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ATMP Sweden Process map Manufacture process map

Manufacture process map

Welcome to the landing site for the ’Manufacture’ of ATMPs. Your role is to ensure that the GMP manufacture facilities are accredited by the local regulatory authority, that an appropriate QMS is in place to manage the process development and GMP manufacture needs of relevant clients. You also have an important role in ensuring appropriate connections to clinics and healthcare for sourcing of start material and development of clinically relevant delivery systems and in use stability programs.

Below you can see our ’process map’ that shows what you need to be considering at what stage of ATMP development. There are other process maps for manufacture, regulatory, product developer and commercial needs, that can give you tips on how to address these needs in your team. The objective here is to have the right people considering the right things at the right time to ensure that your ATMP pipeline moves forward as effectively as possible, good for patients in need, good for your pocket to not waste money and time on inefficiencies.

Manufacture

  • 1. Research adaptation

  • 2. Process Qualification

  • 3. GMP manufacturing

  • 4. Clinical Trials

  • 5. Market Approval and Reimbursement

  • 6. Standard of Care

Process Development

  • Identify analytical development and CMC experts consultant
  • Process/analytics adapted to GMP ready, CMC, defined
  • Develop manufacturing process flow with decisions, production and analytics (IPCs & release testing)
  • Optimise product for quality and reproducibility
  • Assess start material quality compared to alternatives​, alternative sources and availability 
  • Quality by Design (QbD), quality TPP (QTPP) to identify critical quality attributes (CQAs), critical material attributes (CMAs), critical process parameters (CPPs) and a control strategy with specifications for drug substance, drug  product,  excipients and manufacturing steps
  • Risk assessment – infection/animal an d human derived components, contaminants, particles, empty capsids, tumorigenicity/genetic instability, disease genes/genomic analyses, inherent risks, batch failure, side effects, production process (open v closed systems)
  • Classification and related regulations/guidelines
  • Establish appropriate donor consent (for PD purposes)
  • Start material specification – donor eligibility, inclusion/exclusion, testing, preparation, quality and safety
  • Raw materials ​specification, determine quality suitablity with CoO, CoA, CoQ and/or CoC​. Ideally, identify alternate suppliers for raw material
  • Agreements with suppliers – many times this can be lengthy processes that can postpone further actions by several months if the supplier does not already have this kind of documents in place as a standard. It can be difficult to get suppliers to (in writing) ensure the traceability of human derived materials to a sufficient extent.
  • Batch protocol, SOP for manufacture
  • Excipient identification, appropriate testing and if possible (change raw material, add wash) removal – endotoxin, DMSO
  • Develop in-use stability testing development
  • Determine suitability of assays to understand product behaviour and safety. Suitable sensitivity? Consult MPA/EMA/FDA
  • Validate cell counting for manufacture, dose preparation and dispense.
  • Define of product; drug substance (active) and the drug product
  • Determine how many samples are needed for release, retention samples and stability testing
  • Establish GDP transport for start material, storage and clinical delivery
  • Start the process for drawing up the agreements between the different stakeholders involved in the manufacturing at an early stage eg. sponsor-manufacturer, tissue establishment-manufacturer, manufacturer-analysis contractor etc. It is usually when trying to write these agreements you discover gaps in the logistics, responsibilities etc.
  • Develop validation program
  • GDPR requirements in regard to start material and product testing
  • Is lab based process transferrable to GMP/clinical
  • List of GMP facilities/CMOs to use….
  • Staffing, competent people
  • Select a manufacturing site – ensure it has a QMS in place and authorisation for ATiMP Manufacture
  • Establish analytical packages for cell banks…
  • AAV specific manufacture support resource Home page | Gene Therapy Analytical Guide

Process Qualification

  • Process, stability, analytics qualified in GMP
  • Product safety must be validated in Phase I. Sterility, endotoxin, mycoplasma verified compared to pharmacopeia for phase I. Methods are validated in lab but they do a verification on your product.
  • Dose – cell count and viability validated minimum phase II.
  • Validating your process and analytical methods (beyond safety testing) is not a requirement for a phase 1 study, though must be validated prior to pivotal trials (phaseIII/MAA). Compendial safety assays, verified against Ph.Eur (from phase I).
  • Must demonstrate process consistency for Phase I – multiple runs, multiple operators, different weeks
  • Variables affecting the process and assays must be documented and understood towards validation (sample stability, quality attributes understood)
  • The process/product/release assays are still being determined up until Phase III – broad early and then non-negotiable
  • Stability study starts with engineering run and possibly clinical runs for IMPD. Stability reinitiates with changes in product/CMO/assays etc.
  • Cleanrooms/QMS/QP/certificate of GMP compliance
  • Process for intake, registration and traceability of materials/equipment
  • Environmental, aseptic and flow monitoring
  • Plan for routine and batch cleaning of rooms
  • Traceability of human derived components
  • Tech transfer to relevant CMO/GMP facility
  • Comparability (manufacturing process and analytics) following the Tech transfer
  • Qualification of personnel for manufacture or analytics
  • Tissue establishment from MPA for manufacture of pharmaceutical
  • Manufacturing authorisation approval from MPA
  • Wholesale permit for storage and distribution of pharmaceuticals
  • Equipment qualification IQ/OQ/PQ for manufacture or analytics
  • Product specification – analytical tests and acceptance criteria
  • Qualification of cleanroom for manufacture
  • Qualification/Validation of process (simulations and/or engineering/verification/technical runs in controlled environment
  • Use engineering batch to test preclinical program under GLP
  • Establish quality agreement with sponsor/manufacturer
  • Develop stability program and shelf life extension plan – define critical stability indicating parameters
  • GMO application where relevant
  • Manufacturing method documentation complete
  • Verification of analyses
  • Qualification of excipients
  • QP approved material specification
  • Transfer to GMP team
  • Batch records and materials/vendors/qualification
  • Equipment and assay suitability/feasability for IPC (in-process control) and release testing
  • MSAT Manufacturing Science and Technology (between lab small scale and scale up and transfer to GMP)
  • Locked process but GMP/facility suitability optimisation
  • Consistent process on broad specification
  • Vendor qualification dependent on location of manufacture
  • CoA and audit questionnaire, viral safety, leachables, but not as robust as later phase qualification/substitutions (phase II)
  • Aseptic process validation (needed regardless of the stage of development).
  • Documentation and verification for start material MCB, WCB where relevant

Product manufacture

  • Stability testing
  • Handling of any deviations, out of specifications (OOSs), CAPAs and change controls
  • Investigators Brochure/IMPD/ CTD M3.2 & 2.3
  • Initiate stability program on GMP batch
  • In house and external batch testing and review of results
  • Establishment of product specification file (PSF) against which the product is released by QP for issue of CoC and head of QC for issue of CoA.

Clinical Trials

  • Tech transfer, comparability to industrial CMO
  • tweaking manufacture process
  • PhIII/MAA (marketing authorisation application)/BLA (biological license application)/commercialisation suitable manufacture and if needed comparability studies
  • Quality assurance vendor qualification, raw materials…..scale in different phases.
  • Establish appropriate donor consent
  • Process Validation/performance qualification
  • Process characterisation, check design space for CPP, proven acceptable range. Set point but proven acceptable range for product release. 
  • Scale up product and up scale process. Comparability studies.
  • Plan for commercial scale manufacturing site

Market Approval and HTA

  • Commercial scale manufacture

Clinical routine

  • Process refinement, comparability
  • Annual report on batches. Checking for consistency. Continued process verification. Process monitoring. 
  • Affordable, high quality manufacture