Pharmaceutical Quality Information Form (PQIF) - API

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Pharmaceutical Quality Information Form(PQIF) -
API
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Abbreviations

• API Active Pharmaceutical Ingredient
• ASMF Active Substance Master File
• CHMP Committee for Medicinal Products for Human
  Use
• CPMP Committee for Proprietary Medicinal Products
• DMF Drug Master File
• EDQM European Directorate for the Quality of
  Medicines
• FPP Finished Pharmaceutical Product
• ICH International Conference on Harmonization
• OOS Out Of Specification
• PQIF Pharmaceutical Quality Information Form
• QWP Quality Working Party

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Guidelines

• Guideline on Submission of Documentation for
  Prequalification of Multi-Source (Generic)
  Finished Pharmaceutical Products (FPPs) Used in
  the Treatment of HIV / AIDS, Malaria and
  Tuberculosis GuideGeneric
• Guideline on Active Substance Master File
  Procedure CPMP/QWP/227/02 Rev 1
• Guideline on Summary of Requirements for Active
  Substances in the Quality Part of the Dossier
  CPMP/QWP/297/97 Rev 1 corr
• ICH Q3A R Impurities Testing Guideline
  Impurities in New Drug Substances
  CPMP/ICH/2737/99
• ICH Q6A Specifications Test Procedures and
  Acceptance Criteria for New Drug Substances and
  New Drug Products Chemical Substances
  CPMP/ICH/367/96 corr
• ICH Q2A Validation of Analytical Procedures
  Definitions and Terminology CPMP/ICH/381/95
• ICH Q2B Validation of Analytical Procedures
  Methodology CPMP/ICH/281/95

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2. Active Pharmaceutical Ingredient(s) API(s)

• Presentation of information on the API
• Full details as required according to Section 2
  of the
• Guideline on Submission of Documentation for
  Prequalification of Multi-Source (Generic)
  Finished Pharmaceutical Products (FPPs) Used in
  the Treatment of HIV / AIDS, Malaria and
  Tuberculosis GuideGeneric
• Full details according to the Drug Master File
  (Active Substance Master File) Procedure
• Guideline on Active Substance Master File
  Procedure CPMP/QWP/227/02 Rev 1
• With or without certification (EDQM)
• (applicable only to Ph. Eur. - APIs)

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2. Active Pharmaceutical Ingredient(s) API(s) II

• Advantages of the use of a DMF (ASMF)
• Full details of chemistry, manufacturing process,
  quality controls during manufacture process
  validation, quality controls at batch release and
  stability
• Once the DMF (ASMF) is prequalified, reference
  may be made to it in subsequent applications
• Conditions for the reference
• Information on regular updates must be provided
• Version number and date must be assigned

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Deficiencies from prequalification

• DMF (ASMF)
• No version number and no date assigned
• Deficiency letters from WHO/prequalification are
  not addressed
• Instead an update without reference to the
  deficiency list is submitted
• No tabular overview is provided to WHO outlining
  the nature and the extent of the changes
  (updates) compared to the previous version
• Updates are not properly justified/explained
• Change in the route of synthesis
• Change in the last step of purificaton/crystalliza
  tion
• No transparency with the use of DMFs

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2.2 Properties of API(s)

• Categories of APIs
• 2.2.1 API not described in BP, PhInt, PhEur or
  USP
• Considered new, used for the first time in a FPP
• Risk estimation high
• Full information necessary
• 2.2.2 API described in BP, PhInt, PhEur or USP
• In use for a certain period of time
• Information on safety and efficacy available
• Risk estimation low(er)
• Control by the monograph, additional information
  beyond the scope of the monograph necessary

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2.2 Properties of API(s) II

• Categories of Antimalarials
• APIs with existing monographs in major
  international pharmacopoeias
• Amodiaquine, Chloroquine (-phospate, -sulfate),
  Dapsone, Quinine (-sulfate, -phosphate),
  Mefloquine, Sulfadoxine/Pyrimethamine,
  Trimethoprim
• APIs with existing monographs in major
  international pharmacopoeias (recently)
• Arthemether, Artemisinine, Artemotil, Artenimol
  (Dihydroartemisinine), Artesunate,
• APIs without existing monographs in major
  international pharmacopoeias
• Chlorproguanil, Lumefantrine, Naphthoquine,
  Piperaquine, Pyronaridine

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2.2 Properties of API(s) III

• 2.2.1 APIs not described in BP, PhInt, PhEur or
  USP
• a) evidence of chemical structure
• spectral data
• interpretation of data (narrative)
• b) evidence of chemical structure
• Isomerism
• Stereochemistry
• discussion of potential isomeric forms

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2.2 Properties of API(s) III cont.

