Volume 7: Medicines and Cosmetics
6. Ensuring medicinal products complied with the guidelines
1993-96
European guidelines on veterinary medicines
Pharmaceutical products: quantitative studies of risk
German guidelines on the use of bovine and ovine material in medicines
Other European issues
Further meeting of the BSEWG proposed
Medical Devices Agency
Meeting of the Biologicals Sub-Committee
MCA and VMD audits of manufacturers

European guidelines on veterinary medicines

6.245 Final approval for the European guidelines on veterinary medicines was given by the CVMP in January 1993. These guidelines remained almost identical to the CPMP guidelines on human medicinal products. ¹

6.246 The CVMP guidelines became operative on 25 May 1993. ²

Pharmaceutical products: quantitative studies of risk

6.247 In April and May 1993, Dr Richard Kimberlin produced three reports, commissioned by The Wellcome Foundation Limited, to assess quantitatively the BSE and scrapie risk to patients from certain pharmaceutical products. The reports covered:

1. a number of topically applied pharmaceutical products; ³
2. a number of orally administered pharmaceutical products; ⁴ and
3. bovine insulin. ⁵

6.248 The reports were based on 'worst-case' assumptions and therefore aimed to calculate the maximum possible risk to a patient using the product. ⁶ The conclusions compared the risk of contracting CJD from the products studied with the risk of an individual contracting non-iatrogenic, sporadic CJD, which occurs at approximately one case per million people per year. Dr Kimberlin's papers said that this meant the lifetime risk to any one individual of contracting sporadic CJD was about 1 in 10,000. ⁷

6.249 Dr Kimberlin concluded that the maximum risk of contracting CJD from the topical products was 1,900 times less than contracting sporadic CJD. ⁸ For the oral products the estimate was 38,000 times less likely. ⁹ And for the bovine insulin the estimate was 1,000 times less likely. ¹⁰

German guidelines on the use of bovine and ovine material in medicines

6.250 On 28 February 1994, the German Federal Health Office (BGA) issued safety standards for human and animal medicinal products to minimise the risk of BSE/scrapie transmission. ¹¹ Dr Purves told us that the 'new German safety standards had been issued unilaterally without prior discussion at the CPMP and appeared to go further than the existing European guidelines'. ¹² The guidelines were published in the Federal Gazette in Germany in February but did not come to the attention of UK authorities until some months later. ¹³

6.251 Mr Sloggem prepared a paper for the CSM/BSC meeting on 6 July 1994 updating the Committee on BSE. ¹⁴ The German guidelines were covered briefly by the paper and the BSC then asked Mr Sloggem to prepare a detailed paper comparing the CPMP guidelines with the German ones. ¹⁵

Other European issues

6.252 In July 1994, Portugal, as rapporteur to the CPMP, requested that all Member States provide a history of action taken on medicines and BSE since the introduction of the CPMP guidelines. ¹⁶ The French had also made a request to MAFF for an update on BSE in the UK with regard to veterinary medicines. ¹⁷ Mr Sloggem was involved in responding to both of these requests.

6.253 While undertaking this review process Mr Sloggem discovered that the MCA's BSE database was out of date. It had not been updated with information from new licence applications since the UK guidelines came in and still contained only the information received from the original CSM questionnaire. ¹⁸ Dr Purves told us that this discovery prompted improvements to the new MCA database:

By then internal discussions were underway on the new PLUS database which was being set up to record details of product licences and applications. In light of the discovery that the existing BSE database had not been kept up to date, my team put forward a case that the PLUS database should be modified. This modification was requested to allow the input of the bovine materials included in products, not merely as active ingredients but also as excipients or reagents, and the source of such materials. Those discussions went on in early summer 1994. I recall that the administrators in charge of the new Database, PLUS, conceded that it was necessary for the database to be amended as we had suggested. ¹⁹

Further meeting of the BSEWG proposed

6.254 Dr Purves thought the action taken by Germany on medicinal products raised the question of whether a further meeting of the BSEWG was needed. ²⁰ Dr Jefferys thought that the precise issues to be discussed needed to be clearly defined before a decision could be made. He also noted a number of practical difficulties in calling another meeting. ²¹ No further meeting of the BSEWG ever took place.

6.255 The CSM met on 22 and 23 September 1994 and considered (among other things) the German guidelines. ²² The CSM decided that the BSC together with a number of invited experts should meet in November to consider the issues further.

Medical Devices Agency

6.256 On 27 September 1994, the MDD became the Medical Devices Agency (MDA).

Meeting of the Biologicals Sub-Committee

6.257 The BSC meeting was held on 2 November 1994. ²³ At this event Professor Collee, no longer Chairman but attending as an invited expert, was able to raise matters discussed at the BSEWG's fifth meeting in July 1992.

