M. MEHMANDOUST/ Quality of APIs/ Shanghai-China Quality of Active Pharmaceutical Ingredients (APIs) WHO Workshop on GMP and Quality Assurance of HIV products

M. MEHMANDOUST/ Quality of APIs/ Shanghai-China

Quality of Active Pharmaceutical Ingredients (APIs)

WHO Workshop on GMP and Quality Assurance

of HIV productsShanghai – China

28 February - 4 March 2005

Maryam MEHMANDOUST, PhD, consultant to WHOAgence Française de Sécurité Sanitaire des Produits de Santé (AFSSAPS)


WHO Procurement Quality and Sourcing WHO Procurement Quality and Sourcing Project: access to HIV / AIDS drugsProject: access to HIV / AIDS drugs

• 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).(available on WHO web-site: //mednet3.who.int/prequal/ )

• Guide on Requirements for Documentation of Quality for Pharmaceutical Products Related to HIV and AIDS (available on WHO web-site: //mednet3.who.int/prequal/ )

• ICH guidelines (where applicable)


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


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 – Same efficacy

At least equal quality with the comparator / not inferior

Dossier should demonstrate the pharmaceutical equivalence of the FPP including that of the APIFPP: Finished pharmaceutical product


Active pharmaceutical ingredients (API)Content of the dossier

- Nomenclature

- Properties of the API

- Sites of manufacture

- Route(s) of synthesis

- Specifications

-API described in an internationally recognised pharmacopoeia

-API not described in an internationally recognised pharmacopoeia

- Reference Standard

- Container closure system

- Stability testing


API / Content of dossier

NomenclatureInternational non-proprietary name (INN), Compendial name (if relevant), chemical name, laboratory code, Chemical abstarct service (CAS) No., other names such as BAN, USAN…

Properties of API (API described in a pharmacopoeia)

- Evidence of structure: confirmation of structure by comparison with an official Reference Standard using a specific method e.g. IR

- Physico-chemical properties: existence /absence of polymorphism, particle size, solubilities, etc are to be discussed as not covered by the monograph



Properties of API (API not described in a pharmacopoeia)

- Structural formula, relative and absolute stereochemistry, molecular formula, relative molecular mass

- Isomeric nature including stereochemical configuration

- Physico-chemical properties: appearance, existence or absence of polymorphism, solubilities in water and other solvents, partition coefficients, pH solution, melting or boiling points, particle size,…

- Evidence of sructure by appropriate studies: elemental analysis, spectral analyses with interpretation such as IR, NMR, UV characteristics including pH dependent shifts, mass spectrum, X-Ray crystallography, identification of stereochemistry, determination of configuration for each chiral centre



Site(s) of manufacture

Name and street address of each facility involved in the manufacture

State any alternative manufacturer

GMP certificate for each site (if available)

Depending on the number of steps presented in the process (short synthesis e.g. one step) it may be necessary to declare manufacturers/ suppliers of the starting material of the active substance and its mode of preparation



Route(s) of synthesis (API not described in a pharmacopoeia)

Flow diagram of the process including structure of starting materials and intermediates reflecting stereochemistry (if relevant), molecular formulae, reagents, solvents, etc.

Detailed description for each step with quantities of each materials used, operating conditions (T°, pressure, pH, time,….) and yields

Scale of the manufacture/ typical batch size

Last step of purification and cristallisation /mention solvents used

Process controls

Reprocessing (if any) clearly described

Alternate processes (if any) justified and described in details + demonstration that the final quality of the API remains unchanged i.e. same impurity profile or if different, acceptable.



Route(s) of synthesis (API not described in a pharmacopoeia)

Specifications of all reagents, solvents and auxilliary materials demonstrating that they are of suitable quality for the intended use

Specifications of starting materials and isolated intermediates

Identification of critical steps

Introduction of an essential structural element, major chemical transformation, step where significant impurities are introduced or removed, step with impact on solid-state properties/homogeneity (API used in solid dosage forms)

Validation of critical steps, aseptic processing and sterilisation (if applicable)



Route(s) of synthesis (API described in a pharmacopoeia)

Submit a Certificate of Suitability (CoS) for a Ph. Eur. API with relevant annexes + an outline of the route of synthesis

For Pharmacopoeial APIs without a CoS: similar information that for non pharmacopoeial APIs is preferable as the suitability of the monograph is to be demonstrated

As a principle, the impurity profile cannot be known when the route of synthesis is not known

For APIs obtained by fermentation: Ph. Eur. General monograph on « Products of fermentation » (1468) can be used as a reference text



Route(s) of synthesis/ Why is all the information requested necessary?