• 2.2.1 APIs not described in BP, PhInt, PhEur or
  USP
• Properties relevant/critical for the performance
  of the API
• c) potential polymorphic forms
• physicochemical and physical characteristics
  (solubility, hardness, compressibility, density,
  melting point, etc.) may differ
• polymorphism must be controlled
• d) particle size distribution
• requirement for low solubility drugs
  (dissolution, bioequivalence)
• e) additional characteristics
• critical characteristics to be controlled to
  ensure consistent performance of the API (e.g.
  hygroscopicity)

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2.2 Properties of API(s) IV

• 2.2.1 APIs described in BP, PhInt, PhEur or USP
• chemical structure elucidated a) b), control
  of structure by suitable identification tests
• Properties relevant/critical for the performance
  of the API (not necessarily covered by the
  monograph)
• a) potential polymorphic forms
• physicochemical and physical characteristics
  (solubility, hardness, compressibility, density,
  melting point, etc.) may differ
• polymorphism must be controlled
• b) particle size distribution
• requirement for low solubility drugs
  (dissolution, bioequivalence)
• c) additional characteristics
• critical characteristics to be controlled to
  ensure consistent performance of the API (e.g.
  hygroscopicity)

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2.3 Site(s) of manufacture

• Each API-manufacturer to be listed
• Information on the quality of the API must be
  clearly linked to the respective manufacturing
  site (synthesis, production)
• Name
• Street address
• Phone, Fax, Email
• If applicable
• referenced DMFs
• letters of access

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Deficiencies from prequalification

• Quality of API missing
• Detailed quality description on the API provided
  by one manufacturer, alternative manufacturers
  are named without presentation of information on
  the API
• API-manufacturer and quality of API missing
• Alternative API-manufacturers are not listed, but
  are revealed from the FPP-part of the dossier

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2.4 Route(s) of synthesis

• 2.4.1 API not described in BP, PhInt, PhEur or
  USP
• Controls of critical steps and intermediates
• Potential impact on the quality of the API and
  intermediates
• Process conditions, test requirements and other
  relevant parameters to be controlled within
  predetermined limits
• Examples of potentially critical steps
• Mixing of multiple components
• Phase change and phase separation steps
• Steps where control of pH and temperature are
  critical
• Introduction of an essential structural element
  or major chemical transformation
• Introduction/removal of significant impurities to
  the API
• Final purification step
• Steps with an impact on solid state
  properties/homogeneity of the API

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2.4 Route(s) of synthesis II

• 2.4.1 API not described in BP, PhInt, PhEur or
  USP
• Process Validation and/or Evaluation
• All steps that are identified as critical for the
  API to be validated
• All steps covering aseptic processing or
  sterilization to be validated

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2.4 Route(s) of synthesis III

• 2.4.1 API not described in BP, PhInt, PhEur or
  USP
• Manufacturing process development
• Description and discussion of any change to the
  manufacturing process and/or manufacturing site
  in developmental order
• Clinical
• Comparative
• Stability
• Scaleup
• Pilot
• Production

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2.4 Route(s) of synthesis IV

• 2.4.1 API not described in BP, PhInt, PhEur or
  USP
• Impurities
• Identification of potential and actual impurities
  arising from synthesis, manufacture and/or
  degradation
• Potential sources of origin in sequential order
• impurities contained in the starting material
• starting material unreacted
• intermediates unreacted
• by-products (unwanted reaction products)
• reagents
• catalysts
• residual solvents
• degradants
• Elucidation of origin may help to minimize
  impurities

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2.4 Route(s) of synthesis V

• Potential impurities of Artemisinines
• Starting material (extracted from herbal sources)
• GuideGeneric
• Starting materials from vegetable origin should
  be fully charcterized and a contaminant profile
  should be established and submitted.
• CPMP/QWP/297/97 Rev 1 corr
• In the case of substances isolated form herbal
  sources, the potential for impurities arising
  from cultivation and/or preparation (e.g.
  pesticide residues, fumigants, mycotoxins) should
  be addressed.

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2.4 Route(s) of synthesis VI

• Potential impurities of Artemisinines
• Subsequent chemical reactions
• Application of the scheme provided in PQIF
  2.4.1, a) Impurities
• Critical process steps to be controlled
• Stereochemistry of the hydration step -
  stereoselective control method?
• Derivatisation/Ether-/Esterification
  (stereoselectivity?)
• Artemether, Artesunate, Artemotil
• - stereoselective purification procedure?
• - stability of the - ether versus -ester
• Transformation ArtenimolgtgtgtArtemisinine?

