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					Requirements on documentation of API and FPP
        quality and evaluation process


                                                           •
                                          Presenter: Hua YIN
                              Prequalification of Medicines Programme
                                          QSM / EMP / HSS




Slide 1 WHO Prequalification Programme: Training workshop March 2010, Beijing
                                                       Glossary

API                      Active Pharmaceutical Ingredient
APIMF                    Active Pharmaceutical Ingredient Master File
ARV                      Antiretroviral
CoS                      Certificate of Suitability
EDQM                     European Directorate for Quality of Medicines and HealthCare
EoI                      Expression of Interest
FPP                      Finished Pharmaceutical Product
GMP                      Good Manufacturing Practices
ICH                      International Conference on Harmonization
Int. Ph.                 International Pharmacopoeia
PIL                      Patient Information Leaflet
PQ                       Prequalification
PQIF                     Pharmaceutical Quality Information form
RH                       Reproductive Health
SPC                       Summary of Product Characteristics
TB                       Tuberculosis




  Slide 2 WHO Prequalification Programme: Training workshop March 2010, Beijing
                WHO Reference text for Multisource
                 (Generic) products / Definitions

Active Pharmaceutical Ingredient (API)
A substance or compound that is intended to be used in the
manufacture of a pharmaceutical product as a
therapeutically active compound (ingredient)

Pharmaceutical Product
Any preparation for human or veterinary use that is intended
to modify or explore physiological systems or pathological
states for the benefit of the recipient.

Finished Pharmaceutical Product (FPP)
A product that has undergone all stages of production,
including packaging in its final container and labelling.




  Slide 3 WHO Prequalification Programme: Training workshop March 2010, Beijing
                 Guidelines for Product dossier /Quality

Main Generic guide
•       Guideline on Submission of Documentation for Prequalification of
        Multisource (Generic) Finished Pharmaceutical Products (FPPs) Used in
        the Treatment of HIV/AIDS, Malaria and Tuberculosis [under revision]

          Annex 1 - Model Certificate of a Pharmaceutical Product
          Annex 2 - Model Batch Certificate of Pharmaceutical Product
          Annex 3 - Model Stability Report of Active Pharmaceutical Ingredient (API)
          Annex 4 - Model Stability Report of Capsules/Tablets
          Annex 5 - Suggested Structure of the Summary of Product Characteristics (SmPC)
          Annex 6 - Suggested Structure of the Package Information Leaflet (PIL)
          Annex 7 - Presentation of Bioequivalence Trial Information (BTIF)
          Annex 8 - Presentation of Pharmaceutical Quality Information (PQIF)

•       Supplement 1 : Dissolution testing
•       Supplement 2 : Extension of the WHO list of stable APIs (not easily
        degradable)


Slide 4 WHO Prequalification Programme: Training workshop March 2010, Beijing
                 Guidelines for Product dossier /Quality


•       Guidelines for registration of fixed-dose combination medicinal products
•       Guideline on Active Pharmaceutical Ingredient Master File (APIMF)
        Procedure
•       Guidance on variations to a prequalified dossier
•       Guide on Submission of Documentation for Prequalification of innovator
        Finished Pharmaceutical Products (FPPs) used in the treatment of
        HIV/AIDS, malaria and tuberculosis and approved by Drug Regulatory
        Authorities (DRAs) in the International Conference on Harmonization (ICH)
        region and associated countries, including among others the EU, Japan
        and USA
•       Prequalification of Generic products approved by Stringent Regulatory
        Authorities (SRAs) NEW
•       Requalification NEW
•       Alternative procedure for accepting 2nd line TB Product dossiers        New
http://www.who.int/prequal                    Chinese version available


Slide 5 WHO Prequalification Programme: Training workshop March 2010, Beijing
                  Guidelines for Product dossier /Quality


• ICH notes for guidance (When WHO or PQ guidelines
  silent)
for instance:

      –   Q2(R1): Validation of Analytical Procedures
      –   Q3A(R2). Impurities in new drug substances
      –   Q3B(R2). Impurities in new drug products
      –   Q3C(R3). Impurities: Guideline for residual solvents
      –   Q6A. Specifications:
• Other agencies' requirements can be referenced. such as
  EU limits of genotoxic impurities, permitted colorants,
  EDQM limit of TEA 320ppm.