Confirmation that the synthesis actually leads to the right structure/ enantiomer /polymorph

Demonstrate that the quality of materials used during the synthesis are acceptable as quality and purity of the API cannot be assured only by an end-of-the-line control

Knowledge of the impurity profile: Indication on impurities which can be carried over into the final substance from reagents, solvents, starting materials and intermediates, by- products and degradation formed

Sufficient knowledge to judge of the adequacy of specifications with the route of synthesis / appropriateness of tests to control relevant impurities

Regarding a Pharmacopoeial API without CoS, it can be prepared by a different method liable to leave impurities not taken account in the monograph

Demonstrate that the process is well mastered



SpecificationsTo assure that proper identity, strength, quality and purity are

attained together with batch-to-batch consistency

For APIs described in an internationally recognised pharmacopoeia, the requirements of the monograph 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

For APIs not described in an internationally recognised pharmacopoeia, the proposed specifications are to be justified

ICH Nfg Q6A can be used



Specifications

ARVs described in pharmacopoeias (adopted monographs and drafts)

- Ph. Eur.: didanosine, zidovudine, stavudine (adopted) lamivudine, nevirapine (draft)

- USP: lamivudine, zidovudine, nevirapine, saquinavir mesilate, stavudine, indinavir sulfate (adopted)

- International Ph. (draft). zidovudine, didanosine*, abacavir sulfate . indinavir sulfate*, saquinavir and saquinavir mesilate salt*,

nelfinavir mesilate*, ritonavir* . Nevirapine*, efavirenz

Be careful, a draft monograph can be subjet to further amendments!* Monographs which will be soon adopted



Specifications (API not described in a pharmacopoeia) •Description•Identification: specific method (e.g.IR) / comparison with a suitably established primary Reference Standard

- identification for chiral substance as single enantiomer(when

applicable)

•Impurities

- Each specified identified, any unspecified and total of impurities

- Residual solvents

- Residual catalysts (if applicable)•Assay: a non specific method acceptable if identification and impurities tests are specific

- Chiral assay (if applicable) •Additional spec. (if applicable): polymorph and particle size (these may affect performance of the drug), Sterility or microbial contamination,…



Specifications/ API not described in a pharmacopoeia

Impurities

Discussion on potential and actual impurities

Impurities are to be considered not only for their chemical aspects but also for their safety aspects (qualification)

• Organic impuritiesBy-productsStarting materials and / or intermediates not reactedDegradation products of the APIReagents, catalysts

• Residual solvents• Inorganic impurities (reagents, heavy metals, inorganic salts, metal

catalysts)



Specifications/ organic impurities in APIs not described in a pharmacopoeia

•Document impurities of the process

• Give the name of the impurity, discuss its origin: whether from synthesis, purification, storage i.e. degradation • Whether actual samples synthezised for test procedures and structural analyses performed

• Whether suitable analytical methods are available to detect and quantify impurities along with relevant chromatograms

•Provide tests results to demonstrate which impurities are potential and which ones are actually found in different batches

• Propose and justify acceptance criteria taking account of batch results + ICH thresholds of identification + qualification Requirements of ICH Nfg Q3A: Impurities in new drug substances applicable



Specifications/ impurities in APIs not described in a pharmacopoeia thresholds above which there is need for qualification / identification of

impurities according to ICH

•Identification threshold: limit above which, impurities found are to be identified either structurally or by a qualitatif parameter e.g. RT in HPLC system

•API with a daily intake of NMT 2 g: 0.10% or 1 mg (whichever is lower) •API with a daily intake of more than 2g: 0.05%

•Qualification threshold: limit above which, impurities found are to be toxicologically qualified

•API with a daily intake of NMT 2 g: 0.15% or 1 mg (whichever is lower) •API with a daily intake of more than 2g: 0.05%

•Reporting threshold: daily intake NMT 2g: 0.05%, more than 2g: 0.03%



Specifications/ impurities in APIs not described in a pharmacopoeia

•Impurity exceeding ICH qualification thresholds

See first if it is possible to reduce the level ! If not possible, then Qualify!

