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Revised: 22 May 2013

Release of information relating to the approval process for the meningococcal B vaccine (MeNZB) application

Explanatory notes on some issues contained in the minutes of the Vaccine Sub-Committee (VSC) meeting held on 5 July 2004.

Background

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

Introduction

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.

Explanatory notes

Questions 1 to 6 and 33

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.

Questions 7, 8, 10, 11, 13, 17 to 23, 36, 37, 40, 50 and 51, and also Additional point for consideration 2

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).

Questions 15, 16, 34, 35 and 45 to 49

These question sought reassurance that equipment, procedures and test methods were appropriate for the manufacture and quality control of MeNZB.

Questions 9, 24, 25 to 30, 41 to 44, 52 to 55

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.

Questions 3132

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.

Additional point 1

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.

Minutes of the Vaccine Sub-Committee meeting held on 5/7/04 to discuss the assessment of the quality and manufacturing data relating to the Meningococcal B vaccine (MeNZB) produced by Chiron S.r.L.

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.

Conflict of Interest

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.

VSC Recommendation to MAAC

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.

Background

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:

  1. To meet with the MHRA and NIBSC to clarify the final recommendations regarding the quality data on the vaccine submitted to the MHRA for assessment.
  2. To discuss those recommendations with NIBSC to help identify what are the key 'make or break' issues pertaining to the evaluation outcome.

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.

Sterility assurance during manufacture of drug substance and finished product

  1. Bioburden levels should be monitored throughout the manufacture of the drug substance and finished product:
    1. Pre-filtration bioburden limits of ****** prior to final filtration for the Pre-Bulk Concentrate should be set in line with ICH limits.
    2. It should be confirmed that filling occurs within one working day of final filtration.
    MHRA comment:

    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.

    NIBSC comment

    None given on this issue.

    Medsafe recommendation

    Medsafe agrees with the MHRA consideration of this issue.

    VSC comment

    Agrees with above.

  2. The following data should be provided to validate aseptic manufacturing of drug substance and finished product at Chiron S.r.l manufacturing sites:
    1. recent media fills to validate aseptic processing during inoculum preparation and fermentation at ****** site
    2. three most recent media fills to validate aseptic formulation and filling at the ****** site
    3. Ongoing 6-month sterility data for the three batches of formulated bulk produced from ****** purified OMV at Chiron to validate the integrity of the sealed formulation tank.
    MHRA comment:

    MHRA now consider that the additional information supplied by Chiron answers the question. This issue is resolved.

    NIBSC comment

    None given on this issue.

    Medsafe recommendation

    Medsafe agrees with the MHRA consideration of this issue.

    VSC comment

    Agrees with above.

  3. It should be clarified that bacterial contamination of the N. meningitidis culture is evaluated by microscopic smears of Gram-stained smears and by inoculation into appropriate media, where at least 10,000 organisms have been inspected and contaminated culture will be discarded.
    MHRA comment:

    MHRA now consider that the additional information supplied by Chiron answers the question. This issue is resolved.

    NIBSC comment

    None given on this issue.

    Medsafe recommendation

    Medsafe agrees with the MHRA consideration of this issue.

    VSC comment

    Agrees with above.

  4. Sterilisation and/or depyrogenisation validation of immediate containers and formulation tank should be provided for:
    1. Glass bottles used to store purified OMV bulk
    2. Glass vials and rubber stoppers used to store final vaccine.
    MHRA comment:

    MHRA now consider that the additional information supplied by Chiron answers the question. This issue is resolved.

    NIBSC comment

    None given on this issue.

    Medsafe recommendation

    Medsafe agrees with the MHRA consideration of this issue.

    VSC comment

    Agrees with above.

Inactivation of N. meningitidis culture during manufacture of drug substance

  1. Process validation data including inactivation kinetics for manufacturing scale lots should be provided to support the effectiveness of the ****** inactivation process.
    MHRA comment:

    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.

    NIBSC comment

    Agreed with the MHRA consideration of this issue.

    Medsafe recommendation

    Medsafe agrees with the MHRA and NIBSC considerations of this issue.

    VSC comment

    Agrees with above.

  2. It should be confirmed that inactivation results are available prior to commencement of the purification process. An intermediate hold step should be introduced whilst inactivation tests are performed, unless otherwise justified.
    MHRA comment:

    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.

