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The APIC Audit Programme Overview

• API GMP Audits Regulatory Framework
• Directive 2001/83/EC as amended
• Restructuring of the EG GMP Guide
• API Audit expected by Competent Authorities in
  the Future?
• API GMP Audits - Need for Standardisation
• API GMP Audits Problems with ...
• APIC/CEFIC Guidance Document APIC Auditing Guide
• Solution The APIC AUDIT Programme
• Coordination by API Compliance Institute
• Steps in Managing an Audit
• Qualified and Certified Auditors
• Conclusions
• Discussion Major Issues to look for in a GMP API
  Audit

3
The APIC Audit Programme Overview

• API GMP Audits Regulatory Framework
• Directive 2001/83/EC as amended
• Restructuring of the EG GMP Guide
• API Audit expected by Competent Authorities in
  the Future?
• API GMP Audits - Need for Standardisation
• API GMP Audits Problems with ...
• APIC/CEFIC Guidance Document APIC Auditing Guide
• Solution The APIC AUDIT Programme
• Coordination by API Compliance Institute
• Steps in Managing an Audit
• Qualified and Certified Auditors
• Conclusions
• Discussion Major Issues to look for in a GMP API
  Audit

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API GMP Audits Regulatory Framework
Prerequisite for placing on the market ...
_________ ) see Consolidated Directive
2001/83/EC of the European Parliament and of the
Council of 6 November 2001 on the Community code
relating to medicinal Products for human use as
amended by Directive 2002/98/EC, Directive
2004/24/EC and Directive 2004/27/EC and
Commission Directive 2003/63/EC (amending Dir
2001/83/EC, e.g. replacing is Annex 1) and
Consolidated Directive 2001/82/EC of the European
Parliament and of the Council of 31 March 2004
amending Directive 2001/82/EC on the community
code relating to veterinary medicinal products.
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API GMP Audits Regulatory Framework
Responsibilities of the Holder of a MA -
1 -
For Medicinal Products for Human Use
see Directive 2001/83/EC as amended Article 46
(f) ) The holder of a manufacturing
authorisation shall at least be obliged (f) to
comply with the principles and guidelines of good
manufacturing practice for medicinal products and
to use as starting materials only active
substances, which have been manufactured in
accordance with the detailed guidelines on good
manufacturing practice for starting
materials. This point shall also be applicable to
certain excipients, the list of which as well
as the specific conditions of application shall
be established by a Directive adopted by the
Commission (...) ) Citation from the
Consolidated Directive 2001/83/EC of the European
Parliament and of the Council of 6 November 2001
on the Community code relating to medicinal
products for human use as amended by Directive
2002/98/EC, Directive 2004/24/EC and Directive
2004/27/EC ______ MA Manufacturing
Authorisation
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API GMP Audits Regulatory Framework
Responsibilities of the Holder of a MA -
2 -
For Veterinary Medicinal Products see Directive
2001/82/EC as amended Article 50 (f) ) The
holder of a manufacturing authorisation shall at
least be obliged (f) to comply with the
principles and guidelines of good manufacturing
practice for medicinal products and to use as
starting materials only active substances, which
have been manufactured in accordance with the
detailed guidelines on good manufacturing
practice for starting materials. ) Citation
from the Consolidated Directive 2001/82/EC of the
European Parliament and of the Council of 6
November 2001 on the Community code relating to
veterinary medicinal products as amended
by Directive 2004/28/EC. ______ MA
Manufacturing Authorisation
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API GMP Audits Regulatory Framework
Responsibilities of the Distributors
- 1 -
For Medicinal Products for Human Use
see Directive 2001/83/EC as amended Article 46a
) 1. For the purposes of this Directive,
manufacture of active substances used as starting
materials shall include both total and partial
manufacture or import of an active substance used
as a starting material as defined in Part I,
point 3.2.1.1 (b) Annex I), and the various
processes of dividing up, packaging
or presentation prior to its incorporation into a
medicinal product, including repackaging or
re-labelling, such as are carried out by
