Bioanalytical Best Practice in Australia a CPR perspective. by Andrew Dinan Senior Director Bioanalytical Services CPR Pharma Services, Australia

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1 Bioanalytical Best Practice in Australia a CPR perspective by Andrew Dinan Senior Director Bioanalytical Services CPR Pharma Services, Australia

2 Outline History of Bioanalysis in Australia CPR Future Setup Case studies Challenges CPR, Adelaide 2

3 1980 s History in Australia 1990 s Bioequivalence (BE) trials in Universities No BMV guidance to follow individual best practise BE studies continued 1st ever BMV workshop in 1990 Sponsored by AAPS, FDA, FIP, HFB, AOAC Harmonised validation and became the benchmark in Australia CMAX opened 1st dedicated Phase 1 site Bioanalytical unit - ISO & GLP Accreditation 3

4 History in Australia 2000 s FIH studies commenced BE studies USA companies attracted by fast Regulatory framework for mainly NCE FIH studies Small NCE Australian market Reduced dramatically through low cost competition India, China. Lead to closure of 2 Bioanalytical units that were part of phase 1 units in Adelaide (CMAX) and Brisbane (Qpharm) 2001 FDA guidance Adopted as BMV standard in Australia CPR, Adelaide 4

5 2010 s History in Australia FIH studies Continue with Global appeal high quality, fast regulatory framework, R&D tax incentive Global Bioanalytical meetings Attend to know acceptable BMV standards that were NOT in regulatory guidances e.g. ISR, matrix effects, etc. WRIB, EBF, AAPS, GBC, GCC 2012 EMA guidance issued Most Bioanalytical work in Australia supports studies for US, European submission. Therefore AAPS 2001, EMA 2012 guidances followed and associated workshops. 5

6 History in Australia 2010 s BMV still not consistently applied across global CROs CPR reviews many Global CRO Tox and Human assays to support FIH studies conducted in Australia Differences in Whole blood, Matrix effects, lipemic, A&P Acceptance criteria, etc 2020 s the Future BMVs USA, European, Japanese, Canadian, etc Global BMV?? (e.g. ICH GMP??) GBC status?? CPR, Adelaide 6

7 CPR A Specialist Early Phase CRO CPR is the only Australian CRO that has a synergistic combination of 1. Clinical and data management services 2. GLP-accredited Bioanalytical laboratory (PK, PD, ADA) Collaborates with all 6 dedicated clinical Phase I sites across Australia and New Zealand Focus on early phase clinical trials e.g. FIH Phase 1 CPR, Adelaide 7

8 CPR - History University of South Australia 1980 s: Originated within School of Pharmacy BE studies 1996: Centre for Pharmaceutical Research formed (CPR) 2005: CPR became commercial - no longer funded by University CPR Pharma Services Pty Ltd 2009: 20 people Spun out from University as a private company 2007 Australian Government grant approval ~$1M, with matching funds raised in : currently ~90 people CPR, Adelaide 8

9 Our Customers CPR s client portfolio Company type Geography Small-medium pharma main customer Biotech - some Large pharma - limited USA (~ 50%) Australia / NZ Asia Pacific India, South Korea, China Europe High Repeat rate > 80% CPR, Adelaide 9

10 GLP Bioanalytical Services Specialist in regulated bioanalysis Quantitate drug &/or metabolite in biological matrices plasma, serum, urine etc. Supports pharmacokinetic (PK) & pharmacodynamic (PD) evaluation required during the drug development process. Analytical platforms LC/MS/MS for small molecules to polypeptides (50AA ~ insulin), oligonucleotides. Immunoassay for larger biologics i.e. MAbs, proteins. 10

11 Quality Systems 2004 ISO Accreditation Appropriate for clinical sample analysis Quality manual, preventative & corrective action, continuous improvement Technical competence verified by external party NATA 2007 GLP Accreditation Strictly for Pre-Clinical studies But also applied to clinical sample analysis, method validation Successful FDA audit QA verified by Large pharma & Global CRO partners Comply with latest USA/EMA BMV Guidances Attend latest global bioanalytical forums WRIB, EBF, JBF 11

12 Regulatory team at work 12

13 LC/MS/MS Analytical Capability LC/MS/MS Sciex 5*4000s, most common in large pharma & CROs 5500 Qtrap High sensitivity if required Steroids, neurotransmitters dermal / inhalation phase 0, low dose, paediatric studies low volume All LC/MS/MS fully qualified and under change control Service contracts and local engineer available same day 13

14 LC/MS/MS Analytical Capability 14

LC/MS/MS Expertise and Experience R&D team of senior chemists Conduct complex method development Combine team expertise for: Troubleshooting Deliver assay development under

