Volume 7: Medicines and Cosmetics
5. Issue of guidelines
Preparation and issue of joint guidelines between January and March 1989: a chronological account
January 1989
February 1989
March 1989

January 1989

MAFF and DH agree to keep in step

5.3 We have seen from Chapter 3 that towards the end of 1988 Dr Adams (PMO in Medicines Division) had various informal conversations with MAFF colleagues about BSE, including a visit to Mr Bradley in December 1988. Dr Adams told us that around this time it occurred to him it would be helpful to set up a meeting between MAFF and DH, so that officials from MAFF's Central Veterinary Laboratory (CVL) would be on hand to provide advice about BSE and feed into Medicines Division discussions. This was because they needed as clear an understanding as possible of the up-to-date knowledge of the CVL. In addition, MAFF was working on draft guidelines for industry and he felt that the two Departments should keep in touch. He therefore arranged a meeting for 3 January 1989. ¹

5.4 In addition to Dr Adams, Dr Jefferys and Dr Purves attended the meeting from Medicines Division. From MAFF, Dr Little and Mr Kidd came from the veterinary medicines licensing side, as well as Mr Bradley in the CVL.

5.5 At the meeting MAFF explained what action it had taken on veterinary medicines since November 1987, and provided some background information. Medicines Division described the progress of its consideration, and outlined some of its unresolved questions, for example how to define a healthy herd. The two Departments agreed it was 'essential to keep "in step" especially as MAFF concerns about animal vaccines would cause DH great difficulties of supply if current stock had to be lost'. They agreed that MAFF would put revised guidelines to the VPC later that month. This had in any event been the intention (see Chapter 3). Following the meeting of the VPC the two Departments would meet again with expert advisers from the National Institute of Biological Standards and Control (NIBSC) to produce joint guidelines for industry. These would then be published in MAIL, together with a request for information on products. ²

5.6 Following the meeting, Dr Jefferys and Dr Adams sent a joint minute on 9 January to Dr Harris, the DCMO, to update him on the current state of play. They circulated this widely in Medicines Division and sent copies to Dr Pickles and to MAFF. They noted that the importance of MAFF and the Division keeping 'in step' had been recognised, particularly as vaccines were prepared in the same way for humans as for animals and involved the use of foetal calf serum, a potentially infective material. It would, they said, cause great difficulties if current stocks of vaccines were to be lost as, for some vaccines, 'there may be supplies of up to 5 years'. They also mentioned that Medicines Division's database was unable to identify products used, not as an active ingredient, but rather as an excipient or an intermediate in the manufacturing process: this created a much greater problem as bovine albumin, foetal calf serum and bovine nutrient broths were extensively used in the production of all vaccines, as well as in that of other biological and biotechnological products. ³

5.7 Dr Jefferys and Dr Adams also told Dr Harris of the plan for a common set of guidelines on the procedures for collecting and using bovine material. The amalgamation of the two sets of guidelines would mean:

a slight change in emphasis since the MAFF proposals concentrate upon the collection of the bovine material, whereas the initial CSM proposals were concerned more with the production of the medicinal products.

This would allow clarification of the definition of healthy cattle and would give clear advice about the collection of foetal calf serum and bovine albumin. ⁴

5.8 They noted that a proposed joint working group involving NIBSC and BSC members would ensure that the proposals were practicable and capable of implementation in as short a time as possible, and should not damage the supply of important products such as vaccines and monoclonal antibodies for human use. The minute concluded by pointing out that neither MAFF nor Medicines Division had been given sight of Sir Richard Southwood's interim Report and that it would be most helpful if this could be made available. ⁵

5.9 Within MAFF, the conclusions of the meeting were relayed to Mr Scollen, Head of Animal Medicines Division, who on 13 January 1989 sent a minute to Mr Cruickshank to bring him up to date. Mr Scollen noted the difficulty in ensuring that foetal calf serum and other bovine material used in the preparation of biological products was free of contamination. There were safeguards that could be introduced for the future, but Mr Scollen noted that there was also a potential problem over existing stocks of vaccines, most of which were produced with some kind of bovine material. He told Mr Cruickshank of the plan to combine the two sets of guidelines produced independently by Medicines Unit and by DH Medicines Division, 'so that the two Departments are seen by the industry to be speaking with one voice, particularly on a matter where they are so interdependent'. ⁶

5.10 Mr Scollen noted that there was further work to be done in order to judge the need for more extensive action. While there was potentially a need for 'radical - and expensive action' it was also possible, he pointed out, that in the course of a few years they would be able to demonstrate the effectiveness of the action already taken to eliminate BSE:

Extravagant action now to deal with a contingent risk could then seem to be wholly disproportionate. Moreover, new collection methods would not deal with the problem of existing stocks of vaccine. ⁷

Mr Scollen concluded:

In my own view the issues involved centre on an assessment of the risks associated with maintaining or disrupting the supply of vaccines for human health purposes. The issue is therefore one to be addressed first and foremost in the human health context, with MAFF advising on the availability of animal material considered free of contamination. Judgements about what is needed and feasible on the animal medicines front can be more readily taken afterwards. In addition to the meeting on 1 February, I shall be taking up these points with Mr Wilson and his colleagues when they visit Tolworth on 23 January. ⁸

VPC discussion of the draft guidelines

5.11 As planned, the VPC considered MAFF's draft guidelines for industry for the first time on 19 January 1989. They requested a full list of products involved, including all the 'old medicines', ie, those with Product Licences of Right, to assess the likely effect of various control measures and their practicality. Written comments on the draft guidelines were invited, to be discussed at the next meeting in February. ⁹

