Volume 7: Medicines and Cosmetics
6. Ensuring medicinal products complied with the guidelines
1990
Second meeting of the BSEWG
CSM and CDSM receive reports of the BSEWG meeting
Medical devices
Assurances about bovine insulin
CRM meeting
Spongiform encephalopathy in a cat
Q&A briefing: Agriculture Select Committee
Surgical catgut: change to Australasian source
Third meeting of the BSEWG
CSM endorses recommendations of third BSEWG meeting
Restructuring of Procurement Directorate
European working party on human medicines
Fourth meeting of the BSEWG
BSE in Switzerland
CDSM and CSM consider recommendations of fourth BSEWG meeting
VMD reports progress on veterinary medicines to the VPC

Second meeting of the BSEWG

6.129 On 10 January 1990, the second BSEWG meeting took place. The key issues for discussion were the responses to the questionnaire, and products not complying with the guidelines, particularly vaccines and surgical catgut.

Returns to CSM/VPC questionnaire: human medicines

6.130 By this time, 94 per cent of the licence holders had responded to the questionnaire, those responses had been evaluated and the 'appropriate action taken'. ¹ It was decided that the MCA should look at the individual licences held by the 6 per cent of companies who had not yet responded. Those companies whose products were likely to be associated with or to use bovine material would be asked for further information, and a report would be made to the next Working Group meeting.

Non-complying products (other than catgut)

6.131 A paper produced by Dr Rotblat for the meeting considered products other than catgut, using UK sourced cattle and not meeting the guidelines. The BSEWG reiterated its view that where cattle were UK sourced, companies should be encouraged to comply with the guidelines as soon as possible, the timescale to be agreed with the Licensing Authority for each individual product as appropriate. ² The majority of the non-complying products in Dr Rotblat's paper used bovine serum albumin or foetal calf serum from UK sources. ³ Most were vaccines, which we discuss below. However, the paper revealed that, with one exception, no products sourced from high-risk material (brain and lymphoid material) failed to satisfy the guidelines. We consider the exception, a range of allergen products, below.

Vaccines

6.132 In Chapter 5 we discussed the decision taken not to order the immediate replacement of existing stocks of vaccines and the indicative picture of the scale of the problem gleaned from a ring-round of manufacturers. By the time of the BSEWG's second meeting, Dr Rotblat was able to provide more concrete information about the existing stocks of vaccines made using bovine serum albumin or foetal calf serum from UK herds. She indicated that there were four such vaccines, with stocks as follows: ⁴

1. An MMR (measles, mumps and rubella) vaccine with stocks to December 1990 - not yet licensed;
2. A measles vaccine with stocks to September 1990 - not used much now;
3. A Tuberculin PPD with stocks to September 1991 - no other source available;
4. A line of DTP (diphtheria, tetanus, pertussis) vaccines ⁵ with unadsorbed stocks to May 1991 and adsorbed stocks to June 1990 - adsorbed used in preference to unadsorbed (not used much now).

6.133 The minutes of the meeting record:

The Working Group discussed the hazard-to-benefit ratio for the vaccines and decided that the benefits accruing from continuance of the vaccine programme outweighed the very remote risk to the population from the use of bovine material in these products.

It was considered after some discussion that negotiations should take place to ensure that sources are changed as soon as possible and to replace existing stocks with new material whenever feasible. Replacement of Wellcome unadsorbed DTP vaccine, by Wellcome adsorbed vaccine should ensure that the former, which is not much used, is replaced earlier than 1991. In the case of the Tuberculin PPD, no other source is available at present, but the company (Evans) should be asked to move over to the new product and replace stocks as soon as this is feasible. ⁶

Allergen Products

6.134 The only products sourced from high-risk material were a range of allergens, products for treating allergies. The MCA had received a request for advice from the manufacturer, Beechams, which used UK-sourced bovine material, including calf-brain in media, in the production of certain allergen products. The Working Group decided that alternative sterilisation programmes suggested by Beechams would not be effective, and that effective programmes would destroy the usefulness of the bovine material. The BSEWG considered that it was not reasonable to use calf-brain from the UK if other sources were available and advised that the Licensing Authority should insist upon a changeover to Australasian material, within a reasonable timescale. ⁷ The MCA were to reply to the company's request, taking into account the Working Group's views.

