managing gmp, hse and hta regulations in multiproduct atmp … · 2019. 3. 27. · ucl • 2006 –...
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CentreCellGeneTissueTherapeutics
UCLInstitute of Immunity & Infection
Managing GMP, HSE and HTA regulations in multiproduct ATMP manufacturingOwen Bain
AMC Technical MeetingEdinburgh2nd March 2017
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Regulatory history of cell therapy at RFH -UCL
• 2006 – MHRA MA(IMP)• 2007 – first ATIMP released• 2007 – HTA Licence• 2014 – Licensed for ALL types of ATMP after facility
expansion
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Centre for Cell Gene and Tissue Therapeutics• Manufacture and process develop ATMPs
– Autologous tissue engineered products – Autologous MSC product– Allogenic genetically modified MSC cell bank– iPS derived cells– CAR-T cells– Gene therapy for blindness
(LHON)– Facilitate commercial entities
• Cell Medica (Phase III)
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Materials store
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Challenges for ATMPs
• Scientific • Socio-economic• Legal/Regulatory• Developer-related• Logistics
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HTA
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There are different types of ATMPs from a regulatory perspective
• Non medicinal– Not “substantially modified” and “homologous use”
• Directly selected anti-viral T cells using multimer reagents• Prepared and administered in a single operating procedure
• Medicinal– Investigational– Unlicensed (Special or HEC)
• Article 5– 1. A Member State may, in accordance with legislation in force and to fulfil special
needs, exclude from the provisions of this Directive medicinal products supplied in response to a bona fide unsolicited order, formulated in accordance with the specifications of an authorised health-care professional and for use by an individual patient under his direct personal responsibility.
• HEC– Advanced therapy medicinal products which are prepared on a non-routine basis
according to specific quality standards, and used within the same Member State in a hospital under the exclusive professional responsibility of a medical practitioner, in order to comply with an individual medical prescription for a custom-made product for an individual patient.
– Licensed• ChondroCelect, Provenge, Holoclar, Glybera, Strimvelis
• Borderline
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Who regulates?• Non medicinal & Borderline
– HTA• Procurement, Testing, Transport, Processing, Storage, Distribution• SAE/R associated with all above• T&CD only
• Medicinal– HTA or MHRA (T&C D vs Blood Directive)
• Procurement, Testing (donors), Transport to manufacturer• SAE/R associated with above only
– MHRA• ALL processing, Storage, Distribution, Transport to end user• SAE/R associated with manufacture and use
– Reporting dependent upon status of product
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What is not considered as ATMP?
Minimally manipulated cells and tissues for homologous use
•Regulated under EUCTD (2004/23/EC): donation, procurement, processing, storage and distribution across EU
•Eg. Pancreatic islets through digestion of pancreas.
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Non substantial manipulations• Cell separation, concentration, purification• Soaking in antibiotic• Irradiation• Sterilisation• Centrifugation• Freezing• Grinding• Filtering• Cutting• Shaping
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Substantial vs non substantial manipulations
• Tissue dissociation by enzyme digestion to single cells
• 2 enzymes – collagenase/dispase• Substantial manipulation
• Tissue dissociation by enzyme digestion
• Seperates islets from extracellular matrix
• Non-substantial manipulation
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Homologous use
• Bone marrow derived autologous CD34+ cells– For HSCT - HOMOLOGOUS– For improvement of heart function for patients with
chronic myocardial ischemia– Majority of BM cells haematopoietic progenitors– NOT same function (non-homologous)– Classified: Tissue engineered product
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The decision tree for “medicinal” vs “non-medicinal”
• Is the product going to be procured / produced and used in a single surgical procedure?– BMMC in CABG?
• Is the product going to be used homologously?– What is non-homologous?– Adipose cells for synovial fat pad regeneration?
• Is the product “substantially” modified?– Immunologically / physiologically / metabolically
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ATMP classificationAccording to 2001/83 & 1394/2007/EC
• MSC – for GvHD – Somatic cell therapy MP• MSC – for heart disease – Tissue engineered
product• CAR-T – Gene therapy MP
• Tissue engineered trachea – Combined ATMP
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Human Tissues Authority
• Human Tissue (Quality & safety for human application) Regulation 2007– Concerned with
• Procurement, testing, storage, distribution and import/export• Consent and IMD testing
• 2004/23/EC– Traceability from donor to recipient
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Procuring from sites without a licence
• Extension of our licence• All physicians have to be trained under our QMS• Ensure everything following every procedure
- Small details can be easily forgotten but is it is vital they aren’t
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Tissue engineered products• Decellularised allogeneic cadaveric trachea
reconstituted with autologous mesenchymal stromal cells – MHRA approved clinical trial
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Quality control for TEPs
Unlike any other medicinal product
How do you define potency?
2 stage manufacture
Decellularisation
BM derived MSCs
Final primary packaging is bioreactor
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GMP challenges
• Moving from academic project to GMP is TOUGH!• Personnel, Paperwork and Process• ‘High/Premium/GMP’ grade materials
– Are these suitable?– TSE assessment for materials of animal origin - FBS
• Following guidance in Annex 1 for steriles• Validation of new equipment
– IQ/OQ ok, PQ sometimes challenging
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Materials
• Need complete traceability• Increase consistency, and
lower risk of batch failure• Any change in quality profile
may impact quality of the drug product
• Materials like Foetal Bovine Serum from particular countries and certificate of suitability– Viral safety
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Reconstitution
• Not a GMP activity (Directive 2005/28/EC) – Conducted usually by a pharmacist– Involves dissolving/dispersing an IMP or;
Diluting an IMP– Gene therapy – dilution – For cellular products if reconstituting would likely
involve a cell count and so a manufacturing step
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The Genetically Modified Organisms (Contained Use) Regulations 2014Class 1 - Contained use of no or negligible risk, for which containment level 1 is appropriate to protect human health & the environment.
Class 2 - Contained use of low risk, for which containment level 2* is appropriate to protect human health and the environment.
Class 3 - Contained use of moderate risk, for which containment level 3 is appropriate to protect human health and the environment.
Class 4 - Contained use of high risk, for which containment level 4 is appropriate to protect human health and the environment.
Who decides the class?
Genetic modification safety committee – risk assessment- If in a hospital this may already be set up
* Becomes confusing when HSE regs for blood products require CL2 aswell, butsome differences
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Containment measures
Also measures for equipment, system of work, waste
Are these measures in place?How can derisk the process?
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Control of substances hazardous to health (COSHH) 2002
If manufacturing from a blood product, apheresis etc.
- Could be considered biological agent –hazard class II (Can cause human disease and may be hazard to employees, but usually effective prophylaxis available)
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More than just the ‘a couple’ of regulations
• Always keep up to date• New regulations around the corner
• Clinical Trials regulation (536/2014)• GMP for ATMPs/IMPs
• Brexit implications• Risk assess (ICH Q9)
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Thank you for listening
‘We do these things not because they are easy but because they are hard’