6.258 As noted above, there were no further BSEWG meetings. However, in his address to the BSC Professor Collee discussed the continuing need for such a group. He said:

When Professor David Lawson, my Chairman on the Medicines Commission, asked me to comment on the present position with regard to our surveillance of BSE, I made the point that the BSE Working Party had not met since July 1992. There was a danger . . . that the gap might be thought to be reassuring (on the grounds that no business was pressing us to reconvene, and that the evolving scene did not justify a further meeting).

. . . our committees need the continuing assurance that a specialist cross-discipline group is able to give at a time when BSE continues to pose worrying questions in relation to human health and to the safety of some of our medicines and biological products. You and your colleagues on Biologicals may well feel that a separate group is unnecessary and that the BSE business can be adequately transacted within this committee. I would ask you, however, to see the amount of paperwork that only today's discussion has called for on topics relating to BSE. And I would ask you for your indulgence and understanding if my answers to some of the ensuing questions that you will no doubt wish to put to me are answered in guarded, if not evasive terms. By this I imply that I really do need the backing of my scientific advisers on the Working Party and I am uneasily aware of my limitations in such a complex field. ²⁴

6.259 The BSC also discussed the European situation, in particular the German stance. Dr Purves summarised the key points made by the Committee in relation to the German guidelines:

(a) That the UK should not be singled out for any ban on the use of bovine material from a closed herd, as other countries had indigenous cases of BSE. It was stated that a source material from a BSE free closed herd should be acceptable.

(b) All inactivation methods should be validated rather than assumed. The CPMP classification of tissues and approach was acceptable. The German numerical factor system was not acceptable.

(c) The data requirements of the German Guidelines were not feasible in that it was unlikely that suppliers of bovine materials would be able to provide all the data required. A case by case approach was required. ²⁵

6.260 The German guidelines continued to be discussed at the CPMP and BWP meetings in December 1994 and thereafter. Although no agreement was reached between the UK and Germany on the issue of revising the European guidelines, the CPMP confirmed that the current European guidelines would remain in force until such time as they were modified through the ongoing discussions. ²⁶ The impact of the German stance on the export of pharmaceuticals from the UK, and exports of pharmaceuticals generally, are considered in Chapter 7 of vol. 10: Economic Impact.

MCA and VMD audits of manufacturers

6.261 Following the Government's announcement on 20 March 1996 that the most likely explanation for vCJD was exposure to BSE prior to the SBO controls, ²⁷ the MCA undertook an audit of UK medicine manufacturers, in order to reassure itself that proper procedures were being followed. ²⁸ A letter was written to licence holders seeking written confirmation that the 1992 CPMP guidelines were being observed. In addition, inspection visits were made, between 10 and 18 April 1996, to those manufacturers of medicines that might contain material of bovine origin. ²⁹ Inspectors visited 166 sites in all. ³⁰ This audit took place outside the period covered by our terms of reference; however, it is of relevance to that period in indicating what was then thought to be the degree of compliance with the guidelines.

6.262 A report of the audit dated 26 April 1996 said:

The results of the audit:

(a) re-confirmed that no bovine material of UK origin is used in the manufacture of vaccines or other injectable medicines in the UK since 1989. The audit confirms that all injectable products are therefore free from any risk associated with UK bovine materials;

(b) re-confirmed certification of compliance with the 1992 CPMP guidelines;

(c) established that since mid-April 1996 no pharmaceutical product for human use manufactured in the UK uses gelatin derived from materials of UK bovine origin;

(d) established that there are three UK manufacturers of gelatin who supply gelatin certified for pharmaceutical use, and that they do not supply gelatin derived from materials of UK bovine origin to manufacturers of pharmaceutical products for human use in the UK;

(e) established that in respect of tallow derivatives, as a result of a commercial decision virtually all UK manufacturers have moved away from using tallow derivatives which have been refined from tallow of UK bovine origin. However it should be noted that the UK produced a detailed paper on tallow derivatives, which was considered by the special meeting of the CPMP on 15 April 1996. The EMEA opinion of that meeting emphasised that the processes used to produce tallow derivatives which are used in pharmaceutical products are more than sufficient to render them safe. ³¹

6.263 VMD carried out a parallel audit in April 1996. On 4 April the Directorate wrote to all marketing authorisation holders asking them to provide information on the source of any ingredients in their products of bovine origin, to ensure continued compliance with the CVMP guidelines. ³² VMD had to follow up responses from eight companies that did not reply immediately. In the end all but three companies confirmed compliance with the guidelines. VMD was unable to locate responses from these three companies and has since undertaken further investigations. ³³