Principles, Practice and Guided Evolution of Biologics Manufacturing Platforms

Transcription

1 Principles, Practice and Guided Evolution of Biologics Manufacturing Platforms David Beattie R&D Director, Biotech Process Solutions EMD Millipore, a division of Merck KGaA CMC Forum Europe 2011 Barcelona 1

2 What is a Platform? A method, equipment, procedure or work practice that may be applied across multiple products under development or manufacture. Examples: An expression system Chinese Hamster Ovary (CHO) cells A screening system high throughput based on robotics An analytical method imaged capillary electrophoresis A drug product formulation citrate + sucrose + Tween A mode of cell culture perfusion culture A purification unit operation affinity chromatography A complete process comprising multiple operations Platform DSP 2

3 What is a Platform? A method, equipment, procedure or work practice that may be applied across multiple products under development or manufacture. mab A mab B mab C mab D mab E A single company making a variety of related drugs 3

4 What is a Platform? A method, equipment, procedure or work practice that may be applied across multiple products under development or manufacture. Flu A Flu B Flu C Flu D Flu E Flu A Flu B Flu C Flu D Flu E Flu A Flu B Flu C Flu D Flu E An industry making a variety of related drugs 4

5 What are the Benefits? Development effort and overall costs reduced Time to clinic and therefore to market reduced Process improvements leveraged over many products Economies of scale for equipment, components and raw materials Failure rates during GMP manufacturing reduced over time due to accumulated process experience Procedures for in-process and batch release testing become routine, implying risk of errors reduced Faster turnaround in multiproduct facilities Submissions of INDs/IMPDs during early stage development are expected to be facilitated more readily Platform processes are suitable for a modular validation approach, which in turn leads to reduced efforts and costs Overall benefit for industry, health care system and patient 5

6 Merck Serono DSP Platform Project Definition of Platform Baseline purification and analysis strategy for future mab products Standardized materials and methods IPC testing matrix and methods with minimum specifications Purpose of Platform Reduce the time required for DSP development activities Minimize material demand lead times Maximize the utilization of process improvements Establish a standard process for benchmarking to industry expectations 6

7 Unit Op Identification Unit operations selected from historical success and common practices Protein A Chromatography Capture Low ph hold Anion Exchange Chromatography Polish Chromatography Nanofiltration UF/DF Bulk Drug Substance Formulation To achieve optimal versatility, the platform consists of a primary and alternative approach for each operation Bulk Drug Substance Formulation Flexibility! 7

8 Platform Process Control IPC Monitoring Standardized IPC testing matrix Promote reliable data comparison Establish expectations for impurity removal for each operation Establish generic specifications for drug substance Analytical Method P R O A L O W ph A E X P O L BDS Specification Conc. (rpa) X X X N/A Conc. (A280nm) V R F UF DF X X X X X X X B D S Product Specific Purity (SEC) X X X X X X X >95% Monomer Purity (PAGE) X X X X X X X >95% Product Bands Isotypes (ICE) X X X X Compare to RS HCP (ELISA) X X X X X X X <50ppm DNA (qpcr) X X X X X <10pg/mg FLrPA (ELISA) X X X X <5ppm Bioactivity X % of RS 8

9 Case Study: Anti-CD19 The first application of the generic process MabSelect Xtra Low ph hold SartobindQ Charged Membrane cha 30Kd RC CPV Bulk Drug Substance Formulation Primary chosen for Capture, Low ph and Virus Reduction Filtration Alternative chosen for Polish for removal of aggregate to meet purity specification Alternative chosen for UFDF based on yield, placed before VRF due to high NaCl Process Recovery Product Purity Residual Aggregate >65% >99.5% <0.5% Process Impurities All meet spec or <LOQ Repeated for other mabs Success! (?) 9

10 Benefits not realized in Isolation Q1 Year 1 Year 2 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Process Development Ph 1 Production FIM Pre-MCB tested MCB available cdna available Clone generation Pre-clinical formulation Analytical dev Clone selected Process check Formulation selection Formulation check Supportive stability studies Analytical check Pre-clin supply Tox material API release cgmp API prod. DP release Stability studies DP prod. regulatory documentation IND IMPD