distributor of starting materials. ) Citation
from the Consolidated Directive 2001/83/EC of the
European Parliament and of the Council of 6
November 2001 on the Community code relating to
medicinal products for human use as amended by
Directive 2002/98/EC, Directive 2004/24/EC and
Directive 2004/27/EC ) see Annex I of
Commission Directive 2003/63/EC of 25 June 2003,
amending Directive 2001/83/EC of the European
Parliament and of the Council on the Community
code relating to medicinal products for human
use.
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API GMP Audits Regulatory Framework
Responsibilities of the Distributors
- 2 -
For Veterinary Medicinal Products see Directive
2001/82/EC as amended Article 50a ) 1. For the
purposes of this Directive, manufacture of active
substances used as starting materials shall
include the complete or partial manufacture or
the import of an active substance used as a
starting material as defined in Part 2, Section
C of Annex I, and the various processes of
dividing up, packaging or presentation prior to
its incorporation in a veterinary medicinal
product, including repackaging or re-labelling,
such as are carried out by a starting material
distributor. ) Citation from the Consolidated
Directive 2001/82/EC of the European Parliament
and of the Council of 6 November 2001 on the
Community code relating to veterinary medicinal
products as amended by Directive 2004/28/EC.
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API GMP Audits Regulatory Framework
Detailed Guidelines on GMP for APIs
Article 47) / Article 51) The principles of
good manufacturing practice for active
substances used a starting materials referred to
in point (f) of Article 46 (in Article 50(f))
shall be adopted in the form of detailed
guidelines. ) Citation from the Consolidated
Directive 2001/82/EC of the European Parliament
and of the Council of 6 November 2001 on the
Community code relating to veterinary medicinal
products as amended by Directive 2004/28/EC. )
Citation from the Consolidated Directive
2001/83/EC of the European Parliament and of the
Council of 6 November 2001 on the Community code
relating to medicinal products for human use as
amended by Directive 2002/98/EC, Directive
2004/24/EC and Directive 2004/27/EC
Annex 18 of EG GMP Guide
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API GMP Audits Regulatory Framework
Restructuring of EU GMP Guide - 1
-
In order to fulfil the requirements laid
down in article 47 of Directive 2001/83/EC as
amended by Directive 2004/27/EC (relating to
human medicinal products) and Article 51 of
Directive 2001/82/EC as amended by Directive
2004/28/EC (relating to veterinary medicinal
products), the Member States have now agreed
after discussion at EMEAs ad hoc inspections
Services group that Annex 18 will no longer be
considered as annex, but it will form a new, Part
II of the EU GMP Guide (see Ad Hoc GMP
Inspections Services, Concept Paper on the
revision of some annexes to the European GMP
Guide in the context of the GMP for active
substances, May 2005). Within this
restructuring the EU GMP Guide will be presented
in 2 Parts Part I dealing with finished
products Part II dealing with active
substances used as starting materials (applicable
for medicinal products for both, human and
veterinary use).
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API GMP Audits Regulatory Framework
Restructuring of EU GMP Guide - 2
-
Annex 18 EG GMP Guide Good Manufacturing
Practice for Active Pharmaceutical
Ingredients 1.3 Scope This Guide applies to the
manufacture of APIs for use in human
drug (medicinal) products. Draft revision of the
introductory section of the current GMP annex
18. (According to that, the current Annex 18 is
foreseen to become Basic Requirements Part II,
while the current Basic Requirements are to
become Part I). 1.2 Scope These guidelines apply
to the manufacture of active substances for
medicinal products for both human and veterinary
use with the exception of ectoparaciticides.
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API GMP Audits Regulatory Framework
Need for Supplier Qualification

Good Manufacturing Practices Chapter 5
Production (from The rules governing medicinal
products in the European Union, Volume 4, Good
Manufacturing Practices http//dg3.eudra.org)
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API GMP Audits Regulatory Framework
GMP Audits Tool for Supplier Qualification

