Function

Several technical options are being used in the current pipeline of TB vaccine candidates, including live attenuated recombinant TB strains, recombinant BCG, killed whole cells, extracts of TB, vectored vaccines, purified sub-unit vaccines with adjuvants, and nucleic acid. The specific features of each technology are not described in this guidance. Rather, a general description is provided of how a process evolves from the lab into a vaccine manufacturing facility, together with the increased level of control from a target (small-scale in the lab) process towards a market scale standardised process with validated specifications. The process should be efficient (low cost, high yield) and robust (simple, reproducible).

Stage 
A
Perform discovery, safety, immunogenicity and efficacy evaluation in initial animal model
Gate 
A
Progress to proof of concept (POC) studies in animals
Main Activities
  • Select expression system and lab-scale production process for generating pre-clinical material
  • Select specific strain
CRITERIA REQUIRED
  • Suitable expression system and process that can produce target product quantity and quality selected
  • Specific strain(s) selected and history recorded
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Guidance

The criteria to select the production technology, beside in-house knowledge and experience, should be the target quality and quantity of the vaccine to be produced. It will influence the decision for the biological expression system and associated target production process that can deliver the target product criteria. Different production processes can be evaluated for suitability with a non-standardised monitoring of product quantity and quality (research quality). The most critical step is the selection of the biological expression system, as it determines the upstream part of the process and quality features of the product.

An initial step is the selection of strain(s). It is important to document the history of the strain as it will become the source of the Master Cell Bank (MCB) and Working Cell Bank (WCB), or the Master Virus Seed and Working Virus Seed Lot for viral vectors.

A target cGMP compliant process exists for BCG suspension cells and this process could be used as the platform technology for the development of a production process for modified BCG and attenuated Mycobacterium tuberculosis (Mtb) vaccines. Note that the traditional method of pellicle culture of BCG which was established in the pre-GMP era is difficult to match with cGMP guidelines.

At the end of this stage, an expression system and lab-scale process must be selected and used to produce pre-clinical R&D material. This process should, in theory, be based upon initial tests, literature and previous projects, and deliver the estimated quantity and quality of the TB vaccine candidate(s).

Stage 
B
Perform POC studies in animals
Gate 
B
Progress to Pre-Clinical
Main Activities
  • Demonstrate feasibility of process at lab scale
CRITERIA REQUIRED
  • Process demonstrated to be feasible at lab scale
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Guidance

The process parameters are explored and optimised at lab scale. Examples of parameters for cell culture are the expansion of cells, temperature, oxygen, pH, stirrer speed, and concentration of metabolites and vaccine product. For down-stream process (DSP), examples of parameters are temperature, flow rate, salt concentration, or column height for ion-exchange column chromatography. Critical parameters for each step of the process must be identified, and optimum set points and ranges defined experimentally. Critical are the yield, purity and stability of intermediate products.

Caution must be taken with raw material used for culture media and buffers. Lots of raw material should be evaluated to control input and identify, then avoid any variation in process performance and product quality. The same is true for the cells (expression system/ biological source organism) that are used to produce antigen, which must be stable for multiple production runs. A risk assessment would be appropriate to estimate the potential impact of process variations on product quality (based on literature, other development projects, and regulatory requirements).

The product quantity (yield) is optimised assuming that the product quality will not change, which will be demonstrated later. The selected set-points for the different process steps is confirmed with product testing in animals.

Guidelines on process and production of vaccines are: ICH Q7, Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients, Nov 2000, including chapter 12 on Validation (ICH Q7), ICH Q8 Pharmaceutical Development, August 2009 (ICH Q8), ICH Q11 Development and Manufacture of Drug Substances (chemical entities and biotechnological/biological entities), May 2012 (ICH Q11), ICH Q2, Validation of Analytical Procedures: Text and Methodology, Nov 2005 (ICH Q2) and Josefsberg and Buckland 2012.

Stage 
C
Perform Pre-Clinical evaluations
Gate 
C
Progress to preparation for Phase 1, First-In-Human
Main Activities
  • Develop and assess feasibility of manufacturing process at pilot scale (e.g. multiple pilot scale runs)
  • Evaluate real-time and accelerated stability on a pilot-scale lot of a Drug Product (DP)
  • Identify a Good Manufacturing Practices (GMP) facility
CRITERIA REQUIRED
  • Reproducibility acceptable and process at pilot scale fixed. If needed, minor revisions to the process can be applied, within the process specifications
  • Quantity and quality of product meets pre-defined feasibility criteria (TPP)
  • First stability data meets pre-set feasibility criteria (TPP)
  • GMP facility identified
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Guidance

The process is scaled up from lab-scale to pilot, at a scale calculated to generate sufficient material for toxicity studies and Phase I / 2 clinical studies.

MCB and WCB, or a combination of Master and Working Virus Seed Lot combined with a MCB and WCB of complementary host cells, are manufactured according to cGMP guidelines or equivalent quality level. After determining feasibility of the pilot-scale process performed with cells from the WCB, vials are sent for release testing.

Standardised production runs at pilot scale (pre-GMP runs) will confirm feasibility and reproducibility. Indeed, by demonstrating that repeated runs can be performed within certain ranges around the set-points for the relevant process parameters, the reproducibility of the process (or process steps) is established, as required for the pilot process according to GMP guidelines. The variation obtained in parameters which are considered critical should be within the ranges tested at lab scale. At the end of this Stage, the selected process now, at pilot scale, can produce the right quantity of product with the correct quality (drug substance and contaminants) and, no further adjustments are required.