Further correspondence with Sir Richard Southwood

5.12 We noted in Chapter 4 that, following the third meeting of his Working Party, Sir Richard Southwood had written for the second time to Professor Asscher. On 20 December 1988 Sir Richard also wrote to MAFF for the first time to make enquiries about veterinary medicinal products. Sir Richard directed this letter to Dr Little, asking him what steps were being taken by the VPC in its consideration of licence applications for new products. He said that he trusted that any safeguarding steps would also be applied to existing products. He suggested as possible solutions purchase of material from abroad; exclusion of brain and lymphoid tissue directly or in culture media; and avoidance of animals destroyed by brain penetrative stunning. Sir Richard asked if some form of guidance to the industry might be useful. ¹⁰

5.13 Dr Little replied on 26 January 1989. He outlined the discussions that had taken place during the past year with the VPC, and with MAFF's Biologicals Committee (BC), the National Office of Animal Health (NOAH) and individual licence holders. Dr Little said that the VPC had asked for a full list of products involved, 'including all the old medicines to assess the likely effect of various control measures and their practicality'. He explained 'our philosophy in drafting guidelines for consideration by the VPC has been to concentrate on the source and nature of the materials used in the manufacture of veterinary products'. Dr Little indicated some of the difficulties, and added that those dealing with veterinary licensing were working very closely with colleagues in DH to ensure they issued consistent advice to manufacturers. ¹¹

5.14 Professor Asscher also replied to Sir Richard on 26 January. He said that the secretariats of the Committee on Safety of Medicines (CSM), the Committee on the Review of Medicines (CRM) and the Committee on Dental and Surgical Materials (CDSM) had been considering, and seeking to implement, the recommendations made by CSM:

We originally considered the problem of BSE in the light of the 43 products which our computer database showed to include bovine material as an active ingredient. We will now need to consider the possible hazard from the use of bovine material as an intermediate in the manufacture of products. This will include the use of bovine material in nutrient broths, foetal calf serum and the use of bovine serum albumin. You will be aware that these materials are used very extensively in the production of most vaccines, monoclonal antibodies and other biotechnologically derived products.

MAFF are also concerned about such products and they have now produced new draft guidelines regarding the use of bovine material in veterinary medicines: these are currently under consideration by the Veterinary Products Committee.

Following several meetings between Medicines Division officials and their counterparts at MAFF, it is hoped that a joint guideline for the manufacturers of both human and veterinary medicines can now be agreed and published. Therefore a further paper is being produced for consideration by the CSM and its Sub Committees. We will be reconsidering whether our recommendation that '. . . the manufacturing processes are capable of eliminating the scrapie agent' is too stringent. It will also be proposed that the CSM uses the definition of a BSE-free herd which has been proposed by MAFF (you will remember that my Committee deliberately chose the words 'appropriately certified healthy herds' to allow us the freedom to obtain more expert advice from our veterinary colleagues).

We have to consider the impact on the supply of these important products whilst at the same time seeking to maintain public confidence in the vaccination programme. Many vaccines are stored for up to 5 years before being released and this will therefore have to be considered.

For all these products it will be important to ensure that our recommendations are practicable and can be scientifically justified.

Finally, I want to reassure you that CSM intends to take appropriate action in regard of products within its remit and that CRM and CDSM are being kept fully informed of our recommendations. I hope you will agree that the Secretariats and the Committees are giving considerable attention to this important issue. ¹²

February 1989

The Human and Veterinary Medicines Briefing Group (HVMBG)

5.15 Shortly after the VPC had considered MAFF's draft guidelines, the two Departments met again, on 1 February 1989. The group, called the Human and Veterinary Medicines Briefing Group (HVMBG), comprised Dr Jefferys, Dr Adams, Dr Purves and Dr Rotblat from Medicines Division; Dr Minor and Dr Schild from the NIBSC; Professor Collee from the CSM/BSC; Dr Pickles on behalf of the Southwood Working Party; and Mr Kidd, Mr Bradley, Mr Taylor, Mr Scollen and Dr Little on behalf of MAFF. The role of the group was to review papers that had been prepared for the forthcoming CSM meeting and to formulate advice to the CSM on BSE as a whole. Mr Hagger told us:

This was an uncommon way to deal with CSM business (i.e. other than through its established sub-committees) but the BSE issue was unusual in that the CSM was normally concerned with licensing issues for individual products and here it was faced with unusual concerns which could have related to any number of licensed products and had serious implications for the continuing supply of all kinds of medicines, and vaccines in particular. ¹³

5.16 In a minute of 2 February 1989 to Mr Cruickshank, Mr Scollen reported the conclusions of the meeting. According to his minute the briefing group agreed the text of the joint guidelines, and a timetable for their clearance by the advisory committees to make publication in MAIL possible before Easter. In addition, it was agreed that further action, especially on current stocks of affected products, should be determined once the scale of the problem had been more precisely identified with the help of the manufacturers. Any such action, it was agreed, would need to be based on a human health risk/benefit assessment. ¹⁴

5.17 The briefing group also considered an extract from the current draft of the Southwood Report, shown to them by Dr Pickles. The drafting of the Southwood Report is covered in detail in vol. 4: The Southwood Working Party, 1988-89. In relation to medicines the draft read:

5.3.3 . . . All relevant products are being reviewed by the Licensing Authority. However, the Working Party acknowledge that at least some leading pharmaceutical companies have already made appropriate changes in their production processes. There are various steps which could be considered which might reduce the chance of the BSE agent or those bovine tissues most likely to contain it ever entering into pharmaceutical manufacture. For example, only animals never fed ruminant-protein could be used; or serum only taken from animals killed other than by brain-penetrative stunning which might release nervous tissue into the circulation: and the use of brain or lymphoid tissue directly or in culture media could be avoided. In all cases only healthy animals should be used in pharmaceutical manufacture but in the case of BSE it has to be accepted that infection could be present without clinical disease. The production processes are being examined to determine how these might be modified so as to destroy or remove infectious agents; the scrapie agent must now be included in such considerations. ¹⁵

5.18 The reaction of the briefing group to this draft was recorded in Mr Scollen's minute to Mr Cruickshank of 2 February 1989:

There was general dismay at the drafting, which tends to highlight the (theoretical) risk via medicines and to relegate the qualification that the risk is remote. The paragraphs concerned also imply (mistakenly) that numerous, licensed human medicinal products are affected; that some but not all manufacturers have taken necessary action; that various safeguards could readily be introduced into the production and processing of bovine material; and that the Licensing Authority and its advisory committees need to have their attention drawn to the problems.