 Slide 6 WHO Prequalification Programme: Training workshop March 2010, Beijing
                      Assessment Process - Quality
                                        Submission of application
                                                                                PQIF, Dossier
                                             Screening (Internal)


                                       Acceptance for evaluation                PQ reference No.


                                              Pre – Assessment


                                                  Assessment


                        Additional data


                                                Prequalification
                                                Requalification
Slide 7 WHO Prequalification Programme: Training workshop March 2010, Beijing
                        Documentation to be submitted
                            to the WHO PQ team
-         Covering letter
          Clearly indicate the information submitted is true and correct

-        Product dossier
          . Section 1: Characteristics of the FPP
          . Section 2: Active Pharmaceutical Ingredients (APIs)
                       When more than one API used, use separate Section 2
          . Section 3: Finished Pharmaceutical Products (FPPs)
          . Section 4: Interchangeability

-         PQIF: =Quality overall summary. filled out in WinWord format,
          See mock-up PQIF on www.who.int/prequal/ under training material and
          workshops, Hanoi, Vietnam, January 2006

-         Sample


    Slide 8 WHO Prequalification Programme: Training workshop March 2010, Beijing
                                Quality dossier/ Section 1

Information on the FPP
1.1. Details of the Product
     - Name, dosage form and strength of the product
     - Approved generic name (INN)
     - Visual description of the FPP
     - Visual description of the packaging

1.2. Samples to be provided (for visual examination of assessors
     and comparison with the SPC and PIL)

1.3. Regulatory situation in Member States / list countries
     - Countries where a MA has been issued
     - Countries where a MA has been withdrawn
     - Countries where a Marketing Application has been rejected,
     deferred

 Slide 9 WHO Prequalification Programme: Training workshop March 2010, Beijing
                    Quality dossier / Section 2

               Active Pharmaceutical Ingredient
                            (API)




Slide 10 WHO Prequalification Programme: Training workshop March 2010, Beijing
                     Quality dossier / Section 2
               Active Pharmaceutical Ingredient (API)
Scientific data on the API can be submitted using
    following ways and order of preference
       A valid Certificate of Suitability (CoS) or CEP, latest version, with
        all its annexes issued by EDQM, www.edqm.eu

       An APIMF (Active Pharmaceutical Ingredient Master File),
        submitted by the API manufacturer, containing the whole information
        requested in section 2 and presented in CTD format (see APIMF
        guideline)

       Complete submission of data requested in Section 2




    Slide 11 WHO Prequalification Programme: Training workshop March 2010, Beijing
                  Quality dossier / Section 2
            Active Pharmaceutical Ingredient (API)
2.1. Nomenclature

2.2. Properties of the API

2.3. Site(s) of manufacture

2.4. Route(s) of synthesis

2.5. Specifications

2.6. Container- closure system

2.7. Stability testing



 Slide 12 WHO Prequalification Programme: Training workshop March 2010, Beijing
                    Quality dossier / Section 2
              Active Pharmaceutical Ingredient (API)
                             CTD                                              PQIF section 2
S.1 General Information                                      2.1 Nomenclature
- Nomenclature
- Structure                                                  2.2 Properties of API (s)
- General Properties
                                                             - General Properties       pharmacopoieal

                                                             -Eluciation of structure   non-pharmacopieal

S.2 Manufacture                                              2.3 Site(s) of Manufacture
- Manufacturer
- Description of manufacturing process                       2.4 Route(s) of synthesis
- Control of materials                                       - manufacturing process
- Control of critical steps and intermediates
- Process validation                                         -Impurities
- Manufacturing process development
S.3 Characterisation
- Elucidation of structure
- Impurities

