Global Bio Conference 2017 Seoul, Korea 30 June Contract Manufacturing An Experience from Germany and Malaysia A Case Study.

Transcription

1 Global Bio Conference 2017 Seoul, Korea 30 June 2017 Contract Manufacturing An Experience from Germany and Malaysia A Case Study

2 History Pioneering Recombinant Biopharmaceuticals Road to Success In 1986 the pioneers of large scale biopharmaceutical manufacturing, Boehringer Ingelheim, Germany and their cooperation partner Genentech, USA introduced recombinant tissue plasminogen activator ( rt-pa ) to the market as the first ever of complex protein molecules using recombinant mammalian cells. Front edge technology both in biology as well as in manufacturing science defined the production process, and so did the authorities. Any deviation or change in equipment or procedure was considered highly suspect and wasn t allowed at all, to a large extent simply due to limited knowledge, lack of experience and lack of appropriate analytical tools. Now, nearly three decades later, the biopharmaceutical manufacturing landscape is dramatically changed and has undergone serious improvements in those terms. Despite, biopharmaceutical manufacturing is still being considered a challenge, though the center of gravity has moved. The exclusivity of biopharmaceutical drugs derived from recombinant technologies, be it proteins or vaccines, has faded as a beneficial consequence of their established pharmaceutical value: the new challenge is the demand for high productivity at bearable cost all over the world! 2

3 History Pioneering Recombinant Biopharmaceuticals Change of the Manufacturing Landscape The dinosaurs of biopharmaceutical manufacturing to L fermentors had been constructed in the early 1980 s to first compensate by volume the low productivity of the early mammalian cells, a productivity that hardly exceeded 100mg L -1 during the early years. Later in the 1990 s the time came for block buster Monoclonal Antibodies, followed by recombinant Antibodies. And only another decade later, in the 2000 s, cell specific productivity levels of several g L -1 became feasible, and in research even soared up to almost 10g L -1 And there were the expiring patents: for newcomers and copycats there was a totally new room to explore: most obstacles of the past were pretty easy to overcome: - High producer cells are available as are sophisticated analytical tools. - accordingly the production volumes have been reduced significantly: in most cases a fermentation volume of 500 to 2000L easily allows an economic production. - new technologies, namely single-use or disposable equipment, significantly helped to reduce the complexity of the production process itself. - based on gained knowledge and experience authorities have provided an excellent framework of guidelines, most notably the ICH guidelines have provided a leap facilitating international business. 3

4 Facility Design and Engineering Manufacturing Facility Facility for Mammalian Cell Culture Facilities of Boehringer Ingelheim, Biberach and Innobiologics, Nilai 11

5 Biopharma Asia Malaysia Government Funding The Facilities of Innobiologics 5

6 Biopharma Asia Awakening of Asia s Biopharmaceutical Industry Bioeconomy as a Global Focus for Growth Malaysia joins emerging trend of countries establishing Bioeconomy Roadmaps:

7 Process Development and Technology Transfer Facility Design and Process Economics Facility Fit Analysis: General Considerations Analysis of production capacity and economics Product needed (mg, g, kg) Volume per fermentation batch Productivity and variability of fermentation Frequency of fermentation batches Time available for downstream processing Volume per downstream batch Market price for product Requirements on product Level of investment in production plant, cost of goods Flexible use of plant Automation

8 Biopharma Business Facility Design and Process Economics Facility Fit Analysis: Physical Constraints Facility Footprint Head room Load on floor Utilities (water, steam, air ) Labour Head count Available hours Skilled personnel Operational Constraints Changes in sample composition Changes in sample concentration Longer holding times Buffer preparation Technical / Process Equipment Membranes Flux rate Membrane area / device Pumping capacity Chromatography Columns wall effects, packing, distribution system Systems pressure, mixing accuracy Buffer exchange volumes

9 Process Technology Upstream Processing Fermentation Hall L Fermenter Top Cover 9

10 Process Technology Upstream Processing Fermentation Hall - 200L Fermenter Skids 50L/200L SU Fermenter, 200L Cultivation Bag 10

11 Disposables and Single-use Equipment Disposables / Single-use Tool Box: Examples from Downstream Processing Storage Container 3D Bags 2D Bags however, handling still is handy even with more sophisticated containments! 11

