Managing out the risks in existing facilities

Sue Swift PhD, FRSB

UCL Great Ormond Street Institute of Child Health

(London, UK)

The plan

Introduction to our situation and products

How it started and developed

Regulation

Current situation

Risks and mitigation

Summary

Where, what and who

UCL Great Ormond Street Institute of Child Health

GOSH was founded in 1852, was the first hospital in the UK to offer dedicated inpatient care to children. It is a tertiary referral hospital so has many children with rare or treatment resistant diseases

UCL was founded in 1826 to open up higher education in England to those who had been excluded from it and in 1878 admitted women students on equal terms with men.

How we started – staff and premises

• Adrian Thrasher• Bobby Gaspar• Waseem Qasim

• Kate Parsley• Kimberly Gilmour

GTL-CBL built 2001

How we started – patients and products

• The first study from 2001 to 2007 treated 11 Xl-SCID patients for 6 years (1-3/yr)

• Successful development of immune system but some developed leukaemia (4/9 France,1/11 UK)

• More research to improve safety – SIN and lentiviral vectors

• Other products developed based on experience – ADA-SCID, GCD

Boy in bubble

SCID – severe combined immunodeficiency –defective gamma chain of interleukins especially IL2 so no T cell expansion in response to infection or viral challenge

Regulation and licensing

• Clinical trials Directive 2001/20/EC (2004)

• Advanced Therapies Regulation (EC) 1394/2007

• Gene and cell therapies were medicines and had to be manufactured to GMP under licence

• External audit

– Already had employed a clinical trials person

– Employ a QA person

– Establishing a quality system

– Better links with GOSH Pharmacy

– Applying for a manufacturing licence

• Manufacture was infrequent during this period

Working towards licensing• Needed a space for new facilities and the money to build them before we had any

chance of getting a licence

– Located an unused cleanroom facility

– Secured funding from GOSHCC

– Contracted builders

• Modified existing facility

– Tiny office and single change so left shoes outside in corridor

– Nowhere to remove outer clothing so used head to toe grade B clothing to cover ‘outdoor’ clothes

• Strictly controlled access

• Cleaning by contract cleaners and operators

• Validated air quality - grade B (in use)

• Small office and no preparation room

so -80oC freezer, fridge and large centrifuge

(all generating particles) located in aseptic room

Pragmatic approach from MHRA

• Approval to continue manufacturing until new facility ready

• Reviewed new facility plans

• Inspection after IQ/OQ to allow scale-ups and first few production runs

• MIA (IMP) Licence variation for manufacture obtained in 2010

• MS licence variation for gene and cell therapies obtained in 2012

Ian Rees and Elaine Godfrey

What we have now

Two aseptic facilities

• Old (GTL-CBL) office, change, aseptic room containing 1 +pressure isolator, 3 incubators, large centrifuge, fridge, -80oC freezer, ClinicMacs, Wave, Cobe2991, MPC, microscope

• New (GTL-OBW) office, double change, prep room containing large centrifuge, fridge, -80oC freezer, aseptic room containing 2 negative pressure isolators, 4 incubators, Wave, Prodigy, microscope

• Close proximity to room containing controlled rate freezer, LN2v storage and cryoshippers

• Monitoring systems (CO2, temperature, humidity, airflow, particles)

• Good oversight by Pharmacy QA/QP + 2 externals QPs

Layouts

Office

ChangeHatch

Class II

Biosafety

Cabinet

Incubators

2x stacked

Isolator

Bench

Flametamer

Materials

under

bench

Plasmatherm

Sealer

CliniMacs

Cytomate

Microscope

f

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g

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f

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e

z

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Centrifuge

EquipmentValidation maintenance, calibration

Disposables

Documentation

Part of the GOSH Pharmacy PQS with oversight by on-site QA/QP Deviations/exceptionsChange ControlsRisk AssessmentCAPA for self inspections, audits, inspections

Batch Folders:Agreements, approvals, RAsdossier, management plan, labelsraw materials, BMR, results, QP checks and reviews, BRC, CoA, TSE

Clinical Trial Folders

Pharmacy Folders

Qualified Persons (IMPs)(1 + 2)

GOSH PHARMACYChief Pharmacist

(MIA(IMP)17328 and MS 17328 licence holder)

ICH-MCI RESEARCHConsultant in Paediatric

Immunology

Gene and Cell Therapies Steering Group

Clinical Trials Project Managers

(3 specialists + external)

GOSH/ICH R&DContracts, agreements,

monitoring, research governance

Transduced CD34 cells

Transduced T cells

infectious

Transduced Skin sheets

Cellular Therapies Production Manager

Principal Investigators (6)

CTL - Bone Marrow Processing Selection, Freezing, Storage

(5)

Immunology-ICH-MCI Patient and Product Monitoring

Assays (2 specialists + outsourcing)

Cellular Therapies QA Officer

GOSH IMMUNOLOGYConsultant Immunologist HTA

11026 licence holderPrincipal Clinical Scientist

Great Ormond Street Hospital for Children NHS Foundation Trust

GOSH Pharmacy QAQA and Development Manager

QA staff

Transduced CAR T cells

Lab maintenance, stocks, preparation, staff training, DNA

extraction, QA/C (5)

Transduced CD34 cells infectious

Transduced fibroblasts

Transduced T cells

Tissue decellularisation

Modified donor cells

Definitions of multi-product manufacture and campaigned working

Eudralex Volume 4 (GMP) annex 2 Manufacture of Biological active substances and Medicinal Products for Human Use

Definitions:

• Multiproduct facility – A facility that manufactures, either concurrently or in a campaign mode, a range of different biological medicinal substances and products and within which equipment train(s) may or may not be dedicated to specific substances or products.

