Raw Materials: Sourcing and Qualification Testing

Transcription

1 Raw Materials: Sourcing and Qualification Testing Scott R. Burger, MD Advanced Cell & Gene Therapy Technical Applications Track 2 ISCT 2009

2 Sourcing Raw Materials Raw materials for cell/gene therapy manufacturing are often complex, specialized or unique. May require searching beyond conventional reagent manufacturers May require custom manufacture Some aren t quite materials, either Confirm specifications of novel or unusual materials needed, before starting the search. Human serum (AB, autologous) Fetal calf serum, horse serum Monoclonal Abs, recombinant vectors G-CSF, GM-CSF, EPO, TPO, IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-6, IL-7, IL-8, TNF-α, PG-E 2, SCF, FL, Flt3, VEGF, BMP-4, EGF, IGF, PDGF-BB, MIP-1α, MCP-1, TGF-β1, afgf, bfgf N-desulfated O-sulfated heparin J Immunol Methods 2001

3 Quality and Documentation FDA-approved, clinical-grade if possible. Otherwise, highest quality obtainable, and further testing to qualify. Even if FDA-approved, may need additional testing. Testing per approval may not support cell therapy raw material. Composition, specifications - may cross-reference Master File Certificate of Analysis (COA) Packaging, Volumes, Stability Country of origin Closed-system bags often preferable. If using bottles or vials, note closure and access method. Unit volumes appropriate for intended use? Stability, storage requirements suitable for inventory plans?

4 Animal-Derived Materials Avoid if possible. Explore recombinant or non-animalderived alternatives. Bovine serum, porcine trypsin, other enzymes, collagen Establish freedom from species-specific viruses. Other precautions - closed herds, specific countries of origin Requirements for ingredients of animal origin used for production of biologics (9 CFR ) Bovine-derived materials - potential risk of transmissible spongiform encephalopathy (TSE) Proposed Rule: Use Of Materials Derived From Cattle In Medical Products Intended For Use In Humans And Drugs Intended For Use In Ruminants, January 2007 Investigate the raw material of the raw material. Bovine material used upstream in raw material manufacturing?

5 Critical Factors Examples Unique source Problematic source (stable?) Understanding of key characteristics Potential toxicity, immunogenicity, other safety concerns Address with: Sourcing and materials management program Materials qualification testing Qualification of removal from final product

6 Control Points - Raw Materials Cells, Tissues Media, Supplements Solutions, Enzymes Cytokines, Antibodies Preservatives Delivery Devices Scaffolds Cell Therapy Product Manufacturing, Testing Supplier Qualification Qualification Testing Materials Management

7 Qualification Testing Performed to assure quality of raw material received from manufacturer In addition to testing reported on raw material COA Risk-based approach to qualification testing Intrinsic risks of material Results of supplier qualification - balance supplier s limitations More extensive testing needed for higher risk materials, or to compensate for supplier limitations Testing program - in-house, or (qualified) contract testing lab

8 Risk-Based Approach (USP Chapter 1043) Tier 1: low risk, highly qualified HSA, insulin COA, assess removal from final product Tier 2: low risk, well-characterized, GMP-manufactured, used as ancillary material, not animal origin Growth factors, density gradient medium Add supplier qualification Tier 3: moderate risk; not intended for use as an ancillary material, diagnostic or research grade (growth factors, culture medium) Additional testing needed for qualification Tier 4: high risk, potentially toxic, animal-derived (feeder cells, FBS) Source animal, documentation of country of origin

9 Risk Assessment Determines testing required Microbial contamination, infectious disease transmission Sterility, endotoxin, donor screening, adventitious agents Potential for incorrect material, impurities Materials with direct product contact must undergo USP identity testing Electrophoresis, HPLC, IR spectroscopy Inadequate function Enzyme activity, growth factor function, performance in manufacturing process Uniformity, consistency Qualify each lot? Each shipment?

10 Biologics - Human Serum Source from qualified blood center, meets blood donor criteria, ensure appropriate donor pool Serum manufacturing method, calcium concentration Often manufactured from re-calcified donor plasma - high serum calcium concentration, potentially toxic Manufactured from clotted whole blood - more costly, but normal serum calcium concentration Safety Donor screening, sterility testing Purity, Identity ABO typing (confirm AB serum), calcium, other potential contaminants Activity Function in manufacturing process

11 Biologics - Cytokines, Peptides Safety Sterility Purity, identity HPLC, electrophoresis, sequencing Activity Cytokine functional assay(s), peptide binding Function in manufacturing process

12 Cells, Tissues - Critical Raw Material Safety Sterility, adventitious agents Donor screening is an element of materials qualification testing Purity, identity Cell concentration, viability In some situations, immunophenotype, HLA

13 Scaffold Device Bovine-derived collagen membranes, scaffolds, some of which are FDA-approved Still need to qualify based on specific use Heavy emphasis on supplier qualification, country of origin Safety Adventitious agents (animal derived), sterility Physical parameters Composition, thickness, pore size, electrolyte content, strength Function Support for cells

14 Delivery Device Safety Sterility, integrity Function Biocompatibility, risk of inactivating viral vectors, toxicity to cells Delivery effectiveness Qualify loading and delivery of viable, functional cells

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