•Qualification: Process of evaluation of data which establishes the biological safety of an inidividual impurity or an impurity profile.

Significant metabolitesImpurities present in batches used in preclinical and clinical studies for innovatorAdequate data in literature Limited safety studies as per Nfg ICH Q3A

++ Comparison of impurity profile of generic product with the innovator (see US FDA and Health Canada guides)



Specifications/ all types of APIs

•ATTENTION !!! The ICH thresholds for impurities apply only to « ordinary impurities » and not to those which are unusually toxic:

Alkylating agent: Me and Et sulfates, ethylene oxide,…Alkyl (low chain) mesilatesNitroso derivatives,…

These sort of impurities are not always controlled in pharmacopoeial monographs as their presence is related to each manufacturing process

•Absence of such residues to be demonstrated•Capacity of the process to remove them / validated process•Suitable analytical method with a sufficient low LOQ •Suitable limits to be proposed on safety grounds



Specifications/impurities in APIs described in pharmacopoeias

•Discussion on whether the manufacturing process actually leads to impurities described in each individual monograph

Impurities at the limits described in the monograph are generally considered acceptable

•Discussion on whether new impurities could be present (comparing to those mentioned in the monograph). Actually, if the API is obtained by a different method liable to leave new impurities not taken into account during elaboration of the monograph

It should be demonstrated if the pharmacopoeial method is sufficient/suitable to determine these new impurities

If the pharmacopoeial method is not sufficient, another validated method is to be proposed Document the new impurity(ies) or impurity profile, propose suitable limitsRequirements of the Ph. Eur. General monograph « Substances for pharmaceutical use (2034) » are applicable when reference is made to this Ph.



Specifications/All APIs/ Residual solvents

.Residues of solvents used during manufacturing processDetermined by a suitable method, levels found reportedLimits to be set according to ICH Nfgs Q3C and Q3C (M)Solvent used in the final step, to be always controlled in routine

•ICH Q3C: classification of solvents into 3 classes

•Class I solvents: toxic solvents to be avoided unless otherwise justified, ICH limits apply as it is, control with a specific method (GC)•Class 2 solvents: limits can be calculated according to option 1 or 2 (based on daily intake), control with a specific method (GC)•Class 3 solvents: less toxic, generally limited to 0.5%, a non-specific method can be used e.g. loss on drying

•Solvents in table 4: justify the proposed limit on safety grounds



Specifications

All specifications should be justified (e.g. according to ICH Q6A)

Absence of certain specification is to be justified (e.g. absence of control on residual solvent, absence of control of a polymorph, an enantiomer)

In-house analytical procedures should be described in details / to be replicated by an official laboratory

Different methods from those of pharmacopoeias should be validated

Specifications should always reflect batch results (e.g. 3 consecutive lots)



Further discussion on chirality / enantiomeric purity

Most of ARVs are developed as a single enantiomer, registered in ICH regions and claimed as such:

• Stavudine: 2 chiral centres (1 of 4 possible stereoisomers claimed) • Lamivudine: 2 chiral centres (1 of 4 stereoisomers claimed)• Indinavir: 5 chiral centres (1 of 32 possible stereoisomers claimed)• Saquinavir: 6 chiral centres (1 of 64 possible stereoisomers claimed)• Ritonavir: 4 chiral centres (1 of 16 possible stereoisomers)• Nelfinavir: 5 chiral centres (1 of 32 possible stereoisomers) • Tenofovir: 1 chiral centre (1 of 2 possible stereoisomers)• Efavirenz: 1 chiral centre (1 of 2 possible stereoisomers)• etc




Why is this problem important?

