Supported by a sector group of Presented by The APIC Audit Programme Thursday, 13 October 2005 Parallel Session The APIC Audit Programme presented by Dr Tom Buggy, DSM-Anti-Infectives B.V., The Netherlands Dr. Barbara Jentges, Concept GmbH, Germany

Supported by a sector group of Presented by The APIC Audit Programme 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 The APIC Audit Programme – Overview

Supported by a sector group of Presented by The APIC Audit Programme The APIC Audit Programme – Overview

Supported by a sector group of Presented by The APIC Audit Programme _________ *) 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. Prerequisite for placing on the market... Quality Efficacy Safety Placing on the Market *) Chapter 1 Marketing Authorisation 1.No medicinal product (veterinary product) may be placed on the market of a Member State unless a marketing authorisation has been issued by the Competent authorities of that Member State (...)“ Placing on the Market *) Chapter 1 Marketing Authorisation 1.No medicinal product (veterinary product) may be placed on the market of a Member State unless a marketing authorisation has been issued by the Competent authorities of that Member State (...)“ GMP API GMP Audits – Regulatory Framework

Supported by a sector group of Presented by The APIC Audit Programme Responsibilities of the ‚Holder of a MA‘ API GMP Audits – Regulatory Framework 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 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

Supported by a sector group of Presented by The APIC Audit Programme Responsibilities of the ‚Holder of a MA‘ 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 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 API GMP Audits – Regulatory Framework

Supported by a sector group of Presented by The APIC Audit Programme Responsibilities of the Distributors 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 (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. 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 (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. API GMP Audits – Regulatory Framework

Supported by a sector group of Presented by The APIC Audit Programme Responsibilities of the Distributors 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. 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. API GMP Audits – Regulatory Framework

Supported by a sector group of Presented by The APIC Audit Programme 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 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 Detailed Guidelines on GMP for APIs Annex 18 of EG GMP Guide API GMP Audits – Regulatory Framework

Supported by a sector group of Presented by The APIC Audit Programme 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 EMEA’s 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). Restructuring of EU GMP Guide API GMP Audits – Regulatory Framework

Supported by a sector group of Presented by The APIC Audit Programme 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. Restructuring of EU GMP Guide API GMP Audits – Regulatory Framework

Supported by a sector group of Presented by The APIC Audit Programme 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; API GMP Audits – Regulatory Framework

Supported by a sector group of Presented by The APIC Audit Programme 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; Conducting a GMP Audit is a major tool for supplier qualification and gives information about the GMP status Conducting a GMP Audit is a major tool for supplier qualification and gives information about the GMP status API GMP Audits – Regulatory Framework

Supported by a sector group of Presented by The APIC Audit Programme API GMP Audits – Regulatory Framework 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; 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; Competent Authorities expect API Audits - 1-

Supported by a sector group of Presented by The APIC Audit Programme API GMP Audits – Regulatory Framework 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; 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; Competent Authorities expect API Audits - 2-

Supported by a sector group of Presented by The APIC Audit Programme Emphasis on Compliance MAA *) GMP- Documentation _______________________ *) Marketing Authorisation Applicaton and accompanying documents API Manufacture Regulatory Compliance? API GMP Audits – Regulatory Framework

Supported by a sector group of Presented by The APIC Audit Programme The APIC Audit Programme – Overview

Supported by a sector group of Presented by The APIC Audit Programme 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 Guidance for conducting GMP Audits API GMP Audits – Regulatory Framework

Supported by a sector group of Presented by The APIC Audit Programme ISO 19011:2002 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. Standard for Quality Audits API GMP Audits – Regulatory Framework

Supported by a sector group of Presented by The APIC Audit Programme Problems may arise from Audit preparation!?? Flow chart of audit activities API GMP Audits – Need for Standardisation... a lack of standardisation for planning, conducting, and documenting the audit observations.

Supported by a sector group of Presented by The APIC Audit Programme EDQM Inspection Problems may arise from Audit Plan 2006 Audits/Inspections expected from:  Customers  Authorities, e.g. FDA, EDQM, EMEA etc. API GMP Audits – Need for Standardisation... an audit overflow

Supported by a sector group of Presented by The APIC Audit Programme Is the documented cleaning validation sufficient? Does this water quality fulfil the requirements? Problems may arise from API GMP Audits – Need for Standardisation... untrained and helpless auditors

Supported by a sector group of Presented by The APIC Audit Programme Problems may arise from API GMP Audits – Need for Standardisation... unqualified conclusions documented in the audit report

Supported by a sector group of Presented by The APIC Audit Programme API GMP Audits – Need for Standardisation Problems may arise from unqualified conclusions documented in the audit report

Supported by a sector group of Presented by The APIC Audit Programme API GMP Audits – Need for Standardisation Problems may arise from unqualified conclusions documented in the audit report