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2.4 Route(s) of synthesis VII

• 2.4.1 API not described in BP, PhInt, PhEur or
  USP
• Setting the acceptance criteria for impurities
• Maximum daily dose (total daily intake)
• ICH thresholds for drug-related impurities
• Concentration limits for process related
  impurities
• Residual solvents
• Heavy metals
• Available safety and toxicity data
• Documented impurity levels according to the
  scheme provided
• Reference to the analytical procedures used
• Specificity, sensitivity
• Justification of proposed acceptance criteria

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2.4 Route(s) of synthesis VIII

• 2.4.1 API not described in BP, PhInt, PhEur or
  USP
• Setting the acceptance criteria for impurities
• ICH thresholds for drug related impurities ICH
  Q3A (R)

Maximum Daily Dose Reporting Threshold Identification Threshold Qualification Threshold
2g/day 0.05 0.10 or 1mg per day intake (whichever is lower) 0.15 or 1mg per day intake (whichever is lower)
2g/day 0.03 0.05 0.05
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Deficiencies from prequalification

• Methods to assess impurities are not sensitive
  enough to assess impurities
• Quantitation limit (1) far above the
  identification and qualification threshold(0.05
  0.15)
• Listing of impurities limited to those actually
  detected
• Potential impurities are not discussed
• Impurity levels are far above the qualification
  limit without justification

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2.4 Route(s) of synthesis IX

• 2.4.2 Specifications of raw materials and
  intermediates used in the synthesis
• Quality and controls of materials coming into the
  process
• Starting materials
• Raw materials
• Intermediates
• Reagents
• Catalysts
• Solvents
• Specifications

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2.4 Route(s) of synthesis X

• 2.4.2 Specifications of raw materials and
  intermediates used in the synthesis
• Particularly addressing the TSE-safety of all
  materials coming into the process
• Proof of safety by relevant data
• CEP
• Letter of attestation

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2.4 Route(s) of synthesis XI

• 2.4.3 API described in BP, PhInt, PhEur or USP
• Impurities that are not included in the monograph
• Process related impurities
• Key intermediates
• Residual solvents
• Potential organic impurities not covered by the
  monograph

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2.5 Specifications

• 2.5.1 API not described in BP, PhInt, PhEur or
  USP
• Presentation of the API-specification
• Any test that is not performed on a batch to
  batch-basis must be indicated (periodic testing
  or skip testing)

Standard claimed (e.g. in-house, BP, PhInt, PhEur, USP
Reference or version number
Specific test parameter Analytical procedure used Acceptance criteria

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2.5 Specifications II

• 2.5.1 API not described in BP, PhInt, PhEur or
  USP
• Skip testing
• ICH Q6A
• performance of specified tests at release on
  pre-selected batches and/or predetermined
  intervals, rather than on a batch-to-batch basis
  with the understanding that those batches not
  being tested must still meet all acceptance
  criteria established for that product.
• As this represents less than full testing it
  should be justified.
• Any failure to meet acceptance criteria
  established for the periodic test should be
  handled by proper notification (inform WHO
  immediately). If the data demonstrate a need to
  restore routine testing, batch-by-batch release
  testing should be reinstated.

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2.5 Specifications III

• 2.5.1 API not described in BP, PhInt, PhEur or
  USP
• Skip testing
• ICH Q6A
• The concept may be applicable to, f.ex., residual
  solvents and microbiological testing, for solid
  oral dosage forms.
• Since only limited data may be available at the
  time of submission, the concept should generally
  be implemented post-approval (? post
  prequalification)
• GuideGeneric
• Where testing for possible impurities is omitted,
  particular attention must be given to its
  justification
• f. ex. particular method of production
• f.ex. impuritiy has never been detected

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2.5 Specifications IV

• 2.5.1 API not described in BP, PhInt, PhEur or
  USP
• Batch analyses
• Description of the batches
• Results of the batches
• Certificates of Analysis
• Discussion of the results with respect to the use
  of the batch
• Clinical, Comparative etc.

Batch number Batch size Date and site of production Use (e.g. clinical, comparative

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2.5 Specifications V

• 2.5.1 API not described in BP, PhInt, PhEur or
  USP
• Justification of Specifications
• Evolution of tests
• Evolution of analytical procedures
• Evolution of acceptance criteria
• Differences from compendial standards
• f.ex. assay and impurities, heavy metals, residue
  on ignition

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2.5. Specifications VI

• 2.5.1 API not described in BP, PhInt, PhEur or
  USP
• Justification of Specifications
• ICH Q6A
• Justification for each procedure and each
  acceptance criterion with reference to
• relevant development data
• pharmacopoeial standards
• Test data for batches used in toxicology and
  clinical studies
• Results from accelerated and long term studies
• Reasonable range of analytical and manufacturing
  variability
• Alternate justified approaches
• Actual results obtained should form the primary
  basis for any justification

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2.5 Specifications VII

• 2.5.1 API not described in BP, PhInt, PhEur or
  USP
• Reference standards or materials
• ICH Q2B
• Reference standards/materials should be well
  characterized with documented purity
• Source
• Official pharmacopoeial standards
• In-house standards
• Characterization and evaluation of non-official
  standards
• Method of manufacture
• Elucidation of structure
• Certificate of analysis
• Calibration against an official standard (if
  available)

