non pharmacopoeial API: evidence of structure should be brought by elemental
analysis, IR, NMR (proton and carbon), UV, mass with interpretation of spectra, Xray and so on.
- Unequivocal proof of configuration of chiral centres (if applicable) and
geometric isomerism (if applicable) e.g. by single X-ray crystal
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WHO Prequalification and API Requirements – Maryam MEHMANDOUST
3.2.S.3. Characterization
Elucidation of structure and other characteristics
 Particle size distribution for poorly soluble API, routine testing to be
justified according to ICH Q6A
 Polymorphism
– Discussion on polymorphic forms (if applicable)
– Availability of analytical methods to distinguish between the forms
– Demonstration of consistency of production
– Routine control necessary or not, to be justified under 3.2.S.4.
according to ICH Q6A
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WHO Prequalification and API Requirements – Maryam MEHMANDOUST
3.2.S.3. Characterization
Impurities
 Discussion on potential and actual impurities
– Organic impurities
• Non pharmacopoeial APIs (name and origin of impurity, availability of actual samples for
test procedures and structural analysis, suitability of the proposed analytical methods, batch
results, justified limits given ICH Q3A identification and qualification thresholds)
• Pharmacopoeial APIs (whether the process actually leads to impurities described in
individual monograph, whether new impurities may be present in comparison to those
described in the monograph)
– Principle: different routes of synthesis may lead to different impurity profile
– If new impurities present, same requirements as above for non pharmacopoeial APIs
– Residual solvents
• Q3C (R3) and EU note for guidance CPMP/QWP/450/03
• Limit for TEA NMT 320 ppm (option 1) or 3.2 mg/day intake as per EDQM
document PA/PH/ CEP (04) 1 4R
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WHO Prequalification and API Requirements – Maryam MEHMANDOUST
3.2.S.3. Characterization
Impurities
 Discussion on potential and actual impurities (Cont.)
– Metal catalysts
• Residues of metal catalysts to be monitored and acceptance criteria set according to
relevant guidelines e.g. EU note CPMP/SWP/QWP/4446/00
– Genotoxic impurities
• Absence of known, established highly toxic impurities used in the process or formed
as by-product is to be discussed.
• Otherwise, suitable limits for their control are to be proposed.
• Limits to be justified by appropriate reference to specific available guidances (EU
CPMP/SWP/5199/02 or USFDA draft December 2008) or to experimental safety data or
to published data in peer-reviewed journals.
• L. Müller et al. article (Elsevier, 2006) can be used to have examples of known alerting
structures.
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WHO Prequalification and API Requirements – Maryam MEHMANDOUST
3.2.S.4. Control of the API
Specifications
Recognised Pharmacopoeias by WHO PQ are Ph. Int., Ph. Eur., (BP) and USP
APIs described in a pharmacopoeia
Requirements of the monograph claimed apply + those of general monographs and
chapters of that pharmacopoeia (if applicable)
e.g. for Ph. Eur.: requirements of individual monograph + general monograph (2034)+ general
chapter residual solvents (5.4.) + general monograph (1483) on products with TSE risk,.. all
together apply
Pharmacopoeial monograph available but the applicant/manufacturer claims in-house
standards, these can be acceptable only if they are demonstrated as to be at least
equivalent or more stringent than the pharmacopoeial monograph.
Non pharmacopoeial APIs
Justification according to ICH Q6A
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WHO Prequalification and API Requirements – Maryam MEHMANDOUST
3.2.S.4. Control of the API
Analytical procedures
 When a pharmacopoeial related substances method is used, demonstration
should be done that the method is actually suitable for determination of
impurities of the manufacturer's specific route of synthesis.
 Use of a pharmacopoeial method for related substances is not mandatory, an
in-house method can be accepted.
 In case an in-house method is used, the presence or absence of impurities
listed in the transparency list of the pharmacopoeial monograph should be
checked and their relevance for the manufacturer's specific route of synthesis
has to be discussed.