Surgical Catgut

6.135 By January 1990, Ethicon had provided updated information on its progress towards compliance with the guidelines. It had stopped sourcing from UK cattle on 20 November 1989, and the changeover to an Australian source had been moved forward from 1991 to February 1990. The Working Group considered in detail an appropriate strategy for decontaminating Ethicon's manufacturing facilities before the changeover. It asked for reassurances from Ethicon that existing stocks would be replaced as soon as they had the new stocks available. The Group was 'impressed' by the effort being made. ⁸

Reviewing the guidelines

6.136 The Working Group considered that the guidelines had served their purpose well and that there was no need to amend them at this stage. ⁹

The SBO regulations

6.137 So far as the SBO ban, which was now in force in England and Wales, was concerned, the minutes simply record that a copy of the Regulations was attached. It is not clear to us whether there was any discussion by the BSEWG of whether the introduction of the ban called for any reconsideration of the guidelines. ¹⁰

CSM and CDSM receive reports of the BSEWG meeting

6.138 The CDSM met on 17 January 1990 and noted the draft minutes of the January BSEWG meeting. With regard to surgical catgut, the Committee noted Ethicon's proposal to change over to Australian bovine intestine from 5 February 1990 and begin the decontamination of the manufacturing plant on 30 January 1990. They wished to place on record their recognition of the speed with which the company had responded to the recommendations of the BSEWG. ¹¹

6.139 At the CSM meeting on 21 and 22 February 1990 Professor Collee, attending as a member for the second day, reported on the January BSEWG meeting and the Committee noted the minutes of that meeting. ¹²

Medical devices

6.140 By 26 January 1990 one of the two companies with which PD/STD had met in December had managed to bring their practices in line with the guidelines by sourcing material from calves under the age of 6 months, or from overseas. ¹³

6.141 The second manufacturer, Bio-Medical Systems, could not comply with the guidelines for the production of its heart valves and was unlikely to be able to do so in the near future. ¹⁴ PD/STD agreed to organise a further meeting with the company. This took place on 20 February 1990. ¹⁵ The company was at that stage investigating both the possibility of sourcing from West Germany, and suitable sterilisation procedures. However, on 27 April 1990, at a further meeting, Bio-Medical Systems told PD/STD that sourcing its pericardial material from West Germany would be prohibitive in terms of cost and accordingly the manufacture of the heart valve in question would cease from 30 April. Valves remaining on the shelves would be recalled. ¹⁶

6.142 In May PD/STD decided to request a check of the Heart Valve Registry to find out whether anybody who had died of BSE/CJD-related diseases had used a heart valve produced by one of the two manufacturers with whom they had been involved. ¹⁷ Dr Richardson approached Professor Ken Taylor at the Heart Valve Registry and asked him to review causes of death and/or post mortem reports of all registered patients with bovine pericardial valves who had died, to ascertain if there was anything that might suggest encephalopathy. Professor Taylor's investigation did not find anything that indicated a relationship between encephalopathy and bovine pericardial valves. ¹⁸

Assurances about bovine insulin

6.143 Following a request on 14 March 1990 from the British Diabetic Association for information on BSE and bovine insulins, ¹⁹ Dr Jefferys replied on behalf of the CSM. He noted:

The manufacturers of Bovine insulin have responded to our request for information. There are no Bovine insulins sourced from cattle in the UK or Ireland. ²⁰

CRM meeting

6.144 The CRM met on 1 May 1990 and noted that the BSEWG had met in January. The Chairman, Professor Lawson, reported that none of the products likely to come before the CRM was involved in potential concerns regarding BSE. ²¹

Spongiform encephalopathy in a cat

6.145 On 10 May 1990 MAFF announced the discovery of a spongiform encephalopathy in a domestic cat. ²² This is discussed further in vol. 6: Human Health, 1989-96.

