Volume 7: Medicines and Cosmetics
6. Ensuring medicinal products complied with the guidelines
March 1989-March 1996: a chronological account
1989
Preparation for processing the veterinary medicines responses
Meeting of the Joint Committee on Vaccination and Immunisation (JCVI)
Initial consideration of responses to the medical devices questionnaire
Progress in MCA
VMD discussions with ingredient suppliers about the guidelines
Implications for pharmaceuticals of a ban on Specified Bovine Offal
Preliminary review of human medicines responses
MAFF develops detailed proposals for the intended SBO ban
Dr Pickles asks which manufacturers use products covered by the ban
Preparations for public consultation about the SBO ban
MCA updates VMD on progress
Implications of the SBO ban for medicinal products: consideration by Animal Health Division
Veterinary medicines progress report
NOAH's concern about the practicality of the CSM/VPC guidelines
Further consideration of ingredient suppliers
Medical devices: following up non-responses

Preparation for processing the veterinary medicines responses

6.28 Shortly before the questionnaires were sent out, Mr Alastair Gray of MAFF's Medicines Unit circulated a minute stating:

. . . it is important to plan now how to process the information that Licence Holders send in. No doubt there can be an initial handsorting, to determine the numbers of positive cases, but computerising the data will be essential for longterm management of the BSE problem. ¹

6.29 The VMD described to us the manner in which the responses were actually processed:

the first analysis of the returns was carried out by administrative staff who extracted the information contained in the completed questionnaires. A manual record of the returns was made (e.g. noting when a company returned a form and which products were covered). For each company, note was made of the number of Yes's and No's to the question on whether or not the product contained substances of animal origin. Scientific staff then carried out further analysis of the questionnaires and the need for follow up action was done on a case by case basis. The totals for the number of 'positive' responses were derived manually. ²

Meeting of the Joint Committee on Vaccination and Immunisation (JCVI)

6.30 Professor Collee attended a meeting of the JCVI on 21 April 1989. He reported on the HVMBG meeting of 22 February 1989, which he had chaired. With regard to vaccines he informed the JCVI that the risk had been considered by the HVMBG to be remote and speculative, and very much outweighed by the benefits. ³

6.31 The JCVI took their lead from this. Professor Campbell, Chairman of the JCVI, told us that they relied on the advice of the Working Group:

In the light of the Working Group's assessment that the risk to human health from vaccines was remote, BSE had no significant effect on the JCVI's consideration of immunisation and the immunisation programme. ⁴

Initial consideration of responses to the medical devices questionnaire

6.32 PD met on 25 April 1989 to consider responses so far to the medical devices questionnaire. ⁵ Just over 50 per cent of the 330 manufacturers contacted had replied; 28 companies used animal material and 16 of these used bovine-derived material. There was concern at the lack of response by a number of companies, many of whom might use animal materials. It was decided that all English companies would be chased up by phone, while foreign companies would be sent reminder letters.

6.33 The validity of a number of replies was questioned. To check this, a letter was to be sent to a random selection who had replied in the affirmative, requesting further information on why they stated that they were conforming with the guidelines. ⁶

6.34 The minutes also record:

A meeting with MCA on this subject has not been forthcoming despite attempts from PD to arrange one. Mr Hagger had agreed that a PD representative (Mr Burton) should join the sub-committee in MCA which will be discussing responses to the questionnaire issued by the Agency. ⁷

Progress in MCA

6.35 Many licence holders had not replied to the DH questionnaire by the deadline of 1 May 1989, and officials of the newly formed MCA had to chase replies. Because of these delays the first meeting of BSEWG, originally fixed for 5 July 1989, was postponed. ⁸ Dr Rotblat told us one reason for the delay was that many UK licence holders did not manufacture these products within the UK, and it therefore took them some time to gather the necessary information. ⁹ From the telephone calls she received in the few weeks after the guidelines were sent out, it became clear that many manufacturers considered the easiest way of complying with the guidelines was to source from outside the UK, preferably from New Zealand. ¹⁰