The Working Group felt that much of this was, at best, misleading. For example, many manufacturers have been alerted to the problem but there is no reason to believe that they are in a position to take effective, unilateral action. Moreover, the start of MAFF/DH work on the issue comfortably pre-dates the Southwood Committee.

Even if the Report is modified in the light of these reactions, its appearance seems likely to trigger a need for a major public relations job which takes full account of the medicines angle. Consistency between MAFF and DH will be essential and should be achievable. The guidelines themselves could subsequently generate similar pressures since they clearly do not address the issue of current stocks and they could prompt questions - for example - on the standards applicable in the collection of animal material at slaughterhouses for biological medicinal purposes.

While I have no doubts about the Working Group's staged approach and the balance being struck between risks and benefits to human health, this will not be the easiest position to present to a potentially critical public prone to seeing the influence of commercial interests. ¹⁶

Consideration by the Southwood Working Party

5.19 On 2 February 1989 Dr Pickles reported the concerns expressed by the HVMBG in a letter to Sir Richard Southwood:

They have now realised that virtually none of the current essential human or animal vaccines could comply with the CSM guidelines as agreed by their November meeting, and there may be several years of some vaccines in stock to make matters more difficult. Public confidence in the vaccination programme must not be put in jeopardy and yet supplies of some vaccines are very limited. After a late start, it now seems that both human and veterinary sides of the medicines business are working together and putting together a package of measures that seem sensible and workable (and indeed now incorporate all the points you raised with Professor Asscher in your earlier letters, and which I had raised with them separately). ¹⁷

5.20 She suggested that the draft be amended:

If you are content that all is now in hand, a briefer version of 5.3.3 might be adequate. I attach my suggestions. This treats CSM/VPC like HSE: i.e. the problem has been referred to the body with the statutory responsibility in that area and it is then for them to take appropriate action. I also have suggestions for minor alterations to the summary sections to make it clear that the Licensing Authority has already started addressing the problem. ¹⁸

5.21 When the Southwood Working Party met on 3 February 1989, Dr Pickles reported on the 'very satisfactory response' now being made by both the human and veterinary sides, and also on the potentially grave problems to supply of essential vaccines if foetal calf serum were to be considered at risk of being infected. ¹⁹ The Working Party adopted verbatim Dr Pickles's suggested wording for this section of their Report, which eventually read as follows:

5.3.3 The greatest risk, in theory, would be from parenteral injection of material derived from bovine brain or lymphoid tissue. Medicinal products for injection or surgical implantation which are prepared from bovine tissues, or which utilise bovine serum albumin or similar agents in their manufacture, might also be capable of transmitting infectious agents. All medicinal products are licensed under the Medicines Act by the Licensing Authority following guidance, for example from the Committee on Safety of Medicines (CSM), the Committee on Dental and Surgical Materials (CDSM) and their subcommittees. The Licensing Authority have been alerted to potential concern about BSE in medicinal products and will ensure that scrutiny of source materials and manufacturing processes now takes account of BSE agent.

. . .

5.3.5 In these, as in other circumstances, the risk of transmission of BSE to humans appears remote. ²⁰

A draft submission to the Secretary of State: the CMO's reaction

5.22 Following the completion of the Southwood Working Party's Report, Dr Pickles prepared a draft submission from the CMO (Sir Donald Acheson) to the Secretary of State. The draft included the following passage:

In Sir Richard's view the risk to human health is minimal. Nevertheless he has alerted the Licensing Authority and the Health and Safety Executive to potential problems in their areas of responsibility. At the present time, we cannot give any complete guarantee of safety for human medicines that use bovine materials in manufacture, such as most vaccines. However, appropriate action is being taken by Medicines Division following advice from the Committee on Safety of Medicines, the Committee on the Review of Medicines and the Committee on Dental and Surgical Materials and defensive briefing is being prepared for when the report becomes public. ²¹

5.23 This alerted Sir Donald Acheson to the fact that concerns about the safety of vaccines had not yet been resolved. He contacted Dr Pickles, and their conversation led him to ask Dr Harris to look into the matter:

My attention has been drawn to a sentence in Dr Pickles' draft of a submission to the Secretary of State on this matter. It reads: 'At the present time we can't give any complete guarantee of safety for human medicines that use bovine materials in manufacture such as most vaccines.' Having looked at the report I am not able to find any statement which supports this statement of concern. I have, however, therefore spoken to Dr Pickles on the telephone and she reports to me that for some considerable time she has had serious concern about the safety of bovine-based vaccines in the light of the fact it has been discovered that contamination with placental material (which is known to be heavily infected with the BSE particle) is a distinct possibility in the preparation of material for human vaccines derived from foetal serum. This matter as described to me by Dr Pickles gives me sufficient cause for concern to ask you to look into it urgently together with Medicines Division. I shall amend the submission to indicate that the question of the safety of vaccines derived from bovine material is a matter which has not been dealt with directly by Southwood's group, but is one in which I am making urgent enquiries. ²²

5.24 Sir Donald told us that this intervention was quite contrary to his normal practice; he was trying to 'stir up more activity in the Medicines Division'. ²³

