© PharmOut 2016 Advanced Therapy Medicinal Products and GMP Ashley Isbel
© PharmOut 2016
Advanced Therapy Medicinal
Products and GMP
Ashley Isbel
© PharmOut 2016
Session Overview
What are ATMPs?
The State of Regulations
GMP and Other Challenges for ATMP production
Some Solutions
The Future
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What are ATMPs?
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• Cell therapy products – introduction or re-introduction 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.
Advanced Therapy Medicinal Products are:
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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
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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.
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Why are they important?
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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
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How do you make them?
Making ATMPs is difficult and expensive
• Typical cell therapy process
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How do you make them?
Typical CAR-T/TCR-T cell therapy process
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How do you make them?
Typical gene therapy process – DNA production
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How do you make them?
Typical manual engineered tissue process
Near future automated engineered tissue process
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The State of Regulations
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The ATMP field has been active for 25-45 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)
Registered ATMPs
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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
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The Current GMPs for ATMPs
• Mostly academic organisations with resistance to GMP bureaucracy
EMA / PICS Part 1
• Challenges around the specific requirement for sterile manufacturing
Annex 1
• Helps define the GMP line
Annex 2
• Creates a big headache!
Annex 15
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The Future GMPs?
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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”
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GMP and Other Challenges for ATMPs
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GMP Challenges – Starting Materials
• Variability of growth media and ‘active’ biological materials
• Poor supply chain (falsified/adulterated material)
• Pooling – improves consistency and feasibility, but increases viral/contamination risks
Variability
• 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’
Viral control
• Segregation of processing
• Ethics
Management of infected donors
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GMP Challenges - Asepsis
Inherently biological process
Usually no sterilisation step – filtration often not an option
Parenteral or implantable products
Immuno-compromised patients
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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
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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
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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?
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GMP challenges – Process Validation
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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
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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?
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What are the solutions?
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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
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The hot solution – technology & automation
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The hot solution – technology & automation
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The future
Centralised and decentralised centres for production, rather than local
Patient customised solutions to become prevalent
Fully automated production facilities by 2030
Increasing focus on consistent starting materials
Increasing isolation of personnel from process
Move away from autologous/allogenic stem cell transplantation – cell and gene therapy to completely replace by 2030