Updates on PIC/S GMP Standard including Site Master File Guidance

Updates on PIC/S GMP Standard including Site Master File guidance

Good Manufacturing Practice for Medicinal Products Manufacturers

including Site Master File guidance

Presented by:Boon Meow Hoe, Dy Director / Senior GMP Auditor,

Overseas Audit Unit(OAU), Audit Branch (AB)

Audit & Licensing Division (ALD)Health Product Regulatory Group (HPRG)

Health Sciences Authority )HSA)

1

TopicsTopics

(A) An update on PIC/S memberships

(B) PIC/S publications

(C) An update on proposed revision to PIC/S GMP Guide in the pipeline…� in the PIC/S pipeline� in the PIC/S pipeline

� In the EMA (EU) pipeline

(D) Site Master File

(E) Q&A. Discussion

2

An Update on PIC/S MembershipAn Update on PIC/S MembershipAn Update on PIC/S MembershipAn Update on PIC/S Membership

3

PIC/S MembershipPIC/S MembershipSlovenia / Agency for Medicinal Products and Medical Devices (JAZMP)

Submitted & accepted Membership Accession Application on 28 Oct 2008

At last PIC/S COMMITTEE OF OFFICIALS MEETING held on 7 & 8 November 2011 at South Africa/Cape Town, PIC/S accepted Slovenia November 2011 at South Africa/Cape Town, PIC/S accepted Slovenia / JAZMP to join the PIC/S Scheme with effect from 1 January 2012.

40 YEARS ANNIVERSARY AND 40th MEMBERS WITH THE ACCESSION OF SLOVENIA / JAZMP

4

To-date: PIC/S has 40 participating authorities (38 Countries)

Austria

Belgium

Cyprus

Czech Republic

Denmark

Estonia

Latvia

Lithuania

Malta

Netherlands

Poland

Portugal

Switzerland

Ukraine

Norway

Liechtenstein

IcelandSouth Africa

Israel

Estonia

Finland

France

Germany

Greece

Hungary

Ireland

Italy

Romania

Slovakia

Slovenia

Spain

Sweden

United Kingdom

Argentina

Canada

USA

Australia

Singapore

Malaysia

5

SINGAPORE

CANADA

40 PIC/S Members – January 2012

USA

Slovenia

AUSTRALIA

ARGENTINA SOUTH AFRICA

MALAYSIA

ISRAEL

UKRAINE

6

PIC/S PublicationsPIC/S Publications

7

Documents for industry

� PIC/S GMP Guide

� Site Master Files

Documents for inspectorates

� Inspectorates

Documents for inspectors

� Q&A Documents

� Aide-Memoires

Current PIC/S Publications Current PIC/S Publications

� Aide-Memoires

� Guidance documents

Documents for the public

� Information documents

� Press Release

� PIC/S Seminars

� Miscelleneous

8

Documents for industry

� PIC/S GMP Guide� PE 009-9 ZIP-File

PIC/S GMP GUIDE 2009-09-01

� PE 009-9 (Intro)

PIC/S GMP GUIDE (INTRODUCTION) 2009-09-01

� PE 009-9 (Part I)PIC/S GMP GUIDE (PART I: BASIC REQUIREMENTS FOR MEDICINAL PRODUCTS) 2009-09-01

Current PIC/S Publications (Conti.) Current PIC/S Publications (Conti.)

� PE 009-9 (Part II)

PIC/S GMP GUIDE (PART II: BASIC REQUIREMENTS FOR ACTIVE PHARMACEUTICAL INGREDIENTS) 2009-09-01

� PE 009-9 (Annexes)PIC/S GMP GUIDE (ANNEXES) 2009-09-01

� Site Master Files� PE 008-4

EXPLANATORY NOTES FOR INDUSTRY ON THE PREPARATION OF A SITE MASTER FILE 2011-02-15

� PI 019-3SITE MASTER FILE FOR SOURCE PLASMA ESTABLISHMENTS 2007-09-26

� PI 020-3SITE MASTER FILE FOR PLASMA WAREHOUSES 2007-09-25

9

Documents for inspectorates

� Inspectorates

� PICS 1/95 (Rev 5)PIC/S SCHEME 2012-01-12

� PS/INF 21/2002 (Rev 13)PARTICIPATING AUTHORITIES & PARTNERS 2012-01-13

� PIC ConventionPIC CONVENTION 2006-12-07

� PI 002-3QUALITY SYSTEM REQUIREMENTS FOR PHARMACEUTICAL INSPECTORATES 2007-09-25

Current PIC/S Publications (Conti.)Current PIC/S Publications (Conti.)

QUALITY SYSTEM REQUIREMENTS FOR PHARMACEUTICAL INSPECTORATES 2007-09-25

� PI 010-4PROCEDURE FOR HANDLING RAPID ALERTS AND RECALLS ARISING FROM

QUALITY DEFECTS 2010-12-21

� PI 013-3STANDARD OPERATING PROCEDURE PIC/S INSPECTION REPORT FORMAT 2007-09-25

� PI 031-1STANDARD OPERATING PROCEDURE TEAM INSPECTIONS 2012-01-13

� PI 037-1PIC/S RECOMMENDATION ON RISK-BASED INSPECTION PLANNING 2012-01-16

10

Documents for inspectors

� Q&A Documents� PS INF 20 2011 QA DISTRIBUTION ACTIVITIES FOR APIs - MAY 2010 2011-04-06

� Aide-Memoires� PI 009-3 AIDE-MEMOIRE INSPECTION OF UTILITIES 2007-09-25

� PI 021-2 AIDE MEMOIRE ON GMP PARTICULARITIES FOR CLINICAL TRIAL PRODUCTS 2007-09-26

� PI 023-2 AIDE MEMOIRE ON INSPECTION OF QUALITY CONTROL LABORATORIES 2007-09-25

� PI 024-2 AIDE MEMOIRE ON INSPECTION OF BIOTECH 2007-09-25

� PI 025-2 AIDE-MEMOIRE ON MEDICINAL GASES 2007-09-25

� PI 028-1 AIDE-MEMOIRE ON PACKAGING (Entry into force on 1 March 2009) 2009-01-21

Current PIC/S Publications (Conti.) Current PIC/S Publications (Conti.)

� PI 030-1 AIDE-MEMOIRE ON THE INSPECTION OF APIS 2009-01-21

� Guidance documents– Technical guides

� PE 005-3 PIC/S GMP GUIDE FOR BLOOD ESTABLISHMENTS 2007-09-27

� PE 010-3 GUIDE TO GOOD PRACTICES FOR THE PREPARATION OF MEDICINAL

PRODUCTS IN HEALTHCARE ESTABLISHMENTS (PE 010-3) 2008-10-01

� PI 005-3 GUIDANCE ON PARAMETRIC RELEASE 2007-09-27

� PI 006-3 VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION

NON-STERILE PROCESS VALIDATION CLEANING VALIDATION 2007-09-25

� PI 007-6 VALIDATION OF ASEPTIC PROCESSES 2010-12-21

� PI 008-3 PIC/S GUIDE TO INSPECTIONS OF SOURCE PLASMA ESTABLISHMENTS AND

PLASMA WAREHOUSES (INSPECTION GUIDE) 2007-09-25

� PI 011-3 GOOD PRACTICES FOR COMPUTERISED SYSTEMS IN REGULATED GXP ENVIRONMENTS 2007-09-25

� PI 012-3 RECOMMENDATION ON STERILITY TESTING 2007-09-25

� PI 014-3 ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING 2007-09-25

� PI 032-2 TECHNICAL INTERPRETATION OF REVISED ANNEX 1 TO PIC/S GMP GUIDE 2010-01-0811

Documents for the public

� Information Documents

� PIC/S BROCHURE MAY 2011 EDITION 2011-06-09

� PS W 8 2005 PIC/S BLUEPRINT 2006-05-02

� Press Releases (e.g.)

� PR Nov 2011 PRESS RELEASE NOVEMBER 2011 2011-11-18

� PR 02 Jun 2011 PRESS RELEASE NO 2 JUNE 2011 2011-06-09

� PR 01 Jun 2011 PRESS RELEASE NO 1 JUNE 2011 2011-06-09

� Annual Reports


� Annual Reports

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Documents for the public� PIC/S Seminars� B 028 THE INTERFACE BETWEEN GOOD CLINICAL PRACTICES AND MANUFACTURING PRACTICES 2004-10-

27 (Montebello, Canada, October 2002)

� SB 029 THE INSPECTION OF QUALITY CONTROL LABORATORIES 2004-10-27 (Bratislava, Slovak Republic, June 2003)

� SB 030 THE INSPECTION OF API MANUFACTURERS 2007-01-17 (El Vendrell, Spain, June 2004)

� SB 031 PRIMARY PACKAGING MATERIAL, LABELLING & PREVENTION OF MIX-UPS 2007-01-17 (Bucharest, Romania, September 2005)

� SB 032 QUALITY RISK MANAGEMENT AND RELATED ICH TOPICS 2007-01-17 (Düsseldorf, Germany, 31 May - 2 June 2006)

� SB 033 INSPECTION OF MANUFACTURERS OF SOLID DOSAGE FORMS 2008-01-30 (Singapore, November 2007)

� SB 034 GOOD DISTRIBUTION PRACTICES 2008-10-15 (Krakow, Poland, May 2008)

� SB 035 ASEPTIC & STERILE MANUFACTURING FROM API TO FINISHED DOSAGE FORMS 2010-09-06 (Uppsala, Sweden, November 2009)

� SB 036 GMP INSPECTION OF MANUFACTURERS OF TRADITIONAL / HERBAL MEDICINAL PRODUCTS 2011-02-28 Kuala Lumpur, Malaysia, November 2010


Lumpur, Malaysia, November 2010

� SB 037 GOOD PHARMACEUTICAL INSPECTION PRACTICES 2011-12-27 Cape Town, South Africa, November 2011

� Miscelleneous

• PS/INF 1/2010 EXAMPLE OF QUALITY RISK MANAGEMENT IMPLEMENTATION 2010-01-08 An informal Working Group within PIC/S has

developed an example of methodology for the implementation of Quality Risk Management (QRM) in industry.

• This example of methodology is not intended to be issued by PIC/S as a recommendation or as a guideline for industry and / or for GMP

inspectors but it could be used by PIC/S for training purposes.

• Whether this example is used by industry for other purposes is of no concern to PIC/S and will not influence the outcome of PIC/S

inspections.

• PIC/S-PDA&ISPE

JOINT WORKSHOP 2009-01-29 PIC/S co-organised a joint workshop with PDA and ISPE on the Manufacture of Sterile Medicinal Products

(EU-PIC/S GMP revised Annex 1) which took place in Geneva on 13-14 November 2008 (read press release).

13

PIC/S GMP Guide = Introduction + Part I + Part II + 20 Annexes

Part I of the PIC/S GMP Guide

• Originally, the PIC/S GMP Guide (“PIC Basic Standards” of 1972) derives from the WHO GMP Guide and was further developed subsequently.

• In 1989, the EU adopted its own GMP Guide, which – in terms of GMP requirements – was equivalent to the PIC/S GMP Guide. Since that time, the EU and the PIC/S GMP Guides have been developed in parallel and

History of PIC/S GMP Guide History of PIC/S GMP Guide

the EU and the PIC/S GMP Guides have been developed in parallel and whenever a change has been made to one, the other has been amended so that both Guides are practically identical.

Part II of the PIC/S GMP Guide

• On 22 May 2001, PIC/S adopted the “GMP Guide for API” (ICH Q7A) as a stand-alone guide

(PE 007).

• On 29-30 May 2006, PIC/S made it Part II of the current Guide.