12 Disposables and Single-use Equipment Disposables / Single-use Tool Box: Examples from Downstream Processing but look for storage space 12

13 Biopharma Business Biopharma Market and Market Supply Challenges to Biopharmaceutical Manufacturing Under-utilization of a facility has a negative effect on the overall cost structure and can hardly be compensated. Fixed costs are related to size and scale thus small facilities have the advantage of reduced fixed costs ( e.g. investment, operation, maintenance ). This advantage combined with improved flexibility ( which should reflect the ease to adopt to new processes or operational requirements ), should facilitate a reduced cost approach. 13 modified from: Jagschies, G.: Options & Conditions to Manage Plant Capacity for the Best Economical Outcome, IBC s Ab, Carlsbad 2010

14 Biopharma Business Technology Knowhow and Transfer cgmp facility built in EU according to EMA Guidelines Modular construction designed and built by Pharmaplan GmbH, Germany Shipped and established on-site in Nilai, Malaysia

15 Biopharma Business Technology Knowhow and Transfer cgmp facility built in EU according to EMA Guidelines Finished cgmp Facility Modular Steel Structure On-site assembly of the container 3D Model Piping and Ductwork

16 Biopharma Business Innobiologics Sdn Bhd, Malaysia cgmp Fermentation 300L and 1000L

17 Biopharma Business Innobiologics Sdn Bhd, Malaysia cgmp Facility: Media preparation

18 Biopharma Business Innobiologics Sdn Bhd, Malaysia cgmp Facility: Fluid Handling Single-use

19 Biopharma Business CMO Business The Vision of Inno Biologics 19

20 Biopharma Business Scope on Contract Manufacturing as a Business Issues and Criteria for Selecting a CMO 20

21 Contract Manufacturing Business Strategies in Biopharma Assessment of the Potential Partner Technical Assessment facilities, equipment and capacity cgmp compliance quality of personnel resources > technical skills, training > process experience > head count unique technical knowhow and equipment Regulatory Assessment evaluate experience with regulatory issues > access and experience to regulatory agencies > experience with regulatory submissions and inspections > reputation within the industry and regulatory agencies > compatibility with and acceptance of Quality Management Policy 15

22 Biopharma Business Scope on Contract Manufacturing as a Business Key Component in CMO Business: Communication

23 Contract Manufacturing Business Strategies in Biopharma Lack of Operational Skills in Biopharmaceutical Manufacturing Sophistication is put on facility design and operation but dealing with sophisticated technologies, well-trained staff is a key to successful operation! Unfortunately such personnel are not necessarily available where needed. The lack of experienced staff is a major drawback (not only!) in areas just catching up with biotechnology for biopharmaceuticals or biosimilars respectively. Generally industry skills for technical, engineering and management personnel are currently being unmet by education. And with no doubt this conclusion can be projected to nascent biopharmaceutical areas even more. Such lack of skills adds an unproportional risk specifically to technical operations. As early as in 2005 Vitesse Re-SkillingTM, Canada, published an industrial survey on the availability of skills which is well applicable outside Canada and obviously as up-to-date as it was when published. 16

24 Management and Manufacturing Managerial Challenges in Biopharm Production Operational Skills in Manufacturing 17 Training investments in the biopharmaceutical manufacturing sector are, per employee 30%+ above average for all industrial sectors. Skill sets were classified according to their relevance to operations: scientific ( responsibility in the R&D activities ) technical ( responsibility in maintenance and operation of manufacturing processes ) engineering ( responsibility in design and validation of manufacturing processes ) management (responsibility in management of biomanufacturing activities ) Specific skills required by the industry were considered as not adequately addressed by academic and educational institutions: 37% of the technical skill sets 79% of the engineering skill sets 100% of the management skill sets The firm conclusion from the survey is that industry skills for technical, engineering and management personnel are currently being unmet. Source: Vitesse Re-Skilling TM, Canada 2004

