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The Vaccine Subcommittee (VSC) met on 05 April 2004 to discuss the clinical aspects of the application for approval of the Chiron MeNZB vaccine. On the basis of the clinical data, the VSC recommended that the vaccine could be distributed under Section 23 of the Medicines Act 1981, subject to conditions. One of these was that the evaluation of data relating to the composition, manufacture, quality control and stability of this medicine should be completed.
Subsequent to the meeting, the MHRA completed its initial evaluation of the data and as is usual in the evaluation of all new medicines, additional information was requested from the manufacturer.
The MHRA questions were divided into two parts. The first part covered critical points to be addressed before approval of the application was to be considered and the second part covered minor points to be addressed on an ongoing basis.
Chiron's responses to the questions were reviewed by both the MHRA and Medsafe. Medsafe then met with the MHRA, and with NIBSC, to discuss all of the information provided by the company.
This process continued until Medsafe was satisfied that the information provided by the manufacturer demonstrated the composition, manufacture, quality control, and stability of the vaccine to be acceptable.
Medsafe presented a report covering all of the issues to the VSC at a meeting on 5 July 2004. The summary report had been peer reviewed by MHRA and NIBSC to make sure it accurately represented their views.
During the meeting, the VSC concluded that all of the risk-critical issues had been addressed and recommended that MeNZB should be granted provisional consent under Section 23 of the Medicines Act 1981. The VSC noted that outstanding non-critical questions regarding manufacture would be addressed on an ongoing basis.
Chiron committed to supply responses to the non-critical questions as data became available and had supplied responses for most prior to the date of approval.
Minutes of 5 July 2004 VSC meeting
The details of how any vaccine is made and tested are confidential to the manufacturer, but made available to licensing bodies (such as Medsafe and the MHRA) in order that they can be assessed before consideration for approval for use in the community. The material presented to the VSC on 5 July 2004 described the manufacture and quality control of MeNZB in detail, and included discussion of what is (and isn't) important.
In line with the provisions of the Official Information Act 1982, Medsafe has removed certain information which is either commercial-in-confidence or relates to batch numbers or the names of individuals from the minutes which are being released here. Any information removed is identified as ******.
The following comments give an explanation of issues raised in the minutes.
Like many other vaccines, MeNZB is made from the bacteria that it protects against (Neisseria meningitidis group B strain NZ 98/254). The bacteria are grown in pre-sterilised fermenters (sealed to prevent contamination) and then killed (inactivated). Once they are killed, the bacteria aren't infectious. The killed bacteria are then broken up to give Outer Membrane Vesicles (OMVs) which are little bits of the outside of the bacteria. It is these OMVs that are the active ingredient (sometimes also called the drug substance) in the vaccine.
In these minutes, the finished vaccine is sometimes also called the drug product.
When making a vaccine like MeNZB, it is important that:
The manufacturing process in between killing the bacteria and making the finished vaccine need not be totally sterile, but it must be closely monitored to make sure it is very clean. The sterility and cleanliness of the containers used to package it must also be guaranteed. These requirements are described in guidelines issued by international bodies such as the World Health Organisation and the International Council on Harmonisation, and in documents such as the European Pharmacopoeia (for medicines similar to MeNZB). Questions 1 to 6 (and 32) covered how Chiron meets these requirements.
These questions ascertain how each batch of vaccine is suitably similar to the batches that were shown to be safe and effective in clinical trials (as well as to other vaccines known to be safe).
Testing is performed at each stage of manufacture to make sure that the process is performing as expected, and the results of these tests must meet pre-set specifications, just as the results of testing of the active ingredient (drug substance) and finished product must. Chiron also needed to show that the analytical procedures (tests) it uses are suitable (or validated).
These question sought reassurance that equipment, procedures and test methods were appropriate for the manufacture and quality control of MeNZB.
The active ingredient of the vaccine (drug substance) can be stored before being used to make the final product. Chiron needed to show the material would still be suitable for use after storage, and also that the tests used to assess this were appropriate. Similarly Chiron had to show that MeNZB final product will still be active after being shipped to New Zealand and stored in fridges for an approved length of time, and that it had tests that could assess this.
These requirements are described in guidelines issued by the International Council on Harmonisation. These questions were to determine that Chiron met these requirements.
