CASE STUDY: THE USE OF PRIOR KNOWLEDGE IN ESTABLISHMENT OF AN INTEGRATED CONTROL STRATEGY AND CLINICALLY RELEVANT SPECIFICATIONS

Transcription

1 CASE STUDY: THE USE OF PRIOR KNOWLEDGE IN ESTABLISHMENT OF AN INTEGRATED CONTROL STRATEGY AND CLINICALLY RELEVANT SPECIFICATIONS BARBARA RELLAHAN MS, PHD DIRECTOR, PRODUCT QUALITY

2 PRESENTATION OUTLINE Historical perspective on the evolution of manufacturing and testing controls, and product development approaches What is prior knowledge, how is it used in QbD development Use of prior knowledge to development of the integrated control strategy and clinically relevant specifications Case Studies 2

3 EVOLUTION OF MANUFACTURING AND TESTING STANDARDS, AND DEVELOPMENT APPROACHES ICH standardization Q2 Analytical Validation (1994) Q5 Quality of Biotechnological Products ( ) Q6 Specifications (1999) Q7 GMP (2000) CTD (2003) Q3 Impurities (2006) Traditional Empirical development Fixed manufacturing process Quality assured by testing Reactive lifecycle management 3 ICH Q8/Q9/Q10 (11) ( ) Develop a harmonized pharmaceutical quality system applicable across the lifecycle of the product emphasizing an integrated approach to quality risk management and science Systematic/QbD (ICH Q8-11) Systematic evaluation and mechanistic understanding of impact of process on product quality attributes Integrated Control Strategy Preventive lifecycle management and continual improvement Quality and Risk Management Systems, use of prior knowledge

4 WHAT IS PRIOR KNOWLEDGE 1- ICH Q10: prior knowledge (public domain or internally documented); 2- ICH Q11: Prior knowledge can include established biological, chemical and engineering principles, technical literature, and applied manufacturing experience. 3- ICH Q8/Q9/Q10 training materials - (science, GMP, regulations ) Internal knowledge from development and manufacturing including citation in regulatory filings internal company report or notebook, data from other compounds using similar platform technologies External knowledge: scientific and technical publications (including literature and peerreviewed publications) First principles knowledge from texts/papers/other respected sources No citation necessary if well known and accepted by scientific community All product specific, and relevant internal and public knowledge 4

5 KEY STEPS IN IMPLEMENTATION OF QBD FOR A BIOTECHOLOGY PRODUCT (ICH Q8 (R2)) QTPP forms basis of design for the development of the product Product quality attribute assessment (PQAA) ranks the risk of an attribute having a clinical impact to identify quality attributes with higher risk that need to be within an appropriate range/limit to ensure the desired product quality (critical quality attributes) Lifecycle management QTPP Product quality attribute assessment Product Risk Assessment (s) (PQRA) to link material attributes and process parameters to CQAs Control Strategy designed to ensure that a product of required quality will be consistently produced Integrated control strategy Product risk assessment Lifecycle management and continuous improvement 5

6 PRIOR KNOWLEDGE USED FOR ALL MAJOR STAGES OF CONTROL STRATEGY DEVELOPMENT Attribute Identification PQAA assessment guided by list of obligatory and platform quality attributes Attribute criticality assessment PQAA baseline scoring criteria for attributes based on safety (immune and non-immune related) and efficacy (PK and potency) Establish attributes ranges QTPP (desired ranges); specifications (range within which no impact to safety/efficacy) Control establishment and assessment PQRA evaluates control strategy All stages utilize prior knowledge and platform approaches. Info is updated such, contains forward-looking through statements, lifecycle actual results may vary as additional 6knowledge becomes available

7 PRIOR KNOWLEDGE IS CRITICAL TO THE DEVELOPMENT OF CLINICALLY RELEVANT SPECIFICATIONS Traditional ICH Q6B Provides definition of specification, indicates specifications largely based on; - Historical experience - Analytical methods - Consistency lots - Stability considerations Systematic/QbD ICH Q8 (R2) and Q11- Specifications and acceptance criteria based on process/ product understanding (ie, prior knowledge) 7 ICH Q8 Q11 A greater understanding of the product and its manufacturing process can create a basis for more flexible regulatory approaches The degree of regulatory flexibility is predicated on the level of relevant scientific knowledge provided in the registration application Adoption of the principles in this guideline can support the justification of alternative approaches to the setting of specification attributes and acceptance criteria as described in Q6A and Q6B

8 USE OF PRIOR KNOWLEDGE DURING THE ESTABLISHMENT OF CLINICALLY RELEVANT SPECIFICATIONS Clinically relevant specifications are based on risk to clinical performance, not what can be achieved by process (Janet Woodcock, CDER, Evolution In FDA s Approach To Pharmaceutical Quality) Based on ICH guidance and QbD development paradigm, it is appropriate to use risk and science based strategies, which include the use of prior knowledge, to establish specification limits that ensure patient safety and product efficacy if appropriately supported Patient Safety Flexibility 8

9 CLINICALLY RELEVANT SPECIFICATIONS 1 - ATTRIBUTE FOCUSED CONTROL Traditional: Method/Specification Focused QbD: Focus on critical attributes (PQAA), most sensitive method for detection Appearance SE-HPLC rce-hplc CEX-HPLC Potency ph Osmolality Protein concentration Etc Attribute Current Future Size variants - Clips Purity Charge Variants Glycans Identity rce-sds CEX-HPLC Glycan Map Immunoassay Mass spec multiattribute method (MS-MAM) Size variants - HMW SE-HPLC SE-HPLC 9