25 Management and Manufacturing Managerial Challenges in Biopharm Production Critical Skill Shortages in Manufacturing 18 management skills: - cgmp - monitoring, inspections, audits - facility / Process layout and flows - costing of processes scientific skills: - GLP - ICH / FDA / ISO / TPP Rules engineering skills: - equipment validation - cleaning validation - process validation - cgmp - heat transfer - troubleshooting processes - design of processes ( software ) - scale-up considerations ( upstream ) - scale-up considerations ( downstream ) technical skills: - cgmp - ultrafiltration

26 Disposables / Single-use in Praxis Challenges to Biopharmaceutical Production Acquisition of Skills: ca Returnees to China Source: ChinaBio Consulting 2010

27 Management and Manufacturing Managerial Challenges in Biopharm Production Establish CMO Capabilities: Human Resources Situation in Germany Germany follows an almost unique way of education: Dual Apprenticeship ( Alternance ), i.e. a close cooperation between schools/universities and the industry 3 year apprenticeship in a company and in vocational school Delivers (reasonably) experienced and qualified personnel from start of employment Bachelors, Masters, PhD from University, also with apprenticeship during their studies 20 Situation in Malaysia (and in many other countries) Bachelors and Masters from College/University with no practical experience. Theoretical knowledge on biopharmaceutical development and production provided during University studies is very limited. Create a pool of talents and skill-sets by local and abroad training Spend substantial time and efforts (= money) to compile a professional team. Education and training spread over two years.

28 Management and Manufacturing Managerial Challenges in Biopharm Production Establish CMO Capabilities: Hierarchies Situation in Germany Typically organized in a flat hierarchy. Coworkers operate mission oriented, i.e. the company trust and relies on their skills. They have a high degree of freedom at full responsibility for their work, which enforces motivation. Superiors are in control and responsibility of the project plan / timeline. They shall only interact moderately and if required. Situation in Malaysia (and in many other countries) Typically organized in a distinctive hierarchy. Coworkers operate on detailed instructions. Any changes require feedback from a supervisor ( I have to ask my boss ) Superiors are responsible to formulate detailed instructions. Enforced risk of micromanagement. 20

29 Process Transfer Process Design and Process Economics Technology Transfer and Start-up Lessons from process research and pilot phase: Careful analysis and characterization of the lab scale process will indicate potential operational problems. Fundamental difficulties in process chemistry can not be solved during scale-up while difficulties related to scale may not have been foreseen in research. Organizational capabilities become crucial: establish intense networking between all faculties involved: both in process development and technology transfer. The allocation of scientific and engineering resources, i.e. who works on the project and when, is vital and may have a significant impact on performance.

30 Process Transfer Process Design and Process Economics Technology Transfer and Start-up Manufacturing start-up involves transferring and adapting process technology to the commercial manufacturing plant: The manufacturing plant may introduce a new set of process variables, including scale, equipment design and procedures. Due to the extreme degree of complexity of a biotechnical process subtle differences and nuances in the manufacturing environment may have a significant impact on process performance, thus making the transfer and start-up still a challenge. The problem is not with the process that was developed, but with the process eventually implemented in the manufacturing plant. In a worst case unit operations of the proposed process may show to be incompatible with existing equipment, scale or procedures.

31 Management and Manufacturing Managerial Challenges in Biopharm Production Established CMO Capabilities 1. Erythropoietin (Glycoprotein Product -- internal project with Pangen, Korea) 2. VEGFR-- 3/hIgG1Fc (Human Glycoprotein for Australian customer) 3. mab IgG1 (Monoclonal Antibody -- internal project collaboration with Boehringer Ingelheim) 4. mab An6-- CEA (internal project using local grant with CIMAB, Cuba) 5. Darbepoetin (Dev & API production of glycoprotein product for Indian customer) 6. Etarnecept (glycoprotein product for Indian customer) 7. mab An6 Dengue (for local University -- Hybridoma targeted for Diagnostic Kit) 8. Polyclonal Antibody (for local research institute, MARDI, FRIM and others) 9. Antibody purification (novel resin Customer from Germany) 10. mab Anti-- DoA (for local company for diagnostics purpose) 11. mab For clinical phase 1 Tech Transfer & API produc1on (Korean Pharma) 12. mab For clinical phase 2 Tech Transfer & API production (Korean Research Institute)

32 Contact Info