6.146 Dr Pickles circulated a Question and Answer briefing in relation to the announcement, which included the following:

Q. What about cat gut?

A. This is not made from cats these days. In fact most 'cat gut' is synthetic. The Medicines Control Agency, with advice from the Committee on Dental and Surgical Materials, has considered the implications of spongiform encephalopathies for natural 'cat gut' and taken any action that was considered necessary. ²³

Q&A briefing: Agriculture Select Committee

6.147 On 20 June 1990, Mr Love circulated to colleagues in the MCA a copy of a Question and Answer briefing on BSE and medicinal products, which had been prepared for the CMO in advance of his giving evidence to the Agriculture Select Committee. ²⁴ In relation to existing stocks, the brief said that the CSM had agreed with the Southwood Working Party's advice that the risk of BSE being transmitted via medicinal products was remote. It continued:

It was considered essential that existing supplies of medicinal products essential to public health continue to be used whilst companies implemented the guidelines to remove any remote theoretical risk of BSE. ²⁵

6.148 In relation to the vaccination programme the brief noted:

The immunisation programme for children and adults is vital to individuals and the public health. There are very considerable benefits in the prevention of serious or fatal disease. By any reckoning these outweigh the remote and theoretical risk of BSE. ²⁶

6.149 The brief noted that guidelines had been issued to manufacturers in March 1989. A further question asked how the pharmaceutical industry had responded to the guidelines:

The guidelines have been well received, and implemented by the industry. Many companies who previously used UK bovine material have voluntarily changed to sourcing overseas, from countries with competent veterinary services and where BSE has not been reported. Many companies have never used bovine material from UK sources in their products. ²⁷

Surgical catgut: change to Australasian source

6.150 On 12 June 1990, Ethicon, the manufacturer of surgical catgut sutures, confirmed that by 30 June 1990, 100 per cent of 'the sterilised surgical catgut products supplied to the United Kingdom market would be manufactured from raw material of Australian and New Zealand origin.' ²⁸ This met with time to spare the company's target as set out in a position paper provided to the MCA in January 1990. ²⁹

Third meeting of the BSEWG

6.151 The third meeting of the BSEWG was held on 4 July 1990. The group was given a further update on responses to the questionnaire, and discussed vaccines, foetal calf serum, allergen products, topical medicines, and an update on the epidemiological aspects of BSE.

Returns to CSM/VPC questionnaire

6.152 By this time only four replies were outstanding in relation to human medicines and none of those related to a full product licence; all had approval for clinical trials only. Further information was to be sought from these four and reported to the next meeting. ³⁰

6.153 In relation to veterinary medicines, MAFF reported:

. . . most Companies have now changed the source of bovine material and are obtaining it from BSE-free areas for veterinary medicines but there are still stocks held of products that were associated with UK bovine material. ³¹

Update on epidemiological aspects of BSE

6.154 MAFF had provided a paper on epidemiological aspects of BSE. In particular: ³²

1. MAFF's statistics indicated an increasing incidence since July 1989 that could not be attributed to cattle-to-cattle transmission. The increase had occurred contemporaneously in all regions of Great Britain and there was a greater increase in the number of affected herds than in the within-herd incidence.
2. BSE had been confined to the British Isles, apart from cases where cattle were exported. A condition known as 'Downer Syndrome' had been identified in the United States. The US authorities planned post-mortem testing for BSE.
3. BSE had become a notifiable disease in the EC on 1 April 1990. As long as BSE remained confined to the British Isles, 'concern about the use of bovine material in the manufacture of pharmaceuticals is restricted to bovine material originating in the British Isles'. ³³

6.155 The BSEWG was reassured by what it was told, but was concerned that:

. . . where foetal calf serum . . . or other bovine material is sourced from outside [the] UK, it should come from areas known to be BSE-free and having a good veterinary service and adequate animal husbandry. The availability of bovine material from New Zealand and Australia . . . is finite and tending to be taken up so that there is no spare supply capacity. Where material comes from a specific source it should be certified as originating in that country and not imported from elsewhere for re-export. ³⁴

Foetal calf serum

6.156 MAFF reported to the BSEWG that calves under 6 months might be incubating the disease, even though the causative agent or prion was not detectable. ³⁵ This raised issues concerning the use of foetal calf serum and the possible infectivity of vaccines. Commenting on this Professor Collee told us that the question of infectivity in calves had to be separated from the question of infectivity of foetal calf serum. ³⁶ Our discussion in Chapter 5 refers to the reasons why foetal calf serum was considered most unlikely to be infected. In Chapter 7 we also review what happened to research proposals to test the infectivity of bovine serum.

