Third Party Manufacturing IMB Expectations & Experiences
IMB Information Day, 14th October 2010
Dr Cormac Dalton Inspector
Slide 1
Challenges with third parties
Slide 2
Content
• Overview of IMB Third Party Manufacturing Inspection Program at API and Finished Product Manufacturers
• Legal basis for inspection • Triggers for inspections at API sites • Planning & pre-inspection requirements • Some key GMP requirements • Inspection experience to date
Slide 3
IMB Foreign Inspection Program
Third Country Inspection Analysis 30
26
25
21
21
2008
2009
20 15
12 8
10 5
8
4
11
6 3
0 2001
2002
2003
2004
2005
2006
2007
2010
Total # 3rd Country Inspections
• Significant increase in inspections performed over the last decade
Slide 4
IMB Foreign Inspection Program
Third Country Inspection Analysis 30 25 20 15 10 5 0 2001
2002
2003
2004
Total # 3rd Country Inspections
2005
2006
EMA inspections
2007
2008
2009
2010
National Product Inspections
• 120 inspections in total; 11 were at API sites (< 10%)
Slide 5
Geographical breakdown
• Countries where inspections were performed: • Americas:
74
• Middle East:
16
• India:
16
• Japan:
6
• Singapore:
4
• China:
4 Slide 6
Legal basis for inspections - API
• Current requirements for APIs: • Manufacturers of medicinal products are required to use as starting materials only active substances, which have been manufactured in accordance with the detailed guidelines on good manufacturing practice for starting materials
• Article 46, 2001/83/EC (as amended) • Article 50, 2001/82/EC (as amended)
Slide 7
Legal basis for inspections - API
• In addition: • ‘The Competent Authority may also carry out unannounced inspections at the premises of manufacturers of active substances used as starting materials,….whenever it considers that there are grounds for suspecting noncompliance with the principles and guidelines of GMP’
• Article 111, 2001/83/EC (as amended) • Article 80, 2001/82/EC (as amended) • Currently, there is no legal requirement for an API site to be authorised and hold GMP Certificates
Slide 8
Triggers for API inspections
• EMA API GMP Inspection Triggers document (2005): http://www.emea.europa.eu/Inspections/GMPCompproc.html
• Examples of when an inspection may be necessary: • (a) when analysis of a sample of API indicates a noncompliance with the specification or suitability for its use,
• (b) when a report of a serious adverse reaction and/or a recall of a medicinal product occurs when the quality of the API is implicated,
• (c) when requested by the company, seeking GMP certification Slide 9
Legal basis for inspections – finished product
• ‘The Authorization referred to in paragraph 1 shall also be required for imports coming from third countries into a Member State’
• Article 40, 2001/83/EC (as amended) • Article 44, 2001/82/EC (as amended) • Thus all third party manufacturers involved in partial or total manufacture of medicinal products (including sterilisation of APIs) are required to hold a GMP Certificate
• Such sites are listed on the Irish company’s Manufacturer’s / Importer’s Authorisation (MIA)
Slide 10
Inspection planning
• Proposed dates for inspections a minimum of six months notice is required for third country site inspections.
• DUNS number of site(s). Confirmation that a DUNS number will be provided after the inspection if not already available.
• DUNS = Data Universal Numbering System http://www.dnb.com/us/duns_update/
• GPS locations of proposed sites • Days that are suitable (or unsuitable) for performing inspections Slide 11
Inspection planning (continued) • Lines of communication • Contact personnel at each site • 24hr contact details for (a) sites and (b) hotels • Details of Irish company individuals intending to travel • List of proposed accommodation • Travelling arrangements between sites • Fees - contact person for submitting invoices in advance (See IMB Newsletter , Issue 34 (page 6))
• Details of the number of translators that will be provided and by whom Slide 12
General requirements for new sites
• Description of the activities carried out on site • Details of any previous regulatory inspections • Names and countries of authorities • Dates & scope of previous inspections • Details of GMP Certification or equivalent • Clarification required that none of the sites are involved in the manufacture or handling of cytotoxic, biological, high potency, sensitising or beta-lactam containing compounds e.g. penicillins
• Consider impact of revised Chapters 3 & 5 re: ‘dedicated facilities’ Slide 13
General documentation requests
• Letters of invitation from all sites to support visa application requirements (where required)
• Copy of current Site Master File • List of GMP SOPs available in English (some may be requested in advance)
• Copies of Annual Product Reviews / Product Quality Reviews for previous three years inclusive. These may be required in advance of travelling.
