Human Microbiota: proof of concept to production. Michael van der Horst Process Engineer Technical Operations SynCo Bio Partners B.V.

Transcription

1 Human Microbiota: proof of concept to production Michael van der Horst Process Engineer Technical Operations SynCo Bio Partners B.V.

2 SynCo Bio Partners B.V. Who we are and what we do Licensed cgmp CMO Located in Amsterdam, the Netherlands Production Bulk Drug Substance ( L) Live microbial products (LBPs) and microbe derived biopharmaceuticals Oral & parenteral Aseptic fill finish & lyophilization Up to 20,000 vials Bulk lyophilization up to 70L In house QC testing & QA release, stability studies, regulatory support

3 Microorganism Experience Live Microbial Products Bifidobacterium spp. Lactobacillus spp. Lactococcus lactis Oxalobacter formigenes Salmonella typhi Vibrio cholerae Others (non-disclosed) Saccharomyces cerevisiae Production Organisms Escherichia coli Pseudomonas fluorescens Haemophilus influenzae type B Corynebacterium diphtheriae Neisseria meningitidis (group A, C) Bordetella pertussis Pichia pastoris Saccharomyces cerevisiae Cultured under anaerobic conditions Cultured under aerobic conditions

4 The Objective Share experiences & approaches from various Live Biotherapeutic Product cgmp projects Early considerations for process development

5 From Idea to Live Biotherapeutic Product Idea Proof of concept Process development Clinical production Commercial production

6 From Idea to Live Biotherapeutic Product Product Company Contract Manufacturer

7 Manufacturing of product for human use strict regulations (cgmp) Get in touch with CMO(s) at least months before you require cgmp material for your clinical trials Advise from CMO on early stage activities Sufficient time for proposal discussions, site visit(s), contract discussions, and tech transfer Process transfer (small scale) Analytical transfer and qualification GMP demonstration lot GMP clinical supply batch(es)

8 Typical Process Setup for LMPs Inoculation (BHC) Open handling Precultures Fermentation Concentrate Disposable (sterile) systems + wash cells (TFF) Formulation Filling in vials/trays Freeze drying Open handling, Class A; Clean Room

9 The Live Product: Production process Aerobic vs Anaerobic (strict/facultative) Parenteral/sterile product: Oral/non-sterile product: sterile ( monoseptic ) process aseptic process Oral/non-sterile product with list of objectionable organisms:? (patient population)

10 Growing the Live Product: Precultures & Fermentation Production organism; Potential pathogen (Class I, II, III) Genetically modified (GMO, origin of insert) Master Cell Bank / Working Cell Bank License Live microbial in Fill and Finish facility (Cleanroom) Growth medium GMP compatible Free of animal derived components All components pharmacopoeia grade No antibiotics (definitely no β-lactams) Incl. cell bank medium

11 Growing the Live Product: Fermentation choice of reactor Wave Bag Single-use Bioreactor Stainless Steel Reactor Ease of use Cleaning (validation) Aeration Volume

12 Purification and concentration of the Live Product: Centrifugation vs Ultrafiltration Centrifugation (bucket-centrifuge) Open handling Not suitable for large volumes Typical of early stage / bench scale processes Continuous centrifugation Open process, harvest of cells not sterile Large product loss Ultrafiltration / tangential flow filtration Closed/sterile process Concentrate cells Wash out contaminants (diafiltration) Diafiltration buffer Membrane

13 Purification and concentration of the Live Product: Centrifugation vs Ultrafiltration Centrifugation (bucket-centrifuge) Open handling Not suitable for large volumes Typical of early stage / bench scale processes Continuous centrifugation Open process, harvest of cells not sterile Large product loss Ultrafiltration / tangential flow filtration Closed/sterile process Concentrate cells Wash out contaminants (diafiltration) Diafiltration buffer Membrane

14 Stabilizing the Live Product: Viability will be key! Formulation (development) Dilute product with cryoprotective buffer Fill Sugar alcohols / polysaccharides + buffer Target specific range live cells (e.g cfu/ml) Open handlings with Live Microbes in Cleanroom / Class A Aseptic process validation / process simulation for sterile products Vials vs. trays (sampling) Freezing / Freezedrying Viable cell loss 50-95% (depending on organism + cycle) Target specific range live cells (e.g cfu/vial) based on clinical requirement

15 Testing the Product QC release tests validated prior to GMP release! Chemical contamination Residual antifoam Residual proteins (yeast extract) Endotoxins Product content Amount of live cells Identity confirmation Residual moisture and Osmolality Biological contamination Culture purity Medium sterility Absence of objectionable organisms

16 Product release for clinical use Execution manufacturing run Controlled area Execution according to protocol All equipment calibrated All personnel trained for the actions performed All raw materials according specifications Results analytical testing Assay qualified/validated Execution according to protocol All equipment calibrated All personnel trained for the actions performed All raw materials according specifications QA review GMP release of batch by Qualified Person Shelf life of product subject to stability testing

17 When preparing for clinical trials Avoid delays in clinical trials Be aware of the requirements Think ahead during process development If a contract manufacturer is required; start looking for suitable partners well in time!

18 Your partner of choice cgmp Live Microbial Products Come talk to us at our booth Trust us to make it right!