6.36 A minute from Mr Burton of PD/STD dated 2 June 1989 warned his colleagues that the MCA were unlikely to consider BSE formally until September. ¹¹ He explained that this was in part because two meetings of the BSC were to be cancelled, leaving September as the next date when the relevant experts, who would form the BSEWG, would come together. He continued:

3. I also understand that they have difficulty in allocating resources to reviewing the responses they have received.

4. We may need to re-define our approach to the problem of BSE in the light of the above delay.

6.37 Mr Hagger sent a minute to the CMO, Sir Donald Acheson, on 5 June 1989 to report progress. He said that most licence holders had replied and that preparations for a full professional analysis were nearing completion. The exercise had produced a lot of information, which would take time to study before papers could be prepared for the meeting in September. Meanwhile nothing had emerged that appeared to warrant immediate special action. Mr Hagger noted that bovine insulin had previously been mentioned as an area in which precautionary measures might usefully be taken and this was being borne in mind. He added that it might be reassuring to know that such insulin was used in the UK only for a very small group of mainly elderly patients for whom it was difficult to switch to either porcine or genetically engineered insulin. Nevertheless they were on the look out for any such products. Mr Hagger copied this minute widely, including to Mr Scollen, his counterpart in MAFF. ¹²

VMD discussions with ingredient suppliers about the guidelines

6.38 As discussed in Chapter 3, MAFF had been in touch with veterinary medicines manufacturers the previous year about its draft guidelines, and discussions had ensued with some firms about the sourcing of ingredients. Copies of the guidelines and questionnaire had been sent to some ingredient manufacturers, as well as to product licence holders. This was because it was anticipated that licence holders would seek information about the sources of material from their suppliers. One of these supply companies had been having meetings with VMD since the middle of 1988. A minute circulated to others in VMD and the Central Veterinary Laboratory (CVL) by Mr Cameron on 12 May 1989 said:

Whilst the VMD's responsibilities are to product licence holders and for them to encourage improvements in the quality of bought-in materials, it would be of advantage for MAFF to stimulate directly the availability of high quality materials from manufacturers. ¹³

Implications for pharmaceuticals of a ban on Specified Bovine Offal

6.39 During early June 1989, MAFF and DH were considering the introduction of a ban on bovine offal from food for human consumption. The planned approach was to remove high-risk tissues at the slaughterhouse and treat them as unfit meat to ensure they did not enter the human food chain. DH was concerned that the announcement of an SBO ban might draw attention to bovine material used in pharmaceuticals. Sir Donald Acheson told us that, with one 'caveat', he supported the ban as an additional protection for human health without any apparent balancing disadvantage:

My 'caveat' related to concern that an announcement of the SBO [ban] in advance of the anticipated reassurance concerning the safety of vaccines from the CSM might lead to a marked and unwarranted decline in the uptake of vaccines in children. I had in mind a marked and extended previous reduction in the acceptance of whooping cough vaccine which had followed incorrect public allegations by a scientist that the administration of the vaccine carried a significant risk of encephalitis. On the one hand I was aware that during the period 1980-1988, due to incomplete vaccination of our population of children, there had been 123 deaths from measles and 50 from whooping cough in England, together with a many times larger burden of illness and some long-term complications. Against this I had to balance a remote risk of a fatal disease. A warning was given to Ministers to this effect but in the event although the announcement was not delayed as I wished, it fortunately did not provoke an anti-vaccine scare. ¹⁴

6.40 On 6 and 7 June Mr John MacGregor, the MAFF Minister, held two meetings to discuss the proposed SBO ban. The first was with MAFF officials and Dr Metters in preparation for the second meeting the following day with Sir Richard Southwood. These meetings are discussed in detail in vol. 6: Human Health, 1989-96. Dr Metters attended both meetings on behalf of the CMO who was abroad, and raised the CMO's concerns about refocusing attention on bovine constituents of pharmaceuticals. His minute to the CMO of 9 June reported on these meetings. ¹⁵ He noted:

The possibility that MAFF's action may refocus attention on bovine constituents of pharmaceuticals cannot be ruled out. While I put this point more than once, it cut little ice with MAFF officials.