Good Manufacturing Practices Chapter 5
Production (from The rules governing medicinal
products in the European Union, Volume 4, Good
Manufacturing Practices http//dg3.eudra.org)
Conducting a GMP Audit is a major tool
for supplier qualification and gives information
about the GMP status
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API GMP Audits Regulatory Framework
Competent Authorities expect API Audits - 1-
Draft Guidance on the occasions when it is
appropriate for Competent Authorities to conduct
inspections at the premises of Manufacturers of
Active Substances used as starting
materials Principle (...) When an application
for a marketing authorisation, or variation to
change or add a new active substances
manufacturer, is submitted, the applicant will be
required to include a declaration from the
manufacturing authorisation holder that the
active substance(s) concerned has/have been
manufactured in accordance with the detailed
guidelines on good manufacturing practice for
starting materials. ) Citation from Draft
Guidance on the occasions when it is appropriate
for Competent Authorities to conduct inspections
at the premises of Manufacturers of Active
Substances used as starting materials
http//dg3.eudra.org/F2/pharmacos/docs/Doc2005/03_
05/ASM20Inspections20Guidance20_final_20050303.
pdf)
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API GMP Audits Regulatory Framework
Competent Authorities expect API Audits - 2-
Draft Guidance on the occasions when it is
appropriate for Competent Authorities to conduct
inspections at the premises of Manufacturers of
Active Substances used as starting
materials Principle It is expected that the
holder of the manufacturing authorisation will
base such a declaration on carrying out, or
having carried out on his behalf, an audit of the
manufacturers/distributors of the active
substances concerned. Examinination, by
inspectors, of the audit programmes used by
authorisation holders for conducting regular
audits (every 2 3 years)) including review of
audit reports, is one of the primary means by
which Competent Authorities will determine if
manufacturing authorisation holders are in
compliance with the above articles (...) )
Citation from Draft Guidance on the occasions
when it is appropriate for Competent Authorities
to conduct inspections at the premises of
Manufacturers of Active Substances used as
starting materials http//dg3.eudra.org/F2/phar
macos/docs/Doc2005/03_05/ASM20Inspections20Guida
nce20_final_20050303.pdf)
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API GMP Audits Regulatory Framework
Emphasis on Compliance
Regulatory Compliance?
MAA)
GMP- Documentation
API Manufacture
_______________________ )
Marketing Authorisation Applicaton and
accompanying documents
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The APIC Audit Programme Overview

• API GMP Audits Regulatory Framework
• Directive 2001/83/EC as amended
• Restructuring of the EG GMP Guide
• API Audit expected by Competent Authorities in
  the Future?
• API GMP Audits - Need for Standardisation
• API GMP Audits Problems with ...
• APIC/CEFIC Guidance Document APIC Auditing Guide
• Solution The APIC AUDIT Programme
• Coordination by API Compliance Institute
• Steps in Managing an Audit
• Qualified and Certified Auditors
• Conclusions
• Discussion Major Issues to look for in a GMP API
  Audit

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API GMP Audits Regulatory Framework
Guidance for conducting GMP Audits

• WHO GMP Guideline Chapter 5 General advice on
  how to conduct audits in pharmaceutical companies
• Principle
• Items for Self-inspection
• Frequency of Self-inspection
• Follow-up Action
• Quality Audit
• Supplier Audit

