"Attribute Capability Study Format - PDF"
The 2nd QbD Conference QbD in Large Molecules: The A-Mab t d by the Biotech Th A M b case study b th CMC Bi t h Working group Dan Kenett May 5 2010 Jerusalem 1 OUTLINE Background: Therapeutic Monoclonal Antibodies Selected A-Mab chapters: Design of Molecule and Quality Attributes Assessment Upstream Manufacturing Process Development Control Strategy 2 1 OUTLINE Background: Therapeutic Monoclonal Antibodies Selected A-Mab chapters: Design of Molecule and Quality Attributes Assessment Upstream Manufacturing Process Development Control Strategy 3 Therapeutic Monoclonal Antibodies A total of 21 mAb products are approved in the US, with additional products marketed outside the US mAb therapeutics are now being developed and marketed by most major pharmaceutical firms 7 mAbs have global sales of over US$1 billion In 2006 global market = US$20 billion , in 2010 expected to reach US$40 billion over 200 mAb candidates are currently undergoing clinical study Reichert J.M. Current Pharmaceutical Biotechnology 2008, 9, 423-430 4 2 Monoclonal antibody structure Schiesti M. (Sandoz) PMDA symposium 2009 5 Possible natural modes of action of mAbs versus cells cells 6 Schiesti M. (Sandoz) PMDA symposium 2009 3 1975 1986 1994 1997 2002 Cell fusion with cancerous cells recombinant DNA technology 7 Schematics of a manufacturing process of a monoclonal antibody 12000L Upstream Downstream Kozlowski and Swann , Quality by Design for Biopharmaceuticals 2009 8 4 FDA Initiatives and QbD Timeline Small molecule ACE Large molecule A-Mab mock mock case study by case study by CMC Conformia Biotechnology Working Group 2010 9 QbD Mock Case studies Small Molecules (Pharmaceutical) 1. Examplain (P2 module of CTD format) – 2006 EFPIA http://www.efpia.org/Content/Default.asp?PageID=450 2. Acetriptan (ACE) - 2008 cet pta ( C ) 008 Conformia software collaboration with Abbot, AstraZeneca, Eli Lilly, GlaxoSmithKline 3. Illustrain Hcl (S2 module of CTD format)- 2009 target EFPIA Monoclonal Antibody (Biopharmaceuticals) 1. A-Mab - 2009 CMC working group of 7 leading Biotech companies:Amgen, Genentech, Abbot Bio MedImmune, GlaxoSmithKline Bio, Eli Lilly , Pfizer Bio http://www.casss.org/displaycommon.cfm?an=1&subarticlenbr=286 2. Mockestuzumab (S2 and P2 module of CTD format) –2010 target EFPIA 10 5 11 What is A-Mab ? Humanised IgG1 against Lymph-1 (a surface antigen on CD20 B cells) which is expressed at high levels at surface of B cells from NHL (Lymphoma) patients A-Mab stimulates CD20 B cells killing primarily through ADCC and possibly also by CDC It is produced by recombinant DNA technology in CHO cells Delivered by IV administration at a weekly dose of 10mg/kg for 6 weeks http://images.google.com/imgres?imgurl=http://rss.xinhuanet.com/newsc/english/2008-03/11/xin_142030511140539054143.jpg&imgrefurl=http://rss.xinhuanet.com/newsc/english/2008- 12 03/11/content_7765049.htm&usg=__oTBauuUxMAYhD-9QSKw8J0uKqs4=&h=442&w=450&sz=21&hl= 6 The A-Mab chapters 1. Design of Molecule and Quality Attributes Assessment 2. Upstream Manufacturing Process Development A Mab 3. A-Mab Downstream Process Description and Characterization 4. Drug Product 5. Control Strategy 6. Regulatory Section 13 OUTLINE Background: Therapeutic Monoclonal Antibodies Selected A-Mab chapters: Design of Molecule and Quality Attributes Assessment Upstream Manufacturing Process Development Control Strategy 14 7 Initial Target Product Profile TPP=Prospective and dynamic summary of the quality characteristics of a drug product that ideally ill be hi d to id ll will b achieved t ensure th tthat the desired quality, and thus the safety and efficacy, of a drug product is realized Quality attributes of Drug Product not yet defined 15 Design Features of A-Mab The design strategy for A-Mab was: By planning the DNA To maximize clinical performance sequence To minimize potential impact on quality To mitigate risk from the following product attributes: Unpaired cysteine residues (reduced risk of undesirable disulfide bond formation) Potential