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transcript
National Validation Forum IIby Trevor Schoerie
Guidelines
• Restrooms, safety, fire
• Confidentiality – Chatham house rules
• Please relax, enjoy yourself and contribute
• Presentations on PharmOut / TGA websites
• Phone on silent
Program – Day 1
Wednesday, 27th June 2012
Start Time Topic Presenter8:30 9:00 Registration
9:00 9:10 Welcome and Introduction Trevor Schoerie
9:10 9:30 Regulatory update (PIC/S) Trevor Schoerie PIC/S updates, PDA-PIC/S conference in Geneva
9:30 10:10 Reflections on NVF I & DQ Gordon Farquharson International prespective
10:10 10:30 TGA Current Industry issues Mark Dickson - TGA Validation
10:30 11:00 Morning Tea
11:00 11:20 Common Audit Deficiencies Mark Dickson - TGA
11:20 11:40 Risk & criticality assessments John Montalto
11:40 12:20 Computer Systems Andrew Giles - TGA Validation
12:20 12:45 Keepad session Andrew Watson
12:45 13:45 Lunch
Drugs
13:45 14:45 Validation - Industry perspective Paul McDonald
14:45 15:00 Process Validation - Draft EMA vs FDA Eoin Hanley
15:00 15:30 Afternoon Tea
• Day 1 - one stream until afternoon tea
Program - Day 1
Wednesday, 27th June 2012
Start Time Topic - Sterile Stream Facilitator Topic - Non Sterile Stream Facilitator
15:30 17:00
Introduction to Product & FacilityQTPPsCQAsCPPsOverall Risk Assessment
John Montalto *1
Introduction to Product & FacilityQTPPsCQAsCPPsOverall Risk Assessment
Marc Fini *1
17:00 17:00 Day close
• Day 1 - two streams after tea
Program - Day 2
Thursday, 28th June 2012
Start Time Topic - Sterile Stream Facilitator Topic - Non Sterile Stream Facilitator9:00 9:10 Recap from Yesterday John Montalto *1 Recap from Yesterday Marc Fini *1
9:10 10:30QbDControl StrategyRisk Assessment for Validation
John Montalto *1QbDControl StrategyRisk Assessment for Validation
Marc Fini *1
10:30 10:50 Morning Tea Morning Tea
10:50 12:45 DQ, IQ, OQ, PQ John Montalto *1 DQ, IQ, OQ, PQ Marc Fini *1
12:45 13:45 Lunch Lunch
13:45 15:00 Continued Process Verification John Montalto *1 Continued Process Verification Marc Fini *1
15:00 15:30 Afternoon Tea
Sterile and Non Sterile Presenter15:30 17:00 Q and A panel TGA and Industry
17:00 17:00 Day close
• Day 2 - two streams• After tea back to one stream - Q and A
Influences on validation
|1987 | 2000 |2002 | 2004 | 2006 | 2008 2010 | 2011 |
FDA Guide to Process Validation
EU Annex
15
FDA: Pharmaceutical cGMPs For The
21st Century
ICH Q9
FDA: Quality System
Approach to Pharmaceutical
cGMP
PICSVMP
ISPE C&Q Baseline 5
GuideISPE 21st
Century Qualification White Paper
ICH Q8
ASTM E2500-
07FDA
Process Val.
Guidance
Draft EMA
Process Val
ASTM E2500-
07
ICH Q10
ICH Q11
EU / PIC/S Annex
15
Objective
• Review current best thinking / practice
• Consistent national validation approach– For industry sector– Develop a framework
• Start of a journey, practical, value adding validation.
