Lessons Learned from QbD Application of Biologics in Japan: Perjeta Case

Transcription

1 Lessons Learned from QbD Application of Biologics in Japan: Perjeta Case Mikio Suzuki CMC Development Dept., Regulatory Affairs Chugai Pharmaceutical Co.,Ltd.

2 Outline Introduction of Perjeta Timeline up to approval of Perjeta in Japan Overview of Perjeta QbD approach Manufacturing process in Module 1 (Application Form) for QbD approach Specifications & test methods in Module 1 (Application Form) for QbD approach 2

3 Perjeta INN: Pertuzumab Pertuzumab is a full length recombinant, humanized, immunoglobulin IgG1 monoclonal antibody that is directed to sub-domain II of the human epidermal growth factor receptor 2 (HER2) and prevents dimerisation of HER2 with other HER2 members of HER family. Indication is HER2-positive metastatic breast cancer. Manufacturer: Genentech & Roche Status of approval Pertuzumab Dimerization domain (Sub-domain II) HER1/3/4 In 2012: US, Switzerland, Mexico In 2013: EU, Russia, Canada, Australia, Brazil, Korea, Taiwan, Japan, New Zealand, South Africa,. 3

4 Timeline up to approval of Perjeta in Japan ~ 7 ~ 2 ~ PMDA consultation meeting on quality PMDA meeting Filing Q&A Drug Committee Approval PMDA meeting Filing (Dec.) US approval EU approval 4

5 Overview of Perjeta QbD approach Approach to Implementing QbD CQA Identification RRF Analytical Testing Strategy RA Product Attributes Process Development Platform Knowledge Product Understanding Scientific Literature Final CQAs Process Characterization CQA Acceptance Criteria Linkage Studies Control Strategy Design Space & CPP Identification PALM Post Approval Lifecycle Management Plan Process Parameters PC/PV Study Design RRF CPP Identification Decision Tree 5

6 Identification of CQA Impact Scale for Risk Ranking and Filtering Tool for Criticality Assessment of Product Variants and Process-Related Impurities Impact and Rating Very High (20) High (16) Moderate (12) Low (4) None (2) Biological Activity > 100% change 40% 100% change 20% 40% change < 20% change No change PK Immunogenicity Safety > 40% change 20% 40% change with impact on PD 20% 40% change with no impact on PD < 20% change with no impact on PD No impact on PK or PD ATAs detected that may be life threatening ATAs detected that may be associated with non-life-threatening loss of efficacy ATAs detected with effect that can be managed by clinical treatment (i.e., dose titration, medication, etc.) ATAs detected with effect on PK or PD, but no effect on safety or efficacy ATAs not detected or ATAs detected with no effect on PK, PD, safety, or efficacy Irreversible or life-threatening AEs and/or life-threatening loss of efficacy Reversible AEs and/or loss of efficacy that is not life threatening AEs that can be managed by clinical treatment (i.e., dose titration, medication, etc.) Safety or efficacy effect with minimal clinical significance No effect on safety or efficacy 6

7 Identification of CQA Uncertainty Scale for Risk Ranking and Filtering Tool for Criticality Assessment of Product Variants and Process-Related Impurities Rank Uncertainty Description (Product Variants and Host Cell Derived Impurities) 7 Very High No information (new variant). 5 High Published external literature on variant in related molecule. 3 Moderate Nonclinical or in vitro data on this molecule. Data (nonclinical, in vitro, or clinical) on a similar class of molecule. 2 Low Variant has been present in material used in clinical studies. 1 Very Low Impact of specific variant established in clinical studies with this molecule. Risk Scoring for Product Variants and Process-Related Impurities Uncertainty Impact 20 (Very High) 16 (High) 12 (Moderate) 4 (Low) 2 (None) 1 (Very Low) 2 (Low) 3 (Moderate) 5 (High) (Very High)

8 Establishing CQA-AC (CQA-Acceptance Criteria) CQA-AC: Criteria or acceptable levels of CQA in terms of safety and efficacy, is established based on in vitro, nonclinical, and clinical studies For CQA due to safety or immunogenicity concerns, CQA-AC is based on clinical experiences including data obtained from similar products if applicable. For CQA due to potency or PK, CQA-AC is based on in vitro biological assay or non-clinical experiences including data obtained from similar products if applicable. Cumulative impact of all CQAs on potency or PK is within 20% (potency) or 20% to 25% (PK). 8

9 Parameter 1 Identification of CPP Design Space Design Space composed of multivariate acceptable ranges (MARs) for all critical process parameters (CPPs) Impact Ratio Impact Ratio = Process Mean MAR Result Process Mean CQA-TR Impact Ratio numerator Proven Acceptable Range (PAR) Multivariate Acceptable Range (MAR) Parameter 2 CQA-AC LL CQA Output: Process Mean Result at MAR CQA-AC UL CQA-TR LL Impact Ratio denominator CQA-TR UL CQA-AC LL = lower limit of CQA-AC; CQA-AC UL = upper limit of CQA-AC; CQA-TR LL = lower limit of CQA-TR; CQA-TR UL = upper limit of CQA-TR. Impact Ratio > 0.33: High Impact 0.33 Impact Ratio 0.10: Low Impact 0.10 > Impact Ratio: Non Impact 9

