1. © Crown copyright 2005 Safeguarding public health The 2001 Review and its Impact upon Excipient Suppliers Richard Andrews Operations Manager GMP

2. Slide 1 7 th February 2006 Richard Andrews The 2001 Review and its Impact upon Excipient Suppliers © Crown copyright 2005 Agenda Current Guidance and Standards The 2001 Review and Directive 2004/27/EC Potential Risks with Excipients Development of a New Directive A List of 'Certain Excipients'

3. Slide 2 7 th February 2006 Richard Andrews The 2001 Review and its Impact upon Excipient Suppliers © Crown copyright 2005 Current Guidance and Standards No legislative basis in the UK for the inspection of manufacturers and suppliers of pharmaceutical excipients Medicinal product manufacturers are responsible for the quality of their starting materials Certificates of Suitability (TSE and EP materials)

4. Slide 3 7 th February 2006 Richard Andrews The 2001 Review and its Impact upon Excipient Suppliers © Crown copyright 2005 2001 Review Review of existing legislation relating to the manufacture of medicinal products, with the view to clarifying the definitions and scope in order to achieve high standards for the quality, safety and efficacy of these products.

5. Slide 4 7 th February 2006 Richard Andrews The 2001 Review and its Impact upon Excipient Suppliers © Crown copyright 2005 Directive 2004/27/EC Directive 2004/27/EC amends Directive 2001/83/EC on the Community code relating to medicinal products for human use The requirements of the amending directive came into force on October 31st 2005.

6. Slide 5 7 th February 2006 Richard Andrews The 2001 Review and its Impact upon Excipient Suppliers © Crown copyright 2005 Directive 2001/83/EC as Amended Amendments to Title IV: Manufacture and Importation Article 46(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 in accordance with the procedure referred to in Article 121(2).

7. Slide 6 7 th February 2006 Richard Andrews The 2001 Review and its Impact upon Excipient Suppliers © Crown copyright 2005 What has changed? Article 46f of Directive 2001/83/EC as amended obliges manufacturing authorisation (MA) holders to use as starting materials only active substances that have been manufactured in accordance with GMP. In addition MA holders are also obliged to only use 'certain excipients' that have been manufactured in accordance with GMP. The article calls for a new Directive to be developed and adopted on GMP for excipients. The directive shall include a list of the excipients which when used by an MA holder must have been manufactured in accordance with GMP and will specify the GMP principles that should be applied.

8. Slide 7 7 th February 2006 Richard Andrews The 2001 Review and its Impact upon Excipient Suppliers © Crown copyright 2005 Potential Risks with Excipients Excipients are used in the formulation of medicinal products for a variety of reasons: to facilitate bioavailability of product to aid the manufacturing process for aesthetic reasons e.g. taste, colour to stabilise the product e.g. buffers, preservatives to make the product a practical dose size e.g. bulking agent Excipients are an intrinsic part of nearly all medicinal products and therefore they have an impact upon the quality, safety and efficacy of these products.

9. Slide 8 7 th February 2006 Richard Andrews The 2001 Review and its Impact upon Excipient Suppliers © Crown copyright 2005 Potential Risks with Excipients When appropriate controls are not applied the following may occur: presence of extraneous matter e.g. metal, paper, particles cross-contamination with other chemicals (either excipients or APIs or breakdown products) contamination with TSE risk materials not permitted by legislation inconsistent manufacture such that the quality of the final products cannot be assured mis-labelling of containers leading to product mix-up

10. Slide 9 7 th February 2006 Richard Andrews The 2001 Review and its Impact upon Excipient Suppliers © Crown copyright 2005 What is the Purpose of Applying GMP to 'Certain Excipients'? To protect (assure) public health. To ensure consistent standards of manufacture and control are applied. To meet the legal requirement within Directive 2001/83/EC as amended.

11. Slide 10 7 th February 2006 Richard Andrews The 2001 Review and its Impact upon Excipient Suppliers © Crown copyright 2005 Development of a New Directive Article 46(f) 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 in accordance with the procedure referred to in Article 121(2). Outputs required: -List of 'Certain Excipients' -Good Manufacturing Practice principles to be applied

12. Slide 11 7 th February 2006 Richard Andrews The 2001 Review and its Impact upon Excipient Suppliers © Crown copyright 2005 Development of a New Directive Excipients Team formed -Members drawn from European regulatory agencies, EMEA and European Commission Role of the Team -To derive and agree a list of excipients that should appear on the list of ‘certain excipients’ -To determine the GMP principles that should be applied to the materials listed.

