The APIC Audit Programme

The APIC Audit Programme Standardised Cost APIC-certified GMP Compliance A Third Party Audit Programme for API Manufactureres An Initiative of APIC in co-operation with CONCEPT HEIDELBERG A sector group of Coordinated by API Compliance Institute

Necessity for API Manufacturers to Comply with cgmp for APIs - Legal Background - According to the US Food and Drug Law the manufacturer of active pharmaceutical ingredients (APIs) has to comply with the current Good Manufacturing Practices, and the manufacture of APIs is object of FDA inspections. The legal situation in Europe is different: From 30 October 2005 on, cgmp for APIs used in the manufacture of human and/or veterinary medicinal products will be required by law in Europe, but authority inspections at the premises of API manufacturers will only be carried out whenever grounds for suspecting non-compliance with the principles and guidelines of GMP are considered. On the other hand, a competent authority of an EU Member State must be able to satisfy itself that the manufacture and distribution of active substances has been carried out in accordance with the principles of GMP for APIs. According to a recently published EMEA draft guidance, it is therefore planned that when applying for a marketing authorisation (or a variation to change or add a new active substance manufacturer) the applicant has to submit a declaration from the manufacturing authorisation holder that the API concerned has been manufactured according to the GMP for APIs. The competent authorities expect that the manufacturing authorisation holder will base such a declaration on carrying out or having carried out on an audit of the manufacturers/distributors of the active substances concerned. One of the primary means by which the competent authorities will determine whether manufacturing authorisation holders are in compliance with the above articles will be the examination, by inspectors, of the audit programmes used by authorisation holders for conducting regular audits (every 2-3 years), including review of audit reports (see Draft Guidance on the occasions when it is appropriate for Competent Authorities to conduct inspections at the premises of Manufacturers of Active Substances used as starting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, Doc.Ref. EMEA/INS/GMP/50288/2005 from 02 March 2005). What is the APIC Audit Programme? The APIC Audit Programme is a third party audit programme for auditing API manufacturers, distributors and API contract manufacturers and/or contract laboratories. This programme was developed by APIC/CEFIC in cooperation with CONCEPT HEIDELBERG It is the aim of the APIC Audit Programme to offer an independent and turnkey GMP Compliance audit of API manufacturers and/or distributors, including organization, conduct and evaluation of the audit. An APIC Audit within the framework of the APIC Audit Programme can be initiated by an API manufacturer or distributor in order to get independent information about the GMP compliance status, e.g. when preparing for authority inspections. It can also be initiated by the manufacturing authorization holder (the pharmaceutical company) for carrying out audits on its

behalf in order to fulfil the requirements of the European Legislation. APIC audits will be conducted worldwide. The participation in the APIC Audit Programme is on voluntary basis and not limited to members of APIC. How can GMP audits be standardised? There are three basic principles of the APIC Audit Programme for standardizing audits: experienced and trained auditors that are registered as APIC certified auditors standardised process for preparing audits release of audit report by experienced API specialists The audits are conducted by APIC certified auditors who have the professional experience, who have completed an ICH Q7a compliance education course and a special APIC Auditor Training who have participated in regular auditor refresher seminars who have signed a contract laying down the obligations as an auditor in the framework of the APIC Audit Programme The audits are conducted on the basis of the ICH Q7a (Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients) with regard to the APIC Auditing Guide. Save money and optimise the GMP Audit The aims of The APIC Audit Programme are: standardised GMP audits of API manufacturers minimised costs by - decreasing the frequency of audits when making the audit report available to pharmaceutical companies - standardized costs for audits Will Third Party Audits be Accepted by the Authorities? An audit is an important tool for evaluating GMP compliance. A frequently asked question in connection with the APIC Audit Programme is whether a third arty audit will be accepted by the authorities. According to a recently published draft Guidance on the occasions when it is appropriate for Competent Authorities to conduct inspections at the premises of Active Substances used as starting materials it is expected that the holder of the manufacturing authorization 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.

