Volume 7: Medicines and Cosmetics
6. Ensuring medicinal products complied with the guidelines
1991-92
BSE in France
Initial steps towards development of European guidelines
Second thoughts on the exemption from sterilisation and staining of SBO material used for pharmaceuticals
Further consideration of European guidelines
Assurances about contact lens products
Further meeting of the BSEWG proposed
Continuing debate on 'excepted premises'
Consideration of TSEs by WHO
Finalising European guidelines on human medicines
Fifth meeting of the BSEWG
Consideration of the safety of gelatine
CDSM and CSM meetings

BSE in France

6.192 Confirmation of a case of BSE in Normandy was circulated by Dr Matthews to Dr Raine, Dr Purves, Mrs Baker and Mr Sloggem on 4 March 1991. ¹ His minute pointed out that two companies sourced raw material for sutures from France. He went on to say: 'We will presumably need to take urgent action to get the new material sourced from somewhere else, and existing stocks withdrawn from the market.'

6.193 Dr Purves told us that discovery of BSE in Switzerland and France 'emphasised that a European wide approach to BSE was needed'. ²

Initial steps towards development of European guidelines

6.194 On 4 and 5 March 1991 the Biotechnology Working Party (BWP) met in Brussels. ³ The BWP was an ad hoc committee of the CPMP chaired by Dr Schild of the NIBSC. Other UK attendees were Dr Purves, Dr Minor, Dr Kimberlin and Mr Bradley. ⁴

6.195 The German delegation to the BWP put forward a draft guideline on BSE and pharmaceutical products. This document was discussed by the group but discounted as a starting-point because it lacked certain information and agreement on the conclusions and recommendations could not be reached. A further draft was to be prepared by Dr Purves, Dr Minor and the German delegates for the next meeting in May. ⁵ Many of the other European representatives thought that the UK guidelines could be used until more information was available. ⁶

Second thoughts on the exemption from sterilisation and staining of SBO material used for pharmaceuticals

6.196 We consider in vol. 6: Human Health, 1989-96, the introduction of the Bovine Offal (Prohibition) (Amendment) Regulations 1992, which extended the ban over material derived from SBOs and introduced regulations regarding bovine brain removal. We review one part of the development of these regulations in this chapter, the question whether the specific exemption for manufacturing chemists should be removed.

6.197 The question was raised by Miss Bronwen Jones, of MAFF's Meat Hygiene Division (MHD), who circulated a draft submission and draft regulations to Ministers on 6 March 1991. ⁷

6.198 Mr Lawrence, commenting on Miss Jones's draft, observed:

. . . it looks odd to include in the excepted premises a manufacturing chemist for the manufacture of pharmaceutical products. I don't quite see the circumstances when this should be allowed to happen, particularly in view of the Committee on Safety of Medicines' clear guidance that pharmaceutical companies source any necessary bovine raw material from countries which are free from BSE and scrapie. ⁸

6.199 Mr Lewis Baker of MHD, in a minute to Mr Lawrence, pointed out that manufacturers of pharmaceuticals had been exempted originally because the intention of the regulations was to prohibit the use of SBO only in food. He added:

In addition, there was no evidence to suggest that use of sbo in pharmaceuticals posed any risk and I understand . . . this is still the case.

In light of this, and taking into account the guidance which has already been issued by the Committee on the Safety of Medicines, I am not sure how much value there would be in amending the definition of excepted premises to exclude manufacturing chemists. There is clearly a danger that such a move would arouse unnecessary public concern about the safety of pharmaceuticals, although if any evidence of a risk to public health were to emerge we would clearly have to act on it. ⁹

6.200 Mr Lawrence was not persuaded. 'I cannot see how it would arouse public concern, if such materials are not used anyway. What it would do is remove this rather anomalous exemption'. ¹⁰ This debate continued in July (see below).