Enantiomers: distinguished by biological systems

• same or different pharmacologic / pharmacokinetic/ toxicologic activity• same physico-chemical properties except optical activity• specific techniques necessary to identify them, separate, assay and synthesis (e.g. it is easier and less expensive to manufacture the racemic mixture)

(+) and (-) ibuprofene: both anti-inflammatory agents (+) sotalol: antiarrhythmic but (-) sotalol : b-blocker Critical (-) levocetirizine active as 5 mg dosage but () racemic cetirizine marketed as 10 mg Critical (-) lamivudune: selected and registered, (+) lamivudine and racemic mixture () more cytotoxic (EMEA/CPMP/375/96 EPAR) Critical




Batch-to-batch consistency and reproducibility of the manufacture with preclinical and clinical batches (innovator) or with the bio-batch used in the bioequivalence study (Generic products) should be guaranteed

either by suitable controls included in specifications for identity, control of the opposite enantiomer as an impurity or chiral assay of the API

Lamivudine monograph in USP and draft in Ph. Eur.: opposite enantiomer limited to NMT 0.3%

Tenofovir EPAR CPMP/3510/01: enantiomeric purity NLT 98% for the R-isomer claimed

either by control of stereochemistry (control of chirality) through the route of synthesis i.e. appropriate controls on starting materials and intermediates + demonstration that there is no racemiation up to the end

Case of Efavirenz, indinavir, nelfinavir, ritonavir…(tricky as the information is not publicly available for comparison)




Non pharmacopoeial Chiral APIs claimed as a single enantiomer

See the ICH Q6A decision tree, # 5: establishing identity, assay and enantiomeric impurity procedures for chiral NCEs

1. If the substance is chiral and one enantiomer claimed

. Consider need for Chiral identity, chiral assay, enantiomeric impurity

2. Chiral assay or an enantiomeric impurity procedure may be acceptable in lieu of chiral identification

3. An achiral assay + a method for control of the opposite enantiomer is acceptable in lieu of a chiral assay

4. The level of the opposite enantiomer may be derived from chiral assay

5. Stereospecific testing of the drug product is not necessary if racemisation is shown to be insignificatif during manufacture and storage of FPP

Possible to justify not carrying either chiral assay or control of the opposite enantiomer when 3 or more chiral centres present



Further discussion on solid-state-properties: relationship to bioavailability

Polymorphic form or amorphism, solvation or hydration, particle size may affect dissolution and therefore biovailability

Not critical for solution dosage forms or for highly water soluble APIs

Critical for Solid dosage forms or suspension drug products

Polymorphism: occurrence of different crystalline forms for one API with different physical properties which may affect bioavailability, processability and stability of the drug prduct



Further discussion on solid-state-properties/ polymorphism/ relationship to bioavailability (example in the field of ARVs)

Ritonavir, NORVIR Abbott Laboratories: polymorph I and II (Polymorph II thermodynamically more stable and much less soluble)

NORVIR EPAR: EMEA / CPMP / 527/96 •No polymorphism observed at the time of first submission / only form I was known: hard capsules and oral solution marketed•Emergence of form II (reason not yet known!) / contamination of form I•Failure in dissolution at release for hard capsules•Production of hard capsules discontinued/ supply problems•Change in storage conditions of the oral solution•Development, re-formulation and registration of soft capsules



Further discussion on solid-state-properties/ relationship to bioavailability ICH Q6A decision tree, # 4: investigation the need to set acceptance criteria for polymorphism in drug substances and drug products

1. Screening in different solvents to check if different forms can occur? If YES

whether test method are available to detect and to quantify different forms e.g. solid state IR, X-ray powder diffraction, thermal analysis (DSC, TGA), …

2. Do different forms have different properties: solubility, stability, melting point?

If YES, whether drug product performance (efficacy, stability) can be affected?

If YES, set specification for polymorph content in routine control for the API

3. For critical dosage forms, is there an adequate control in FPP available to follow polymorph changes e.g dissolution testing? If YES OK

If NO, monitor polymorph form during manufacturing and storage of FPP and set acceptance criteria



Further discussion on solid-state-properties/ polymorphism/ Few points to consider

Rare are pharmacopoeial monographs which describe only one polymorph

If the phenomenon of polymorphism is known, a general statement may be available: « the substance exhibits the phenomenon of polymorphism ».

The absence of such statement does not mean that the API does not represent this phenomenon. The phenomenon may be merely not known!

