updates on pic/s gmp standard

8/10/2019 Updates on PIC/S GMP Standard

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Updates on PIC/S GMP Standard

nc u ng te aster e gu ancePresented 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)

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(A) An update on PIC/S memberships

(B) PIC/S publications

(C) An update on proposed revision toPIC/S GMP Guide in the pipeline

In the EMA (EU) pipeline

(D) Site Master File

(E) Q&A. Discussion

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A C A C

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

Submitted & accepted Membership Accession Application on 28 Oct2008

At last PIC/S COMMITTEE OF OFFICIALS MEETING held on 7 & 8,

/ JAZMP to join the PIC/S Scheme with effect from 1 January 2012.

40 YEARS ANNIVERSARY AND 40th

MEMBERS WITH THEACCESSION OF SLOVENIA / JAZMP

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

A

B

C

C

D

E

ISouth Africa

Israel

F

F

G

G

H

I

I

Argentina

Canada

USA

Australia

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SINGAPORE

CANADA

40 PIC/S Members January 2012

USA

AUSTRALIA

ARGENTINASOUTH AFRICA

MALAYSIA

ISRAEL

UKRAINE

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PIC/S PublicationsPIC/S Publications

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Documents for industry

PIC/S GMP Guide

Site Master Files

Documents for inspectorates

Inspectorates

Documents for inspectors

Q&A Documents

Current PIC/S PublicationsCurrent PIC/S Publications

Aide-Memoires

Guidance documents

Documents for the public

Information documents

Press Release

PIC/S Seminars

Miscelleneous

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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

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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 002-3


- -

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

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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


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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 (Dsseldorf, 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 KualaLumpur, Malaysia, November 2010


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

Miscelleneous

/ 1/2010 A A AA A20100108 A G IC/ () .

IC/ / G

IC/ . IC/ IC/

.

C/DA& 20090129 IC/ DA IE

(EIC/ G A 1) G 1314 2008 ( ).

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

IC/ G G

Originally, the PIC/S GMP Guide (PIC Basic Standards of 1972) derivesfrom the WHO GMP Guide and was further developed subsequently.

In 1989, the EU adopted its own GMP Guide, which in terms of GMPrequirements was equivalent to the PIC/S GMP Guide. Since that time,

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

whenever a change has been made to one, the other has been amendedso that both Guides are practically identical.

IC/ G G

22 2001, IC/ G G AI (ICH 7A) (E 007).

2930 2006, IC/ II G.

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IC/ G G

Revisions History of PIC/S GMP GuideRevisions 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 editors 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 Editors co-ordinates 15


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

Date VersionNumber

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)

5 April 2007 PE 009-6

,

(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 Editors 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


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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 notPIC/S)

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

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

PIC S has not ublished released an new chan es

Changes to PIC/S GuideChanges to PIC/S Guide

since last revision -- Version: PE-009-9 released on 1 Sept2009

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A new consultation procedure between PIC/S and the

Harmonisation of guidance documentsHarmonisation of guidance documents

EA C C IC/

uropean e c nes gency a een scusse norder 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 current

documents and endorsement of new documents, includingthe sharing of early drafts in order to facilitate appropriateinvolvement in the adoption process.

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Adopted by PIC/S Adopted by PIC/S

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

Status:

Adopted and entered into force on 1st January 2012.

20


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In theIn the PIC/SPIC/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

A 6 (

)

A

31 2010.

BA

A 7 (

)

A

1 2009.

BA

A 11 (C ) A BA

.

A 13 (

)

A

31 2010

BA

A 14 (

)

A

30 2011.

A

C 4 (D) A

30 2011.

BA

(AI)

A

31 2010.

BA

21


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


EU/EMA PIC/S

G Part III of GMP Guide wascreated and include:Site Master File;ICH Q9; andICH Q10

TBA

: F

E

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

The revised documententered into force on 1

.

2011, the PIC/S Secretariatadded a footnote into therevised SMF without formallyamending the document. Thefootnote indicates that aD-U-N-S reference is requiredfor Site Master Filessubmitted to EU/EEAauthorities for manufacturingsites located outside of theEU/EEA.