• Focus on Process vs Outcome
Thank you
International GMP TrendsTrevor Schoerie
with thanks to Bob Tribe
Slide 10
Overview
Update on PIC/S1
2
Future expected changes to EU & PIC/S GMP Guides3
4
GMP deficiencies reported by PIC/S authorities
US FDA & PIC/S membership5
Recent Changes to PIC/S GMP Guide
40 PIC/S MemberAuthorities (at 1.1.2012)
EUROPEAN UNION Member States Agencies (27)
Austria Belgium Czech Rep(H&V) CyprusDenmark Estonia Finland France (H&V)Germany Greece Hungary IrelandItaly Latvia Lithuania Malta Netherlands Poland Portugal Romania Slovak Rep. Slovenia Spain SwedenUK
Malaysia
Singapore
South Africa
Australia
Canada
Argentina
Israel
USA Ukraine
Switzerland Liechtenstein
IcelandNorway
4 Partners
EDQMEMA
UNICEFWHO
Indonesia
Taiwan
Slide 12
Applicants currently being assessed for PIC/S membership
– Indonesia– Taiwan– Thailand– Philippines– New Zealand
– Brazil– Iran– UK (veterinary)– Japan– South Korea
The GMP Regulatory Authorities of:
Slide 13
Agencies showing an interest in joining PIC/S
– Hong Kong (pre-accession)– Armenia (pre-accession)– PR of China– Russia– Hungary (vet)
– Saudi Arabia– Croatia– Bulgaria– Turkey– Nigeria
The GMP Regulatory Authorities of:
Recent PIC/S Training Seminars
Biotechnology France, 2000Inspection of Utilities Czech Rep, 2001 Interface between GCP and GMP Canada, 2002Inspection of QC laboratories Slovak Rep, 2003Inspection of APIs Spain, 2004Packaging/Labelling/Prevention of Mix-ups Romania, 2005Risk Management Germany, 2006Inspection of Solid Dosage Forms Singapore, 2007Inspection of GDP Poland, 2008Sterile Aseptic Manufacturing Sweden, 2009 Inspection of Traditional/Herbal Medicines Malaysia, 2010 *Good Inspection Practices South Africa, 2011 * *
* 120 participants from 44 different countries* 128 Participants from 57 different countries
(Booklets/CDs of Seminar proceedings available for purchase at www.picscheme.org )Slide 14
Future PIC/S Seminars
• Qualification & Validation Kiev Ukraine, Oct. 2012
• Topic yet to be decided Canada, 2013
(NB: Open to GMP inspectors only, including inspectors from non-PIC/S countries)
Slide 15
Joint PIC/S – Industry Workshops
• ISPE – PIC/S Workshop on Quality Risk Management.(Singapore, November 2007)
• PDA – PIC/S Workshop on the Manufacture of Sterile Medicinal Products – revised Annex 1 to PIC/S GMP Guide.(Geneva, November 2008)
• PDA – PIC/S Workshop on Inspection Practices & Trends.(Geneva, 9-10 May 2012)
• ISPE – PIC/S Workshop (topic yet to be determined).(venue yet to be determined, 2013)
Slide 16
Information Sharing Within PIC/S
● Reports of GMP inspections (local & overseas). ● List of planned foreign inspections.● Names & contact details of inspectors.● List of competencies within each Inspectorate.● Local training events arranged by Inspectorates.● Database* &/or list of licensed manufacturers.● Rapid Alerts and Drug Recalls.● Surveillance activities.
* EudraGMP database is publicly accessible & searchable.
Slide 17
GMP Requirements of Different Countries
Slide 18
Country GMP CommentsAustralia & NZ PIC/S Older version applies (version PE 009-8)
ASEAN countries PIC/S Current version applies (version PE 009-9)
Taiwan PIC/S Current version applies (version PE 009-9)
Hong Kong WHO But will adopt PIC/S GMP in about 2 years
South Korea KGMP Presently filling gaps to be equivalent to PIC/S
Japan JGMP Presently filling gaps to be equivalent to PIC/S
China China GMP Based on EU & WHO GMPs
Singapore, Malaysia, Thailand, Indonesia, Philippines, Vietnam, Laos, Cambodia, Brunei.
Contains revised Annex 13 on “Manufacture of Investigational Medicinal Products”.
Top 10 GMP Deficiencies found by PIC/S Member Authorities
• Questionnaire sent to all PIC/S member authorities & applicant authorities in late 2011 seeking info. on: Top 10 most frequently cited GMP deficiencies. Top 10 most severe GMP deficiencies (critical &/or major).
• Period covered 1 July 2010 – 30 June 2011.
• Questionnaire limited to finished dosage forms (not APIs).• Responses:
29 (of 39) PIC/S member authorities provided data. 6 (of 9) applicant authorities provided data.
Slide 20
Source: Presentation by H. Smallenbroek (IGZ, Netherlands) & B. Meow Hoe (HSA, Singapore) on “Review of similarities & differences of top 10 deficiencies cited by PIC/S participating authorities”, PIC/S Seminar, Cape Town, Nov’11. Will be repeated (& further discussed) at PDA-PICS Workshop, Geneva 9-10 May 2012.
Top 10 Most Frequently Cited GMP Deficiencies (PIC/S Member Authorities)
(July 2010 – June 2011)
1. Documentation on manufacturing2. Design & maintenance of premises3. Documentation – quality systems elements/procedures4. Personnel issues – training5. Design & maintenance of equipment6. Cleaning validation7. Process validation8. Product Quality Review9. Supplier & contractor audit10. Calibration of measuring & testing equipment
Slide 21
Source: Presentation by H. Smallenbroek (IGZ, Netherlands) & B. Meow Hoe (HSA, Singapore) on “Review of similarities & differences of top 10 deficiencies cited by PIC/S participating authorities”, PIC/S Seminar, Cape Town, Nov’11. Will be repeated (& further discussed) at PDA-PICS Workshop, Geneva 9-10 May 2012.