deamidation sites in the CDRs (reduced risk of deamidation) O-linked glycosylation sites (reduced risk of heterogeneity and impact on bioactivity) N-linked glycosylation sites in the CDRs (reduced risk of heterogeneity and impact on bioactivity) Acid labile (DP) sequences (reduced risk of fragmentation) Oxidation sites in the CDR 16 8 Quality Attributes of Quality attributes that can vary quantitatively and qualitatively in a process monoclonal antibodies 17 Systematic Identification of critical Quality Attributes 18 9 Overview of A-Mab Product Realization Process 19 Overview of A-Mab Product Realization Process 20 10 Platform Knowledge 21 Quality Attribute Risk Assessment Tools Three types of tools for assessing criticality of quality attributes are presented as examples: Risk ranking (Tool #1) Criticality = Impact x uncertainty Preliminary hazards analysis (PHA) (Tool #2) Criticality = Severity (safety,efficacy) x Likelihood (probability of AE due to out of range) A safety assessment decision tree for evaluating process-related impurities that do not have biological activity based on ISF(Tool #3) The impurity safety factor ( p y y ) (ISF) = LD50 ÷ Level in Product Dose 22 11 Quality Attribute Assessment Tool #1 Impact: The impact ranking of an attribute assesses either the known or potential consequences on safety and efficacy. The impact ranking attribute s considers the attribute‘s effect on: 1. efficacy, either through clinical experience or results using the most relevant potency assay(s), 2. pharmacokinetics/pharmacodynamics (PK/PD), 3. Immunogenicity 4. safety. 23 Impact : Definition and Scale for Tool #1 24 12 Uncertainty: Definition and scale for Tool #1 25 Criticality: Definition Criticality (Risk Score) = Impact × Uncertainty All quality attributes are assigned a degree of criticality (criticality continuum) based on their respective risk score. Risk scores range between a low of 2 to a high of 140. 26 13 Examples of Quality Attribute Risk Assessment with Tool#1 (WHO) 27 A-Mab examples of Tool #1 Aggregation Moderate high DNA None Moderate The individual impact category with the highest ranking determines the overall impact ranking for an attribute 28 14 Summary of Quality attribute Risk assessments Vary according to mode of action Critical quality attribute includes H and VH 29 Critical Quality attributes and target ranges 8 Quality Attributes 30 15 OUTLINE Background: Therapeutic Monoclonal Antibodies Selected A-Mab chapters: Design of Molecule and Quality Attributes Assessment Upstream Manufacturing Process Development Control Strategy 31 32 16 Design Space for Bioreactor Production with Reliability Control Space Based on the Overall Reliability of dimension Design space for culture duration 15 days the Process (Predictive Bayesian Reliability approach) Regions in dark-red possess > 99% reliability to satisfy all the CQA limits 20-40% and determine the Control Space 2-11% To achieve a response surface model by DOE suitable to define a Design space N=40 bioreactor runs (4 blocks of 10, ~12 weeks) X-Mab data 33 Design space for Production Bioreactor 34 17 Design space examples in A- Mab Upstream production bioreactor Low pH viral inactivation Drug product compounding Drug product sterile filtration Bioreactor engineering 35 OUTLINE Background: Therapeutic Monoclonal Antibodies Selected A-Mab chapters: Design of Molecule and Quality Attributes Assessment Upstream Manufacturing Process Development Control Strategy 36 18 QbD vs Traditional approach for the Control Strategy 37 Risk Assessment Approach used through Development Lifecycle and for setting Control Strategy Prior knowledge and early development experience used to identify parameters and attributes that must be considered for process characterization studies 38 19 Risk Assessment Approach used through Development Lifecycle and for setting Control Strategy The cumulative process understanding serves as the basis for the late-phase risk assessments used to finalize selection of Critical Process Parameters (CPPs) that underpin the proposed design spaces and control strategy. 