Pharmaceutical Inspection

Cooperation Scheme
Thai Pharmaceutical Industry
Conference
Bangkok, 8 May 2006

Robert Tribe
Former Chairman of PIC/S

Overview

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Role & functions of PIC/S

Benefits of PIC/S membership
PIC/S GMP Guide & expected changes
PIC/S inspection procedures
PIC/S deficiency classification
PIC/S as a catalyst for harmonization

PIC/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.

Achievement 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.
4

Main features of PIC/S

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Commenced operating on 2 Nov. 1995

Existed as PIC from Oct 1970 to Nov95

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

A cooperative arrangement between GMP

regulatory authorities; ie. not a legal treaty.
A forum for:

No obligation for member authorities to accept

inspection reports of other members.
PIC & PIC/S operate in parallel but jointly
referred to as PIC/S.

PIC versus PIC/S

PIC
Convention
Between countries
A formal treaty
Has legal status
Focus on inspections
Mutual recognition
of inspections
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PIC/S
Scheme
Between agencies
An informal arrangement
Has no legal status
Focus on training & guidelines
Exchange of information

PIC/S 2006 Membership

GMP Inspectorates of:
Australia
Austria
Belgium
Canada
Czech Rep. (x2)
Denmark
Finland
France
Germany
Greece
7

Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Malaysia
Netherlands
Norway
Poland

Portugal
Romania
Singapore
Slovak Rep.
Spain
Sweden
Switzerland
United Kingdom
UNICEF*
* Observer status

29 PIC/S Members at January 2006

CANADA

AUSTRALIA

LIECHTENSTEIN

AUSTRIA

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

AUSTRALIA

Accession Dates

(1)

Accession to PIC

Austria
Denmark
Finland
Iceland
Liechtenstein
Norway
Portugal
Sweden
Switzerland
UK
Hungary
Ireland
Romania
Germany
Italy

May 1971
May 1971
May 1971
May 1971
May 1971
May 1971
May 1971
May 1971
May 1971
May 1971
Aug 1976
Dec 1977
May 1982
Sept 1883
Aug 1990

Accession to PIC/S
Nov 1999
Nov 1995
Jan 1996
Nov 1995
Nov 1995
Nov 1995
Jan 1999
Feb 1996
Feb 1996
Jun 1999
Dec 1995
Feb 1996
Nov 1995
Dec 2000
Feb 2000

Accessions Dates

(2)

Accession to PIC

10

Belgium
Sep 1991
France
Dec 1992
Australia
Jan 1993
Netherlands
Czech Rep.
Slovak Rep.
Spain
Canada
Singapore
Greece
Malaysia
Latvia
Czech Rep (vet)
Poland
UNICEF (observer status) -

Accession to PIC/S
Feb 1997
Feb 1997
Nov 1995
Nov 1995
Jan 1997
Jan 1997
Jan 1998
Jan 1999
Jan 2000
Jan 2002
Jan 2002
Jan 2003
Jul 2005
Jan 2006
Jan 2006

How PIC/S Operates

Secretariat (Geneva based)
Executive Bureau (Chairman, two Deputy Chairmen, two
Members of PIC/S Committee)

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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

Benefits of PIC/S Membership

(1)

For Regulatory Authorities:

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Accession forces improvements ie. Discipline.

Cost savings more effective use of resources.
Training (Seminars, Joint Inspections, etc.).
Involvement in developing international GMPs.
Promotion of harmonisation of GMP inspections.
Sharing of information & experiences.
Networking & personal contacts.

Benefits of PIC/S Membership

(2)

For Industry:
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Reduced duplication of inspections

Cost savings
Export facilitation
Enhanced market access

Australian pharmaceutical exports

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Australian manufactured
pharmaceutical exports

$A3 billion in 2005

2nd only to export of automobiles in

manufactured goods category

Now ahead of wine

exports

Australian pharmaceutical industry

turnover

$A15 billion in 2005

Australian pharmaceutical industry

employed

36,000 people

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

Applicants being assessed

for PIC/S membership

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Argentina
Estonia
Israel
Lithuania

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Oman
Russia
South Africa
Ukraine
US FDA

Agencies showing interest

in joining PIC/S

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Thailand (application lodged)

Indonesia
Philippines
Brazil
Cyprus
Slovenia
Taiwan

Accession Procedure
Essential Documents:
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Pharmaceutical Inspection Cooperation Scheme

Guidelines for Accession to PIC/S (PIC/S 1/98)

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(PIC/S 1/95)

Application form and Questionnaire on National

Inspection Systems (PS 2/99-2)
Recommendations on quality system requirements
for pharmaceutical inspectorates (PI 002-2)

Accession Procedure
Steps to Accession
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General interest & commitment, eg. attend Seminars.

Written application to Secretary + supporting
documents.
PIC/S Committee appoints Rapporteur to evaluate.
Applicant invited to Committee meeting to answer
questions of Rapporteur and Committee.
PIC/S delegation undertakes assessment visit
(assesses Inspectorates procedures & Quality System, &
observe 3 or 4 inspections).

