CGMP BASIC REQUIREMENT. cGMP Basic Requirements Quality System Definitions Regulations Requirements.
cGMP Production on RFH Campus
Transcript of cGMP Production on RFH Campus
cGMP Production on RFH Campus
Dr Mark W LowdellDirector of Cellular Therapy
Royal Free HospitalUCL Medical School
London, UK
Paul O’GormanLaboratory of Cellular Therapeutics
Royal Free Hospital
How are cell therapy trials regulated?
• Pre 2004– 1995 Council of Europe begins proposals for regulation of clinical cell &
tissue therapies– 1997 UK DoH publishes CoP and voluntary accreditation scheme via MCA
(MHRA)– 1999 POG LCT accredits to voluntary scheme– cGMP not required; proposal for EU GTP standards akin to FDA
• 2004 Clinical trials directives enacted – include “substantially modifiedsomatic cells” as IMP for the first time. cGMP manufacture requiredplus MA (IMP) and Qualified Person.
• 2007 First LCT product to be deemed an IMP by MHRA
• 2009 ATMP Regulations published– Procurement of starting material regulated by HTA and requiring licence– “nonsubstantial” defined– Inclusion of HEC for one-off, non-trial products
How are cell therapy medicinalproducts regulated?
• Investigational: MA(IMP) and QP required– Clinical trials directives for conduct (GCP)
– Annex 1-13 of medicinal products directives
– ATMP regulations 2009 for manufacture (cGMP)
– HTA Quality & Safety Regulations
• Non-investigational: MA(Specials) (or HES) and QC required– Annex 1-13 of medicinal products directives
– ATMP regulations 2009 for manufacture (cGMP)
– HTA Quality & Safety Regulations
Both require full cGMP production
cGMP requirements
• cGMP production– Document control
– Staff training
– Materials qualification, control & tracking
– Equipment qualification and validation
– Environmental control & monitoring• Air borne particles (in process and at rest)
• Viable particles (settle plates, finger dabs and product testing)
• “Open” –
– A in a B background (A in C in US)
– In isolators in D background
• “Closed” – D environment
– Released products control & tracking• AR/SAR reporting
Paperwork more important than facility
How did we meet cGMP at RFH?
• New labs designed in 1999 to GTP standards in US– Grade C background– No Grade B gowning required so single stage change
• Opened in 2000• 2004 apparent that cGMP standards will be applied in UK
– Grade B background needed• Increased air volume exchange – no recirc possible• Increased differential pressures – increased fan speeds
– Grade B gowning• Stage 1 change area needed
– BUT:• cGMP gowning not compatible with human tissues (HOWIE rules)• Wash hand basin required in de-gowning area
– Facility design imperfect for minimisation of X-contamination• Process design to overcome limitations of facility design
EU vs FDA for “open” processes
EU cGMP requires ISO5 in ISO5 background (at rest) but ISO7 background in operationFDA cGMP requires ISO5 in ISO7 background at rest and in operation (effectively a “C”)
3,500,000
3,500,0002,000350,000
2,000350,00003,500
03,50003,500
5m0.5µm5m0.5µm
GradeMaximum permitted number of particles / m2 at or above size specified
A ISO5
B ISO5
C ISO7
D ISO8
At Rest In Operation
20,000
20,000
Not Defined Not Defined
How did we meet cGMP at RFH?
Stage 2Change
Class C
Stem cell and pre-IMP processing LaboratoryLab 1 - Class B
La
b2
-C
lass
B
Lab 4 - Class B
CO2 incubator
Fridge / freezer
Transfer hatch
Bench
Critical work area
(under bench)
Class II microbiological cabinetClass A
Wash hand basin
28.26m3
40.8m3
18.0m3
15.9m3
8..8m3
Lab 3 - Class B
StoreRoom
Quarantine
LockerRoom
&Stage 1Change
Class C lab
The RFH cGMP facility
Lab 2
Lab 3
Lab 4
How did we meet cGMP at RFH?
