operation of a pilot plant for clinical lots of ...operation of a pilot plant for clinical lots of...
TRANSCRIPT
Operation of a pilot plant for clinical lots of biopharmaceuticals
Neophytos Papamichael, PhD
Quality Assurance GMP | Braunschweig
Workshop “Biopharmaceutical process development and regulatory issues”
Universidade Federal do Rio de Janeiro,
6th.-7th. August 2009
Operation of a pilot plant for clinical lots of biopharmaceuticals
Contents
• Introduction to the Fraunhofer ITEM and Division
• GMP pilot plants
• Quality system requirements in a development environment
• Project development overview and examples
• Outlook
Operation of a pilot plant for clinical lots of biopharmaceuticals
Introduction
Operation of a pilot plant for clinical lots of biopharmaceuticals
Fraunhofer Institute for Toxicology and Experimental MedicineHannover, Germany, www.item.fraunhofer.de
The institute in figures (2008):
Founded 1981
Employees 246
Institute budget € 22 million
(Industrial funding 50%)
Laboratory/office space approx. 7,500 m²
Fraunhofer Institute for Toxicology and Experimental Medicine | Pharmaceutical Biotechnology Division, Braunschweig SiteBraunschweig, Germany, www.item.fraunhofer.de
The division in figures (2008):
Transfer to ITEM 2008
Employees 40
Budget 2008-2013 € 27 million
(Payroll/Investment/Building)
GMP plants 3
Operation of a pilot plant for clinical lots of biopharmaceuticals
Campus of
Operation of a pilot plant for clinical lots of biopharmaceuticals
AachenSchmallenberg
Hannover
St. Ingbert
Stuttgart
Leipzig
Golm
Freising
Fraunhofer Life Sciences Group
IBMT (Biomedical Engineering)IGB (Interfacial Engineering and Biotechnology)IME (Molecular Biology and Applied Ecology)ITEM (Toxicology and Experimental Medicine)IZI (Cell Therapy and Immunology)IVV (Process Engineering and Packaging)
ITEM embedded in and chairs the Fraunhofer Life Sciences Group
Operation of a pilot plant for clinical lots of biopharmaceuticals
•Screening-assay for antimycoticsubstances
•Databases (gene expression profiles)
•DNA-arrays (breast cancer, pathogenic fungi)
•2-D-DNA-gel-electrophoresis for universal differential transcription analysis
•Cartridge for protein and nucleic acid isolation using magnetic beads
•Vascular model demonstrating blood vessel flow characteristics •Demonstration of 3 separate brain models for stroke cell therapy
•Pulsatile bioreactor for physiological in-vitro-cultivation of 3D-tissues
•3D-skin model
•Cell therapy
•Clinical trials phases I and II: asthma, allergic rhinitis, COPD
•Segmental lung application
•Development of API manufacturing processes
•GMP manufacturing of APIs and drugs for clinical trials
ITEM embedded in and chairs the Fraunhofer Life Sciences Group:
Operation of a pilot plant for clinical lots of biopharmaceuticals
•Founded 1966as GMBF•Natural products•Strong engineeringBiochemical Engineering Division
•1995: Shift towards molecular biology•Establishment of GMP unit
•2001: Shift focus to infection research
•2006: Name change to reflect research focus
•1.1.2008: Transfer to
National research centre for biochemical engineering
Pharmaceutical Biotechnology Division
Operation of a pilot plant for clinical lots of biopharmaceuticals
Client types:
• Academic institutions (1990’s) – starting development of biopharmaceuticals (very early entry in product life cycle, poor understanding of costs involved and effort required)
• Small biotech startups (1990’s) – needed access to scale-up and clean room facilities
• Biotech bubble bursts 2001! Financing became difficult.
• Generic manufacturers (2000-2006) - seeking market potential in off-patent biologicals (biogenerics, biosimilars)
• Virtual biotech companies (2004-now) – require complete product development after drug discovery (small scale, pilot scale, transfer to GMP production)
Operation of a pilot plant for clinical lots of biopharmaceuticals
Pharmaceutical Biotechnology Division – bridging the gap in the FhG ITEM GXP Platform...