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API GMP Audits Regulatory Framework
Standard for Quality Audits
ISO 190112002 Guidelines for quality and/or
environment management systems auditing This
international standard provides guidance on the
management of audit programmes, the conduct of
internal or external audits of quality and/or
environmental management systems, as well as on
the competence and evaluation of auditors. It is
intended to apply to a broad range of potential
users, including auditors, organizations
implementing quality and/or environmental
management systems, organisations needing to
conduct audits of quality and/or environmental
management systems for contractual reasons, and
organizations involved in auditor certification
or training, in certification/registration of
management systems, in accreditation or in
standardization in the area of conformity
assessment.
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API GMP Audits Need for Standardisation
Problems may arise from ...
- 1 -
Flow chart of audit activities
... a lack of standardisation for planning,
conducting, and documenting the audit
observations.
Audit preparation!??
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API GMP Audits Need for Standardisation
Problems may arise from ...
- 2 -
... an audit overflow
Audit Plan 2006
EDQM Inspection

• Audits/Inspections expected from
• Customers
• Authorities, e.g. FDA,
• EDQM, EMEA
• etc.

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API GMP Audits Need for Standardisation
Problems may arise from ...
- 3 -
... untrained and helpless auditors
Is the documented cleaning validation sufficient?
Does this water quality fulfil the requirements?
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API GMP Audits Need for Standardisation
Problems may arise from ...
- 4 -
... unqualified conclusions documented in the
audit report
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API GMP Audits Need for Standardisation
Problems may arise from ...
- 5 -
... unqualified conclusions documented in the
audit report
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API GMP Audits Need for Standardisation
Problems may arise from ...
- 6 -
... unqualified conclusions documented in the
audit report
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API GMP Audits Need for Standardisation
Solution APIC Auditing Guide

• APIC Auditing Guide
• (including 4 Annexes)
• Secrecy Agreement
• Questionnaire
• Aide Memoire
• Audit Report

ACTIVE PHARMACEUTICAL INGREDIENTS COMMITTEE
(APIC) Auditing Guide          
August 2002
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http//apic.cefic.org
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The APIC Audit Programme Overview

• API GMP Audits Regulatory Framework
• Directive 2001/83/EC as amended
• Restructuring of the EG GMP Guide
• API Audit expected by Competent Authorities in
  the Future?
• API GMP Audits - Need for Standardisation
• API GMP Audits Problems with ...
• APIC/CEFIC Guidance Document APIC Auditing Guide
• Solution The APIC AUDIT Programme
• Coordination by API Compliance Institute
• Steps in Managing an Audit
• Qualified and Certified Auditors
• Conclusions
• Discussion Major Issues to look for in a GMP API
  Audit

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The APIC Audit Programme
Coordination of the APIC Audit Programme
For the purpose of managing the audits In the
framework of the APIC audit Programme, the API
Compliance Institute was founded on 19 Dec
2002 http//www.api-compliance.org
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The APIC Audit Programme
What are the aims?

• Standardized GMP Audits in compliance with the
• principles laid down in the CEFIC/APIC
  Auditing Guide
• Experienced and trained auditors that are
  registered as APIC certified auditors
• Standardized process for preparing and conducting
  audits
• Release of audit report
• Controlled Costs
• Standardized audit costs

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The APIC Audit Programme
Phases of an Audit

• Steps in Managing an Audit
• Pre Audit Information
• Preparation of the Audit
• Performing the Audit
• Reporting and Response
• Follow up
• Possible Breakdown

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The APIC Audit Programme
Appendix A Secrecy Agreement
1 The purpose of disclosure of the information
is to enable the Auditors to conduct their audit
in the facilities of the customer with a view
into the quality related procedures. 2 The
Auditor herewith declares his independence and
assures the Auditee of not being employed or
supported by a competing company of the
Auditee. 3 The audit will be conducted in a
way that is in accordance with the European
Competition Law. It has to be taken care during
the audit that no sensitive and/or technical
information is given to the Auditors if the
latter are working for a competing company. The
Auditee reserves the right to refuse to disclose
requested confidential information by the
Auditor.
Purpose of this agreement is to protect
the knowledge of the auditee to not be abused by
the auditor.
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The APIC Audit Programme
Appendix B Pre-Audit Questionnaire
... It is the purpose of the questionnaire to
facilitate the preparation of the auditors for
the audit at your company and to make it as
efficient as possible. (...) Every information
provided (...) will be treated strictly
confidential ...