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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 CoO

meeting (Switzerland/Geneva ) in May 2012

The proposed revised Annex 6 was initiated as a consequence of the restructuringof the GMP Guide and the need to modify the requirements of Part II of the Guide

Revisions to the GMP Guide in theRevisions to the GMP Guide in the PIC/SPIC/S pipelinepipeline

what should be considered as a starting material as opposed to a bulkpharmaceutical product. The opportunity has also been taken to update the annexin 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 whichextent (i.e. per individual cylinder, batch or customer?). It was proposed the bestway 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 sealingof cylinders and mobile cryogenic vessels to authorise devices in addition to seals

(e.g. Cylinders and mobile cryogenic vessels should be fitted with tamper-evidentseals or devices). 23


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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.

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

A 7 E G G. A 7


.

G A C (GAC) .

7 E A 7 :

H

G A .

C , . A

.

/

G A C .

24


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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

A ricultural and Collection Practice or e uivalent and if not a l a ro riate

E


controls in line with QRM.

Italy / AIFA is in favour of the original EU version. AIFA has also counterproposed:

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


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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 theherbal substance / preparation are in compliance with Good Agricultural andCollection 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 orequivalent would be added).

26


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Proposed Revision of ANNEX 11 (Computerised Systems) andChapter 4

Status:

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



Key proposed changes:

C 4

27


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REVISION OF ANNEX 13 MANUFACTURE OF INVESTIGATIONALMEDICINAL PRODUCTS

Status:


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


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

28


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

(i) A/GA : ( 26 1, ) '' ,

/ /

. ( 26 1 )

'' , : " 300

".


.

(ii) I/IC (.. " 2C8C"). I ,

" ", A 13,

30.

It was proposed to integrate the above comments as footnotes in the revised Annex 13

of the PIC/S GMP Guide.

29


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

Status:



,

meeting (Switzerland/Geneva ) in May 2012

:

3

D G B

30


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CHAPTER 4 of the GMP Guide (Documentation)

Status:

At EU level, this revised Chapter 4 (Documentation)has come into operation

on 30

th

June 2011. (Same as Annex 11 on Computerized systems)



: A 11

G ( )

F,

I (, )

;

, , I;

();

; .

31


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Re i ion to the GMP G ide in theRe i ion to the GMP G ide in the PIC/SPIC/S pipelinepipeline


33/162

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

E..4.29 There should be written policies, procedures, protocols, reports and the associated

records of actions taken or conclusions reached, where appropriate, for the followingexamples:

- Validation and qualification of processes, equipment and systems;- Equipment assembly and calibration;

- Technology transfer;

- Maintenance, cleaning and sanitation;

-


, ,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

R i i h GMP G id i hR i i h GMP G id i h PIC/SPIC/S i lii li


34/162

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.



Changes:

The proposed revised Part II was initiated in order to incorporateprinciples of QRM corresponding to similar changes made to Part I,Chapter 1 of the Guide. A new section on QRM was introduced as section2.2. The remaining sections of chapter 2 are renumbered. No otherchanges have been made.

34


35/162

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 conce t -- Not ado ted b


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 Guidefor collection of GMP related documents which are not themselves GMPguidelines and have no statutory force (i.e. non-binding documents) butwhich complement the GMP guidelines and related regulatory proceduressuch as inspections. It is expected that in the future, further documentswill 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

P d R i i t th EU GMP G idP d R i i t th EU GMP G id I th EU (EMA)I th EU (EMA)


36/162

Proposed Revisions to the EU GMP GuideProposed 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

I C 1 2 New texts of chapter 1 proposedduring last EMAs GMP/GDP IWGmeeting. Revision of chapter 2 willbe done after consolidation ofchapter 1.

Participating Authoritiesrequested to send theirfeedback on proposedrevisions by 15 Feb 2012.

I C 3 5

(D F)

EMAs Safety Working Party haspublished Concept Paper ondevelopment of toxicological tools.

Participating Authorities areinvited to comment onproposed Concept Paper

I C 5(AI

)

Slight changes proposed during last

EMAs GMP/GDP IWG meeting.

New draft is invited for

comments till 15th Feb 2012.

