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GE Healthcare DCVMN Introduction to PD for Vaccine Introduction to process development for vaccine production DCVMN 10 March 2017 Need for updated vaccine processing and process optimization for global access Process development and optimization training workshop—DCVMN Taipei Speakers Dr. Mats Lundgren Mia Bennemo Customer Applications Director, Life Sciences Senior Research Engineer, Life Sciences GE Healthcare, Sweden GE Healthcare, Sweden 29256323AA I Mar. 2017 3 Preliminary agenda • Introduction to process development • Upstream process development for vaccine production • Downstream process development • Process economy • Quality by design (QbD) in process • Group discussion exercise—how to development overcome technical and economical • Practical exercise: QbD challenges in DCVMN companies • Future scenarios, wrap up discussion • Analytics and test • Lunch break 29256323AA I Mar. 2017 4 Introduction to process development for vaccine production 29256323AA I Mar. 2017 5 Outline • Vaccine process history • Why is process development for vaccines important? • Vaccine processing • Single-use technologies for vaccine manufacturing • Conclusions 29256323AA I Mar. 2017 6 Historic vaccine timeline 1955 : Injectable polio vaccine introduced 2006 : First cancer 1796 : Edward Jenner vaccine 1986 : First develops smallpox 1967 : Smallpox HPV vaccine recombinant vaccine eradication program human vaccine started 1979 : Smallpox eradicated from the world 1885 : Pasteur develops rabies vaccine 1962 : Oral polio 2010 : First vaccine introduced 1994 : Last case of therapeutic 1943 : Egg-based polio in the cancer vaccine influenza vaccine Americas approved 29256323AA I Mar. 2017 7 The evolution of vaccine processes • First generation processes: • Focus on upstream, optional inactivation • Second generation processes: • Separation based on centrifugation, filtration • Currently developed processes: • Quality based approach: QbD • Focus on entire process including purification and virus safety 29256323AA I Mar. 2017 8 Historic vaccine timeline: propagation 1955 : Injectable polio vaccine introduced 2006 : First cancer 1796 : Edward Jenner vaccine 1986 : First develops smallpox 1967 : Smallpox HPV vaccine recombinant vaccine eradication program human vaccine started In vivo In ovo Primary cell line Diploid cell line Continuous cell line 1979 : Smallpox eradicated 1885 : Pasteur from the world develops rabies vaccine 1962 : Oral polio 2010 : First vaccine introduced 1994 : Last case of therapeutic 1943 : Egg-based polio in the cancer vaccine influenza vaccine Americas approved 29256323AA I Mar. 2017 9 Historic vaccine timeline: purification 1955 : Injectable polio vaccine introduced 2006 : First cancer 1796 : Edward Jenner vaccine develops smallpox 1967 : Smallpox 1986 : First HPV vaccine vaccine eradication program recombinant started human vaccine Non-purified Filtration Filtration/centrifugation Chromatography Quality by design 1979 : Smallpox eradicated 1885 : Pasteur from the world develops rabies vaccine 1962 : Oral polio 2010 : First vaccine introduced 1994 : Last case of therapeutic 1943 : Egg-based polio in the cancer vaccine influenza vaccine Americas approved 29256323AA I Mar. 2017 10 The history of polio vaccines and GE 1955 1960 1960s 1970s 1980s 2010s Inactivated polio Attenuated polio Collaboration New IPV Switch to Vero Updating the IPV vaccine (IPV) vaccine launched between Prof. Van purification cell production processes using launched (Salk (Sabin type) Wezel (RIVM/NVI method using using Cytodex™ 1 modern Type) Netherlands) and GE's microcarriers technology from GE (former chromatography GE Pharmacia) around resins microcarrier cultures of primary monkey cells 29256323AA I Mar. 2017 11 Polio vaccine process 1. 2. 3. 5. 6. 7. 4. Cell Cell Production & Chromato- Chromato- Virus inactivation & Concentration expansion 1 expansion 2 filtration graphy 1 graphy 2 sterile filtration UPSTREAM DOWNSTREAM 1 Cytodex™ 1 (3g/L, 15 L) 3 0.45/0.22 µm serum containing media, trypsination removal of cell debris on depth filters cell transfer 4 Tangential flow filtration (TFF), 100 kD flat sheet 2 Virus concentration Cytodex 1 (3 g/L, 40 L) recirculation grow cells to 5 × 10 6 cells/mL 5 trypsination, cell transfer Sepharose™ CL 6B resin cell debris and host cell protein (HCP) removal 3 Lower reactor temperature at infection 6 wash cells to change to serum-free media DEAE Sephadex™ A50 resin purification, DNA, and HCP removal 7 0.025 % formaldehyd,13 days, 37 °C 7 0.2 µm Production system Vaccine type Reference Vero cell line Polio vaccine (IPV). Naked virus (~ 30 nm). Type 1, 2, and 3 subtypes in the Netherlands Vaccine Institute (NVI) vaccine. (Sabine –OPV, Sabine-IPV, Salk-IPV) - Vaccine 29, p.7188– 7196, 2011 - www.plosone.org, 1 December 2013, Vol. 8, Issue 12 29256323AA I Mar. 2017 12 Why is process development for vaccines important? 