Quality of Active Pharmaceutical Ingredients (APIs)

1
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 WHOAgence Française de
Sécurité Sanitaire des Produits de Santé (AFSSAPS)
2
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)

3
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

4
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)

At least equal quality with the comparator / not
inferior
Same Safety Same efficacy
Dossier should demonstrate the pharmaceutical
equivalence of the FPP including that of the
API FPP Finished pharmaceutical product
5
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

6
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
7
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

8
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

9
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.

10
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)

11
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

12
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 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

13
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

14
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

15
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,

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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)

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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

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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

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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)

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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

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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.

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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

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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)

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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 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

25
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

26
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 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)

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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
• If the substance is chiral and one enantiomer
  claimed
• . Consider need for Chiral identity, chiral
  assay, enantiomeric impurity
• Chiral assay or an enantiomeric impurity
  procedure may be acceptable in lieu of chiral
  identification
• An achiral assay a method for control of the
  opposite enantiomer is acceptable in lieu of a
  chiral assay
• The level of the opposite enantiomer may be
  derived from chiral assay
• 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

28
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

29
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

30
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

31
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

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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

33
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

34
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

35
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

36
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

37
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

38
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

39
API / Content of dossier

• Stability
• Re-test period of the API
• Storage conditions (ICH general case)
• Long term zones I and II 25? 2C/ 60?5 RH,
  zones III and IV 30? 2C/ 65?5 RH (See Nfg
  ICH Q1F)
• Intermediate 30? 2C/ 65?5 RH (to be
  performed if  significant change  occurs in
  accelerated condition)
• Accelerated 40? 2C/ 75?5 RH
• long term condition for zone IV is under
  discussion and may be changed to 30C/70 RH
  or 30C/75 RH
• APIs to be stored in a refrigerator Long term
  5? 3C, Accelerated 25? 2C/ 60?5 RH, in a
  freezer Long term -20C ? 5C

40
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

41
API/conclusion of the assessor, data available in
the dossier
Structure, Physicochemical properties, mode of
preparation, specifications
Well-defined quality
Impurity profileBioavailability
Acceptable qualitysafe - efficacious
Validation of the processValidation of
analytical methods
Reproducibility of the quality
Stability data, re-test period, stress testing
Maintenance of the quality
Traceability GMP
Who does what and where ?
42
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.

43
Complementary Useful References

• Specifications
• ICH Topic Q6A Specifications. Test Procedures
  and Acceptance Criteria for New Drug Substances
  and New Drug ProductsChemical 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.

44
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).

45
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.

46
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.

47
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_at_apoteket.se