39 Final Categorization of Process Parameters for A-Mab Control Strategy 40 20 Example: Risk Assessment Results for Process Parameters in the N-1 and Production Bioreactor 41 Categorization of Process parameters examples in A-Mab Protein chromatography Low ph viral inactivation Cation exchange chromatography Anion exchange chromatography Small virus retention filtration Drug product compounding 42 21 Control Strategy for commercial manufacturing Output of Risk assesment Tool #1 Each CQA is evaluated independently to ensure that the proposed control strategy will deliver each CQA within its acceptable ranges established for safety and efficacy. A Failure Mode and Effects Analysis (FMEA) approach was used 43 Example: Final Risk Assessment Results for Process Parameters in the Production Bioreactor Glycosylation: 8 WC-CPP, 3 CPP Glycosylation: 5 WC-CPP, 0 CPP Initial Process parameters categorization …And after Design space (Control space) fine tuning 44 22 Process Capability Scales for Severity, Occurrence and Detection The overall score (RPN=SxOxD) was calculated for each unit operations 45 Scoring for Process Capability Risk Assessment of Unit Operations 46 23 Examples of Process Capability Risk Assessment (Risk assessment #3) 47 A-Mab Control Strategy Control Strategy Product Understanding 48 24 Elements of the Control Strategy 49 Elements of the Control Strategy 50 25 Specifications Tests Based on the enhanced product and process understanding, specification tests are significantly reduced compared to traditional approaches. Some specification testing has been moved to in-process tests (including PAT) while other tests were eliminated because operation within the process design space provides a high degree of assurance that the process will deliver consistent product quality 51 52 26 Example: Control elements for Oligosaccharide Profile Process capability risk assesment; RPN=30 Low 53 Example: Integrated Control Process capability risk elements for Aggregation assesment RPN 30 Low 90 Med. 300 High 1000 High 54 27 Control elements for Aggregate1 and Oligosaccharide2 profile in A-Mab CQA Process Input Procedural Process In- Specification Process Stability Characterization capability material control parameter process Monitoring Testing Testing Risk Testing control tests Aggregate High Y Y N N Y Y Y Y Oligosaccharide Low Y Y Y N N Y N Y profile 1 summary of control elements assigned to various downstream process steps 2 control elements assigned to bioreactor production Arrow indicates differences 55 Control strategy examples in A- Mab Upstream Downstream Drug product compounding Drug product sterile filtration Drug product filling, stopping, capping 56 28 Quality Attribute Ranges for A-Mab Process For the purposes of this case study, only a selected number of quality attributes were considered to define the Control Strategy. Normally, the approaches presented here would be expanded to include all critical quality attributes LRV=log reduction value 57 Summary A-Mab is a document for public consumption and ultimately a backbone for further discussion between industry and agencies across 2009-2010 and beyond First comprehensive exemplification of a Mock Biotech product developped with QbD principles Essential in order to overcome “conceptual hurdles” facing those involved in applying QbD Science based driven all the way Risk assessment tools used for identification of CQA and categorization of Process parameters Illustration of a complex Design Space for the Bioreactor production stage and of the innovative Engineering Design Space concept The Control Strategy provides a high degree of assurance that the product quality specifications are met. 58 29 Take away from A-Mab Traditional Product Development Quality by Testing (reactive) Product=Process Enhanced Product Development Quality by Design (proactive) Targetted Product Characterised and controlled Process Product=Characterised 59 And thanks to the Biotech CMC Working Group for this inspiring masterpiece !!! 60 30