External Gmp Audit Letter Template

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					Medicines and Healthcare products
       Regulatory Agency

   How to obtain and maintain a
     Manufacturer‟s Licence

                    Chris Brown
                 Technical Manager
          Laboratories and Licensing Group
        Inspection and Enforcement Division
                       MHRA
Types of Manufacturer’s Licences

  „Full‟ Manufacturer‟s– permits the manufacture
   (formulation) and assembly (packaging) of medicinal
   products

  Assembly Only – permits assembly only of medicinal
   products

  Manufacturer‟s (Specials) – permits manufacture and
   assembly of unlicensed medicinal products (Specials).
   These products are for the special need of a patient
   where there is no licensed alternative available
Overview of the Licensing Process


  Completed application form received by MHRA

  Information processed and assessments made

  Authorisation granted (or not)

  Ongoing maintenance - Variations
                       - Routine Inspections
                       - Renewals
Completed Application Form Received


   Application form received by staff in the Licensing Office

   Form checked for completeness and queried as necessary

   Discrepancies resolved

   Database (BLIS) populated

   Move to assessment
                    Assessment

 Predominantly an Inspectorate activity

 Sites identified on the application are visited

 Facilities and activities are investigated

 Personnel to be used in key roles are judged for suitability

 Approval or rejection of site and personnel
         Authorisation Granted

 When assessment is complete and recommendations have been
  made the authorisation is drawn up

 Provided the relevant fees have been received by MHRA the
  authorisation is sent to the applicant

 When granted the authorisation may differ from the initial
  application

 MHRA may decide not to grant an authorisation
    Maintaining the Authorisation


 Authorisation holders are required by law to submit a variation in writing to
  MHRA detailing changes to an authorisation and have the changes approved
  before they occur

 Administrative variation – dealt with by the Licensing Office

 Standard variation – requires assessment and possibly an inspection visit

 Renewal every five years – authorisation must not change

 After a variation has been approved or an authorisation has been renewed a new
  authorisation document is issued
                                   Fees

 MHRA is self-funding and recovers costs by levying fees

 Fees are reviewed and, as necessary, revised annually

 MHRA fees are approved by Parliament and published as a Statutory Instrument

 For an authorisation there are fees for:
   the initial application
   ongoing regular inspections
   making a variation
   the annual service fee

 There is not a fee for renewing an authorisation
                    IT Systems

 MHRA makes extensive use of IT facilities and has a number of
  large, bespoke database systems

 The database used to manage Manufacturer‟s and Wholesale
  Dealer‟s licences and Inpectorate activities is called BLIS

 BLIS is a powerful system, holding structured data for both
  current and superseded version of licences, managing the
  workflow of the licensing process and maintaining details of
  inspection visits to sites

 Notwithstanding, BLIS and other MHRA IT systems are now
  „long in the tooth‟ and will shortly be replaced by systems
  developed under the Sentinel project
                    Non-compliance

 Failure to comply with the provisions of the licence may be detected e.g. at
  routine inspection, through product failure

 Action taken will depend on the scale of the non-compliance and the willingness
  of the authorisation holder to address it

 Critical deficiencies and persistent non-compliance will be referred to a cross-
  Agency group (IAG) for consideration

 Based upon IAG recommendations the Licensing Authority may exercise a
  range of powers including:
   requiring named personnel to be removed from an authorisation
   requiring a manufacturing facility not to be used
   suspension or revocation of an authorisation
Medicines and Healthcare products
       Regulatory Agency

   How to obtain and maintain a
     Manufacturer‟s Licence


         Any Questions?
Medicines and Healthcare products
       Regulatory Agency

  Proposals for Manufacturing Licences for
  Registered Traditional Herbal Medicines


           Bernadette Sinclair-Jenkins
        Manager, Policy & Borderline Unit
        Inspection & Enforcement Division
       Medicines and Healthcare products
              Regulatory Agency
Medicines and Healthcare products
       Regulatory Agency

                     Agenda
 Who will require licences for manufacture
 Licensing requirements
  Medicines and Healthcare products
         Regulatory Agency
Art. 16g(1) applies (amongst other things) Arts. 40 to 52 of
Directive 2001/83
The activities of manufacture/importation must be authorised
 (Art.40)
In order to obtain an authorisation the applicant must (Art.41)
Specify the products/dosage forms
Have suitable and sufficient premises, equipment and
 laboratories

Have at his disposal at least one Qualified Person (QP)
   Medicines and Healthcare products
          Regulatory Agency

      The Qualified Person (Arts. 48, 49, 50, 51 and 52)
Persons who meet the eligibility criteria of Arts. 49 and 50
Authorisations for manufacture must name at least one
Have specific responsibilities concerning the certification of
 batches
Medicines and Healthcare products
       Regulatory Agency