6.41 Dr Metters told us that he:

. . . was certainly trying to tell MAFF that if we go for a bovine offal ban, there will be further attention into how this was affecting pharmaceuticals. We had already taken action on pharmaceuticals by that point, but it would cause adverse publicity. ¹⁶

6.42 Following the meeting on 7 June, Dr Metters advised the Secretary of State and others in DH about the further precautionary measures that MAFF were proposing. ¹⁷ Mr Hagger received a copy of this submission and passed it to others in MCA. ¹⁸

6.43 At an MCA meeting on 12 June 1989, Dr Jefferys reported that Mr MacGregor proposed to ban the use of bovine offal in human food. With an announcement expected the following day, it was thought that undoubtedly the political profile of BSE would be raised again. ¹⁹

Preliminary review of human medicines responses

6.44 The reason for the MCA meeting on 12 June was to undertake a preliminary review of the replies from licence holders to the human medicines questionnaire. Mr Love chaired the meeting as Mr Hagger was on leave. Also present were Dr Adams, Dr Rotblat, Dr Raine, Dr Purves, Mr Armstrong, and Mr Burton from PD/STD.

6.45 By this time approximately 50-60 per cent of those contacted had replied. At the meeting, products were allocated to seven categories (in descending order of risk) for discussion by the BSEWG when it met in September. ²⁰

1. Products with bovine brain/lymphoid tissue as ingredients and administered by injection.

2. Products with bovine ingredients (other than brain/lymphoid tissue) and administered by injection.

3. Tissue implants, open wound dressings, surgical materials, dental and ophthalmic products with bovine ingredients.

4. Products with bovine ingredients and administered topically.

5. Products with bovine ingredients and administered orally.

6. Products with other animal/insect/bird ingredients.

7. Products with materials produced from animal material by chemical processes eg. stearic acid, gelatin and lanolin.

6.46 It was also agreed that, in the meantime, on the basis of the information provided by licence holders, Dr Rotblat and Dr Purves were to prepare a paper for the BSEWG on the first two categories, and Dr Adams and Dr Raine on the third. ²¹ No action was to be taken on the remaining products for the present. By the time of this meeting, officials had already had discussions with one manufacturer of sutures (Ethicon), which, it was reported, was producing a detailed submission on the subject. ²²

6.47 Dr Rotblat told us:

My recollection is that Dr Kimberlin's views were the major influence behind the way in which we chose to categorise the responses . . . Dr Purves and I were asked to prepare a paper for presentation to the working group. ²³

6.48 Those at the meeting discussed several points for action including: ²⁴

1. The priority was for the MCA to arrange its response data into an easily manipulable form as quickly as possible;
2. The MCA was still holding off from detailed consideration of oral products for the time being;
3. The MCA was attempting to draw up a list of common animal-derived raw materials used in non-injectable products in the hope that these could be submitted to the BSEWG and then dismissed from the enquiries;
4. Non-licensed injectables made from bovine brain and lymph tissue were discussed. It was agreed that PD/STD would provide details of any such 'named-patient' products to Mr Love for consideration by the MCA.

6.49 It was also agreed that the MCA would liaise more directly with MAFF in future. According to the minutes this was prompted because:

MAFF had diverged from MCA at the time the Guidelines were sent out and all matters relating to veterinary medicines were being handled directly by MAFF. Concern was expressed that MAFF could be developing independent policies in the face of pressure from their food sections. ²⁵

6.50 This desire for closer contact between the MCA and MAFF coincided with Dr Rutter, the new director of the VMD, making a similar request to Mr Hagger at the end of June 1989. A minute from Mr Hagger to other MCA officials stated:

1. Dr J M Rutter, the Director of the Veterinary Medicines Directorate, asked to be kept in touch with MCA developments on BSE. He has seen my minute of 5 June to [CMO]'s office summarising progress to date and would like the Veterinary Medicines Directorate (VMD) to be involved in any meetings that we hold as well as being kept in touch with other significant developments.