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2.5 Specifications VIII

• 2.5.1 API not described in BP, PhInt, PhEur or
  USP
• Reference standards or materials (in-house)
• Primary (absolute) standard
• Documented purity (with purification procedure)
• Assay by two independent procedures, one of which
  must be specific
• Mass balance must be achieved
• Assay value and all impurities found must amount
  to 100 (relative to the analytical procedure)
• All further impurities (residue on
  ignition/inorganic substances, loss on drying
  etc.) must be considered to determine the
  absolute assay value
• Secondary (working) standard
• Documented purity with reference to the primary
  (absolute) standard
• Intervals of control of content and duration of
  use

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2.5 Specifications IX

• 2.5.1 API not described in BP, PhInt, PhEur or
  USP
• Validation of analytical procedures
• Stability indicating potential
• Any in-house analytical procedure needs to be
  validated
• ICH Q2A, ICH Q2B
• Assay and impurities
• Stress testing provides degradants that may occur
  during storage
• Isolation of impurities and (stable) degradants
  in the development phase
• In situ generation of potential degradants
• Validation of analytical procedures for assay and
  impurities/degradants
• Spiking experiments with isolated
  degradants/impurities
• In situ use of stressed samples
• Peak purity analysis of API-peaks

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2.5 Specifications X

• 2.5.2 API described in BP, PhInt, PhEur or USP
• Name the monograph
• Name any test methods referenced in the monograph
  but not appearing in it
• List of tests beyond the scope of the monograph
• Residuals, particle size, polymorphs, loss on
  drying
• Generic guide
• Whenever an API has been prepared by a method
  liable to leave impurities not controlled in the
  pharmacopoeial monograph, these impurities (based
  on 3 to 10 batch analysis results) including
  residual organic solvents, as well as their
  maximum tolerance limits should be declared and
  controlled by a suitable test procedure.

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Specifications XI

• 2.5.2 API described in BP, PhInt, PhEur or USP
• Additional requirements
• Generic guide
• The quality of the API should meet not only the
  requirements of specific monographs but also
  those described in the general monographs of a
  pharmacopoeia on APIs, excipients and other
  substance for pharmaceutical use.
• f. ex. Substances for pharmaceutical use (PhEur)
• f. ex. Control of impurities for substances for
  pharmaceutical use (PhEur)

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2.5 Specifications XII

• 2.5.2 API described in BP, PhInt, PhEur or USP
• Validation of analytical methods
• Pharmacopoeial methods are considered validated,
  however, there is common understanding that
  certain parameters need to be adapted
• New chapter USP lt1226gt Verification of analytical
  procedures
• Pharmacopoeial Forum 31, No. 2, March/April 2005
• System suitability test
• PhEur 2.2.46
• Insufficient Precision (RSDs) leads to OOS
  results
• 3 x s 2 (assay specification)
• Validation with respect to the stability
  indicating nature of the methods
• For impurities/degradants not covered by the
  monograph
• If the pharmacopoeial method is modified

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Deficiencies from prequalification

• Pharmacopoeial acceptance criteria are not
  considered for APIs described in the
  pharmacopoeia
• API cannot be adequately controlled by wider
  ranges
• Acceptance ranges of test parameters are much
  wider than actual test results.
• Acceptance ranges do not control the quality of
  the API
• Only one type of Reference standard is provided
  and simply represents API from a normal batch.
• In-house absolute reference standards are not
  validated against available official standards.
• Pharmacopoeial methods are modified but impurity
  profile is not adapted.
• f.ex. Impurity A (in-house method) is different
  from Impurity A (pharmacopoeial method)

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2.6 Container closure system

• Description of the container closure system(for
  storage and shipment of the API)
• Primary packaging material
• Identity of materials of construction of each
  primary packaging component
• Reference to specification for each packaging
  component
• Description
• Identification
• Drawings of critical dimensions
• Secondary packaging material
• Non-functional (briefly)
• Functional

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2.6 Container closure system II

• Discussion of the suitability of the container
  closure system
• Choice of material
• Function of material
• f.ex. protection
• Moisture, light, oxygen
• Safety of material
• Compatibility with API
• Sorption
• Leaching

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2.6 Container closure system III

• Artemisinines
• Storage conditions PhInt
• Should be kept in a well closed container,
  protected from light and kept in a cool place
• Discussion of the suitability of the container
  closure system with respect to
• Protection from light
• f.ex. types/colour of inner and outer bags/drums
• Protection from oxygen and moisture (well-closed)
• f.ex. type of inner/outer container
• f.ex. use of seals, joints, gaskets