Top 10 Most SevereGMP Deficiencies (PIC/S Member Authorities)
(July 2010 – June 2011)
1. Design & maintenance of premises2. Contamination, potential for (chemical, physical, microbial)3. Design & maintenance of equipment4. Sterility assurance5. Batch release procedures6. Process validation7. Cleaning validation8. Investigation of anomalies9. Documentation – quality systems elements/procedures10. Regulatory issues – noncompliance with marketing authorisation
Slide 22
Source: Presentation by H. Smallenbroek (IGZ, Netherlands) & B. Meow Hoe (HSA, Singapore) on “Review of similarities & differences of top 10 deficiencies cited by PIC/S participating authorities”, PIC/S Seminar, Cape Town, Nov’11. Will be repeated (& further discussed) at PDA-PICS Workshop, Geneva 9-10 May 2012.
Top Ten GMP Deficiencies found by MHRA (UK)(from MHRA web site Aug 2011)
1. Investigation of Anomalies
2. Quality management
3. Quality management (Change Control)
4. Validation Master Plan & Documentation
5. Corrective Action/Preventative Action (CAPA)
6. Complaints and Product Recall
7. Documentation
8. Equipment Validation
9. Quality Management –Product Quality Review
10. Investigation of Anomalies - OOS
Slide 23
Categories of US FDA Warning Lettersfor GMP non-compliance (2010)
%Records & reports 29
Production & process controls 26
Laboratory controls 17
Equipment 9
Control of components 6
Organisation & personnel 5
Packing & labelling controls 4
Building & facilities 3
Slide 24
Recent PIC/S Guidance Documents
• PIC/S Document PI 032-2Technical Interpretation of Revised Annex 1 to PIC/S GMP Guide.
• PIC/S Document PS/INF 1/2010Example of Quality Risk Management Implementation.
• PIC/S Document PI 038-1Aide-Memoire on Assessment of Quality Risk Management Implementation.
• PIC/S Document PI 037-1Recommended Model for Risk-Based Planning in the GMP Environment.
• PIC/S Document PS/INF 20/2011Q & A document regarding distribution activities for Active Pharmaceutical Ingredients (APIs).
• PIC/S Document PI 031-1SOP on Team Inspections.
• All available from: www.picscheme.org
Slide 25
Process of Amending the PIC/S GMP Guide
• PIC/S GMP Guide usually amended to mirror the amendments made to the EU GMP Guide.
• Usually a 12 months delay in making the amendments.• In past, PIC/S & EU GMP Guides have been very similar:
• Only differences:• The term “authorised person” used instead of “Qualified Person” (QP).• No Annex 16 (QP) in PIC/S GMP Guide.
• EMA & PIC/S have agreed to harmonise their GMP Guides & Guidance documents.
• However, some significant differences starting to appear.
Slide 26
Current Differences in Content of EU & PIC/S GMP Guides
Slide 27
PIC/S GMP Guide (Sept’09) EU GMP Guide (Feb’11)
Part IBasic Requirements for Med. Products
Part IBasic Requirements for Med. ProductsChapter 4 Documentation
Part IIBasic Requirements for APIs
Part IIBasic Requirements for APIs
No Part III Part IIISite Master FileQ9 - Quality Risk ManagementQ10 - Pharmaceutical Quality SystemsMRA Batch Certificate
Annexes1 – 20
Annexes1 – 19Annex 11: Computerised Systems
Specific Gaps
Part I , Part II & annexes
EU/EMA PIC/S
Part I -- Chapter 4 (Documentation)
Adopted and has come into operation on 30th June 2011.
TBA
Part II (API) – introduction of QM principles
Adopted and has come into operation on 31st July 2010.
TBA
Part III of the GMP guide Part III of GMP Guide was created and include:
Site Master File; ICH Q9; and ICH Q10
Site Master File: Formal integration into EU system PIC/S version of Site Master File approved and published by EC.
Specific Gaps
Part I , Part II & annexes EU/EMA PIC/SAnnex 6 (Manufacture of medicinal gases)
Adopted and has come into operation on 31st July 2010.
TBA
Annex 7 (Manufacture of herbal medicinal products)
Adopted and has come into operation on 1st September 2009.
TBA
Annex 11 (Computerised systems) Adopted and has come into operation on 30th June 2011.
TBA
Annex 13 (Manufacture of investigational medicinal products)
Adopted and has come into operation on 31st July 2010
TBA
Annex 14 (Manufacture of products derived from human blood or human plasma)
Adopted and has come into operation on 30th November 2011.
TBA
EU Chapter 4 Documentation
Critical documentation, including raw data (for example relating to validation or stability), which supports information in the Marketing Authorisation should be retained whilst the authorization remains in force. It may be considered acceptable to retire certain documentation (e.g. raw data supporting validation reports or stability reports) where the data has been superseded by a full set of new data. Justification for this should be documented and should take into account the requirements for retention of batch documentation; for example, in the case of process validation data, the accompanying raw data should be retained for a period at least as long as the records for all batches whose release has been supported on the basis of that validation exercise.
