Role and responsibility of a GMP inspectorate

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Role and responsibilityof a GMP inspectorate

• Twinning Programme
• TR02 AG 01
• Ankara, May 2005
• Arno Bauermeister

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Overview
tasks of GMP inspectorates
manufacturing authorisation
GMP inspections
import authorisation
enforcement and sanctions
official batch release
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manufacturing authorisation

• manufacturing authorisation document issued by
  the competent authority for a manufacturer
  allowing manufacturing activities
• gt without a valid manufacturing authorisation
  manufacturing is not allowed
• is also required for vaccines intended only for
  export to other countries

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manufacturing authorisation

• the manufacturer / importer must
• specify the veterinary medicinal products and
  pharmaceutical forms which are to be manufactured
  or imported
• specify the place where they are to be
  manufactured and/or controlled
• have at his disposal suitable and sufficient
  premises, technical equipment and control
  facilities
• have at his disposal the services of at least one
  qualified person (QP)
• provide particulars in his application to
  establish his compliance with these requirements.

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manufacturers / importers obligation

• the authorised manufacturer / importer must
• have at his disposal the services of staff
  complying with the legal requirements as regards
  both manufacture and controls
• give prior notice to the competent authority of
  any changes regarding the licensed activities
• immediately inform the competent authority if the
  qualified person (QP) is replaced unexpectedly
• allow the representatives of the competent
  authority access to his premises at any time

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manufacturers / importers obligation

• the manufacturer / importer must
• enable the QP to carry out his duties,
  particularly by placing at his disposal all the
  necessary facilities
• comply with the principles and the guidelines on
  GMP
• use as starting materials only active substances
  which have been manufactured in accordance with
  the detailed GMP guidelines for starting
  materials
• keep detailed records of all veterinary medicinal
  products supplied by him, including samples

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manufacturers / importers obligation

• The following information at least shall be
  recorded in respect of each transaction, whether
  or not it is made for payment
• date
• name of the veterinary medicinal product
• quantity supplied
• name and address of the recipient
• batch number.
• These records shall be available for inspection
  by the competent authorities for a period of at
  least three years.

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import authorisation

• in the case of veterinary medicinal products
  manufactured within the EU
• each batch of veterinary medicinal products has
  been manufactured and checked in compliance with
  the laws and in accordance with the requirements
  of the marketing authorisation
• in the case of veterinary medicinal products
  coming from third countries, even if manufactured
  in the EU
• each production batch imported has undergone in a
  EU Member State a full qualitative analysis, a
  quantitative analysis of at least all the active
  substances, and all the other tests or controls
  necessary to ensure the quality of veterinary
  medicinal products in accordance with the
  requirements of the marketing authorisation

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GMP inspections

• GMP inspection
• on-site assessment of the compliance with the
  Community GMP principles performed by officials
  of Community Competent Authorities
• GMP inspection covers
• GMP compliance
• compliance with hthe requirements of the
  marketing authorisation

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GMP inspection legal basis

• Directive 1991/412/EEC, Article 3
• By means of the repeated inspections the Member
  States shall ensure that manufacturers respect
  the principles and guidelines of GMP.
• For the interpretation of these principles and
  guidelines of GMP, the manufacturers and the
  competent authorities refer to the detailed
  guidelines published by the Commission in the
  "Guide to good manufacturing practice for
  medicinal products" and in its annexes

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GMP compliance legal obligation

• Directive 1991/412/EEC, Article 4
• The manufacturers shall ensure that the
  manufacturing operations are carried out in
  accordance with GMP and with the manufacturing
  authorisation.
• For veterinary medicinal products imported from
  third countries, the importer shall ensure that
  the veterinary medicinal products have been
  manufactured by manufacturers duly authorised and
  conforming to GMP standards, at least equivalent
  to those laid down by the EU.

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types of GMP inspections
GMP inspections
general GMP inspection
re-inspection
product or process related inspection

• regular
• periodic
• planned
• routine

• follow-up of corrective actions required during
  the previous inspection

• problem oriented
• after complaints

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GMP inspections

• GMP inspections cover all areas of the
  manufacturing site along the EU GMP guide
  including
• quality management
• personnel
• premise and equipment
• documemntation
• production
• quality control
• contract manufacture and analysis
• complaints and product recall
• self inspections
• special annexes (e.g. on sterile manufacturing or
  veterinary vaccines)

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inspection techniques

• prepare inspection (read Site Master File and
  related documents)
• inspect documentation, make copies
• inspect premises and equipment
• inspect personnels behaviour
• inspect management
• ask staff on what, how and why they do something

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how to do a GMP inspection

• 3 phases
• preparation of the inspection
• conduct of the inspection on the site
• follow-up of the inspection

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preparation of the inspection

• ask company for Site Master File (SMF)
• examine previous inspection report
• consider changes that happened since ther last
  inspection
• consider complaints, products defects and other
  incidents that may have happened since the last
  inspection
• such incidents can also trigger a GMP inspection!