S.4 Control of Drug Substance                                2.5 Specifications

S.5 Reference Standards or Materials
S.6 Container Closure System                                 2.6 Container Closure System

S.7 Stability testing                                        2.7 Stability testing

 Slide 13 WHO Prequalification Programme: Training workshop March 2010, Beijing
                  Quality dossier / Section 2
            Active Pharmaceutical Ingredient (API)

 Generic Guideline is under revision.

 The PQIF format to be consistent with the CTD format

 Focus on CTD format
      S.1 General Information
      S.2 Manufacture
      S.3 Characterisation
      S.4 Control of Drug Substance
      S.5 Reference Standards or Materials
      S.6 Container Closure System
      S.7 Stability testing



 Slide 14 WHO Prequalification Programme: Training workshop March 2010, Beijing
                                S.1 General Information

S.1.1 Nomenclature
    International non-proprietary name (INN), chemical name,
     Chemical abstarct service (CAS) No., other names such as BAN,
     USAN…

S.1.2 Structure
     – Chemical structure, sterochemistry , molecular formula and
       relatively molecular mass




Slide 15 WHO Prequalification Programme: Training workshop March 2010, Beijing
                                S.1 General Information


S.1.3 General properties
     – Physical description
     – Solubility in water (effect of pH), and organic solvents
     – Solid state/crystallography (eg polymorphism,
       including solvation/hydration, amorphous character)
     – Hygroscopicity
     – Particle size, etc
       Such information which relevant to formulating,
       processing and performance of the FPP


Slide 16 WHO Prequalification Programme: Training workshop March 2010, Beijing
                                         S.2 Manufacture

 Information on the manufacturer

 A flow diagram of the process

 A description of the manufacturing process (including, for example,
  starting materials, reagents, solvents, catalysts,critical steps, and
  reprocessing) and the controls intended to result in the routine and
  consistent production of API.

 A description of the Source and Starting Material and raw materials
  used in the manufacture of the API; When the synthetic route
  consists limited number of steps (e.g. One to three), information of
  starting material should be provided (e.g route of
  synthesis/specification)


 Slide 17 WHO Prequalification Programme: Training workshop March 2010, Beijing
                                         S.2 Manufacture

 A discussion of the selection and justification of critical
  manufacturing steps, process controls, and acceptance
  criteria. Discuss critical process intermediates;

 A description of process validation and/or evaluation.

 A brief summary of major manufacturing changes made
  throughout development and conclusions from the
  assessment used to evaluate product consistency. The
  QOS should cross-refer to the non-clinical and clinical
  studies that used batches affected by these
  manufacturing changes.


 Slide 18 WHO Prequalification Programme: Training workshop March 2010, Beijing
                                 2.3.S.3 Characterisation

 A summary of the interpretation of evidence of structure
  and isomerism.
 For API described in a pharmacopoeia

   Confirm the structure by comparison with an official
   Reference Standard using a specific method e.g. IR




 Slide 19 WHO Prequalification Programme: Training workshop March 2010, Beijing
                                     S.3 Characterisation
3.2 Impurities
 Identification of potential and actual impurities arising from
  synthesis, manufacture and/or degradation, with an indication of
  their origin:
         Impruities contained in the starting material
         Starting material unreacted
         Intermediates unreacted
         By-products (unwanted reaction products)
         Degradants
         Reagents,Catalysts,Residual solvents

 Summary of the levels of the actual impurities detected in the batch
  samples (e.g. non clinical, clinical, toxicological studies, stability)
 Justification for selecting the limits, based on safety and toxicity
  data when applicable. ICH Q3A

 Slide 20 WHO Prequalification Programme: Training workshop March 2010, Beijing
                          S.4 Control of Drug Substance