Transitional Provisions for QPs criteria
for qualifications and experience
  - Herbal Forum Paper
  - 2 scenarios (i) life science graduate
                 (ii) non graduate
                    experienced manager
Medicines and Healthcare products
       Regulatory Agency

    Authorisation Holders’ Obligations (Art. 46)
 To have suitable staff
 To notify the competent authority of proposed
  changes
 To allow inspections
 To enable the QP to carry out his duties
 To comply with GMP
Medicines and Healthcare products
       Regulatory Agency

Standard Provisions for Manufacturer’s
Licences SI No 1971/972 as amended
  Covers   - premises and staff
           - provision of information to licensing
             Authority
           - prior notice of structural alterations to
             premises
           - compliance with GMP
Medicines and Healthcare products
       Regulatory Agency


       - recall procedures
       - notification to Licensing Authority if
         changes to premises, operations etc
       - allow inspections
       - have a QP
       - distribute products to authorised persons
TRADITIONAL HERBAL MEDICINES
    DIRECTIVE WORKSHOP

        INSPECTION
         PROCESS
TRADITIONAL HERBAL MEDICINES
    DIRECTIVE WORKSHOP

               Pre-Inspection
   Application registered by Licence Office
   Application referred to Inspectorate
   Application assigned to Inspector
   Inspector contacts Applicant
   Inspection arranged
   Confirmed by letter/fax/e-mail
TRADITIONAL HERBAL MEDICINES
    DIRECTIVE WORKSHOP

                  Opening Meeting
 Introductions
 Scope & Purpose
 Licence (Application)
 Site Master File - Management Structure
 (Changes & responses)
 Post Inspection
 Documents required
TRADITIONAL HERBAL MEDICINES
    DIRECTIVE WORKSHOP

         Inspection process
         Walk & Talk - visit plant, observe processes
         Read & Talk - documentation & records
         (Access & availability)

 Personnel                         Documentation
 Premises & equipment              Contracting
 Processing                        Quality Systems
 Storage & Distribution            Complaints & recalls
 Quality Control                   Self Inspection
TRADITIONAL HERBAL MEDICINES
    DIRECTIVE WORKSHOP

                  Closing Meeting
 Inspector’s Preparation - time & space
 Overview of operation
 Deficiencies found
 Clarification
 Notification to applicant & Action by applicant
TRADITIONAL HERBAL MEDICINES
    DIRECTIVE WORKSHOP

              Post Inspection
   Post Inspection Letter to applicant
   Response(s) to inspector
   Recommendation to Licensing Office -
          Support or Refusal (IAG)
   Action on Licence
   Routine Re-inspections
TRADITIONAL HERBAL MEDICINES
    DIRECTIVE WORKSHOP

        INSPECTION
         PROCESS
       Any Questions ?
TRADITIONAL HERBAL MEDICINES
    DIRECTIVE WORKSHOP

        INSPECTION
        STANDARDS
TRADITIONAL HERBAL MEDICINES
    DIRECTIVE WORKSHOP

  Standards


  Rules & Guidance for Pharmaceutical Manufacturers
  - “Orange Guide”


  Fitness For Purpose
TRADITIONAL HERBAL MEDICINES
    DIRECTIVE WORKSHOP

     Quality Management
     Some issues:
     Change control
     Incident investigation & action
     QC release & status control
     QP certification
TRADITIONAL HERBAL MEDICINES
    DIRECTIVE WORKSHOP

   Personnel
   Independence of Production & QC
   Sufficient Qualified Personnel
   Training
TRADITIONAL HERBAL MEDICINES
    DIRECTIVE WORKSHOP

 Premises (I)
 Fitness for Purpose
 Prevent Contamination- Containment & Segregation
 Minimise errors- Layout & Workflow
TRADITIONAL HERBAL MEDICINES
    DIRECTIVE WORKSHOP

 Premises (II)
 Siting
 Design
 Structure & Finish
 Services - Lighting, Piped services, Drains, Ventilation
 Security
TRADITIONAL HERBAL MEDICINES
    DIRECTIVE WORKSHOP

    Equipment & Plant (I)
    Fitness for Purpose
    Cleaning
    Maintenance
    Calibration
TRADITIONAL HERBAL MEDICINES
    DIRECTIVE WORKSHOP

    Equipment & Plant (II)
    Air handling
    Water
    Balances
TRADITIONAL HERBAL MEDICINES
    DIRECTIVE WORKSHOP