14

Part I of the PIC/S GMP Guide

Revisions History of PIC/S GMP Guide Revisions History of PIC/S GMP Guide

Date Version Number Reasons for revision

21 December 2000 PH 1/97 (Rev.) • Revision of Annex 14• Renumbering of all annexes• Change in the editor’s address and insertion of copyrightstatement

• Inclusion of revision history

10 August 2001 PH 1/97 (Rev. 2) � Amendment of para. 42 of Annex 1� Revision of Annex 6� New Annex 15� New Annex 17� Amendment to the glossary

15 January 2002 PH 1/97 (Rev. 3) � New Annex 4� New Annex 5� Reference to Annex 18 of EC GMP Guide

1 September 2003 PE 009-1 � Amendment of Annex 1 (mainly section 3)

1 July 2004 PE 009-2 � Revision of Annex 13

� Change in the Editor’s co-ordinates 15

Revisions History of PIC/S GMP Guide (Conti.)Revisions History of PIC/S GMP Guide (Conti.)

Date Version

Number

Reasons for revision

1 January 2006

1 June 2006

1 August 2006

PE 009-3 � Revision of Chapter 1 (Add PQR)

PE 009-4 o Revision of Chapter 6 (Add On-Going stability Programme)

PE 009-5� Corrections to revision of Chapter 6

� Revision of Chapter 8 (add requirements on counterfeit products)

� Reorganisation of the PIC/S GMP Guide in Part I, Part II and Annexes

5 April 2007 PE 009-6

� Reorganisation of the PIC/S GMP Guide in Part I, Part II and Annexes (EU level came into operation in Oct 2005)

� Incorporation of PE 007 (APIs guide) as Part II

� New Annex 19 (EU level came into operation on 1 Jun 2006)

� Revision of the Introduction

� Change in the Editor’s co-ordinates

1 September 2007 PE 009-7 � Revision of General Introduction (“History”) and Introduction to Part II

� Deletion of footnotes in Chapter 6 (Part I) and Annex 13

15 January 2009 PE 009-8

� Revision of Chapter 1 (Part I) (Add QRM)

� Revision of Annex 1

� New Annex 20 (QRM) (EU level came into operation in Mar 2006)

1 September 2009 PE 009-9 � Revision of Annex 3 – Manufacture of Radiopharmaceuticals (EU level came into operation on 1 Mar 2009) 16

ChangesChanges

An update on revision to PIC/S GMP Guide…

� Adopted by PIC/S

� In the PIC/S pipeline (i.e. adopted by EMA but not PIC/S)

� In the EMA (EU) pipeline (i.e. not adopted by both EMA and PIC/S)

17

… No change since last HPRG Regulatory Workshop 2011 conducted on 20 January 2011

… PIC/S has not published / released any new changes

Changes to PIC/S GuideChanges to PIC/S Guide

… PIC/S has not published / released any new changes since last revision -- Version: PE-009-9 released on 1 Sept 2009

18

A new consultation procedure between PIC/S and theEuropean Medicines Agency (EMA) had been discussed in

Harmonisation of guidance documentsHarmonisation of guidance documents

EMA Consultation Consultation PIC/S

European Medicines Agency (EMA) had been discussed inorder to ensure further improvements in theharmonisation between the EU and the PIC/S GMPGuides and related documents. This new procedure aimsat informing each party of ongoing revisions of currentdocuments and endorsement of new documents, includingthe sharing of early drafts in order to facilitate appropriateinvolvement in the adoption process.

19

Adopted by PIC/S …Adopted by PIC/S …

PIC/S Recommendation for Risk-based Inspection Planning in the GMP Environment

Status: Adopted and entered into force on 1st January 2012.

20

In the In the PIC/S PIC/S pipelinepipeline (i.e. adopted by EMA but not PIC/S)(i.e. adopted by EMA but not PIC/S)

Part I , Part II & Annexes

EU/EMA PIC/S

Annex 6 (Manufacture of medicinal

gases)

Adopted and has come into

operation on 31st July 2010.

TBA

Annex 7 (Manufacture of herbal

medicinal products)


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)


operation on 31st July 2010

TBA

Annex 14 (Manufacture of products

derived from human blood or

human plasma)


operation on 30th November 2011.

TPA

Part I -- Chapter 4 (Documentation) Adopted and has come into


TBA

Part II (API) – introduction of QM

principles


operation on 31st July 2010.

TBA

21

In the In the PIC/S PIC/S pipelinepipeline (i.e. adopted by EMA but not PIC/S)(i.e. adopted by EMA but not PIC/S)


EU/EMA PIC/S

Part III of the GMP guide Part III of GMP Guide was created and include:�Site Master File;�ICH Q9; and �ICH Q10

TBA

Site Master File: Formal

integration into EU system

PIC/S version of Site Master File approved and published by EC.

The revised document entered into force on 1 January 2011. On 15 Feb

integration into EU systemJanuary 2011. On 15 Feb 2011, the PIC/S Secretariat added a footnote into the revised SMF without formally amending the document. The footnote indicates that a D-U-N-S reference is required for Site Master Files submitted to EU/EEA authorities for manufacturing sites located outside of the EU/EEA.

22

REVISION OF ANNEX 6 – “MANUFACTURE OF MEDICINAL GASES”

Status:

At EU level, this revised Annex 6 has come into operation on 31st July 2010.

PIC/S level: Not adopted yet, it is likely to be adopted at next PIC/S CoOmeeting (Switzerland/Geneva ) in May 2012

• The proposed revised Annex 6 was initiated as a consequence of the restructuring of the GMP Guide and the need to modify the requirements of Part II of the Guide for applicability to medicinal gases. There was also a need to define more clearly

Revisions to the GMP Guide in the Revisions to the GMP Guide in the PIC/SPIC/S pipeline…pipeline…

for applicability to medicinal gases. There was also a need to define more clearly what should be considered as a starting material as opposed to a bulk pharmaceutical product. The opportunity has also been taken to update the annex in general.

• On 1 Feb 2012, we received the following progress update:

(i) Australia/TGA had underlined that a number of terms were unclear or needed to be better defined, e.g. paragraph 29 required traceability without specifying to which extent (i.e. per individual cylinder, batch or customer?). It was proposed the best way to address this issue was for PIC/S to adopt a “Question & Answer” document.

(ii) Canada/HPFBI suggested to amend paragraphs 35 and 36 dealing with the sealing of cylinders and mobile cryogenic vessels to authorise devices in addition to seals (e.g. “Cylinders and mobile cryogenic vessels should be fitted with tamper-evident seals or devices”). 23

REVISION OF ANNEX 7 - “Manufacture of Herbal Medicinal Products”

Status:

At EU level, this revised Annex 7 has come into operation on 1st Sept 2009.


• The proposal is based on the revision of Annex 7 to the EU GMP Guide. Annex 7 has been

revised to also apply to active substances used as starting materials for the manufacture of

herbal medicinal products following the adoption of ICH Q7A as Part II of the EU GMP Guide.


herbal medicinal products following the adoption of ICH Q7A as Part II of the EU GMP Guide.

• Good Agricultural and Collection Practice (GACP) requirement was introduced.

Paragraph 7 of EU Annex 7 reads as follows:

“Herbal medicinal product manufacturers must ensure that they use only herbal starting

materials manufactured in accordance with GMP and the Marketing Authorisation dossier.

Comprehensive documentation on audits of the herbal starting material suppliers carried out

by, or on behalf of the herbal medicinal product manufacturer should be made available. Audit

trails for the active substance are fundamental to the quality of the starting material. The

manufacturer should ensure that the suppliers of the herbal substance / preparation are in

compliance with Good Agricultural and Collection Practice.”

24

REVISION OF ANNEX 7 - “Manufacture of Herbal Medicinal Products” (Conti.)

Revised paragraph 7 regarding “GACP requirement”

• Australia / TGA has expressed its concerns on the compulsory requirement for

GACP-compliance. TGA has thus counter proposed:

“The manufacturer should verify, where appropriate, whether the

suppliers of the herbal substance / preparation are in compliance with Good

Agricultural and Collection Practice (or equivalent) and – if not – apply appropriate

Ensure that


Agricultural and Collection Practice (or equivalent) and – if not – apply appropriate

controls in line with QRM.”

• Italy / AIFA is in favour of the original EU version. AIFA has also counter proposed:

“The manufacturer should ensure that the suppliers of the herbal substance /

preparation are in compliance with Good Agricultural and Collection Practice

(published by the European Medicines Agency or by WHO) in order to perform

appropriate controls in line with QRM.”

25

REVISION OF ANNEX 7 - “Manufacture of Herbal Medicinal Products” (Conti.)

The final proposal: Revised paragraph 7 regarding “GACP requirement”

Taking into both proposals made by Australia / TGA and Italy / AIFA into consideration:

“….The manufacturer should verify, where appropriate, whether the suppliers of the herbal substance / preparation are in compliance with Good Agricultural and Collection Practice* and – if not – apply appropriate controls in line with QRM.”


* EMA, WHO or equivalent

(This reference to the EMA or WHO take the form of a footnote and the words “or equivalent” would be added).

26

• Proposed Revision of ANNEX 11 (Computerised Systems) and Chapter 4

Status:

At EU level, this revised Annex 11 has come into operation on 30th Jun 2011.



Key proposed changes:

• Revised in parallel with Chapter 4

27

REVISION OF ANNEX 13 – “MANUFACTURE OF INVESTIGATIONAL

MEDICINAL PRODUCTS”

Status:


PIC/S level: Not adopted yet, it is likely to be adopted at next PIC/S CoOmeeting (Switzerland/Geneva ) in May 2012.

Key Changes


Key Changes

The revision was initiated in order to reinforce the principle of independence between production and quality control functions in cases where the number of personnel involved is small. Changes have been made to sections 36 and 37 in order to supplement, for investigational medicinal products, the guidance for reference and retention samples given in Annex 19. A few editorial changes have been made in the interest of consistency with terminology used throughout the GMP Guide.

28

On 1 Feb 2012, we received the following progress update:

(i) Australia/TGA highlighted the following issue: “the proposed text (in particular paragraph

26b and Table 1, entry b) allows that for closed 'blinded' trials, the labelling does not include

any information regarding name/identifier and strength / potency of the clinical trial

material. This may lead to confusions in hospital pharmacies and can easily be avoided by

including a requirement (within clause 26b and Table 1 entry b) to include in the labelling a

statement of both the 'verum' and the placebo, for example: "acetylsalicylic acid 300mg or

placebo tablets". Such a labelling requirement would still leave the blinded character of the

trial intact while avoiding confusion in case of emergency.”


trial intact while avoiding confusion in case of emergency.”

(ii) Israel/ISCP commented that there was no mention of required labels for cytotoxic products

or articles requiring special storage conditions (e.g. "store at 2°C-8°C"). In addition, the

term "immediate container", which was outmoded in the revised Annex 13, still appeared in

paragraph 30.

It was proposed to integrate the above comments as footnotes in the revised Annex 13 of the PIC/S GMP Guide.

29

Proposed Revision of ANNEX 14 (Medicinal Products Derived from Human Blood or Plasma)

Status:


PIC/S level: Not adopted yet, it is likely to be adopted at next PIC/S CoO



Key changes:

- Plasma for fractionation from 3rd countries

- Demarcation between GMP and Blood legislation

30

CHAPTER 4 of the GMP Guide (Documentation)

Status:

At EU level, this revised Chapter 4 (Documentation)has come into operation on 30th June 2011. (Same as Annex 11 on Computerized systems)



Key changes:

• Revised in parallel with Annex 11

• Revised section on “Principle”

• Revised section on “Required GMP documentation (by type)” –

�inclusion of Site Master File,

�“Instructions (directions, or requirements) type” –

�Specifications;

�Manufacturing formulae, Processing, Packaging and Testing Instructions;

�Procedures (SOPs);

�Protocols; and

�Technical agreements.31

CHAPTER 4 of the GMP Guide (Documentation) (Conti…)�“Records/Report type”-

� Records;

� Certificates of Analysis;

� Reports

• Revised section on “Generation and control of documentation”• All types of document should be defined and adhered to. The requirements apply equally to all forms of document media types.