Further consideration of European guidelines

6.201 As planned, the German representatives to the BWP, assisted by Dr Minor and Dr Purves, prepared a redrafted set of European guidelines for the May 1991 BWP meeting. ¹¹ Dr Purves told us: 'Although the document was in a different format to the UK guidelines the salient points of the UK guidelines were incorporated'. ¹²

6.202 The draft guidelines were tabled at the CPMP meeting in June 1991 and it was agreed that the document should be put out for consultation to interested parties. ¹³ Dr Purves asked Mrs Shersby to circulate the draft guidelines to other parts of DH, to VMD and to the members of the BSEWG for comments. ¹⁴

Assurances about contact lens products

6.203 Following a query from Dr Pickles about bovine material in contact lens products, Dr Raine replied on 10 July 1991 that '[c]ontact lens care products containing bovine catalase were scrutinised in 1989 in light of the Joint CSM/VPC guidelines for industry'.

Further meeting of the BSEWG proposed

6.204 A further meeting of the BSEWG had been tentatively suggested for 29 October 1991. However, Dr Jefferys 'questioned whether there were any new issues or agenda items and expressed the view that, if there were not, there was no need for the working party to meet'. ¹⁵ Dr Purves confirmed that there were no pressing items requiring advice and therefore a meeting was not required. ¹⁶

Continuing debate on 'excepted premises'

6.205 When Miss Jones produced a further draft submission on the proposed amendment to the bovine offal regulations, Mr Lawrence said:

I realise that the intention of the Regulations is to prohibit the use of sbos in food. But I remain convinced (as I said in my minute of 17 April to Lewis Baker) that the premises of a manufacturing chemist which are used for the production of pharmaceuticals should be deleted from the definition of excepted premises, unless there is a legal obstacle to doing this. If we do so I see no reason why such a measure should arouse public concern. It can be explained simply by indicating that we are bringing it into line with current practice and advice from the Committee on the Safety of Medicines that UK bovine materials should not be used in the manufacture of pharmaceuticals. ¹⁷

6.206 Accordingly, Miss Jones's submission to Ministers on 31 July said: ¹⁸

The definition of 'excepted premises' currently includes the premises of manufacturing chemists which are used for the production of pharmaceuticals. Such premises are exempted from the main requirements of the Regulations because the intention is to prohibit the use of specified bovine offal in food, (pharmaceuticals do not fall within the definition of food) and because there is no evidence to suggest that the use of such material in the manufacture of pharmaceutical products poses any risk to public health. Nevertheless, the Committee on the Safety of Medicines has, as a precautionary measure, issued guidance that specified bovine offal should not be used for this purpose.

Ministers are asked to decide whether they wish manufacturing chemists to be removed from the list of excepted premises. There is clearly a danger that such a move would arouse unnecessary public concern about the safety of pharmaceuticals which is, in fact, not in question. On the other hand, it could be explained by indicating that we are simply bringing the Regulations into line with current practice and advice from the Committee on the Safety of Medicines that UK bovine materials should not be used for this purpose.

6.207 The submission was copied widely, including to DH.

6.208 The Parliamentary Secretary, Mr Maclean, decided that the exemption for manufacturing chemists should be removed. This was reflected in revised draft consultation documents circulated by Mr Baker on 19 August 1991, ¹⁹ and in the consultation letter and draft amendment regulations circulated by Miss Jones on 21 August 1991. ²⁰ The amendment regulations, which came into force in March 1992, did not include a manufacturing chemist in the definition of 'excepted premises'. ²¹ However, manufacturing chemists may still have been covered by the general exemption for premises used for the manufacture of products other than food. ²²

Consideration of TSEs by WHO

6.209 On 12-14 November 1991, the WHO met in Geneva to discuss transmissible spongiform encephalopathies and concluded that the careful selection of source material was the best way of securing safety from the remote risk posed by bovine materials in medicinal products and medical devices. Those present were of the view that the measures being taken in the UK were sufficient at that time to minimise the risk to all species including humans. ²³

Finalising European guidelines on human medicines

6.210 The draft European guidelines on BSE and medicinal products were amended following comments from interested parties, and the revised document was approved by the BWP at its meeting on 25-26 November 1991. The guidelines were endorsed by the CPMP on 11 December 1991. ²⁴

6.211 On 1 May 1992, the CPMP guidelines, entitled 'Minimising the Risk of Transmitting Agents Causing Spongiform Encephalopathy via Medicinal Products', came into effect. ²⁵

6.212 The CPMP guidelines applied to:

all medicinal products which contain active ingredients and/or excipients derived from bovines, as well as medicinal products for which the production process involves bovine materials.