6.157 Professor Collee told us:

I recall that we considered the risk posed by foetal calf serum and bovine serum albumin in great detail at the time. I believe that I had sought the advice of Dr David Taylor and others in advance of this meeting; I wanted their views on the likelihood of the BSE agent being present in such bovine material. I believe I had also asked about the risk of maternal transmission in cattle and the risk of contamination of the material in the course of its collection. The minutes state that the Working Party regarded the risk from vaccines as very remote. The bovine materials involved were very low risk and, as a result, the risk from vaccines could generally be described as very remote rather than merely remote. ³⁷

6.158 The Working Group reiterated its earlier view that the risk relating to serum was low. Taken together with the fact that the risk of transmission of BSE was theoretical and the view that the benefit of availability of vaccines outweighed any potential hazard from their use, the use of foetal calf serum was accepted. ³⁸

Allergen products

6.159 The Working Group returned to the products identified in January as being of concern. Discussion and correspondence with Beecham's about its range of products were continuing. Some products used calf-brain and ox-liver in culture media used in the production of allergens, others used animal hides and hair. The BSEWG considered that where bovine material was used it was essential that the licence holder complied with the guidelines, unless the material used was derived from milk or casein. Discussions with the company were to continue and would be reported to the next meeting. ³⁹

Non-complying vaccines

6.160 The BSEWG also reviewed the situation regarding the four non-complying vaccines considered at its second meeting in January, ie, MMR, Tuberculin PPD, Measles and DTP. ⁴⁰ The Working Group had before it a paper prepared by Dr Rotblat on the current situation with regard to vaccine stocks and the progress being made in manufacturing new batches. ⁴¹ The paper included copies of letters from both the manufacturers involved, Evans Medical and Wellcome Biotech, which had been sent to Dr Purves in June.

6.161 The letter from Evans Medical, the manufacturer of the MMR, Tuberculin PPD and Measles vaccines, said: ⁴²

Bovine constituents include serum, peptone and glycerol beef broth. Serum and peptone are used in the manufacture of Measles antigen and Measles Vaccine . . . and also the, as yet unlicenced, Rubella antigen and vaccine and the MMR vaccine. Glycerol beef broth is used in Tuberculin production.

A. SERUM. Undetectable in Finished Product. Aseptic donor serum from New Zealand has been evaluated and is satisfactory. Such serum is now on order . . . and will be used for all future batches.

B. PEPTONE (Ex milk casein, present in Finished Product).

Alternative peptone . . . containing no components of British origin, has been used in preliminary trials with satisfactory results. Results of further trials on freeze-drying following blending with peptone-containing diluent are expected mid July 1990. If satisfactory, we expect to switch to this source of peptone in September 1990.

C. GLYCEROL BEEF BROTH

This is used in Tuberculin Seed Culture and is purchased from local beef supplies (i.e. not certified BSE-free herds). Subject to satisfactory results from current trails we expect to submit a Product Licence Variation to eliminate glycerol beef broth from all future production.

D. STOCK LEVELS (at 31/5/90)

Measles Antigen	-	approx 3 million doses	) Mainly export
Measles Vaccine (single)	-	Nil	) e.g Unicef,
Measles Vaccine (10-dose)	-	733,536 doses	) (3 months supply)
Rubella antigen	-	approx 1 million doses
Rubella vaccine	-	60,000 doses
MMR vaccine	-	184,029 doses
Tuberculin	-	300 litres bulk at 100,000 units/ml(ie, approx 18 months supply).