Delegation report issued (to applicant & Committee).

Committee decides on membership.

PIC/S GMP Guide

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PIC/S GMP Guide to GMP for Medicinal Products

(PE 009-3, 1 Jan 2006)
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(1)

Chapter 1 revised to include Product Quality Review.

Virtually identical to EC GMP Guide

Plus Annexes, covering:

(main difference = Qualified Person vs authorised person)

Sterile Medicinal Products
Biologicals
Radiopharmaceuticals
Veterinary medicinal products
Medicinal gases
Herbal medicinal products

PIC/S GMP Guide

(2)

Plus Annexes, covering:

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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)

PIC/S GMP Guide

Future Changes Expected

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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

Other PIC/S GMP Guides

PIC/S GMP Guide for Blood Establishments

(PE 005-2, 18 September 2004)

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
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PIC/S Conference in Canberra 1996:

- consensus obtained to prepare international GMP.

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PIC/S draft document prepared during 97 & 98.

ICH Q7 took over the work of PIC/S mid-1998 to
enable industry to become involved:
- ICH involves 3 regions (USA, Europe & Japan).

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ICH GMP Guide finalised in November 2000 after

extensive public consultation.
Most countries have adopted the ICH document
as a GMP requirement for APIs.

Some PIC/S Recommendation

& Guidance Documents
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Validation (master plan, IQ/OQ, process, cleaning)

Validation of Aseptic Processes
Inspection of Isolator Technology
Sterility Testing
Parametric release
Guidance on Good Practices for Computerised Systems
in Regulating GXP Environments
Aide-memoire Inspection of Utilities
Quality Systems for Inspectorates
SOP on PIC/S inspection report format
SOP on Rapid Alerts
All available at www.picscheme.org

PIC/S Guidance Documents

issued on 1 January 2006

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Aide-memoire on the inspection of

pharmaceutical QC laboratories.
Aide-memoire on the inspection of
manufacturers of clinical trial products.
Aide-memoire on the inspection of
biotechnology manufacturers.
Available at www.picscheme.org

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PIC/S Training Tools for

GMP Inspectors

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Training Seminars (one per year)

Joint Visits Groups

Expert Circle meetings

Recent PIC/S Seminars

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

Future PIC/S Seminars

Risk management

Germany, 2006

Inspection of solid dosage forms

Singapore, 2007

Good Wholesaling Practices

Latvia, 2008

(NB: Open to GMP inspectors only)

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Expert Circle Groups

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Medicinal Gases
Human Blood and Tissues
Hospital Pharmacy
Biotechnology
Computerized system
APIs

Aim: - Develop draft guidance documents

- Training in specialized field
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PIC/S Joint Visits

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Started in 1987.
About 30 groups, with each group comprising
3 inspectors from 3 different countries.
1 inspection per year per country
Benefits:

for
for
for
for

training purposes
uniform GMP interpretation
uniform inspection procedures
mutual confidence

PIC/S Relationship with EU

EMEA representative attends PIC/S

Committee meetings as an observer
PIC/S-EU liaison officer attends EU
Inspectors meetings at EMEA as an observer
A harmonised consultation procedure:

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EU & PIC/S usually adopt each others GMP Guides

& guidance documents

PIC/S Liaison with

other organisations
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WHO:
- prequalification of essential drugs for WHO priority

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

GMP inspections, etc.

EDQM
- The European Department for the Quality of Medicines:
training purposes; assist with API inspections, etc.

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ICH,
- API GMP Guide; Q9 Quality Risk Management Guideline
UNICEF
- Assist with UNICEFs GMP inspections

for

Quality System requirements

for Pharmaceuticals Inspectorates

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Reference document : PI 002-2, 1 October 2004

Purpose is to adopt a common standard for Quality
System requirements in order to:

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(1)

achieve consistency in inspection standards between

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

Quality System requirements

for Pharmaceuticals Inspectorates

Main Topics:
z Quality Manual
z Administrative Structure
z Organisation and Management
z Documentation and Change Control
z Records
z Inspection Procedures
z Inspection Resources
z Internal Audit
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(2)

Quality System requirements

for Pharmaceuticals Inspectorates

(3)

Main Topics (contd):

z Quality Improvement and Corrective/Preventive Action
z Complaints
z Issue and Withdrawal of Licences & GMP Certificates
z Handling of Suspected Quality defects & Rapid Alert System
z Liaison with Official Medicine Control Laboratory
z Subcontracting and Assessing
z Publications
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Joint Reassessment Program

Goals
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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]).

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To verify the implementation of PIC/S Quality

System Requirements for Inspectorates.
To help maintain consistency among PIC/S member
authorities.

Typical PIC/S Inspection

of a Medicine Manufacturer
Before the inspection:
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The need for inspection determined from computerised

schedule.

Lead inspector assigned.

Inspection team selected.
Company notified (typically 1 weeks notice, but unannounced inspection

Inspection team reviews documentation on file:

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Inspection frequency based on various risk factors, eg. product

types, result of last audit, complaints/recalls, testing failures, etc.

may be undertaken).