Some of the raw materials used to make MeNZB, like many other medicines, are manufactured from animal tissues or fluids. For many years now, the use of materials made from ruminants in medicines has been strictly controlled, although there is no evidence to date that Transmissible Spongiform Encephalopathies (or TSEs, of which BSE is one) have been transmitted by the use of products of bovine origin in medicines. Precautions are taken to prevent the raw materials being made from tissues or fluids that could carry TSEs. These questions were making sure that the raw materials used to make MeNZB were proven as being safe in this regard.
Chiron's factories are inspected to make sure they are using procedures that meet international standards. These standards are called Good Manufacturing Practice (GMP). These requirements are described in guidelines issued by international bodies such as the World Health Organisation and the Pharmaceutical Inspection Convention. This question sought confirmation that the sites making Chiron MeNZB vaccine met these standards.
Present: Richard Robson, Rod Ellis-Pegler, Stewart Reid, David Holdaway, Tim Blackmore, and Jeff Weston.
Medsafe Observers:
Rob Allman, Leong Goh, Stewart Jessamine, Adrian Britt, Alison Macdonald.
Stewart Reid declared his conflict of interest due to his involvement in the meningococcal vaccine strategy. The Chairman noted this conflict and invited him to take part in the meeting. Stewart indicated that he would abstain himself from expressing an opinion on any recommendation and this was accepted.
The VSC recommends that MeNZB vaccine should be granted provisional consent under section 23 of the Medicine's Act 1981.
The VSC recommended that the MHRA questions covering minor points, numbers 33-55, which are not a barrier to consent, be addressed on an ongoing basis by Chiron.
The manufacturing and quality data (Module 3, with Module 2 summaries) from Chiron was assessed by the Medicines and Healthcare Products Regulatory Authority (MHRA) and further discussed with National institute of Biological Standards and Control UK (NIBSC).
During the week commencing 14 June 2004, Stewart Reid and Rob Allman had several meetings and teleconferences with the ******and ****** of the MHRA in London and subsequently with ****** of NIBSC. The objective of these meetings was:
Clinical data were discussed by the VSC on 5/4/04 and a recommendation made that the data supported provisional consent subject to satisfactory manufacturing and quality data.
A report prepared by Rob Allman, team leader evaluation, was used as the basis for discussion by the VSC. The report covered the questions raised by the MHRA and gave commentary on their resolution. This report follows below and now includes the VSC comments.
The MHRA questions were divided into two parts. The first part covered points which should be addressed before approval of the Provisional Consent application.
MHRA now consider that the additional validation information supplied by Chiron allows for a higher bioburden limit to be acceptable. Chiron also provided further clarification of the process. This issue is resolved.
None given on this issue.
Medsafe agrees with the MHRA consideration of this issue.
Agrees with above.
MHRA now consider that the additional information supplied by Chiron answers the question. This issue is resolved.
None given on this issue.
Medsafe agrees with the MHRA consideration of this issue.
Agrees with above.
MHRA now consider that the additional information supplied by Chiron answers the question. This issue is resolved.
None given on this issue.
Medsafe agrees with the MHRA consideration of this issue.
Agrees with above.
MHRA now consider that the additional information supplied by Chiron answers the question. This issue is resolved.
None given on this issue.
Medsafe agrees with the MHRA consideration of this issue.
Agrees with above.
MHRA now consider that the additional information supplied by Chiron answers the question, as data from a laboratory scale study, coupled with in-process testing to demonstrate inactivation, is acceptable for a provisional consent. MHRA recommend that Chiron commit to provide data on a more detailed laboratory scale validation study. This issue is resolved.
Agreed with the MHRA consideration of this issue.
Medsafe agrees with the MHRA and NIBSC considerations of this issue.
Agrees with above.
MHRA now consider that the additional information supplied by Chiron allows for ****** of material prior to it being proven to be inactivated. This is based on the acceptance of the inactivation study from the previous question and also additional information from Chiron regarding the centrifugation process. This issue is resolved.
None given on this issue.
Medsafe agrees with the MHRA consideration of this issue.
Agrees with above.
MHRA now consider that the additional information supplied by Chiron is acceptable. This issue is resolved.
None given on this issue.
Medsafe agrees with the MHRA consideration of this issue.
Agrees with above.
MHRA recommended that Medsafe seek guidance from NIBSC on this issue as
they considered vesicle integrity as a key safety issue.
MHRA subsequently considered the additional information supplied by Chiron to
resolve the issue.
This issue is resolved.
NIBSC confirmed that immunogenicity (IgG ****** and safety as measured by endotoxin level) were the best possible surrogate measures of vesicle integrity.