6.162 The letter from Wellcome Biotech, the manufacturer of the line of DTP vaccines, said: ⁴³

The sourcing of beef for media preparation was changed to non UK sources in September 1988. Bovine milk is not included in the UK BSE manufacturing guidelines. However, Wellcome has pursued a policy for bovine milk derivatives used in media manufacture to exclude UK sources, with implementation completed during 1989.

Residual vaccine stocks manufactured prior to the changes in media sources are now confined to Diphtheria and Tetanus. Due to the protracted lead times for certain biologicals, component stocks of Diphtheria and Tetanus manufactured prior to the changeover will be incorporated in blends and formulations of Diphtheria, Tetanus and Pertussis combinations until December 1990 to supply the market through to 1992/93, based on average offtake.

6.163 In preparing her paper Dr Rotblat had also obtained from Mr Coleman of PD, via Mr Burton, comments on these letters and information on vaccine suppliers. ⁴⁴

6.164 The first of the four vaccines discussed by the BSEWG was the unlicensed MMR vaccine. Dr Rotblat had ascertained that other companies had licences for this type of product and were producing sufficient quantities to meet demand. The Working Group decided that the vaccine should be granted a licence only if the components of bovine origin complied with the guidelines. The company had changed to a New Zealand source and future production would comply with the guidelines. However, the Working Group recommended that existing trial batches prepared using UK sourced bovine materials should not be marketed. ⁴⁵

6.165 The second product was the Tuberculin PPD. No other source of this product was available, and there were stocks to cover up to September 1991. The product was derived from glycerol beef broth made from bovine muscle, but the licence holder had reported that it was changing over to peptone broth as quickly as possible, and that stocks were to be replaced 'as appropriate'. The Working Group felt that replacement of stocks should be encouraged as quickly as practicable. However, glycerol broth was very low on the list for potential infectivity, and the hazard of having no stocks outweighed the potential risk from using the product with its current composition. ⁴⁶

6.166 The third product was the measles vaccine. The manufacturer was changing to a New Zealand source. No stocks of single vaccine were currently available and other stocks would be depleted within three months. ⁴⁷

6.167 As for the line of DTP vaccines, the company had changed the source of its bovine media. However, existing stocks of non-complying media were still to be incorporated into the final product. The Working Group recommended that a meeting be held with the company to discuss future plans and bring forward the time by which all bovine components in the manufacture of the vaccines would comply with the guidelines. ⁴⁸

Topical medicinal products

6.168 The safety of topically applied medicinal products was reconsidered at this meeting. The Working Group had before them a paper prepared by Dr Winship. He explained that advice had been given to the cosmetics industry regarding the use of bovine offal (see Chapter 8), and said that in view of this more recent concern it had been considered advisable to look into topical medicinal products again. He had found that the use of bovine offal in topically administered medicinal products appeared to be confined to products from two companies who got their material from Germany. Dr Winship recommended, and the BSEWG agreed, that no further action was required in relation to licensed topical medicinal preparations. ⁴⁹

Medical devices

6.169 Mr Burton had prepared a briefing note on medical devices for the BSEWG, but did not actually present it at the meeting. ⁵⁰ His note stated that, of the two remaining companies using UK bovine material, one had changed to a non-UK source and the other had ceased to make its product.

CSM endorses recommendations of third BSEWG meeting

6.170 On 25 July 1990 the CSM received a report from Professor Collee of the BSEWG meeting earlier in the month. The Committee noted the minutes of that meeting and endorsed the recommendations of the Working Group. ⁵¹

Restructuring of Procurement Directorate

6.171 On 1 August 1990, the Procurement Directorate was reorganised: the procurement role was transferred from the STD to the newly created NHS Supplies Authority. The STD was renamed the Medical Devices Directorate (MDD). ⁵²

European working party on human medicines

6.172 Up to now consideration of the implications of BSE for human medicinal products had been at a UK level. On 11 October 1990 the European Community's Committee on Proprietary Medicinal Products (CPMP) decided that a working party should be set up to monitor the implications of BSE for the circulation of human medicinal products. ⁵³

Fourth meeting of the BSEWG

6.173 The BSEWG held its fourth meeting on 31 October 1990. The main issues discussed were the range of allergen products, one remaining non-complying vaccine, and a new development - the transmission of BSE to a pig.