6.213 They also covered:

the use of such materials in procedures which are indirectly associated with the manufacturing process, for example, in test media used in the validation of plant and equipment to avoid cross-contamination. ²⁶

6.214 All products were to be considered on a case-by-case basis taking into account: the selection and processing of source materials; the age and geographic origin of the individual source animal; the intended use of the product; its stipulated dose and route of administration; the production process; and quality control. ²⁷

6.215 The main focus of the guidelines was the sourcing of bovine material used in manufacture. Sourcing was allowed from countries 'which have not reported cases of BSE, if they have an effective veterinary service capable of detecting a low incidence of disease and if BSE is reportable'. Additionally, it was recommended that the risk of BSE from feeding SBO material to ruminants should be avoided. ²⁸ Materials could also be sourced from countries with a 'low incidence' of BSE if a number of precautionary measures were taken, including destroying all affected carcasses, and not using any progeny of affected animals. ²⁹

6.216 Guidance was also given about the relative infectivity of different types of tissue. Category 1, classified as 'High Infectivity', included brain, spinal cord and eyes. Lymph nodes, spleen and tonsils were all said to be of medium infectivity. ³⁰ The guidelines said that 'these potential risks, amongst other criteria, should be considered for the selection of source materials'. ³¹ This advice, which allowed for other factors to be taken into account, was somewhat less rigorous than the CSM/VPC guidelines, which stated that '[n]o brain or neural tissue, spleen, thymus and other lymphoid tissue, placental tissue or cell cultures of bovine origin should be used in manufacture'. ³²

6.217 Similarly, the CPMP guidelines stated:

the potential risks will be influenced by the circumstances in which tissues were removed, especially by contact of material of a low-risk group with that of a high-risk group. Thus the contamination of some tissues may be increased if infected animals are slaughtered by penetrative brain stunning, or if the brain and/or spinal cord is sawed. ³³

6.218 They added:

body fluids should be collected with minimal damage to tissue, and cellular components should be removed; e.g., fetal blood should be collected without contamination from placenta and amniotic fluids. ³⁴

6.219 This contrasts with the more specific requirements set out in the CSM/VPC guidelines: ³⁵

no tissue is to be used in relevant medicinal products when collected post-mortem from a bovine animal after brain penetrative stunning.

all tissue collected from the bovine animal should be taken using sterile equipment. Needles, syringes, scalpel blades etc should be disposable items.

. . .

for serum: all cellular components must be removed.

For foetal calf serum: great care should be taken to avoid contamination by placenta and foetal fluids. All cellular components must be removed.

6.220 Manufacturers throughout the EC were required to comply with the new provisions. However, Dr Purves told us that the practical assessment of licence applications went on as before because, in his opinion, 'the [CPMP] guidelines incorporated the principles of the CSM/VPC guidelines'. ³⁶

6.221 The CPMP guidelines applied only to human medicines at this stage. Before the guidelines could be adopted in relation to veterinary medicines, they had to be approved by the Committee for Veterinary Medicinal Products (CVMP) ³⁷ following a public consultation process. The Working Party on Immunological Medicinal Products, a sub-group of the CVMP, of which Dr Lee was a member ³⁸ first considered the guidelines in May 1992. ³⁹

Fifth meeting of the BSEWG

6.222 A fifth and last meeting of the BSEWG took place on 8 July 1992. Key issues for discussion at this meeting were sourcing of material for sutures from France and possible infection of foetal calf serum.

Products containing French sourced bovine material

6.223 As noted in 6.194, the occurrence of BSE in France and Switzerland had prompted concerns about sutures sourced from France. ⁴⁰ The Working Group noted that at least two suture manufacturers sourced from France, although 'the sutures material was supplied in minuscule amounts to the UK'. ⁴¹ Two specific questions were asked:

1. Are sutures sourced in France of concern to the Working Group?
2. What is the relevance of the BSE guidelines to sutures?

