PRELIMINARY PROGRAM Midwest Discussion Group Co-Chairs

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PRELIMINARY PROGRAM

Midwest Discussion Group

Co-chairs:

James Carroll, Pfizer, Inc. Kathy Lee, Eli Lilly and Company

Eli Lilly and Company Campus June 2, 2016

Table of Contents

Conference Program Partners………………………………………………………………..…3

Acknowledgements…………………………………………………………………………….4

General Information……………………………………………………………………………5

Scientific Program Summary…………………………………………………………………..6

Program and Speaker Abstracts………………………………………………………………..7

Roundtable Discussion Point Sheets…………………………………………………….…….10

Note Paper……………………………………………………………………………………..17

The Organizing Committee gratefully acknowledges the Conference Program Partners for their generous support of this inaugural Midwest Discussion Group

Program Partners

AbbVie, Inc.

Agilent Technologies

Cook Pharmica, LLC

Covance, Inc.

Eli Lilly and Company

Pfizer, Inc.

Acknowledgements

Special Thanks to all the Program Committee Members who helped develop this Midwest Discussion Group

Program Committee Leslie Bloom, Pfizer, Inc. Kathy Lee, Eli Lilly and Company Michael Boyne, BioTech Logic Michelle Lytle, Eli Lilly and Company James Carroll, Pfizer, Inc. Khalid Mahmood, Eli Lilly and Company Sarah L. Demmon, Eli Lilly and Company Ed Moore, University of Illinois John (J.R.) Dobbins, Eli Lilly and Company Ned Mozier, Pfizer, Inc. John Dougherty, Eli Lilly and Company Lakshmy Nair, Baxter Healthcare Don Eisenhauer, AbbVie, Inc. Joshua Pecenica, Purdue University Will Hatcher, Cook Pharmica Lesley Redfern, AbbVie, Inc. Julie Heflin, AbbVie, Inc. Ashley Ruth, CDER, FDA Michelle Frazier, AbbVie, Inc. Veda Walcott, Cook Pharmica

Roundtable Facilitators Eric Adamec, Eli Lilly & Company Roland Buhler, AbbVie, Inc. Holly Cargill, Pfizer, Inc. Brian DiPaolo, AbbVie, Inc. Brad Evans, Pfizer, Inc. David Fetterolf, BioTech Logic, Inc. Julie L. Heflin, AbbVie, Inc. Ravindra Kumar, Covance Tom Lerch, Pfizer, Inc. Jose Martinez-Velez, Cook Pharmica Chi Nguyen, Eli Lilly & Company Trang Nguyen, Eli Lilly and Company Agnes Thaiya, Pfizer, Inc Milka Zayas, Cook Pharmica

CASSS Staff Stephanie L. Flores, CAE, Executive Director Anna Lingel, Registration Manager Linda Mansouria, CMP, CMM, Conference Manager

General Information

Name Badges Please wear your name badge throughout the day.

Registration The registration desk will be open at 8:00 a.m. to 3:00 p.m. We will accept walk-in registrations.

Roundtable Session There are 6 roundtable topics for you to determine which table topic you would like to be involved in the discussion. The 6 table topics are:

Table Topic 1: Transferring Processes and Analytical Methods to CMOs/CROs

Table Topic 2: Phase Appropriate Comparability Assessments

Table Topic 3: Powering Bioassays for Transfer Comparability Table Topic 4: Bridging Analytical Methods Table Topic 5: Statistical Based Approach for Analytical Method Transfer Table Topic 6: Tech Transfer Considerations for Breakthrough Therapy Designation Table Topic 7: Transfer Considerations for Inspections (Post Approval Commitments) Tables are set with 10 seats to a table. Table topics are on a first come, first serve basis. These roundtables will include two facilitators, whose role is to help assist the discussion and ensure a lively exchange, and a scribe, whose role is to make general, anonymous notes about the discussion so others can have a chance to view the discussion even if they could not participate. The discussion notes will be shared with all attendees during the summary period of the program.