Complex systems need to be understood, well documented, validated, and adequate controls should be in place. Many documents

(instructions and/or records) may exist in hybrid forms, i.e. some elements as electronic and others as paper based. Relationships and

control measures for master documents, official copies, data handling and records need to be stated for both hybrid and homogenous

systems. Appropriate controls for electronic documents such as templates, forms, and master documents should be implemented.

Appropriate controls should be in place to ensure the integrity of the record throughout the retention period. …

• Revised section on “Retention of documents”


• Revised section on “Retention of documents”� It should be clearly defined which record is related to each manufacturing activity and where this record is located.

Secure controls must be in place to ensure the integrity of the record throughout the retention period and validated where appropriate.

� Specific requirements apply to batch documentation which must be kept for one year after expiry of the batch to which it relates or at least five years after certification of the batch by the Qualified Person, whichever is the longer. For investigational medicinal products, the batch documentation must be kept for at least five years after the completion or formal discontinuation of the last clinical trial in which the batch was used. Other requirements for retention of documentation may be described in legislation in relation to specific types of product (e.g. Advanced Therapy Medicinal Products) and specify that longer retention periods be applied to certain documents.

� For other types of documentation, the retention period will depend on the business activity which the documentation supports. 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.

32

CHAPTER 4 of the GMP Guide (Documentation) (Conti…)

• Revised section on “Other” – E.g.

“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


- 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.”

33

REVISION OF Part II (Basic Requirements for Active Substances used as Starting Materials)

Status:

At EU level: this revised Part II has come into operation on 31 July 2010.

PIC/S level: Not adopted yet, it is likely to be adopted at next PIC/S CoO meeting (Switzerland/Geneva ) in May 2012

Changes:


Changes:

• The proposed revised Part II was initiated in order to incorporate principles of QRM corresponding to similar changes made to Part I, Chapter 1 of the Guide. A new section on QRM was introduced as section 2.2. The remaining sections of chapter 2 are renumbered. No other changes have been made.

34

• Proposed new Part III of the GMP guide

Status:

EU Level :Both revision to SMF explanatory notes and Part III

concept - adopted and published at EU level.

PIC/S Level : Revision to SMF explanatory notes adopted with effect

from 1 Jan 2011; Part III concept -- Not adopted by


from 1 Jan 2011; Part III concept -- Not adopted by

PIC/S yet

• SMF has also become a standard expectation of EU authorities.

• It is proposed to create a new informational Part III of the EU GMP Guide for collection of GMP related documents which are not themselves GMP guidelines and have no statutory force (i.e. non-binding documents) but which complement the GMP guidelines and related regulatory procedures such as inspections. It is expected that in the future, further documents will be added to the new Part III [E.g. introductory part of GMP Guide, ICH documents (Q9 and Q10) are proposed to be included in Part III].

35

Proposed Revisions to the EU GMP Guide Proposed Revisions to the EU GMP Guide ---- In the EU (EMA)In the EU (EMA)pipelinepipeline (i.e. Not adopted yet)(i.e. Not adopted yet)


EU/EMA PIC/S

Part I – Chapter 1 and 2 New texts of chapter 1 proposed during last EMA’s GMP/GDP IWG meeting. Revision of chapter 2 will be done after consolidation of chapter 1.

Participating Authorities requested to send their feedback on proposed revisions by 15 Feb 2012.

Part I – Chapters 3 and 5

(Dedicated Facilities)

EMA’s Safety Working Party has published Concept Paper on development of toxicological tools.

Participating Authorities are invited to comment on proposed Concept Paper

Part I – Chapters 5 (API Slight changes proposed during last New draft is invited for Part I – Chapters 5 (API

pedigree)

Slight changes proposed during last EMA’s GMP/GDP IWG meeting.

New draft is invited for comments till 15th Feb 2012.

Part I –Chapters 5 (control

of starting materials)

Q&A was prepared, awaiting

approval.

Q&A is invited for comments till 15th February 2012.

Part I – Chapter 6 (Quality

Control)

Work on text has been started; first draft will be available for next EMA’s GMP/GDP IWG meeting.

After first draft will be shared with PIC/S.

Part I –Chapter 7 (Contract

Manufacturer and Analysis)

Last draft sent for publication by

EC.

will be shared with PIC/S.

Part I – Chapter 8 (notification of product shortage)

First draft should be available for next EMA’s GMP/GDP IWG meeting.

First draft will be shared with PIC/S once it is available.

36

Proposed Revisions to the EU GMP Guide Proposed Revisions to the EU GMP Guide ---- In the EU (EMA)In the EU (EMA)

pipelinepipeline (i.e. Not adopted yet) (i.e. Not adopted yet)


EU/EMA PIC/S

Annex 2 (Biologicals) Final draft prepared and was shared with PIC/S. Adopted and sent to EC for publication.

Will be tabled for adoption at next PIC/S CoO(Switzerland/Geneva) in may 2012.

Annex 16 (update of text) Proposed overall revision of annex Concept paper from EMA will Annex 16 (update of text) Proposed overall revision of annex 16 – Concept paper will be ready for next EMA’s GMP/GDP IWG meeting.

Concept paper from EMA will be shared with PIC/S once available.

GDP Guide GDP Guideline approved for public consultation. The work should be coordinated with PIC/S working group.Format of GDP licence approved for pilot phase till end of 2011.

Ongoing work of PIC/S working group. Proposed EU GDP guide are to be sent to PIC/S PA for their comments and local public consultation. (this has to be confirmed by chair of PIC/S working group as discussed at last PIC/S committee meeting).

37

Part I – Proposed Revision of CHAPTER 1 (Quality Management ) &

CHAPTER 2 (Personnel)

Status:

EU/EMA: New texts of chapter 1 proposed during last EMA’s GMP/GDP IWG meeting. Revision of chapter 2 will be done after consolidation of chapter 1.

PIC/S: Participating Authorities requested to send their feedback on proposed revisions by 15 Feb 2012.

Revisions to the GMP Guide in the Revisions to the GMP Guide in the EMA(EU)EMA(EU) pipeline…pipeline…

Proposed changes made to Chapter 1 is to harmonise with ICH Q10 (Part III) – A pharmaceutical quality system designed for the entire product lifecycle.

• The following key changes are recommended to be added to Chapter 1:

- Quality Management System

�Achieve Product Realisation

�Establish and Maintain a State of Control

�Facilitate Continual Improvement

38

Part I – Proposed Revision of CHAPTER 1 (Quality Management ) &

CHAPTER 2 (Personnel) Continue …

• Quality Manual (or equivalent)

• Management responsibilities

• CAPA

Revisions to the GMP Guide in the Revisions to the GMP Guide in the EMA(EU)EMA(EU) pipeline…pipeline…

• Process Performance and Product Quality Monitoring

• Management of Outsourced Activities and Purchased Materials

• Management Review & monitoring of the QMS

� formalised periodic review process

� internal and external factors to be considered

� output from review process (documentation, timely and effective communication of results)

39

Part I – Proposed revision of CHAPTER 3 (Premises and Equipment) &

CHAPTER 5 (Production)

Status:

EU: EMA’s Safety Working Party has published Concept Paper on development of toxicological tools.

PIC/S: Participating Authorities are invited to comment on proposed Concept Paper

Key Proposed Changes:

“Dedicated and self-contained Facilities”

Proposed Revisions to the EU GMP Guide in the Proposed Revisions to the EU GMP Guide in the EMA(EU)EMA(EU) pipeline…pipeline…

“Dedicated and self-contained Facilities”

CHAPTER 3 -- PREMISES AND EQUIPMENT (Existing)

3.6. In order to minimise the risk of a serious medical hazard due to cross-contamination,

dedicated and self-contained facilities must be available for the production of particular

medicinal products, such as highly sensitising materials (e.g. penicillins) or biological

preparations (e.g. from live micro-organisms). The production of certain additional

products, such as certain antibiotics, certain hormones, certain cytotoxics, certain highly

active drugs and non-medicinal products should not be conducted in the same facilities. For

those products, in exceptional cases, the principle of campaign working in the same facilities

can be accepted provided that specific precautions are taken and the necessary validations

are made. The manufacture of technical poisons, such as pesticides and herbicides, should

not be allowed in premises used for the manufacture of medicinal products. 40



CHAPTER 5 – PRODUCTION (Existing) -- Prevention of cross-contamination in production

5.18. Contamination of a starting material or of a product by another material or product

must be avoided. This risk of accidental cross-contamination arises from the uncontrolled

release of dust, gases, vapours, sprays or organisms from materials and products in process,

from residues on equipment, and from operators' clothing. The significance of this risk

varies with the type of contaminant and of product being contaminated. Amongst the most

hazardous contaminants are highly sensitising materials, biological preparations containing


hazardous contaminants are highly sensitising materials, biological preparations containing

living organisms, certain hormones, cytotoxics, and other highly active materials. Products

in which contamination is likely to be most significant are those administered by injection,

those given in large doses and/or over a long time.

41



• CHAPTER 5 – PRODUCTION (Existing) -- Prevention of cross-contamination in production

5.19 Cross-contamination should be avoided by appropriate technical or organisational

measures, for example:

a) production in segregated areas (required for products such as penicillins, live vaccines, live bacterial

preparations and some other biologicals), or by campaign (separation in time) followed by appropriate

cleaning;

b) providing appropriate air-locks and air extraction;


b) providing appropriate air-locks and air extraction;

c) minimising the risk of contamination caused by recirculation or re-entry of untreated

or insufficiently treated air;

d) keeping protective clothing inside areas where products with special risk of cross contamination are

processed;

e) using cleaning and decontamination procedures of known effectiveness, as ineffective cleaning of

equipment is a common source of cross-contamination;

f) using “closed systems” of production;

g) testing for residues and use of cleaning status labels on equipment.

42



Chapter 3 – 3.6 & Chapter 5 – 5.18 & 5.19

Lack of clarity I existing GMP Guide w.r.t. when a medicinal product should be manufactured in

dedicated , self-contained facility.

• Proposed amendment on 3.6 –“dedicated facilities” – to include ICH Q9 – QRM principles

• Risk assessment should include a toxicological evaluation of the product being manufactured

in a shared facility.


• The need to develop a “Toxicological tool” to conduct toxicological assessment (absence of

guidance w.r.t. a method of deriving acceptable exposure limits for cross contamination

between products manufactured using shared facilities) – Concept paper agreed by EMA’s

Safety Working Group (SWG) and GMP/GDP IWF in Sept 2011. First draft to be discussed at

next meeting in Feb 2012.

43

Proposed amendment to CHAPTER 5 : Production (API pedigree)

Status:

EU: Slight changes proposed during last EMA’s GMP/GDP IWG meeting.

PIC/S: New draft is invited for comments till 15th Feb 2012.

Key proposed changes

� Qualification of Suppliers of Starting Materials

� Supply chain traceability for starting materials

Proposed Revisions to the EU GMP Guide in the Proposed Revisions to the EU GMP Guide in the EMA (EU)EMA (EU) pipeline…pipeline…

� Supply chain traceability for starting materials

� Testing for starting materials

� Control of contamination (Dedicated facilities)

44

Proposed amendment to CHAPTER 5 : Production (API pedigree)

What is Pedigree?

• A pedigree is a family tree for an active pharmaceutical ingredient (API) tracing its history or supply chain from critical raw material(s) used in the manufacture of the API to the manufacturer of the dosage form.

Proposed Revisions to the EU GMP Guide in the Proposed Revisions to the EU GMP Guide in the EMA (EU)EMA (EU) pipeline…pipeline…

• The pedigree should be reviewed periodically to ensure that it is up to date (Chapter 1 proposal)

• GMP Guide revision (Chapter 5 proposal):Pedigree = Traceability

45

Proposed revision of CHAPTER 6 (Quality Control)

Status:

EU: Work on text has been started; first draft will be available for next EMA’s GMP/GDP IWG meeting.