I C 5(

)

&A ,

.

Q&A is invited for commentstill 15th February 2012.

I C 6 (

C)

Work on text has been started; firstdraft will be available for next EMAsGMP/GDP IWG meeting.

After first draft will be sharedwith PIC/S.

I C 7(C

A)

EC.

will be shared with PIC/S.

Part I Chapter 8(notification of productshortage)

First draft should be available fornext EMAs GMP/GDP IWG meeting.

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

36

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


37/162

Proposed Revisions to the EU GMP GuideProposed 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

A 2 (B) Final draft prepared and was sharedwith PIC/S. Adopted and sent to EC

for publication.

Will be tabled for adoption atnext PIC/S CoO

(Switzerland/Geneva) in may2012.

16 Concept paper will be ready fornext EMAs GMP/GDP IWG meeting.

be shared with PIC/S onceavailable.

D GDP Guideline approved for publicconsultation. The work should becoordinated with PIC/S working

group.Format of GDP licence approved forpilot phase till end of 2011.

Ongoing work of PIC/Sworking group. Proposed EUGDP guide are to be sent to

PIC/S PA for their commentsand local public consultation.(this has to be confirmed bychair of PIC/S working groupas discussed at last PIC/Scommittee meeting).

37

i i h G G id i hi i h G G id i h ( )( ) i lii li


38/162

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

CHAPTER 2 (Personnel)

Status:

EU/EMA: New texts of chapter 1 proposed during last EMAs 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 revisionsby 15 Feb 2012.

Revisions to the GMP Guide in theRevisions to the GMP Guide in the EMA(EU)EMA(EU) pipelinepipeline

Proposed changes made to Chapter 1 is to harmonise with ICH Q10 (PartIII) 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

R i i t th GMP G id i thR i i t th GMP G id i th EMA(EU)EMA(EU) i lii li


39/162

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 theRevisions to the GMP Guide in the EMA(EU)EMA(EU) pipelinepipeline

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 effectivecommunication of results)

39

Proposed Revisions to the EU GMP Guide in theProposed Revisions to the EU GMP Guide in the EMA(EU)EMA(EU) pipelinepipeline


40/162

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

CHAPTER 5 (Production)

Status:

EU: EMAs Safety Working Party has published Concept Paper on development oftoxicological tools.

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

Key Proposed Changes:

-


CA 3 AD ()

3.6. I ,

, (.. )

(.. ).

, , , ,

. F

, ,

. , , . 40



41/162



CA 5 DC ()

5.18. C

.

, , , ,

, ' .

. A


, , , .

,

/ .

41



42/162



CA 5 DC ()

5.19 C

, :

) ( , ,

), ( )

;

) ;

pp ( )( ) p pp p

)

;

)

;

) ,

;

) ;

) .

42



43/162



C 3 3.6 & C 5 5.18 & 5.19

I G G ...

, . 3.6 ICH 9

.


(

...

) C EA

G (G) G/GD IF 2011. F

F 2012.

43

Proposed Revisions to the EU GMP Guide in theProposed Revisions to the EU GMP Guide in the EMA (EU)EMA (EU) pipelinepipeline


44/162

Proposed amendment to CHAPTER 5 : Production (API pedigree)

Status:

EU: Slight changes proposed during last EMAs 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


Supp y c ain tracea i ity or starting materia s

Testing for starting materials

Control of contamination (Dedicated facilities)

44



45/162

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 rawmaterial(s) used in the manufacture of the API to themanufacturer of the dosage form.


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

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

45

Proposed Revisions to the GMP Guide in theProposed Revisions to the GMP Guide in the EMA (EU)EMA (EU) pipelinepipeline


46/162

Proposed revision of CHAPTER 6 (Quality Control)

Status:

EU: Work on text has been started; first draft will be available for

next EMAs GMP/GDP IWG meeting.PIC/S: After first draft will be shared with PIC/S.