Batch analyses

Results of at least 3 consecutive recent primary batches from each site
Primary batches should be at least of pilot size, 10% of maximum commercial
batch size at time of acceptance of the APIMF
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WHO Prequalification and API Requirements – Maryam MEHMANDOUST
3.2.S.4. Control of the API
Justification of specifications
 inclusion OR omission of certain main/ critical tests and
acceptance criteria,
 any difference with pharmacopoeial limits if wider,
 any modification of pharmacopoeial tests,
 Specifications of non pharmacopoeial APIs to be justified as per
ICH Q6A
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WHO Prequalification and API Requirements – Maryam MEHMANDOUST
3.2.S.5. Reference Standards
or Materials
 For pharmacopoeial APIs: use an official Reference Standard.
 Working standard to be qualified against the official RS
 For non pharmacopoeial APIs
 A primary and/or a working standard are to be established
 Description of how this RS/WS has been set in terms of Identity (full structural
analyses) and Assay
The purity must be determined using an absolute procedure as follows: 100%
minus organic impurities (determined by an absolute assay procedure) minus
inorganic impurities, minus water content and minus residual solvents.
Certificate of Analysis + instructions for storage and duration of use
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WHO Prequalification and API Requirements – Maryam MEHMANDOUST
3.2.S.7. Stability testing
WHO guideline on stability testing of APIs and FPPs, TRS 953,
2009, annex 2

Forced degradation studies in stress condition
– Help to know about the intrinsic stability of the API
–
Help to know about the degradation pathways and degradation
products formed
–
Help to know whether the analytical method is suitable to determine
degradation products/ and whether it is stability-indicating
It is possible not to perform stress testing if the information can be
found in scientific literature
35 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
WHO Prequalification and API Requirements – Maryam MEHMANDOUST
3.2.S.7. Stability testing
Forced degradation studies in stress condition
 Requirement: 1 API batch
 Stress Conditions
- temperature, in 10° increments above accelerated (i.e. 50°C, 60°C …)
- humidity (75% or greater)
- oxidation and photolysis, where appropriate
- susceptibility of the API to hydrolysis across a justified range of pH values when in
solution or suspension
- photostability testing: generally as per Q1B,
Omission of photostability testing can be justified if pharmacopoeial monograph for
the API states, "Protect from light"
36 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
WHO Prequalification and API Requirements – Maryam MEHMANDOUST
3.2.S.7. Stability testing
Regulatory stability testing

serves to define a re-test period for the API

to recommend a storage condition
Definition of 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 conditions
If a re-test period cannot be defined, The API is to be tested before
manufacture of each lot of drug product
37 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
WHO Prequalification and API Requirements – Maryam MEHMANDOUST
3.2.S.7. Stability testing
Re-test period of the API
 Selection of batches (at least 3 primary)
– Primary batch of API should be at least pilot scale
– Manufactured by the same synthesis as production batches and the same
manufacturing procedure simulating the final process
 Same packaging than that proposed for storage /distribution
 Parameters to be tested: those susceptible to change during
storage such as assay, degradation products, physico-chemical
characteristics if relevant
 Analytical methods same as release OR if different, should be
validated and demonstrated to be stability indicating
38 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
WHO Prequalification and API Requirements – Maryam MEHMANDOUST
3.2.S.7. Stability testing
Retest period of the API
General case
Study
Storage condition
Minimum time period covered by
data at submission
Long term*
25°C± 2°C / 60% RH ± 5% RH 12 months or 6 months as
30°C± 2°C / 65% RH ± 5% RH appropriate
30°C± 2°C / 75% RH ± 5% RH
Intermediate
30°C± 2°C / 65% RH ± 5% RH 6 months
Accelerated
40°C± 2°C / 75% RH ± 5% RH 6 months
* The storage condition of long term stability testing is determined by
the climatic condition under which the API is intended to be stored
39 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
WHO Prequalification and API Requirements – Maryam MEHMANDOUST
3.2.S.7. Stability testing
Climatic zones and long term testing conditions
 Long term stability testing conditions are determined by the climatic
condition under which the API is intended to be stored.