   Documentation
   Specifications - as registered, please
   Master Formulae
   Instructions      - Key steps, SOP references
   Procedures        - what you want to happen
   Records           - no rumours
   Fit for purpose
TRADITIONAL HERBAL MEDICINES
    DIRECTIVE WORKSHOP

   Production
   Issues:
             Materials control
             Cross contamination
             Packaging
             Defined processes as registered
TRADITIONAL HERBAL MEDICINES
    DIRECTIVE WORKSHOP

Validation
     Equipment, Process, Cleaning, Computers
     Consistency & effectiveness of performance
             Plan & programme
             Protocols
             Acceptance criteria
             Reports - Conclusions
TRADITIONAL HERBAL MEDICINES
    DIRECTIVE WORKSHOP

Quality Control
     Specifications, Test methods, Records
     Compliance with what is registered
     Out of Specification results
     Quarantine
     Decision - “Sentencing”
     Action: Release - Rejection
TRADITIONAL HERBAL MEDICINES
    DIRECTIVE WORKSHOP

  Contracting
  Incoming & Outgoing contracts
  Manufacture & Services
        Technical agreements
        Provision of information
        QP responsibilities
        Who does what
TRADITIONAL HERBAL MEDICINES
    DIRECTIVE WORKSHOP

  Quality Review
  History
  Output & yields
  Performance trends
  Complaints   Non-Conformances   Recalls
TRADITIONAL HERBAL MEDICINES
    DIRECTIVE WORKSHOP

  Self Inspection
  To GPMP
  Regulatory compliance
  Independence & objectivity
  Be your own Inspector
TRADITIONAL HERBAL MEDICINES
    DIRECTIVE WORKSHOP

      INSPECTION
      STANDARDS
      Any Questions?
QUALITY MANAGEMENT SYSTEM
FOR HERBAL MANUFACTURERS

        John Taylor
                    Quality




The sum of all of the features and
 characteristics of a product or service that
 determine its ability to satisfy customer needs
  Quality management system for
           manufacturers


 A quality management system is the
  organisational structure, responsibilities,
  procedures, processes and resources for
  implementing quality management
    Regulatory basis for a quality
management system for manufacturers


  Implementation and maintenance of a formal
   quality management system provides the
   structure to meet many of the requirements
   set out in Directive 2003/94/EC
  Objectives of the quality management
                  system
The quality management system should ensure that :
 customer requirements and expectations are met
 activities comply with regulatory requirements
 products are of the desired quality and composition
 products are correctly packaged and labelled
 processes are clearly defined and supported
 quality records are maintained
 staff are adequately trained
Essential elements of the documented
    quality management system
 Quality policy statement
 Organisation chart : responsibilities
 Management representative
 General description of the system
 Arrangements for review of the system
 Procedures for document and record control
 Other relevant standard operating procedures
  Standard operating procedure




An authorised, controlled, written description
 of the operations to be carried out
     Good documentation practice

Good documentation constitutes an essential
 part of the Quality Assurance system
Clearly written documentation prevents errors
 from spoken communication and permits tracing
 of batch history
Specifications, manufacturing formulae and
 instructions, procedures and records must be
 free from errors and available in writing
The legibility of documents is of paramount
 importance
   Quality management system
            procedures

As a guide, all procedures that relate to the
 quality of the operations and which can affect
 the quality of the products should be
 established in writing and reviewed regularly
 to ensure that they are current and remain
 capable of providing the degree of quality
 assurance demanded
          Written procedures (e.g.)
 receipt of starting and       validation/qualification
  packaging materials
                                batch release
 material storage and issue
                                training
 sampling and testing
                                internal audit
 equipment use, calibration
                                clothing, hygiene, health
 maintenance
                                complaints
 cleaning/sanitisation
                                recalls
 pest control
                                returns
 status labelling
                                document control
 environmental control and
                                distribution
  monitoring
Written procedure for control of SOPs
  format for SOPs and the numbering system
  origination and revision
  authorisation
  method of distribution of new documents
  designation of controlled copies
  withdrawal of superseded documents
  review of existing SOPs and re-issue
  revision history
  archives
  control of external documents
                      Records:
should be made when each action is taken
should be completed clearly and legibly. Alterations
 to entries should permit the reading of the original
should enable traceability of all significant activities
should be handled in such a way as to prevent their
 damage or loss
should be easily retrievable
should be retained for an adequate period,
 consistent with relevant legislation
  Monitoring, measurement and
          improvement
Internal audit
Internal monitoring of processes
Customer satisfaction measurement
Outcome measures
Measures of performance against target
Corrective action
Preventive action
Continual improvement
          Continual improvement
Inputs                Management review