10 CLINICALLY RELEVANT SPECIFICATIONS 2 - OPTIMIZE TESTING POINT IPC vs Specification/RTRT o Stability o Non CQAs used as process consistency measures have action limits not rejection limits Removal of stability tests for attributes that are not stability indicating Is routine testing required o o o Remove redundant tests that control the same attribute and/or are performed at multiple points in the process Removal of tests for impurities with well understood mechanisms for removal and proven process capability (eg. HCP, DNA, Protein A) Remove tests for quality attributes that are well controlled during manufacturing and where adequate detections are in place to identify issues. Monitor only after changes made for comparability 10

11 CLINICALLY RELEVANT SPECIFICATIONS 3 - IDENTIFYING AN ACCEPTABLE ATTRIBUTE RANGE QAs should have a range within which safety and efficacy may be defended without direct clinical exposure (clinically qualified range) Variation of attribute levels within the clinically qualified range (CQR) will not result in a meaningful difference in clinical activity compared to that established in the clinical trials The CQR will vary based on the QA s potential impact to product quality determined by prior knowledge, biological impact of the product attribute, and clinical experience with the product Low severity QAs: the acceptable range may go significantly beyond clinical exposure High severity QAs: the acceptable range will be based on clinical exposure Attribute Severity Acceptable range tied to clinical exposure 11

12 IDENTIFYING A CLINICALLY QUALIFIED RANGE Information used to assess attribute impact and set specifications/control strategy include: Pre-clinical and clinical experience, including dose escalation studies, age of the material used, MoA, immunogenicity Product specific information including the degradation pathways, and biological and physicochemical characterization of purified or enriched attribute pools Prior knowledge based on relevant experience and literature - In vivo assessment of attribute levels - In vitro immunogenicity assessments Attribute Severity Acceptable range tied to clinical exposure 12

13 DEFINING A CLINICALLY RELEVANT RANGE LOW CRITICALITY ATTRIBUTE - mab DIMERS HMW Dimer Species Levels well controlled by process/raw material controls Is a common degradation pathway for liquid drug products stored at 2-8 C and is detected by SE-HPLC 13

14 DEFINING A CLINICALLY RELEVANT RANGE LOW CRITICALITY ATTRIBUTE- mab DIMERS Sample Relative Potency (%) Drug substance 108 Monomer pool 105 HMW pool (82% HMW) 90 Product maby Stability data indicate increase in HMW species during storage due to increase in dimers, no higher order aggregates form even under accelerated/stressed conditions In vitro data from purified HMW pool indicates low impact to potency Dimers have a low valency and therefore have a low risk of impacting immunogenicity Acceptable range can be established beyond clinical experience with a low risk to safety and efficacy 14

15 SUCCESS BUT WITH MIXED REGULATORY ACCEPTANCE DP release (SE-HPLC HMW) DP stability (SE-HPLC HMW) Region 1 0.7% 1.0% Region 2 1.5% 2.0% Region 3 0.7% 1.0% Now have additional information on immunogenicity from an internal study which supports low immunogenicity risk TI = 0.3% release, 0.8% stability 15

16 DEFINING A CLINICALLY RELEVANT RANGE LOW CRITICALITY ATTRIBUTE NON-CDR DEAMIDATION Non-CDR deamidation Levels well controlled by process/raw material controls Is a common degradation pathway for liquid drug products stored at 2-8 C and is detected by CEX-HPLC in the acidic peak CQAs that may also be present in the acidic peak are monitored directly via other tests 16

17 DEFINING A CLINICALLY RELEVANT RANGE LOW CRITICALITY ATTRIBUTE NON-CDR DEAMIDATION (Product mabx) Potency Product Characterization (Forced Degradation Studies) % Non-CDR The increase in acidic peak during DP storage is due to an increase in non-cdr deamidation In vitro data from potency assays, experience from other Amgen mabs, and literature indicate low risk to impacting potency or PK Modification is present on naturally occurring IgG molecules and is therefore of low risk to immunogenicity Acceptable range can be established beyond clinical experience with a low risk to safety and efficacy. May be appropriate to remove monitoring of non- CDR deamidation from routine testing strategy 17

18 SUCCESS BUT WITH MIXED REGULATORY ACCEPTANCE DP Release (Acidic Peak) DP Stability (Acidic Peak) Region 1 18% 22% Region 2 18% 25% Region 3 18% 25% Difference in stability acceptance criterion between regions resulted in shorter expiry period in Region 1 compared to Regions 2 and 3 TI = 18.1% release, 24.5% stability 18

19 DEFINING A CLINICALLY RELEVANT RANGE HIGH CRITICALITY ATTRIBUTE- GLYCAN Effector Function Glycan Glycan % Tolerance Interval 2.7 to 11.0 Proposed Specification 4.8 to 10.0 Glycan classified as CQA due to impact on effector function Direct correlation between glycan levels and effector function Correlation used to establish control range Proposed range was narrowed compared to the statistically derived range (but still wider than clinical min/max range) due to potential clinical impact 19

20 KNOWLEDGE MANAGEMENT EXAMPLES Prior Knowledge captured in the PQAA (mab) Biological relevance site **Examples of prior knowledge, not comprehensive 20

21 NEXT STEPS Prior knowledge needs to be documented in a form that is easily communicated/understood for use in process/product development activities and regulatory filings Industry needs to work with regulators to identify type and extend of information/data needed to support establishment of clinically relevant control strategies and specification ranges Industry needs to identify and address gaps in the understanding of attribute impact and publish findings in literature to build cross-product/cross-industry knowledge database 21

22 THANK YOU Acknowledgments Darrin Cowley Barry Cherney Jetta Wypych Linda Narhi Andrew Lennard Bob Kuhn 22