Excipact - IPEC-AMERICAS

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EXCIPACT TM

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Minimising the risks, maximising the benefits

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Certification Standards for Pharmaceutical

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Excipients:

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Good Manufacturing practices

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Good Distribution Practices

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14 Requirements for Auditor Competency and 3rd Party

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Audit Organisations providing Certification

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21 Prepared by:

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Excipact TM: Excipient GMP and GDP Certification Scheme

27 Excipact TM: Excipient GMP and GDP Certification Scheme

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29 CONTENTS

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31 Background & Introduction Page 3

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33 Acknowledgements

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35 General Introduction

Page 7 How to use the excipient certification scheme

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37 Certification Standards

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GMP Annex

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Page 23 GDP Annex

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40 3 Party Audit Organisation Page 37 Auditor Competency Requirements

41 Requirements 42

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Auditor Competency Study Guide Quality management system requirements for 3rd

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party audit organisations

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45 Appendices

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46 Glossary

47 References

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49 Background & Introduction 50 51 The safety of medicines for patients is paramount to all those involved in the supply chain, 52 viz., the pharmaceutical industry, suppliers of raw materials, national and regional health 53 care agencies, care givers and regulators. To assure the quality of medicines produced, risks 54 in the supply chain need to be evaluated and minimized, and this includes not only active 55 pharmaceutical ingredients (APIs) but also pharmaceutical excipients.

56 There are a great many different excipients used in medicines and on average over 80% of 57 the volume of each medicinal product are excipients. The pharmaceutical excipient market 58 value is estimated to be 3 bn., or 0.5 % of the total pharmaceutical market according to 59 industry experts. Few excipients are manufactured solely for pharmaceutical use; most are 60 made for other markets, such as food and cosmetics.

61 With proposed legislation requiring GMP and GDP for excipients in Europe and the USA, 62 excipient suppliers will be faced with an avalanche of customer and customer-led 3rd party 63 audits to ensure they and their products meet these new requirements. Excipient suppliers, 64 distributors and the pharmaceutical industry are committed to the supply and use of high 65 quality excipients throughout the supply chain and aim to control this by self-regulation.

66 As a result, a group of industry experts from European Fine Chemical Group (EFCG), 67 International Pharmaceutical Excipients Council (IPEC) Europe, IPEC Americas, European 68 Association of Chemical Distributors (FECC), and Pharmaceutical Quality Group (PQG) have 69 worked together since 2008 on the development of a certification scheme for excipients 70 suppliers ? now known as EXCIPACT TM.

71 These parties are in agreement that an international pharmaceutical excipient good 72 manufacturing practice (GMP) and good distribution practice (GDP) certification scheme will 73 help to ensure the safety of pharmaceutical excipients throughout the supply chain, 74 especially where certification is based on the IPEC-PQG GMP and the IPEC GDP Guides..

75 The EXCIPACT TM scheme provides for an independent certification of manufacturers and 76 suppliers of excipients as a means of ensuring patient safety, improving assurance of 77 supplier quality, while minimizing the overall supply chain costs. At the outset, the Excipact 78 TM Project Global Steering Committee set the following principles and deliverables for the 79 various project teams:

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? "International": an excipient manufacturer's certification should have the same

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acceptance and value anywhere in the world.

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? "Inclusivity": The scheme should provide quality standards and be applicable to as

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many excipients as possible.

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? "Accessibility": The scheme should be accessible from as many 3rd party

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organizations as possible.

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? "Evolution not revolution": Existing best practices, guides and standards should be

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utilised and adapted wherever possible.

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? "Simplicity": The overall scheme should be as simple as possible.

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91 Key deliverables:

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? GMP and GDP standards suitable for 3rd party auditing

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? Definition of auditor competency for the delivery of the scheme

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? Certification scheme rules for 3rd party audit organisations

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? Publication, communication and ongoing maintenance of the schemes, standards

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and guides developed

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98 EXCIPACT TM - Current Status

99 The EXCIPACT TM project teams have drafted the audit standards, auditor competency and 100 3rd party audit organisation requirements. This edition has been updated following

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101 membership comment and feedback. The purpose of this edition is to allow for a review of 102 the document by stakeholders and any others with an interest, prior to finalisation and 103 implementation. 104

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105 Acknowledgements

106 Excipact TM is the result of a huge amount of effort and commitment from a large team of 107 people spanning two continents and many countries. These individuals are members of the 108 partner organisations that comprise Excipact TM and without which this standard could not 109 have been prepared.

