Current Good Manufacturing Practice Vaccines by bjp11375


									Current Good Manufacturing

                   Mary Malarkey
Director, Office of Compliance and Biologics Quality
   Center for Biologics Evaluation and Research
         FDA Science Board; April 15, 2005
          Summary:Vaccine CGMP

 Statutes and regulations
 Unique challenges with Vaccines
     Problems   observed in the industry
   Pharmaceutical GMPs for the 21st Century:
    a Risk-Based Approach
     Programs already in place at CBER
     Additional impact of initiative on vaccines
   Recent Lessons – other initiatives

   Vaccines are biological products as defined in
    section 351(i) of the Public Health Service Act
   Vaccines are drugs as defined in section 201(g) of
    the Federal Food, Drug and Cosmetic Act (FDCA)
   Vaccines are licensed after submission, review
    and approval of a biologics license application
    (BLA) in accordance with section 351(a) of the
   Vaccines are licensed biological drugs

   Like other pharmaceutical human drugs:
     Vaccines  are investigated clinically (IND) in
      accordance with 21 CFR Parts 50 and 312;
     Preparation of vaccine drug products is held to
      21 CFR Parts 210-211, ie the same CGMP
   Vaccines are also held to the licensing and
    biologics standards, as applicable, in 21
    CFR Parts 600-680
    Unique challenges with Vaccines

   Unlike a substantial number of injectable
    pharmaceuticals, vaccines are administered to a
    large population of patients that are most often
    young and healthy.
   Starting materials may have inherent bioburden,
    e.g. egg-based vaccines or may be infectious until
    inactivated e.g. bacterial vaccines.
   From beginning to end, the manufacturing process
    for a vaccine can take several months to a year.
   In some cases, older products, licensed many
    years ago.
    Unique challenges with Vaccines

   As with other biological products, vaccines:
     Must  be processed under defined
      conditions/controls throughout production to
      consistently produce a safe, pure and potent
      product and preclude the introduction of
      environmental contamination
     Cannot withstand heat sterilization without
      affecting product quality
          Must be “aseptically” processed
    Unique challenges with Vaccines

   The defined conditions/controls for vaccines
    would include but not be limited to, where
       Bioburden testing of the product at various points in the
        manufacturing process.
       Segregation of pre- and post-inactivation steps and
        appropriate methods for inactivation testing
       Cleaning of facilities and equipment using procedures
        shown to be effective for removal of residual product
        and bioburden
       Monitoring of the manufacturing environment to
        continuously assess conditions
    Unique challenges with Vaccines

   Aseptic processing?
       Product is filter sterilized at some point during the
        manufacturing process
       For vaccines, this may be earlier in the process than
        many products.
            Once conjugated to an adjuvant, sterile filtration no longer
       Subsequent steps must be carefully controlled to avoid
        introduction of contaminants.
       All materials that contact the product are sterilized.
       Careful adherence to aseptic technique/practice by
                  Problems Observed

   What problems have we observed in the vaccine
       Defined conditions/controls not in place throughout the
        manufacturing process, has resulted in failures at the
        end of production that cannot be adequately
        investigated due to lack of data
       Issues with segregation of pre- and post-inactivation
       Inadequate cleaning procedures that result in cross-
            Problems Observed

 Environmental   monitoring data collected but
  not adequately evaluated or investigated when
  levels exceeded or same organisms identified in
  the in-process or final product.
 Inadequacies in aseptic processing:
    Validation doesn’t simulate actual manufacturing
    Poor aseptic technique observed during aseptic
               Problems Observed

   Many of these observed problems represent
    deficiencies in the manufacturer’s Quality
   Many of these observed problems are not atypical
    to the pharmaceutical industry, as a whole.
   Many of these observed problems were discussed
    at length and assessed under the GMP Initiative.
       What do we mean by Quality
   Key points:
     Management   involvement and responsibility at
      all levels
     Adequate systems for identifying and
      correcting problems to prevent recurrence and
      proactively identifying trends to prevent
      problems for occurring
      Pharmaceutical CGMP for the 21st
      Century: A Risk-Based Approach
   CBER membership on the CGMP Steering
    Committee and working groups established under
    the initiative
   A risk and science-based approach to CGMP
   Many working group charges already in place for
    CBER regulated biological drug products,
    including vaccines
   CBER membership on the Council on
    Pharmaceutical Quality, the body charged with
    implementation of the working group products
                  Programs in Place:
                  Prior to Approval
   What was already in place at CBER?
     Integrated review and inspection process
        Biologics License Application review committee
         consists of members from the Office of Vaccines
         Research and Review, the Division of
         Manufacturing and Product Quality, OCBQ, the
         Office of Biostatistics and Epidemiology, and other
         CBER components
        The same components participate in pre-IND, IND,
         pre-BLA and, as necessary, BLA meetings with
         sponsors. Provide advice and guidance on all
         aspects, including facility design and CGMP
                  Programs in Place:
                  Prior to Approval
   Pre-license inspection conducted by review
       DMPQ lead inspector – covers facilities and CGMP
       Product reviewer(s)/scientist(s) participate
       ORA invited to participate
   Resolution of issues prior to approval
   Same paradigm for pre-approval inspections for
    significant changes to the application (21 CFR
    601.12) e.g. new or renovated facility
                   Programs in Place:
                     Post Approval
   Team Biologics Program – established 1997 and
    began vaccine inspections in 1999
       Highly specialized team of ORA investigators
       Product specialist participation in inspections extremely
        important for complex vaccine manufacturing processes
   Improvements being made to program based on
    evaluation, e.g.
       Implementation of a Quality Management System to
        ensure continuous feedback
       Regular communications between investigators and
        product specialists; continuous training.
            Programs in Place:
 All Team Biologics findings are reviewed at
 If action is recommended by Team
  Biologics, a complete evidentiary and
  scientific review is undertaken at CBER
  and, if CBER concurs, sent to the Office of
  General Counsel for review and
       Impact of the Initiative on
 GMP Steering Committee recognized issues
  related to Quality Systems, in addition to
  other issues, and working groups were
  formed to address
 Several working group products directly
  impact the vaccine industry
             Guidance to Industry

