managing gmp, hse and hta regulations in multiproduct atmp … · 2019. 3. 27. · ucl • 2006 –...

CentreCellGeneTissueTherapeutics

UCLInstitute of Immunity & Infection

Managing GMP, HSE and HTA regulations in multiproduct ATMP manufacturingOwen Bain

AMC Technical MeetingEdinburgh2nd March 2017

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

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)

Materials store

Challenges for ATMPs

• Scientific • Socio-economic• Legal/Regulatory• Developer-related• Logistics

HTA

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

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

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.

Non substantial manipulations• Cell separation, concentration, purification• Soaking in antibiotic• Irradiation• Sterilisation• Centrifugation• Freezing• Grinding• Filtering• Cutting• Shaping

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

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

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

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

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

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

Tissue engineered products• Decellularised allogeneic cadaveric trachea

reconstituted with autologous mesenchymal stromal cells – MHRA approved clinical trial

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

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

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

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

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

Containment measures

Also measures for equipment, system of work, waste

Are these measures in place?How can derisk the process?

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)

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)

Thank you for listening

‘We do these things not because they are easy but because they are hard’