PIC/S: After first draft will be shared with PIC/S.


Proposed Revisions to the GMP Guide in the Proposed Revisions to the GMP Guide in the EMA (EU)EMA (EU) pipeline…pipeline…


• Analytical method transfer

46

Proposed Revision of CHAPTER 7 (Contract Manufacture and Analysis – to be renamed as “Outsourced Activities”)

Status:

EU : Last draft sent for publication by EC.

PIC/S : will be shared with PIC/S.




• Harmonise with ICH Q10 guideline (Outsourced activities -ICH terminology)

• Proposed revised Chapter 7 provides updated guidance on outsourced GMP regulated activities beyond the current scope of contract manufacture and analysis operations. The title of the Chapter has been changed to reflect this.

47

Proposed Revision of CHAPTER 8 (Complaints and Product Recall)

Status:

EU: First draft should be available for next EMA’s GMP/GDP IWG meeting.

PIC/S: To be shared with PIC/S once available


To consider a revision in the light of discussions at a meeting of Quality


To consider a revision in the light of discussions at a meeting of Quality Defect contact points held at EMA on 7-8 October 2009 on product shortage notifications and to introduce specific Quality Risk Management concepts in the context of this chapter.

i.e. reporting where product shortage arises due to manufacturing issues

48

Proposed Revision of ANNEX 2 of the GMP Guide (Biological Medicinal Products)

Status:

EU :Final draft prepared and was shared with PIC/S. Adopted and sent to EC for publication. The European Commission will decide about the entry into force of the revised EU Annex 2.

PIC/S :Consulting PIC/S Participating Authorities, in particular, non-EEA


PIC/S :Consulting PIC/S Participating Authorities, in particular, non-EEA Participating Authorities, on some unresolved issues .

Key proposed changes

“Annex 2 of the EU GMP Guide has been revised as a consequence of the restructuring

of the GMP Guide, new manufacturing technology and concepts, the increased breadth of biological products to include several new product types such as transgenic derived products and the Advanced Therapy Medicinal Products, (ATMPs) together with associated new EU legislation. The GMP guidance drawn up for the latter products is to meet the requirements of Article 5 of Regulation 1394/2007 and to align with details in Directive 2009/120/EC.”

49

Good Distribution Practice (GDP) Guide

StatusEU : Public consultation ended on 31 Dec 2011, coordinated with PIC/S GDP

working group.

PIC/S: From a GDP Working Group, forming an Expert Circle on GDP – 1st meeting proposed to be conducted on 18-20 April 2012 in Helsinki/Finland with a view to adopt EMA’s revised Guidelines on Good Distribution Practice.

Other Revisions to the GDP Guide in the Other Revisions to the GDP Guide in the PIC/SPIC/S pipeline…pipeline…

Reasons for change: The content of the EMA Guidelines on Good Distribution Practice published in 1994 is no longer adequate. It needs to be reviewed to take into account advancements of practices for an appropriate storage and distribution of medicinal products in the European Union. Moreover, it should take into account the amendments to the Community Code which have been introduced with Directive 2011/62/EU of the European Parliament and of the Council amending Directive 2001/83/EC on the Community code relating to medicinal products for human use, as regards the prevention of the entry into the legal supply chain of falsified medicinal products.

50

PIC/S Explanatory Notes for pharmaceutical manufacturers on the

preparation of a site master file

SMFSMF

preparation of a site master file (SMF)

(PE 008-4 dated 1 January 2011)Revision adopted on 1 January 2011

51

PIC/S Explanatory Notes PIC/S Explanatory Notes for pharmaceutical manufacturers on the for pharmaceutical manufacturers on the preparation of a site master file (SMF)preparation of a site master file (SMF)–– (PE 008(PE 008--4 dated 1 January 2011)4 dated 1 January 2011)

Revision adopted on 1 January 2011Revision adopted on 1 January 2011

Status:

�At PIC/S level: this revised document has been adopted and has

come into operation on 1 January 2011 (First time in history that a document is adopted by PIC/S before EU level)

�At its meeting in Kuala Lumpur (8-9 November 2010), the PIC/S Committee has adopted the revision of the Explanatory Notes for Industry on the Preparation of a Site adopted the revision of the Explanatory Notes for Industry on the Preparation of a Site Master File (PE 008-4).

�The main objectives of the revision are the simplification of the document and the implementation of requirements in relation with quality risk management.

�On 15 February, the PIC/S Secretariat added a footnote into the revised SMF without formally amending the document. The footnote indicates that a D-U-N-S reference is required for SMFs submitted to EU/EEA authorities for manufacturing sites located outside of the EU/EEA.

�At EU level: this revised document has also been adopted

(Ref:Brussels, SANCO/C8/AM/sl/ares(2010)1064603). 52

PIC/S Explanatory Notes PIC/S Explanatory Notes for pharmaceutical manufacturers on the for pharmaceutical manufacturers on the preparation of a site master file (SMF)preparation of a site master file (SMF)–– (PE 008(PE 008--4 dated 1 January 2011)4 dated 1 January 2011)

Revision adopted on 1 January 2011Revision adopted on 1 January 2011

Both documents are almost identical.

53

PIC/S new SMF GuideRev. 4 (PE 008-4)

1 Jan 2011

EU new SMF Guide10 Feb 2011

1. Document History

2. Introduction

3. Purpose

4. Scope

SMF SMF (Table of Contents))

5. Content of SMF

6. Revision History

7. Appendices for a Site Master File

54

Purpose of the Site Master File

• A Site Master File is a dossier prepared by the manufacturer that contains specific information about the Quality Management systems, policies and activities of the Company, Manufacturing Site and/or quality control of manufacturing operations carried out by the Site.

• This Explanatory Note is a guide to prepare a Site Master File that • This Explanatory Note is a guide to prepare a Site Master File that can be utilized in planning and conducting GMP inspections.A Site

Master File is essential for pharmaceutical companies as it is the basis for the regulatory authority to prepare for a GMP inspection.

• The SMF has become compulsory in the EU/EEA as the revised Chapter 4 of the EU GMP Guide has already come into operation on 30th June 2011(the SMF will be included in Part 3 of the EU/EEA GMP Guide). The Commission has published the EU/EEA SMF on its website. 56

Format of the Site Master FileFormat of the Site Master File

• SMF should contain information on the Sites GMP related activities.

• SMF is a detailed document but should not exceed 25-30 pages plus Appendices.

• Dossier should have an Edition Number, and effective and expiry dates and should be updated and reviewed to ensure it is dates and should be updated and reviewed to ensure it is representative of current Site activities.

• Format and headings should follow the outlined guidance notes.

57

Scope of the Site Master FileScope of the Site Master File

These Explanatory Notes apply to the preparation and content of the SMF. Manufacturers should refer to regional / national regulatory requirements to establish whether it is mandatory for manufacturers of medicinal products to prepare a SMF.

These Explanatory Notes apply for all kind of manufacturing operations such as production, packaging and labelling, testing, relabelling and repackaging of all types of medicinal products. The outlines of this guide repackaging of all types of medicinal products. The outlines of this guide could also be used in the preparation of a SMF or corresponding document by Blood and Tissue Establishments and manufacturers of Active Pharmaceutical Ingredients.

58

Overview on changesOverview on changes

• Several possibilities regarding the indication of the geographic location of the site have been added

• A listing of the GMP inspections conducted in the past 5 years must be included in the Site Master File

• Higher importance is attached to the topic "supplier qualification" (the indication of the supply chain is now required)

• Introduction of the PQR point • Introduction of the PQR point

• New requirement on the description of relevant utilities (steam, compressed air, nitrogen, etc.)

• Concrete information on the storage of documents outside the premises is required

• Description of the system which ensures appropriate environmental conditions during transportation

• Measures taken against illegal infiltration in the supply chain

59

New RequirementsNew RequirementsNotes address supply chain with Risk Management and incorporate

ICH Q 8, 9 and 10

General Company Information• GPS details must be provided to ensure accurate location of the facility

• Information on GMP inspections, dates, relevant authority and outcomes

• Quality Management System of the Company• Information regarding relevant standards for the company (ISO, ICH etc)

• Dates and approvals for accreditation's and certified activities

• Description of validation and change control policies

• Actual names of responsible person(s) and QP(s) ;additional detail on their role

• Information on PAT and real time release

• Included Company Risk Management policies, qualification and oversight of suppliers

• Compliance with TSE guidelines

60

1. GENERAL INFORMATION ON THE MANUFACTURER

1.1 Contact information on the manufacturer (also see 4.1)

4th bullet point - Identification number of the site as e.g. GPS details,

D-U-N-S (Data Universal Numbering System) Number (a unique identification number provided by Dun & Bradstreet) of the site or any other geographic location system1.

Why?

SMF (Changes)SMF (Changes)

Why?

This new requirement is to better identify the location of manufacturing site(s). These additional data are GPS co-ordinates, and (if available) a DUNS number.

• The purpose is to provide more reliability of the site location. Experience showed that the way the applicants express their address may be either incomplete or inconsistent.

• The GPS coordinates or DUNS number will allow NDRA to unambiguously identify the location of a manufacturing site.

60

Identification number: DUNS (Data Universal Numbering System)

What?

An unique, separate and distinct nine-digit number assigned to each business location developed and maintained solely by a private company known as Duns & Bradstreet (D&B).

This D&B DUNS Number is used by industries and organizations around the world as a global standard for business identification and tracking.


world as a global standard for business identification and tracking.

This number can be applied for through the company website (http://www.dnb.com/).

Local contact: Dun & Bradstreet (Singapore) Pte Ltd

Tel: (65) 6513 – 8347, Fax : (65) 6778-4627

Address :20 Harbour Drive, PSA Vista #06-02, Singapore 117612

(There is a charge of SGD 37.45 (inclusive of 7% GST) per DUNS Number request).

Your D-U-N-S ® Number will be sent to you within 3 days from receipt of the request and payment confirmation.

61

Identification number: GPS details,

GPS CO-ORDINATES (Global Positioning System)

Which system (or datum)?

�Provide GPS co-ordinates as per the WGS 84 system (World Godetic System).

Which unit should be used for GPS coordinates?

�Latitude (North or South) and longitude (East or West), preferably expressed in the


�Latitude (North or South) and longitude (East or West), preferably expressed in the format: DD MM SS,S (Degrees Minutes Seconds to 1 decimal place).

�Alternatively the latitude and longitude may be expressed in Degrees to at least 5 decimal places or Degrees Minutes to at least 3 decimal places.

62

Identification number: GPS details,

Which location?

�Co-ordinates should preferably identify the main entrance of the manufacturing site

involved in the production . If the location for which the co-ordinates are given is not

the main entrance, this should be specified clearly in the application form.

How to measure/obtain GPS coordinates?


How to measure/obtain GPS coordinates?

�Preferably, use a GPS device, calibrated with the units and system mentioned above.

or

�Use Google Earth to identify the site entrance and copy the co-ordinates displayed in

the lower part of the map, with the format of the units and system mentioned above.

63

Identification number: DUNS (Data Universal Numbering System)

GPS details,

Other geographic location system

PIC/S Foot note: 1 : A D-U-N-S reference is required for Site Master Files submitted to EU/EEA authorities for manufacturing sites located outside of the EU/EEA.


Notes: EDQM -- Since 15 April 2011, applicants for new certificates of suitability (CEP) or revisions of CEPs are requested to provide information in the application form to better identify the location of their manufacturing site(s). These additional data are GPS co-ordinates, and (if available) a DUNS number. (i.e. Providing the DUNS number is not mandatory in the framework of the submission of a CEP dossier).