Slide 14
General documentation requests
• Details of regulatory applications submitted: • Drug Master File (DMF) to the IMB • CEP application to EDQM • Copies of DMFs may be required in advance
• Copy of Master Batch Record (translated)
Slide 15
Inspection of third party API sites • Confirmation that the API(s) will be used in drug products manufactured in Ireland or that the API(s) will be used products for which an Irish Product Authorisation
• Details of the Marketing Authorisation Holder(s) • Details of the manufacturer(s) responsible for drug product manufacturer & batch release in the EU
• Confirmation that the site has been audited by the intended drug product manufacturer and that a QP declaration of compliance with GMP is available
• A copy of the audit report may be requested in advance Slide 16
IMB Expectations
• The Irish company requesting an inspection of a third party manufacturer should have the following in place:
• Audit performed at the intended site • Schedule in place for periodic subsequent audits • Technical Agreement in place with the third party • Full knowledge of the supply chain • QP declaration with respect to GMP compliance and the basis for providing such declaration clearly defined
Slide 17
Key responsibilities for the QP
• The QP should be satisfied that activities conducted at the third party are in compliance with GMP and the Marketing Authorisation
• Some key areas of focus: • • • • •
Technical agreements Documentation Supply chain knowledge Testing within the EEA Annex 16 - Certification by a Qualified Person and Batch Release
Slide 18
Technical Agreements • Contract manufacture and analysis must be correctly defined, agreed and controlled in order to avoid misunderstandings which could result in a product or work of unsatisfactory quality – ref: Chapter 7 (Principle)
• Managing changes to the Marketing Authorisation, including updates to the Active Substance Master File
• Managing changes at the third party • Contract laboratory within EEA (if appropriate) • Note – Chapter 7 of the GMP Guide under revision http://www.ema.europa.eu/Inspections/docs/64867809en.pdf Slide 19
Documentation
• The QP should have access to: • Audit reports of the facility • Batch manufacturing & testing records • Deviations • Annual Product Reviews / Product Quality Reviews • Testing data as generated within the EEA (where required)
Slide 20
Supply Chain Knowledge
• The QP should have knowledge of the supply chain and the controls and measures in place to assure the supply chain
• This includes: • • • •
The third party’s supply chain & management Checks performed on goods receipt Supporting documentation The role of ‘agents’ within the supply chain
• See IMB Information Day 2008 Materials Management - IMB - 2008 Slide 21
Finished product testing within the EEA
• The QP should have knowledge of testing performed within the EEA, where required.
• Technical Agreement with ‘contract’ laboratory • Assessment of comparative analytical data • Investigation launched where discrepancies identified • The presence of an Mutual Recognition Agreement (MRA) may negate the requirement for additional testing in the EEA
Slide 22
Mutual Recognition Agreements (MRA)
• Current status of MRAs - 2010 • Countries with fully operational MRA • Australia, New Zealand and Switzerland • Countries with limited operational MRA • Canada (excludes blood, plasma & biotech products) • Japan (inclusive of non-sterile medicinal products only) • For information on current status of MRAs http://www.ema.europa.eu/Inspections/MRA.html
Slide 23
Annex 16 – Certification by a QP
• A QP should maintain his knowledge and experience up to date in the light of technical and scientific progress and changes in quality management relevant to the products which he is required to certify.
• If a QP is called upon to certify a batch of a product type with which he is unfamiliar, for example because the manufacturer for whom he works introduces a new product range or because he starts to work for a different manufacturer, he should first ensure that he has gained the relevant knowledge and experience necessary to fulfil this duty.
