Challenges with Establishing a Control Strategy for Biosimilars

Transcription

1 Challenges with Establishing a Control Strategy for Biosimilars FDA/PQRI Conference on Advancing Product Quality Bethesda, MD October 5 th Barbara Rellahan MS, PhD Director, Product Quality Amgen Inc

2 Integrated Control Strategy The term control strategy refers to the combination of input, procedural and testing controls that ensure a process consistently delivers product meeting product quality attribute requirements The level of control for each individual quality attribute is determined on the basis of the criticality level of the attribute the capability of the process to consistently deliver product that meets product quality expectations An integrated control strategy includes: Procedural controls Raw material controls In process control (IPCs) testing Process monitoring and product data monitoring Release specification testing 2 Stability testing Process validation Characterization testing Control of process variation Comparability testing

3 Lifecycle Management of a Biosimilar Clinical Development Post Approval Analytical Similarity Reference product profile defines the target; Design product/process to meet similarity expectations based on characterized reference product range Formalized integrated control strategy with continued process verification Cell Line DS/DP Process Development Clinical Production Process Validation Reference Product Characterization Stand Alone Product Control strategy needs to ensure process consistently meets biosimilar product quality expectations and can support commercial production demands

4 Development/Evaluation of an Integrated Control Strategy is an Iterative Process Performed Throughout a Product s Lifecycle QTPP Development: RP is target Post Approval: Biosimilar is target PQAA PQRA Quality Target Product Profile (QTPP): The Quality Target Product Profile is defined as a prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the drug product (ICH Q8 (R2)) Product Quality Attribute (PQAA): Scores attributes based on risk to safety (immunogenicity + toxicology) and efficacy (potency + PK). Highest S/E score = attribute severity score Integrated Control Strategy Product Quality Risk (PQRA): Evaluates control based on attribute severity, occurrence (unit op impact), and detection (test strategy/capability) 4

5 Biosimilar Integrated Control Strategy Challenges Development of a control strategy for a biosimilar follows the same principles and looks very much like that of an innovator product. Points to consider for a biosimilar product are: Condensed clinical development period, introduction of the commercial process for first in human trial Establishment of attribute control ranges Translation of Tier 1 similarity assessment criteria into QTPP target range Difficult to identify full allowable attribute range of reference product (RP). Biosimilars may be required to have tighter acceptable ranges compared to RP Establishment of specifications Post approval comparability 5

6 Timing is Optimized to Support Control Strategy Development Innovator Pre-clinical Phase 1 Phase 2 Phase 3 Filing Launch/ Post-Launch Prior Knowledge Process Understanding Product Understanding Commercial Process Development (CPD) Process/Product Characterization (P&PC) Process Qualification (PPQ) Continued Process Verification PQR PQR PQR Lifecycle Management QTPP/PQ PQ PQ PQ Raw Material Raw Material Raw Material Identify process improvement needs, commercial analytical requirements, and PC strategy Evaluate risk of commercial process prior to PV and refine as controls as appropriate 6 Finalize commercial control strategy (i.e. routine testing) Reevaluate to maintain and, if needed, improve control

7 Biosimilars Have a Condensed Clinical Development Period Pre clinical Ph1 Phase 3 Filing Launch/ Post Launch RP characterization CPD Biosimilar product/process understanding P&PC PPQ Continued Process Verification PQR PQR Lifecycle Management QTPP/PQ Raw Material PQ Raw Material Identify process improvement needs, commercial analytical requirements and PC strategy Evaluate risk of commercial process prior to PV and refine as controls as appropriate Finalize commercial control strategy (i.e. routine testing) 7 Reevaluate to maintain and, if needed, improve control

8 Challenges of a Condensed Clinical Development Period Commercial process implemented at first in human study initiation PPQ preparation, including design of the commercial control strategy, may need to be initiated prior to completion of all process/product characterization work Analytical similarity assessment is a repetitive and iterative operation conducted throughout process development. Target reference product (RP) attribute ranges may therefore change during development as experience with the RP increases but needs to be locked down as product nears marketing application submission Team needs to be flexible and respond quickly to new information 8

9 Challenges with Establishment of Attribute Acceptable Ranges 1 1) Translation of Tier 1 analytical similarity expectations into a QTPP target range FDA expectations for what constitutes a Tier 1 attribute are unclear. Creates uncertainly around process capability expectations for select CQAs Tier 1 attributes are subject to very tight assessment criteria, these may translate into very tight control limits but, Tier 1 assessment uses equivalence margins that are difficult to translate directly into a QTPP target range Yi Tsong, FDA, DIA/FDA statistics Forum 2015

10 Challenges with Establishment of Attribute Acceptable Ranges 1 Tier 1 equivalence margins are difficult to translate into QTPP target ranges Tier 1 equivalence margin is a relative measure of the difference in means VS Tier 2 assessment criteria provide a range based on an estimate of the RP standard deviation 90% CI On Mean Difference Individual values 1.5 SD +1.5 SD Mean X SD Mean + X SD 10