64

1.2 Authorised pharmaceutical manufacturing activities of the site.

- ..

- …

- …

- List of GMP inspections of the site within the last 5 years; including dates and name/country of the Competent Authority having performed the inspection. A copy of current GMP certificate (Appendix 3) or reference to the EudraGMP database should be included, if available.


2. QUALITY MANAGEMENT SYSTEM OF THE COMPANY

2.1 Description of the quality management system of the company

• Provide information on quality management systems, maintenance of the systems and senior management responsibilities

• Provide reference to the relevant standards (i.e. ISO, ICH)

• Provide information of accredited and certified activities carried out by the company

65

SMF (Changes)

2. QUALITY MANAGEMENT SYSTEM OF THE COMPANY (Conti…)

2.2. Release procedure of finished products

- Detailed description of qualification requirements (education and work experience) of the Authorised Person(s) / Qualified Person(s) responsible for batch certification and releasing procedures;

- General description of batch certification and releasing procedure;

- Role of Authorised Person / Qualified Person in quarantine and release of finished products and in assessment of compliance with the Marketing Authorisation;

- The arrangements between Authorised Persons / Qualified Persons when several Authorised Persons / Qualified Persons are involved;

- Statement on whether the control strategy employs Process Analytical Technology (PAT) and/or Real Time Release or Parametric Release.

66

2.3 Management of suppliers and contractors

- A brief summary of the establishment/knowledge of supply chain and the external audit program;

- Brief description of the qualification system of contractors, manufacturers of active pharmaceutical ingredients (API) and other critical materials suppliers;

- Measures taken to ensure that products manufactured are compliant with TSE (Transmitting animal spongiform encephalopathy) guidelines.

- Measures adopted where counterfeit/falsified products, bulk products, active pharmaceutical ingredients or excipients are identified;


pharmaceutical ingredients or excipients are identified;

- Use of outside scientific, analytical or other technical assistance in relation to manufacture and analysis;

- List of contract manufacturers and laboratories including the addresses and contact information and flow charts of supply-chains for outsourced manufacturing and Quality Control activities; e.g. sterilisation of primary packaging material for aseptic processes, testing of starting raw materials etc, should be presented in Appendix 4;

- Brief overview of the responsibility sharing between the contract giver and acceptor with respect to compliance with the Marketing Authorisation (where not included under 2.2).

67

2. QUALITY MANAGEMENT SYSTEM OF THE COMPANY (Conti…)

2.4 Quality Risk Management (QRM)

- Brief description of QRM methodologies used by the manufacturer;

- Scope and focus of QRM including brief description of any activities which are performed at corporate level, and those which are performed locally. Any


performed at corporate level, and those which are performed locally. Any application of the QRM system to assess continuity of supply should be mentioned.

2.5 Product Quality Reviews

- Brief description of methodologies used

68

4. PREMISES AND EQUIPMENT

4.1 Premises

- Short description of plant; size of the site and list of buildings. If the production for different markets, i.e. for local, EU, USA, etc. takes place in different buildings on the site, the buildings should be listed with destined markets identified (if not identified under 1.1);

- Simple plan or description of manufacturing areas with indication of scale (architectural or engineering drawings are not required);

- Lay outs and flow charts of the production areas (in Appendix 6) showing the room


- Lay outs and flow charts of the production areas (in Appendix 6) showing the room classification and pressure differentials between adjoining areas and indicating the production activities (i.e. compounding, filling, storage, packaging, etc.) in the rooms;

- Lay-outs of warehouses and storage areas, with special areas for the storage and handling of highly toxic, hazardous and sensitising materials indicated, if applicable;

- Brief description of specific storage conditions if applicable, but not indicated on the lay-outs.

69

4.2.3 GMP critical computerised systems

- Description of GMP critical computerised systems (excluding equipment specific

Programmable Logic Controllers (PLCs).

5. DOCUMENTATION


- Description of documentation system (i.e. electronic, manual);

- When documents and records are stored or archived off-site (including pharmacovigilance data, when applicable): List of types of documents/records; Name and address of storage site and an estimate of time required retrieving documents from the off-site archive.

70

6. PRODUCTION

6.1. Type of products(references to Appendix 1 or 2 can be made):

- Type of products manufactured including

§ list of dosage forms of both human and veterinary products which are manufactured on the site

§ list of dosage forms of investigational medicinal products (IMP) manufactured for any clinical trials on the site, and when different from the


manufactured for any clinical trials on the site, and when different from the commercial manufacturing, information of production areas and personnel

- Toxic or hazardous substances handled (e.g. with high pharmacological activity and/or with sensitising properties);

- Product types manufactured in a dedicated facility or on a campaign basis, if applicable;

- Process Analytical Technology (PAT) applications, if applicable: general statement of

the relevant technology, and associated computerised systems.

71

6.2 Process validation

• - Brief description of general policy for process validation;

• - Policy for reprocessing or reworking.

8. DISTRIBUTION, COMPLAINTS, PRODUCT DEFECTS AND RECALLS

8.1 Distribution (to the part under the responsibility of the manufacturer)

- Types (wholesale licence holders, manufacturing licence holders, etc) and locations


- Types (wholesale licence holders, manufacturing licence holders, etc) and locations

(EU/EEA, USA, etc.) of the companies to which the products are shipped from the site;

- Description of the system used to verify that each customer / recipient is legally entitled to receive medicinal products from the manufacturer;

- Brief description of the system to ensure appropriate environmental conditions during transit, e.g. temperature monitoring/ control;

- Arrangements for product distribution and methods by which product traceability is maintained;

- Measures taken to prevent manufacturers’ products to fall in the illegal supply

chain.

72

Appendices of Site Master Files

• Appendix 1 - Copy of valid manufacturing authorization

• Appendix 2 - List of products (dosage forms and/or APIs)

manufactured including for dosage forms the INN-names of APIs used

• Appendix 3 - Copy of valid GMP Certificate

• Appendix 4 - Organizational charts

• Appendix 5 - Lay outs of production areas including process,

equipment, waste and personnel flows

• Appendix 6 - Schematic drawings of water systems

• Appendix 7 - List of major production and laboratory equipment

used indicating the frequency for re-qualification

• Appendix 8 - List of contractors including the addresses and

contact information

73

Q & AQ & A

74

THANK YOUTHANK YOUTHANK YOUTHANK YOUTHANK YOUTHANK YOU

Together we will meet the challenges of the future

75

TOPIC: APPLICATION OFQUALITY RISK MANAGEMENT

Good Manufacturing Practice for Medicinal Products ManufacturersGood Manufacturing Practice for Medicinal Products Manufacturers

QUALITY RISK MANAGEMENT

Presented by:Lai Weng Fai Acting Director / Senior GMP Auditor

Licensing & Certification Branch (LCB)15 February 2012

1

OUTLINE OF PRESENTATIONOUTLINE OF PRESENTATION

Quality Risk Management (QRM) —

Brief Background

Implementing QRM — Expectations

Areas of Application - Examples

Summary

2

QRM QRM —— Brief Background Brief Background tbctbc

• Risk management — has been part of the pharmaceutical industry for

many years.

– GMP requirements are designed to address risk.

o The holder of a manufacturing authorisation must ... ensure that

medicinal products ... are fit for their intended use ... and do not

place patients at risk due to inadequate safety, quality or efficacy. place patients at risk due to inadequate safety, quality or efficacy.

[Chp 1, Principle]

o The responsibilities placed on any one individual should not be so

extensive as to present any risk to quality. [Chp 2 , Clause 2.1]

o the specific GMP requirements for sterile products (PIC/S GMP

Guide, Annex 1) are designed to mitigate the risk of sterility

failure.

3

QRM QRM —— Brief Background Brief Background tbctbc

– GMP specifies a risk based approach.

o A risk assessment approach should be used to determine the

scope and extent of validation [Annex 15, Principle].

o A risk analysis of the sterility assurance system focused on an

evaluation of releasing non-sterilised products should be

performed” [Chp 17, Clause 3.7]performed” [Chp 17, Clause 3.7]

– Specifications in pharmacopoeial monographs include tests for known

potential contaminants.

4

QRM QRM —— Brief BackgroundBrief Background• PIC/S GMP Guide – greater emphasis on formalising these processes and

using formal risk management tools.

• From a GMP perspective, we are only concerned with risks associated with

product quality (Purity, Identity, Potency, Safety, etc.)

– i.e., Quality Risk Management.

• Manufacturer is responsible for assessing risks to the medicinal products • Manufacturer is responsible for assessing risks to the medicinal products

and managing these risks to an acceptable level.

5

Implementing QRM Implementing QRM —— Expectations Expectations tbctbc

In the PIC/S GMP Guide (since 15 Jan 2009):

Chapter 1 – Quality Management [Principle]

• To achieve the quality objective reliably there must be a comprehensively

designed and correctly implemented system of Quality Assurance

incorporating Good Manufacturing Practice, Quality Control and Qualityincorporating Good Manufacturing Practice, Quality Control and Quality

Risk Management. It should be fully documented and its effectiveness

monitored.

• The basic concepts of Quality Assurance, Good Manufacturing Practice,

Quality Control and Quality Risk Management are inter-related.

6


In the PIC/S GMP Guide (since 15 Jan 2009):Chapter 1 – Quality Management

Quality Risk Management

1.5 Quality risk management is a systematic process for the assessment,

control, communication and review of risks to the quality of the

medicinal product. It can be applied both proactively and medicinal product. It can be applied both proactively and

retrospectively.

7

1.6 The quality risk management system should ensure that:

- the evaluation of the risk to quality is based on scientific

knowledge, experience with the process and ultimately links to

the protection of the patient;

- the level of effort, formality and documentation of the quality

risk management process is commensurate with the level of

risk.


Quality

Risk

Degree to which a set

of inherent properties

of a product, system or process

fulfills requirements

combination of the

probability of occurrence of harm and

8

probability of occurrence of harm and

the severity of that harm (to the patient)

Systematic process for the assessment,

control, communication and review

of risks to the quality of the

drug (medicinal) product

across the product lifecycle.

It can be applied both proactively and

retrospectively.

& Management

QRM


What do GMP auditors look out for?• Written Policy/Procedure

– Various aspects of business operations where QRM will be applied.

– General approach to both planned and unplanned risk assessment.

– Methods to be used (commensurate with risk level).– Methods to be used (commensurate with risk level).

• Implementation of QRM within company’s QMS

– Relevant procedures updated & integrated with QMS.

– Formal methods defined (where applied).

– Training of staff involved in QRM activities.

– Involvement of senior management in the identification &

implementation of QRM principles within the company.

9


• Systematic Approach

– Local SOPs guide user into performing and documenting risk analysis.

– System of archival and on-going review of significant risk assessments

used to justify operational activities, validations, etc.

– One-off risk assessments should be documented, approved and

retained.retained.

– Evidence of proactive and retrospective risk assessments in place

where required.

10


• Outcomes of assessment

– Risk-based decisions are well informed, science-based and

comprehensible, and taken by decision –makers with appropriate

competence & authority.

– Ultimate linkage to patient safety.

– Assumptions & supporting reasons properly documented.– Assumptions & supporting reasons properly documented.

• Justifiable assessments

– Level of efforts/resources deployed in the QRM activity commensurate

with the criticality of the identified problem.

�High potential risk → more thorough evaluation & report.

�Low potential risk → may be a one line justification.

11


QRM Issues Commonly Observed1. Failure to apply/consider QRM

2. Inappropriate/incorrect application of QRM

– Inadequate or no assessment of impact on product quality/linkage to

patient safety.patient safety.

– Lack of scientific evidence supporting decisions.

– Lack of process understanding and/or regulatory requirements.

– Review of assessments without systematic approach.

– Risk management used to justify a preconceived outcome.

– Invalid assumptions made to suit the preconceived outcome.

– Variable tolerance of risk → inconsistent decision-making.