5.25 Having taken these steps, Sir Donald recast the submission to Ministers to advise:

I am also putting work urgently in hand to satisfy myself that everything possible has been done to ensure . . . that transfer of the BSE agent in human and veterinary medicinal products does not occur. ²⁴

Medicines Division's response to the CMO's concerns

5.26 The CMO's minute to Dr Harris prompted Medicines Division to give urgent consideration to establishing the present situation on vaccines. A meeting was held on 13 February 1989, attended by professionals and administrators from the Division. In Dr Jefferys's absence, Dr Adams took the lead. ²⁵ A manuscript minute by Mr L Whitbread records that those present agreed that a number of steps should be taken, including:

1. Children's vaccines and the companies manufacturing them would be identified by Mr Love and Mrs Alderman.
2. The companies would be telephoned by Dr Rotblat and asked
   1. whether the vaccines contained bovine material;
   2. the source of the material; eg, country of origin;
   3. the bulk stock of vaccines post-1980; and
   4. the length of time it would take to switch to another product.
3. Mr Love would then write seeking more detailed information.
4. A working group would be established to consider the Southwood Report and the paper to the CSM. Mr Hagger would clear this with Professor Asscher. It was proposed that the group should comprise Professor Collee, Dr Tyrrell, Dr Kimberlin, Dr Minor, Dr Schild, Dr Martin, Dr Pickles and various MAFF representatives. ²⁶

We discuss the establishment and deliberations of this group in Chapter 6.

5.27 A further meeting was held the next day to discuss the outcome of Dr Rotblat's enquiries. ²⁷ Urgent telephone calls had been made, enabling Dr Adams to report to Dr Harris that they had contacted all the major vaccine product licence holders whose products were likely to be used in children. ²⁸ He said that many manufacturers used bovine material. The information given was diverse and incomplete; many companies stressed that they could not give an accurate assessment without detailed research. He set out an overview, which we include in full below.

1. SKF have polio, measles, mumps, rubella, rotavirus vaccines. All use bovine serum from a UK source and bovine commercial product from unknown source. Some agent comes from the USA and New Zealand.

2. Wellcome gave us most information (see Appendix 2). All their vaccines apart from yellow fever, cholera and typhoid contain bovine material:

Oral polio; up to 1988, foetal calf serum was used from UK and New Zealand (pooled); since 1988 foetal calf serum only from New Zealand. Large stocks are held.

Rubella; bulk was made before 1979 from foetal calf serum from UK and New Zealand. None has been made as there are some 15 years stock.

Diphtheria; UK bovine beef muscle and ox heart is used but since the end of 1988 this has been sourced from Eire. There are 1,250 litres of stock.

Tetanus; this involves bovine material from the UK mainly Scottish. There are 21,000 litres of stock.

Pertussis; uses bovine material from the UK. There are 63,000 litres of stock.

They consider that to switch to a non-UK source will take a minimum of 6-18 months and to switch to a non-bovine source will take a minimum of five years.

3. Merck Sharp & Dohme have measles, mumps, MMR, rubella vaccines. These are sourced from the USA and the company believes that US material only is used. ²⁹

4. Evans Medical have a measles vaccine using bovine serum from the UK. There are 440,000 units of stock.

- They have also got MMR using bovine serum from the UK.

5. Merieux have influenza, rubella, measles, MMR vaccines likely to be used in children. Of those they think that only MMR contains bovine material which is probably a French origin.

6. Cyanamid have diphtheria/tetanus and pertussis on clinical trial [. . .]; These use veal material, some of which has come from the UK and has been made by Wellcome (see above).

7. Duphar Laboratories have influenza vaccines which are made up in egg medium.

8. The Secretary of State has a number of licences. We understand that the inactivated polio vaccine is no longer being used. There is a stock of smallpox vaccine. We have not been able to determine the source material. (Made in sheep very unlikely to contain bovine ingredients).

9. Porton Products have a cellular triple vaccine in which Wellcome material of UK bovine source has been used.

As far as I can see Wellcome are the sole supplier of pertussis vaccine which uses bovine casein digest.

You should also be aware that DH has made arrangements for meningococcal vaccine to be available, on a named patient basis, from SKF and Merieux. Both companies use bovine media in production. ³⁰

Briefing to MAFF Ministers

5.28 We discuss in vol. 6: Human Health, 1989-96 the meeting that took place on 14 February 1989 with the MAFF Minister, Mr John MacGregor, to discuss the recommendations in the Southwood Report, the timing of its publication and its handling. ³¹

5.29 Mr Lawrence had circulated briefing material prior to the meeting, including a briefing note, which said of the risks associated with medicinal products:

The Working Party concludes that the risks of transmission of BSE to cattle and other species, including man, through the use of medicinal products are remote. However, they recommend that the attention of the Licensing Authority; the Committee on Safety of Medicines (CSM), the Committee on Dental and Surgical Materials, and the Veterinary Products Committee, be drawn to the emergence of BSE so that they can take appropriate action. ³²

5.30 The briefing material included a copy of the draft MAFF/DH guidelines. Mr Lawrence's note indicated that these were currently being considered by the CSM and the VPC, and that they represented a 'counsel of perfection'. He pointed out a number of considerations:

1. The use of defined, BSE-free sources would be severely restrictive. Although there were undoubtedly farms that could ostensibly meet the criteria, they could not be certain that non-detection of BSE equated in all cases with freedom from the disease. New Zealand and Australia appeared to be the safest sources, but their supply was unlikely to match demand.
2. Suppliers of primary and intermediate materials, from whom pharmaceutical companies purchased ingredients, were not covered by the Medicines Act. Licence holders would therefore have to obtain assurances from their suppliers that the guidelines were being adhered to. If this could not be satisfactorily achieved then the product licence might have to be withdrawn.
3. The guidance on collection techniques conflicted with normal practice in abattoirs. This was unlikely to matter if reliable, BSE-free sources were used, although a risk of cross-contamination might remain.
4. The recommended sterilisation treatment was generally inappropriate to biological medicines, which it would destroy, but would be suitable for some tools and equipment. ³³

