pharmaceutical quality information form pqif api l.
Download
Skip this Video
Loading SlideShow in 5 Seconds..
Pharmaceutical Quality Information Form (PQIF) - API PowerPoint Presentation
Download Presentation
Pharmaceutical Quality Information Form (PQIF) - API

Loading in 2 Seconds...

play fullscreen
1 / 41

Pharmaceutical Quality Information Form (PQIF) - API - PowerPoint PPT Presentation


  • 196 Views
  • Uploaded on

Pharmaceutical Quality Information Form (PQIF) - API. Abbreviations. API A ctive P harmaceutical I ngredient ASMF A ctive S ubstance M aster F ile CHMP C ommittee for M edicinal P roducts for H uman Use CPMP C ommittee for P roprietary M edicinal P roducts

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'Pharmaceutical Quality Information Form (PQIF) - API' - tola


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
abbreviations
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

Dr. Birgit Schmauser, BfArM, Bonn

guidelines
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/227/02Rev 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]

Dr. Birgit Schmauser, BfArM, Bonn

2 active pharmaceutical ingredient s api s
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)

Dr. Birgit Schmauser, BfArM, Bonn

2 active pharmaceutical ingredient s api s ii
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

Dr. Birgit Schmauser, BfArM, Bonn

deficiencies from prequalification
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/crystallization
    • No transparency with the use of DMFs

Dr. Birgit Schmauser, BfArM, Bonn

2 2 properties of api s
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

Dr. Birgit Schmauser, BfArM, Bonn

2 2 properties of api s ii
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

Dr. Birgit Schmauser, BfArM, Bonn

2 2 properties of api s iii
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

Dr. Birgit Schmauser, BfArM, Bonn

2 2 properties of api s iii cont
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)

Dr. Birgit Schmauser, BfArM, Bonn

2 2 properties of api s iv
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)

Dr. Birgit Schmauser, BfArM, Bonn

2 3 site s of manufacture
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

Dr. Birgit Schmauser, BfArM, Bonn

deficiencies from prequalification13
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

Dr. Birgit Schmauser, BfArM, Bonn

2 4 route s of synthesis
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

Dr. Birgit Schmauser, BfArM, Bonn

2 4 route s of synthesis ii
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

Dr. Birgit Schmauser, BfArM, Bonn

2 4 route s of synthesis iii
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

Dr. Birgit Schmauser, BfArM, Bonn

2 4 route s of synthesis iv
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

Dr. Birgit Schmauser, BfArM, Bonn

2 4 route s of synthesis v
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.

Dr. Birgit Schmauser, BfArM, Bonn

2 4 route s of synthesis vi
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 Artenimol>>>Artemisinine?

Dr. Birgit Schmauser, BfArM, Bonn

2 4 route s of synthesis vii
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

Dr. Birgit Schmauser, BfArM, Bonn

2 4 route s of synthesis viii
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)]

Dr. Birgit Schmauser, BfArM, Bonn

deficiencies from prequalification22
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

Dr. Birgit Schmauser, BfArM, Bonn

2 4 route s of synthesis ix
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

Dr. Birgit Schmauser, BfArM, Bonn

2 4 route s of synthesis x
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

Dr. Birgit Schmauser, BfArM, Bonn

2 4 route s of synthesis xi
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

Dr. Birgit Schmauser, BfArM, Bonn

2 5 specifications
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)

Dr. Birgit Schmauser, BfArM, Bonn

2 5 specifications ii
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.

Dr. Birgit Schmauser, BfArM, Bonn

2 5 specifications iii
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

Dr. Birgit Schmauser, BfArM, Bonn

2 5 specifications iv
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.

Dr. Birgit Schmauser, BfArM, Bonn

2 5 specifications v
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

Dr. Birgit Schmauser, BfArM, Bonn

2 5 specifications vi
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

Dr. Birgit Schmauser, BfArM, Bonn

2 5 specifications vii
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)

Dr. Birgit Schmauser, BfArM, Bonn

2 5 specifications viii
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

Dr. Birgit Schmauser, BfArM, Bonn

2 5 specifications ix
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

Dr. Birgit Schmauser, BfArM, Bonn

2 5 specifications x
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.

Dr. Birgit Schmauser, BfArM, Bonn

specifications xi
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)

Dr. Birgit Schmauser, BfArM, Bonn

2 5 specifications xii
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 <1226> Verification of analytical procedures
          • Pharmacopoeial Forum 31, No. 2, March/April 2005
        • System suitability test
        • PhEur 2.2.46
        • Insufficient Precision (RSD=s) 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

Dr. Birgit Schmauser, BfArM, Bonn

deficiencies from prequalification38
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)

Dr. Birgit Schmauser, BfArM, Bonn

2 6 container closure system
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

Dr. Birgit Schmauser, BfArM, Bonn

2 6 container closure system ii
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

Dr. Birgit Schmauser, BfArM, Bonn

2 6 container closure system iii
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

Dr. Birgit Schmauser, BfArM, Bonn