29256323AA I Mar. 2017 13 What are the challenges for vaccine producers? Design of aged processes Adaptation to changing markets Access to new vaccine technology • Many “weak steps”, low yield, • Markets for classic vaccines • Virus-like particles (VLP) • low robustness shrink in developed markets with High safety • Low immunogenicity high prices • Lack of platforms, re-use of • Complex processes technology modules • Need to remove hurdles for • rec Antigens and adjuvants • Open handling and regulatory investment and improvement, • Easy processing concerns including regulatory hurdles • Good safety • Immunogenicity dependent • Regulatory practice does not • Reduce cost for highest standard on adjuvant support new technology production technology implementation • …and more • Viral vectors • CAPEX demand very high due • Overcome lack of flexibility in • Plasmids, mRNA to weak processes production infrastructure • Cells • Economy very dependent on • Technologies in its infancy scale CAPEX = capital expenditure 29256323AA I Mar. 2017 14 What are the challenges for vaccine producers? Design of aged processes Adaptation to changing markets Access to new vaccine technology • Many “weak steps”, low yield, • Markets for classic vaccines • Virus-like particles • low robustness shrink in developed markets with High safety • Low immunogenicity high prices • Lack of platforms, re-use of • Complex processes technology modules • Need to remove hurdles for • rec AntigensImplement and adjuvants Improved • Open handling and regulatory investmentFlexible, and right- improvement, • Easy processingplatform scalability,concerns • Good safetytechnologies combine includingscaled regulatory hurdles combine yield and • Immunogenicityupstream dependent • Regulatory practice does not production process • Reduce cost for highest standard on adjuvant and support new technology infrastructure robustness implementation productionand facilities technology • downstream with modern …and more • Viral vectors • CAPEX demand very high due • Overcome lack of flexibility in technology • Plasmids, mRNA to weak processes production infrastructure • Cells • Economy very dependent on • Technologies in its infancy scale 29256323AA I Mar. 2017 15 Process development—trends and solutions • Quality must never be compromised • You always need to spend enough time and money to understand what the process does to the product • Your process will be most efficient in terms of time and cost, if you build its performance on solid understanding 29256323AA I Mar. 2017 16 Vaccines are difficult to characterize Monoclonal antibodies Vaccines Implications Often well-characterized Often difficult to characterize Less definitive analytical comparability pathways Less ability to monitor product Quality in mid-process Clear link to mechanism of Difficult to establish clinical Challenging to improve process action (MoA) and/or biomarker potency surrogates post-licensure surrogate for clinical performance Consistent process and product Sometimes more complex, less Variability over product/process predictable process/product life cycle Therapeutic patient population Prophylactic patient population “Process is product” philosophy to assure Quality Well-understood process; good Less understood process; Empirical process models for detectability for test methods difficult to measure attribute linking parameter inputs to changes Quality outputs More stringent threshold for reporting manufacturing changes 29256323AA I Mar. 2017 2017 -03- 13 A-VAX case study objectives I Substantial changes in quality systems and regulatory approaches might be needed • Apply QbD to develop a robust vaccine manufacturing process. This includes: • Risk-based approaches to vaccine development • Leveraging of science to gain process and product understanding • Continuous improvement • Merging of process and analytical controls for vaccine manufacturing • Make the rationale for development more transparent in regulatory submissions 29256323AA I Mar. 2017 18 A-VAX case study objectives II Substantial changes in quality systems and regulatory approaches might be needed • Document techniQues for safe and effective vaccines to reach market more Quickly • Strive to make reviews more efficient; decrease the number of post- approval supplements needed • Develop realistic examples to better illustrate how QbD can be applied within the development space and overall product Quality system • Highlight and/or develop tools, frameworks, etc., to enable ICH Q8, Q9, Q10, and Q11 implementation strategies • Tie key benefits with the strategies illustrated in the case study 29256323AA I Mar. 2017 19 Note of caution on A-VAX It should be understood that that
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