Challenges in Commercialization of Autologous Cell Therapy Products. Bryan Silvey & Kanti Thirumoorthy Kite Quality

Transcription

1 Challenges in Commercialization of Autologous Cell Therapy Products Bryan Silvey & Kanti Thirumoorthy Kite Quality

2 Aspects Unique to Autologous Cell Therapy: Product Challenges Complex starting material (patient apheresis) leads to a complex product. Manual process needs special focus in a commercial manufacturing site Urgent patient needs when therapy is intended as last line Considerations Understanding the complex product requires complex assays (multi color flow, culture based methods) High variability No defined reference standards Manual process needs special focus in a commercial manufacturing site This necessitates rapid safety methods (for sterility and mycoplasma) validation and comparable sensitivity to compendial methods 2

3 Risk Based Approach Is Taken to Deliver Product of Desired Safety, Quality and Efficacy Use of biological materials and complex manipulation steps have different risks as per the type of product A certain level of flexibility is needed to implement measures appropriate to the specific characteristics of the process and product Responsibility of implementing control and risk mitigation strategy on the manufacturer Totality of the mitigation measures must be assessed for potential implications for the quality, safety and efficacy of the product, and risks to human health and environment 3

4 Aspects Unique to Autologous Cell Therapy: Supply Challenges One patient is one lot (just in time manufacturing) Patient specific product lot Cell therapy is a new industry Considerations No final product inventory means Manufacturing capacity in line with demand raw material inventory and vendor control are critical Chain of custody is paramount Product traceability validation strategy from vein to vein Many of the raw materials are only available from single source, and may be even only in research grade 4

5 Aseptic Processing Needs to Deliver Safe and Efficacious Product Each patient is a separate lot for autologous products Establish a multiproduct facility with adequate control If multiple lots in the same suite, then clear flow plans are needed Multi-product facility acceptable with risk mitigation to prevent mix-ups and cross-contamination Adequate operational and technical control measures Validated cleaning and decontamination procedures 5

6 Aspects Unique to Autologous Cell Therapy: Regulatory Challenges Regulations, by and large, are not geared for autologous therapy Considerations Communications with Agencies and obtaining advice is important. Guidance for facility qualification, multi product facility, Aseptic process validation and others do not address the multiple lots that would be constantly produced in commercial program Complex product, and method variability result in wide specifications Use of Risk based approach and clearly articulated justification strategy to be written in MAA/BLA Justification of specifications strategized and agreed with Agency 6

7 Communications with Regulatory Agencies and Obtaining Advice Is Very Important Guidance for FDA reviewers and sponsors: Content of CMC Information for Human Gene Therapy IND s (FDA) Guidelines on Good Manufacturing Practice for Advanced Therapy Medicinal Products for Investigational and Authorized Products (EMA) There is an acknowledgement in both these guidelines on the challenges due to complexity of starting materials, and small batch sizes Technology changing rapidly due to being in the forefront of innovation Note: FDA guidance is only for IND, EMA guidance was recently approved, and covers authorized products as well 7

8 Aspects Unique to Autologous Cell Therapy: Quality Challenges Apheresis centers are suppliers of a critical raw material Patient specific lots Considerations Audit of apheresis centers, which are traditionally GCP centers, as per GMP Vein to vein traceability needs to be validated Apheresis and infusion centers to be monitored and audited as vendors prior to launch Single source, may be non GMP raw materials in process Testing reagents are very unique with no defined reference standards Vendor quality monitoring very critical These vendors and their monitoring may be just as critical 8

9 Product Traceability Must Be from Vein to Vein Autologous products need validated processes to return the product to the patient Establish a product tracking and segregation system Control to span across apheresis center, manufacturing site, infusion center 9

10 Aspects Unique to Autologous Cell Therapy: Manufacturing Challenges Final Product comprises of living cells Manual process Considerations Final product cannot be sterilized or filtered Facility design and closed processes Emphasis on training In-process controls Patient specific lots Manufacturing capacity, resources and demand alignment 10

11 Autologous Therapies Have Many Challenges in Order to Deliver A Safe and Efficacious Product Variability in cells Vendor controls Potential for adventitious contamination Aseptic processing needs Inability to sterilize the final product Limited amount of product manufactured Need for short turn-around time Product traceability from vein to vein 11

12 Factors that May Cause lot failure - outside manufacturer s control Genetic Composition of the Patient Materials Nature of the Disease Prior Treatment and their Effect 12

13 If a lot fails. While in other medicines 1 or 2% lot failure may be acceptable; this is not so in autologous therapy Failure to release a lot means a patient does not get a dose If the failure is not due to a process error, but due to the nature of the apheresis material If there is a chance that the patient may benefit from the dose.. 13

14 When a lot fails. FDA allows for a clinical IND into which this patient is to be transferred and treated Patient monitored as part of clinical study ATMP guideline (EMA) allows for patient treatment if manufacturer provides justification that lot is safe QP accepts justification Treating physician accepts and agrees patient will benefit However, authorized product owner must operationalize as per these guidelines so that, in the event of a lot failure, an investigation can be conducted, justification approved, treating physician involved and finally patient treated in a short interval 14

15 Challenges in autologous cell therapy may be many. If a clear strategy is developed and discussed with regulatory agencies, then processes enacted, successful commercialization of products can be accomplished 15

16 Thank You 16