2. The VMD is in a similar position on the BSE exercise to MCA. They have held exploratory talks with 2 companies. ²⁶

MAFF develops detailed proposals for the intended SBO ban

6.51 In early June Mr Lawrence of Animal Health Division initiated preparation of a statutory instrument to implement the SBO ban. ²⁷ Mr Fry took on the task of preparing instructions for the legal department. He proposed treatment along the lines of that required in the Meat (Sterilisation and Staining) Regulations 1982. ²⁸ This would require offal to be sterilised or stained and sent to certain specified destinations. ²⁹

6.52 Regulation 17(1)(a) of those regulations permitted condemned meat to be sent unstained, under a movement permit to:

a hospital, medical or veterinary school, laboratory or similar institution for instructional or diagnostic purposes, a rennet manufacturer or a manufacturing chemist for the manufacture by him of pharmaceutical products.

6.53 Mr Fry prepared instructions for MAFF lawyers on the basis that a similar exception would need to be provided in the new SBO legislation. ³⁰

6.54 However, on 20 June Mr Fry wrote to Mr Lawrence regarding points for final clarification. He said: 'I understand that whilst it is acceptable for hospitals, medical and veterinary schools etc to receive these bovine offals we would not want them to go to rennet manufacturers or manufacturing chemists.' ³¹ We infer that he was concerned because products from rennet manufacturers and manufacturing chemists might still be able to enter the human food chain.

Dr Pickles asks which manufacturers use products covered by the ban

6.55 We discuss in Volume 6 the consideration given to occupational risks and BSE. As part of that process, Mr Maslin sent a list of cattle products to the Health and Safety Executive (HSE). This prompted Dr Pickles to write to him on 3 July 1989:

I was interested to see the list of by-products sent to the HSE. Those of particular concern included:

small intestines: sutures (I thought the source was ovine but you are checking this)

spinal cord: pharmaceuticals

thymus: pharmaceuticals

Are you able to give me more information on which UK manufacturers use these materials? Our proposed ban on bovine offal for human consumption would not affect these uses, I assume. ³²

6.56 Mr Maslin passed the note down the line in Animal Health Division and a handwritten note on Dr Pickles's minute from Mr Mark Hawkins, one of his staff, reported back:

1. A few companies make sutures out of intestinal linings, worth around £300 k p.a; probably some sheep used as well, but minimal.

2. Virtually all spinal cord goes for rendering, with just a very small amount going for pharmaceutical use.

3. About 30% of thymus production goes for pharmaceutical use (approx £132 K pa).

Incidentally, some spleen also goes for pharmaceutical uses (approx £170 K pa) . . . Is Hilary serious about her final sentence? I would have thought that a) the staining would make these materials unusable (this is also MLC's view) and b) if they are unfit for consumption, they are certainly unfit for medication. Has she forgotten iatrogenic CJD? ³³

Preparations for public consultation about the SBO ban

6.57 On 7 July 1989 Mr Cruickshank sent a submission to the Minister seeking his views on certain exemptions from the proposed SBO ban and agreement to a draft public consultation letter. ³⁴ The latter sought comments from interested parties and an annex set out the proposals for the new regulations. ³⁵

6.58 The consultation letter explained the proposed regulations. paragraph 8.1 included pharmaceutical manufacturers as a destination to which unstained/unsterilised SBO could be sent. ³⁶ It stated:

8.1 It would be permissible to move unstained and unsterilised specified bovine offal from a slaughterhouse, or other place of slaughter, to a pharmaceutical manufacturer or to a hospital, medical or veterinary school, laboratory or similar institution for instructional or diagnostic purposes. Any such movement would however have to be in accordance with a movement permit issued under the Regulations.

6.59 paragraph 8.1 remained in the final consultation letter that was sent out on 26 July 1989. ³⁷ We note that the list of organisations consulted did not include any pharmaceutical manufacturers, or their representatives.

6.60 On 7 July, Dr Pickles wrote to Mr Maslin about the content of the consultation letter and questioned the inconsistency in approach of allowing the use of small intestines for sausage casings.

