Q U A L I T Y A N D O P E R A T I O N S T R A C K 7 4 / 2 5 / 1 4 1 3 : 4 5 - 1 5 : 1 5
Manufacturing Cellular Products for
International Clinical Trials
Olive J Sturtevant, MHP,MT (ASCP)SBB, CQA Director of CTQA
Objectives:
To provide an overview of some of considerations and
challenges with multi-center / international clinical trials
especially for US Academic Institutions & Manufacturing
Facilities
To review some challenges with the EU PICs and API
regulations especially for a US Academic CT
manufacturers
Discuss the use of new tools to share and capture
Brief Overview of Cells Manufactured by DFCI-CMCF Product Volumes and Types
YEAR 2013 2014 Proj Bone Marrow Products 70 74 Apheresis Products 1106 1161 Cord Products 10 11 DLI Products 22 23 Total Products 1208 1268
Stem Cell Products 2013 2014 Proj
Gene Therapy-HSCT 8 17 Cancer Vaccines 230 490 Immunotherapy CAR-T cells 1 15 CD4Treg 5 15 TCRab/CD19 1 8 Viral CTL 8
other T and NK cells 4 Regenerative Med MSC 3 36 Limbal SC 4 DC 5 10 Renal 3 8 Other Other 94 105 350 720 Novel CT Totals
Difficulties Identified By European Medical Research
Councils (EMRC)
Three major issues are emerging:
Persisting differences in administrative processes and in the
interpretation of existing regulations and other processes have led to even higher levels of complexity – especially in multinational clinical trials.
Today, the sponsor of a clinical trial needs to have a very detailed
knowledge of every country’s requirements for clinical trial authorizations – from both competent authorities and ethics committees.
The sponsor has to integrate different national requirements to the
protocol and may need parallel submission in multinational trials.
Ambiguous definitions, as identical terms may be interpreted
differently from one country to another, or even within the same country.
Taken from recent work on clinical research
Eight Major Issues
Lack of knowledge of and applying legislation
regulations amongst different countries
Differing Ethic Committees /IRBs
Lack of expertise/resources across all centers
Lack of standard definition of roles and responsibilities
of investigators and sponsors
Payment for Insurance
Standard of care
Different rules for ADRx (Adverse Events)
Importation of Drug Products
Requirements & Compliance with GMPs for
Manufacturing of Advance Therapy Medicinal
Products
Moving Applications and Protocols through
Regulatory and Review Boards
FDA and EU authorities, local authorities
Gene Therapy trials – RAC (Recombinant DNA
Activities Committee)
US Academic based – Scientific Review
Committees, Biohazard, Institutional Review
Boards, Institutional Biosafety committee, etc.
Multiple Sites or One?
Clinical
Patient screening and assessments
Collections
Donor screening, assessments or testing
Manufacturing
Processing QC testing
Special release testing
Treatment
Administration of the products Assessment post infusion
Immediate and long term follow-up
Qualifying Other Sites
Develop Selection Criteria
Site Selection & Feasibility Questionnaire (SSFQ)
Send to prospective participating sites to determine if they are able to meet
DF/HCC and protocol requirements.
Review SSFQs by the DF/HCC Sponsor prior to extending protocol
participation to an external site.
A Protocol Feasibility Questionnaire(PFQ) may be used for sites
that have previously participated in a Multi-Center Protocol conducted by the same disease group and have previously completed the SSFQ for their site within the past year.
Prospective participating sites that have satellite sites that will
also be participating in the research must complete a Satellite Feasibility Questionnaire for each satellite site.
Use of a Similar Questionnaire for
Collection and Manufacturing Services
Quality Systems
Facility Master File
Facility site qualifications
Classified vs not classified space
Equipment
Personnel qualifications
Accreditations requirements
Manufacturing and testing ability
Special Requirements for
Testing and Manufacturing Services
Ability to screen and tests donors according to local
and international regulations
Use of a centralized site for some tests
Pathology and Genetic assessments
Radiological services
Similar for QC testing
Centralized specialized testing, CFUs, VCN, etc.