12


QRM Issues Commonly ObservedIn general, in a typical audit process:

� Auditors will review the QRM processes as part of the QMS section of the

audit (e.g. product complaints, recalls, deviations, PQR, etc.).

� Auditors will be pragmatic regarding the level of scrutiny and degree of � Auditors will be pragmatic regarding the level of scrutiny and degree of

formality expected of the outcome of QRM exercise.

� Auditors will be flexible and ready to debate/accept outcome based on

good science.

� If necessary, auditors may request company to produce a formal

summary of the risk assessment, key decisions and conclusions, or take

copies of complex assessments for further evaluation outside of the

audit.

13


QRM Non-Conformities (NC)� NCs will be categorised dependent on the significance of the findings, the

activities undertaken by the manufacturer and the number of

observations relating to the incorrect application of QRM.

� QRM-related NCs may be grouped with other QMS-related NCs (QRM is

expected to be an integral part of the QMS).expected to be an integral part of the QMS).

� Major NC will generally be cited where the manufacturer is completely

lacking a QRM system.

� Critical NCs may reference QRM where the risk assessments have

inappropriately supported release of products that pose a threat to

patient safety.

14


QRM Non-Conformities (NC)� If the manufacturer has not undertaken an appropriate approach to

implementing the new requirements, an NC will be reported and will

usually be cited as an ‘minor' NC against the relevant part of the GMP

standard.

� Wherever companies demonstrate they are meeting the minimum � Wherever companies demonstrate they are meeting the minimum

expectations , no NC will be cited.

15

Areas of ApplicationAreas of Application tbctbc

Risk Assessment

Risk Analysis

Risk Identification

InitiateQuality Risk Management Process

A General

QRM Process

Model

16

Team approach

Risk Review

Ris

kC

om

mu

nic

ation

Risk Evaluation

unacceptable

Risk Control

Risk Reduction

Review Events

Risk Acceptance

Output / Result of theQuality Risk Management Process

Risk

Managem

entto

ols

Areas of Application Areas of Application tbctbc

Core Principles of Quality Risk Management:

1) Compliance with applicable laws.

Risk assessment should be used to assess how to ensure compliance and

to determine the resulting prioritization for action — not for a decision

regarding the need to fulfill applicable regulations or legal requirements.

2) Risk can only be effectively managed when it is identified, assessed,2) Risk can only be effectively managed when it is identified, assessed,

considered for further mitigation, and communicated.

— 4 stages of effective QRM process (risk assessment, risk control, risk

communication & risk review).

3) All quality risk evaluations must be based on scientific and process-

specific knowledge and ultimately linked primarily to the protection of the

patient (Figure 1 next).

17


18

Figure 1 – Quality risk evaluation pyramid


Core Principles of Quality Risk Management:

4) Effective risk management requires a sufficient understanding of the

business, the potential impact of the risk, and ownership of the results of

any risk-management assessment.

5) Risk assessment must take into account the probability of a negative event

in combination with the severity of that event.in combination with the severity of that event.

— Definition of risk = Probability of occurrence of harm and

severity of that harm

6) It is not necessary or appropriate to always use a formal risk-management

process (e.g., standardized tools).

— use of informal risk management process (e.g. empirical assessment) is

acceptable for less complex areas which have lower potential risk.

19


Risk assessment supporting tools:

• Determine the appropriate risk assessment tool/methodology

– A key early step in the execution of a risk analysis .

• No single best choice of risk assessment tool/methodology

– The selection based on:

o the depth of analysis required

o complexity of the subject risk of concern

o the familiarity with the assessment tool

• Risk ranking and filtering and flowcharting

– most popular tools used for basic risk-assessment activities.

20


Risk assessment supporting tools:

• Failure Mode Effect Analysis (FMEA)

– appeared to be the most frequently used methodology for more

advanced risk analysis.

• Often a combination of various tools may be required to facilitate risk

assessment.assessment.

21

PIC/S GMP Guide – Annex 20 on Quality Risk Management

Appendix 1 – Risk Management Methods & Tools

• Not an exhaustive list.

1) Basic Risk Management Facilitation Methods

2) Failure Mode effects Analysis (FMEA)

Areas of Application Areas of Application tbc

Common risk management toolsCommon risk management tools

22

2) Failure Mode effects Analysis (FMEA)

3) Failure Mode, Effects & criticality Analysis (FMECA)

4) Fault Tree Analysis (FTA)

5) Hazard Analysis & Critical Control Points (HACCP)

6) Hazard Operability Analysis (HAZOP)

7) Preliminary Hazard Analysis (PHA)

8) Risk Ranking & Filtering

9) Supporting Statistical Tools


Common risk management toolsCommon risk management tools

23


Severity categorization Severity categorization –– an e.g.an e.g.

24


Some Examples

25

Some Examples

[1] Equipment Replacements[1] Equipment Replacements——Functional EquivalenceFunctional Equivalence tbc

Background

• Obligation to ensure that manufacturing equipment is properly designed,

installed, tested, operated, and maintained throughout their service

lifetimes.

• Manufacturing equipment will likely require both preventive and

corrective maintenance activities that may involve the replacement of corrective maintenance activities that may involve the replacement of

parts within the systems.

• Appropriate change controls to be applied to parts replacements

→ ensure that manufacturing equipment remains in a validated state.

• If replacement parts are exactly identical to the original parts

→ little issue with change control considerations.

26


• However, it is not uncommon for procuring and installing replacement

parts that are not identical to the original parts.

– due to changes affected by parts suppliers (e.g., product re-designs,

discontinuations).

• A risk-management approach used to assess

→ whether replacement parts are functionally equivalent (i.e., like-for-→ whether replacement parts are functionally equivalent (i.e., like-for-

like) with original parts

→ ensure proper change control while also preventing unnecessary

revalidation activities.

27


• In this case study, a risk-management approach was taken by the

manufacturer to identify the following:

– Risks associated with equipment parts changes that might adversely

impact the validated state of manufacturing equipment

– Risks associated with the process of determining whether original and

replacement parts are functionally equivalentreplacement parts are functionally equivalent

– Proper roles and responsibilities of the team of SME involved

What are the outputs?

– A generic, robust, and repeatable process for performing

functional-equivalence assessments.

– Define organizational roles and responsibilities supporting the

process.

28


Risk Question & Risk Assessment Method

• Risk question:

Who should be involved to assess whether replacement parts are

functionally equivalent with original parts?

• Company chooses to develop one risk assessment model for overall • Company chooses to develop one risk assessment model for overall

(generic) assessment of functional equivalence to achieve these aims:

– Identify potential gaps, inconsistencies, and redundancies within the

process that had historically been used for replacement parts

functional equivalence determinations.

– Identify new or improved activities.

29



• The team examined the risk question and core activities involved in the

historical functional equivalence assessment process. Identified the

following observations:

– Functional equivalence assessment process was historically dependent

upon human judgment, expertise, and experience.upon human judgment, expertise, and experience.

– Process risks (e.g., potential breakdowns of the process) were

qualitative in nature and difficult to quantify with specificity.

• Risk assessment team selected Fault Tree Analysis (FTA) as risk

assessment method.

– FTA is well suited for analysis of qualitative fault conditions that may

be related to human performance factors.

30


Risk Identification, Analysis & Evaluation

• The risk assessment process involved

– a review and analysis of the change control system

→ to determine how equipment parts replacements could potentially

cause unwanted or undetected change to the equipment's validated

state. state.

• The analysis was organized into the fault tree structure (Figure 1 next).

31


Figure 1 – Fault Tree Analysis

[Equipment changes &

validation impact]

32


Figure 1 – Fault Tree AnalysisFigure 2 – Fault Tree Analysis

[Functional equivalence

assessment]

33


Risk Control

For each of the 2 areas of significant risk identified in the FTAs, associated risk

control plans were established, as follows:

• Training curricula were created to define the training and qualification

criteria for personnel initiating functional equivalence assessments.

• Roles and responsibilities for each functional area participating in • Roles and responsibilities for each functional area participating in

functional equivalence assessments were elaborated in the form of

executable checklists .

→ thorough and consistent assessment to be done.

34


Risk Control

• This approach resulted in:

– Minimising both gaps and redundancies in the assessment efforts

– Creating a common assessment record format to facilitate overall

review of the assessment package

– Functional area checklist details unique areas of consideration for the – Functional area checklist details unique areas of consideration for the

assessment and with assessment conclusions and signatures of the

assessor(s).

�Example of a checklist from Engineering function at Table 1

� (see next).

35


Table 1 –

Checklist

template

36


Risk Documentation & Communication

• The outputs of this risk management effort comprise the documented

justification for revisions to the quality system documents:

– Training and qualification curricula for personnel initiating change

controls where functional-equivalence will be assessed

– Equipment change control standard operating procedures on the – Equipment change control standard operating procedures on the

functional equivalence assessment process for parts replacements

– Maintenance systems inventory process control flow.

• Training is required to be performed on these updated documents and

training records are periodically audited for compliance.

37

[1] Equipment Replacements[1] Equipment Replacements——Functional EquivalenceFunctional Equivalence

Risk Review

• Routine internal audits and document reviews are performed throughout

each of the functions impacted by this risk assessment (i.e., training,

change control, and equipment maintenance).

• Adverse findings or trends identified during these audits/reviews

→ provide indication whether the risk assessment needs to be revised or → provide indication whether the risk assessment needs to be revised or

fine tuned.

38

[2] Process Deviation[2] Process Deviation——Empty Product CapsulesEmpty Product Capsules tbc

Background

• A finished product manufacturer produces pain-free capsules, which are

indicated as an anti-epileptic and for treatment of neuropathic pain.

• Multiple customer complaints of empty capsules were received.

– Lot ABC was fully distributed in the market and no stock of the

affected batch remains within company control. affected batch remains within company control.

• There is no evidence of product tampering.

• Batch record review indicated that during processing, a loose dosator was

replaced on the encapsulation equipment.

• Following replacement and prior to resuming encapsulation,:

→ perform acceptance testing of capsules (as per SOP) → product met

requirements.

39


Background

• Further investigation revealed that the loose dosator caused empty

capsules to be produced.

• This empty capsule removal system includes a reservoir for holding empty

capsules rejected during the manufacturing process.

– Loose dosator → atypically high number of reject empty/low fill – Loose dosator → atypically high number of reject empty/low fill

capsules were produced → overflowing of holding reservoir.

• The reservoir was physically located over the acceptable capsule flow.

– Holding reservoir overflowed → potential for rejected capsules to fall

back into the acceptable capsule exit chute → re-introduced to the lot.

40



• Risk Question:

Do a small number of potential low fill or empty capsules in a single batch

of product pose an unacceptable risk to patients, and secondarily, to the

company?

• In this case study, the risk factors are more qualitative than quantitative. • In this case study, the risk factors are more qualitative than quantitative.

• Failure Mode Effects Analysis (FMEA) is specifically designed to

systematically study processes for possible failure modes and then to

develop actions to mitigate these failure modes.

• Need to consider additional element — detectability of the defect.

– Is it possible for the pharmacist or the patient to readily detect empty

capsules?

41



• The FMEA technique is an optimal tool for this application as this standard

methodology includes all three risk components (i.e., probability, severity,

and detectability).

• Hence, the risk methodology selected for the subject case study is: FMEA.

42



• FMEA process involves the identification of potential risks that could be

caused by empty capsules in the market & possible consequences of each

risk.

– sufficient data may not always be available

– risk identification based on best available data, scientific knowledge – risk identification based on best available data, scientific knowledge

and historical experience

• Examples of potential risks:

– patients may receive empty capsules,

– product supply shortage

– audit observation from internal auditor/regulatory authority

– etc.