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conduct of the inspection

• initial meeting
• inspector explain conduct of the envisaged
  inspection
• inspect all areas
• usually following the material flow of the
  process
• daily wrap-up
• explain was has been inspected
• name deficiencies found
• closing meeting
• explain conclusion / outcome of the inspection

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inspection follow-up

• draft GMP inspection report
• send inspection report to the inspected company
  and ask for comments
• assess companys comments
• write final inspection report and send it to the
  company
• in case of non-compliance
• sanctions and enforcement measures

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GMP inspection report

• Format described in Compilation of Community
  Procedures
• content
• short company description
• inspection date, name of inspectors
• report on inspection activities undertaken
• findings, observation, deficiencies
• miscellaneous
• recommendations
• summary and conclusions

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GMP deficiencies

• make clear, objective, specific description, with
  enough detail
• make clear reference to the relevant requirement
  of the GMP guide
• classify all the deficiencies as
• critical
• major
• other

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GMP deficiencies

• critical
• a deficiency which has produced, or leads to a
  significant risk of producing either a product
  which is harmful to the human or veterinary
  patient or a product which could result in a
  harmful residue in a food producing animal

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GMP deficiencies

• major
• a non-critical deficiency
• which has produced or may produce a product,
  which does not comply with its marketing
  authorisation
• or
• which indicates a major deviation from EU Good
  Manufacturing Practice
• or
• (within EU) which indicates a major deviation
  from the terms of the manufacturing
  authorisation
• or
• which indicates a failure to carry out
  satisfactory procedures for release of batches or
  (within EU) a failure of the Qualified Person to
  fulfil his legal duties
• or
• a combination of several other deficiencies,
  none of which on their own may be major, but
  which may together represent a major deficiency
  and should be explained and reported as such

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GMP deficiencies

• other
• A deficiency which cannot be classified as either
  critical or major, but which indicates a
  departure from GMP.
• A deficiency may be other either because it is
  judged as minor, or because there is insufficient
  information to classify it as a major or critical.

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inspection interval

• How often to inspect?
• Compilation of Community Procedures
• Inspections should be carried out at least every
  two years. Large companies may be inspected
  department by department, a full general GMP
  inspection being completed at least every five
  years. The interval between inspections should
  never exceed 3 years as lack of continuity may
  give rise to lower awareness of current GMP or
  allow significant deficiencies to develop.

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enforcement and sanctions

• Member States shall take all appropriate measures
  to ensure that the manufacturing processess used
  in the manufacture of immunological veterinary
  medicinal products are completely validated and
  batch-to-batch consistency is ensured.
• A Member State, the Commission or the Agency may
  require a manufacturer established in a third
  country to undergo an inspection.

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enforcement and sanctions

• Member States shall take all necessary measures
  to ensure that supply of a veterinary medicinal
  product is prohibited and that the medicinal
  product concerned is withdrawn form the market
  where
• risk-benefit assessment of the veterinary
  medicinal product is unfavourable
• the veterinary medicinal product has no
  therapeutic effect on the species of animal for
  which the treatment was intended

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enforcement and sanctions

• Member States shall take all necessary measures
  to ensure that supply of a veterinary medicinal
  product is prohibited and that the medicinal
  product concerned is withdrawn form the market
  where
• the qualitative and quantitative composition of
  the veterinary medicinal product is not as
  stated
• the recommended withdrawal period is inadequate
  to ensure that foodstuffs obtained from the
  treated animal do not contain residues which
  might constitute a health hazard to the consumer
• the control tests have not been carried out, or
  any other requirement or obligation relating to
  the grant of the manufacturing authorisation has
  not been complied with.
• The competent authority may confine the
  prohibition on supply and withdrawal from the
  market solely to the contested production
  batches.

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enforcement and sanctions

• The competent authority of a Member State shall
  suspend or withdraw the manufacturing
  authorisation for a category of preparations or
  for all preparations if any of the requirements
  laid down in Article 45 are no longer met.
• The competent authority of a Member State may
  either suspend manufacture or imports of
  veterinary medicinal products from third
  countries or suspend or withdraw the
  manufacturing authorisation for a category of
  preparations or for all preparations in the event
  of non-compliance with the provisions regarding
  manufacture or imports from third countries.

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official batch release

• Directive 2001/82/EC, Article 82
• Where it considers it necessary for reasons of
  human or animal health, a Member State may
  require the marketing authorisation holder for an
  immunological veterinary medicinal product to
  submit samples of batches of the bulk product
  and/or veterinary medicinal product for control
  by an Official Medicines Control Laboratory
  before the product is put into circulation.

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official batch release

• After studying the control reports the state
  laboratory responsible for the control shall
  repeat, on the samples provided, all the tests
  carried out by the manufacturer on the finished
  product, in accordance with the relevant
  provisions shown in the dossier for marketing
  authorisation.
• Unless the Commission is informed that a longer
  period is necessary to conduct the tests, Member
  States shall ensure that this control is
  completed within 60 days of receipt of the
  samples.

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useful websites

• http//pharmacos.eudra.org
• http//www.emea.eu.int
• http//perf.eudra.org
• http//www.zlg.de

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Thank you for your attention !
Arno Bauermeister Zentralstelle der Länder für
Gesundheitsschutz bei Arzneimitteln und
Medizinprodukten Sebastianstraße 189 53115
Bonn Tel. [phone] Fax [phone]
44 E-Mail arno.bauermeister_at_zlg.nrw.de