• Campaigned working – The manufacture of a series of batches of the same product in sequence in a given period of time followed by strict adherence to accepted control measures before transfer to another product. The products are not run at the same time but may be run on the same equipment.

• Batch - For autologous and donor-matched situations, the manufactured product should be viewed as a batch.

Interpretation of the rules as relate to our small scale, phase I/II cutting edge

advanced therapy product manufacture

We manufacture a range of products so are a multi-product facility

Manufacture has open and closed phases

Open phases are done one at a time – campaigned working in isolators

Closed phases run concurrently – incubators or bioreactors

Multi-product manufacturing

Manufacture activity currently includes:

• GMO, non-GMO

• IMPs and Specials

• Scale-ups (full size pre-clinical run)

• Patient-specific and non patient specific

• Virally and/or microbiologically infected starting cells

• Manufacture duration of 3 days to 8 weeks

• Non manufacturing activities - staff validations, engineer visits, monitoring, cleaning

• Open processing – thymus, skin

• Semi-closed processing – CD34 transduction, T cell selection, transduction and editing

• Closed processing – in development especially for CAR T cells

• Continual changes in planned dates and availabilities due to numerous teams involved

• Restricted days available for receiving cells or administering drug product

• Frequent changes of timing due to patient status as often very ill

Multi-use (sessional)of both Gene Therapy facilities in 2015

0

5

10

15

20

25

30

35

1 2 3 4 5 6 7 8 9 10 11 12

Med Prods

QC

Cancelled

Scale-ups

Broth run

Engineer

Other

Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec

Perceived risks and mitigation

GMO, non-GMO

• Project and GMO risk assessments are approved for all products manufactured

• We aim to understand the product, the type of vector, potential interactions

• Always a specialist scientist and academic clinician involved in planning

IMPs, Specials and scale-ups (full size pre-clinical run)

• These are very similar in manufacture/GMP terms

• Any issues relating to incomplete testing, changes are recorded and risk assessed

• Training is a key element so experienced GMP people are matched to new staff

Patient-specific and non patient specific

• Confusion between products is avoided by use of dedicated incubators and staff

• Detailed and checked documentation and labelling

• Cross contamination is avoided by dedicated sessions for manipulations

More perceived risks and mitigation

Infected starting cells (viruses and/or microbes)

• Cross-contamination avoided by single use of facility

• Containment level and risk to staff

• Use of antibiotics (avoid low level infection)

• Impact or risk/benefit for patient

• Autologous/allogeneic/non patient specific

• HIV infected cells and lentiviral vectors

Manufacture duration of 3 days to 8 weeks

• Risk of contamination expected to increase with duration of process

• Non-routine nature of the work makes staff very careful

• An appreciation of the patients involved makes staff extremely vigilant

Non-manufacturing activities - staff validations, engineer visits

• Supervision of broth runs by staff in different teams

• Supervision of engineers in with Haz-tab cleans afterwards

And even more perceived risks and mitigation

Open processing • For tissue as starting material (e.g. thymus, skin)• Microbiological contamination difficult to avoid• Consider use of antibiotics for a short period

Semi-closed processing• Validation in progress (e.g. cell selection processes) • Cost of validation is high due to cell numbers and tubing sets• Still need a clean room with grade A area

Closed processing• Not totally closed at present• Validation required (high cost)• Integrity testing on disposable tubing sets

Other considerations

Raw Materials• QC check/approvals linked to use• Aliquots with sterility testing or direct from manufacturer• Dedicated use per production run• Bulk materials stored off-site with back-up and tracking

Equipment • Availability (diary planning, pre-production checklist)• Clean before and after use• Incubator and HPV decontamination• Monitoring and back-up

Spillage and Waste • Cleaning schedule (daily, weekly, pre and post production)• Instructions for spillage in manufacturing facility, transport and administration site• Bagged and autoclaved before disposal

Campaign(ed) working

• Incubators or bioreactors dedicated to a single product

• Only one product is manipulated/handled in any one session

• Clear instructions on what processes can/cannot run concurrently

• Line clearance and cleaning including biocide of isolators between sessions

• Full decontamination of incubators between product incubation

• HPV decontamination where virology is positive or in doubt

• Cleaning of centrifuges between sessions

• Separate teams per product or full change of clothing between sessions

• Restricted smart-card access

Challenges

Diary planning• Continual changes in dates and availabilities due to numerous teams involved• Restricted days available for receiving cells or administering drug product• Frequent changes of timing due to patient status as often very ill

Staffing • Staff from different teams available for every manufacture run • Variable duration and processing stages with concurrent manufacture • Availability of staff for all aspects of the process

Pharmaceutical Quality System• Maintaining a robust system with few staff and non-routine manufacture runs

• 15 IMP and special products manufactured, 0 contaminated

• 23 scale-ups completed, 1 contaminated

• 3 Grade A micro OOSEs

• Very low environmental monitoring micro OOSEs

• High pass rates for personnel validations

• No more DP related leukaemias (safer vectors)

• No known activation of HIV infection with lenti-viral vectors

Contamination rate in 2015

Summary

• Due to our unique position of being physically linked to a tertiary referral children’s hospital and a focussed academic research group we have developed a key role in clinical translation of gene and cell therapies

• Research is resulting in many new products with potential life saving activity

• Many of the diseases we treat are rare so there may be only one patient per year for any specific clinical trial

• Dedicated facilities for such products is not appropriate in terms of cost and effort

• Multi-product manufacture is possible with strict adherence to GXP and the added benefit of interactive expertise and experience

• We have an extensive risk management approach to avoid the pitfalls and potential errors caused by our cutting edge translational activities

• The model traditionally applied to Pharma for manufacture of medicines does not easily fit small innovative units such as ourselves