Processdevelopment /
GMPmanufacturing
GCPclinical trials phases I/II
GLPpre-clinical development
GXP
Operation of a pilot plant for clinical lots of biopharmaceuticals
Pharmaceutical Biotechnology Division - Scope of operation:
• GMP-Cell banking (MCB/WCB generation and storage in LN2 atmosphere)
• Culture medium development and optimisation• API manufacturing process development (USP, DSP)• Process validation studies• Cleaning validation studies• Analytical procedure development and validation to ICH guidelines• Stability studies for purified bulk and intermediates• Non-GMP (pre-clinical) and GMP manufacturing of APIs• GMP-manufacturing of final dosage forms for clinical trials
(individual therapy; future expansion to ampoules, vials and small bottles to 50 ml planned)
• Consultancy services including mock auditing
• Pharmaceutical documentation (development reports, validation reports, master batch production and control records, …)
Operation of a pilot plant for clinical lots of biopharmaceuticals
GMP pilot plants
Operation of a pilot plant for clinical lots of biopharmaceuticals
GMP-Pilot Plants .• GMP I: 460 m², operative 1997 (microbial fermentation, animal cell culture,
purification)
• GMP II: 930 m², operative 2008 (microbial fermentation, animal cell culture, purification, cell banking). Planned extension of GMP II to include aseptic Fill & Finish (vials and ampoules; capacity 60 min-1; online 2010/2011)
• GMP III: 130 m², operative 2001 (cell banking)
• Aseptic Fill & Finish (Hannover) : 100 m² (small scale supply of clinical trial drugs; in process of qualification/validation, application for manufacturing authorisation 2009)
Non-GMP facilities .• Microbial cell culture pilot plant (200 l fermentation)• Animal cell culture pilot plant (70 L bioreactor)• Downstream processing development labs• Analytical labs• Support areas (central autoclaves, cold storage, etc.)
Operation of a pilot plant for clinical lots of biopharmaceuticals
558 m² total area225 m² clean area
Facility GMP II in building Y (1) Basement
BL2 / class C(10 000)
• Microbial Cultivation• Cell Culture• Primary Separation
(centrifugation, homogenisation, micro- and ultrafiltration, depth filtration)
• In-process control lab
BL2 / class D(100 000)
Operation of a pilot plant for clinical lots of biopharmaceuticals
• Media preparation• Cleaning• Purification
(ultrafiltration, chromatography, etc.)
• Cold room processingand storage
376 m² total area342 m² clean area
Facility GMP II in building Y (2) Upper floor
BL2 / EU class C(10 000)
BL2 / EU class D(100 000)
Operation of a pilot plant for clinical lots of biopharmaceuticals
• Multi-use facilities, campaign production
• Easy to clean surfaces (powder-coated steel, stainless steel walls and ceilings, silicone sealed; monolithic pharmaterazzo floor; flush-fitted windows and light units)
• Free space around process equipment affording easy access and cleaning
• Rear-side of cabinets silicone sealed to prevent dust collection
• Highly automated process equipment (low manpower requirements, low human error rate, closed systems)
• Central waste disposal system (automated, coordinated with central CIP system; process streams, floor drains)
Facility design (GMP II):
Operation of a pilot plant for clinical lots of biopharmaceuticals
• 6 air systems:
- Central fresh air supply
- 3 recirculated systems (basement, upper floor class D, upper floor class C)
- Central exhaust air system (filtered for BL2)
- Cold room air recirculation and supply
• 3 level air filtration (F6, F9 and EU13 final HEPA filters)
• Temperature and humidity control
Air handling systems in the GMP II facility:
Operation of a pilot plant for clinical lots of biopharmaceuticals
• Central water supply of deionised water
• Production of purified water by reverse osmosis (approx. 300 kg/h; 3000 l holding vessel; supply ring)
• Production of 1100 kg/h clean steam from deionised water
• Production of WFI from clean steam (approx. 100 kg/h; held at 80°C; 1000 l holding vessel; supply ring)
Water types in the GMP II facility:
Operation of a pilot plant for clinical lots of biopharmaceuticals
• Central Clean-In-Place system (configurable: cleaning agent concentration, temperature, duration, rinse water types [deionised, AP, WFI], optional drying with heated air; ring system supplies all major process equipment)
• GMP grade washer for small articles (stainless steel, glass, plastics; configurable)
• Mobile Clean-In-Place system for other equipment (configurable)
• Central waste disposal system (automated, coordinated with CIP system)
Cleaning process equipment in the GMP II facility:
Operation of a pilot plant for clinical lots of biopharmaceuticals
• Clean room monitoring
- Airborne particulates
- Microbial level (airborne, surfaces)
- Differential pressures
- Temperatures
• Storage
- Refrigerator, freezer temperatures