The existence of a pharmacopoeial monograph for an API does not exclude the FPP manufacturer to perform study on polymorphism if it may occur

Same as above is applicable when a CoS is available, unless if the CoS covers clearly only one form. In this case, there is specific mention in the sub-title



Further discussion on solid-state-properties/ polymorphism/ Few points to consider

One of factors affecting polymorphism or solvation is the final solvent used in the process and isolation conditions of the API

When a change is made to the final crystallisation solvent, evidence is to be provided that no change in solid state form of the API has occured

If polymorphism exists and is critical, the form used in clinical trials and /or in the bio-batch used in the bioequivalence study should be defined as well as that proposed for commercial batches

Generally, the same polymorph should be maintained: from clinical to commercial batches and over the shelf-life

Different polymorphs may be only allowed if it is demonstrated that there is no impact with regard to the quality, processability and performance of the FPP



Further discussion on solid-state-properties/ Particle size

For APIs intended to be used in solid or suspension drugs

Particle size can have a significant effect on dissolution rates, bioavailability and/or stability

Carry out testing for particle size distribution

Set an appropriate acceptance criteria

The particle size distribution should be similar to that used for the biobatch / clinical lots

See the ICH Q6A decision tree, # 3: setting acceptance criteria for drug substance particle size distribution



Reference Standards• For pharmacopoeial APIs: use an official Reference Standard

(USP, Ph. Eur., Int. Ph., JP)

• For non-pharmacopoeial APIsA primary and/or a working standard are to be establishedDescription of how this RS/WS has been established in terms of:

• Identity (full structural analyses)

• Purity (determination of impurities content, residual solvent content, water content, determination of purity by an absolute method such as DSC)

• Assay (by an absolute method i.e. titration) + Certificate of Analyses



Container / closure system

•Description of the bulk storage container / primary packaging

•Specifications and identification of materials

•Choice of material to be justified: compatibility of the API with materials of the conatiner is to be demonstrated

by stability results obtained

sorption, leaching to be studied mainly in case of liquid APIs



Stability

• Forced degradation studies in stress conditionTo be carried out by exposition to heat, moisture, oxidation, light, variation of pH 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

For an existing API, it is possible not to perform stress testing•Demonstration of compliance with the pharmacopoeial monograph, if the monograph includes degradation products

•Submission of relevant data published in the literature


API / Content of dossierStability• Re-test period of the API

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

• After the end of re-test period, a batch of the API should be re-tested for compliance to its specifications and then immediately used•To define a re-test period

Conduct ICH formal studies for ARV: ICH Nfgs Q1A(R2), Q1F, Q1E

• If re-test period not defined, The API is to be tested before manufacture of each lot of drug product

According to the pharmacopoeial monograph (if available)According to the specifications already approved



Stability• Re-test period of the API

Parameters to be tested: attributes susceptible to change during storage and affecting the quality, safety and efficacy should be followed

• Assay, degradation products, enantiomeric purity (if applicable), polymorphic form and particle size (if applicable)

Analytical methods should be validated and demonstrated to be stability-indicating if different from those used at release

Selection of batches• At least 3 batches (ICH says minimum of pilot scale) manufactured according to the same process described in the dossier




Storage conditions (ICH general case):•Long term: zones I and II: 25° 2°C/ 60%5% RH, zones III and IV: 30° 2°C/ 65%5% RH (See Nfg ICH Q1F) •Intermediate: 30° 2°C/ 65%5% RH (to be performed if « significant

change » occurs in accelerated condition)

•Accelerated: 40° 2°C/ 755% RH• long term condition for zone IV is under discussion and may be changed to: 30°C/70% RH or 30°C/75% RH

APIs to be stored in a refrigerator: Long term 5° 3°C, Accelerated 25° 2°C/ 60%5% RH, in a freezer: Long term -20°C 5°C




Testing frequency: every 3 months during the first year, every 6 months during second year, then annually

At time of submission (minimum data to be available)

12 months long term + 6 months accelerated + 12 months intermediate (if applicable)

Extrapolation: if real time data can be supported by results of accelerated and intermediate conditions, the re-test period may be extended beyond the end of real times studies (see ICH Q1E)

•Real time data are always to be submitted (when available) up to the end of retest period accorded


API/conclusion of the assessor, data available in the dossier

Validation of the processValidation of analytical methods

Impurity profileBioavailability

Structure, Physicochemical properties, mode of preparation,

specifications

Stability data, re-test period, stress testing

Who does what and where ?Traceability

GMP

Well-defined quality

Acceptable qualitysafe - efficacious

Reproducibility of the quality

Maintenance of the quality


Complementary Useful References (list not exhaustive)

Manufacture of the API: - Guideline for Submitting Supporting Documentation in Drug Applications for the Manufacture of Drug Substances, CDER, FDA, 1987.