110 European Fine Chemicals Group (EFCG)

111 The European Fine Chemicals Group - a sector group of CEFIC, the European Chemicals 112 Industry Council - was formed in 2004 to be the forum, the focus and the voice for European 113 Fine Chemical Manufacturers. The issues affecting its members' competitiveness drive 114 EFCG. One such issue is the need for certifiable, enforceable, adequate and appropriate 115 quality standards for pharmaceutical excipients destined for use in European medicines.

116 For further information visit efcg.

117 Federation of European Chemical Distributors (FECC)

118 The European Association of Chemical Distributors (FECC) is the European voice of the 119 chemical distribution industry. With a growing membership of companies and national 120 associations, FECC represents over 1200 companies many of which are small and medium 121 sized enterprises. Members service a very wide range of industries and meet the 122 manufacturing requirements of sectors as diverse as electronics, paints and textiles to 123 cosmetics food, feed and pharmaceuticals, each with their own diverse demands and 124 purchase volumes.

125 For further information visit

126 International Pharmaceutical Excipients Council (IPEC)

127 IPEC is an international industry association formed in 1991 by manufacturers and end-users 128 of excipients. It is an association comprising three regional pharmaceutical excipient industry 129 associations covering the United States, Europe and Japan (which are known respectively 130 as IPEC-Americas, IPEC Europe and JPEC). IPEC's objective is to contribute to the 131 development and harmonisation of international excipient standards, the introduction of 132 useful new excipients to the marketplace and the development of good manufacturing 133 practice for excipients.

134 IPEC first published its GMP Guide for Bulk Pharmaceutical Excipients in 1995 and it was 135 revised in 2001 to align it with ISO 9001:2000 and again in 2006 to bring it fully up to date 136 This document has also been adopted by the USP and has been published as general 137 chapter with only minor editorial changes to make it suitable for that publication.

138 IPEC also published the Good Distribution Practices Guide for Pharmaceutical Excipients in 139 2006.

140 For further information visit

141 Pharmaceutical Quality Group (PQG)

142 The PQG was formed in 1977 to promote development of a consistent approach to 143 pharmaceutical quality and good manufacturing practice. The group has since expanded, 144 and in 1990 the PQG published three codes of practice to cover pharmaceutical raw 145 materials, printed and contact packaging materials. In 1995 the codes were revised and were 146 integrated with ISO 9002:1994. The code for raw materials was revised and reissued as PS 147 9100:2002 Pharmaceutical excipients, an application standard and GMP guide for 148 pharmaceutical excipients.

149 For further information visit

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151 IPEC and PQG greatly appreciate and acknowledge the many hours of hard work the 152 following individuals devoted to creating this Guide and the generous support provided by 153 their employers: 154 Global Steering Committee 155 156 Auditor Competency Team 157 Communications Team 158 GMP Annex Team 159 GDP Annex Team 160 3rd Party Audit Organisation Requirements Team 161 Review and Proofing Team 162 163 Excipact TM Realisation Teams 164 Legal Team 165 Business Planning Team 166 Communications Team 167 3rd Party Audit Organisations Team 168 Stakeholder Management Team 169 170 Details to appear later

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171 General Introduction

172 As of the date of preparation of these Excipact TM Standards, Good Manufacturing practice (GMP) is 173 not mandated in law in either Europe or the USA for ingredients used in the manufacture of 174 pharmaceuticals. Excipients have no such legal requirement. Yet excipients may pose a hazard to the 175 end patient safety. Thus, the requirement to have a robust quality system in place that assures the 176 quality and purity of excipients remains an imperative, particularly as recent events with fraudulent 177 claims of pharmaceutical raw material purity have resulted in so many tragedies.