 A summary of the specification, analytical procedures and
  validation of the methods should be included.
For Pharmacopoeial API
 The current monograph always applicable
 Additional critical specifications not included in monograph e.g.
      – particle size & polymorphic form
      – impurities, resulting from specific synthesis process
      – residual solvents (specific to process)

 Analytical procedures should be verified under actual condition of
  use, such as specificity, precision, and stability of the sample
  solution


 Slide 21 WHO Prequalification Programme: Training workshop March 2010, Beijing
                  S.5 Reference Standards or Materials

 For pharmacopoeial APIs:

   use an official Reference Standard (USP, Ph. Eur., Int.
   Ph.) as primary standard

 For non-pharmacopoeial APIs

   Description of how primary and/or a working standard
   has been established

 Provide Certificate of Analyses, including storage
  instuctions and duration of use

 Slide 22 WHO Prequalification Programme: Training workshop March 2010, Beijing
                       S.6 Container closure system
 Description of the packaging

 Identification of materials and components of the packaging

 Specifications of these materials

 Justification for choice of these materials, e.g.

      - protection against light, humidity

      - compatibility of the used materials with the API,
      interactions between the API and the closure such as
                     sorption, leaching (mainly in case of a liquid API)




Slide 23 WHO Prequalification Programme: Training workshop March 2010, Beijing
                                            S.7 Stability
 Stress study
    – to know different degradation pathways of an API
      and degradation products formed
    – to demonstrate the intrinsic stability of the API
    – To demonstrate the stability indicating power of the
      analytical procedure used

     Reference can be done to the literature, if the above
                 information is there available




Slide 24 WHO Prequalification Programme: Training workshop March 2010, Beijing
                                              S.7 Stability
 Formal stability study
    – To establish a re-test period
    – To determine the storage / labelling statement

    Definition of the re-test period

     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 storage
     conditions



  Slide 25 WHO Prequalification Programme: Training workshop March 2010, Beijing
                                             S.7 Stability
 A summary of the studies undertaken
      –   conditions,
      –   batches,
      –   packaging
      –   Stability-indicating quality parameters
      –   analytical procedures)

 A brief discussion of the results and conclusions

 The proposed storage conditions, retest date or shelf life.

 The post-approval stability protocol should be included




 Slide 26 WHO Prequalification Programme: Training workshop March 2010, Beijing
                    Quality dossier / Section 3

         Finished Pharmaceutical Product

                                                     (FPP)



Slide 27 WHO Prequalification Programme: Training workshop March 2010, Beijing
                 Quality dossier / Section 3
           Finished Pharmaceutical Product (FPP)
3.1. Manufacturing and marketing authorization
3.2. Pharmaceutical development
3.3. Formulation
3.4. Sites of manufacture
3.5. Manufacturing process
3.6. Manufacturing process controls of Critical steps and intermediates
3.7. Process validation and Evaluation
3.8. Specifications for excipients
3.9. Control of the FPP
3.10. Container/closure system (s) and other packaging
3.11. Stability testing


 Slide 28 WHO Prequalification Programme: Training workshop March 2010, Beijing
                 Quality dossier / Section 3
           Finished Pharmaceutical Product (FPP)


3.12. Container labelling

3.13. Product information for health professionals (SmPC)

3.14. Patient information and package leaflet

3.15. Justification for any differences to the product in the country
      OR countries issuing the submitted WHO-type certificate(s)

Same as CTD, only different in numbering. Product information
   listed at the end which are included in CTD module 1.



 Slide 29 WHO Prequalification Programme: Training workshop March 2010, Beijing
                    Quality dossier / Section 3
              Finished Pharmaceutical Product (FPP)
3.1. Manufacturing and Marketing Authorization

-        Valid manufacturing authorization for pharmaceutical
         production including the pharmaceutical form applied
         for

-        Marketing authorization to demonstrate the product is
         registered / licensed in accordance with national
         requirements




    Slide 30 WHO Prequalification Programme: Training workshop March 2010, Beijing
                       3.2. Pharmaceutical development

The aim is to build a quality product by design.