Scientific Program Summary

THURSDAY, June 2, 2016 08:00 – 15:00 Registration 08:00 – 09:00 Registration and Continental Breakfast

09:00 – 09:30 CASSS Welcome and Introductory Comments John Dougherty, Elly and Company

09:30 – 10:15 FDA Recommendations for Comparability Studies to Support Manufacturing Changes Joslyn Brunelle, CDER, FDA

10:15 – 11:00 Biopharmaceutical Method Transfer as Part of the Quality System Jeff Staecker, BioPhia Consulting, Inc.

11:00 – 11:15 AM Break

11:15 – 12:00 Panel Discussion Moderated by: James Carroll, Pfizer, Inc. and Kathy Lee, Eli Lilly and Company

Panel Members: Joslyn Brunelle, CDER, FDA David Fetterolf, BioTech Logic Ashley Ruth, CDER, FDA Jeff Staecker, BioPhia Consulting, Inc.

12:00 – 13:00 Lunch

13:00 – 13:45 Roundtable Discussions

13:45 – 14:15 PM Break and Roundtable Summaries Created

14:15 – 15:00 Summary of Roundtable Discussions by Table Facilitators

15:00 – 15:15 Closing Remarks David Fetterolf, BioTech Logic, Inc. and Khalid Mahmood, Eli Lilly and Company

Program Abstract

Successful Strategies for Tech Transfer Transfer of manufacturing processes is critical part of drug development to accommodate transition to commercial process, scale changes and site changes. These may occur within an organization or to contract manufacturing facilities. Issues such as scale, equipment, facility infrastructure, and analytical methods transfer should be considered in order to ensure consistency of product quality attributes. The phase of development drives the amount of data needed to support successful transfer of a manufacturing process using a risk-based approach. Generally, early phase transfers require less data. However, by phase 3 and post-licensure/approval the expectations are that a more thorough evaluation will be performed and rigorous analytical comparability data will be evaluated. Depending on the changes required to transfer the process and the evaluation of the analytical comparability data, additional clinical studies may be required to support the manufacturing site transfer. Analytical methods are often transferred during drug development and post-licensure/approval. Again the methods may be transferred to laboratories within company (e.g. analytical development labs to QC for clinical material batch release testing), or to contract analytical labs. The US FDA expects method transfer to occur under a transfer protocol that details the parameters evaluated with predetermined acceptance criteria. Considerations for successful transfer include sufficient number product lots tested at both the originating laboratory and the new laboratory as well as a statistically sound evaluation of the data generated at both labs.

This workshop will provide insight into the transfer of a manufacturing process and the transfer of analytical methods to alternative sites that commonly occur during drug development.

Speaker Abstracts

FDA Recommendations for Comparability Studies to Support Manufacturing Changes Joslyn K Brunelle, CDER, FDA Manufacturers of biotechnology products frequently make changes to manufacturing processes of products both during development and after approval. Common manufacturing changes include: scale up, site changes, changes in equipment, new cell line/master cell bank, and/or formulation changes. Pre-change and Post-change products should be assessed for comparability, which involves an analysis of relevant physicochemical and biological characterization data to assess whether there are any significant differences in the quality attributes of the product. For many biotechnology products, quality attributes include potency and both product-related and process- related impurities. Analytical comparability exercises typically include some combination of release testing, extended characterization methods, and stability studies (real time and stressed conditions). However, the amount of information varies depending on your stage of development (Phase 1, Phase 3, or post-approval). If comparability cannot be demonstrated, then non-clinical or clinical studies may be needed to assess whether any differences would negatively impact the safety or efficacy of the product. The basic principles of ICH Q5E (Comparability of Biotechnological/Biological Products Subject to Changes in their Manufacturing Process) will be outlined. Examples of comparability studies at different stages of clinical development will be provided.

Biopharmaceutical Method Transfer as Part of the Quality System Jeffrey Staecker, Principal Consultant for BioPhia Consulting, Inc. Approaches to non-compendial biopharmaceutical analytical method transfer often focus on a point-in-time comparison between a Sending Unit (SU) and Receiving Unit (RU) without fully integrating the method transfer process into the larger Quality System (QS). Many components of the QS that should be comprehended for a transfer include risk management, analytical lifecycle management, documentation, and contractor management. Confidence in a test method initially comes from method validation but ongoing confidence in the method depends on other components of the QS including managing the analytical method lifecycle process. The purpose of a method transfer is to provide assurance that the validated method post-transfer provides results consistent with the existing product control strategy needs by leveraging method transfer as part of a larger QS. A simpler way of stating this is that a method transfer should have no, or negligible, adverse impact on drug safety or efficacy risk. This talk will focus on using a risk-based approach for method transfers and integration of method transfers into the analytical lifecycle management process. Utilization of a risk-based approach requires evaluation of current method performance relative to the specifications/targets established f