    NIBSC comment

    None given on this issue.

    Medsafe recommendation

    Medsafe agrees with the MHRA consideration of this issue.

    VSC comment

    Agrees with above.

Outer Membrane Vesicle integrity and size

  1. In-process controls for vesicle integrity and size:
    1. It should be confirmed how particle size is measured and what action limits are applied following
    2. In-process control for particle size following ****** should be retained until further manufacturing data are available, unless otherwise justified
    3. The applicant should introduce an in-process control for yield following sterile filtration as a surrogate for consistency of drug substance manufacturing process with respect to vesicle aggregation and size (******).
    MHRA comment:

    MHRA now consider that the additional information supplied by Chiron is acceptable. This issue is resolved.

    NIBSC comment

    None given on this issue.

    Medsafe recommendation

    Medsafe agrees with the MHRA consideration of this issue.

    VSC comment

    Agrees with above.

  2. The manufacturer should validate their production process to ensure that vesicles are of a consistent quality with regard to size range, aggregation and integrity (since this is likely to effect immunogenicity). ****** and other orthogonal methods (e.g. FACS-based methods) would provide reassurance. Data regarding vesicle size and integrity should be provided for NIPH MenB OMV clinical lots and the first three industrial-scale MeNZB lots manufactured at Chiron S.r.l.
    MHRA comment:

    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 comments

    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 recommendation

    Medsafe agrees with the MHRA and NIBSC considerations of this issue.

    VSC comment

    Agrees with above.

  3. Stability-indicating protocols:
    1. Analytical methods used to monitor stability of drug substance and finished product are stated to be stability-indicating methods. It should be explained whether these methods would be able to detect changes in vesicle size or integrity that may affect vaccine immunogenicity.
    2. Ongoing stability trials for three process development drug substance lots and industrial-scale finished product lots should include stability-indicating tests that monitor vesicle size and integrity (to validate the production process), unless otherwise justified.
    MHRA comment:

    MHRA deferred a response on this question to Medsafe, in light of the response and resolution to the previous question.

    NIBSC comments

    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.

    Medsafe recommendation

    On the basis of the resolution of question 8 above, the question of stability of vesicle integrity is not of concern.

    VSC comment

    Agrees with above.

Drug substance Specifications

  1. The following tests should be introduced in drug substance specifications:
    1. a test for appearance
    2. identity test (******) should additionally include a specification for immunogenic antigens specific to the New Zealand strain
    3. A specification for antigen purity (%) should be included (sum of the % protein for each of the ****** antigens)
    4. A certificate of analysis should be provided for the reference standard (clinical batch ****** ) used for identity and protein composition in drug substance release tests.
    MHRA comment:

    MHRA considered that the information and commitments provided by Chiron to clear the point. This issue is resolved.

    NIBSC comments

    NIBSC deferred comment to the MHRA.

    Medsafe recommendation

    Medsafe agrees with the MHRA consideration of this issue.

    VSC comment

    Agrees with above.

Analytical Procedures and Validation

  1. Ongoing validation data should be provided for
    1. identity, ****** content, DNA content and ****** content in drug substance specifications
    2. identity, aluminium content and immunogenicity in finished product specifications
    MHRA comment:

    Chiron supplied some additional data, and MHRA noted that further information was still outstanding.

    NIBSC comments

    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 recommendation

    Medsafe has to assess the risk/benefit of a lack of this data in relation to all considerations around the vaccine.

    VSC comment

    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.

Manufacturing of finished product

  1. The maximum batch size and batch size range should be defined. It should be confirmed that there is no blending of batches so that each batch is derived from drug substance manufactured from a single master and working seed. The master and working seed used to prepare MeNZB vaccine clinical lots should be confirmed.
    MHRA comment:

    MHRA considered the additional information and commitment supplied by Chiron to resolve the issue.
    This issue is resolved.

    NIBSC comments

    None given on this issue.

    Medsafe recommendation

    Medsafe agrees with the MHRA consideration of this issue.

    VSC comment

    Agrees with above.

  2. Updated batch analysis should be provided:
    1. Ongoing process validation and finished product batch data should now be available
    2. Batch data should be provided for final bulks used to produce 25 mcg/ml batches (******) and 50 mcg/ml (******)
    MHRA comment:

    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.

    NIBSC comments

    Agreed with the MHRA comment.