10 Identification of CPP Worst case linkage studies Designation of CPP (High-Impact CPP/Low- Impact CPP) / non-cpp 10

11 CTD Module 1, 2.3, 3 in Japan Can Module 1 be made simpler if QbD approach is applied because companies have obtained the deep knowledge of manufacturing process and quality attributes? Module 1 (Application Form) Legally binding Manufacturing Process (PCA/MCN item), Spec.& test methods. Module 2.3 (QOS) Supportive information for HA review Module 3 11

12 Module 1 (Manufacturing Process) in QbD approach MCN items: items which are confirmed not to adversely affect quality and safety of final product (Notification No dated Feb. 10, 2005) Assessment Process Parameters M1 (Application Form) Proposed Category High-Impact CPP Low-Impact CPP Non-CPP Partial Change Application (PCA) item Minor Change Notification (MCN) item Not described Impact ratio In Module 1, the following information should be described Steps needed for quality assurance critical steps, important apparatuses, important process parameters.. (Notification No dated Feb. 10, 2005) 12

13 PMDA s position for Non-CPP Even if a process parameter is classified as non-cpps, such PPs should be also described in M1 Because: 1.Quality is assured by all PPs including non-cpps 2.Effects on CQAs are unknown when processes are operated outside the investigated ranges (MAR), therefore non-cpps can not be considered as PPs which affect CQA little 3.It is necessary for PPs to be described appropriately in M1 so that outline of manufacturing process can be understood 13

14 Module 1 (Manufacturing Process) in QbD approach Non-CPP of Affinity Chromatography step as an example Assessment M1 (Application Form) Process Parameters Proposed Approved Impact ratio High-Impact CPP Low-Impact CPP Non-CPP PCA item MCN item Not described PCA item MCN item Not described Information of process parameters in M1 was almost the same as traditional approach s one 14

15 Module 1 (Manufacturing Process) in QbD approach Assessment M1 (Application Form) Process Parameters Proposed Approved Impact ratio High-Impact CPP Low-Impact CPP Non-CPP 28 PCA item MCN item Not described PCA item PCA item MCN item Not described MCN items is items which are confirmed not to adversely affect quality of final product (Notification No dated Feb. 10, 2005) 15

16 PMDA s position for Low-Impact CPP Effects on CQAs are unknown when processes are operated outside the investigated ranges (MAR), therefore Low-Impact CPPs can not be considered as MCN PPs which do not affect on efficacy & safety and can be changed without prior approval CQA-AC Quality Impact Low-Impact CPP: based on impact on CQA within this range? Unknown; impact on CQA outside of the range MAR parameter 16

17 PMDA s position for MCN classification Case C: No EOF within the range of planned DSp, and realistically expected range of PPs is far from EOF. Case C: Other PPs ranked as medium risk MCN This idea was also presented by Takagi, PMDA, in some symposium (e.g., 9 th DIA annual meeting 2012) Okuda H., Joint Research Report (Health and Labor Sciences Research Grants in 2011),R&D of Drug Substances by the Methodology of Quality by Design 17

18 Question for MCN classification Is it impossible for companies to define MCN items based on assessment within the investigated range of PPs? What is realistically expected range of PPs? Should companies determine the edge of failure (EOF)? Is it possible to determine the degree of criticality for PPs based on assessment within the investigated range? 18

19 Our opinion for MCN classification Companies have obtained the deep knowledge of manufacturing process, process parameters and quality attributes of the product through QbD approach Based on scientific assessment within the investigated ranges (MAR) including statistical consideration, MCN can be claimed Regulatory requirement: change for MCN items needs implementation of appropriate validation and change control From regulatory perspective, the classification based on realistic, scientific assessment may be one of companies incentive for QbD approach in Japan 19

20 Design Space Our proposal: Design Space is defined as MARs of CPPs (High/Low-impact CPP) PMDA s position: MARs of not only CPPs but also non-cpp should be included in Design Space, because the quality is assured under control of all parameters including non-cpp within investigated range (MARs) Our amendment: Design Space is expanded to MARs of all process parameters including non-cpps Design Space was accepted in Japan 20

21 Module 1 (Spec. & test methods) in QbD approach ICH Q6B: Specifications Acceptance criteria should be established and justified based on Data obtained from lots used in preclinical and /or clinical studies Data from lots used for demonstration of manufacturing consistency Data from stability studies Relevant development data mean 3SD, 95/99TI, etc. In Perjeta case, CQA-AC 21

22 Module 1 (Spec. & test methods) in QbD approach Specifications based on CQA-AC are reasonable in QbD approach with Design Space! Because CQA-AC is established based on a risk assessment considering efficacy and safety, and is independent from manufacturing consistency Design Space is constructed to assure CQA-AC The product quality probably has a variety within CQA-AC when process parameters are operated within Design Space Therefore, when Design Space is accepted, specification should be based on CQA-AC Specifications are wider due to independence from manufacturing consistency 22

23 PMDA s position for Specifications Inquiry from PMDA Proposed DS/DP specifications should be reconsidered based on manufacturing data and lot analyses for drug substance and drug product used in the clinical studies. Safety and efficacy is assured by clinical studies using lots which is confirmed manufacturing consistency, therefore, specification should be based on data of lots used for demonstration of manufacturing consistency and lots used in clinical studies. 23

24 - Innovation all for the patients - 24