. . . as it is currently worded it looks as if sausage casings are a risk but you are excluding them from the ban because it would otherwise be inconvenient/expensive. I presume MAFF is content that whatever treatment is given to small intestines to prepare casings means that there is no remaining contamination with lymphoid tissue. Unless you can give me that reassurance, a 'risk' must remain. Whilst you know that I am not myself persuaded this risk is one we need take action about, the inconsistency with the other steps you are taking cannot be disguised. ³⁸

6.61 Also on 7 July, Mr Maslin wrote to Mr Cruickshank. ³⁹ In relation to pharmaceuticals, he noted:

We are permitting unstained unsterilised offals to go to pharmaceutical manufacturers. One product they make is gelatin. The use of this in pharmaceuticals should of course be covered by the guidance issued by DH but I am not clear whether it also goes from this source into the human food chain through jellies, etc. Can Mr Hutchins advise please urgently. If it does, do we know whether gelatin is a 'risk' product? ⁴⁰

MCA updates VMD on progress

6.62 Following Dr Rutter's request to Mr Hagger to be kept informed (see paragraph 6.50 above), Mr Armstrong in the Information Section of the MCA wrote to Dr Rutter on 19 July 1989 to update him on the MCA's progress. ⁴¹ He indicated that 65 per cent of product licence holders had replied, of which a large proportion used no animal products. He said that none of the replies examined so far had given any immediate cause for concern. He also set out the seven categories of risk for assessment purposes that had been agreed at the MCA meeting on 12 June (see paragraph 6.45 above). A handwritten note on the minute from Dr Rutter asked Dr Lee to arrange for a similar update on VMD's progress to be sent to the MCA.

Implications of the SBO ban for medicinal products: consideration by Animal Health Division

6.63 The preparation of the SBO ban prompted consideration by Animal Health Division of a number of issues, some of which were relevant to medicinal products. On 27 July 1989, Mr Maslin circulated a minute to MAFF officials asking, among other things, for views on:

1. The production of sutures from bovine intestine; and
2. The use of spinal cord, thymus and spleen for pharmaceutical purposes. ⁴²

6.64 On sutures Mr Bradley replied:

It is anticipated that the standard processing of ovine and bovine intestines to produce catgut for surgical, musical and sporting purposes goldbeaters skin and the like removes the mucosa and muscle layers and with it any lymphoid tissue present. Catgut is essentially formed of the collagenous tissues of the gut wall. However I recommend the process is investigated both in regard to the removal of lymphoid tissue and the chemical and sterilising processes used in manufacture. Alternative sources of suture are available but surgeons are likely to be adamant that for certain procedures natural catgut is essential. Human and Veterinary Surgeons are involved in this.

6.65 As for spinal cord, thymus and spleen, Mr Bradley said:

Unless these tissues are collected from unexposed animals there is a potential risk of agent being present and that risk increases with the age of the infected animal. If such tissues are permitted to be used for pharmaceutical manufacture the industrial processes used must be effective in removing infectivity or reducing it to an acceptable level depending on the use of the final product.

It is important also to recognise risks of cross-contamination between tissues in abattoirs before release.

The VMD and DOH have already provided guidelines for preparation of products licensed under the Medicines Act for human and veterinary use. There needs to be some consistency in approach. ⁴³

6.66 On 24 August 1989, Mr Kyle, Assistant Chief Veterinary Officer for Communicable Diseases, wrote to Mr Meldrum about the draft regulations and stated 'I am surprised that Article 11(1)(a) appears to permit the unrestricted use of specified bovine offals for the manufacture of pharmaceutical products. It may be that Medicines Directorate are to cater for this in some other regulation and, if so a cross-reference here would be appropriate'. ⁴⁴ Mr Kyle passed this letter on to Mr Maslin on 1 September 1989 with the handwritten note on the bottom 'No one else on the veterinary side seems to have commented, so I had better copy this to you to incorporate in any comments you put forward.'

Veterinary medicines progress report

6.67 On 4 August, Dr Aileen Lee, who was to be the VMD's representative at the BSEWG, wrote to inform Mr Armstrong of the MCA about the BSE questionnaire returns for veterinary medicines. ⁴⁵ She told him that replies had been received from 186 of the 245 licensees. These companies manufactured 3,239 products, and of these 303 had been found to contain material of bovine, ovine or caprine origin. Dr Lee stated that section 44 letters ⁴⁶ would be sent to the 59 non-respondents, and follow-up letters would be sent to companies which had submitted returns for only some of their products, or where the information given on a positive return was incomplete. She added that initial analysis of the 303 positive responses would begin soon.