13. Slide 12 7 th February 2006 Richard Andrews The 2001 Review and its Impact upon Excipient Suppliers © Crown copyright 2005 List of 'Certain Excipients' - Process In developing a list of ‘certain excipients’ the Excipients team wanted to involve key stakeholders from the beginning Input was therefore requested from both regulators and industry Three Questionnaires were prepared and distributed targeting: -Excipient manufacturers -Medicinal Product manufacturers -Member states

14. Slide 13 7 th February 2006 Richard Andrews The 2001 Review and its Impact upon Excipient Suppliers © Crown copyright 2005 List of 'Certain Excipients' - Questionnaires Topics covered by the Questionnaires: Examples of cases where an excipient has or potentially had caused a risk to patient health. Suggestions for materials that should be included on a list of 'certain excipients' and why. Whether the list should name individual materials, material groups or be based on the materials use. Views on whether the respondents felt that a list of 'certain excipients' would add value in terms of patient safety. What audit approaches were being employed What standards were audits being performed against

15. Slide 14 7 th February 2006 Richard Andrews The 2001 Review and its Impact upon Excipient Suppliers © Crown copyright 2005 List of 'Certain Excipients' – Questionnaires Review of Responses There was no clear consensus of views relating to whether or not a Commission Directive should be prepared. Many respondees welcomed a document outlining the GMP requirements for excipient manufacturers. Regarding the key question about whether a list of 'certain excipients' would add benefit 18 respondees stated “yes”, 15 “no” and 7 gave no opinion. As to how the list of 'certain excipients' should be defined - 3 respondees suggested listing individual names, 7 material groups, 4 based upon usage, 1 name and group and 3 gave no response. It was clear that most pharmaceutical companies perform audits of excipient manufacturers using a wide variety of standards, including: IPEC GMPsWHO-GMPHACCP ISO 9000:2000ICH Q7ACompany internal standards 21 CFR 210 and 21121 CFR 820National Food Code Requirements PQG PS 9100:2002EU GMP

16. Slide 15 7 th February 2006 Richard Andrews The 2001 Review and its Impact upon Excipient Suppliers © Crown copyright 2005 List of 'Certain Excipients' – Questionnaires Review of Responses Many respondents outlined the difficulties in having a specific list of excipients as the same material could be used in many different products, some of the uses could be defined as high risk whereas others could be defined as low risk. Other key difficulties were that excipient manufacturers’ main customers are food or cosmetics industries with pharmaceutical supply accounting for only a small proportion of the output. Requiring such companies to meet stringent GMP requirements may lead them to withdraw from the pharmaceutical market and thus lead to product shortages.

17. Slide 16 7 th February 2006 Richard Andrews The 2001 Review and its Impact upon Excipient Suppliers © Crown copyright 2005 List of 'Certain Excipients' - Options Potential Approaches for defining the list of 'certain excipients': Individually named excipients Grouped by material type Based upon material usage Define the minimum standard for all excipients and then identify the additional requirements for the listed 'certain excipients'.

18. Slide 17 7 th February 2006 Richard Andrews The 2001 Review and its Impact upon Excipient Suppliers © Crown copyright 2005 List of 'Certain Excipients' - Process Excipients Team agreed to adopt a risk assessment approach to define which excipients should appear on the list. Benefits of using this approach are: -Fits with current regulatory thinking – ICH Q9 -The specific use of an excipient can help define the risk category.

19. Slide 18 7 th February 2006 Richard Andrews The 2001 Review and its Impact upon Excipient Suppliers © Crown copyright 2005 List of 'Certain Excipients' - Process A list of Risk Criteria was developed Based on the responses from industry and regulatory agencies to the 2004 questionnaire a list of possible excipients was established. The items on this list were then subject to a risk based analysis using FMEA (Failure Mode Effect Analysis) techniques and each material was assigned a Risk Priority Number (RPN). A cut off value of < 25 was set.