Additional NIBSC assessment using ****** has indicated consistency of batches with respect to vesicle size and integrity.
Medsafe agrees with the MHRA and NIBSC considerations of this issue.
Agrees with above.
MHRA deferred a response on this question to Medsafe, in light of the response and resolution to the previous question.
NIBSC have not looked at vesicle stability over time. They commented that it might be that vesicle breakdown would be picked up by ****** testing, and any loss in immunogenicity detected by the ****** ****** , but this would need to be confirmed. Studies at the Netherlands Vaccine Institute have investigated the stability of a recombinant OMV vaccine. These studies suggest that OMV's are relatively stable under normal storage, but under conditions that lead to vesicle damage and PorA denaturation, a reduction in immunogenicity is observed.
On the basis of the resolution of question 8 above, the question of stability of vesicle integrity is not of concern.
Agrees with above.
MHRA considered that the information and commitments provided by Chiron to clear the point. This issue is resolved.
NIBSC deferred comment to the MHRA.
Medsafe agrees with the MHRA consideration of this issue.
Agrees with above.
Chiron supplied some additional data, and MHRA noted that further information was still outstanding.
NIBSC noted that if some form of ****** or SBA is used as part of demonstrating vaccine consistency, then the assay should be validated. NIBSC's feeling was that this need not be a bar to provisional consent providing there is an undertaking to provide validation data in due course.
Medsafe has to assess the risk/benefit of a lack of this data in relation to all considerations around the vaccine.
The VSC agreed that while this lack of validation data is not a barrier to consent under section 23, it was essential for consideration of consent under section 21.
MHRA considered the additional information and commitment supplied by
Chiron to resolve the issue.
This issue is resolved.
None given on this issue.
Medsafe agrees with the MHRA consideration of this issue.
Agrees with above.
MHRA considered the additional information supplied by Chiron as making it
acceptable to grant provisional consent whilst awaiting full validation
reports.
This issue is resolved.
Agreed with the MHRA comment.
Medsafe agrees with the MHRA and NIBSC considerations of this issue.
The VSC agreed that while this lack of data is not a barrier to consent under section 23, it was essential for consideration of consent under section 21.
MHRA indicated that the additional information supplied by Chiron resolved
the issue.
This issue is resolved.
None given on this point.
Medsafe agrees with the MHRA consideration of this issue.
Agrees with above.
MHRA considered the additional information supplied by Chiron as making it acceptable to grant provisional consent whilst awaiting full validation reports.
This issue is resolved.
Agreed with the MHRA comment.
Medsafe agrees with the MHRA and NIBSC considerations of this issue.
The VSC agreed that while this lack of validation data is not a barrier to consent under section 23, it was essential for consideration of consent under section 21.
MHRA considered the additional information supplied by Chiron as making it acceptable to grant provisional consent. They also noted that the aluminium content specification should be tightened when further information is available.
This issue is resolved.
None given on this point.
Medsafe agrees with the MHRA consideration of this issue.
The VSC agreed that while this lack of validation data is not a barrier to consent under section 23, it was essential for consideration of consent under section 21.
MHRA considered that the proposed endotoxin limit for the drug substance of
not more that ****** and the drug product of not more than ****** should be
accepted as the interim specifications as the endotoxin level is not
considered to be a safety issue. However, Chiron should review the endotoxin
limits after production of the first 10 full-scale batches of vaccine.
This issue is resolved.
NIBSC noted that the levels of endotoxin in the vaccine are reasonable, consistent with the safety profile of the vaccine in the phase 1 study and well within the proposed specification based on the NIPH vaccine. In addition the endotoxin level is reasonably consistent from batch to batch. To consider the level of endotoxin in the context of other commonly used vaccines, the level of endotoxin in this OMV vaccine is typically one log higher than for the MenC conjugate and two logs lower than in the whole cell pertussis vaccine.
Medsafe agrees with the MHRA and NIBSC considerations of this issue. However, Chiron must review the endotoxin limits after production of the first 10 full-scale batches of vaccine in line with the MHRA recommendation.
Considerable discussion took place on this issue. Endotoxins are an integral component of all gram -ve bacterial vaccines. The VSC accepted that the endotoxin specification as proposed by Chiron was acceptable with the proviso that the endotoxin limit be reviewed by Medsafe after production and assessment of the first 10 full scale batches.
MHRA confirmed there original comments, but on face-to-face discussion questioned the relevance of the ****** pyrogenicity test to an intramuscular vaccine. Discussion indicated that this should be considered as a measure of consistency rather than a release criterion.