43



• Numerical ratings for the FMA analysis are based on the following criteria:

1) Severity of the failure

2) Frequency of the failure

3) Ability to detect the parameter

• A numerical ranking of 1–3 is applied to each evaluated hazard, as

demonstrated in the example FMEA risk-score ranking table using a three-

point ranking scale (Table 1 next).

44


Table 1

45



• In the FMEA analysis, the company determined:

– If risk evaluation score moderate or greater → appropriate risk

mitigating actions required to lower the risk to an acceptable level.

– if the score for an evaluated hazard > 9 → corrective measures to the

reduce risk of failure will be taken.reduce risk of failure will be taken.

• If after attempting risk mitigation, the score could not be lowered below 9,

the resulting risk would not be accepted.

• For those items with a score below the defined threshold, risks will be

accepted. Conclusions are documented.

• An example worksheet for calculating the Risk Evaluation Score for this

analysis is presented in Table 2 (next).

46


Table 2

47


Risk Control

• Risk reduction and acceptance decisions focused on patient safety.

• Despite the apparently low number of empty/low fill capsules that may be

present, there was no assurance that the numbers of empty capsules in

the market was low.

• Capsule shell is opaque → a pharmacist or patient unable to detect an • Capsule shell is opaque → a pharmacist or patient unable to detect an

empty or partially filled capsule readily.

48


Risk Control

• Most importantly, the potential medical consequence for some patients

due to receiving and administering an empty or partially filled capsule was

severe.

• As a result of the potentially high risk associated with some patients taking

empty/low-fill capsules, and the inability of the company to implement empty/low-fill capsules, and the inability of the company to implement

appropriate risk mitigating actions to lower this risk (i.e., severity and

ability to detect) to an acceptable level, the decision was taken to initiate

a product recall.

49



• Site procedures require preparation and Quality division endorsement of a

deviation report.

• The risk assessment output was incorporated into a number of existing

work processes and their associated documentation.

• To prevent re-introduction of rejected product to the product, an • To prevent re-introduction of rejected product to the product, an

automated sensor was incorporated into the empty capsule reject

reservoir. When activated, this sensor automatically shuts down the

encapsulation machine should rejected capsules in the reservoir reach the

sensor level, thereby preventing overflow.

• The overflow sensor with automated equipment shutdown was applied to

all encapsulation machines at the firm.

50

[2] Process Deviation[2] Process Deviation——Empty Product CapsulesEmpty Product Capsules


• Additionally, the results of the FEMA analysis and recommendation for

product recall were presented at an internal management meeting :

– Minutes of risk analysis and associated conclusions were documented.

– Affected regulatory agencies were formally notified of the recall

decision.decision.

Risk Review & Conclusion

• To gain additional understanding of the extent of the defect that reached

the market through:

– Evaluation of product complaints.

– Adverse event reports.

– Further examination of product received from the product recall.

51

[3] [3] GMP SelfGMP Self--Inspection Inspection tbc

Background

• Formal self-inspection - an integral part of an effective quality system in a

GMP-compliant pharmaceutical manufacturing facility.

• Involved periodic internal audits of site operations (e.g., quality,

manufacturing, engineering, logistics) and associated systems with

potential GMP impact. potential GMP impact.

• Overall administration of the internal audit program is the responsibility of

the quality control (QC) unit.

• The QC unit is responsible to identify the focus, frequency and resources

to support the internal audits as well as to determine the effectiveness of

the conducted audits.

• Internal audits are typically conducted according to a predetermined

schedule and on a regular basis.

52


Background

• The manufacturing site is a diverse finished product facility.

• Ideally, the site would be able to perform internal audits of all site

operations and systems within a given calendar year … but not always easy

to do so.

• One potential approach to administer an effective internal audit system is • One potential approach to administer an effective internal audit system is

to determine audit frequency based upon the criticality of the various

operations.

• The site maintains a list of current operations and also periodically reviews

and understands the performance of these operations and associated

systems.

• The company’s management recognizes that there are certain internal

systems that could benefit from additional attention.

53


Background

• Site management wants to ensure that resources are applied to those

operations having the highest potential for GMP impact.

• Use of quality risk management (QRM) as a tool to effectively prioritise a

and allocate resources for internal audits of various functional areas.

54



• Risk Question:

What is the optimal internal audit schedule to ensure that those

operations and associated systems with the greatest potential impact on

product quality and, therefore, potentially the patient, are audited on a

more frequently than those determined to be less critical?more frequently than those determined to be less critical?

• An internal audit is a diverse activity with more qualitative characteristics

than quantitative ones.

• Therefore, the selected risk assessment tool will produce a qualitative

description of risk (e.g., high, medium, or low).

• An additional objective of the selected tool — assist in the organization of

data as the assessment moves to the next stage of the process.

55



• The developed list of site operations and associated systems ensures

identification of the potential risks.

• Hence, a complex risk assessment tool is not required. A simple tool that

allows for qualitative analysis and evaluation is sufficient.

• Risk assessment methodology selected: Risk ranking and filtering.• Risk assessment methodology selected: Risk ranking and filtering.

56


Risk Identification & Analysis

• The site has prepared a master list identifying all operations and

associated systems which have potential impact on product quality

(Table 1 next).

57


Table 1 —

Risk evaluation

score

58



• The risk analysis stage of the QRM process estimates the potential harm(s)

associated with each potential risks.

• The analysis may be qualitative or quantitative in nature, or a combination

of the two.

• The risk score will be determined by combining the probability/likelihood • The risk score will be determined by combining the probability/likelihood

of a problem in a given site operation and the outcome.

• The risk evaluation score is calculated as follows:

(Probability Score × Outcome Score) = Risk Evaluation Score

• Numerical value of 1, 2, or 3 is assigned to correspond with a low,

medium, or high risk analysis determination, respectively.

59



• The probability and outcome scores and subsequent risk evaluation scores

for the selected operations are presented in Table I.

• If desired, the evaluation could be further modified to include

consideration of the length of time since the last audit was performed.

• Formula for determining the risk evaluation score can be modified to • Formula for determining the risk evaluation score can be modified to

include the time since the last audit as follows:

(Probability Score x Outcome Score) + (Years since last audit) =

Risk Evaluation Score

• With application of QRM, the site is now able to better prioritize resource

utilization to focus auditing efforts on those areas with the highest risk

scores.

60


Risk Control

• Risk is reduced by identifying site operations above a specific threshold

score from the risk ranking, and scheduling internal audits for those

operations.

• Inherent risk will be accepted for those site operations which are below

that threshold. that threshold.

• For those operations, an internal audit will be deferred until audits have

been completed for those operations with a higher risk ranking.

61


Risk Review

• During development of annual schedule — review the risk assessment

process and assumptions made.

• The site will confirm that included operations/systems are still in use,

remove those that are not and add any new operations/systems to the

process.process.

• Examples of changes that may potentially impact risk of site operational

systems include:

– changes to control systems

– changes to equipment and processes

– changes in suppliers/contractors

– organizational restructuring

62



• Communication of the utilized QRM process should include all key

stakeholders of the affected departments to ensure organizational buy-in

and support.

• Documentation needed and endorsed by site Quality Unit:

– Output of QRM process– Output of QRM process

– The audit schedule

– Associated risk analysis justifying the approach

– Effective communication to stakeholders.

63

Summary Summary tbc

The concept of QRM is not necessarily new to pharmaceutical

manufacturers and inspectors in GMP environments. But there is a greater

emphasis now on adopting more formalised approaches to QRM.

Effective QRM facilitates better and more informed decisions, and provide

regulators with greater assurance of a company’s ability to deal with

potential risks.potential risks.

The degree of rigor and formality of QRM should reflect available

knowledge and be commensurate with the complexity and/or criticality of

the issue to be addressed.

When integrated in quality systems, QRM is intended to enable and

enhance compliance with regulatory requirements and science-based

decisions.

If QRM is done properly, there should be increased assurance of quality

(and possibly cost savings).

64

SummarySummaryThe QRM process should not be used as an excuse to delay or avoid

compliance gaps/issues or complying with regulatory requirements.

There is no “one size fits all” risk management methods for all application

areas.

Manufacturer is responsible for identifying areas of application,

identifying risk to product quality and managing that risk.identifying risk to product quality and managing that risk.

QRM will be reviewed at each GMP audit.

Auditors will be flexible and ready to debate/accept outcome based on

good science.

65

Further ReadingFurther ReadingT. Frank et al., Pharm. Technol. 35 (7), (8), (10), (12) 2011

PIC/S Guide to GMP (PE 009-9) & Annex 20 (www.picscheme.org)

QRM – Implementation of ICH Q9 in the pharmaceutical field, PS/INF

1/2010

Application of hazard analysis and critical control point (HACCP)

methodology to pharmaceuticals, Quality assurance of pharmaceuticals. methodology to pharmaceuticals, Quality assurance of pharmaceuticals.

A compendium of guidelines and related materials. Vol. 2, 2nd updated

edition. Good manufacturing practices and inspection. Geneva, WHO,

2007.

ICH Q9 Briefing Pack (www.ich.org)

ICH Q8/Q9/Q10 Training Material (www.ich.org)

www. tga.gov.au

www.mhra.gov.uk

66

Thank you for your attention!Thank you for your attention!

67

HPRG JOINT REGULATORY WORKSHOP Year: 2012

Case Study – Review of a Quality System Procedure

INTRODUCTION:

THE COMPANY PTE LTD is a local manufacturer of a range of western pharmaceutical products in various

finished dosage forms and is in the midst of conducting its routine self inspection. You are one of the

auditors in the inspection team and you are provided with a copy of the supplier qualification

procedure1 for review. (Please refer to your workshop folder for the copy.)

TASK:

Review the SOP and

i) identify (by circling it) the possible non-conformities against the PIC/S GMP Guide and

ii) Identify areas for improvement (if any).

Please note that the associated documents and forms related to the SOP are not needed to complete

this case study.

OUTCOME OF SOP REVIEW:

The outcome of the review will be presented at the end of the case study.

1 The content of this document, including the name of the company and name of the signatories are

fictitious and is written for the purpose of this workshop. Any resemblance to actual names or scenario

should be deemed as mere coincidence.

THE COMPANY PTE LTD

Title: RAW MATERIAL SUPPLIER ASSESSMENT, APPROVAL AND

MONITORING

Document No.: QA-2043-03

Doc Type: SOP Dept: Quality Assurance (QA) Supersedes: QA-2043-02

Prepared by:

Ctrlalt Del

Written by:

Wolverin

Approved by:

Yearofdra Gon

Page Number: 1 of 5

Effective Date: 30/09/2010

Date: Date: Date:

1.0 PURPOSE

Procedure to approve suppliers of Raw Materials (including primary packaging material) for production use

in accordance with the current GMP requirements for finished pharmaceutical products.

Note: References to Raw Materials throughout this procedure include primary packaging materials.

2.0 RESPONSIBILITY

2.1 Quality Assurance (QA) is responsible for:

2.1.1 Implementation of the procedure.

2.1.2 Review of all supplier approval documentation to ensure it is in compliance with this

procedure, GMP requirements and that only supplier that are capable of supplying

materials which meet THE COMPANY PTE LTD requirements are approved.

2.1.3 Maintenance of regulatory filings and notifications as a result of new/changed suppliers.

2.1.4 Assessment of impact of changes to THE COMPANY PTE LTD products and notification

where deemed necessary.

2.2 Supply Chain (SC) is responsible for:


2.2.2 Maintaining the Approved Suppliers List.

2.2.3 Ensuring that materials are ordered from approved suppliers

2.2.4 Serve as primary contact and coordinator with suppliers.

2.3 Quality Control (QC) is responsible for:


2.3.2 Ensuring that analysis of samples is performed as per documented procedures and that

results are submitted for filing as per this procedure.

3.0 SCOPE

The procedure provides for approving of all suppliers of Raw Materials for THE COMPANY PTE LTD

manufacturing facility.