Final returns to CSM/VPC questionnaire

6.174 By this time all outstanding replies to the human medicines questionnaire had been received. The final four replies received gave no cause for concern: none of the companies used bovine material sourced from the UK. ⁵⁴ Annex 2 provides a summary of the responses made to the questionnaires for human medicines, veterinary medicines, and medical devices.

6.175 MAFF reported that where action was still outstanding, measures were being taken to follow-up respondees. They were still waiting for some assurances that appropriate action had been carried through. It was noted that a paper would be put to the VPC shortly. ⁵⁵

Allergens: an update

6.176 The Working Group were told about SmithKline Beecham progress in complying with the guidelines, which now seemed satisfactory. With respect to the specific animal ingredients, they noted:

Cow-hair - The preferred source would be Australia or New Zealand or a closed herd in the UK. It is understood that SKB has a closed herd in the UK, used to obtain sera for the production of their vaccines, and the company should be encouraged to use this source, since they were concerned that decontamination procedures necessary for overseas sources and required by the anthrax regulations could denature the material and alter its antigenicity.

Beef-Veal - from Holland. The licence holder should be advised to specify that the veal is from milk-fed cows.

Mycological Media - containing ox-liver sourced from Italy as a component are acceptable as the source is not UK, provided that the usual assurances are given concerning good animal husbandry and an adequate veterinary service.

Bacteriological Media - A peptone based medium now replaces the brain heart medium used previously. Since this is highly refined and autoclaved at 132ºC for 80 minutes, the Working Group considered the use of this material acceptable. ⁵⁶

Vaccines

6.177 The BSEWG again reviewed the situation concerning the stocks of the DTP vaccines. It considered that the secretariat should explore with the licence holder whether the unadsorbed vaccines (which had limited usage) should be replaced with batches that complied with the guidelines, especially where the stock-out date extended beyond 1991. The Working Group recognised that there 'may be some commercial loss to the licence holder but it is unlikely to be very large'. ⁵⁷ The adsorbed vaccines, about which the BSEWG made no recommendation, had stocks that would run out between June 1991 and December 1991. ⁵⁸ These are different stock-out dates for this line of vaccines from those provided to the BSEWG on 10 January 1990 (refer to paragraph 6.131 above). These updated estimates, based on Wellcome's most recent demand forecasts, had been sent to Dr Rotblat in September. ⁵⁹

Foetal calf serum

6.178 The Working Group again discussed foetal calf serum, considering the potential for contamination during the delivery of the calf. It noted that the guidelines might need to be extended should further investigations reveal deficiencies in cleanliness in this area. ⁶⁰

The pig

6.179 The Working Group was told of an important new development - BSE had recently been transmitted experimentally to a pig. It considered the implications for medicinal products using porcine material, such as heparin, insulin, a heart valve and heparin-coated blood collection tubes. ⁶¹ Professor Collee told us that the Working Group:

. . . noted that the condition had resulted from a massive dose given by an unnatural route; we regarded the likelihood of infection developing as a result of oral ingestion as being extremely remote. The Working Party considered the paper relating to medicinal products containing porcine material. Our unanimous view was that since transmission of spongiform encephalopathy had only been seen under experimental conditions and in a single animal only, no action with regard to human medicines or devices was warranted. ⁶²

6.180 In a minute to Dr Metters the previous month Mr Hagger had indicated that there were no licensed medicinal products on the UK market with which high-risk porcine tissues could be associated. ⁶³

Dural implants

6.181 At the request of the CDSM, the Working Group advised on a licence application for a dural implant derived from bovine pericardium. It was considered that the bovine material would be acceptable provided the selection complied with the guidelines and it was sourced from outside the UK. Validated sodium hydroxide disinfection procedures would also be insisted upon. ⁶⁴ In the absence of an unequivocal declaration by the company that the source herd management met the guidelines, a clear statement that the cattle had never been fed ruminant protein would be required. ⁶⁵