Site Master File, marketing authorisations, etc.

Complaints, recalls, product testing results, etc.
Last inspection report.

Lead inspector prepares inspection plan (sent to company).

Inspection conducted.

Typical PIC/S Inspection

(contd)

After the inspection:

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Caucus of inspection team (on site).

Deficiency report prepared on-site (some PIC/S members only).

Closing meeting with company:

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Deficiencies classified into Critical, Major & Other.

attendance sheet completed.

Deficiency Report given to company.
discussion encouraged.
Written response requested within 4 weeks.

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

and conclusion of inspection.

Objective evidence of corrective action assessed by lead inspector.

If response judged OK, inspection closed out.
If response not OK, refer to independent committee.
Final Inspection Report prepared & sent to company after review by
an inspection manager.

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:
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no or grossly inadequate air filtration to minimise airborne

contaminants.
lack of sterilisation validation.
inadequate segregation of manufacturing of high risk products, such
as penicillins, cephalosporins, antineoplastics, steroids, hormones,
resulting in a risk of contamination.
cleaning program not followed combined un-validated cleaning
procedures and evidence of dirty premises/equipment.
evidence of gross pest infestation.
falsification or misrepresentation of analytical results.
raw materials not tested (including proper identification testing) to
ensure compliance with specifications.
no master batch documents.

PIC/S Classification of GMP deficiencies

Major Deficiency
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A non-critical deficiency that:

has produced or may produce a product which does not comply
with its marketing authorisation; and/or
indicates a major deviation from the Code of GMP; and/or
indicates a major deviation from the terms of the
manufacturing licence or GMP approval (overseas
manufacturers); and/or
indicates a failure to carry out satisfactory procedures for
release of batches; and/or
indicates a failure of the person responsible for QA/QC to
fulfil his/her duties; and/or
consists of several other deficiencies, none of which on its own
may be major, but which may together represent a major
deficiency and should be explained and reported as such.

Examples of Major GMP Deficiencies

Some Examples of Major Deficiencies:

z damage

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(holes, cracks, peeling paint) to walls/ceilings in manufacturing

areas where product is exposed
z design of manufacturing area that does not permit effective cleaning
z insufficient manufacturing space that could lead mix-ups
z no raw material sampling area
z sanitary fittings not used on liquid/cream manufacturing equipment
z stored equipment not protected from contamination
z inadequate initial and ongoing training and/or no training records
z cleaning procedures not documented and/or no cleaning records
z production equipment cleaning procedures not validated
z reduced QC testing of raw materials without data to certify suppliers
z incomplete testing of raw materials
z test methods not validated

PIC/S Classification of GMP deficiencies

Other
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Deficiency (or Minor Deficiency)

A deficiency that cannot be classified as either critical or

major, but indicates a departure from good manufacturing
practice.
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.
One-off minor lapses or less significant issues are usually not
formally reported, but are brought to the attention of the
manufacturer.

Examples of Other GMP Deficiencies

Examples of Other Deficiencies:

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Use of white-out correction fluid on manufacturing

documents.
Person making alteration to batch document did not initial
the change.
Equipment not calibrated by the due date

PIC/S Inspection report Format

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Described in PIC/S Inspection report Format,

SOP PI-013-2, 1 July 2004.
This covers:

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Summary of inspection activities

Inspection observations (+ve)
Deficiencies (-ve)
Assessment of SMF
Summary of GMP compliance status

Identical to the format used by EU Inspectorates

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 manufacture
Sir Derrick Dunlop (Davenport Incident Enquiry)

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Recent Developments
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FDA applies for PIC/S membership (Sept05).

Poland became member on 1.1.06.
UNICEF became observer on 1.1.06.
PIC/S web site upgraded.
PIC/S Blueprint issued.
New Executive Bureau:

Chairman
1st Dep. Chairman
2nd Dep. Chairman
Member
Member

J Morenas (France)
J Kurz (Austria)
M Keller (Switzerland)
E Pelkonen (Finland)
P Hargraeves (UK)

PIC/S Blueprint
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(issued on 23.12.05)

A roadmap for PIC/S for the next decade.

A prospective and retrospective paper reviewing
PIC/S mandates and goals in a changing
environment.
Sets out a number of objectives and actions for
the next 10 years.
Aims to raise PIC/S visibility and explain the
benefits of PIC/S membership.
Aims to make PIC/S more of a global organisation
rather than European focussed.
Available from: www.picscheme.org

www.picscheme.org

Summary
PIC/S A Catalyst for Harmonization
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Strengths of PIC/S:

PIC/S therefore in a good position to:

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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.

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.

PIC/S contact details

PIC/S Secretariat
P.O. Box 5695
CH - 1211 GENEVA 11
Tel:
Fax:
Email:
Web site:
62

+41.22.7389216
+41.22.7389217
daniel.brunner@picscheme.org
www.picscheme.org

And Finally

Thank You
Any Questions?
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