    Medsafe recommendation

    Medsafe agrees with the MHRA and NIBSC considerations of this issue.

    VSC comment

    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.

Re-processing

  1. It should be confirmed that there is no reprocessing of drug substance or finished product batches.
    MHRA comment:

    MHRA indicated that the additional information supplied by Chiron resolved the issue.
    This issue is resolved.

    NIBSC comments

    None given on this point.

    Medsafe recommendation

    Medsafe agrees with the MHRA consideration of this issue.

    VSC comment

    Agrees with above.

Vaccine homogeneity

  1. Mixing:
    1. Mixing parameters (rate, time, temperature) should be defined throughout manufacture of the drug substance and finished product.
    2. Stepwise mixing throughout manufacture of finished product should be validated under 'worst case' conditions.
    MHRA comment:

    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.

    NIBSC comments

    Agreed with the MHRA comment.

    Medsafe recommendation

    Medsafe agrees with the MHRA and NIBSC considerations of this issue.

    VSC comment

    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.

  2. Homogeneity of the formulated bulk and final vaccine:
    1. It should be confirmed that homogeneity of the formulated bulk and final vaccine has been validated or is routinely tested in each lot.
    2. Validation data used to set homogeneity specifications in respect of aluminium concentration in should be submitted. The pre-defined acceptance limits (******) may need to be tightened when more manufacturing data are available.
    3. Homogeneity data in respect of aluminium content should be provided for the first three consistency lots (******) manufactured at the ****** site.
    MHRA comment:

    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.

    NIBSC comments

    None given on this point.

    Medsafe recommendation

    Medsafe agrees with the MHRA consideration of this issue.

    VSC comment

    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.

Finished product specifications

  1. The levels of endotoxin in drug substance and finished product lots should be tightened in line with the submitted batch data.
    MHRA comment:

    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 comments

    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 recommendation

    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.

    VSC comment

    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.

  2. Pyrogen assay in finished product specifications:
    1. Pyrogens Ph.Eur. test methods and acceptance criteria should be applied in release tests, unless otherwise justified
    2. The challenge dose (mcg/kg) used for the Pyrogens test should be the maximum non-pyrogenic dose obtained for clinical lots found to be safe (non-reactogenic) in clinical trials.
    MHRA comment:

    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 comments

    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 recommendation

    Medsafe agrees with the NIBSC consideration of this issue.

    VSC comment

    Agrees with above.

  3. Consideration should be given to development of a serum bactericidal assay to monitor potency in final bulk specifications and during finished product stability.
    MHRA comment:

    MHRA recommended that Medsafe seek guidance from NIBSC.

    NIBSC comments

    NIBSC noted the following:

    1. The ultimate measure of immunogenicity is response in humans. This has been demonstrated in the clinical trials.
    2. The correlation between human and animal immunogenicity is poor.
    3. NIBSC agrees with Chiron that ****** is more discriminatory than SBA in this context.
    4. NIBSC is of the opinion that ****** is the most appropriate release and stability criterion for potency and that animal SBA is not helpful as a release or stability criterion.
    Medsafe recommendation

    Medsafe agrees with the NIBSC consideration of this issue.

    VSC comment

    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.

  4. Specifications should be introduced for immunogenicity (IgG titre per challenge dose) in final bulk lots. The lower immunogenicity specification (shelf-life specification) should be at least equivalent to that measured for clinical lots (NZ strain/formulation) found to be safe and immunogenic in clinical trials.
    MHRA comment:

    MHRA noted the acceptability of the ****** test methodology and noted Chiron's commitment to develop a specification.

    NIBSC comments

    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 recommendation

    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.

    VSC comment

    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.

  5. ****** assay
    1. The ****** assay in final bulk specifications should be adapted to measure specific IgG titres against protective antigens (******) in the MenZB vaccine rather than non-specific anti-OMV IgG titres raised against the bacterial suspension.
    2. The purpose of the dose-response curve (******) should be justified.
    3. The reference standard used in the immunogenicity assay should be stated.
    4. The animal source used in immunogenicity tests is stated to affect the ****** titres. The animal source (****** strain and supplier) should be written into SOPs. New animal sources should be cross-validated in the immunogenicity assay against those used to determine immunogenicity in clinical lots.
    MHRA comment:

    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 comments

    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 recommendation

    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.

    VSC comment

    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.