5.31 Anticipating the likely response from the industry, the briefing note added:

Although NOAH . . . accept the need for guidelines, they have not seen the draft, which they may find more rigorous than expected. They may respond by pressing for assistance in complying with the guidelines (eg. by introducing a BSE-free farm certification scheme, extension of Medicines Act controls to primary source suppliers). Any proposals would need to be considered in relation to their likely effectiveness in improving the supply of BSE-free material. ³⁴

5.32 At the meeting itself, on 14 February, the CMO advised Mr MacGregor that a special working party (HVMBG) was scheduled to meet on 22 February to consider the implications of BSE for medicinal products. It was hoped it would offer some reassurance on this area, and he suggested that it would not be sensible to publish the Southwood Report until after the meeting. There was discussion about whether medicinal material should be sourced from countries with a significant sheep population where sheep material might be fed to cattle. Sir Richard Southwood, while highlighting the lack of certainties, was of the view that they should be careful in sourcing material in this way. Mr Meldrum, CVO, pointed out that the issue was complex: some countries might ostensibly be free of BSE while having an underlying problem with the disease in subclinical form. It was agreed that they would have to wait for the outcome of the meeting on 22 February to be clear on this issue. ³⁵

VPC approves the guidelines

5.33 The VPC met on the following two days. It considered a further draft of the joint guidelines, which had been revised since it saw them on 19 January. These revised draft guidelines provided:

1. Scope
It is intended that all products licensed under the Medicines Act 1968 for human or veterinary use, that are administered parenterally or to the eye or to open wounds, should conform to these guidelines if they contain material from a bovine source, or if bovine material has been used during their manufacture.

Although these guidelines relate to BSE and materials of bovine origin, they should also be considered as applicable to material from sheep, goats, deer, and some other animals susceptible to scrapie-like agents.

2. Cattle source
Bovine material should come from cattle, taken from a closed herd in the female line since 1980, in which no animal has been clinically suspected of having BSE, and which has not been fed rations containing ruminant derived protein during that period.

3. Tissues excluded
No brain or neural tissue, spleen, thymus and other lymphoid tissue, placental tissue or cell cultures of bovine origin should be used in the manufacture of medicinal products.

4. Collection techniques
All possible measures should be taken to avoid contamination of the bovine material with BSE agent, in particular:

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

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

c. it is recommended that whenever possible, source animals should be calves up to 6 months old.

d. for serum: all cellular components must be removed.

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

5. Sterilisation
When sterilisation procedures are used they should be demonstrated to be capable of inactivating scrapie-like agents - at present thought to be autoclaving using a porous load cycle at 134°C-138°C for 18 minutes at 30 psi.

6. Product
Whenever possible, the product should be terminally sterilised by a validated method. ³⁶

5.34 The VPC agreed the guidelines subject to the following specific comments:

1). Members asked for clarification of paragraph 4a. It was explained that under the BSE Order, the head had to remain intact. Clarification was provided on the methods of slaughter that could be allowed.

2). It was considered that subject to CSM advice, pancreas should be included at paragraph 3. ('Tissues excluded'), and this paragraph could apply to material of other species not just bovine origin.

3). It was considered that paragraph 4c should be expanded to exclude animals fed ruminant derived protein.

4). With reference to paragraph 2, it was considered that in practice it could not be guaranteed that animals had not been fed rations containing ruminant derived protein.

5). It was considered that bovine serum albumin should also be included in paragraph 4e.

6). Members also asked for clarification about the recommendation to use calves under 6 months of age. ³⁷

Second meeting of the Human and Veterinary Medicines Briefing Group

5.35 The HVMBG met for a second time on 22 February 1989 to agree advice for the CSM meeting on the next day. A number of officials from MAFF, Medicines Division and other divisions of DH, as well as representatives of the CSM/BSC, were present, along with the following invited experts: Professor Asscher, Professor Sir John Badenoch, Dr Kimberlin, Dr Martin (a member of the Southwood Working Party) and Professor M D Rawlins. They considered the Southwood Report itself, the proposed joint guidelines, a draft letter to licence holders and a draft questionnaire.

5.36 The group noted that the Southwood Working Party considered the most likely source of BSE to be cattle feed containing protein derived from scrapie-infected sheep and were of the opinion that it was unlikely that there would be any implications for human health. Nevertheless, the 'slight theoretical risk of BSE being transferred to humans was considered to be more likely from products used parenterally or by implantation rather than by the oral route'. ³⁸

5.37 The group noted:

Normally, in matters where there is as little knowledge as there is in the case of BSE, CSM would have been advised to take no action but to monitor the situation. Due to the publication of the Southwood Report, this option is not open. It is not feasible to go to consultation with industry on the matter due to lack of time, and the fact that this might be seen as our being led by industry. VPC had given broad approval to the draft guidelines. ³⁹

5.38 A handwritten note of the meeting made by Mr Will Burton, attending on behalf of the Supplies Technology Division (STD) of the Procurement Directorate (PD) of the NHS, indicates that the decision to go as far as issuing guidelines was not an easy one. ⁴⁰ A number of those present raised concerns, for instance about causing unnecessary alarm and about the difficulty in formulating guidelines. Mr Burton's note records that the CSM would have preferred to speak of consultations with industry rather than guidelines and would have preferred to approach industry in the spirit of talking to each other. ⁴¹ In considering the draft guidelines, the group noted:

These are to be seen as a 'gold standard', and may be modified in the light of experience. It is intended that they should be parallel with those issued on the veterinary side, but not identical because they have more difficult problems to handle (BSE being a speculative hazard in man). ⁴²

5.39 The group agreed that it would be better 'to try to eliminate BSE at source' and discussed the possibility of maintaining or identifying and certifying 'risk-free herds'. ⁴³ They felt that 'to issue rules on oral products would challenge our concepts on foods, and cause problems with regard to gelatin capsules.' The VPC had expressed anxiety about animal vaccines and 'it was felt that in future we may need to ensure that bovine ingredients are not obtained as by-products of abattoirs'. Herds might have to be specifically maintained for this purpose. In considering excluded tissues, they noted that to exclude the intestine would eliminate heparin (most of which, though, was porcine) and catgut, and were of the view that the pancreas should not be excluded as this would eliminate bovine insulin.

