Vaccine Development Process Map

Master Seed Bank

Summary of the area

In order for any vaccine to be manufactured to GMP it is necessary to first produce a ‘Master Seed Bank’ which is the progenitor of all batches of the vaccine which are subsequently produced. In early phase development a batch for clinical use is typically produced directly from the master seed whereas for large scale manufacture a large working seed stock will be produced from the master, and batches are produced from the working seed. The master seed must be consistent (clonal, not containing variants), well characterised and produced using materials suitable for GMP manufacture, in a GMP certified clean room. All starting materials and raw materials should be fully traceable. A certificate of analysis is required before the master seed can be transferred to a second GMP manufacturer.

Frequently materials produced in research labs are not suitable for use as starting materials to generate a master seed due to lack of information about the history of the materials, or potential for contamination with other micro-organisms. The cleanest solution is frequently to re-derive the starting materials by e.g. transfection of a GMP-certified cell bank with plasmid DNA or viral DNA that has been phenol/chloroform extracted to remove all protein and therefore TSE risk, followed by cloning.

Novel mammalian cell banks will require testing for any possible adventitious agents. Risk of TSE contamination may be mitigated by extensive dilution during generation of the seed stock. Assays to characterise the product (identity, purity, potency) should be defined prior to producing the master seed. Assays for purity should test for any other vaccines/viruses/bacteria that were handled in the lab producing the starting materials as well as for mycoplasma if mammalian cells were used.

What are the critical steps within the process?

Definition of the starting materials that will be used to generate the master seed.

  • Are all components fully traceable? Is all documentation available?
  • What animal-derived materials have been used? If bovine serum has been used was it from a TSE-free source? Bacterial growth medium frequently contains animal-derived components.
  • A risk assessment should then be completed and used to define the production and testing strategy for the master seed
  • Will cloning be required?

Generation of the starting materials should then take place in isolation from other lab work to avoid any possible contamination with other materials

Starting materials and required raw materials are transferred to a GMP clean room for master seed production and vialling

Testing of the master seed is conducted according to the agreed specification and a certificate of analysis is issued

Are there any bottlenecks within this process? Who owns the bottleneck?

In the UK, the majority of smaller research groups do not have the knowledge and experience to produce starting materials, or the dedicated lab space which is required. Access to a GMP facility is required to produce the master seed stock.

How could the bottlenecks be resolved?

The UK needs more small scale GMP manufacturing capacity with associated process development/GLP labs to allow the production of starting materials and seed stocks. Discussions between a Qualified Person and research labs at an early stage is needed to define the steps to be taken towards production of the master seed and the assays that will be required.

Are there any rate limiting capacity issues?

Availability of QPs is very restricted. Small scale GMP manufacturing facilities do not have enough capacity. Development of assays suitable for testing the master seed and vaccine produced from it will be required.

Additional comments

There is a lack of awareness of the requirements for master seed stock generation in many research labs conducting pre-clinical research, and this can result in a lengthy delay in the production and certification of master seed stocks before GMP manufacture can commence.

The issue should be addressed at an early stage for any pre-clinical research projects that are planning to progress to GMP manufacture and clinical trials. Small scale GMP facilities will produce the master seed stock as well as the first batch of vaccine for clinical use but companies who will take over large scale manufacture may lack confidence in materials produced by small academic facilities, so early communication is to be recommended if it is anticipated that large amounts of the vaccine will be required.