EU Chapter 4 DocumentationSection 4.29
There should be written policies, procedures, protocols, reports and the associated records of actions taken or conclusions reached, where appropriate, for the following examples:• Validation and qualification of processes, equipment and systems;• Equipment assembly and calibration;• Technology transfer; Maintenance, cleaning and sanitation;• Personnel matters including signature lists, training in GMP and
technical matters; clothing and hygiene and verification of the effectiveness of training. Environmental monitoring; Pest control; Complaints; Recalls; Returns; Change control; Investigations into deviations and non-conformances; Internal quality/GMP compliance audits; Summaries of records where appropriate (e.g. product quality review); Supplier audits.
Expected Changes to Part 1 of the PIC/S GMP Guide
NB: Changes are usually initiated by EMA and adopted by PIC/S soon after the EU GMP Guide is amended.
• The concepts of ICH Q10 (Quality Systems) to be incorporated into Chapter 1 of Part 1 of the GMP Guide. New sections will likely include: Pharmaceutical Quality Management System. Process Performance, Product Quality Monitoring System & Product Quality
Review. Management of Outsourced Activities and Purchased Materials. Management Review on the Quality Management System. Monitoring of Internal & External Factors Impacting the Quality Management
System. Outcomes of Management Reviews and Monitoring.
(NB: this drafting currently being undertaken by EMA)
Slide 32
Expected Changes Chapters 3 & 5of the PIC/S GMP Guide
Clarification of the GMP requirements for “certain highly active drugs” mentioned in clauses 3.6 & 5.18.
Likely approach:• Beta-lactam antibiotics & live pathogenic organisms to be
handled in dedicated facilities.• Shared facilities may be used for highly active drugs, provided:
• A formal assessment of the risks is undertaken.• Input from a toxicologist is involved in this assessment (risk ID stage).
• Detailed guidance on the toxicological assessment approach to be included as an Annex to the GMP Guide (probably voluntary).
• Draft of revision expected to be published later in 2012.
(NB: this drafting currently being undertaken by EMA)Slide 33
Expected Change to Chapter 5of the PIC/S GMP Guide
Additional requirements on “Qualification of Suppliers” in Chapter 5. Likely approach:
– Selection, qualification, approval and maintenance of suppliers to be part of a manufacturer’s Quality System.
– Supply chain traceability to be established & associated risks formally assessed and periodically verified (APIs & excipients).
– Audit API manufacturing facilities to confirm GMP compliance.– For each delivery of raw material (API & excipient) the containers to
be checked for integrity of package, including tamper evident seal.
– Clarification of analytical testing expectations of manufacturers with respect to raw materials.
(NB: this drafting currently being undertaken by EMA)
Slide 34
Expected Changes to other areasof the PIC/S GMP Guide
• Chapter 6 (Quality Control):Will identify minimal requirements for the transfer of analytical methods.
• Annex 15 (Qualification and Validation):Will maintain consistency with the new lifecycle approach to process validation and in light of ICH Q8, Q9 & Q10.
• Annex 17 (Parametric Release):Will provide more guidance on real time release testing.
• Part II (APIs):Will include references to QM & QRM.
(NB: this drafting currently being undertaken by EMA)
Slide 35
EU draft Guideline on Process Validation
• Issued 29 March 2012. • Harmonised with US
FDA lifecycle approach (of Jan’11), i.e. process design, process qualification, continual process verification.
• Regulators increasingly expect to see a lifecycle approach to validation.
Slide 36
Impact of US FDA’s PIC/S Membership
Observations:• Appears to be an increase in information-sharing:
Wider access to FDA database of inspections for PIC/S member authorities.
Inspection reports (non-redacted) provided on request.• Limited joint inspections.
Mainly restricted to program of API inspections arranged between FDA, EMA & TGA.
• Slow to recognise the inspection results of PIC/S member authorities (FDA overseas inspections continue).
• Some FDA guidance documents could eventually be adopted by PIC/S – and vice versa.
Slide 37
US FDA Issues“Global Engagement” Report (on 23.4.12)
(covers foods, drugs & medical devices)
Slide 38http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm301191.htm
FDA’s “Global Engagement” Report
Reasons:• Imports of drugs have grown rapidly over past 7 years, at about 13% per
year.• Mostly from low cost countries such as China & India.• Increasing risks of counterfeits, adulteration, diversion & fraud.• FDA lacks resources to inspect & monitor all overseas sites.Report Proposes:• Over next 12 months, partner with foreign counterparts to create a
“coalition of regulators” to build & strengthen the product safety net worldwide.
• Build a global data-information system & network and proactively share real-time data with other regulators.
• Use risk-based approaches to determine priorities.
Slide 39
Thank you for your time