- Liquid nitrogen tanks (limit alarms)
- Cold room temperatures
• Water quality (cf. European Pharmacopoeia)
- Conductivity
- Microbial contaminants incl. identification of organisms to genus / species level
- Endotoxin
- TOC
- Nitrates
- Heavy metals
Monitoring:
Operation of a pilot plant for clinical lots of biopharmaceuticals
GMP II: Pilot Plant for Production of Biopharmaceuticals for Clinical TrialsBasementBasement: : CultivationCultivation and and primaryprimary separationseparation
65 L Bioreactor, 500 L Bioreactor
Operation of a pilot plant for clinical lots of biopharmaceuticals
GMP II: Pilot Plant for Production of Biopharmaceuticals for Clinical TrialsBasementBasement: : CultivationCultivation and and primaryprimary separationseparation
Disk Stack Separator
Operation of a pilot plant for clinical lots of biopharmaceuticals
GMP II: Pilot Plant for Production of Biopharmaceuticals for Clinical TrialsBasementBasement: : CultivationCultivation and and primaryprimary separationseparation
Homogeniser
Operation of a pilot plant for clinical lots of biopharmaceuticals
GMP II: Pilot Plant for Production of Biopharmaceuticals for Clinical TrialsUpper floor: Purification
BioProcess Chromatographysystem
Operation of a pilot plant for clinical lots of biopharmaceuticals
GMP II: Pilot Plant for Production of Biopharmaceuticals for Clinical TrialsUpper floor: Infrastructure
GMP-grade Washer
Operation of a pilot plant for clinical lots of biopharmaceuticals
GMP II: Pilot Plant for Production of Biopharmaceuticals for Clinical TrialsUpper floor: Infrastructure
Chamber Autoclave
Operation of a pilot plant for clinical lots of biopharmaceuticals
GMP II: Pilot Plant for Production of Biopharmaceuticals for Clinical TrialsBasement: Infrastructure
Clean Steam, Purified Water,
Water for Injection
Operation of a pilot plant for clinical lots of biopharmaceuticals
The new aseptic fill & finish unit in Hannover
80 m² clean rooms EU classes D / C / B; class A processing
Approval: Q4/2009 ( scheduled)
Suite 1
Suite 2
D
CB
Operation of a pilot plant for clinical lots of biopharmaceuticals
Quality system requirements
in a development environment
Operation of a pilot plant for clinical lots of biopharmaceuticals
Quality Assurance during Development
Annex 13 of the EU GMP-Guideline states:
• Investigational medicinal products should be produced in accordance with the GMP Guidelines
• Other EU Guidelines should be taken into account where relevant and as appropriate to the stage of development of the product
• The application of GMP is intended to ensure that trial subjects are not placed at risk, and that the results of clinical trials are unaffected by inadequate safety, quality or efficacy arising from unsatisfactory manufacture
Operation of a pilot plant for clinical lots of biopharmaceuticals
Quality Assurance during Development
Annex 13 of the EU GMP-Guideline states:
• Production processes for investigational medicinal products are not expected to be validated to the extent necessary for routine production but
- premises and equipment are expected to be validated
- for sterile products, the validation of sterilising processes should be of the same standard as for products authorised for marketing
- when required, virus inactivation/removal and that of other impurities of biological origin should be demonstrated
Operation of a pilot plant for clinical lots of biopharmaceuticals
EU Regulations
• Directive 2003/94/EG
• EU GMP Guideline (Parts 1 and 2) and Annexes
• EU Points to Consider documents
• European Pharmacopoeia
International
• ICH Guidelines
• CFR / FDA Guidelines
• USP
• PIC/S
German Laws and Regulations
• Drug Act (AMG)
• Drug and API Manufacturing Ordinance (AMWHV)
• German Pharmacopoeia
Operation of a pilot plant for clinical lots of biopharmaceuticals
Inspections
• Local competent authority (in Lower Saxony / Germany this is the StaatlichesGewerbeaufsichtsamt = State Trade and Industrial Inspectorate)
• For certain products (e.g. vaccines, sera, blood products) higher competent authority is the Paul Ehrlich Institute
• For all other products higher competent authority is the Federal Institute for Drugs and Medical Devices
• Inspection by EMEA is required for the central authorisation procedure (to date does not affect us)
Manufacturing authorisation
• Issued by local competent authority
• Novel products will require renewed inspection
• Similar products require notification and documentation
• Original manufacturing license (GMP 1)1999
• Last inspection 2008 with extension of license to GMP 2
• Original manufacturing license (GMP 1)1999
• Last inspection 2008 with extension of license to GMP 2
Operation of a pilot plant for clinical lots of biopharmaceuticals
For products going into clinical trials:
• Investigative Medicinal Product Dossier (IMPD) required (Directive 2001/20/EG).