Centralize testing for product characterization,
Sterility, Mycoplasma, Endotoxin
PICs Pharmaceutical Inspection Co-operation Scheme (Guide to GMP for Medicinal Products)
20-Sections (Annexes)
Relevant sections to Cellular Therapy Manufacturing
Annex 1: Manufacture of Sterile Medicinal Products
Annex 2 Manufacture of Biological Medicinal Substances and Products
for Human Use
Annex 8: Sampling of Staring and Packaging Materials Annex 11: Computerized Systems
Annex 13: Manufacture of Investigational Medicinal Products
Annex 14: Manufacture of Medicinal Product Derived from Human
Blood or Plasma
Annex 15: Qualification and Validation
Annex 18: GMP Guide for Active Pharmaceutical Ingredients Annex 19: Reference and Retention Samples
Annex 20: Quality Risk Management
Annex 1: Manufacture of Sterile Medicinal Products
Facility standards - Classifications
Air – HVAC requirements
“In operation” classification may be demonstrated during
normal operations, simulated operations or during media fills as worst-case simulation is required for this.
EN ISO 14644-2 provides information on testing to demonstrate
continued compliance with the assigned cleanliness classifications.
Environmental Monitoring Aseptic Processing
Frequent monitoring methods such as settle plates, volumetric air and surface sampling (e.g. swabs and contact plates).
Results from monitoring should be considered when reviewing batch documentation for finished product release.
Surfaces and personnel should be monitored after critical operations. Additional microbiological monitoring is also required outside
production operations,
After validation of systems, cleaning and sanitization. Three media fills per person repeated every 6 months
Recommended limits for microbiological monitoring of clean areas during operation:
If alert and action limits are exceeded operating procedures should prescribe corrective action.
Annex 1 Manufacture of
Sterile Medicinal Products
Validation of aseptic processing should include a nutrient
media fill
Process simulation should mimic the actual
manufacturing steps as closely as possible
Three consecutive satisfactory simulation tests
per shift and repeated at defined intervals and
after any significant modifications to HVAC
Normally at least twice per year per shift / process /
EudraLex Rules Governing Medicinal Products in the EU Vol 4, EU Guidelines to GMP Medicinal Products for Human and Veterinary Use,
Part 1, Chapter 3 Quality Management
General 3.5 Preventing Unauthorized Entry
Premises and Equipment
Not only for manufacturing space
Manufacturing
Badge in and out
EudraLex The Rules Governing Medicinal Products in the European Union Volume 4 EU Guidelines for Good Manufacturing Practice for
Medicinal Products for Human and Veterinary Use Part 1 Chapter 3: Premises and Equipment
3.18 Storage of sufficient capacity to allow orderly
storage of various categories of materials and
products: starting and packaging materials,
intermediate, bulk and finished products, products
in quarantine released, rejected or recalled materials
Standardizing Documents
or
“Use of Per Institutional SOPs or
Controlled Procedures”
Consents and protocols
Screening tools
SOPs
Batch Records
Labels
Data repositories
CRF
What language(s) or
dialect(s)
Date format (dd/mm/yyyy)
Patient identifiers
Name / no name
Surname,
Study IDs
Site Master File
Part III of the GMP (Good Manufacturing Practice)
guidelines on the preparation of the site master file
Site master File: document describing the GMP
related activities of the manufacturer
http://ec.europa.eu/enterprise/newsroom/cf/itemd
Develop Clinical Protocol Specific Data and Safety
Monitoring Plan (DSMP)
DF/HCC Multi-Center International Data and Safety
Monitoring Plan (DSMP) template.
The DSMP should be tailored to the study and serves
as a reference for the Participating Site(s) outlining
the expectations for participating in a DF/HCC
Multi-Center Protocol.
Annex 2 - Part A. General guidance
Documentation
Biological starting materials
Auto and Donor Matched the manufactured product is a batch Full traceability (30 years)
For ATMPs, traceability requirement regarding human cells including
hematopoietic cells must comply with the principles laid down in
national legislation (In the EEA, these are Directives 2004/23/EC and 2006/86/EC)
Research and Quality Agreements between the responsible parties
should define traceability and retention periods
Production – Starting Materials
Raw Materials (e.g. cryoprotectants, feeder cells, reagents,
culture media, buffers, serum, enzymes, cytokines, growth
factors) should be clearly defined.