6.68 The VMD told us that the follow-up action

. . . was taken by VMD staff through correspondence with the licence holders and suppliers of media. Telephone discussions were also held to ascertain that appropriate action was being taken. . . .

Assessment of compliance with the CSM/VPC Guidelines was based on written evidence from the company. In addition, informal discussions would have taken place at inspections of manufacturing sites with checks on suppliers' batch certificates in the manufacturing premises as part of the routine audit of the company's system of records and quality assurance system. Documentation on the source of bovine serum would be checked at these inspections. ⁴⁷

NOAH's concern about the practicality of the CSM/VPC guidelines

6.69 The joint guidelines gave rise to some concerns among veterinary product manufacturers. On 19 July 1989, Miss Green of NOAH wrote to Mr Whitbread of the MCA:

Many NOAH members are concerned over the relevance and practicality of certain aspects of the guidelines and have been advised by MAFF that comments would be useful and are best addressed to the Department of Health as it was you [DH] that fronted the exercise. ⁴⁸

6.70 She said that it was impossible to produce most types of bovine virus vaccines (and possibly some bacterial vaccines) without the use of cell cultures of bovine origin. Miss Green added that the stipulation in the guidelines that bovine material should come from herds which had never had a case of BSE and had not been fed ruminant protein since 1980 would seriously curtail medicines production, as it was unlikely that such herds existed.

6.71 On receipt of Miss Green's letter, Dr Adams sent a minute to Dr Jefferys. ⁴⁹ He observed that all the difficulties raised by NOAH had already been foreseen by the MCA. A reply was eventually sent to Miss Green on 24 August 1989 saying that the Licensing Authority was continuing its study of animal materials used in medicinal products in the light of the replies to the questionnaire and that NOAH's comments would be taken into account. ⁵⁰ The comments were put to the BSE Working Group's first meeting in September 1989 (see below) but the Group concluded no action was warranted. ⁵¹

Further consideration of ingredient suppliers

6.72 Oxoid, one of the ingredient suppliers with whom VMD had been in touch (see paragraph 6.38 above) wrote to Dr Rutter on 14 August 1989 about their recent steps aimed at assessing the risk of BSE transmission by culture media and culture media raw materials. ⁵² They had proposed formulae for assessing risk and had reworked their production schedules. They were also looking at sourcing from low-risk geographic areas.

6.73 A handwritten note to Mr Cameron from Dr Lee commenting on this letter noted:

It will certainly be very helpful to us when assessing BSE risk from media ingredients to have available full details of the preparation of these ingredients. I must say, however, that it would be most helpful if Oxoid would supply the information to the product licence holders for them to provide it to us. The product licence holders are, after all, responsible for the quality of the product and I think they ought to know. In addition, it can be very difficult if we have to tell a company that something is not satisfactory but we cannot tell them why or discuss it with them. ⁵³

Medical devices: following up non-responses

6.74 At its regular BSE review meeting on 21 August 1989, PD/STD was told that, despite letters and telephone calls to the companies that had not responded to the questionnaire, the response rate was still only around 66 per cent. ⁵⁴ Many of them were UK companies. It was decided that a definitive list was needed of the companies in the UK and Europe who had not responded. Those companies were to be sent a second reminder. ⁵⁵

6.75 Of the companies who had returned questionnaires, 46 used animal material of some form; 26 used bovine material, of which 2 sourced their material (pericardium tissue) from the UK. ⁵⁶

6.76 To check the accuracy of responses, further information had been requested from 10 companies whose initial responses stated that their products conformed with the guidelines. Only five had replied to this further request and two of these had changed their responses. The minutes note that the non-responding companies were to be chased. ⁵⁷ The meeting also agreed that a discussion document on sterilisation procedures, 'Inactivating scrapie-like agents', needed further work and that more information should be sought about abattoir systems.