Zone I: temperate
21°C/45%RH
Zone II: subtropical/mediterranean
25°C/60%RH
Zone III: hot/dry
30°C/35%RH
Zone VIa: hot/humid
30°C/65%RH
Zone VIb: hot/very humid
30°C/75%RH
40 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
WHO Prequalification and API Requirements – Maryam MEHMANDOUST
3.2.S.7. Stability testing
- Testing frequency: every 3 months the first year, every 6 months the second
year and then annually
- For an API, “significant change” is failure to meet the specification for any
parameter
- Extrapolation: possible either according to WHO PQ supplement 2 or
according to ICH Q1E
Exception for NOT easily degradable APIs, see the list in Supplement 2
6 months long term data at submission (either ICH condition 25°C/60% RH OR
30°C/65% RH OR 30°C/75% RH) + 6 months accelerated ICH 40°C/75% RH
A re-test period of 24 months can be accorded
Stability study should be continued to cover the re-test period accorded
commitment will be requested to submit complementary data
41 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
WHO Prequalification and API Requirements – Maryam MEHMANDOUST
3.2.S.7. Stability testing
Definition of stable API
An API is considered as stable if it remains within the
defined/regulatory specifications when stored for at least 2 years at
25°C/60% RH or at the alternative storage condition 30°C/65% RH
and for at least 6 months at 40°C/75% RH (Main generic guide)
0°C / 75% RH.
Recommended labelling statements
A storage statement should be established for the labelling based
on the stability evaluation of the pharmaceutical product
42 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
WHO Prequalification and API Requirements – Maryam MEHMANDOUST
3.2.S.7. Stability testing
Recommended labelling statements for APIs
appendix 3 to WHO stability guideline
Testing conditions under which stability of API
is demonstrated
Recommended labelling statement
25°C /60 % RH (long term)
40°C/ 75% RH (accelerated)
Do not store above 25°C
25°C /60 % RH (long term)
Do not store above 25°C
30°C /65 % RH (intermediate, failure of accelerated)
30°C /65 % RH (long term) OR
30°C /75 % RH (long term)
40°C/ 75% RH (accelerated)
Do not store above 30°C
5°C ± 3°C
Store in a refrigerator
(2 to 8°C)
-20°C± 5°C
Store in a freezer
43 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
WHO Prequalification and API Requirements – Maryam MEHMANDOUST
Prequalification of APIs
 New project in the pipeline of WHO PQ
 Procedure adopted by the WHO EC in October 2008 and published
in WHO Technical Report Series, N0. 953, 2009 as annex 4.
 Listing of Prequalified APIs and their manufacturer/ site
 Principles of the procedure similar to Prequalification of Medicines
–
–
–
–
–
–
Publication of list of APIs in Expression of Interest
Assessment of API dossier
Inspection of manufacturing sites
Random sampling and testing
Handling of complaints and recalls
Maintenance of Prequalification status
44 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
WHO Prequalification and API Requirements – Maryam MEHMANDOUST
Prequalification of APIs
 Stand-alone API dossier as per CTD (no relation with an FPP in contrary to an
APIMF)
 Requirements for assessment of quality as for the APIMFs
 Holders of APIMFs can request to switch to this new procedure, without dossier
assessment, in condition:
– Positive outcome of assessment of their APIMFs have been notified
– Positive outcome of inspection of the site
 Changes to be documented as per relevant change control procedures and
communicated to WHO
 Recognition of evaluation of relevant APIs by Competent authorities applying
stringent standards such as USFDA, EMEA and EDQM but not limited to.
– Share of certain information with WHO PQ
 Alternatively, a drug master file as prepared for and submitted to a Drug
Regulatory Authority of the ICH region can be submitted to WHO PQ.
45 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
WHO Prequalification and API Requirements – Maryam MEHMANDOUST
Thank you
for your attention
46 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
WHO Prequalification and API Requirements – Maryam MEHMANDOUST