 Empirical (minimal)- essential product development for all
                                             products
 Enhanced-                                  Quality by Design
                                             Critical understanding of product
                                             and process
                                             Regulatory relief


 Slide 31 WHO Prequalification Programme: Training workshop March 2010, Beijing
                       3.2. Pharmaceutical development
Empirical product development
– Select the product profile (FPP) based on S&E and quality
– Investigate quality attributes of the formulation components such as
  API, excipients etc.
– Establish critical quality attributes
– Determine an appropriate manufacturing process and scale up
  (process optimization)
– the container closure system
– microbiological attributes
– Documentation
Develop a formulation similar to the innovator product. Reduce risk
  pertaining to compatibility, manufacturability, stability and
  bioavailability


 Slide 32 WHO Prequalification Programme: Training workshop March 2010, Beijing
                   3.2. Pharmaceutical development

1.    Physico-chemical characteristics of the APIs
       – solubility     (composition)
       – water content (stability)
       – hygroscopicity (stability)
       – particle size  (solubility, bioavailability, suspension properties,
                                             stability …)
         – polymorphism (solubility, bioavailability, stability)

     Data obtained from literature : Books, Journals, International
      Pharmaceutical Abstracts, Chemical Abstracts, Analytical
      Abstracts, Internet ……

     Experimental data (if necessary)

 Slide 33 WHO Prequalification Programme: Training workshop March 2010, Beijing
                         3.2. Pharmaceutical development


2. For fixed-dose combination (FDC) products
            Compatibility of APIs with each other
            WHO Guidelines for registration of fixed-dose combination
             medicinal products
              WHO TRS 929 (on WHO Prequalification website)

3. Choice of excipients, e.g.
            Compatibility with API(s)
            Intended functions and concentrations in product
            Characteristics (flowability, density, water content, etc)
            Safety aspects, e.g. TSE risk, to be addressed


 Slide 34 WHO Prequalification Programme: Training workshop March 2010, Beijing
                   3.2. Pharmaceutical development


4. Selection, optimisation of manufacturing process

       Rational behind the choice (e.g. why a non over kill process
        as a sterilisation process instead of terminal sterilisation in
        final container)
       Critical steps & In process controls
       Overages (justification)
       Unsatisfactory processes to be rectified




 Slide 35 WHO Prequalification Programme: Training workshop March 2010, Beijing
                      3.2. Pharmaceutical development

5. Comparative dissolution testing
         –     See Supplement 1

       A tool in selection of the formulation and optimisation of the
        process
         –     compare formulation(s) with innovator product
         –     a basic strategy in development to maximize the chances of
               bioequivalence

       Comparison of pivotal batches to commercial batches
       post-approval changes
       Setting of dissolution specifications- a discriminatory
        dissolution method



    Slide 36 WHO Prequalification Programme: Training workshop March 2010, Beijing
                       3.2. Pharmaceutical development

comparative dissolution testing (cont’d)
1.        Three media - 900 ml or less - all at 37°C
             – Buffer pH 1.2 or 0.1M HCl
             – Buffer pH 4.5
             – Buffer pH 6.8

         Water may be used additionally (not instead of)
2.        Paddle at 50 or basket at 100 rpm
3.        Twelve units of each product in all 3 media
4.        Dissolution samples collected at short intervals, e.g.
             – 10, 15, 20, 30, 45 and 60 minutes
             – Analyse samples for all APIs, when applicable


5.        Calculate similarity factor f2




     Slide 37 WHO Prequalification Programme: Training workshop March 2010, Beijing
                   3.2. Pharmaceutical development

6. Details of batches studied
     Provide a summary of development of the FPP from pre-
      formulation to production scale.