5.40 Anxiety was expressed at the meeting over problems with the availability of supply of vaccines if companies could not comply with the guidelines; failures of supply could lead to epidemics. The group noted that Dr Adams and Dr Rotblat had contacted companies holding licences for vaccines, and some had begun to take action. It was felt that most companies would welcome guidelines on this subject. ⁴⁴

5.41 The HVMBG also recommended that a working group, associated with the CSM/BSC and initially proposed at the Medicines Division internal meeting on 13 February, should be set up. ⁴⁵

5.42 Dr Martin told us in relation to this meeting:

I was left with the impression that those on the human medicine side regarded BSE as an animal problem and that we . . . were being excessively apprehensive. ⁴⁶

Consideration by the CSM

5.43 The CSM met the next day, and heard a detailed report on the previous day's meeting from Professor Collee. It had before it a paper giving it an update on the steps taken since the last CSM meeting on BSE and the action proposed by Medicines Division, together with the relevant documentation. ⁴⁷

5.44 The paper proposed that the guidelines would be issued in a letter to all licence holders, who would also be requested by means of a questionnaire to supply details to Medicines Division. The Division and MAFF officials had sought to ensure that the guidelines would be practicable and capable of implementation over as short a time period as possible, and that they would not damage the supply of important products such as vaccines and monoclonal antibodies for human use.

5.45 On existing stocks of vaccines the paper noted:

A particular problem which will need to be considered is that of products (vaccines in particular) which have been produced and are awaiting distribution. It has to be recognised that for some vaccines there may be supplies of up to 5 years. Thus a question on the stocks of the product has been included. The Committee's advice on this issue will be sought at a later date. ⁴⁸

5.46 We consider the action subsequently taken in relation to existing stocks in Chapter 6.

5.47 At its meeting the CSM considered in detail drafts of a CSM position statement, the letter to licence holders and questionnaire, and the guidelines to industry. It also considered proposals for a Working Party, its terms of reference and membership. It approved the various documents, and the proposal to set up a Working Party on BSE. It also recognised 'the need for research into BSE in relation to medicines manufacture'. ⁴⁹

5.48 Professor Asscher told us that the CSM had now finalised its policy on BSE and medicines and he was pleased that the whole process had taken only three months from the date that the problem was first presented to the CSM. ⁵⁰

5.49 The first part of the position statement read:

The Committee on Safety of Medicines (CSM) has considered the safety of human medicines in the light of the report of the Working Party on Bovine Spongiform Encephalopathy (BSE) - the Southwood Report. The CSM agrees with the Southwood Working Party that the risk to man of infection via medicinal products is remote. As a precautionary measure, and for the sole aim of seeking to guard against what is no more than a theoretical risk to man, the CSM and the Veterinary Products Committee have agreed joint guidelines on good manufacturing practice for the manufacturers of human and veterinary medicines who use bovine, or other animal materials either as an ingredient or in the production process. ⁵¹

Joint CSM/VPC guidelines

5.50 The approved guidelines read as follows:

1. Scope

It is recommended that all products licensed under the Medicines Act 1968 for human or veterinary use, that are administered parenterally or to the eye or to open wounds, should in general conform to this guidance if they contain material from a bovine source, or if bovine material has been used during their manufacture.

2. Tissues excluded

No brain or neural tissue, spleen, thymus and other lymphoid tissue, placental tissue or cell cultures of bovine origin should be used in manufacture.

Cattle source for all other tissues

Bovine material should come from animals, taken from a closed herd in the female line since 1980, in which no animal has been clinically suspected of having BSE, and which has not been fed rations containing ruminant derived protein during that period.

3. Collection techniques

All possible measures should be taken to avoid contamination of the bovine material with BSE agent, in particular:

no tissue is to be used in relevant medicinal products when collected postmortem 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.

it is recommended that whenever possible, source animals should be calves up to 6 months old.

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.

4. Sterilisation of equipment

When sterilisation procedures are used, they should be demonstrated to be capable of inactivating scrapie-like agents - at present thought to be autoclaving using a porous load cycle at 134°C-138ºC for 18 minutes at 30 psi.

5. Product

Whenever possible the product should be terminally sterilised by a validated method.

Although these guidelines relate to BSE and materials of bovine origin, they should also be considered as generally applicable to material from sheep, goats, deer and other animals susceptible to scrapie-like agents. These guidelines may need to be updated in the light of further scientific knowledge. ⁵²

5.51 The questionnaire contained the following questions:

1. Company name

2. Do you make use of animal materials in any way in any of your products?

If your answer to Q2 is 'No' please sign and date this form below and return it as shown in the letter.

If your answer is 'Yes' please complete the remainder of this form (using a separate [sheet] for each product with continuation sheets if necessary).