178 These tragedies have taught us that it is not enough to apply standards only to the manufacture of the 179 excipient. The distribution of the excipient must also be included. Excipient quality can be better 180 assured if all steps in the supply chain, from manufacturer through to user, adopt suitable standards 181 that are capable of independent verification ? i.e. Good Distribution Practices (GDP). Patients can be 182 as much at risk from failures in the supply chain as from failures in manufacture, no matter how 183 caused.

184 Legislators and regulatory authorities in both Europe and the USA continue to address the 185 weaknesses in the application of GMP and GDP to pharmaceutical excipients so as to minimise 186 patient risk. The FDA has clearly stated that they expect each drug product manufacturer to have 187 physically audited every API and excipient supplier they use. There are similar moves in place in 188 Europe where similar requirements are proposed. Such requirements, even justified, pose an 189 administrative burden for excipient users and their suppliers alike. How to resource and find time to 190 conduct all these audits? Some excipient supplier sites could be asked to host hundreds of audits as a 191 result of these initiatives. In recognition of these issues the authorities have clearly stated that the drug 192 product manufacturer can utilise 3rd party audit organisations to perform the audits. Thus a 3rd party 193 audit organisation could perform the audit reducing the burden in time and resources for both excipient 194 user and excipient supplier. But for such 3rd party audit organisations to be accepted within this 195 industry both the standard used to assess excipient suppliers and the competency of their auditors 196 must be addressed.

197 Many excipient suppliers are already registered to the Quality Management System standard, ISO 198 9001 and this provides an excellent framework to build and develop systems suitable for the supply of 199 pharmaceutical excipients. This is the basis for the Excipact TM standards by providing two annexes to 200 ISO 9001 to cover both GMP and GDP requirements. Thus excipient manufacturers would be 201 assessed to ISO 9001 and the Excipact TM GMP annex together, whereas distributors would be 202 assessed to ISO 9001 and the Excipact TM GDP Annex together. If an excipient supplier conducted 203 both manufacturing and distribution activities they could be assessed to both the GMP and GDP 204 Annexes.

205 The remaining sections of Excipact TM cover the requirements for 3rd party audit organisations for 206 auditor competency and for quality system requirements for these organisations. The former is based 207 on ISO 19011, Guidelines for Quality or Environmental Management System Auditing, whereas the 208 latter is based on ISO 17021, Conformity assessment -- Requirements for bodies providing audit and 209 certification of management systems.

210 Together these standards will ensure pharmaceutical excipient suppliers implement best practices to 211 assure excipient safety and that 3rd party audit organisations can provide a credible service to the 212 pharmaceutical industry and their regulatory authorities.

213 The Excipact TM international pharmaceutical excipient GMP and GDP certification scheme will 214 provide manufacturers, suppliers and users of excipients with additional confidence that suppliers of 215 these critical components of drug products are safe to use.

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EXCIPACT TM Annex to ISO 9001:2008: Additional requirements for GMP for Pharmaceutical

Excipients 218 Foreword to this Annex 219 Many excipient manufacturers and distributors are already registered to ISO 9001, "Quality 220 Management Systems ? Requirements", and as a consequence Excipact TM has developed this 221 annex to that standard to allow such organisations to be assessed simultaneously to ISO 9001 222 and to the requirements for GMP for pharmaceutical excipients. This annex to ISO 9001:2008 is 223 based on the Joint IPEC-PQG Good Manufacturing Practices Guide for Pharmaceutical 224 Excipients 2006. The guidance ("how to do") in that document has been converted to an 225 auditable standard ("what to do") and then the parts already covered by ISO 9001:2008 226 removed. This annex is the result. 227 228 Organisations that manufacture and distribute excipients can opt to be certified to this annex and 229 the corresponding GDP Annex together or separately depending on their business 230 arrangements. 231 232 The main text that follows is based on the headings in ISO 9001:2008 and the details are the 233 GMP requirements: 234 235 Texts in Bold are ISO 9001 Headings

236 237 Standard Texts are GMP requirements 238 Italicised texts are taken directly from ISO 9001:2008 to provide context to the Annex statements 239 immediately following. 240 241 For full comprehension this annex should be read in conjunction with ISO 9001:2008. A copy of 242 that standard is not included herein for copyright and licensing reasons. 243

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