6.224 The BSEWG concluded on the first question that 'the risk associated with material from France now would appear to be many orders of magnitude less than material [previously] sourced from the UK'. ⁴² Nevertheless, the Working Group 'expressed the view that where a demonstrably safer source is available then a company should use it'. ⁴³ In drawing these conclusions the BSEWG noted:

The recent cases of BSE in France, and 11 cases in Switzerland appeared to have no link with the UK . . .

. . . it was admittedly unlikely that France and Switzerland would get the same type of epidemic as in the UK . . .

In connection with sutures, it was noted that the BSE Guidelines indicated that a country with a low incidence of BSE [such as France] . . . was suitable as a source of raw material if the other aspects of the Guidelines were complied with. ⁴⁴

6.225 On the second question, the Working Group 'indicated that . . . the CPMP BSE Guidelines should be applied to surgical sutures although no other member state applied the Guidelines to these materials'. ⁴⁵

Vaccines

6.226 The Working Group was told that the line of DTP vaccines, the only outstanding vaccine of concern (see paragraph 6.179 above), had now been replaced with a new batch using material from New Zealand cattle. This was the last vaccine to be replaced. ⁴⁶

6.227 In summary, four human vaccines did not comply with the CSM/VPC guidelines in March 1989: one measles, one MMR, one Tuberculin PPD and a line of DTP. The MMR vaccine had not yet been licensed and was never marketed. The other three vaccines had achieved compliance by the end of 1990. Non-complying stocks of the measles vaccine were exhausted by September 1990. In May 1991, it was estimated that non-complying stocks of the Tuberculin PPD would last until December 1991. However, the BSEWG encouraged replacement of these stocks as quickly as possible. As for the DTP vaccine, non-complying stocks were estimated to last until the end of 1991 (adsorbed) and at least until September 1992 (unadsorbed). The BSEWG encouraged all stocks to be replaced by the end of 1991. The table at Annex 4 summarises the action taken on non-complying human vaccines.

Medical Devices

6.228 MDD had been working for some time on a paper on sterilisation of animal tissues in medical devices, which was introduced to the meeting by Mr Burton. The content of the paper took account of earlier contributions from the Working Group, and from industry. It was also intended that the CPMP guidelines on the inactivation of viruses would be incorporated. The BSEWG agreed that the paper should now be presented to the CSM and CDSM. ⁴⁷

Foetal calf serum

6.229 The Working Group again considered the possible infection of foetal calf serum. ⁴⁸

6.230 Professor Collee stated that continued vigilance was necessary, particularly given the widespread use of foetal calf serum in a variety of biological products including vaccines and recombinant DNA technologies.

6.231 Recent evidence indicated foetal lambs might be infected with scrapie. However, it was noted that the BSE analogy with scrapie did not necessarily hold good, as there was much less dissemination of the BSE agent in tissue outside the central nervous system than there was with scrapie.

6.232 The establishment of Australasian foetal calf serum as the 'gold standard' gave rise to certification problems in relation to products from other areas.

6.233 The BSEWG noted that, as well as sourcing appropriately, the collection of foetal calf serum should be carried out with due care and attention. In this respect, procurement methods in some countries might not have been critically controlled. The method of collection could be improved in some cases because cross-contamination with BSE would be most likely from specified offal.

Consideration of the safety of gelatine

6.234 During 1992 concerns arose about the safety of gelatine, which was widely used in oral medicinal products. On 21 July 1992, Dr Minor, Head of Virology at NIBSC, wrote to Professor Collee: ⁴⁹

At a recent meeting in Heidelberg a gentleman from a gelatin manufacturing concern presented an account of the process which was very worrying. As you know, the assumption has been that gelatin is produced under such vigorous conditions that it gives no cause for concern, but the process he described was, to me, shockingly mild. Moreover he claimed that any old cow bone went into the production vat, including spine and skull . . .

