slide1 n.
Skip this Video
Loading SlideShow in 5 Seconds..
Introduction to WHO Prequalification of Medicines Programme Essential requirements PowerPoint Presentation
Download Presentation
Introduction to WHO Prequalification of Medicines Programme Essential requirements

Loading in 2 Seconds...

play fullscreen
1 / 39

Introduction to WHO Prequalification of Medicines Programme Essential requirements - PowerPoint PPT Presentation

  • Uploaded on

Introduction to WHO Prequalification of Medicines Programme Essential requirements. Dr Milan Smid and many team colleagues WHO Prequalification of Medicines Programme Amman, June 2013. Steps in WHO prequalification. I. Expression of Interest. Product dossier SMF. Inspections.

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

Introduction to WHO Prequalification of Medicines Programme Essential requirements

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

    Introduction to WHO Prequalification of Medicines Programme

    Essential requirements

    Dr Milan Smid and many team colleagues

    WHO Prequalification of Medicines Programme

    Amman, June 2013


    Steps in WHO prequalification



    of Interest

    Product dossier




    Additional information

    and data






    Maintenance and monitoring

    application requirements full dossier generic product application
    Application requirements - Full dossier Generic Product application
    • Covering letter, in English, confirming that the information submitted in the product dossiers is true and correct.
    • Product dossier (including full BE report where applicable), in English, in CTD format and the QOS-PD + QIS + BTIF/BW forms ALL completed in word format
    • A product sample
    • A site master file, for each manufacturing site
    how to submit an application
    WHO/CF workshop, New Delhi, November 2012 How to Submit an application
    • Submit electronic copy ONLY of Dossier in CTD format and Forms on CD/DVD To WHO Geneva
    • After dossier has been accepted for assessment and has been allocated a WHO reference number you will be notified to proceed to step 2
      • Updated or finalised Dossier and Forms (paper copies + CD/DVDs) incorporating any improvements or changes requested in step 1 and samples To UNICEF- Copenhagen
      • Submit Site Master File & Contract Research Organization Master File (CROMF) (hard copies +CD/DVDs) to Genevaaddress
    data requested for prequalification
    Data requested for prequalification

    An application to prequalify an FPP typically has three parts, relevant Good Practices have to be followed during manufacture and control:


    Information on the preparation and control of the API.



    Information on the preparation and control of the FPP.


    S & E

    Safety and efficacy data, e.g. commonly replaced

    by demonstration of bioequivalence

    data requested for prequalification guideline for applicants
    Data requested for prequalification guideline for applicants
    • Consists of two parts:
      • Preparation of product dossiers (PDs) in Common Technical Document (CTD) format
        • The preparation guideline
      • Guideline on submission of documentation on multisource (Generic) Finished Pharmaceutical Product (FPP): Quality part
        • Main quality guide
    • Being implemented since September 2010
    adapting the ctd nds new drug to ctd ands generic
    Adapting the CTD-NDS (new drug) to CTD-ANDS (generic)

    Not Part of

    the CTD




    Module 1



    Module 2






    The CTD






    Study Reports


    Study Reports


    Module 3

    Module 4

    Module 5

    main sub sections of 3 2 s drug substance api
    Main sub-sections of 3.2.S. Drug Substance (API)
    • 3.2.S.1 General information
    • 3.2.S.2 Manufacture
    • 3.2.S.3 Characterization
    • 3.2.S.4 Control of the API
    • 3.2.S.5 Reference standards or materials
    • 3.2.S.6 Container closure system
    • 3.2.S.7 Stability
    main sub sections of 3 2 p drug product fpp
    Main sub-sections of 3.2.P. Drug Product (FPP)
    • 3.2.P.1 Description and Composition of the FPP
    • 3.2.P.2 Pharmaceutical development
    • 3.2.P.3 Manufacture
    • 3.2.P.4 Excipients
    • 3.2.P.5 Control of the FPP
    • 3.2.P.6 Reference standards or materials
    • 3.2.P.7 Container closure system
    • 3.2.P.8 Stability
    specific quality documents quality summaries templates qis qos
    Specific quality documents: quality summaries (templates - QIS/QOS)

    The instructions for the QOS-PD (quality over all summary) run throughout the quality guideline

    Instructions for the QIS are in Section 3.2 and preface the QIS (quality information summary) template

    key aspects of quality assessment
    Key aspects of quality assessment
    • To ensure that all future batches, throughout their shelf life, will perform as the clinical/biobatch
      • Characteristics of the API batch used in the biobatch, details of FPP manufacturing process and quality attributes of the thebiobatch are critical reference information
    • To ensure that processes are adequately described and controlled and that they are validated
    • To ensure that the level of impurities in the API and FPP are within safe limits
    • To ensure that container closure system will protect the product from chemical, physical and biological deterioration and that it's compatible with the product
    • To ensure that analytical methods used at different stages are reliable and reproducible
    fpp prequalification and f our options for submission of api information
    FPP Prequalification and four options for submission of API information