This clearly states that third party audits are being accepted. Similar third party programmes have already been established in other areas: ARC (Audit Repository Center), a PDA-associated company, offers auditing programmes for the audit of software suppliers, the IPEC (International Pharmaceutical Excipients Council) provides Third Party Auditing Programmes for excipient suppliers. With regard to the acceptance of Third Party Audits IPEC member Irwin Silverstein said "lawyer with both industry and FDA experience have been involved in developing the program and (that) nobody has raised a concern that the third party audit would present more of a problem than having your own people do the same audit". (Gold Sheet, Vol 34, No. 1, January 2000). *) A declaration from the manufacturing authorization holder that the active substance(s) concerned has(have) been manufactured in accordance with the detailed guidelines on good manufacturing practice for starting material. Who Coordinates the APIC Audit Programme? The APIC Audit Programme will be coordinated by the API Compliance Institute. The API Compliance Institute was founded on 19 December 2002. The basis for the activities of the API Compliance Institute is constituted by a contractual agreement between APIC, a sector group of CEFIC, and CONCEPT HEIDELBERG. It is the mission of the API Compliance Institute to standardize GMP audits of API manufacturers and to minimize the costs. For further information about the APIC Audit Programme, please visit the web page of the API Compliance Institute. http://www.api-compliance.org The APIC Audit Programme - Step by step - A GMP audit can be initiated by but is not limited to: Manufacturers of active pharmaceutical ingredients as well as - Agents, brokers, distributors, repackers and relabellers of APIs - Contract manufacturers of API manufacturers - Contract laboratories of API manufacturers Pharmaceutical companies that manufacture either medicinal products for human use or veterinary medicinal products in order to fulfil their obligations according to Directives 2001/83/EC and 2001/82/EC as amended.

The following flow chart describes the steps from the initial contact with the company (auditee) to the finalisation of the audit report. IMPORTANT: As the APIC Audit Programme is a worldwide third party auditing programme. The audits will be conducted in English and the Audit Report will be written in English.

Preliminary Talks Before placement of an order by an interested customer the API Compliance Institute will have preliminary talks on the following topics, among others: Scope of the audit, steps of the audit process, expected time inputs and expected costs, etc. Provided the customer signed a contract with the API Compliance Institute the order is considered awarded an the further steps can be followed. Preparation for the Audit For gaining initial information about the company (auditee) and to effectively plan the audit a questionnaire will be sent to the company (auditee) in advance. After return of the completed questionnaire to the API Compliance Institute, auditors will be selected upon the information given in the questionnaire. The questionnaire will also be handed on to the selected auditors for their preparation. The company (auditee) will appoint a contact person (audit representative) responsible for the handling of the audit. Selection of APIC Certified Auditors In general, the APIC Compliance Institute will select two certified auditors from their register. The company (auditee) will be notified of the names of the auditors. The company (auditee) is entitled to reject the appointed auditors, but will be asked to explain the reasons for rejecting the auditor. In these cases new auditors are going to be selected. Preparation and Execution of the Audit Before the audit the company (auditee) will receive an audit plan from the auditors, detailing the major topics of the audit and a tentative schedule. Immediately after the audit all major observations and remaining questions will be discussed and clarified during the final wrap up. If, for any reason, a re-audit of follow-up audit deems to be necessary, the date for the re- (follow-up) audit as well a s the selection of the auditors will be set by the API Compliance Institute. An additional order is required. Finalizing the Audit Report At the latest, within a period of 4 weeks after the audit, the company (auditee) will receive a draft audit report. The audit report will include a management summary as well as a detailed list of observations. The company (auditee) may respond to the observations, proposing corrective actions, responsibilities and time frames. The final audit report is being released by APIC before sending it to the company (auditee). The company (auditee) will receive the original audit report for use without limitations.

The Auditors In general, the audits will be conducted by two auditors who are registered as APIC certified auditors. APIC certified auditors will undergo extensive training programmes as described on page 2 of this brochure and have to verify their professional experience. APIC will authorise a register of certified auditors who are allowed to conduct the audits within the framework of the APIC Audit Programme. Validity The basic audit report is valid for three years. Prior to the expiration, a new audit for the renewal of the validity can be carried out at the company s (auditee s) site. Costs The average costs for a GMP Audit conducted by two qualified APIC auditors will be EURO 8.400,-- plus VAT, plus travel expenses. Contact If you are interested in joining The APIC Audit Programme, please contact us for further information: Dr Barbara Jentges P.O. Box 10 17 64 69007 Heidelberg, Germany Phone +49-(0) 6221-84 44 0 Fax +49-(0) 6221-84 44 34 E-mail: jentges@concept-heidelberg.de OR Mr Pieter van der Hoeven, CEFIC Active Pharmaceutical Ingredients Committee (APIC) Av. E. Van Nieuwenhuyse 4 / box 2 1160 Brussels, Belgium Phone +32 2 676 72 02 Fax +32 2 676 73 01 E-mail : pvd@cefic.be