20. Slide 19 7 th February 2006 Richard Andrews The 2001 Review and its Impact upon Excipient Suppliers © Crown copyright 2005 List of 'Certain Excipients' - Output The result of this analysis was a draft list containing the following excipients: Animal derived excipients with a known TSE risk Human derived excipients, in particular albumin Sodium chloride used for injections Propylene glycol Glycerine Pyrogen-free excipients, e.g. glucose, mannitol, sorbitol, xylitol Sterile excipients, e.g. aluminium phosphate, sodium carbonate, lactose, media for fermentation

21. Slide 20 7 th February 2006 Richard Andrews The 2001 Review and its Impact upon Excipient Suppliers © Crown copyright 2005 List of 'Certain Excipients' - Consultation Draft list and risk assessment tools provided to industry Industry associations performed their own risk assessments and the results were fed back to Excipients Team. In general industries view on which excipients should be included on the list was similar to that of the Excipients Team. Other comments included: -The objective of introducing GMP for excipients is not clear -Glycerine and propylene glycol should be removed from the list as problems in the past were caused by criminal activity. -Detectability of risk was not considered by the risk assessment tool. -Application of good practice should also cover the supply chain. -The IPEC PQG GMP guide should be used for excipient manufacture and the WHO guide for distribution.

22. Slide 21 7 th February 2006 Richard Andrews The 2001 Review and its Impact upon Excipient Suppliers © Crown copyright 2005 List of 'Certain Excipients' - Consultation Industry association representatives were invited to meet with the Excipients Team to discuss the different views, to establish the basis for an impact assessment, decide which products should be contained in the list and what GMP principles should be applied. The main concerns presented by Industry at the meeting were: -The problem to be resolved and the aim of the Directive are unclear -Detectability should be part of the risk management process -GMP will not resolve the problem of fraud and adulteration -The application of GMP for excipients to the distribution chain -The inclusion of non-sterile excipients used in parenteral preparations and substances with a known history of fraud, such as propylene glycol and glycerol.

23. Slide 22 7 th February 2006 Richard Andrews The 2001 Review and its Impact upon Excipient Suppliers © Crown copyright 2005 List of 'Certain Excipients' - Consultation A template to be used for the evaluation of GMP requirements for 'certain excipients' was also presented. The template had been designed to collect information on the current situation for the 'certain excipients' / excipient categories under discussion in preparation for an impact assessment with respect to: -the detailed requirements available in other sectors (e.g. food, cosmetics: HACCP, ISO Standards) -the extent of current application of GMPs for excipients on a voluntary or mandatory basis both by excipient and by pharmaceutical manufacturers -the justification of additional requirements compared to those currently used or required by legislation

24. Slide 23 7 th February 2006 Richard Andrews The 2001 Review and its Impact upon Excipient Suppliers © Crown copyright 2005 List of 'Certain Excipients' – Next Steps The list of categories / substances currently under discussion to be further reviewed. Discrepant views between industry and the regulators regarding the categories of excipients to be incorporated into sterile products as well as regarding glycerine and propylene glycol to be resolved. Concerning the development of GMP principles the current requirements and the status of application of different standards utilised by pharmaceutical and excipient manufacturers are to be analysed and the need for possible additional elements compared to current practice identified.

25. Slide 24 7 th February 2006 Richard Andrews The 2001 Review and its Impact upon Excipient Suppliers © Crown copyright 2005 List of 'Certain Excipients' – Progress to date The European Commission held a further meeting with representatives from different industry organisations including EFPIA, EGA, APIC, FECC, Eyecare industry, AESGP which resulted in the following: Two questionnaires will be published on the European Commission Website covering the following categories: -animal derived excipients with potential TSE risk -human/ animal derived excipients with a potential viral contamination risk -excipients claimed to be sterile and used without further sterilisation -excipients claimed to be pyrogen / endotoxin controlled -propylene glycol, glycerine

26. Slide 25 7 th February 2006 Richard Andrews The 2001 Review and its Impact upon Excipient Suppliers © Crown copyright 2005 List of 'Certain Excipients' – Progress to date One questionnaire will be for excipient manufacturers and the other for excipient users, with the aim of gathering data on: -The different quality standards currently applied to excipients that fall into the agreed categories. These questionnaires are expected to be available mid February and responses should be made where possible via trade organisations. In addition the Industry proposed high level GMP principles for a directive are to be sent to the Excipient Team for review. Finally it was noted that Industry would like a GMP Part III for excipients to be developed, based on the IPEC guide.

27. Slide 26 7 th February 2006 Richard Andrews The 2001 Review and its Impact upon Excipient Suppliers © Crown copyright 2005 Thank You

28. Slide 27 7 th February 2006 Richard Andrews The 2001 Review and its Impact upon Excipient Suppliers © Crown copyright 2005 Contact Details Richard Andrews - Operations Manager GMP e-mail: richard.andrews@mhra.gsi.gov.uk tel:+44 (0)1904 610556 MHRA Hunter House 57 Goodramgate York YO1 7FX