         Activities


                      Results
                      Outcome measures
                      Customer satisfaction measures
                      People satisfaction measures
                      Performance against target
         Management review

The quality manual
Changes and change control
Customer complaints and feedback
Resources
Internal and external audit reports
Monitoring and measurement data
Corrective and preventive actions
Inspection finding: quality management
                 system
 The quality management system has lapsed in a number of
  areas such that there is no longer an adequately functioning
  independent quality unit:
      there is no independence of the roles of production
       manager, quality controller and QP
      product is inspected and released by the warehouse
       supervisor who has a stamp of the QP’s signature
      area clearance, batch number and expiry date checks
       are no longer carried out by a designated responsible
       person. Checks are no longer recorded.
      control of packaging components is outside the quality
       system
        Inspection finding: records

 Batch packaging records were deficient in that certain
   critical information was not included, notably:
     the names of the persons responsible for the
      packaging operations;
     records of identity checks and in-process controls;
     samples of the printed components used, including
      overprinting;
     quantities and reference numbers of printed
      components issued, used, destroyed and returned to
      stock, together with appropriate reconciliation
Benefits of working to a formal quality
         management system

  Provides a structured approach to activities
  Instils a discipline in personnel
  Provides a basis for consistency
  Provides a benchmark against which to
   measure performance
  Provides a means for identifying and
   implementing quality improvements
   Achieving successful inspection
             results (1)
Create good first impressions (external/internal)
Make the inspector feel welcome
Ensure that key personnel are available
Have key documents available:
     quality manual/SOPs
     licence documents
     records (transactions, training, monitoring,
                   calibration, etc.)
    Achieving successful inspection
              results (2)
Do not try to mislead or deflect the inspector
If you do not know the answer to a question, find
 someone who does
Ask the inspector to clarify any point that you do
 not understand
BUT ABOVE ALL:
     know your organisation and your
      responsibilities
     be familiar with the relevant “Good Practices”
                             SOP template

     Ref. No.                        (COMPANY)                                    Issue No.
                           STANDARD OPERATING PROCEDURE
Title :

Written by:                                                 Sign                    Date

Authorised by:                                              Sign                    Date

          Effective date                  Review date                       Page 1 of



1.        SCOPE                (the purpose of the SOP and what it covers)

2.        GENERAL              (general provisions – if required)

3.        SPECIFIC             (description of the operations, responsibilities, etc.)

4.        REVISION HISTORY            (Issue No.     Effective date    Changes)
                  SOP for internal audits

     Ref. No.                HERBAL MANUFACTURERS LTD                         Issue No.

       001                 STANDARD OPERATING PROCEDURE                             01

Title :                          INTERNAL AUDITS

Written by:             A. Author                         Sign                     Date

Authorised by:          A. Authorised person              Sign                     Date

          Effective date                 Review date                    Page 1 of 2

           1 May 2004                     1 May 2006


1.        SCOPE

          This procedure describes the arrangements for performing and reporting
          internal audits of operations in Herbal Manufacturers Ltd.
      SOP for internal audits (2)



2.   GENERAL

     All operations and activities that fall within the scope of the quality
     management system must be reviewed periodically to assess whether they
     meet the required quality standards. Audit findings must be reported to
     senior management in a timely manner and appropriate action taken to
     correct non-conformities identified during the audit.
      SOP for internal audits (3)


3.   SPECIFIC

     An audit programme must be drawn up to define:
           - the operations to be audited
           - the frequency of audit
           - the person(s) responsible for carrying out the audits
           - the method of reporting
           - the method of implementing and verifying corrective action

     The audit process should include assessment of:
           - compliance with the documented procedures
           - corrective action taken in response to the previous audit
           - effectiveness of training programmes
           - opportunities for improvement
      SOP for internal audits (4)


3.   SPECIFIC (cont.)

     A written report must be prepared by the auditor, normally within two weeks
     of the audit. The report must include:
             - a description of the operations/activities covered
             - the auditor’s observations
             - details of adverse findings

     Senior management, together with the auditor, must formulate appropriate
     corrective action to address the non-conformities. Implementation and
     effectiveness of corrective action should be verified at the next routine audit,
     or at a specially arranged follow-up audit if necessary.

     Audit reports and records of corrective action must be retained for at least
     five years.
       SOP for internal audits (5)




4.   REVISION HISTORY

     Issue No.   Effective date   Changes

     001/01      1 May 2004       None (first issue)
John Taylor
MHRA
Market Towers
1 Nine Elms Lane
London SW8 5NQ

Tel: +44 (0)20 7084 2461
Fax: +44 (0)20 7084 2595

john.taylor@mhra.gsi.gov.uk

				
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Description: External Gmp Audit Letter Template document sample