Analytical method transfer

46



47/162

Proposed Revision of CHAPTER 7 (Contract Manufacture and Analysis tobe renamed as Outsourced Activities)

Status:

EU : Last draft sent for publication by EC.PIC/S : will be shared with PIC/S.


oposed e s o s to t e G Gu de t eoposed e s o s to t e G Gu de t e ( U)( U) p pe ep pe e

Harmonise with ICH Q10 guideline ( ICH )

Proposed revised Chapter 7 provides updated guidance on outsourcedGMP regulated activities beyond the current scope of contract

manufacture and analysis operations. The title of the Chapter has beenchanged to reflect this.

47



48/162

Proposed Revision of CHAPTER 8 (Complaints and Product Recall)

Status:

EU: First draft should be available for next EMAs GMP/GDP IWG meeting.

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


pp ( )( ) p pp p

Defect contact points held at EMA on 7-8 October 2009 on productshortage notifications and to introduce specific Quality Risk Managementconcepts in the context of this chapter.

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

48



49/162

Proposed Revision of ANNEX 2 of the GMP Guide (BiologicalMedicinal Products)

Status:

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

pp ( )( ) p pp p

onsu ng ar c pa ng u or es, n par cu ar, non-

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 astransgenic derived products and the Advanced Therapy Medicinal Products, (ATMPs)together with associated new EU legislation. The GMP guidance drawn up for thelatter products is to meet the requirements of Article 5 of Regulation 1394/2007and to align with details in Directive 2009/120/EC.

49

Other Revisions to the GDP Guide in theOther Revisions to the GDP Guide in the PIC/SPIC/S pipelinepipeline


50/162

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 meetingproposed to be conducted on 18-20 April 2012 in Helsinki/Finland with a viewto adopt EMAs revised Guidelines on Good Distribution Practice.

Reasons for change: The content of the EMA Guidelines on Good DistributionPractice published in 1994 is no longer adequate. It needs to be reviewed to takeinto account advancements of practices for an appropriate storage and distributionof medicinal products in the European Union. Moreover, it should take into accountthe amendments to the Community Code which have been introduced with

Directive 2011/62/EU of the European Parliament and of the Council amendingDirective 2001/83/EC on the Community code relating to medicinal products forhuman use, as regards the prevention of the entry into the legal supply chain offalsified medicinal products.

50

SMFSMF


51/162

PIC/S Explanatory Notes forpharmaceutical manufacturers on there aration of a site master file

SMFSMF

(SMF)(PE 008-4 dated 1 January 2011)

Revision adopted on 1 January 2011

51

PIC/S Explanatory NotesPIC/S Explanatory Notes for pharmaceutical manufacturers on thefor pharmaceutical manufacturers on thepreparation 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)


52/162

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 hascome into operation on 1 January 2011 (First time inhistory that a document is adopted by PIC/S beforeEU level)

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

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

On 15 February, the PIC/S Secretariat added a footnote into the revised SMF withoutformally amending the document. The footnote indicates that a D-U-N-S reference isrequired for SMFs submitted to EU/EEA authorities for manufacturing sites locatedoutside 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 NotesPIC/S Explanatory Notes for pharmaceutical manufacturers on thefor pharmaceutical manufacturers on thepreparation 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)


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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 arealmost identical.

53

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

1 Jan 2011

EU new SMF Guide10 Feb 2011

SMFSMF (Table of Contents))


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1. Document History

2. Introduction

3. Purpose

4. Scope

( ))

5. Content of SMF

6. Revision History

7. Appendices for a Site Master File

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Purpose of the Site Master File


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Purpose of the Site Master File

A Site Master File is a dossier prepared by the manufacturer thatcontains specific information about the Quality Managementsystems, policies and activities of the Company, Manufacturing Site

and/or quality control of manufacturing operations carried out bythe Site.

can be utilized in planning and conducting GMP inspections. A Site

Master File is essential for pharmaceutical companies as itis the basis for the regulatory authority to prepare for aGMP inspection.

The SMF has become compulsory in the EU/EEA as the revisedChapter 4 of the EU GMP Guide has already come into operation on30th June 2011(the SMF will be included in Part 3 of the EU/EEAGMP Guide). The Commission has published the EU/EEA SMF on

its website. 56


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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 expirydates and should be updated and reviewed to ensure it is

representative of current Site activities.

Format and headings should follow the outlined guidance notes.