• Consideration of QP participation in audits Slide 24
Company audits
• Company audits should be conducted with the following considerations:
• Should be conducted by personnel with appropriate technical background
• Should ensure that the auditor does not have any conflict of interest (in the case of a contracted auditor)
• Should be conducted against relevant Chapters / Annexes of the GMP Guide
Slide 25
Company audits (continued)
• In addition: • The audit duration should be appropriate to the complexity of activities on site
• The audit should adopt the principles of risk management (ICH Q9) for:
scheduling planning executing
Slide 26
Audit reports - format
• There is no mandatory style / format for audit reports • Regulatory formats include Compilation of Community Procedures (for finished products) – see references
• Should be of sufficient detail to enable the QP execute his/her duties
• Clearly identify area inspected and areas not inspected • Technically complex areas should be well defined e.g. aseptic processing
Slide 27
Sample deficiencies from inspections
• This section is delivered as follows: • Deficiencies identified at the Contract Giver site (within the EEA)
• Deficiencies identified at the Contract Acceptor site (outside the EEA)
• Deficiencies identified at API sites, where QP declarations had been provided to support Marketing Authorisation applications (outside the EEA)
Slide 28
Deficiencies at Contract Giver sites
• The management of batch release activities relating to sterile contract manufactured products was deficient in that:
• the company had not provided appropriate training relating to subcontracted sterile manufacturing processes to some QPs responsible for the release of such products to the market place,
• no audit had been performed to date at the contract manufacturing site by the Contract Giver
Slide 29
Deficiencies at Contract Giver sites
• With respect to the manufacture of Product X • the technical agreement between both parties did not identify roles and responsibilities for the generation of Product Quality Reviews (PQRs),
• no PQR was received from the contract manufacturer for the calendar year 2008,
• the provision of data in the PQR for the calendar year 2007 in a language other than English did not enable a critical assessment of the data reported.
Slide 30
Deficiencies at Contract Giver sites
• Two batches of Product X, manufactured outside the EEA, were QP released from the manufacturing site in Ireland with a declaration of compliance to the appropriate MA to the QP in another EU Member State who had responsibility of release to market. This was not the case, as the foil packaging material employed in the packaging process at the contract manufacturing site did not comply with the registered details in the dossier.
Slide 31
Deficiencies at Contract Giver sites
• The technical agreement between Contract Giver & Contract Acceptor contained the following text:
• ‘an independent testing organisation approved and licenced by the appropriate regulator or a consultant of recognised repute can be employed to resolve disputes in finished product testing results’
Slide 32
Deficiencies at Contract Acceptor sites
• The Annual Product Review procedure did not make reference to the EU GMP guide and all the relevant requirements as described in Chapter 1
Slide 33
Deficiencies at Contract Acceptor sites
• Technical agreements were considered deficient in that the agreement did not adequately describe the shared responsibility in maintaining the API program (the list of approved API manufacturers).
• No audits of API manufacturers had been performed by the 3rd Party Manufacturer and audit reports were not available on site.
Slide 34
Deficiencies at Contract Acceptor sites
• The Technical Agreement between Company A (API manufacturer), and Company B (Finished Product manufacturer), that concerned the testing of the API did not include the testing laboratory at company C (contract laboratory) as a party of the agreement.
• All three companies were located outside the EEA
Slide 35
Deficiencies identified at API sites
• The Annual Product Reviews reviewed for X and Y were deficient for the following reasons:
• There was no assessment provided under the various headings to adequately assess the consistency of the process, appropriateness of existing specifications for raw materials and finished products, to highlight trends and potential product quality issues, assess any significant process or equipment changes or modifications and to identify areas for potential product and process improvement
Slide 36
Deficiencies identified at API sites
• The design, operation and control of the Purified Water System was considered deficient in that:
• There was no user requirement or design protocol specifying the company’s requirements for the design of the water system
• A number of deadlegs were observed in the pipe-work associated with the circulating ringmain
Slide 37
Deficiencies identified at API sites
• The standard of finish and general house keeping and maintenance in the API Centrifuge and Rotary Drier Area in Plant 1 was not GMP compliant and of a satisfactory standard to prevent contamination of the purified API without additional containment controls
Slide 38
Final words
• Increased inspection activity at third party sites at the request of companies
• The level of risk is proportional to the level of sub contracting and this risk needs to be managed
• Key inspection focus: • QP oversight • Technical Agreements (See IMB Newsletter issue 34) • Exchange of information Batch records & deviations Annual Product Quality Reviews Change management Slide 39
Useful References
• PIC/S Aide Memoires • PI 030 - Inspection of API manufacturing sites • PI 023 - Inspection of QC Laboratories http://www.picscheme.org/publication.php?id=14
• EMA – Inspection Report Format • http://www.ema.europa.eu/Inspections/GMPCompproc.html
• A guidance document to facilitate the planning of such inspections will be made available on IMB website
Slide 40
Acknowledgements
• Thanks to the Compliance Department of the Irish Medicines Board
• Special thanks to Ms Yvonne Maloney & Ms Emily Hassett, Planning Managers
• Thank you for listening •
[email protected] •
[email protected] • +353-1-6764971
Slide 41