• GMP requirements apply to all clinical trial phases, but degree and scope of application reflect clinical trial phase
• Examples:
- Cleaning validation not required before Phase III material produced
- Analytical method validation requires
- Validation lots (infamous 3 lots!) required at end of Phase III development
In view of introduction of ICH Q8, Q9, Q10 in EU regulations and the FDA GMPs for the 21st century initiative including the newly updated guideline on validation, this will most probably no longer apply
Division of Pharmaceutical Biotechnology
Operation of a pilot plant for clinical lots of biopharmaceuticals
Head of InstituteProf. Uwe Heinrich
Up-StreamProcessing (microbial)
Dr. Anton Roß
Up-Stream Processing (cell culture)
Dr. S. Duvar / Dr. V. Hecht
Down-Stream ProcessingDr. Jens Paulsen
Quality AssuranceDr. Neophytos Papamichael
Head of DivisionDr. Holger Ziehr
Quality ControlDr. Luma Baydoun
Divisional Organisational Chart / FhG ITEM, Braunschweig Site
Fill & FinishDr. Holger Ziehr
Operation of a pilot plant for clinical lots of biopharmaceuticals
Head of InstituteProf. Uwe Heinrich
Head of ProductionDr. Anton Roß
Head of QCDr. Luma Baydoun
Qualified PersonsDr. Holger Ziehr
Dr. Luma Baydoun
Quality AssuranceDr. Neophytos Papamichael
GMP Organisational Chart / FhG ITEM, Braunschweig Site
Operation of a pilot plant for clinical lots of biopharmaceuticals
Materials Management
• Qualification of vendors
• Testing of materials:
- Raw materials (chemicals, cell substrates [microorganisms / mammalian cells], media; water, steam, gases)
- Process aids with direct / indirect contact with product or critical for correct operation (filters, tubing, chromatography materials)
- Intermediates / product
Released storageRejected storage
Quarantine storage
Operation of a pilot plant for clinical lots of biopharmaceuticals
Quarantine label
Quarantine label
OrderOrder
AnalysisAnalysis
SpecificationSpecification
Supplier
Goods Receipt (QC)Sampling
Goods Receipt (QC)Sampling
Quarantine label
Release label
ReleaseReleaseRejectReject
Materials management
Material transfered to production
area(unopened)
Material used(partially)
Unusedmaterial
destroyed orused in R&D
Operation of a pilot plant for clinical lots of biopharmaceuticals
CAPA SystemCAPA System
Investigation /Final Assessment /
Definition of Actions
CAPA close-out(Documentationand execution
checks)
MaßnahmenauftragMaßnahmenauftragAction disposition
Execution
Deviation Change
Internalinspections
Supplierqualification
OOX
Critical /major
External auditsAction tracking
Qualification /Validation
Production
Other events
Initial Assessment / Definition of Actions
Minor
CAPA: Deviations / Changes / Inspections management
• No Product Quality Review
• Integrated handling
Operation of a pilot plant for clinical lots of biopharmaceuticals
• Qualification and Validation: Major equipment qualification based on risk analysis according to FMEA method (DQ, IQ, OQ, in certain cases PQ). Most important as system components:
- Air handling
- Water and clean steam systems
- Autoclaves
- CIP-System and GMP washer
- T-controlled areas (refrigerators, cold rooms, freezers, liquid nitrogen storage)
• Cleaning verification, validation at Phase III
• Process validation: Validation studies on filtration, virus and endotoxin removal, media fills; reproducibility and consistency; stability
Operation of a pilot plant for clinical lots of biopharmaceuticals
Project development overview and examples
Operation of a pilot plant for clinical lots of biopharmaceuticals
GMP phase of product development is like the tip of an iceberg…
early product development requires more resources in time and manpower!
Operation of a pilot plant for clinical lots of biopharmaceuticals
Costs and time requirements of a “typical” GMP project
Resource requirements
0
5
10
15
20
25
30
35
40
45
Lab scale Scale-up Non-GMP manuf. GMP manuf.
[%]
Project phases
123 6 9 150
Duration (months)
Process development: lab scale
Process development:pilot scale
Non-GMPmanufact.
API-GMPmanufact.