• Dual standard operation– Non-cGMP production
• Labs operated to Class B air standard BUT …• Gowning to Class C standard
– cGMP production• All labs operate to cGMP with full class B gowning
• Campaign use of Labs– Lab 1 is preparation lab for starting material
(the only lab to be used for non-cGMP work)– Lab 2 is preferred lab for short process cGMP manufacture– Lab 3 is preferred lab for mid length cGMP manufacture (2 days)– Lab 4 is the only lab for long-term cGMP manufacture (lines) and
for islet cell production (most “open” procedure currently)– No access to Lab 4 when Lab 3 is in operation and vice versa
Gowning and access
• Non-cGMP production – “A” in a “D” background
Sterile docker used to makemost processed “closed”Although some are “open”
Gowning and access
• cGMP production - “A” in a “B” background
Our first cell therapy IMP - TaNK
• Pre-clinical testing
– Regular research data repeated to GLP standards
2.01.3520.0010
0.40.286.009
2.21.4710.108
2.71.8416.707
4.42.9923.006
3.02.0224.905
2.01.3614.504
2.11.4128.903
4.02.7337.902
3.62.4525.901
x10^7/kgx10^9x10^9Donor
CD56CD56MNC STABILITY OF CTV-1 PHENOTYPETHROUGH 28 MEDIA CHANGES
0 2 4 6 8 10 120
5
10
15
20
CD2
CD3
cCD3
CD4
CD5
CD7
CD8
CD15
CD19
CD33
CD34
CD56
HLA-DR
70
80
90
100
Week
%P
OS
ITIV
E
RPMI +10%fcs XVIVO-100.0
2.5
5.0P1
P2
P3
P4
P5
P6
Comparison of CTV-1 proliferation in TC flasks (RPMI+10%FCS )with cells cultured in T-cell expansion bag in X-VIVO 10
Frozen vials of CTV-1 from same previous passage were thawed and cultured in either RPMI+10%FCS
or X-VIVO 10. Initial cell conc. for both 0.5x106/ml. Cells were split 50:50 every 48hours (except P5 were cellsfed after 72hrs)with fresh medium and cell conc. checked.
Ce
llc
ou
nt/
ml
Our first cell therapy IMP - TaNK
• Pre-clinical testing
– Regular in vitro research data repeated to GLPstandards
– No animal model (xenogeneic system inappropriate forsafety or efficacy – e.g Tegenero)
Our first cell therapy IMP - TaNK
• Pre-clinical scale-up
– Anti-CD56 selection reagent
– Immunomagnetic sorting system
Our first cell therapy IMP - TaNK
• Pre-clinical scale-up problems– Validation
• Product definition? (e.g. MSC)
• Gold Standard reference analyte?
• Validated GLP assays?
• GLP labs?
– PSF design• Starting materials are human cells and thus highly variable
• Functional assays impossible to validate to usual pharmaceuticalstandards
Our first cell therapy IMP - TaNK
• Manufacturing for phase I/II trial
– Release criteria• Lack of reference analyte
• Highly variable functional assays
• In vitro potency assays not available on thawed product
• Viability not available on thawed product
• Sterility not available on fresh product
Our first cell therapy IMP - TaNK
• Current status
– Trial commenced 10 months late
– 14 patients enrolled and 8 treated in 18 months (1 offtrial)
– No deaths in treated group
– 7/8 patients responded to treatment
– Trial closed
Grade BLab 1
Grade B corridor
Grade BLab 2
Grade BLab 3
Grade BLab 4
Male
sta
ge
1
Fem
ale
sta
ge
1
Grade DT&CD processing
&QC
CL IICL II
CL
II
CL II
CL IICL II
Gene Rx culture lab
Gene Rx preparation lab
CO
2
CO2 CO2 CO2 CO2
CO2 CO2 CO2 CO2
CO
2+
4C
+4C
CLII
CO2 CO2 CO2 CO2
+4C
CL
IIC
LII
Stage 2 change
CL
IIC
LII
Gra
de
CT
&C
Dp
rocessin
g
+4C
+4C +4C +4C
+4C
+4C
Grade C Lab
Qu
ara
nti
ne
Go
od
sS
tore
LN2CO2 CO2 CO2 CO2
Grade B -ve
Grade B -ve
AirLock
Planned cGMP facility for RFH
Conclusions
• Increasingly we will have to move to full cGMP compliance
• This is less about facilities than systems
• Process can be used to overcome inadequacies of design
• Pragmatism is the order of the day – don’t “gold plate” theregulations
• BUT ………
Sometime even the best process can’tovercome the design!!!