GMP Clearance Requirements for Medicines Manufactured Overseas Hongxia Jin Director Licensing & Certification, Manufacturing Quality Branch Medical Devices and Product Quality Division, TGA 2017 ARCS Annual Conference August 2017
Presentation • Assessment of overseas manufacturers and GMP clearance • Evidence requirements for desk top assessment • Sponsor responsibilities • Challenges • Current initiatives • Roadshows GMP Clearance Requirements for Medicines Manufactured Overseas 1
Approval of Medicine Manufacturers • All medicine manufacturers must receive an approval from the TGA before manufacture and supply, subject to exemption provisions and other requirements • Approvals – demonstrate compliance to the principles of Good Manufacturing practice – Australian manufacturers - GMP licence – Overseas manufacturers - GMP clearance to product sponsors • An application must be lodged via the TGA business portal (licence, GMP clearance or GMP certification) GMP Clearance Requirements for Medicines Manufactured Overseas 2
Assessment of O/S Medicine Manufacturers GMP clearance • GMP Clearance process is a non-statutory mechanism used to verify that overseas manufacturing sites comply with the principles of good manufacturing practice • GMP clearances are required for the purpose of ARTG registration and listing, and continued supply once products are registered or listed • GMP clearances are granted to Australian sponsors for a specific time period • Two pathways to obtain a GMP clearance: – Desk top based assessment – TGA on-site inspection GMP Clearance Requirements for Medicines Manufactured Overseas 3
GMP Clearance Data 7,000 6,000 Number Of Applications 5,000 4,000 3,000 2,000 1,000 0 FY 10/11 FY 11/12 FY 12/13 FY 13/14 FY 14/15 FY 15/16 FY 16/17 Clearance Applications 2,418 3,900 3,941 4,222 4,048 5,657 6,506 GMP Clearance Requirements for Medicines Manufactured Overseas 4
GMP Clearance – Desk top assessment pathway • If current evidence is available from a recognised regulator using an equivalent standard and it covers the required scope, a GMP Clearance may be issued to the Australian sponsor via desk top assessment pathway The TGA reserves the right to undertake an inspection of an overseas manufacturing site, irrespective of any other evidence supplied • Evidence required will vary depending on the international agreements, location of the manufacturer, the competent authority and complexity of the manufacturing process – MRA assessment – Compliance verification (CV) assessment G MP Clearance Requirements for Medicines Manufactured Overseas 5
GMP Clearance - Desktop based assessment – MRA Mutual Recognition Agreement (MRA): • MRAs - treaties between Australia and other countries and are enforceable under international law • The parties to an MRA recognise and accept the certification issued by the relevant regulatory agency in each country in relation to manufacturers located within that country. • Evidence required for MRA assessment – GMP certificate – The manufacturer must be located within the boarder of the MRA partner – The manufacturer must be assessed against an equivalent GMP standard – The inspection must be recent – The inspection must cover the scope of the clearance application – The manufacturer must be rated acceptable 6 GM P Clearance Requirements for Medicines Manufactured Overseas
GMP Clearance - Desktop based assessment – MRA Countries which are recognised participants in an MRA (or equivalent) with Australia Austria France Latvia Poland Belgium Germany Liechtenstein Portugal Canada Greece Luxembourg Singapore Cyprus Hungary Malta Spain Czech Republic Iceland Netherlands Sweden Denmark Ireland New Zealand Slovak Republic Finland Italy Norway Switzerland United Kingdom GMP Clearance Requirements for Medicines Manufactured Overseas 7
GMP Clearance - Desktop based assessment – MRA Common “deficiencies” for MRA applications: • Scope not supported by GMP certificate • Human investigation medicinal GMP Certificate provided instead of human medicines • Expired certificate provided • Manufacturer’s authorisation/Establishment licences provided instead of GMP certificates GMP Clearance Requirements for Medicines 8 Manufactured Overseas