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

These Explanatory Notes apply for all kind of manufacturing operations suchas production, packaging and labelling, testing, relabelling andrepac ag ng o a ypes o me c na pro uc s. e ou nes o s gu e

could also be used in the preparation of a SMF or corresponding documentby Blood and Tissue Establishments and manufacturers of ActivePharmaceutical Ingredients.

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Several possibilities regarding the indication of the geographiclocation of the site have been added

A listing of the GMP inspections conducted in the past 5 yearsmust 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 P R oint

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

Concrete information on the storage of documents outside thepremises is required

Description of the system which ensures appropriateenvironmental conditions during transportation

Measures taken against illegal infiltration in the supply chain

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Notes address supply chain with Risk Management and incorporateICH 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 ofsuppliers

Compliance with TSE guidelines

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SMF (Changes)SMF (Changes)


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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 anyother geographic location system1.

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

The purpose is to provide more reliability of the site location. Experienceshowed 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



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Identification number: DUNS (Data Universal Numbering System)

What?

An unique, separate and distinct nine-digit number assigned to each businesslocation 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 .

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 andpayment confirmation.

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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?

,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 5decimal places or Degrees Minutes to at least 3 decimal places.

62



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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 Filessubmitted to EU/EEA authorities for manufacturing sites located outside ofthe EU/EEA.

Notes: EDQM -- Since 15 April 2011, applicants for new certificates ofsuitability (CEP) or revisions of CEPs are requested to provide informationin the application form to better identify the location of theirmanufacturing site(s). These additional data are GPS co-ordinates, and(if available) a DUNS number. (i.e. Providing the DUNS number is notmandatory in the framework of the submission of a CEP dossier).

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1.2 Authorised pharmaceutical manufacturing activities of the site.

- ..

-

-

- List of GMP inspections of the site within the last 5 years; including dates andname/country of the Competent Authority having performed the inspection. A copyof current GMP certificate (Appendix 3) or reference to the EudraGMP databaseshould 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 ofthe systems and senior management responsibilities

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

Provide information of accredited and certified activities carried out bythe company

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SMF (Changes)


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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 certificationand releasing procedures;

- General description of batch certification and releasing procedure;

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

- The arrangements between Authorised Persons / Qualified Persons when severalAuthorised 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



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2.3

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

- Brief description of the qualification system of contractors, manufacturers of activepharmaceutical 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, activep armaceu ca ngre en s or exc p en s are en e ;

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

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

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

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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 areerformed at cor orate level and those which are erformed locall . An

application of the QRM system to assess continuity of supply should be mentioned.

2.5 Product Quality Reviews

- Brief description of methodologies used

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4. PREMISES AND EQUIPMENT

4.1 Premises

- Short description of plant; size of the site and list of buildings. If the production fordifferent markets, i.e. for local, EU, USA, etc. takes place in different buildings onthe site, the buildings should be listed with destined markets identified (if notidentified under 1.1);

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

-classification and pressure differentials between adjoining areas and indicating the

production activities (i.e. compounding, filling, storage, packaging, etc.) in therooms;

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

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

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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 (includingpharmacovigilance data, when applicable): List of types ofdocuments/records; Name and address of storage site and an estimate of

time required retrieving documents from the off-site archive.

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6. PRODUCTION6.1. 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 aremanufactured on the site

list of dosage forms of investigational medicinal products (IMP)manufactured for an clinical trials on the site and when different from thecommercial manufacturing, information of production areas and personnel

- Toxic or hazardous substances handled (e.g. with high pharmacological activityand/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.

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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 themanufacturer)

- 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 conditionsduring transit, e.g. temperature monitoring/ control;

- Arrangements for product distribution and methods by which product traceability ismaintained;

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

chain.

72

Appendices of Site Master Files


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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

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74


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THANK YOUTHANK YOUTHANK YOUTHANK YOUTHANK YOUTHANK YOU

Together we will meet thechallenges of the future

75


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TOPIC: APPLICATION OF

Presented by:

Lai Weng FaiActing Director / Senior GMP AuditorLicensing & Certification Branch (LCB)

15 February 2012

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A

.

/

A 4 A 2011.


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