3. PL/CTC/CTX number and product name

4. Animal material (specify type of tissue)

5. Animal species (eg bovine, ovine etc)

6. Purpose of inclusion or use (eg active, excipient, in-process use)

7. Country(ies) of origin of collected material

8. Does this medicinal product conform to the guidelines?

9. If not, by when (calendar month/year) do you expect to apply the guidelines to this product?

10. Based on known usage patterns, by what date (calendar month/year) do you expect present stocks (i.e. bulk stocks and finished product) to be exhausted?

11. Other comment (if any) - please use the reverse of this form

Please give company contact person (Name, Position, Address, Telephone No.) ⁵³

Discussion of the Southwood Report and Medicines with Ministers

5.52 We discuss in vol. 6: Human Health, 1989-96 a meeting of the Minister of Agriculture, Mr John MacGregor, the Secretary of State for Health, Mr Kenneth Clarke, the CMO and officials on 23 February 1989. The meeting was held for Ministers to deal with the two main outstanding issues of concern - vaccines and baby food - prior to the publication of the Southwood Report on 27 February. As to the first of these, Ministers were informed that the CSM and the VPC had concluded that the risk of transmission of BSE through vaccines was remote, but 'so as to be doubly sure in the future, they intended to take the opportunity to improve standards throughout the field of biologically derived medicinal products'. It was noted that additional guidelines for users of bovine materials had been prepared and would be issued in March. ⁵⁴

5.53 We also consider in Volume 6 the discussion of the Southwood Working Party Report by the Cabinet later that day. We note here that the minutes record that, in the light of the Working Party's recommendations on vaccines, guidelines were about to be issued recommending that manufacturers of medicinal products use non-bovine sources wherever possible. ⁵⁵

Briefing for public handling of the outcome of the CSM meeting

5.54 Mr Hagger reflected the outcome of the CSM meeting in a note entitled 'Briefing on Human Medicines' that went to the CMO's private secretary on 23 February, along with a copy of the guidelines, the questionnaire, the CSM's position statement, and a set of relevant questions and answers on BSE and the safety of medicines. ⁵⁶ The note was circulated widely among officials in DH and also to a few officials in MAFF. The question and answer briefing read as follows:

1. Can BSE be transmitted to patients by medicines?

The Southwood Report suggests that there may be a remote theoretical risk of BSE being transmitted to patients by the use of injectable medicines derived from bovine material. The CSM agreed that the risk is remote.

2. Which medicines are affected?

Bovine material is used as an active ingredient in some medicines, for example, the older bovine insulins. Bovine material is also used in small quantities in the production and manufacture of many biological and biotechnologically derived medicines including vaccines and monoclonal antibodies.

3. Are the risks greater with some medicines than with others?

Theoretically, injectable (parenteral) products might seem to pose a greater risk than oral medicinal products, but the CSM agreed that the risk from either is remote.

4. How are medicines affected?

Bovine material is used both as an active ingredient (for example in products such as bovine insulin) and in very small quantities in the production and manufacture of a wider range of medicines.

5. Are some of the products available over the counter from pharmacies or shops?

A range of products available over the counter may contain bovine material as an active ingredient or an excipient, including oral products and injectable insulin which is obtainable only from a pharmacy. But the CSM agrees that any risk of transmission of the agent by medicines is remote.

6. Are existing stocks safe?

The CSM agreed with the Southwood Working Party that the risk of transmission of BSE via medicinal products to man is remote and there is therefore no reason to question the safety of existing products.

7. Are there alternatives to the use of bovine material in medicinal products (including vaccines)?

Certain products such as insulin are now produced by using genetic engineering techniques. While it might be possible to replace bovine materials by using other ingredients or manufacturing methods in some other products, the Licensing Authority would need to be satisfied about the safety of such products before they could be made generally available. It would take some time to undertake the work needed to introduce such a change.

8. Which patients are at risk?

Although bovine material has been used in a wide range of medicinal products, it is not possible to say that any particular patients are at risk since we have no evidence of transmission of BSE to man.

9. What risks exist to those who have already used these medicines?

There is no evidence to suggest that people who have used medicines containing bovine material are at any risk from contracting BSE. ⁵⁷

10. How long will it be before risks are quantified?

It is very difficult to answer this question since we are talking only about a theoretical risk. It is one of the issues which will be considered by the new Consultative Committee on Research which has been established by the Government. The Committee on Safety of Medicines are also establishing a working party to advise them on BSE and human medicines.

11. What action is the Licensing Authority taking to ensure proper scrutinising of source materials and manufacturing processes?

The Licensing Authority has sought the advice of the Committee on the Safety of Medicines, the Veterinary Products Committee and other outside experts. Guidelines on good manufacturing practice have been produced and are being sent to all manufacturers.

12. Will the guidelines be published?

They will be sent to all manufacturers of licensed products shortly.

13. What is being done to reassure parents and doctors about vaccines?

The benefits of immunisation are well founded and not affected by the remote theoretical risk from the use of bovine material in vaccines. We see no reason to take any special steps to reassure parents and doctors at present. We are also taking the advice of the Joint Committee on Vaccination and Immunisation (the expert Committee which advises the Health Department on immunisation). If it proves necessary, the message about the benefits of immunisation can be addressed generally in the publicity material and the professional advice on immunisation provided for parents and doctors.

14. What advice is the Government giving about its vaccination programme?

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 for BSE.

15. Is the vaccination programme put at risk because of BSE?

No. The measures being taken about the use of bovine material in medicines are merely precautionary against a remote and theoretical risk.

