pic vs pics presentation

Robert TribeFormer Chairman of PIC/S

Thai Pharmaceutical Industry Conference

Bangkok, 8 May 2006

Pharmaceutical Inspection Cooperation Scheme

2Overview

z Role & functions of PIC/Sz Benefits of PIC/S membershipz PIC/S GMP Guide & expected changesz PIC/S inspection proceduresz PIC/S deficiency classificationz PIC/S as a catalyst for harmonization

3PIC/S Goal

To lead the international development, implementation and maintenance of harmonised GMP standards and quality systems of inspectorates in the field of medicinal products.

4Achievement of the PIC/S Goal

PIC/S Goal is achieved by:z Developing and promoting harmonised GMP

standards and guidance documents.z Training competent authorities, in particular

GMP inspectors.z Assessing (and reassessing) GMP Inspectorates.z Facilitating the co-operation and networking for

competent authorities and international organisations.

5Main features of PIC/S

z Commenced operating on 2 Nov. 1995- Existed as PIC from Oct 1970 to Nov95

z A cooperative arrangement between GMP regulatory authorities; ie. not a legal treaty.

z A forum for:- networking and confidence building- Exchange of information and experience on GMP- Focus on Quality Systems for Inspectorates- Focus on training of inspectors- International harmonisation of GMP

z No obligation for member authorities to accept inspection reports of other members.

z PIC & PIC/S operate in parallel but jointly referred to as PIC/S.

6PIC versus PIC/S

PIC PIC/S

Convention SchemeBetween countries Between agenciesA formal treaty An informal arrangementHas legal status Has no legal statusFocus on inspections Focus on training & guidelinesMutual recognition Exchange of information

of inspections

7PIC/S 2006 Membership GMP Inspectorates of:

Australia Hungary PortugalAustria Iceland RomaniaBelgium Ireland SingaporeCanada Italy Slovak Rep.Czech Rep. (x2) Latvia SpainDenmark Liechtenstein SwedenFinland Malaysia SwitzerlandFrance Netherlands United KingdomGermany Norway UNICEF*Greece Poland

* Observer status

8CANADA

AUSTRALIA

2929 PIC/S PIC/S MembersMembers at at January 2006January 2006AUSTRALIA LIECHTENSTEINAUSTRIA MALAYSIA

BELGIUM NETHERLANDS

CANADA NORWAY

CZECH REPUBLIC (x2) POLAND

DENMARK PORTUGAL

FINLAND ROMANIA

FRANCE SINGAPORE

GERMANY SLOVAK REPUBLIC

GREECE SPAIN

HUNGARY SWEDEN

ICELAND SWITZERLAND

IRELAND UNITED KINGDOM

ITALY UNICEF

LATVIA

9Accession Dates (1)

Accession to PIC Accession to PIC/S

Austria May 1971 Nov 1999Denmark May 1971 Nov 1995Finland May 1971 Jan 1996Iceland May 1971 Nov 1995Liechtenstein May 1971 Nov 1995Norway May 1971 Nov 1995Portugal May 1971 Jan 1999Sweden May 1971 Feb 1996Switzerland May 1971 Feb 1996UK May 1971 Jun 1999Hungary Aug 1976 Dec 1995Ireland Dec 1977 Feb 1996Romania May 1982 Nov 1995Germany Sept 1883 Dec 2000Italy Aug 1990 Feb 2000

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Accessions Dates (2)

Accession to PIC Accession to PIC/S

Belgium Sep 1991 Feb 1997France Dec 1992 Feb 1997Australia Jan 1993 Nov 1995Netherlands - Nov 1995Czech Rep. - Jan 1997Slovak Rep. - Jan 1997Spain - Jan 1998Canada - Jan 1999Singapore - Jan 2000Greece - Jan 2002Malaysia - Jan 2002Latvia - Jan 2003Czech Rep (vet) - Jul 2005Poland - Jan 2006UNICEF (observer status) - Jan 2006