NIBSC noted that the test provides a crude indication of the potential reactogenicity of a vaccine, but its relevance for an intramuscular dose is questionable. NIBSC felt that the ****** assay gives a more accurate and reproducible measure of the endotoxin that is available to elicit a reactogenic response. However, NIBSC did note that the ****** test is not able to provide information on whether more ****** is released following administration. NIBSC advised that this was not an issue about which Medsafe should be concerned.
Medsafe agrees with the NIBSC consideration of this issue.
Agrees with above.
MHRA recommended that Medsafe seek guidance from NIBSC.
NIBSC noted the following:
Medsafe agrees with the NIBSC consideration of this issue.
Considerable discussion of this issue of potency testing occurred. The VSC acknowledged that the definitive potency test is the response in humans and that current immunogenicity tests in animals do not correlate well with the response in humans. Accordingly no ideal potency test is available. The VSC accepted that the ****** IgG ****** was the most appropriate potency test to give an indication of whether or not individual vaccine batches are immunogenic.
MHRA noted the acceptability of the ****** test methodology and noted Chiron's commitment to develop a specification.
NIBSC commented that the ****** ****** provides evidence that the vaccine is immunogenic but is not a surrogate for efficacy. In the absence of a reliable animal surrogate of protection, emphasis should be on the consistency of new batches of vaccine with a) those produced by NIPH and b) those shown to elicit a bactericidal response in the phase 1 trial in New Zealand. Perhaps the simplest way to look at this is to ensure consistency of the antigen profile by ****** and ****** .
Medsafe agrees with the MHRA that Chiron needs to develop a specification that reflects the immunogenicity of the material used in the clinical trials.
Medsafe agrees with the NIBSC consideration of this issue and has to assess the risk/benefit of a lack of this specification in relation to all considerations around the vaccine. On this basis, it would appear acceptable to release vaccines based on the ****** profile of the bulk active until this specification is developed.
Considerable discussion of this issue of potency testing occurred. The VSC acknowledged that the definitive potency test is the response in humans and that current immunogenicity tests in animals do not correlate with response in humans. Accordingly no ideal potency test is available. The VSC accepted that the ****** IgG ****** was the most appropriate potency test to give an indication of whether or not individual vaccine batches are immunogenic. The VSC agreed that while this lack of specification is not a barrier to consent under section 23, it was essential for consideration of consent under section 21.
MHRA made the general comment that the methods used to determine the
qualitative and quantitative antigen content of the vaccine are considered
appropriate.
This issue is resolved.
NIBSC indicated that the use of ****** would allow confirmation of the presence of the key antigen (PorA). This addresses point 1 of this question.
Medsafe agrees with the MHRA and NIBSC considerations of this issue.
With regards to point 2 of this question, Chiron has provided justification for use of ****** dose. With regard to points 3 & 4, Chiron has indicated that data will be supplied as part of the test validation.
i) and ii) agrees with above
iii) and iv) The VSC agreed that while this lack of validation is not a barrier to consent under section 23, it was essential for consideration of consent under section 21.
MHRA recommended that Medsafe seek guidance from NIBSC on this issue. MHRA later advised that the methods used to determine the qualitative and quantitative antigen content of the vaccine are considered appropriate.
NIBSC advised that the question of orthogonal methodology should be considered as a vaccine development tool, but not a manufacturing issue.
Medsafe agrees with the NIBSC consideration of this issue.
Agrees with above.
MHRA considered the point cleared.
No comment given on this point.
Medsafe agrees with the MHRA consideration of this issue.
Agrees with above.
MHRA considered the point cleared.
No specific comment given on this point.
Medsafe agrees with the MHRA consideration of this issue.
Agrees with above - see also question 28 for the final resolution of the shelf life issue.
Initially, MHRA referred a decision on this issue to Medsafe. Subsequently,
MHRA noted the acceptability of the ****** test methodology and noted Chiron's
commitment to develop a specification.
MHRA have accepted the observed fluctuations are due to the use of a second
****** strain in the testing.
This issue is resolved.
NIBSC confirmed that the key potency release criteria will be the OMV IgG ****** and the key safety criterion will be the endotoxin (******) assay.
Medsafe agrees with the MHRA and NIBSC considerations of this issue.
Agrees with above.
MHRA confirmed that this issue should be addressed.
No comment given on this point.
Medsafe agrees with the MHRA consideration of this issue. Chiron should be able to address this issue immediately.