Comparability

  1. The applicant should demonstrate comparability of clinical and Chiron manufacturing consistency lots using orthogonal methods (e.g. dye image 2D-gel electrophoresis).
    MHRA comment:

    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 comments

    NIBSC advised that the question of orthogonal methodology should be considered as a vaccine development tool, but not a manufacturing issue.

    Medsafe recommendation

    Medsafe agrees with the NIBSC consideration of this issue.

    VSC comment

    Agrees with above.

  2. It is noted that validation of the ****** assay in drug substance specifications is ongoing. Validation parameters including accuracy and range, limits of detection and quantification should be provided to provide sufficient confidence the comparative impurity profile of the clinical and manufacturing batches.
    MHRA comment:

    MHRA considered the point cleared.

    NIBSC comments

    No comment given on this point.

    Medsafe recommendation

    Medsafe agrees with the MHRA consideration of this issue.

    VSC comment

    Agrees with above.

Stability of drug substance and finished product

  1. Stability data would support a shelf life of 12 months at 2-8 °C for the drug substance, providing the observed increases in endotoxins in Chiron process and manufacturing batches can be justified with respect to toxicity and clinical significance.
    MHRA comment:

    MHRA considered the point cleared.

    NIBSC comments

    No specific comment given on this point.

    Medsafe recommendation

    Medsafe agrees with the MHRA consideration of this issue.

    VSC comment

    Agrees with above - see also question 28 for the final resolution of the shelf life issue.

  2. Stability data do not support the assignment of a shelf-life for MeNZB vaccine for the following reasons:
    1. The stability-indicating protocol should include a validated immunogenicity assays (e.g. ****** for detection of specific IgG titres against 'protective' antigens or serum bactericidal assay) that may better correlate with protection.
    2. A shelf-life specification for immunogenicity should be set based on the minimum immunogenicity of clinical batches that were shown to be safe and immunogenic in clinical trials.
    3. Fluctuations in anti-OMV IgG titres during storage should be explained with respect to the clinical significance. ******
    MHRA comment:

    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 comments

    NIBSC confirmed that the key potency release criteria will be the OMV IgG ****** and the key safety criterion will be the endotoxin (******) assay.

    Medsafe recommendation

    Medsafe agrees with the MHRA and NIBSC considerations of this issue.

    VSC comment

    Agrees with above.

  3. The aluminium hydroxide bulk should be used within its registered shelf-life (i.e. the expiry date of MenZB vaccine should not exceed the expiry date of the aluminium hydroxide used).
    MHRA comment:

    MHRA confirmed that this issue should be addressed.

    NIBSC comments

    No comment given on this point.

    Medsafe recommendation

    Medsafe agrees with the MHRA consideration of this issue. Chiron should be able to address this issue immediately.

    VSC comment

    Agrees with above.

  4. Consideration should be given to introducing chromatographic methods or 2D dye electrophoresis to monitor any degradants, impurities or aggregates in stability protocols for drug substance and finished product, until further manufacturing data are available.
    MHRA comment:

    MHRA recommended that Medsafe seek guidance from NIBSC on this issue.

    NIBSC comments

    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 recommendation

    Medsafe agrees with the NIBSC consideration of this issue.

    VSC comment

    Agrees with above.

  5. Real-time (******) and stress (******) stability data should be provided for MeNZB manufacturing test run (******) and the first GMP manufacturing batch ****** manufactured at Chiron and GMP Manufacturing Pilot roll out batches ****** .
    MHRA comment:

    MHRA confirmed that this issue should be addressed.

    NIBSC comments

    No comment given on this point.

    Medsafe recommendation

    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.

    VSC comment.

    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

    1. the shelf life may be reduced as more real time data become available
    2. that Chiron be requested to provide real time stability data at 15 months in addition to the normal time points of 12 and 18 months to ensure that the 18 month extrapolation is valid.
  6. At the end of the finished product shelf life it should be demonstrated that the degree of adsorption will not be less than for batches used in clinical testing in line with Vaccines for Human Use Ph.Eur.
    MHRA comment:

    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

  7. Cumulative stability trials should be initiated to take into account the use of aged intermediates, adjuvant and drug substance during manufacture and subsequent storage of the finished product. The protocol should be submitted to the Competent Authorities for review.
    MHRA comment:

    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.

    NIBSC comments

    No comment given on this issue.