11 Benefits not realized in Isolation Q1 Year 1 Year 2 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Cell Line Process Analytical FIM Formulation Ph 1 Production Generation Development Development Development And Release Pre-MCB tested MCB available cdna available Clone generation Analytical dev Pre-clinical formulation Clone selected 30+ mos to FIM! Process check Formulation selection Formulation check Supportive stability studies Analytical check Pre-clin supply Tox material API release cgmp API prod. DP release Stability studies DP prod. regulatory documentation IND IMPD

12 Benefits not realized in Isolation Cell Line Generation Platform Stable pool Staining and sorting highest fluorescing cells Early Phase Development replaced by Platform Fit and Adaptation Analytical Platform Several sorting rounds Cloning Sorted cells growth Formulation Platform Purification Platform Bulk Drug Substance Formulation Lesson Learned: full benefit only from Total Chain Platform 18 mos to FIM!

13 Involve all the Stakeholders Hydroxyapatite: calcium-phosphate crystal with a zero point charge at neutral ph Extremely sensitive to acidic conditions Extremely powerful for polishing mabs! In non-platform process, column degradation occurs after cycling Visible loss of resin and bed cracking At lab scale, up to 50 cycles run without issue But, rapid and limiting increase in backpressure only at production scale Lesson Learned manufacturing colleagues need a strong voice in setting Platform and non-platform information can be relevant Column inlet pressure (Bar) Cycle 1 Cycle 20 Cycle 50 elution load Batch No

14 Using the Platform to create a Viral Clearance Knowledge Base Development History and Prior Process Knowledge are core to QbD Just as we use accumulated performance knowledge from multiple projects to design the Platform, we also look to accumulated virus clearance data to optimize the effectiveness Objectives: Improve design space using viral clearance as response factor Amortize clearance data over many projects Reduce validation workload during early clinical phases Efficient use of data accumulated on generic platform process(es) Conductivity (ms/cm) Clearance factors in function of the ph and the conductivity ph MLV> 4 MLV<4 MVM>4 MVM<4 SV40>4 SV40<4 Reo3>4 Reo3<4 Reconcile two apparently contradictory needs of process development: reducing cost and duration of development while simultaneously increasing process understanding 14

15 Platform Evolution A platform process should not be regarded as a static, longlasting procedure. In contrast, it should be reviewed within agreed life-cycle periods and undergo changes by controlled implementation of improvements and uptake of innovations. Moreover, Processes of the Future can and should be based on the learnings from the Platform more Knowledge Management 15

16 Platform Evolution: Process Compression mab Chromatography Steps at 2 g/l Plant Design: 5,000L Tank 5,000L Tank 5,000L Tank Protein A Virus Hold Cation Exchange Hold Tank Anion Exchange Hold Tank Input 12,000 2 g/l 2,850 L 8.2 g/l 3,280 L 7.1 g/l 1,530 L 13.7 g/l 3,060 L 6.9 g/l 3,060 L 6.9 g/l Output 2,850 L 8.2 g/l 3,280 L 7.1 g/l 1,530 L 13.7 g/l 3,060 L 6.9 g/l 3,060 L 6.9 g/l Virus UF/DF

17 Platform Evolution: Process Compression mab Chromatography Steps at 5 g/l Plant Design: 5,000L Tank 5,000L Tank 5,000L Tank Protein A Virus Hold Cation Exchange Hold Tank Anion Exchange Hold Tank Input 12,000 5 g/l 7,200 L 8 g/l 8,300 L 7 g/l 4,580 L 11 g/l 9,160 L 5.7g/L 9,160 L 5.7g/L Output 7,200 L 8 g/l 8,300 L 7 g/l 4,580 L 11 g/l 9,160 L 5.7g/L 9,160 L 5.7g/L Virus UF/DF

18 Platform Evolution: Process Compression What if you could remove intermediate hold tanks by direct loading of elution steps? Plant Design: 5,000L Tank Input Outpu t Protein A 12,000 5 g/l 7,200 L 8 g/l Direct loading of Pro A elution and Virus Hold on CEX media column Cation Exchange 7,200 L 8 g/l 4,580 L 11 g/l Direct loading of CIEX elution on to membrane adsorber Anion Exchange 4,800 L 10 g/l 4,800 L 10 g/l Hold Tank 4,800 L 10 g/l Virus UF/DF