      Provide a comparison of formulas (tabulated form) of:
        – bio-batche(s) (clinical / bioequivalence),
        – development batches,
        – stability batches,
        – batches for validation/production




 Slide 38 WHO Prequalification Programme: Training workshop March 2010, Beijing
                                       3.3. Formulation

    Formula in tabulated form for :
        –      Administration unit (e.g. one tablet),
        –      Typical batch
                 - Precise any overage,
                 - Precise quantity adjustment of the API,
                 - Precise q.s. for excipient.

     Excipients :
        –     State function (e.g. lubricant, disintegrant),
        –     Precise technical grade (e.g. micronised, purified water),
        –     describe also those removed during process (e.g. water),
        –     Describe also those not always added (e.g. acid & alkali for pH
              adjustment,
        –     Capsule shells, inked imprints on dosage form,
        –     Also gas (inert atmosphere).


Slide 39 WHO Prequalification Programme: Training workshop March 2010, Beijing
                                3.4. Manufacturing sites


     Name and street address of each facility where any
      aspect of manufacture occurs including production,
      sterilisation, packaging and quality control. Indicate
      the Unit, block if any.

     Include any alternative manufacturers

     Certificate issued by the Competent DRA according to
      WHO Certification scheme for each site where a major
      step of manufacturing is performed

     Submit a valid GMP certificate


Slide 40 WHO Prequalification Programme: Training workshop March 2010, Beijing
                             3.5. Manufacturing process
    A flow diagram giving the steps of the process and where
     materials enter the process. The critical steps and points at
     which process controls, intermediate tests or final product
     controls are conducted should be identified.

    Description of manufacturing/packaging including
        –     Steps of the process
        –     Scale of production
        –     Equipment by type (e.g. tumble blender) & working capacity
        –     Process parameters for steps, (e.g. time, temperature, pH)
        –     Environmental conditions, e.g. relative humidity for hygroscopic FPPs.,
              area class for sterile FPPs
        –     Alternative methods




Slide 41 WHO Prequalification Programme: Training workshop March 2010, Beijing
                             3.5. Manufacturing process
    Proposal for reprocessing – justified with data.

    Copy of master formula.

    Batch manufacturing record – real batch (Biobatch)

    Sterile products – sterilisation steps and/or aseptic procedures.




Slide 42 WHO Prequalification Programme: Training workshop March 2010, Beijing
3.6. Manufacturing Process Controls of Critical steps and
                    Intermediates


      Identification of critical steps with test methods and justified
       acceptance criteria

      Information on quality of isolated intermediates, test methods
       and justified acceptance criteria to control them




  Slide 43 WHO Prequalification Programme: Training workshop March 2010, Beijing
                      3.7. Process Validation and Evaluation


 Each critical step of the manufacturing process must be
  validated

 Other steps in the process must be under control to
  maximize the probability that the finished product meets
  all quality and design specifications




 Slide 44 WHO Prequalification Programme: Training workshop March 2010, Beijing
                      3.7. Process Validation and Evaluation


 To understand the sources of variation

 To detect the presence and degree of variation

 To understand the impact of variation on the process and
  ultimately on product attributes

 To control the variation in a manner commensurate with
  the risk it represents to the process and product




 Slide 45 WHO Prequalification Programme: Training workshop March 2010, Beijing
                      3.7. Process Validation and Evaluation


The following unit operations are generally accepted as critical for
  most pharmaceutical processes:

 Blending operations

 Encapsulation

 Tablet compression

 Sterilization procedures

 Lyophilization




 Slide 46 WHO Prequalification Programme: Training workshop March 2010, Beijing
                      3.7. Process Validation and Evaluation


Validate the performance of manufacturing processes that
  may be responsible for causing variability in the product:

 Mixing homogeneity

 Tablet/capsule weight variation

 Disintegration time

 Dissolution rate and time

 pH of aqueous solutions

 Slide 47 WHO Prequalification Programme: Training workshop March 2010, Beijing
                 3.7. Process Validation and Evaluation
                                            New Generic FPPs

 Information form product development studies and primary batches
  should be used in designing the validation protocol

 Differences in design, operating principles, size, etc. between pilot
  and production batches should be highlighted

 Protocol should be linked to the lot of FPP used in bioequivalency
  studies

 Comparative dissolution profiles of process validation batches
  against dissolution profile of the bio lot should be provided

 Commitment to undertake validation of three consecutive batches
  should be provided


 Slide 48 WHO Prequalification Programme: Training workshop March 2010, Beijing
                    3.7. Process Validation and Evaluation
Validation protocol should include
        brief description of the process with summary of critical steps and parameters to be
         followed during validation,
        specifications of the FPP at release, details of analytical methods.
        In-process controls with acceptance criteria (cross reference)
        Additional testing intended to be carried out
        sampling plan,
        unifromity of dosage units is essential for FDCs,
        proposed timeframe

Validation report when submitted should include
     results for each batch, certificates of analysis, batch production records,
     report on unusual findings, modifications, observations and conclusions




    Slide 49 WHO Prequalification Programme: Training workshop March 2010, Beijing
                 3.7. Process Validation and Evaluation
                                              Established FPPs


 Details of the batches manufactured in the last several
  years, 10- 25 consecutive batches

 Formulation and description of method of manufacture,
  including in-process control test

 Specification and test methods

 Changes to formulation or process, if any, or compliance
  problems

 Comprehensive report using retrospective validation

 Slide 50 WHO Prequalification Programme: Training workshop March 2010, Beijing
                           3.8. Specifications for excipients

-        Pharmacopoeial excipients
         Copy of the pharmacopoeial monograph used for control + certificates of
         analysis
-        Non pharmacopoeial substances
            –     Details for manufacturing process,
            –     Characterisation
            –     Controls
            –     Safety (non-clinical , clinical data )
            –     Certificates of analyses

- For excipients of animal, human, microbial origin
         - TSE (Transmissible Spongiform Encephalopathy) risks and viral safety
         should be addressed
         - TSE CEP preferred
Permitted colorants are those allowed in UE, USA and Japan



    Slide 51 WHO Prequalification Programme: Training workshop March 2010, Beijing
                                     3.9. Control of the FPP

2 sets of specifications are possible: at release and at shelf-life
        (list of attributes non exhaustive)

       Description of the FPP /appearance
       Identification of API
       Assay of API: ± 5% of the label claim at release and ±10% at the end of shelf-
        life
       Degradation products
       Pharmaceutical tests e.g. dissolution, disintegration (where applicable)
       Uniformity of dosage units (mass or content)
       Identification of colorants, identification and assay of anti-oxidants, chemical
        preservatives
       Microbial contamination, Sterility, bacterial endotoxins


    Slide 52 WHO Prequalification Programme: Training workshop March 2010, Beijing
                                     3.9. Control of the FPP

        Monographs of Ph. Int., USP, BP are acceptable for the FPP +
         complementary tests

        If non-pharmacopoeial FPP, note for guidance ICHQ6A
         applicable

        Justification

        Description of all analytical procedures in details if not
         described in a pharmacopoeial monograph

        Validation of analytical methods and/or demonstration of
         applicability for pharmacopoeial methods

        Batch analyses for 3 lots with details of each lot (batch no, size,
         date of manufacture, use of batch)

    Slide 53 WHO Prequalification Programme: Training workshop March 2010, Beijing
                             3.10. Container-closure system

        Discussion on the choice of container
            –     Choice of the material
            –     Protection against light and humidity
            –     compatibility/interaction of materials in contact with dosage form
            –     Safety of materials used

        Detailed description of the container
            –     Specifications of the container with dimensions and drawings
            –     Specifications of materials in contact with FPP
            –     Identification of components e.g. IR for plastic materials


        Description of the secondary packaging


    Slide 54 WHO Prequalification Programme: Training workshop March 2010, Beijing
                                     3.11. Stability testing


The purpose of stability testing is to provide evidence on how the
    quality of a FPP varies with time under the influence of a variety
    of environmental conditions such as temperature, humidity
    and light, to
     - establish a shelf-life for the FPP,
     - determine the storage conditions
     - determine the in-use stability.