A number of other BSE working party members were present at the meeting, including John Purves, Richard Kimberlin and David Taylor, so it is possible that the matter was raised [at the BSE Working Group meeting of 8 July 1992].

There is no indication that this issue had, in fact, been raised at the BSEWG meeting.

6.235 Dr Taylor also wrote to Professor Collee: ⁵⁰

Like Philip [Minor], I was not impressed by the reassuring noises made . . . at the Heidelberg meeting. However, I am not really familiar with gelatin manufacturing processes in the UK . . . I would certainly be concerned if it is produced by a similar procedure to the German process described at the meeting.

6.236 On 31 July 1992, Dr Kimberlin wrote to Professor Collee about Dr Minor's observations. ⁵¹ He concluded:

(a) The general assumption that gelatin is of very low risk with regard to BSE contamination is still tenable.

(b) Any uncertainty would be if the source material included significant amounts of brain and spinal cord from countries which either had reported BSE or were at risk of getting BSE cases, and which did not have a specified offals ban.

(c) In these circumstances it might be reasonable to require either that these potential risk tissues were excluded from the source material, or that validation studies were carried out which were capable of demonstrating a clearance factor appropriate to the potential contamination.

6.237 On 5 August 1992, Dr Tyrrell wrote to Professor Collee. He had seen Dr Minor's letter of 21 July and he thought it was 'necessary to get more details . . .'. ⁵²

6.238 As a result of these concerns, and acknowledging the help he had received from Dr Minor and Dr Kimberlin, Professor Collee produced a written opinion on gelatine and BSE. ⁵³ He said:

It is possible that gelatin is of low risk with regard to BSE contamination, but there are justifiable anxieties when the source material includes brain and spinal cord of cattle (or sheep) from countries with known cases of BSE or at risk of having BSE cases.

Validation studies to demonstrate the safety of processing and extraction procedures in this context would be commendable, but there are very significant practical difficulties and such an exercise would take some years.

It is reasonable to press for assurances with regard to quality and sourcing, analogous to those sought with respect to catgut sutures, in relation to gelatin manufactured for use in the pharmaceutical industry . . . Full compliance with the BSE guidelines should be required for the starting material.

6.239 Dr Purves told us: 'We would have taken Professor Collee's recommendation into account when we were subsequently assessing applications for product licences for gelatin.' ⁵⁴

6.240 However, Professor Collee's suggestion was not without difficulties. On 28 August 1992, Dr Minor wrote to him. ⁵⁵

. . . [there] may be a slight difficulty raised by the sentence in your summary requiring full compliance with the BSE guidelines. In the European version of the document . . . gelatin is specifically singled out as a product which given assurances of adequate collection and processing is unlikely to present any risk of contamination. The implication to me is that the source animal probably does not matter . . .

6.241 Dr Tyrrell received a copy of Professor Collee's paper in September and Mr Lowson circulated it to other members of SEAC as well as to Mr Meldrum, the CVO. ⁵⁶ It was suggested that a short note be put together on the subject for discussion at the next SEAC meeting. SEAC's advice in relation to gelatine is considered in detail in Chapter 3 of vol. 11: Scientists after Southwood.

6.242 On 11 September 1992, Mr Meldrum wrote to Mr Lowson about the paper. ⁵⁷ He said, 'I am a little concerned at the comment that the raw materials should be sourced from a BSE-free country. I have no difficulty with the definition applying to Australia and New Zealand, but not to other countries where they do not have an active surveillance system.' He went on 'I am worried at the possibility that we may be clobbering the UK even though we have got excellent controls in place, but still be ignoring the unknown and unquantifiable risks from overseas.'

CDSM and CSM meetings

6.243 At the CDSM meeting on 15 July 1992 the Committee considered two suture products sourced in France and said that, on grounds of quality and safety, it might be unable to advise the Licensing Authority that licences should be granted. ⁵⁸

6.244 When the CSM met in September 1992 the concerns about gelatine were raised, but the CSM deferred consideration of the subject until a later date. At the same time it noted the report of the fifth meeting of the BSEWG, and was told by Dr Rotblat that there was no cause for concern regarding the use of foetal calf serum. ⁵⁹