Advanced Therapy Medicinal Products and GMP. Ashley Isbel

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1 Advanced Therapy Medicinal Products and GMP Ashley Isbel

2 Session Overview What are ATMPs? The State of Regulations GMP and Other Challenges for ATMP production Some Solutions The Future

3 What are ATMPs?

4 Advanced Therapy Medicinal Products are: Cell therapy products introduction or reintroduction of whole human cells (normal or modified) to generate an immune response in patients with deficient immunity Gene therapy products - introduction of normal or modified genetic material (usually DNA) into a patient to alleviate a genetic deficiency Engineered tissue products the manipulation/growth of biological tissue for implantation/use on tissue deficient patients.

5 Cell Therapies Cell Therapies Melanoma, Leukaemia, Lymphoma Mostly B-Cell More treatments in develpment Gene Therapies Haemophilia, Cystic Fibrosis, Muscular Dystrophy, some imminodeficiences More treatments in development Engineered Tissue Cartilage Corneas Bone More treatments in development

6 Why are they important? ATMPs are showing outstanding results in difficult to treat conditions Personal, customised medicines, providing next level breakthroughs Gene therapies showing promise in repairing/curing genetic disorders Cell therapies able to target and destroy disease cells while minimising damage to healthy cells Engineered tissue repairing tissue that the body is unable to repair naturally cartilage, corneas, etc.

7 Why are they important?

8 Why are they important? It s an extraordinary development that has turned cancer treatment upside down. At the back of our minds everyone is thinking the c word (cure), Dr. Dominic Wall, Chief Scientific Officer, Cell Therapies, Sept 2015

9 How do you make them? Making ATMPs is difficult and expensive Typical cell therapy process

10 How do you make them? Typical CAR-T/TCR-T cell therapy process

11 How do you make them? Typical gene therapy process DNA production

12 How do you make them? Typical manual engineered tissue process Near future automated engineered tissue process

13 The State of Regulations

14 Registered ATMPs The ATMP field has been active for years depending on the specific area, but only recently gaining traction as effective treatments are becoming a reality Europe 6 ATMPs received Marketing Authorization (1 withdrawn) 1 gene therapy, 3 engineered tissues, 2 cell therapies 165 applications for ATMP categorisation 14 MA submissions USA 12 ATMPs received Marketing Authorization 11 cell therapies, 1 gene therapy 6 are simple cord blood products 2 overlap with Europe (Imylgic and Provenge)

15 GMP Production or Clinical Trials? Currently, the vast majority of ATMPs developed are in clinical trials. Many are in extended (seemingly perpetual) clinical trials. Why? Applying GMP is difficult Getting MA is very difficult Establishing a reimbursement model that works commercially remains a major concern

16 The Current GMPs for ATMPs EMA / PICS Part 1 Mostly academic organisations with resistance to GMP bureaucracy Annex 1 Challenges around the specific requirement for sterile manufacturing Annex 2 Helps define the GMP line Annex 15 Creates a big headache!

17 The Future GMPs?

18 The Future GMPs? ATMP specific GMP Has undergone public consultation Specific for ATMPs, trying to be flexible Standalone replaces GMP guide and annexes (but based on existing guide) Applicable to IMPs and MA But ATMP manufacturers generally unhappy. Don t want two sets of rules Prefer interpretation of existing GMPs or Implementation of new Annex And Very interesting comment from Dutch regulator on ATMP GMP Panel: I am very sure that the ATMP GMP will be adopted. I am equally sure that manufacturers and regulators will not use it

19 GMP and Other Challenges for ATMPs

20 GMP Challenges Starting Materials Variability Variability of growth media and active biological materials Poor supply chain (falsified/adulterated material) Pooling improves consistency and feasibility, but increases viral/contamination risks Viral control FBS is typically irradiated but HS/HPL is not Other VI methods UV, nanofiltration, HTST, chemical treatment can be problematic for growth media In most cases, not possible to inactivate viruses in active Management of infected donors Segregation of processing Ethics

21 GMP Challenges - Asepsis Inherently biological process Usually no sterilisation step filtration often not an option Parenteral or implantable products Immuno-compromised patients

22 GMP challenges - Characterisation Characterisation has different meaning for ATMPs than for conventional medicines Identity, purity, potency bioactivity tumourigenicity, genetic stability Assays/bioassays may not be as precise

23 GMP challenges - Processing Scale Typically very small scale production Often one patient per batch Reliability Processes are not fail safe and have relatively high incidence of failure Optimisation Focus is on successful process, not optimised process

24 GMP challenges Process Validation High variability in processes materials, manual processing, process length, bioassays, administration Applying QbD as defined within Q8,- Q10 difficult. Q11 (drug substances) and yet to be published Q12 (product lifecycle management) helping Due to high variability, can 3 batches be justified?

25 GMP challenges Process Validation

26 GMP challenges regulator findings Poor application of SOPs, deviations, validation, change control, records, etc. Poor compliance with EM, qualification, media fill design and frequency Poor segregation of responsibilities, esp. relating to release for supply Responsibility/ownership around material supply/storage Computer systems capability and CSV hospital systems Non-compliant QC analysis for release Lack of supplier qualification

27 Other challenges Ethics Harvesting of human materials for use in other humans has ethical implications. EU particularly sensitive Embryonic stem cells Skilled resources There are not enough highly skilled biologists in this field already Cost Currently, the cost of most ATMPs is prohibitive. Commercialisation is uncommon as a result Logistics centralised, decentralised, local?

28 What are the solutions?

29 What are the some of the solutions? Plant based/synthetic growth media Some promise in alleviating cost/quality issues associated with biological media NK cell lines Master cell banks can be established perpetual, consistent source of material Leveraging big pharma experience Involve suppliers and vendors in quality issues Standardisation of analysis and process Engage with interested parties on reimbursement options Embrace QbD

30 The hot solution technology & automation

31 The hot solution technology & automation

32 The future Move away from autologous/allogenic stem cell transplantation cell and gene therapy to completely replace by 2030 Increasing isolation of personnel from process Increasing focus on consistent starting materials Fully automated production facilities by 2030 Patient customised solutions to become prevalent Centralised and decentralised centres for production, rather than local