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How PIC/S Operates

Secretariat (Geneva based) Executive Bureau (Chairman, two Deputy Chairmen, two

Members of PIC/S Committee)

PIC/S Committee (usually the Chief Inspector of each Agency) Small Budget (members pay annual membership fee) Good relationships and collaboration (family atmosphere) Training opportunities (eg. Seminars, Joint visits) Information exchange (eg. inspection reports, Rapid Alerts) Development of GMP Guides & guidance documents

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Benefits of PIC/S Membership (1)

For Regulatory Authorities:z Accession forces improvements ie. Discipline.z Cost savings more effective use of resources.z Training (Seminars, Joint Inspections, etc.).z Involvement in developing international GMPs.z Promotion of harmonisation of GMP inspections.z Sharing of information & experiences.z Networking & personal contacts.

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Benefits of PIC/S Membership (2)

For Industry:z Reduced duplication of inspectionsz Cost savingsz Export facilitationz Enhanced market access

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Australian pharmaceutical exports

36,000 peopleAustralian pharmaceutical industry employed

$A15 billion in 2005Australian pharmaceutical industry turnover

Now ahead of wine exports

2nd only to export of automobiles in manufactured goods category

$A3 billion in 2005Australian manufactured pharmaceutical exports

Source: The Bulletin magazine, 14 February 2006, page 28.

Source: The Australian Pharmaceutical Industry and its Global Context, Working Paper No. 7, September 2002

Mr George Messinis, Centre for Strategic Economic Studies, Victoria University of Technology, Melbourne

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Applicants being assessed for PIC/S membership

z Argentinaz Estoniaz Israelz Lithuania

z Omanz Russiaz South Africaz Ukrainez US FDA

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Agencies showing interestin joining PIC/S

z Thailand (application lodged)z Indonesiaz Philippinesz Brazilz Cyprusz Sloveniaz Taiwan

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Accession Procedure

Essential Documents:z Pharmaceutical Inspection Cooperation Scheme

(PIC/S 1/95)

z Guidelines for Accession to PIC/S (PIC/S 1/98)z Application form and Questionnaire on National

Inspection Systems (PS 2/99-2)z Recommendations on quality system requirements

for pharmaceutical inspectorates (PI 002-2)

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Accession Procedure

Steps to Accessionz General interest & commitment, eg. attend Seminars.z Written application to Secretary + supporting

documents.z PIC/S Committee appoints Rapporteur to evaluate.z Applicant invited to Committee meeting to answer

questions of Rapporteur and Committee.z PIC/S delegation undertakes assessment visit

(assesses Inspectorates procedures & Quality System, & observe 3 or 4 inspections).

z Delegation report issued (to applicant & Committee).z Committee decides on membership.

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PIC/S GMP Guide (1)

z PIC/S GMP Guide to GMP for Medicinal Products(PE 009-3, 1 Jan 2006)z Chapter 1 revised to include Product Quality Review.

z Virtually identical to EC GMP Guide(main difference = Qualified Person vs authorised person)

z Plus Annexes, covering:Sterile Medicinal ProductsBiologicalsRadiopharmaceuticalsVeterinary medicinal productsMedicinal gasesHerbal medicinal products

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PIC/S GMP Guide (2)

Plus Annexes, covering: Sampling of starting & packaging materials Liquids, creams & ointments Metered dose aerosol products Computerised systems Ionising radiation Investigational Medicinal Products Products Derived from Human Blood or Plasma Qualification and Validation Parametric release

(PIC/S GMP Guide available at www.picscheme.org)

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PIC/S GMP Guide Future Changes Expected

z To be consistent with changes expected to be made to the EU GMP Guide:- Expansion of Chapter 6 to cover Ongoing Stability

Monitoring. * (expected to commence on 1.6.06).- Addition of a new Annex 19 covering Reference Samples &