15 LC/MS/MS Expertise and Experience R&D team of senior chemists Conduct complex method development Combine team expertise for: Troubleshooting Deliver assay development under tight deadlines Experience Drug chemistries sugars, nucleotides, enantiomers, steroids, prodrugs, immunosuppressants, neurotransmitters, peptides. Drug conjugates, nanoparticles 15

16 Dihydroartemisin Small molecules All tests pass with fast protein precipitation assay However, haemolysed blood the response decreased for drug by -95% Assay re-developed with solvent extraction where the purity/source of solvent was important Postulated that the drug was reacting with free radicals in haemolysed blood and solvent impurities MOA is within red blood cells makes sense to react with lysed cells Testosterone Testosterone assay developed for 20ul cord serum from newborns Random contamination seen Vital that all surfaces in the assay process are swabbed/cleaned of deposited testosterone from males 16

17 Small Molecules Nanoparticle Nanoparticle designed to release cytotoxic drug in the biological system Cytotoxic load in vast excess to free drug, 100,000 ng/ml equivalent in nanoparticle (Total) ~100 ng/ml free (1,000 fold excess) Stability investigation covering temperature, plasma species, whole blood vs. plasma, chemical inhibitors, ph Solution on ice with acid stabiliser & control time of exposure Stability acceptable and was fully validated NCE Urine stability failed at -20 C, passed at -80 C Investigations uncovered correlation with excessive ph change 17

18 Australian venomous creatures CPR, Adelaide 18

19 Peptides High level Expertise Over a decade of experience (2001 on) with Bioanalysis of intact peptides in plasma 15%, 4/6 criteria small molecule criteria Key Learnings Keeper solution to prevent surface adsorption Solution chemistry optimisation to prevent aggregations e.g. Amyloid beta peptides Weak cation exchange SPE for Arginine containing peptides Optimise Resolution settings Good IS analog or SIL Shallow gradients and high column temperature Examples fully validated Glucagon, Vessel Dilator Various NCE peptides 19

20 Oligonucleotides New areas Pure standard technical feasibilities conducted for clients: Antisense strand - ~5kDa Theoretical LLOQ 1ng/ml SiRNA ~ 15kDa Theoretical LLOQ 10ng/ml Current 6 month project with University of South Australia Bioanalysis of oligos Protein MS Tryptic digest for signature peptide Also assessing very large peptides for intact analysis 70 AA s e.g. IGF-1. 20

21 Immunoassay/Ligand Binding Services Quantitative PK analysis of macromolecules, including monoclonals Biomarkers Immunogenicity (anti-drug assays) Neutralising antibody assays Reagent labelling and affinity purification Fully GLP Compliant 21

22 What We Measure: Molecule Type Recombinant Proteins Monoclonal Antibodies Oligonucleotides Fusion Proteins Biosimilars Bioanalytical Services Supporting Drug Development in Australia 22

23 Australia s Contribution to Biosimilar Validation First Consensus White Paper on Assay Validation Requirements. Bioanalytical Services Supporting Drug Development in Australia 23

Immunoassay Case Study Project: Validation of PK and ADA Assays for a Monoclonal Antibody for a small Biotech company. Drug is a Pentameric IgM Molecule. Assay performed on the MSD system.

24 Immunoassay Case Study Project: Validation of PK and ADA Assays for a Monoclonal Antibody for a small Biotech company. Drug is a Pentameric IgM Molecule. Assay performed on the MSD system. Client has worked with a global CRO who had performed over 150 runs of method development and still could not get the assay to perform. Clinical Trial in complex Disease interference matrix. Global CRO had been working on the assay for 12 months. Interferences solved using some novel techniques. CPR started work and completed the Method Development and Method Validation within 3 months. Sample Analysis completed and met the timelines set by the client. With client s permission data is to be published in poster format. Presented with client s permission, November 2014 Bioanalytical Services Supporting Drug Development in Australia 24

25 Immunoassay Case Study (contd.) Bioanalytical Services Supporting Drug Development in Australia 25

26 Summary Early phase clinical trial specialists, offering clinical and bioanalytical services, as individual components or a full service Track record of quality and timely delivery (with high repeat business) CPR Pharma Services, Australia : integrated solution for the Asia-Pacific region CPR, Adelaide 26

27 Future Bioanalysis A-Pac Past to Present 1st Asia-Pacific Bioanalytical Workshop China 6 th Japanese Bioanalytical Forum (JBF) Started nd China Bioanalytical Forum (CBF) Started 2013 Future??? 2nd Asia-Pacific Bioanalytical Workshop??? Expert presentations science, regulatory Training courses and workshops for the regions workers of the future! In Australia...All Welcome!! CPR, Adelaide 27

28 Thank You! Thank you for your kind invitation to present today!! South Australia CPR, Adelaide 28

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