   Issuance of Final Guidance on Sterile Drug Products
    Produced by Aseptic Processing; September 2004.
       Includes recommendations on aseptic processing
        that begins earlier in the process, such as the case
        with vaccines.
   Issuance of Draft Guidance for Industry on Quality
    System Approaches to Pharmaceutical CGMP;
    September 2004.
       Provides the agency’s current thinking on Quality
        System principles
       Comments to the docket under review by the
        working group.
       GMP Harmonization Analysis
            Working Group
   What was our charge?
     “..toperform a formal analysis of 21 CFR 210
      and 211 against EU GMPs, PIC/S and other
      GMP regulations across the Agency.”
     The intent of the analysis was to highlight the
      differences in these various regulations and
      report back possible recommendations for
      modifications to the CGMP regulations.
Working Group Representation

         CDER
         CDRH
         CFSAN
          CVM
          OCP
          ORA
            What did we compare?

   21 CFR 210 and 211 – Drug GMPs
   EU GMP
   21 CFR 110 –Food GMPs
   21 CFR 120 – Juice HACCP
   21 CFR 820 – Device GMPs (QSR)
   21 CFR 226 – Type A Medicated Articles
          What did we conclude?

 More similarities than differences between
  the various regulations
 Differences often commodity related, e.g.
  sanitation and personnel practices for foods
 Presented to GMP Steering Committee;
  June 25, 2004.
        What are the next steps?

 Modifications to Parts 210/211 will be
  undertaken using an incremental approach
 Continued pursuit of International
  Harmonization through ICH and PIC/S
        What are the goals of the
 to encourage timely detection and response
  to emerging defects or indications that
  product quality has been compromised
 to provide further clarity and modernize the
 to harmonize various aspects of parts 210
  and 211 both internationally and with other
  Agency regulations.

   In September 2004, FDA announced it will apply
    to Pharmaceutical Inspection Cooperation Scheme
       Membership consists of inspectors/investigators from
        countries around the world
       Opportunity to discuss approaches, obtain information,
        and harmonize, where possible.
       CBER has been active in this area with respect to blood
        and blood products for many years.
       Seek to expand to vaccines
               Recent Lessons:
         Additional Vaccine Initiatives
   Biological drug manufacturers, including vaccine
    manufacturers, have been subject to routine GMP
    inspections every two years.
       Starting in FY05, influenza vaccine manufacturers will
        be inspected annually due to complex issues associated
        with this product (e.g. “new” product each year)
       Analysis of other manufacturers being performed to
        consider increased coverage for other medically
        necessary products, particularly those produced off-
            Partnering with Foreign
   Chiron experience made clear the need for
    information sharing with our foreign regulatory
   Had established an agreement with Chiron and the
    British Medicines and Healthcare Products
    Regulatory Agency (MHRA) that allowed sharing
    in that case
   On February 14, 2005, signed a general, formal
    confidentiality agreement with MHRA allowing
    sharing in all cases
 Have agreements in place with other
  regulatory counterparts of countries where
  vaccines are or may be manufactured for
  U.S. use (e.g. Health Canada, EMEA)
 Actively pursuing other agreements to
  facilitate sharing of information on
     Outreach to the Vaccine Industry

   Recognition of the need for increased
    communication pre- and post- approval
   Workshop or possible “roundtable” under
   Sessions on vaccines planned or being planned at
    several conferences in FY05 and FY06, e.g.:
       GMP by the Sea in August 2005
       European conference on vaccines October 2005
    Outreach to Vaccine Industry

   Meetings with individual vaccine
     to discuss new technologies and other changes
     to increase capacity and manufacturing control.
     to provide advice on potential pathways to
     approval and facilitate approval of new
     vaccines, whenever possible.

   Manufacturers of vaccines are required to follow
    the CGMP regulations in Parts 210-211, and
    additional standards in Parts 600-680, as
   Vaccines pose a unique challenge to industry and
   The agency has issued useful guidance for this
    industry and is pursuing an incremental approach
    to modifications to Parts 210-211

   Our approach to regulation of vaccines has been
    reviewed and is being modified based on recent
   Partnering with our foreign regulatory
    counterparts is key to ensuring communication in
    this global industry
    Increased outreach to the vaccine industry to
    increase communication and facilitate
    improvements; approvals of new vaccines.

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