• Chapters of Appendix B
• General Information about the company
• Quality related information
• Product related information
• GMP related information
• Comments from the auditee
• Requested documents (e.g. CEP, DMF)

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The APIC Audit Programme
Appendix C Aide Mémoire
General remark Chapters 1 to 19 of this Aide
Mémoire refer to the appropriate chapters of
ICH Q7a. Chapter 20 relates to aspects of
Quality Management Systems according to ISO.
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The APIC Audit Programme
Appendix D Audit Report Template - 1 -

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The APIC Audit Programme
Appendix D Audit Report Template - 2 -
Key for Classification of observations
Serious
Major
Minor
   
Recommendations
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The APIC Audit Programme
Who can participate?

• Participation
• Voluntary basis
• Open to all API manufacturers, API contract
  manufacturers, contract laboratories, API traders
  world-wide

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IMPORTANT The auditee is free to use the audit
report without limitations. The audit report can
not be received by (and/or bought from) APIC or
Concept!
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The APIC Audit Programme
Qualified and certified Auditors

• Prerequisites for conducting an audit
• Educational background and professional
  experience
• Participation in special Auditor
  Training Courses
• Auditor Seminar
• Refresher Seminar
• Valid contract between auditor
  CONCEPT HEIDELBERG
• Certification as APIC Auditor

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The APIC Audit Programme
Qualified vs Certified Auditors
Interested Person
Educational Background and Experience
Important Employees of authority
and/or government cant be certified as
APIC Auditors because of conflict of interests !!
Database with Qualified APIC Auditors
Participation in the Auditor Seminar

• Participation in Refresher
• Seminar within 3 years after
• qualifying as APIC auditor
• Valid Contract with
• Concept Heidelberg

Selection for execution of an audit
Database with Certified APIC Auditors
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The APIC Audit Programme
Practical Part

• Auditors (First qualification seminars in January
  2003)
• 40 qualified Auditors
• 13 certified Auditors
• Conducted Audits so far (all of them were
  initiated by API manufacturers)
• 1 Pilot Audit conducted in September 2003
• 3 Audits in 2004
• further audits are being conducted in 2005

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The APIC Audit Programme
Critical Remarks
API manufacturers are not sure whether the
pharmaceutical industry and the authorities will
accept these audit reports for their supplier
qualification. The pharmaceutical companies
on the other hand have their own audit policy and
internal staff who is responsible for conducting
supplier audits More information is needed
about the advantages of the APIC Audit Programme
communicated to both, the pharmaceutical industry
and the authorities.
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The APIC Audit Programme Overview

• API GMP Audits Regulatory Framework
• Directive 2001/83/EC as amended
• Restructuring of the EG GMP Guide
• API Audit expected by Competent Authorities in
  the Future?
• API GMP Audits - Need for Standardisation
• API GMP Audits Problems with ...
• APIC/CEFIC Guidance Document APIC Auditing Guide
• Solution The APIC AUDIT Programme
• Coordination by API Compliance Institute
• Steps in Managing an Audit
• Qualified and Certified Auditors
• Conclusions
• Discussion Major Issues to look for in a GMP API
  Audit

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Discussion
Major Issues to look for in a GMP API Audit
Question What are the major issues to look for
in a GMP Audit of an API Manufacturer?
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The APIC Audit Programme Overview

• API GMP Audits Regulatory Framework
• Directive 2001/83/EC as amended
• Restructuring of the EG GMP Guide
• API Audit expected by Competent Authorities in
  the Future?
• API GMP Audits - Need for Standardisation
• API GMP Audits Problems with ...
• APIC/CEFIC Guidance Dcoument APIC Auditing Guide
• Solution The APIC AUDIT Programme
• Coordination by API Compliance Institute
• Steps in Managing an Audit
• Qualified and Certified Auditors
• Conclusions

Thank you for your attention.