- Drug substance: Chemistry, manufacturing and controls information, CDER, FDA, January 2004 (draft).

- Note for Guidance on Chemistry of the New Active Substance, CPMP/QWP/130/96, Rev 1.

- Quality (Chemistry and Manufacturing) Guidance: New Drug Submissions and Abbreviated New Drug Submissions (Draft), Health Canada, 2001.

- ICH Q7A: Good Manufacturing Practice for Active Pharmaceutical Ingredients.

- Validation of manufacturing processes, Quality assurance of Pharmaceuticals, Volume 2, WHO, Geneva, 1999, page 53.

- Ph. Eur. General monograph « Products of fermentation », monograph No. 1468.


Complementary Useful References

Specifications:

- ICH Topic Q6A: Specifications. Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products:Chemical Substances.

Impurities:

- ICH Topic Q3A(R): Impurities testing guideline: Impurities in New Drug Substances.

- ICH Topic Q3C and Q3C(M): Impurities: Residual solvents.

- Specifications for class I and class 2 residual solvents in active substances, CPMP/QWP/450/03.

- ANDAs: Impurities in Drug Substances, CDER, FDA, November 1999.

-Identification, Qualification, and Control of Related Impurities in Existing Drugs (Draft), Health Canada, 1999.



Impurities (cont.)

- Ph. Eur. Genreral monograph « substances for pharmaceutical use », monograph No. 2034.

- Ph. Eur. General chapter 5.10. Control of impurities in substances for pharmaceutical use.

- Control of impurities of pharmacopoeial substances, CPMP/QWP/1529/04.

- Guideline on the limits of genotoxic impurities, CPMP/SWP/5199/02 (draft)

- Specification limits for residues of metal catalysts, CPMP/SWP/QWP/4446/00 (draft).

Polymorphism:

- ICH Topic Q6A: Specifications.

- ANDAs: pharmaceutical solid polymorphism, CDER, FDA, December 2004

(draft).


Complementary Useful ReferencesEnantiomeric purity:

- ICH Topic Q6A: Specifications.

- FDA ’s Policy Statement for the Development of New Stereoisomeric Drugs, CDER, FDA, last version 1997.

- Investigation of Chiral Active Substances, CPMP, III/3501/91.

- Stereochemical issues in Chiral Drug Development, Health Canada, 2000.

Validation of analytical methods:

- ICH Topic Q2A: Validation of Analytical Methods: Definitions and Terminology.

- ICH Topic Q2B: Validation of Analytical Procedures: Methodology.

-WHO Expert Committee on specifications for pharmaceutical preparations, 32nd report, WHO, 1992.

-Quality Assurance of Pharmaceuticals, Volume 1, WHO, Geneva, 1997, pp. 119-124.


Complementary Useful ReferencesStability:

- WHO Guidelines for stability testing of pharmaceutical products containing well-established drug substances in conventional dosage forms, WHO Technical Report Series, No. 863, 1996.

- Stability Testing of Existing Drug Substances and Products (Draft), Health Canada, 1997.

- Note for Guidance on Stability testing of Existing Active Substances and Related Finished Products, CPMP/QWP/122/02/rev 1.

- ICH Topic Q1A(R2): Stability Testing of New Drug Substances and Products.

- ICH Q1F: Stability Data Package for Registration in Climatic Zones III and IV.

- ICH Topic Q1E: Evaluation of stability data.

- Declaration of storage conditions: A) in the product information of medicinal products B) for active substances, CPMP/QWP/609/96/Rev 1.



Web-site addresses

- WHO: www.who.int/medicines/- EMEA(EU): www.emea.eu.int/human medicines/guidance documents- EU Commission: pharmacos.eudra.org -FDA: www.fda.gov/cder/ -Health Canada: www.hc-sc.gc.ca

WHO collaborating centre for Chemical Reference Substances

Apoteket AB, produktion & Laboratorier

Centrallaboratoriet, ACL, Prismavägen

S-141 75 Kungens Kurva / SWEDEN

[email protected]

Documents

M. MEHMANDOUST/ Quality of APIs/ Shanghai-China Quality of Active Pharmaceutical Ingredients (APIs) WHO Workshop on GMP and Quality Assurance of HIV products