19 Platform Evolution: Process Compression Performance Results from Direct Elution Connected Process Pool Feed (MAb spike/non-expressing CHO) Protein A Pool (ProSep Ultra Plus) Cation Exchange Pool (Eshmuno S) HCP (ppm) Leached Protein A (ppm) Aggregate (%) 295,000 NA NA Yield (%) < 2* Anion Exchange Pool (ChromaSorb) Overall Connected Process Overall Control Process (with intermediate holds) < 3* < 2* < 3* < 2* < 3* < 2* Comparable performance for Connected Process

20 Platform Evolution: Process Compression Virus Clearance Results from Direct Elution Connected Process Chromatography Step Column Volumes (CV) Buffer on-column inactivation Virus Conc. (Log) on-column inactivation Buffer Traditional Process Virus Conc. (Log) Traditional Process CIEX EQ 4 Load 6 (load density = 50mg/mL) CIEX Wash 3 Low ph Hold 0.5 (Total step time = 0.5hr, for oncolumn inactivation) CEX Elution 6* 50mM Sodium Acetate, 25mM NaCl, ph mM Sodium Acetate, 25mM NaCl, ph 5.4 Protein A Pool 6.5 Protein A Pool mM Sodium Acetate, 150mM NaCl, ph mM Sodium Acetate, 150mM NaCl, ph mM Sodium Acetate, w/nacl, ph mM Sodium Acetate, 25mM NaCl, ph Not performed N/A mM Sodium Acetate, w/nacl, ph Post Elution 3 EQ and EQ w / 1M NaCl Pooled 2.2 EQ and EQ w/ 1M NaCl Pooled 3.5 Below LOD for Wash, Hold, Elution and Strip

21 Evolution: Improving Robustness Evaluation of Virus Removal Fitration for multiple mabs Mass Capacity (kg/m2) 0 MAb A (11.4 g/l) MAb B (5.2 g/l) MAb C Lot A (18 g/l) MAb C Lot B (18 g/l) MAb D Lot A (26 g/l) MAb D Lot A (13 g/l) MAb D Lot B (15 g/l) MAb E Lot A (14 g/l) MAb E Lot A (7 g/l) MAb F (6 g/l) MAb G (6 g/l) MAb H (4.5 g/l) MAb I (4.5 g/l) MAb K (10 g/l) MAb L (10 g/l) MAb M (6 g/l) MAb N (2 g/l) MAb O (2 g/l) MAb Q (15 g/l) MAb R (8 g/l) MAb S (14 g/l) MAb T (5 g/l) MAb U (12 g/l) MAb X (17.6 g/l) MAb Y (22.5 g/l) MAb Z (1 g/l) Avg. 6.5 kg/m 2 Mass Capacity over Protein concentrations 1-26 g/l Clearly not robust!

22 Evolution: Improving Robustness Used Platform Knowledge to use a Cation Exchange shield filter to remove aggregates that were primary limiter of capacity Mass throughput (g/m2) Vpro alone V-Pro with CEX shield filter MAb1 MAb2 MAb3 MAb4 MAb5 MAb6 MAb7 MAb8 MAb9 MAb10 MAb11 MAb12 MAb13 MAb14 MAb

23 Where are We Now? Development effort and overall costs reduced Time to clinic and therefore to market reduced Process improvements leveraged over many products Economies of scale for equipment, components and raw materials Failure rates during GMP manufacturing reduced over time due to accumulated process experience Procedures for in-process and batch release testing become routine, implying risk of errors reduced Faster turnaround in multiproduct facilities Submissions of INDs/IMPDs during early stage development are expected to be facilitated more readily Platform processes are suitable for a modular validation approach, which in turn leads to reduced efforts and costs Overall benefit for industry, health care system and patient 23

24 Acknowledgements EBE Concept Paper Team inc. Enda Moran and Piers Alin Pascal Valax Jim Nolan Neil Soice Richard Pearce