Quality of Active Pharmaceutical
Ingredients (APIs)
WHO Workshop on GMP and Quality Assurance
of HIV products
Shanghai – China
28 February - 4 March 2005
Maryam MEHMANDOUST, PhD, consultant to WHO
Agence Française de Sécurité Sanitaire des Produits de Santé
(AFSSAPS)
M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
WHO Procurement Quality and Sourcing
Project: 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)
M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
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
M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
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 API
FPP: Finished pharmaceutical product
M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
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
M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
API / Content of dossier
Nomenclature
International 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
M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
API / Content of dossier
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
M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
API / Content of dossier
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
M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
API / Content of dossier
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.
M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
API / Content of dossier
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)
M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
API / Content of dossier
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
M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
API / Content of dossier
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 endof-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
M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
API / Content of dossier
Specifications
To 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
M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
API / Content of dossier
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
M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
API / Content of dossier
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,…
M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
API / Content of dossier
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 impurities
By-products
Starting
materials and / or intermediates not reacted
Degradation products of the API
Reagents, catalysts
Residual solvents
• Inorganic impurities (reagents, heavy metals, inorganic salts, metal
•
catalysts)
M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
API / Content of dossier
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
•
M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
API / Content of dossier
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%
M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
API / Content of dossier
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
metabolites
Impurities present in batches used in preclinical and clinical studies for
innovator
Adequate 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)

M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
API / Content of dossier
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) mesilates
Nitroso 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
M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
API / Content of dossier
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 limits
Requirements of the Ph. Eur. General monograph « Substances for
pharmaceutical use (2034) » are applicable when reference is made to this Ph.
M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
API / Content of dossier
Specifications/All APIs/ Residual solvents
.Residues of solvents used during manufacturing process
Determined by a suitable method, levels found reported
Limits 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
M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
API / Content of dossier
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)
M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
API / Content of dossier
Further discussion on chirality / enantiomeric purity
Most of ARVs are developed as a single enantiomer, registered in ICH
regions and claimed as such:
• Stavudine:
• Lamivudine:
• Indinavir:
• Saquinavir:
• Ritonavir:
• Nelfinavir:
• Tenofovir:
• Efavirenz:
• etc
2 chiral centres (1 of 4 possible stereoisomers claimed)
2 chiral centres (1 of 4 stereoisomers claimed)
5 chiral centres (1 of 32 possible stereoisomers claimed)
6 chiral centres (1 of 64 possible stereoisomers claimed)
4 chiral centres (1 of 16 possible stereoisomers)
5 chiral centres (1 of 32 possible stereoisomers)
1 chiral centre (1 of 2 possible stereoisomers)
1 chiral centre (1 of 2 possible stereoisomers)
M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
API / Content of dossier
Further discussion on chirality / enantiomeric purity
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
M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
API / Content of dossier
Further discussion on chirality / enantiomeric purity
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 Risomer 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)
M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
API / Content of dossier
Further discussion on chirality / enantiomeric purity
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
M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
API / Content of dossier
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
M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
API / Content of dossier
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
M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
API / Content of dossier
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
M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
API / Content of dossier
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
M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
API / Content of dossier
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
M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
API / Content of dossier
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
M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
API / Content of dossier
Reference Standards
• For pharmacopoeial APIs: use an official Reference Standard
(USP, Ph. Eur., Int. Ph., JP)
• For non-pharmacopoeial APIs
A primary and/or a working standard are to be established
Description 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
M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
API / Content of dossier
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
M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
API / Content of dossier
Stability
• Forced degradation studies in stress condition
To
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
M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
API / Content of dossier
Stability
• 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
M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
API / Content of dossier
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

M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
API / Content of dossier
Stability
•
Re-test period of the API
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/ 755% 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
M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
API / Content of dossier
Stability
•
Re-test period of the API
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

M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
API/conclusion of the assessor, data available in the dossier
Well-defined quality
Acceptable quality
safe - efficacious
Reproducibility of the quality
Maintenance of the quality
Who does what and where ?
Structure, Physicochemical
properties, mode of preparation,
specifications
Impurity profile
Bioavailability
Validation of the process
Validation of analytical methods
Stability data, re-test period,
stress testing
Traceability
GMP
M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
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.
M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
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.
M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
Complementary Useful References
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).
M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
Complementary Useful References
Enantiomeric 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.
M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
Complementary Useful References
Stability:
- 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.
M. MEHMANDOUST/ Quality of APIs/ Shanghai-China
Complementary Useful References
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
who.apl@apoteket.se
M. MEHMANDOUST/ Quality of APIs/ Shanghai-China