THE COMPANY PTE LTD


MONITORING


Supersedes: QA-2043-02

Doc Type: SOP Dept: Quality Assurance (QA) Page Number: 2 of 5


4.0 DEFINITIONS

Approved supplier A supplier which is fully approved for the supply of Raw Materials for production

use.

Non manufacturing material A material or item that is not used in the manufacturing process but is used in some

ancillary capacity where there is no direct product contact e.g. boiler salt, battery

acid, sodium hypochlorite.

Critical raw material A raw material which is the active ingredient of a product or which has major impact

on formulation of the product as categorized by SC.

Primary Packaging Materials Packaging that is intended to be in direct contract with the product.

5.0 PROCEDURE – RAW MATERIALS SUPPLIERS

5.1 The need for a new supplier and/or material is identified by the department using the material or SC. In

the case of new product development, process development, new product support or research and

development, material must be at a minimum provisionally qualified before it is going to be used in

manufacturing.

5.2 SC will identify potential suppliers and will initiate initial discussions regarding pricing, raw material and

service requirements. As part of this, SC will confirm the suppliers ability to provide material meeting

THE COMPANY PTE LTD requirements by either:

5.2.1 Forwarding a copy of the THE COMPANY PTE LTD specifications and requirements for the

material to the supplier for confirmation they can supply to those requirements and/or

5.2.2 Request copy of the suppliers specification for the material being evaluated, this will be

reviewed internally at THE COMPANY PTE LTD to confirm it meets requirements.

5.3 If the supplier is an existing approved supplier of other Raw Materials, SC & QA will determine and

document if existing questionnaires or scope of supply cover the new material and can be applied to

the new approval.

5.4 If deemed necessary above, SC submits questionnaire to the prospective supplier for completion area.

5.5 SC will request any samples of material required.

5.5.1 Non-Critical Raw Materials - Three samples from three different lots of material

(min 30g each).

5.5.2 Critical Raw Materials – Three samples from three different lots of material (min 150g each).

THE COMPANY PTE LTD


MONITORING





NOTE: In exceptional circumstances, if the supplier cannot provide 3 samples from 3 different batches,

this will be assessed with QA and a risk assessment performed to develop a rationale for alternative

sample submission requirements. This must be reviewed and approved by Site Director and QA.

5.7 Samples received are submitted to QC for testing with the Supplier Approval Sheet with

section 1 completed.

5.8 QC Analysis of Raw Materials

5.8.1 Each sample is assigned the next sequential QC number and detail of the sample recorded in

the QC number register. The QC number of each sample and the corresponding supplier’s lot

number must be recorded on the Supplier Approval Sheet.

5.8.2 Samples are analyzed as per the current version of the relevant monograph. If there is no

current monograph available, testing is performed per the supplier’s specification/certificate of

analysis. The completed analysis requisition is reviewed by the QC supervisor.

5.8.3 On completion of QC testing, all critical Raw Materials must be Use-tested. For non-critical Raw

Materials, QC Management may decide that further analysis or Use testing is required.

5.8.4 Where Use testing is required, the sample will be submitted to the R&D Dept accompanied by

a ‘Use Test Request Sheet’ (QAD-025).

5.8.5 The R&D Dept will submit the product formulated from the material to the QC Dept

accompanied by the completed Use Test Request sheet recommending material acceptance or

otherwise.

5.8.6 The completed analysis requisition and Use test sheet is reviewed by the QC department.

5.8.7 On completing QC analysis of the Use test, QC Management fills Section 2 of the Supplier

Approval Sheet.

5.9 An on-site audit is not mandatory, the need for an on-site audit will be determined based on risk

factors such as intended use of the material, criticality of the Raw Material and other risks as deemed

appropriate. This will be documented on the supplier approval form. Audit is normally carried out by

the Marketing Department.

5.10 For suppliers of critical Raw Materials, an on-site audit is always recommended.

5.10.1 If an audit is recommended but cannot be performed within the timeframe that the material is

required, the supplier may be approved once the audit has been added to the supplier audit

schedule subject to all other requirements for supplier approval have been completed and are

satisfactory. This will be justified and documented on the supplier approval form.

5.11 If the review of QC and Use testing is acceptable, then the supplier is approved.

THE COMPANY PTE LTD


MONITORING





5.12 If the review of QC and Use testing concludes that the supplier cannot be approved then a

determination will be made as to whether continue with this supplier and work with them to

determine the reason for the failure and correct it or to find another supplier.

5.14 If the supplier is deemed acceptable, the paperwork is completed and the Approved Suppliers List

updated by SC. Completed documentation is filed as per documentation section below. Orders may be

placed with the supplier for approved products. SC will issue an MSDS for new Raw Materials to

Safety (as necessary) who in turn will circulate it to all relevant functional areas.

NOTE: For non-manufacturing material which has no product contact, detailed testing and evaluation is

not required.

6.0 SUPPLIER MONITORING

6.1 Problems with suppliers subsequent to approval must immediately be brought to the attention of QA

and SC by raising the Material Feedback Sheet (QAD-188)

6.2 SC will communicate these to the supplier and will request a written response.

6.3 The response will be reviewed by QA and SC for acceptability. Further clarification/corrective action will

be requested if deemed necessary.

6.4 If the response remains unsatisfactory, the supplier maybe removed from the Approved Suppliers List

6.5 On an annual basis, suppliers of critical Raw Materials will be contacted to identify any changes to their

details which will have an impact on the goods they provide.

6.5.1 Audit or re-audit of existing suppliers may be performed if deemed warranted based on poor

performance during the year or as part of the investigation of a material issue.

7.0 REGULATORY REQUIREMENTS

7.1 Where the supplier/manufacturer of a Raw material is changed, QA must assess the impact of this

change on the quality of product manufactured. This assessment must be filed with the supplier

approval documentation.

7.1.1 Where applicable a regulatory submission may be necessary to comply with regulatory

requirements of the products registered.

THE COMPANY PTE LTD


MONITORING





8.0 RELATED DOCUMENTS

Supplier Approval Sheet (QAD-135)

Supplier Assessment Questionnaire (QAD-162)

Use Test Request Sheet (QAD-025)

Service Supplier Qualification Sheet (QAD-194)

Service Supplier Assessment Questionnaire (QAD-193)

Approved Supplier List

Workshop 5Workshop 5Good Manufacturing Practice for Medicinal Products ManufacturersGood Manufacturing Practice for Medicinal Products Manufacturers

CASE STUDY – REVIEW OF A QUALITY SYSTEM

PROCEDUREPROCEDURE

Presented by:Ng Liong Thiam

Dy Dir (GMPL Unit)

Audit Branch (AB)

Introduction Introduction

• A GMP case study on the review of a quality system procedure of a

pharmaceutical manufacturer.

• Main purpose of case study is to encourage active participation and

information sharing on the application of GMP principles.

• The quality system documents that we will be reviewing today is a

procedure on supplier qualification.

• Give an overview on the aspect of supplier qualification

Overview of Supplier QualificationOverview of Supplier Qualification• Purchasing of starting material for production use

• important function

• involve staff with knowledge of the suppliers

•Starting material should only be purchased from approved suppliers

named in the relevant specification.

•All aspects of requirements of the starting material is to be discussed

with the suppliers:

•Specification

•Control and production aspects including handling

•Labeling and packaging requirement

•Approach taken for complaints and rejection

•Supply requirement

•Others

Overview of Supplier QualificationOverview of Supplier Qualification

• Changes in supply of raw materials should be subject to a formalized

change control process.

• The purchase, handling and control of primary and printed packaging

material should be accorded attention similar to that given to starting

materials.materials.

Overview of Supplier QualificationOverview of Supplier Qualification

• Supplier qualification system and procedure(s) should be established

• Gathering information and identify potential suppliers

• Questionnaires

• Supplier records (if any)

• Others

•Assessing of suppliers including the material to be supplied

• QC testing

• Use testing

• Site inspections

• Review of track records (if applicable)

Overview of Supplier QualificationOverview of Supplier Qualification• Supplier qualification system and procedure(s) should be established (cont)

•Approving of suppliers

• review of assessment made e.g. testing report, audit report etc

• supply agreement (if applicable)

•formalize the approval/rejection process including

•the updating of approved supplier list

• Monitoring of suppliers

•document all transaction including supply problem, quality

problem, and complaints

• follow-up on CAPA and complaint (if any)

• conduct periodic audit or re-audit (if necessary)

• updating of changes by supplier

• periodic review of qualification status

Case Study ExerciseCase Study Exercise

• Introduction

• Mocked up and written for the purpose of this workshop

•Local manufacturer in midst of conducting its self inspection and

you are one of the internal auditors

•Task•Task

•Review the SOP

•Identify possible non conformities against GMP Guide and

•Identify area for improvement (if any)

• SOP Review

• Given some time to review the SOP and discuss

•Associated documents and forms to the SOP are not required to

complete the case study

•Outcome will be presented after the SOP review

Review of Case StudyReview of Case Study

• Approval section on page 1 inadequate – there is no functional titles

for the signatory

• Header section of page 1 - the effective date is earlier than the

approved date which means SOP is effective before approval

• Paragraph 4 on Definition – the term non-critical raw material was not

defined (to differentiate it from the critical raw material) which will

explain the rational for the difference in sampling requirement as

mentioned in paragraph 5.5 between the two groups of material

• Paragraph 5.8 on QC Analysis is too detail for this procedure – should

be parked under the QC procedure (and put under responsibility of QC)


• Missing subsection: 5.6 and 5.13

• Paragraph 5.9 Auditing by Marketing Department: In this case, the

Marketing Department should have the adequate GMP training in

order to assess effectively the supplier. As far as possible, QA should

take part in the audit.take part in the audit.

• Paragraph 5.9 states that an audit is not mandatory and based on a

number of risk factors – however it fall short of giving guidance on risk

factors when an on-site audit has to be performed

• Paragraph 5.10.1 – the use of material before audit when it has been

deemed necessary is an issue – should be covered by applying risk

minimisation factors such as additional sampling


• Paragraph 5.11 Supplier Approval –reviewing only the QC report and

Use testing report for approval not adequate.

Should also include others like the questionnaire, the audit report, the

previous track records (if any) etc.

Any gap identified should be clarified and evaluated as to whether the

approval process can proceed.approval process can proceed.

• Paragraph 5.14 & 6.4 states SC will update the supplier list – such list

should also be approved by QA who is the “owner” of this SOP.


• Supplier monitoring inadequate

• Paragraph 6.1 to 6.4 suggest monitoring for acceptability is only on

problem area (if any) – this should be more detailed to include

other key performance indicators e.g. Supply track records,

response to request etc

• Paragraph 6.5 - Changes to the supplier of critical raw material

should be pre-notified by the supplier on their own accord in a

timely manner for review and approval (if necessary) – not only

annually.

• Paragraph 6.5.1 - A maximum time interval between two audits

should be determined for critical raw-material suppliers.


• Paragraph 8 on related documents section is inadequate:

• Approved Suppler List should be a controlled document with a

unique document number (i.e. QAD number)

• Material Feedback Sheet (QAD-188) mentioned in paragraph 6.1 is

not referenced under this sectionnot referenced under this section

• Service supplier document (QAD-194 and QAD-193) not referred

to in this SOP was listed here

• Missing reference essential to this SOP – e.g. Change Control

procedure, guidance documents on how to perform on-site audits

ConclusionConclusion

• The list of possible non-conformities and areas for

improvement presented as the outcome of the case study in

the previous slides is not to be taken as exhaustive.

• A copy of this presentation is available at the counter on your

way out after the workshop session.way out after the workshop session.

• Thanks to the Steering Committee of the PIC/S Expert Circle on

API for sharing a model of the case study presented during the

4th Expert Circle Meeting on API held in Singapore in Oct 2011.

THANK YOU THANK YOU

Updates on PIC/S GMP Standard including Site Master File Guidance

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