    S & E









    the apimf procedure
    The APIMF Procedure
    • The API manufacturer supplies the FPP manufacturer with the open part of their APIMF. The FPP manufacturer use this information to complete the necessary sections of their submission.
    • The API manufacturer supplies the FPP with a letter of access.
    • The FPP manufacturer attaches the open part of the APIMF and the letter of access to their FPP submission.
    • The API manufacturer sends the open and closed sections of their APIMF directly to WHO. It is held in confidence.
    the apimf procedure1
    The APIMF Procedure

    APIMF holder

    FPP applicant

    Letter of Access

    APIMF submission to APIMF focal point



    APIMF assessment

    APIMF acceptance

    FPP assessment

    FPP prequalification

    advantages of the apimf procedure
    Advantages of the APIMF Procedure
    • It allows the submission of confidential information by the API manufacturer without disclosure to the FPP applicant.
    • One APIMF may be used to support multiple FPP applications without the need for repeated evaluations.
    • It is applicable to both pharmacopoeial and non-pharmacopoeial APIs.
    • The APIMF holder prepares and maintains the APIMF information and answers all queries directly.
    • Normally all API-related changes would require the submission of a variation from associated FPP manufacturers.
    notable requirements
    Notable Requirements
    • Number of batches required to establish the FPP shelf-life
    • Uniformity demonstration for the biolot instead of process validation report for pilot batches
    • process validation/pharmaceutical development requirements for “established” generics
    accelerated procedure for accepting rh and 2 nd line tb dossiers for assessment
    Accelerated procedure for accepting RHand 2nd Line TB dossiers for assessment
    • Stability Data at the time of submission only, may be reduced to no less than 3 months accelerated, plus 3 months long-term data, for not less than two primary batches of at least pilot scale. One of the primary batches should be the batch that was used for bioequivalence studies.
    • In some cases, several years of long-term stability data on batches under uncontrolled storage conditions may also be accepted from Zone IV countries.
    • NB all prequalification requirements for final acceptability of the dossier remain in effect, without exception, including but not limited to the submission of updated stability data during the assessment period as it becomes available, and a commitment to provide:
      • stability data on three production batches, and
      • process validation of three consecutive production batches to be completed prior to marketing.
    scope of who pq guidance on variations to a pre qualified medicinal product
    Scope of WHO PQ guidance on Variations to a Pre-qualified medicinal product
    • applies to quality part of product dossiers for an API or an FPP.
    • notification requirements for API-related changes differ depending on the manner in which API information was submitted with the original FPP application.
    • FPPs that rely upon the APIMF or CEP procedure have reduced reporting requirements.
    • Variations for FPPs prequalified on the basis of SRA approval should be approved by the same SRA and WHO PQP notified of the approval of the changes.

    Procedure for prequalification of pharmaceutical products requires holders of WHO-prequalified products to submit a quality review after five years from the date of prequalification of the product, or when requested to do so by PQP (whichever date is earlier)

    demonstration of bioequivalence
    Demonstration of bioequivalence

    Bioequivalence study


    PD studies



    In vitro



    comparators for the prequalification programme
    Comparators for the Prequalification Programme
    • Innovator product with established Q,S, and E sourced from well regulated market (ICH process countries). Guidance on selection and the to be provided documents should be followed.
    • The comparator should be selected from the comparator list (
    • Other comparators must be justified. Recommended to consult WHO at:
    • Remember: Comparator is not always identical with a comparator required by national regulatory authority!
    tested product
    Tested product
    • GMP
    • batch size
      • pilot batch
      • commercial batch
    • not smaller than 100 000 units or 10 % of industrial batch size (whichever is higher)
    • difference regarding the content of the investigative products (T and R) should preferably not be more than 5 %
    • strength with the largest sensitivity to detect differences in the two products
    analytical methods
    Analytical methods
    • FDA Guidance for Industry
      • Bioanalytical method validation, May 2001
    • ICH Guidance for industry
      • Validation of analytical methods: definitions and terminology, June 1995
      • Validation of analytical procedures: methodology, November 1996
    • EMA guideline
      • Bioanalytical method validation, 2011
    quality of bioequivalence studies
    Quality of Bioequivalence Studies

    Good Clinical Practice (GCP)is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve theparticipation of human subjects.Compliance with this standard provides public assurance that the rights, safety and well-being of trials subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible.

    frequent gcp non compliances
    Frequent GCP non-compliances
    • No informed consent, complex language
    • Ethics committee not independent
    • Dosing procedure is inadequately documented, no drug accountability
    • Certificates of analysis are not consistent with study products or not sufficiently detailed
    • No testing on addictive substances performed
    • Withdrawals are improperly documented
    • Meals not standardized and not documented
    • Storage of blood samples is not monitored
    • Method of calculation of PK parameters is not specified
    • Insufficient explanation of outliers
    • Chromatograms not consistent with data
    who bcs based biowaiver
    WHO BCS-based biowaiver