Supported by a sector group of Presented by The APIC Audit Programme ACTIVE PHARMACEUTICAL INGREDIENTS COMMITTEE (APIC) Auditing Guide API GMP Audits – Need for Standardisation Solution: APIC Auditing Guide APIC Auditing Guide (including 4 Annexes): –Secrecy Agreement –Questionnaire –Aide Memoire –Audit Report August 2002

Supported by a sector group of Presented by The APIC Audit Programme

Supported by a sector group of Presented by The APIC Audit Programme The APIC Audit Programme – Overview

Supported by a sector group of Presented by The APIC Audit Programme APIC Audit Programme is the realisation of the APIC Auditing Guide

Supported by a sector group of Presented by 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 For the purpose of managing the audits In the framework of the APIC audit Programme, the ‚API Compliance Institute‘ was founded on 19 Dec The APIC Audit Programme

Supported by a sector group of Presented by The APIC Audit Programme  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 What are the aims? The APIC Audit Programme

Supported by a sector group of Presented by The APIC Audit Programme Steps in Managing an Audit ØPre Audit Information ØPreparation of the Audit ØPerforming the Audit ØReporting and Response ØFollow up ØPossible Breakdown Phases of an Audit The APIC Audit Programme

Supported by a sector group of Presented by 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. Purpose of this agreement is to protect the knowledge of the auditee to not be abused by the auditor. The APIC Audit Programme

Supported by a sector group of Presented by 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: A.General Information about the company B.Quality related information C.Product related information D.GMP related information E.Comments from the auditee F.Requested documents (e.g. CEP, DMF) Chapters of Appendix B: A.General Information about the company B.Quality related information C.Product related information D.GMP related information E.Comments from the auditee F.Requested documents (e.g. CEP, DMF) The APIC Audit Programme

Supported by a sector group of Presented by 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. 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. The APIC Audit Programme

Supported by a sector group of Presented by The APIC Audit Programme Appendix D: Audit Report Template The APIC Audit Programme

Supported by a sector group of Presented by The APIC Audit Programme Urgency Classification rating The condition will seriously affect the quality of products, regulatory compliance. The condition violates essential GMP-rules and basic quality assurance practices. Immediate action should be taken. Example: Violation of regulatory documents, e.g. DMF or CEP. All observations that will lead to failure of an authority inspection. The condition may affect the quality of the product, regulatory compliance. The condition violates GMP-rules and quality assurance practices. Action is recommended. Example: Not following own procedures and SOPs. The condition may not affect the quality of the product,, regulatory compliance. The condition violates current GMP-rules. Example: Violation of formal aspects of documentation, e.g. missing sugnature in batch record R Recommendation for quality, safety or efficiency improvement. No GMP violation. Example: Industry best practices, e.g. APIC How to do ICH Q7a - Document Appendix D: Audit Report Template Serious Major Minor Recommendations Key for Classification of observations The APIC Audit Programme

Supported by a sector group of Presented by The APIC Audit Programme Participation Voluntary basis Open to all API manufacturers, API contract manufacturers, contract laboratories, API traders world-wide Who can participate? The APIC Audit Programme

Supported by a sector group of Presented by The APIC Audit Programme 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! 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!

Supported by a sector group of Presented by The APIC Audit Programme 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 Qualified and certified Auditors The APIC Audit Programme

Supported by a sector group of Presented by The APIC Audit Programme Educational Background and Experience Educational Background and Experience Participation in the Auditor Seminar Participation in the Auditor Seminar Database with Qualified APIC Auditors Database with Qualified APIC Auditors  Participation in Refresher Seminar within 3 years after qualifying as APIC auditor  Valid Contract with Concept Heidelberg  Participation in Refresher Seminar within 3 years after qualifying as APIC auditor  Valid Contract with Concept Heidelberg Selection for execution of an audit Selection for execution of an audit Database with Certified APIC Auditors Database with Certified APIC Auditors Interested Person Qualified vs Certified Auditors The APIC Audit Programme Important: Employees of authority and/or government can’t be certified as APIC Auditors because of conflict of interests !! Important: Employees of authority and/or government can’t be certified as APIC Auditors because of conflict of interests !!

Supported by a sector group of Presented by The APIC Audit Programme Practical Part The APIC Audit Programme 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 Audits in further audits are being conducted in 2005

Supported by a sector group of Presented by The APIC Audit Programme Critical Remarks The APIC Audit Programme 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.

Supported by a sector group of Presented by The APIC Audit Programme The APIC Audit Programme – Overview

Supported by a sector group of Presented by The APIC Audit Programme Major Issues to look for in a GMP API Audit Discussion Question: What are the major issues to look for in a GMP Audit of an API Manufacturer?

Supported by a sector group of Presented by The APIC Audit Programme The APIC Audit Programme – Overview Thank you for your attention.