Paper on sterilisation of animal tissues in medical devices

6.182 MDD sought comments from the Working Group on the 'Control of Harvesting Techniques' chapter of its paper 'Guidance on Chemical Methods for the Sterilization of Animal Tissues used in Medical Devices'. ⁶⁶ Minor changes were suggested but it was thought that detailed comment on the content would be more appropriate from some other body such as the BSC and then the CDSM. ⁶⁷

BSE in Switzerland

6.183 On 14 November 1990 Dr Sprang, Director of the IKS (the Federal Swiss regulatory authority for pharmaceuticals), telephoned Dr Jefferys about BSE in Switzerland and the action being taken with regard to pharmaceuticals. ⁶⁸ Later that day Dr Jefferys sent a minute reporting on his conversation to a number of people in MCA as well as Dr Metters and Dr Pickles. That minute said: ⁶⁹

There has been one confirmed case of BSE in Switzerland and the public position is that two cases are under investigation. In confidence Dr. Sprang tells me that there are 12 other likely cases.

. . . The pharmaceutical authorities are considering their response and at one stage were considering banning all pharmaceutical products containing bovine material. I think they have now realised that this would pose very considerable difficulties considering the use of bovine material is widespread as an intermediate in vaccines and other products. The Swiss authorities already have a copy of our guidelines and we are bringing together a package of information which will be sent to them later today which we hope will be of help in their discussions . . .

Pharmaceuticals have been highlighted as a major issue in Switzerland and we will have to watch the position carefully . . . I hope following my lengthy conversation that the Swiss will be following a similar procedure to that which we undertook in the UK.

Mr. Love has already arranged for a search to be made of our new database so that we can identify any products using Swiss material and consider whether any action is necessary.

. . .

The Swiss authorities will be circulating their decisions through the CPMP and PER rapid alert networks. I therefore suspect that this item will appear on the CPMP agenda at its December meeting and this may bring forward the date of the proposed BSE Working Party.

6.184 A note by Dr Metters in manuscript on this minute said that the CMO would wish to know of the cases of BSE in Switzerland and of the action there regarding pharmaceuticals.

CDSM and CSM consider recommendations of fourth BSEWG meeting

6.185 The CDSM meeting on 21 November 1990 considered the dural implants that had been discussed at the BSEWG meeting on 31 October. ⁷⁰ The Committee was unable to advise the grant of a product licence for the bovine pericardium implant. ⁷¹ However, the documents we have seen do not give us the basis of this decision.

6.186 When the CSM met on 22 November, it endorsed the recommendations of the BSEWG. Professor Collee, attending as a guest member, reported to the CSM that, as far as vaccines were concerned:

We are still worried about this matter, and it is right that we should continue to send signals to CSM and JCVI that present evidence allows us to give no absolute assurance but some relative assurance. Meanwhile, it seems unreasonable to allow vaccines that have some association with UK sourced bovine products to be used when they could be replaced with batches that have been processed in compliance with the guidelines. Accordingly . . . our line of advice to CSM is hardening and I would like you to count me amongst the hawks in this. ⁷²

VMD reports progress on veterinary medicines to the VPC

6.187 VMD continued to take follow-up action on the veterinary medicines questionnaire and compliance with the guidelines. Its second progress report, for the VPC's December 1990 meeting, described the action various manufacturers were taking to comply with the guidelines and also highlighted decisions that were taken on existing stocks of veterinary vaccines. The report stated:

Most of the companies have now made satisfactory arrangements. The VMD has recently written again to the small number of companies where further information and reassurance on satisfactory progress is required. The replies received to some of these may need to be considered by the Committee in the future. In the meantime, the following are being brought to the attention of the Committee.

1. A number of products for external use contain lanolin from UK sheep. A number of oral products contain gelatin from UK cattle. Such products were defined as outside the scope of the Guidelines and it is proposed that no action is taken with regard to these.