Total approx. 100 – 150 FTE-months per project
Includes analytical development
Transfer and adaptation, e.g. centrifugation steps
Production of reference and non-clinical test substance (PharmTox), product characterisation; initial validation of
analytical methods; initial stability tests
Includes qualification of external laboratories, final validation of analytical
methods
but “typical” is quite variable! Projects can last a few months to
several years
but “typical” is quite variable! Projects can last a few months to
several years
9. Solubilisation
10. Centrifugation
11. Diafiltration
12. Protein chain mix
13. Co-Refolding
14. Depth filtration
15. Concentration/Diafiltration
16. Lactosyl Sepharose
17. Endotoxin reduction
18. Diafiltration
19. Filling
rMLA Inclusion Bodies
9. Solubiisation
10. Centrifugation
11. Diafiltration
rMLB Inclusion Bodies
Operation of a pilot plant for clinical lots of biopharmaceuticals
Project example 1: mistletoe lectin (Aviscumin)
The process at a glance:
• Total of 19 unit operations• Step 1- 8: cultivation, harvesting , cell
disintegration, inclusion body preparation• Step 9-18 purification• E. coli BL 21• 2 x 150 L bioreactor (A-chain, B-chain)• Batch process, IPTG-induction• Batch size: >2 g (API)• Status: API in clinical trials
Operation of a pilot plant for clinical lots of biopharmaceuticals
Project example 2: Erythropoietin (EPO)
The process at a glance:
• 16 Unit operations• Step 1- 8: cultivation, harvesting,
microfiltration ultrafiltration• CHO• 5 L bioreactor →150 L bioreactor• perfusion process• 9 purification steps• Batch size: > 2g• Status: approved
Depth filtration
Blue Sepharose chromatography
Diafiltration
Q Sepharose chromatography
Filtration
Reversed phase chromatography
MacroPrep HighS chromatography
Ultrafiltration
Superdex chromatography
Filtration
Viral removal (filtration)
Filling
2.5 l perfused concentrate
Operation of a pilot plant for clinical lots of biopharmaceuticals
Project example 3: DNA / plasmids
The process at a glance:
• 16 Unit operations• Step 1- 4: cultivation, harvesting• E. coli• 150 L bioreactor• batch process• 12 purification steps• Status: clinical trials• Batch size > 1g purified plasmid
Generic API manufacturing process
E. Coli / plasmid cell mass
Resuspension
Alkali lysis
Na acetate Precipitation
Centrifugation
Concentration
CaCl Precipitation
Centrifugation
Diafiltration
Phenyl Sepharose chromatography
Q Sepharose chromatography
UF concentration
Sterile filtration
Operation of a pilot plant for clinical lots of biopharmaceuticals
Project example 4: Bacteriophages MCB Phage stock
Inoculum
Phage lysate
Incubation
Lysis culture
Depth filtration
Sterile filtration
Medium
Sterile filtration• Synthetic Medium: no TSE / BSE risk• Disposables / dedicated use, WAVE®
bioreactor (20l)
• Sterile filtered intermediate / phage lysate
• Reduction of MOI -> increase in phage titer
Operation of a pilot plant for clinical lots of biopharmaceuticals
Project example 4: Bacteriophages Lysate
Ultrafiltration
Bulk - API
Ion exchangechromatography
Size exclusionchromatogaphy
Sterile filtration
Benzonase
330 ± 7,5 nm330 ± 7,5 nm
94 ± 3,0 nm94 ± 3,0 nm (Head)
(Tail)
Operation of a pilot plant for clinical lots of biopharmaceuticals
Clients 1997 - 2009
MediGene AGMunich/Martinsried
Germany
Unilever Biotechnology Application Centre BVBussum
The Netherlands
Dompé Farmaceutici s.p.a.MilanItaly
B.R.A.I.N. GmbHZwingenberg
GermanyMadaus AG
CologneGermany
Fermentas ABVilnius
Lithuania
ZMBHHeidelbergGermany
Mologen AGBerlin
Germany
Viscum AG Zwingenberg
Germany
BiogeneriX AGMannheimGermany
Bioceuticals Arzneimittel AGBad VilbelGermany
Hexal Biotech ForschungsGmbHHolzkirchen
Germany
F. Hoffmann La-Roche Ltd.Basel
Switzerland
PolyPhag
PolyPhag GmbHViersen
Germany
Operation of a pilot plant for clinical lots of biopharmaceuticals
Outlook
Operation of a pilot plant for clinical lots of biopharmaceuticals
Fraunhofer ITEM objectives:
• Single-stop partner for development, production, pre-clinical and clinical testing of (respiratory) medical products
• Optimisation of microbial fermentation and mammalian cell culture as primary manufacturing routes, efficient downstream processing
• Production of APIs and final dosage forms for clinical trials tointernationally recognised GMP quality levels
• Standardisation of production vehicles – antibody/antibody fragments and DNA/plasmid production platforms for speedy first in human trials
• Consultancy services in GXP
Operation of a pilot plant for clinical lots of biopharmaceuticals
Thank you
for your attention