Who pq and_api

WHO Prequalification and API Requirements

Maryam MEHMANDOUSTPrequalification of Medicines Programme

QSM / EMP / HSS

Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009

Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009WHO Prequalification and API Requirements – Maryam MEHMANDOUST2 |

GlossaryGlossary 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


UN / WHO Prequalification Medicines Programme

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


Prequalification Medicines Programme Principles of Quality assessment procedure

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


Prequalification Medicines Programme How does it work?

Prequalification Medicines Programme How does it work?

Compliance

Corrective actions

Compliance

Assessment Inspections

PrequalificationListing

Maintenance and monitoring

-Product dossier -Site Master File

Response to questions

Expression of Interest


Prequalification Medicines Programme TB drugs in the latest (9th) Expression of Interest

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


Prequalification Medicines Programme Anti-malarials in the latest (8th) Expression of Interest

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)


Prequalification Medicines Programme ARVs in the latest (9th) Expression of InterestPrequalification 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


Reproductive Health in the latest (4th) EOIAntivirals 2nd EOI

Reproductive Health in the latest (4th) EOIAntivirals 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 Ph. Int., USP, draft Ph. Eur.

Mifepristone

Misoprostol Ph. Eur.

Influenza-specific antiviral drugs Oseltamivir Ph. Int. (December 2008), draft Ph. Eur., draft USP

Zanamivir Non pharmacopoeial


Prequalification Medicines Programme Guidelines for the assessment of product dossiers/quality API

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)


Prequalification Medicines Programme Guidelines for the assessment of product dossiers/quality

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


How to submit data on APIs in PQ product dossier- Section 2

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


CEP OptionWhat to provide in the PQ dossier?

CEP OptionWhat 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


APIMF Option / Procedural aspects 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 non-

pharmacopoeial – Biological APIs out of scope of the APIMF procedure (like in EU)



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)



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


Requirements and format for the API/CTDAPIMF or data in the dossier

Requirements and format for the API/CTDAPIMF or data in the dossier

CTDPQ dossier section 2S.1 General Information - Nomenclature- Structure

- General Properties

2.1 Nomenclature

2.2 Properties of API (s)

S.2 Manufacture- Manufacturer- Description of manufacturing process- Control of materials- Control of critical steps and intermediates- Process validation- Manufacturing process development

S.3 Characterisation- Elucidation of structure- Impurities

2.3 Site(s) of Manufacture

2.4 Route(s) of synthesis- API not described in pharmacopoeia- Specifications of raw materials and intermediates used in synthesis- API described in a pharmacopoeia

S.4 Control of Drug Substance

S.5 Reference Standards or Materials

2.5 Specifications

S.6 Container Closure System

S.7 Stability testing

2.6 Container Closure System

2.7 Stability testing


Requirements and format API Section/ CTD

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


3.2.S.2. ManufactureManufacturer(s)

3.2.S.2. ManufactureManufacturer(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


3.2.S.2. ManufactureDescription 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




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.


3.2.S.2. ManufactureControl 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





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.





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.




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.


3.2.S.2. Manufacture Controls of critical steps and Intermediates

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)


3.2.S.3. Characterization3.2.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, X-ray and so on.

- Unequivocal proof of configuration of chiral centres (if applicable) and geometric isomerism (if applicable) e.g. by single X-ray crystal


3.2.S.3. Characterization3.2.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


3.2.S.3. CharacterizationImpurities


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




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.


3.2.S.4. Control of the APISpecifications

3.2.S.4. Control of the APISpecifications

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


3.2.S.4. Control of the API3.2.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 sitePrimary batches should be at least of pilot size, 10% of maximum

commercial batch size at time of acceptance of the APIMF


3.2.S.4. Control of the API3.2.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


3.2.S.5. Reference Standards or Materials

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


3.2.S.7. Stability testing3.2.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



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"



Regulatory stability testing serves to define a re-test period for the API to recommend a storage condition

Definition of re-test periodPeriod 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



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



Retest period of the APIGeneral case

StudyStorage conditionMinimum time period covered by data at submission

Long term*25°C± 2°C / 60% RH ± 5% RH30°C± 2°C / 65% RH ± 5% RH30°C± 2°C / 75% RH ± 5% RH

12 months or 6 months as appropriate

Intermediate30°C± 2°C / 65% RH ± 5% RH6 months

Accelerated40°C± 2°C / 75% RH ± 5% RH6 months

*The storage condition of long term stability testing is determined by the climatic condition under which the API is intended to be stored



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



- 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 accordedcommitment will be requested to submit complementary data



Definition of stable APIAn 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 statementsA storage statement should be established for the labelling based on the stability evaluation of the pharmaceutical product


3.2.S.7. Stability testing Recommended labelling statements for APIs

appendix 3 to WHO stability guideline

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)30°C /65 % RH (intermediate, failure of accelerated)


30°C /65 % RH (long term) OR30°C /75 % RH (long term) 40°C/ 75% RH (accelerated)


5°C ± 3°CStore in a refrigerator(2 to 8°C)

-20°C± 5°CStore in a freezer


Prequalification of APIsPrequalification 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


Prequalification of APIsPrequalification 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.


Thank you for your attention

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