8 or the method rather than reliance on a standard equivalency testing approach. In addition to the point-in-time transfer ongoing method monitoring of results at the RU is critical to maintain method performance

Roundtable Discussion Points

TABLE 1 TOPIC: Transferring Processes and Analytical Methods to CMOs/CROs FACILITATORS: Jose Martinez-Velez, Cook Pharmica Agnes Thaiya, Pfizer, Inc.

SCRIBE: Will Hatcher, Cook Pharmica

SCOPE: Open discussion on Transfer Process and Analytical Method Transfer Process from the CMO’s/CRO’s perspective. Participants are encouraged to provide insights on the bullet points according their area of expertise and experience.

BULLET POINTS FOR DISCUSSION: 1. What are the regulatory guidances/expectations on process and method transfer? FDA 2. How do the strategies vary based on the phase of development (IND vs BLA) 3. What are the responsibilities of the transferring and receiving laboratories? 4. What are the criteria and approach you have used for risk based testing? 5. What are the considerations for selection of acceptance criteria? 6. What are the most likely failures during method transfer? What are the challenges? 7. How are deviations documented with regards to acceptance criteria handled?

TABLE 2 TOPIC: Phase Appropriate Comparability Assessments FACILITATORS: Brian DiPaolo, AbbVie, Inc. Tom Lerch, Pfizer, Inc.

SCRIBE: J.R. Dobbins, Eli Lilly and Company SCOPE: This table will discuss phase-appropriate analytical comparability requirements and strategies that are used during development and technology transfers. The discussion will focus on challenges and successful examples used throughout development, commercialization and post-licensure with a global perspective in mind.

BULLET POINTS FOR DISCUSSION: 1. How does a comparability strategy differ for a manufacturing process change versus the transfer of an existing process to different manufacturing site? 2. What type of analytical comparability protocol/plan is used for early versus late clinical development? a. Are pre-defined acceptance criteria included? What if results indicate that materials are not comparable? b. Formal versus informal c. Number of batches needed? d. Release versus Extended Characterization versus Stability 3. How is comparability handled when you have limited data sets and/or limited number of batches? 4. How is comparability impacted by the changes in analytical methods through development? 5. How have analytical comparability plans been communicated to Health Authorities? a. Included as part of a Health Authority meeting? b. Submitted prior or after initiating? c. Are interim reports shared with Health Authorities?

TABLE 3

TOPIC: Powering Bioassays for Transfer Comparability FACILITATORS: Ravindra Kumar, Covance, Inc. Milka Zayas, Cook Pharmica

SCRIBE: Josh Pecenica, Recent M.S. Graduate of Purdue University Bhavin Parekh, Eli Lilly and Company

SCOPE:

This table will discuss the strategies applied to execution, trouble-shooting, compliance, and tech transfer for bioassays. Table members will provide areas of challenge and success for bioassays in relation to pharmacokinetics, dose-responsiveness, techniques and new approaches while keeping a global perspective in mind.

BULLET POINTS FOR DISCUSSION: 1. What regulatory documents are there specific to bioassay tech transfer? Are there specific guidelines for international standardization?

2. What basic expectations does the originating lab have for the receiving lab?

3. What statistical techniques do people use to assure that performance of the assay is adequately similar to claim that the transfer is successful? (For example, how close do values such as EC50 or potencies need to be from the originating lab vs. the receiving lab?)

4. What training is done to assure the accuracy of replication in the receiving lab? Furthermore, what would be an appropriate strategy to accurately test the Òreceiving labÓ personal have been accurately trained, and are doing the procedure correctly?

5. Discuss the future of laboratory practices/techniques that will become the standard for bioassay development. What techniques/practices are currently being fazed-out?

TABLE 4

TOPIC: Bridging Analytical Methods

FACILITATORS: Julie L. Heflin, AbbVie, Inc. Chi Nguyen, Eli Lilly & Company

SCRIBE: Ned Mozier, Pfizer, Inc.