Retention Samples.* (expected to commence on 1.6.06).- Revision of Annex 1 (cleanroom classification; aseptic filling).- Revision of Annexes 2, 3, 6 & 7 to provide supplementary

guidance on the PIC/S GMP Guide for APIs. **

* http://www.pharmacos.eudra.org/f2/eudralex/vol-4/home.htm** http://ww.emea.eu.int/Inspections/docs/CP%20A2to7.pdf

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Other PIC/S GMP Guides

z PIC/S GMP Guide for Blood Establishments(PE 005-2, 18 September 2004)

z PIC/S GMP Guide for APIs (identical to the ICH Q7A GMP Guide and Annex 18 to the EC GMP Guide)(PE 007-2, 25 October 2004)

(These GMP Guides available at www.picscheme.org)

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PIC/S Involvement in the ICH Q7A GMP Guide for APIs

z PIC/S Conference in Canberra 1996:- consensus obtained to prepare international GMP.

z PIC/S draft document prepared during 97 & 98.z ICH Q7 took over the work of PIC/S mid-1998 to

enable industry to become involved:- ICH involves 3 regions (USA, Europe & Japan).

z ICH GMP Guide finalised in November 2000 after extensive public consultation.

z Most countries have adopted the ICH document as a GMP requirement for APIs.

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Some PIC/S Recommendation & Guidance Documents

z Validation (master plan, IQ/OQ, process, cleaning)z Validation of Aseptic Processesz Inspection of Isolator Technologyz Sterility Testingz Parametric releasez Guidance on Good Practices for Computerised Systems

in Regulating GXP Environmentsz Aide-memoire Inspection of Utilitiesz Quality Systems for Inspectoratesz SOP on PIC/S inspection report formatz SOP on Rapid Alerts

All available at www.picscheme.org

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PIC/S Guidance Documents issued on 1 January 2006

z Aide-memoire on the inspection of pharmaceutical QC laboratories.

z Aide-memoire on the inspection of manufacturers of clinical trial products.

z Aide-memoire on the inspection of biotechnology manufacturers.

Available at www.picscheme.org

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PIC/S Training Tools for GMP Inspectors

z Training Seminars (one per year)

z Joint Visits Groups

z Expert Circle meetings

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Recent PIC/S Seminars

Manufacture of Sterile Products Iceland, 1995Computer Systems Australia, 1996GMP Standards for APIs Australia, 1996Manufacture & Inspection of APIs Finland, 1997Quality Systems for Inspectorates Netherlands, 1998Non-technical Aspects of Inspection UK, 1999Biotechnology France, 2000Inspection of Utilities Czech Rep, 2001 Interface between GCP and GMP Canada, 2002Inspection of QC laboratories Slovak Rep, 2003Inspection of APIs Spain, 2004Primary Packaging Material, labelling &Prevention of mix-ups Romania, 2005

(Booklets/CDs of Seminar proceedings available for purchase)

Representatives from Indonesia and Turkey participating in the PIC Seminar on Computer Systems, Sydney, September 1996

1996 Seminar, Sydney: 90 participants from 30 different countries

2004 Seminar, Spain: 103 participants from 41 different countries

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Future PIC/S Seminars

z Risk management Germany, 2006

z Inspection of solid dosage forms Singapore, 2007

z Good Wholesaling Practices Latvia, 2008

(NB: Open to GMP inspectors only)

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Expert Circle Groups

z Medicinal Gasesz Human Blood and Tissuesz Hospital Pharmacyz Biotechnologyz Computerized systemz APIs

Aim: - Develop draft guidance documents- Training in specialized field

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PIC/S Joint Visits

z Started in 1987.z About 30 groups, with each group comprising

3 inspectors from 3 different countries.z 1 inspection per year per countryz Benefits:

- for training purposes- for uniform GMP interpretation- for uniform inspection procedures- for mutual confidence

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PIC/S Relationship with EU

z EMEA representative attends PIC/S Committee meetings as an observer

z PIC/S-EU liaison officer attends EU Inspectors meetings at EMEA as an observer

z A harmonised consultation procedure:- EU & PIC/S usually adopt each others GMP Guides