    Active substances selected for biowaiving by WHO


    • Lamivudine (BCS 3)
    • Stavudine (BCS 1)
    • Zidovudine (BCS 1)
    • Abacavir sulphate (BCS 3)
    • Emtricitabine (BCS 1)


    • Levofloxacin (BCS 1)
    • Ofloxacin (BCS 1)
    • Ethambutol ((BCS 3)
    • Isoniazid (BCS 3)
    • Pyrazinamide (BCS 3)
    International norms, standards and guidelines used in inspection activities to ensure wide applicability

    • Guidelines for good clinical practice (GCP) for trials on pharmaceutical products. World Health Organization, 1995 (WHO Technical Report Series, No. 850), Annex 3.

    • Additional guidance for organizations performing in vivo bioequivalence studies. WHO Technical Report Series, No. 937, 2006, Annex 9

    • Guidelines for the preparation of a contract research organization master file. World Health Organization, WHO Technical Report Series, No. 957, 2010 Annex 7, Page 271.
    generics approved by sra
    Generics approved by SRA
    • 1. Applicants should submit the following documentation:
      • A letter of undertaking (template attached) with a clear statement by the responsible person that the information submitted is true and correct.
      • A QA-certified copies of the Marketing and Manufacturing Authorizationsissued by the relevant SRA.
      • An original or certified copy of WHO-type Certificate of a Pharmaceutical Product, issued by one of the SRAs, together with the
      • approved Summary of Product Characteristics (SPC), or an equivalent thereof, including Patient Information Leaflet (PIL) and Labelling.
      • Assessment report(s) issued by the relevant SRA (expected to be replaced by specifications and control methods).
    • 2. Evidence of minimum five (5) years of current and continuous manufacturing experience and a copy of the last Annual Product Report. (expected to be deleted).
    generics approved by sra1
    Generics approved by SRA
    • A sample of the FPP(s) in market packaging and certificate of analysis should be provided.
    • Undertaking:
      • authorizes WHO PQP to publish "Main characteristics of the prequalified medicinal product" on its website;
      • will inform WHO prequalification programme with a copy of the regulatory acceptance letter of any change to the main characteristics of the product immediately after the variation has been approved by the relevant SRA.
      • if the change affects the information in SmPC, PIL and/or container labels (immediate and outer) in electronic format
      • c) has nominated a responsible employee for communication with WHO on any issues, including quality failures
    gmp inspections by who
    GMP Inspections by WHO
    • Inspections are conducted before prequalification, on an on-going basis and in special circumstances
    • Initial inspection target: <180days from dossier receipt
    • Re-inspection frequency determined on a risk basis
    • Inspections are normally announced 1-2 months in advance
    • Inspections conducted by a Stringent Regulatory Authority are taken into account when planning inspections
    gmp inspections by who1
    GMP inspections by WHO
    • Inspections are conducted by a team
      • A WHO inspector leads the team
      • An inspector from another Regulatory Authority (usually a PIC/S member) assists
      • The Regulatory Authority of the country of manufacture is invited (and encouraged) to accompany the team
      • Inspection report provided within target of 30 days
      • Closed out after review of corrective actions
    inspections of fpp manufacturers
    Inspections of FPP manufacturers
    • Normally over 4 days
    • Covers all aspects of GMP
      • Quality management, Quality assurance, Premises, Equipment, Documentation, Validation, Materials, Personnel
      • Utilities (e.g. HVAC, water) . . .
    • Also data verification (dossier) including stability data, validation (process), development batches and bio batches
    • Quality control laboratory – specifications, reference standards, methods of analysis, validation and qualification
    classification of observations
    Classification of observations

    Critical Observation An observation that has produced, or may result in a significant risk of producing, an API that, when used in a finished product, is harmful to the user.

    Major Observation A non-critical observation thathas produced or may produce a product which does not comply with its prequalification application (including variations); and/or

    • indicates a major deviation from the GMP guide; and/or
    • indicates a failure to carry out satisfactory procedures for release of batches; and/or
    • indicates a failure of the person responsible for QA/QC to fulfill his/her duties; and/or
    • consists of several other deficiencies, none of which on its own may be major, but which may together represent a major deficiency and should be explained and reported as such.

    Other Observation An observation that cannot be classified as either critical or major, but indicates a departure from good manufacturing practice.

    analysis of inspection of observations
    Analysis of inspection of observations

    Total number of Observations

    Average number of observations


    Ask if you are not sure, PQP contacts are:

    • Dossiers and assessment:
    • Inspections:
    • Quality control:
    • General:
    • Tele/videoconferences are possible

    Thank you for the attention