At the end of this Stage, the process is fixed for manufacturing of Phase 1 GMP material. Later changes in the process can be required. It will have to be demonstrated that the implemented process changes do not affect the product quality attributes (product comparability). For TB vaccine candidates, later changes in the production process would likely need clinical bridging studies.

Stage 
D
Perform GMP and toxicity studies and prepare Clinical Trial Application
Gate 
D
Progress to First-In-Human/Phase1
Main Activities
  • Complete technical transfer to GMP manufacturer and develop manufacturing process (pilot and/or Phase 1 scale) for production of (DS) and formulation of (DP)
  • Manufacture Good Manufacturing Practices (GMP) Master and Working seeds and banks
  • Produce a batch for toxicology studies (pre-GMP or GMP)
  • Qualify process for safety-related aspects (adventitious agents, mycoplasma, sterility)
  • Produce GMP Clinical Trial Material (CTM) for FIH
CRITERIA REQUIRED
  • Manufacturing process at Phase 1 scale locked
  • Master and Working seeds and banks produced under GMP, released for cGMP
  • Batch for toxicology studies produced with a process equivalent to the process used in GMP
  • Safety-related aspects of the process qualified
  • FIH CTM produced under GMP, in sufficient quantity to support FIH/Phase 1, Toxicology, QC, archives and possibly Phase 2
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Guidance

At the end of this pre-clinical development, a detailed report presents the production process with a rationale for each specified step and data. The standardised production process is also described in concept documents (standard procedures and production protocols). From this point, the process is fixed and can be transferred to Manufacturing and documents used for Tech transfer.

The MCB and WCB now have to be released for use in production runs according to cGMP. The Phase 1 material is produced according to cGMP and to pre-set criteria generated previously. The documents are approved by production experts and QA.

Stage 
E
Perform, First-in-human/Ph1
Gate 
E
Progress to Ph2
Main Activities
  • Optimise process, as necessary. For well-characterised product as confirmed by Critical Quality Attributes (CQA); for less defined product, optimisation within existing specified ranges
  • Manufacture Good Manufacturing Practices (GMP) Phase2 Clinial Trial Material (CTM), if necessary
  • Define scale-up process for commercial batches
CRITERIA REQUIRED
  • Process performing according to the preset procedures and specifications. Process changes and deviations documented.
  • GMP Phase2 CTM available
  • Process (including formulation) finalised at relevant scale by process and scale up validation according to strategy (and including risk assessment)
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Guidance

Further process development involving scale-up towards targeted market scale and process validation are the aims of Stage E.

A live attenuated TB vaccine is used as an example. The anticipated dose is relatively low and, therefore, the scale could be 10 to 100L bioreactors, even for vaccines requiring multi-million doses because one mL of reactor volume could contain 10 doses. Minimal purification is required with low impact on yield, while loss can be caused by lyophilisation. Another example is non-live vaccine. A target of 1 mL equivalent of reactor volume to produce the required purified antigen dose is already challenging assuming a DSP yield 50%, target dose 10 µg, meaning that for a multi-million dose requirement multiple 1000L reactor runs would be required. In any event, the scale-up process for commercial batches should be defined at this stage.

Stage 
F
Perform Ph2 (including Pre-POC) studies
Gate 
F
Progress to Ph2b Efficacy
Main Activities
  • Increase scale of the process, if required, for commercial batches
CRITERIA REQUIRED
  • Commercial scale-up process determined
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Guidance

Activities related to process development, scale up and validation described in Stage E continue during Stage F, up to process and scale for Phase 3 / commercial product.

Stage 
G
Perform Ph2b Efficacy
Gate 
G
Progress to Ph3
Main Activities
  • Plan manufacturing batch for Phase 3
  • Establish final commercial-scale manufacturing process
  • Process validation: demonstrate that ranges for given specifications are valid
  • Validate facilities and equipment used
  • Scale up to commercial level
CRITERIA REQUIRED
  • Plan for manufacturing Phase 3 CTM available
  • Plan for consistency runs finalised
  • Process validation: specifications for process at relevant scale proven
  • Commercial manufacturing strategy in place
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Guidance

The process must be validated at this stage. For validation, it is recommended to use a down-scale model, where the set-points and specified ranges are confirmed for each unit process by monitoring CQA. If this model cannot be used, the multiple runs performed at a larger scale must demonstrate that the product meets pre-set criteria (CQA as recorded in the BoT, QTPP) and that critical process parameters stay within the original ranges tested during preclinical development. Otherwise, rework is required to implement a revised process, possibly besides process development and validations, running the risk of requirement for bridging clinical studies.

The final developed process and scale are used for the manufacturing of Phase 3 material. It has reached a stage close to the volume required for manufacturing for the market. The 3-5 consecutive consistency runs performed at market scale (according to GMP guidelines)  finalise the process validation work, and will also generate the vaccine product to be used for Phase 3.

Stage 
H
Perform Ph3
Gate 
H
Progress to licensure
Main Activities
  • Manufacture Clinical Trial Material (CTM) for Phase 3
  • Prepare consistency batches of vaccine (final formulation, at market scale) for registration
CRITERIA REQUIRED
  • Phase 3 material produced with no major out-of-specs for the production process
  • Consecutive consistency runs completed and product batches for Phase 3 testing available; consistency between batches documented, confirming process consistency
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Guidance

Provided that all pre-set criteria for product and process are confirmed, meaning that no major out-of-specification issues occurred, the production process can be executed for routine manufacturing.