& guidance documents

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PIC/S Liaison with other organisations

z WHO:- prequalification of essential drugs for WHO priority

programmes (HIV/AIDS, malaria, TB, etc.); assist with WHOs GMP inspections, etc.

z EDQM- The European Department for the Quality of Medicines: for

training purposes; assist with API inspections, etc.

z ICH,- API GMP Guide; Q9 Quality Risk Management Guideline

z UNICEF- Assist with UNICEFs GMP inspections

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Quality System requirements for Pharmaceuticals Inspectorates (1)

z Reference document : PI 002-2, 1 October 2004z Purpose is to adopt a common standard for Quality

System requirements in order to:- achieve consistency in inspection standards between

PIC/S member authorities, &- thus help facilitate mutual recognition of inspections.

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Main Topics:z Quality Manualz Administrative Structurez Organisation and Managementz Documentation and Change Controlz Recordsz Inspection Proceduresz Inspection Resourcesz Internal Audit

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Main Topics (contd):z Quality Improvement and Corrective/Preventive Actionz Complaints z Issue and Withdrawal of Licences & GMP Certificatesz Handling of Suspected Quality defects & Rapid Alert Systemz Liaison with Official Medicine Control Laboratoryz Subcontracting and Assessingz Publications

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Joint Reassessment Program

Goals

z To verify that PIC/S member authorities maintain compliance with the requirements of the Scheme (as described in paragraph 8 of the Scheme [PIC/S 1/95 modified]).

z To verify the implementation of PIC/S QualitySystem Requirements for Inspectorates.

z To help maintain consistency among PIC/S memberauthorities.

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Typical PIC/S Inspection of a Medicine Manufacturer

Before the inspection:z The need for inspection determined from computerised

schedule.- Inspection frequency based on various risk factors, eg. product

types, result of last audit, complaints/recalls, testing failures, etc.z Lead inspector assigned.z Inspection team selected.z Company notified (typically 1 weeks notice, but unannounced inspection

may be undertaken).z Inspection team reviews documentation on file:

- Site Master File, marketing authorisations, etc.- Complaints, recalls, product testing results, etc.- Last inspection report.

z Lead inspector prepares inspection plan (sent to company).z Inspection conducted.

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Typical PIC/S Inspection (contd)

After the inspection:z Caucus of inspection team (on site).z Deficiency report prepared on-site (some PIC/S members only).

- Deficiencies classified into Critical, Major & Other.z Closing meeting with company:

- attendance sheet completed.- Deficiency Report given to company. - discussion encouraged. - Written response requested within 4 weeks.

z Objective evidence of corrective action assessed by lead inspector.z If response judged OK, inspection closed out.z If response not OK, refer to independent committee.z Final Inspection Report prepared & sent to company after review by

an inspection manager.- This contains summary of inspection findings (+ve & -ve observations)

and conclusion of inspection.

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PIC/S Classification of GMP deficiencies

Critical Deficiency

A deficiency that has produced, or may result in a significant risk of producing, a product that is harmful to the user.

(A critical deficiency is a serious situation that will result in regulatory action being considered and a definite connection between the deficiency and a harmful product must be able to be reasonably made. If this connection cannot be reasonably made, the deficiency should be recorded as major).

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Examples of Critical GMP Deficiencies

Some Examples of Critical Deficiencies:z no or grossly inadequate air filtration to minimise airborne

contaminants.z lack of sterilisation validation.z inadequate segregation of manufacturing of high risk products, such

as penicillins, cephalosporins, antineoplastics, steroids, hormones, resulting in a risk of contamination.

z cleaning program not followed combined un-validated cleaning procedures and evidence of dirty premises/equipment.

z evidence of gross pest infestation.z falsification or misrepresentation of analytical results.z raw materials not tested (including proper identification testing) to

ensure compliance with specifications.z no master batch documents.