Agrees with above.
MHRA recommended that Medsafe seek guidance from NIBSC on this issue.
NIBSC confirmed that the use of chromatographic methods or 2D dye electrophoresis is a product development issue and should not be used as a criterion in support of licensure.
Medsafe agrees with the NIBSC consideration of this issue.
Agrees with above.
MHRA confirmed that this issue should be addressed.
No comment given on this point.
Medsafe agrees with the MHRA consideration of this issue and Chiron will be asked to supply this data as soon as possible.
Chiron supplied additional stability data on 2 July 2004 in relation to the following batches:
******
******
******
Based on advice received from ****** of the MHRA on 1 July, it is considered acceptable to extrapolate shelf life data by a factor of 2 when there is only limited data available, provided that the shelf life data which is available shows satisfactory results to date.
With regard to the shelf life of the vaccine, the available data provided by Chiron on 2 July, coupled with advice from the MHRA on extrapolation, indicates that a shelf life of 18 months is appropriate for the vaccine until further data is available.
It should be noted that stability data on NIPH batches which does extend to 24 months exists. This appears to show no clear trends in stability until the 12-month time point. At 12 and 18-month time points, 5 of the 14 batches analysed appear to show a decrease in immunogenicity. In some cases this extends to the 18-month time point, but immunogenicity appears to return at the 24-month time point. This apparent inconsistency is thought to be due to the use of differing strains of ****** in the testing programme. The significance is therefore unclear.
To summarise it is therefore recommended to assign an 18-month shelf life, which must be reviewed by Medsafe as further data from the Chiron produced batches becomes available.
Considerable discussion around this issue took place much of which centred on the data relating to NIPH produced vaccine. The recommendation of the VSC is to accept the pragmatic position recommended by MHRA; viz. that a shelf life of 18 months can be granted on the basis of 9 months real time stability data. However the committee noted that
MHRA considered the additional information supplied by Chiron to resolve
the issue.
This issue is resolved.
No comment given on this point.
Medsafe agrees with the MHRA consideration of this issue.
Agrees with above
MHRA confirmed the issue should be addressed, but should be addressed as a post marketing commitment and should not hold up approval of the vaccine.
No comment given on this issue.
Medsafe agrees with the MHRA consideration of this issue.
The VSC agreed that while this lack of data is not a barrier to consent under section 23, it was essential for consideration of consent under section 21.
MHRA considered the additional information supplied by Chiron to resolve
the issue.
This issue is resolved.
No comment given on this point.
Medsafe agrees with the MHRA consideration of this issue.
Agrees with above.
MHRA considered the additional information supplied by Chiron to resolve
the issue.
This issue is resolved.
NIBSC comments
No comment given on this point.
Medsafe recommendation
Medsafe agrees with the MHRA consideration of this issue.
VSC comment
Agrees with above.
During discussion with MHRA, the issue of appropriate GMP certification was raised, following on from a comment in the initial MHRA report. Information from Chiron indicates that this vaccine was not subjected to audit during the most recent certification. However, the manufacture is covered by the GMP certification.
MHRA considered the additional information supplied by Chiron to resolve
the issue.
This issue is resolved.
No comment given on this point.
Medsafe agrees with the MHRA consideration of this issue.
Agrees with above.
Subsequent to the original submission, Chiron has proposed an increase to the specification for this parameter.
MHRA considered that endotoxin does not rise on storage.
NIBSC commented that bearing in mind the question of solubility (****** would be insoluble if the OMV broke down completely) it wouldn't necessarily follow that a vaccine with a higher ****** ratio would release more endotoxin. So it is difficult to predict whether the clinical effect would be significantly different from the lower ratio batches. We see the ****** assay as the safety test. The ****** ratio is more a measure of vaccine consistency than safety, i.e. how much ****** antigen the vesicles contain. NIBSC understands the Medsafe concern because on the face of it, ****** sounds like a very "dirty" vaccine. However, in this case, the endotoxin is part of the membrane and it is this membrane that keeps the antigens in the correct conformation to elicit a protective response. If Medsafe were still concerned about batches with the higher ratio, would it be possible to use these later in the roll out to permit time for a small safety study to compare low and high ratio batches?
Medsafe agrees with the NIBSC consideration of this issue.
Agrees with above.
Chiron has already provided some responses and a commitment to others. These points have not been reviewed in depth by Medsafe, but would not hold up any approval which might be given due to their minor nature.