    Medsafe recommendation

    Medsafe agrees with the MHRA consideration of this issue.

    VSC comment

    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.

TSE safety

  1. EDQM certificate ****** should be provided.
    MHRA comment:

    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.

  2. It should be confirmed that no other ruminant materials are used in the production of ****** .
    MHRA comment:

    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.

Additional points for consideration

  1. GMP certification

    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 comment:

    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.

  2. ****** ratio

    Subsequent to the original submission, Chiron has proposed an increase to the specification for this parameter.

    MHRA comment:

    MHRA considered that endotoxin does not rise on storage.

    NIBSC comments

    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 recommendation

    Medsafe agrees with the NIBSC consideration of this issue.

    VSC comment

    Agrees with above.

The second part of the MHRA questions covered minor points which should be addressed on an ongoing basis.

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.

Manufacture of the drug substance

  1. Sterilisation validation of the antifoam used during fermentation should be provided.
  2. An overall time period for the purification process should be provided and validated. Data from the Process Development Department should be provided to support the ****** hold time at not more than ****** for the cooled fermentation harvest
  3. ******used during purification steps:
    1. Specifications and ****** operating parameters (******) of ****** should be defined.
    2. Maximum lifetimes of ****** should be defined. Particular attention should be paid to the potential carry over of endotoxins.
  4. It is assumed that in-process control alert and action limits will be defined when more production data are available.

Seed lot system

  1. The manufacturer should detail the anticipated utilisation rate of the working seed for production and the expected interval between generation of new working seeds. It should be confirmed if new working seeds will be manufactured at Chiron or NIPH.

Analytical Procedures

  1. Total protein: each assay run should be validated by recovery of a positive control at defined protein concentrations (within the linear range of the standard curve).
  2. Protein composition (antigen purity):
    1. It should be confirmed if ****** is performed under non-reducing conditions to detect oligomeric forms
    2. Consideration should be given to determining antigenic composition and purity using an orthogonal method (******) that is capable of detecting protein degradation products.
  3. It is noted that validation of the ****** assay is ongoing. Validation parameters (accuracy over the linear range, limit of detection and quantification) for ****** assay should be provided to provide sufficient confidence in the impurity profile of the submitted batches and ****** clearance data for the "new" process.

Stability of drug substance

  1. It should be confirmed that the stability study for process development lots also investigated the formation of aggregates, yield following filtration of the stored pre-bulk concentrate and bioburden levels following storage.
  2. The drug substance should be stored protected from ****** since the ****** is unstable.
  3. Stability Protocol:
    1. The protocol for the accelerated stability trial at 25 °C should be extended to 6 months
    2. Given the observed increases in endotoxins during storage, an additional test for ****** quantification should be performed at the end of the real-time stability study.
    3. Sterility should be monitored at the end of the real-time study
    4. Stability data should be provided for drug substance lots in the intended glass storage containers
  4. Data should be provided to support the statement that there is no adsorption of antigens to the glass containers.

Manufacture of finished product

  1. Measures taken to avoid cross-contamination with other vaccines manufactured at the ****** site should be outlined.
  2. The temperature at which formulation and filling occur should be defined. Any excursions from the normal storage conditions of ****** should be justified.
  3. The maximum fill time should be defined. ******
  4. It should be confirmed when process validation will be available.
  5. Representative certificates of analysis should be provided for excipients.

Analytical Procedures

  1. It should be confirmed that the method used to determine osmolarity complies with Osmolality Ph.Eur. <2.235>.
  2. Cross-validation data between the ****** and ****** methods for aluminium hydroxide content should be provided before using the new method.

Stability of finished product

  1. It is noted that stability updates have been provided for MeNZB batches ****** . The three real-time month data update at 2-8 °C for batch ****** is inconsistent with data provided in the dossier.
  2. It is noted that batch numbers of NIPH NZ OMV vaccine and MenBvac used to bridge stability data for MeNZB vaccine are not consecutive. It should be explained why 'missing' batch numbers were not entered into stability trials.
  3. The vaccine suspension should be stored upright and inverted in vials during stability trials, in accordance with Quality of Biotechnological Products: Stability Testing of Biotechnological/Biological Products, CPMP/ICH/138/95.

Shipping validation

  1. Shipping validation data should be provided to support transport of Master and Working Seeds, Pre-Bulk Concentrate (drug substance) and finished product lots (to NZ importation site).