national validation forum ii - pharmout€¦ · pic/s gmp guide (sept’09) eu gmp guide (feb’11)...

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

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

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:

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


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


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.


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.


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