11 Challenges with Establishment of Attribute Acceptable Ranges 2 * *Schiestl, M. et al Acceptable changes in quality attributes of glycosylated biopharmaceuticals. Nat Biotech 29: ) QTPP attribute target ranges may change over the course of development. RP range available on the market during the development of a biosimilar may not be reflective of the allowable attribute range for the reference product Biosimilar manufacturers may be restricted to a much tighter attribute range compared to that of the innovator

12 Areas of Uncertainty for the Biosimilar Integrated Control Strategy Establishment of Specifications Regulatory expectations for commercial specifications are not completely clear EU guidance The selection of tests to be included in the specifications (or control strategy) for both drug substance and drug product is product specific and should be defined as described in ICH Q6B US guidance No specific reference to expectations for development of a biosimilar controls strategy in guidance documents 12

13 Areas of Uncertainty for the Biosimilar Integrated Control Strategy Establishment of Specifications An enhanced, quality by design approach is being used for establishment of the biosimilar specifications. Incorporate extensive product and process knowledge to optimize control strategy and reduce redundant testing Specification acceptance criteria will be based on biosimilar process and product knowledge, and historical data DS specification example Parameter Test Method Acceptance Criteria Identity ELISA Pass Purity SE-HPLC 1.5% HMW Bacterial endotoxins 0.2 EU/mg Adventitious agents Bioburden 10 CFU/10 ml Process impurity clearance validation Optimized IPC testing Drug product specification testing Stability testing Potency Bioassay 80% to 120% relative potency 13

14 Areas of Uncertainty for the Biosimilar Integrated Control Strategy Establishment of Specification Acceptance Criteria Base on biosimilar historical data or incorporate RP information into range? Specification acceptance criteria should primarily be based on the biosimilar s historical data since that is reflective of pre clinical and clinical experience, with consideration for process capability Minor differences in clinically inactive components may be present between the RP and biosimilar that could impact specification acceptance criteria (eg, C terminal lysine variant by CEX HPLC) Per ICH Q8 (R2) The degree of regulatory flexibility is predicated on the level of relevant scientific knowledge provided Use of RP knowledge should be allowed if justified by process and product understanding

15 Specification Acceptance Criteria Hypothetical example Biosimilar process understanding Defect Biosimilar product understanding RP range TIUL TI LL RP range BS Actual BS Predicted Biological Activity Attribute A Based on demonstrated process control, and process and product understanding (including that of the reference product), it may be acceptable to use RP characterization data to justify acceptable ranges for some attributes

16 Expectations for Post Approval Comparability is Another Area of Uncertainty for the Biosimilars Definitions Comparability Comparison of pre change and post change products from the same manufacturer: Knowledge of product clinical experience, process history, and control strategy Similarity Comparison of a biosimilar product to a reference product from a different manufacturer: Gaps in prior knowledge (animal, safety, and critical studies) 16

17 Areas of Uncertainty for the Biosimilar Integrated Control Strategy Post approval comparability EU Guidance: It is acknowledged that the biosimilar will have its own lifecycle. When changes to the manufacturing process (active substance and/or finished product) are introduced during development, a comparability assessment (as described in ICH Q5E) should be performed. there is no regulatory requirement for re demonstration of biosimilarity once the Marketing Authorisation is granted. Health Canada Guidance: Once a Notice of Compliance (NOC) is issue for a Subsequent Entry Biologic it is considered to be a new biologic drug (i.e. a "stand alone" product) and regulated accordingly. After a manufacturing change to the Subsequent Entry Biologic or reference biologic drug, a Subsequent Entry Biologic sponsor is not required to reestablish its similarity to its reference biologic drug. US Guidance: No specific reference to biosimilar post approval comparability expectations in guidance documents 17

18 Areas of Uncertainty for the Biosimilar Integrated Control Strategy Post approval comparability After approval, biosimilar products should be considered stand alone products and utilize comparability to support process changes Biosimilar manufacturer s can not be locked into the process being used at the time of MA approval. They need to have the ability to make process changes post approval Once approved as a biosimilar, the biosimilar manufacturer can not be tied to the attribute profile of the reference product that is currently on the market since there may be changes in the RP profile compared to the original profile the biosimilar met to gain regulatory approval Comparability assessments have a long history of providing a robust assessment of the impact of process changes on product quality and are sufficient to control/limit biosimilar attribute shifts after post approval changes Post approval continued process verification and product monitoring are sufficient to control/limit process drift 18

19 Summary Biosimilars have a condensed clinical development period Biosimilar s have a unique lifecycle in that during development the characterized reference product range is the target for process development, whereas after approval the biosimilar should become a stand alone product Biosimilar specifications should primarily be established based on the biosimilar s historical knowledge and experience though the characterized RP range may be considered if justified appropriately Comparability should be used to support post approval manufacturing changes as this will ensure the quality attribute ranges of the biosimilar s remain consistent with those of the biosimilar s pre clinical and clinical experience including the analytical similarity assessment that supported biosimilar approval

20 Acknowledgements Rick Burdick Barry Cherney Gino Grampp Simon Hotchin Margaret Karow Tony Mire-Sluis 20