Source, qualifications and testing, along with source documents Qualify before use
Have process in place to reject CT product batch if QC testing of raw material fail
Identification testing of all starting materials
Compliance with the requirements appropriate to manufacturing stage
Reference: Part I and Annex 8 for biological medicinal
products and Part II for biological substances
Production – Starting Materials
(e) The transport of human tissues and cells to the manufacturing site must be controlled by a written agreement between the
responsible parties. The manufacturing sites should have documentary
evidence of adherence to the specified storage and transport conditions. (f) Continuation of traceability requirements started at tissue
establishments through to the recipient(s), and vice versa, including materials in contact with the cells or tissues, should be maintained.
(g) A technical agreement should be in place between the responsible parties (e.g. manufacturers, tissue establishment, Sponsors, MA Holder) which defines responsibilities of each party, including the RP.
Production – Starting Materials
for Gene Therapy
(a) For products consisting of viral vectors, the starting materials are the components from which the viral vector is obtained,
master virus seed or the plasmids to transfect the packaging cells and the
MCB of the packaging cell line
(b) For products consisting of plasmids, non-viral vectors and genetically modified micro-organisms other than viruses or viral vectors, the starting materials are the components used to generate the producing cell,
the plasmid, the host bacteria and the MCB of the recombinant microbial cells
(c) For genetically modified cells, the starting materials are the components used to obtain the genetically modified cells,
the starting materials to manufacture the vector and the human or animal cell
preparations.
(d) The principles of GMP apply from the bank system used to manufacture the vector or plasmid used for gene transfer
Quality Control for Release Testing
Process Control in place for Batch Certification or COA prior to
completion of final product QC tests
The procedure for batch certification and release may be carried out in
stages before and after full QC analytical test results are available:
Use of rapid microbiological tests may help
Designated review
Assessment of batch processing records,
Results from environmental monitoring (where available), Deviations from normal procedures,
Available analytical results
Training
Do you train and standardize the whole process
patient selection to infusion or just in-lab
manufacturing?
Patient selection criteria
Esoteric markers, pathology slides, radiology, etc
Collection
Processing
Infusion
Validations
How to compare performance
Product assessments
Single QC lab for all sites vs each processing
facility
All tests or just esoteric test (RCR, RCL)
Source material
Supplies/reagents/equipment
Periodic reassessments
Same or Equivalent
Supplies & Reagents
Critical Supplies / Reagents / Study drug
Equipment
QC tests / methods
CLIA approved lab
Central lab or each site
Flow Cytometry Gating strategies CFU assays
ELISA, PCR, etc Pathology
Challenges in Exporting Products to EU Countries
Multiple and varying regulations
Shipping Advance Therapy Medicinal Products
Need of a broker / Competent Authority to accept ATMP
Product on your behalf
Need to establish a process to qualify US Academic
Manufacturing Facilities as EU acceptable GMP
facilities
Communication is Vital, yet Challenging
Face to face vs WebEx
Frequency
Time zones
Language and cultural differences
Use of Centralized Documents and Clinical
Research Documents
SOPs, batch records, CRF
Measuring performance - Dashboards
e-Trial Master File documents
Inspection ready
Challenges of Shared
e-Information Systems / Data Base
Annex -11
Applications should be validated and infrastructure qualified Documented Risk Management System for both clinical and lab
based systems
Formal agreements with 3rd party providers (including in-house IT
departments)
21 CFR part 11 Compliance
Need appropriate Risk Management Patient safety and
protection of PHI
Data integrity Product quality
Cloud Technology vs Portal system
eTrial Master Files
Cloud allows academic centers as well as small and
medium businesses with technology
Working together in a collaborative space
Web-base document management systems
Document management, exchange and tracking across all
centers and groups (CRO, investigators, sponsors,
manufacturing sites, etc)
Web-base data capture systems
Outsource or not
Need for Web Based Regulatory Repository
Create a common web-based repository of
information about national laws and regulations for
performing clinical trials.
Provide a list the key information and documents;
How to start, conduct a clinical trial
How to report events
List of key contacts and links to the Internet sites of
International Collaborations for Novel CT Trials
Continue to work together setting up and managing multi-center
clinical trials is complex
Academic researchers for non-commercial purposes form a substantial
and critical role in medical research and there is an increasing need for Academic Centers to participate in / or run Multicenter Cell Therapy Clinical Trials
Rare Diseases
Personalized Medicine trials Advancement of Science
This will not be possible without national or local support and it is vital
to keep patients and general public actively involved to partner and push for national support for the advancement of these novel trials