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Major Deficiency

A non-critical deficiency that:z has produced or may produce a product which does not comply

with its marketing authorisation; and/orz indicates a major deviation from the Code of GMP; and/orz indicates a major deviation from the terms of the

manufacturing licence or GMP approval (overseas manufacturers); and/or

z indicates a failure to carry out satisfactory procedures for release of batches; and/or

z indicates a failure of the person responsible for QA/QC to fulfil his/her duties; and/or

z consists of several other deficiencies, none of which on its ownmay be major, but which may together represent a major deficiency and should be explained and reported as such.

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Examples of Major GMP Deficiencies

Some Examples of Major Deficiencies:z damage (holes, cracks, peeling paint) to walls/ceilings in manufacturing

areas where product is exposedz design of manufacturing area that does not permit effective cleaningz insufficient manufacturing space that could lead mix-upsz no raw material sampling areaz sanitary fittings not used on liquid/cream manufacturing equipmentz stored equipment not protected from contaminationz inadequate initial and ongoing training and/or no training recordsz cleaning procedures not documented and/or no cleaning recordsz production equipment cleaning procedures not validatedz reduced QC testing of raw materials without data to certify suppliersz incomplete testing of raw materialsz test methods not validated

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Other Deficiency (or Minor Deficiency)

z A deficiency that cannot be classified as either critical or major, but indicates a departure from good manufacturing practice.

z A deficiency may be other either because it is judged as minor, or because there is insufficient information to classify it as major or critical.

z One-off minor lapses or less significant issues are usually not formally reported, but are brought to the attention of the manufacturer.

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Examples of Other GMP Deficiencies

Examples of Other Deficiencies:z Use of white-out correction fluid on manufacturing

documents.z Person making alteration to batch document did not initial

the change.z Equipment not calibrated by the due date

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PIC/S Inspection report Format

z Described in PIC/S Inspection report Format, SOP PI-013-2, 1 July 2004.

z This covers: Summary of inspection activities Inspection observations (+ve) Deficiencies (-ve) Assessment of SMF Summary of GMP compliance status

z Identical to the format used by EU Inspectorates

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GMP Serving Public Safety

Some useful Truisms/Clichs related to GMP:

If you do it, document it If you document it, do it If it isnt written down, it never happened

The quality of the product ultimately depends upon the quality of the people involved in its control and manufactureSir Derrick Dunlop (Davenport Incident Enquiry)

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Recent Developments

z FDA applies for PIC/S membership (Sept05).z Poland became member on 1.1.06.z UNICEF became observer on 1.1.06.z PIC/S web site upgraded.z PIC/S Blueprint issued.z New Executive Bureau:

- Chairman J Morenas (France)- 1st Dep. Chairman J Kurz (Austria)- 2nd Dep. Chairman M Keller (Switzerland)- Member E Pelkonen (Finland)- Member P Hargraeves (UK)

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PIC/S Blueprint (issued on 23.12.05)

z A roadmap for PIC/S for the next decade.z A prospective and retrospective paper reviewing

PIC/S mandates and goals in a changing environment.

z Sets out a number of objectives and actions for the next 10 years.

z Aims to raise PIC/S visibility and explain the benefits of PIC/S membership.

z Aims to make PIC/S more of a global organisation rather than European focussed.

Available from: www.picscheme.org

www.picscheme.org

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PIC/S A Catalyst for Harmonization

z Strengths of PIC/S:- Large membership which is increasing rapidly.- Criteria for membership is uniformly high.- Focus is on training of GMP inspectors.- Contributes to the development and revision of GMP Guides

& guidance documents.z PIC/S therefore in a good position to:

- Establish and maintain a uniformly high benchmark for all Inspectorates to meet.

- Improve uniformity of GMP inspections (training & guidance).- Help facilitate the harmonization of GMP inspection

standards internationally.- Help reduce the duplication of inspections.

Summary

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PIC/S contact details

PIC/S SecretariatP.O. Box 5695CH - 1211 GENEVA 11

Tel: +41.22.7389216Fax: +41.22.7389217Email: [email protected] site: www.picscheme.org

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And FinallyAnd Finally

Thank YouThank You

Any Questions?Any Questions?