16. Are there any risks from BSE to anyone who has already been vaccinated?

The Southwood report describes the possibility as remote (para 8.2) but has alerted the Licensing Authority to the potential concern. This has led to plans to issue guidance to the pharmaceutical industry as a precautionary measure. ⁵⁸

5.55 The following day Mr Hagger sent a minute to the Private Secretary to Mr Clarke, the Secretary of State, referring to the document of the previous day and enclosing an amended set of questions and answers. Q8 was a new addition, the previous Q9 had been deleted, and Q7 now excluded the reference to vaccines and the answer had been shortened. The new Q8 read as follows:

8. Why can't we eliminate the use of bovine materials in all medicines?

It might be possible to find alternative ingredients and methods but development of this kind takes time and requires careful testing. ⁵⁹

March 1989

Issue of joint CSM/VPC guidelines by DH

5.56 The CSM/VPC guidelines and questionnaire (see paragraphs 5.52-5.53 above), as approved on 23 February, were sent to all licensed manufacturers and product licence holders on 9-10 March, under cover of the letter approved by the HVMBG and CSM. Mr Hagger told us that approximately 4,000 letters were sent out by DH, on the basis of the MAIL address list. ⁶⁰ The covering letter read:

Dear Licence Holder

Bovine Spongiform Encephalopathy: Guidance on good manufacturing practice and request for information

The Secretary of State for Health and the Minister for Agriculture have received the Report of the Working Party on Bovine Spongiform Encephalopathy, chaired by Sir Richard Southwood ('the Southwood Report'). One of the recommendations concerns medicinal products licensed under the Medicines Act 1968 and 1971, and the licensing authority has been asked to take account of the BSE agent and to take appropriate action.

The Committee on Safety of Medicines (CSM) in consultation with the Chairman of CRM and CDSM has considered the Southwood Report and agrees that the risk to man of infection via medicinal products is remote.

As a purely precautionary measure, the CSM and the Veterinary Products Committee have agreed joint guidelines for the manufacturers of human and veterinary medicines who use bovine, or other animal, materials as either an ingredient or in the production process. A copy of the guidelines is overleaf. It is felt that the guidance represents a standard that . . . is deemed to be 'best practice' for the future, and steps should be taken to implement it. However, it is realised that this guidance may not be fully applicable in all circumstances.

In order to update and complete our data on medicinal products, you are asked to fill in the attached form giving information about animal materials used in any of your medicinal products as specified in the guidelines (para 1). Information should be given on any ingredient of animal origin as an active constituent, as an excipient, or used in their manufacture (e.g. serum, enzymes, broth etc). In particular we are interested in the expected pattern of bulk and finished product where appropriate. ⁶¹

5.57 Recipients were asked to return the completed questionnaires by 1 May 1989.

5.58 A letter was also sent to suppliers of medical devices. That, and the events surrounding it, are described in paragraphs 5.64-5.79 below.

Issue of joint CSM/VPC guidelines by MAFF

5.59 A slightly different covering letter was sent to all licence and certificate holders for veterinary medicinal products on 15 March 1989. It was sent to 248 companies, which marketed between them 3,239 products. The MAFF letter stated:

Dear Licence Holder

SPONGIFORM ENCEPHALOPATHIES OF BOVINE, OVINE AND CAPRINE ORIGIN: GUIDANCE ON GOOD MANFACTURING PRACTICE AND REQUEST FOR INFORMATION

The Minister of Agriculture, Fisheries and Food and the Secretary of State for Health have received the Report of the Working Party on Bovine Spongiform Encephalopathy (BSE), chaired by Sir Richard Southwood ('The Southwood Report'). One of the recommendations concerns medicinal products licensed under the Medicines Acts 1968 and 1971, and the licensing authority has been asked to take account of the BSE agent and to take appropriate action.

On the 10th March 1989, 2398 farms had at least one confirmed case of BSE, the total number of cases being 3395. This represents an annual incidence in cows of 1 per 1,000 of the population at risk. These figures demonstrate the serious nature of the problem.

As a purely precautionary measure, the Veterinary Products Committee (VPC) and the Committee on Safety of Medicines (CSM) have agreed joint guidelines for the manufacture of veterinary and human medicines which use material of bovine, ovine and caprine origin either as an ingredient or in the production process. A copy of the guidelines is attached. They represent a standard that is deemed to be 'best practice' for the future, and steps should be taken to implement them. Where a company will find it impossible to meet the guidelines, or, where an alternative process is in use which is thought to give equivalent or better protection than the guidelines, details should be provided at (11) on the attached form.

Since BSE has been made a notifiable disease it is important that the licensing authority is aware to what extent material of bovine, ovine and caprine origin are used in the manufacture of licensed veterinary products (including products subject to Animal Test Certificates and Animal Test Exemptions and Emergency Vaccines).

In order to update and complete our data on veterinary medicinal products, you are asked to complete the attached form giving information about material of bovine, ovine and caprine origin used in any of your veterinary medicinal products as specified in the guidelines (para 1). Information may be required from the supplier or manufacturer of the ingredient or material, in which case you should arrange for the information to be supplied (Commercial in Confidence) either through you or sent directly to the Medicines Unit. The country of origin of animals used to prepare the ingredient or material should be stated. Any information sent in (from yourselves or your suppliers) must be clearly cross-referenced to indicate the licence/certificate to which it refers.

A separate form should be completed in respect of each veterinary medicinal product and where necessary continuation sheets should be attached. I have enclosed a list of your veterinary medicinal products. Please inform us of any omissions. Nil returns are required. ⁶²

5.60 The deadline for the return of the questionnaire was the same, 1 May 1989.

MAFF meeting with NOAH on the guidelines: Continued concern about public reaction

5.61 When NOAH and MAFF next met, on 21 March 1989, the BSE guidelines were discussed. The minutes record that Dr Little suggested that the Southwood Report had so far turned out to be a 'damp squib', but stressed that care must be taken to ensure that certain elements of the press did not get the wrong impression about the safety of vaccines, both human and veterinary, and cause major problems. He pointed out that the guidelines 'took into account the fact that a high standard was being set, and also accepted that certain manufacturers may have other equivalent methods of attaining the required standard'. ⁶³