  To know about length of the time and conditions where efficacy,
             safety and quality of the FPP are maintained

 Slide 55 WHO Prequalification Programme: Training workshop March 2010, Beijing
                                     3.11. Stability testing
WHO stability Guideline in TRS 953

     3 batches, at least pilot scale (10% of production scale or 100
      000 whichever is greater)

     (exception for 2nd line TB products: 2 pilot batches at time of
      submission)

     in the claimed commercial packaging (container-closure)

     Storage conditions and frequency of testing according to WHO
      stability guideline in TRS 953

     Unless otherwise justified, 30°C / 75% RH is the recommended
      storage condition for Prequalification

 Slide 56 WHO Prequalification Programme: Training workshop March 2010, Beijing
                                        3.11. Stability testing
        Parameters susceptible to change over storage should be followed:

         . appearance
         . Assay
         . degradation products
         . Assay of antioxidants and chemical preservatives, check also for their efficacy
         . Dissolution testing (limits should remain unchanged to release)
         . Microbial contamination, sterility, bacterial endotoxins

        Minimum stability data to be submitted at time of submission:
                 Long term 12 months or 6 months or 3 months (as appropriate according to
                  Supplement 2 to the Main Generic guide and exception for TB 2nd line
                  products)
                 6 months intermediate 30°C/65% RH
                 6 months accelerated 40°C/75% RH

        In-use stability data (if applicable)




    Slide 57 WHO Prequalification Programme: Training workshop March 2010, Beijing
                                3.12. Container labelling

     Outer packaging : Where no outer packaging, on immediate
     packaging, e.g. HDPE bottle.
        Labelling should include at least the following :
        –   The name of the FPP.
        –   Method of administration.
        –   A list of API(s) (using INNs if applicable) showing the amount of each present in a
            dosage unit, and a statement of the container, e.g. number of dosage units, weight or
            volume.
        –   List of excipients known to be a safety concern for some patients, e.g. lactose, gluten,
            metabisulfites, parabens, ethanol, or tartrazine.
        –   Instruction on use.
        –   The batch number assigned by the manufacturer.
        –   The expiry date in an uncoded form.
        –   Storage conditions or handling precautions that may be necessary.
        –   Directions for use, and any warnings or precautions that may be necessary.
        –   The name and address of the manufacturer, company responsible for placing the
            product on the market.




Slide 58 WHO Prequalification Programme: Training workshop March 2010, Beijing
                                 3.12. Container labelling
Blisters and strips should include, as a minimum, the following
     information


         – Name, strength and pharmaceutical form of the FPP
         – Name of the manufacturer, company responsible for
           placing the product on the market
         – The batch number assigned by the manufacturer
         – The expiry date in an un-coded form




 Slide 59 WHO Prequalification Programme: Training workshop March 2010, Beijing
                               3.13. Product information

     Summary of product characteristics (SmPC)- for
      Health Professionals
         –      Aimed at medical practitioners and health professionals
         –      Changes to SmPC to be approved by WHO

     patient information leaflet (PIL)
         –      In conformance with SmPC


http://www.who.int/prequal/WHOPAR/WHOPARGUIDE/WHOPARGuidApplApp3v2_0.pdf




 Slide 60 WHO Prequalification Programme: Training workshop March 2010, Beijing
Thank you
for your attention




Slide 61 WHO Prequalification Programme: Training workshop March 2010, Beijing

				
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