2. Lungworm vaccines are produced by harvesting larvae from the faeces of UK production calves. These calves are less then 6 months of age. Since faecal material is classed as a very low risk tissue for scrapie infectivity and the vaccines are given orally, it is proposed that no action is taken.

3. Three products are manufactured in bovine origin brain heart infusion broth. Two of the three are fish immersion vaccines. The bovine material used for one of these has never been of UK origin and the other manufacturer has indicated that he has now changed to a non-UK source.

Coopers-Pitman Moore have a product licence for a bovine mycoplasma vaccine, Bovulin, which also requires brain heart infusion broth during manufacture. However this product has not been marketed since licensing.

It is considered that the use of any bovine brain material is to be discouraged. The two fish vaccine manufacturers have been trying to find an alternative growth medium. It is proposed that pressure is maintained on these two manufacturers to finalise this work.

It is proposed that Coopers-Pitman Moore is told that an alternative medium should be found before undertaking manufacture of product for sale.

4. Media from Unipath (formerly called Oxoid) is used by a small number of companies to prepare vaccines. Some of the media contain a bovine soup stock of UK origin. . . . The soup stock is prepared from bones from EC approved abattoirs and is autoclaved for 80 minutes at 132°C. It is considered that this is satisfactory treatment for this material.

5. Some of the questions on the BSE questionnaires were interpreted differently by different companies. As a result, it is thought that we are likely to have incomplete data on when all stocks of batches of products made before changes to comply with the guidelines will be used up. Coopers-Pitman Moore and SKF have provided the information.

Coopers-Pitman Moore have some batches of bacterial vaccines which are likely to be used till 1994. Further information is being sought from the company.

SKF have bulk viral vaccines made with serum from the UK which would normally last for another 4 years or so. They do not have the manufacturing capacity to replace all these bulks with new stocks. The company has proposed to give priority to manufacture of fresh bulks of their large animal products and would expect to have this completed by December 1992 at the latest. The UK serum used was filtered and cell free. It consisted of foetal serum or donor calf serum. The latter was collected from calves less than three years old and were thought to have received no animal protein for most if not all of their lives. It is proposed that the company should be encouraged to change to fresh bulks as soon as possible for all products but that no action is taken in the meantime against existing stocks. ⁷³

6.188 The VPC considered this report at its 13 December 1990 meeting and agreed that:

1. Bovine brain material must not be used during manufacture (see sub-paragraph 4 of paragraph 6.189 above);
2. Full information on the herd history of the source of donor calf serum used in manufacture of SKF's bulk viral vaccines was required (see sub-paragraph 5 of paragraph 6.189 above);
3. Dr Taylor ⁷⁴ was to be consulted on whether the autoclave treatment of bovine soup of UK origin was satisfactory (see sub-paragraph 3 of paragraph 6.189 above); and
4. Any action should conform to current EC regulations on BSE. ⁷⁵

6.189 We have not seen any minutes of further meetings at which the follow-up to the veterinary products questionnaire may have been discussed. However, the VMD provided us with a table outlining the 143 products that did not comply with the CSM/VPC guidelines and the outcome of compliance measures taken (see Annex 3). We have also been provided with some supporting documentation. ⁷⁶

6.190 In relation to compliance the VMD told us:

The speed at which the companies concerned were able to move away from the use of bovine/ovine material carrying a potential risk of BSE/scrapie was dependent upon both the complexity of their manufacturing processes and the availability of alternative sources of supply of suitable material which would neither compromise safety/efficacy nor lead to risks from contamination by other agents. With regard to serum used 'in process' manufacturers had changed to non-UK sources by December 1990. Where companies needed to make more significant changes to manufacturing processes this required a longer lead time e.g. to make fundamental changes to bacterial growth media. With the exception of 1 fish vaccine, which remains under review, VMD's records indicate that all manufacturers had complied with the CSM/VPC Guidelines by 1992. ⁷⁷

6.191 It is clear from the VMD report to the VPC at paragraph 6.189 that at least some veterinary vaccine stocks that did not comply with the guidelines remained in use until several years after the guidelines had been put in place.