GMP Clearance - Desktop based assessment – CV Compliance Verification (CV) assessment • Compliance verification assessments are permitted when there is an international cooperation arrangement with the competent authority: MRA regulators outside own country US FDA inspections PIC/S authorities within own country • Compliance Verification involves a detailed assessment by the TGA of specified documentary evidence provided by the sponsor/manufacturer GMP Clearance Requirements for Medicines Manufactured Overseas 9
GMP Clearance - Desktop based assessment – CV CV – non sterile dosage form and non sterile APIs • Current GMP Certificate • a copy of the most recent inspection report • A list of all regulatory inspections conducted within the past 3 years • Details of any regulatory actions in the past 3 years • Site Master File, Quality Manual or equivalent • List of products intended for supply in Australia • GMP agreement between the sponsor and the manufacturer* • Copy of the procedures for release for supply of products included in the Clearance application* 10 GMP Clearance Requirements for Medicines Manufactured Overseas
GMP Clearance - Desktop based assessment – CV CV – Additional Evidence for sterile/biotech APIs and Sterile Dosage forms – Every document included in the previous slide – Validation Master Plan – Latest Product Quality GMP Clearance Requirements for Medicines Manufactured Overseas 11
GMP Clearance - Desktop based assessment – CV CV – Evidence for QC Testing Laboratories and Contract Sterilisers: • Current GMP Certificate or relevant ISO certificate • a copy of the most recent inspection report • A list of all regulatory inspections conducted within the past 3 years • Details of any regulatory actions in the past 3 years • Quality Manual/Laboratory Manual or equivalent • A list of tests a laboratory is authorised to perform • GMP agreement between the sponsor and the contract testing laboratory or steriliser* • For botanical ingredients, evidence that authenticated standard reference materials are used 12 GM P Clearance Requirements for Medicines Manufactured Overseas
GMP Clearance – Desk Top Assessment Pathway Common “deficiencies” for CV applications: • Incomplete application: – GMP agreement, when applicable – A copy of the most recent inspection report – Latest Product Quality Review (PQR), when applicable – List and details of regulatory Inspections in the last three years – Manufacturer's declaration for APIs (when not covered during most recent inspection), when applicable • Inadequate evidence supporting the scope of applications G MP Clearance Requirements for Medicines Manufactured Overseas 13
GMP Clearance – Desk Top Assessment Pathway GMP clearance assessment outcome: • Issue a GMP clearance • Issue a GMP clearance with condition(s), or issue a GMP clearance with reduced scope • Not issue a GMP clearance GMP Clearance Requirements for Medicines Manufactured Overseas 14
GMP Clearance Assessment Pathways US FDA (all locations) or PIC/s Regulator (outside MRA Regulator PIC/s Regulator (own country) or own country) or Product / Activity (own country) MRA Regulator (outside own All non-PIC/s regulators or country) No Certification available MRA Clearance Compliance Verification – Type B TGA on-site inspection Non Sterile Medicines or non Sterile API MRA Clearance Compliance Verification – Type C TGA on-site inspection Sterile Medicines or Sterile API (including biotech) MRA Clearance Compliance Verification – Type C TGA on-site inspection Contract Testing Laboratories MRA Clearance Compliance Verification – Type D TGA on-site inspection Contract Sterilisers GMP Clearance Requirements for Medicines Manufactured Overseas 15
GMP Clearance – sponsor responsibilities • Maintain evidence of GMP compliance for all overseas manufacturing sites used in the manufacture of their registered or listed medicine and are responsible for these nominated sites at all times • Prior to submission , ensure that: – All information provided in the application is accurate, current and does not contradict the corresponding information contained within the evidence provided – The scope of the application is relevant to the activities carried out by the manufacturing site and is reflected in the evidence provided – All required evidence is attached when submitting the GMP certification or clearance application or provided to TGA directly by the manufacturer – For GMP clearance applications, that signed and effective GMP/Quality/Technical agreements are in place and meet the relevant requirements, if required 16 GMP Clearance Requirements for Medicines Manufactured Overseas
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