SCOPE: Changes in analytical methodology over the development of a molecule are a normal occurrence. Companies must bridge between the different methods used to support the clinical development of the molecule to assure the critical quality attributes. However, companies continue to face challenges on how to successfully bridge the analytical methods used throughout development.

This round table discussion will focus on these issues through open discussion of current strategies. BULLET POINTS FOR DISCUSSION: 1. What is the impact of changing methods? (pre and post approval) a. Regulatory impact b. Receiving lab site impact (do they have the instruments, training, etc) c. Cost associated with the change 2. What drives an analytical method bridging study? (pre and post approval) a. Change in analytical instrumentation b. Change in rare/critical reagents c. Optimized or new chromatography (columns, gradients, etc) 3. What sample types are required to be tested for bridging studies? (pre and post approval) a. Clinical/commercial lots b. GLP tox lot(s) c. Clinical/commercial stability samples d. Historical reference standards e. Force degraded samples 4. How is the bridging study designed? (pre and post approval) a. Head-to-head comparison? b. Statistical based comparison? c. Does the protocol include pre-defined acceptance criteria? 5. The bridging study results should be presented in… (pre and post approval) a. Comparability protocol b. Briefing documents c. IND/IMPD updates d. BLA filing

TABLE 5

TOPIC: Statistical Based Approach for Analytical Method Transfer

FACILITATORS: Eric Adamec, Eli Lilly & Company Brad Evans, Pfizer, Inc.

SCRIBE: Edwin Moore, University of Illinois

SCOPE: Per the FDA Guidance for Industry document titled “Analytical Procedures and Methods Validations for Drugs and Biologics”, analytical method transfer is typically managed under a transfer protocol that details the parameters to be evaluated in addition to the predetermined acceptance criteria that will be applied to the results. However, no guidance is provided on how to compute the predetermined acceptance criteria. USP general chapter <1224> on Transfer of Analytical Procedures does mention that acceptance criteria should be based on method performance and historical data from stability and release results and also that statistical principles based on the difference between mean values, established ranges, and an estimate of the variability of the method should be used. This table will examine aspects that might be considered in generating acceptance criteria for statistically based approach to method transfer.

BULLET POINTS FOR DISCUSSION:

1. With regard to method transfer, what does success look like? 2. How should the acceptance criteria be established? Is a statistical approach always best or should rules of thumb be considered for some transfers? 3. Which data (validation + robustness + pre-validation studies) should be considered in generating statistical acceptance criteria? 4. How comprehensive (e.g. nominal storage condition and stressed storage condition batches) should the transfer study be compared to the validation study? Should the same statistical acceptance criteria apply to all test samples (e.g. stressed vs unstressed) involved in the transfer protocol? What factors influence the sample size needed for statistical comparison? 5. What aspects of the validation parameters should be considered? a. Comparison of lab averages b. Comparison of lab precision c. Analytical method range d. System suitability 6. What kind of experiment design should be considered? For example, do we need to have the same number of independent setups at both the originating and receiving labs? What if the originating lab does not have the time/resources to do more than one setup?

TABLE 6

TOPIC: Tech Transfer Considerations for Breakthrough Therapy Designation FACILITATORS: David Fetterolf, BioTech Logic, Inc. Holly Cargill, Pfizer, Inc.

SCRIBE: Michelle Frazier, AbbVie, Inc. SCOPE:

BULLET POINTS FOR DISCUSSION:

TABLE 7

TOPIC: Transfer Considerations for Inspections (Post Approval Commitments) FACILITATORS: Roland Buhler, AbbVie, Inc. Trang Nguyen, Eli Lilly and Company

SCRIBE: Ashley Ruth, CDER, FDA SCOPE: Inspectional preparation activities need to be completed prior to and after a submission for a transfer of manufacturing activities. These activities require careful and detailed planning to assure compliance with regulation and with the application. The scope of this activity will be those items to support the content of the application and the anticipated FDA inspection.

BULLET POINTS FOR DISCUSSION: This round table discussion will focus on these issues through open discussion of current strategies.

ANALYTICAL METHOD TRANSFERS 1) What are the considerations prior to analytical method transfers as part of planning? 2) What are some of the timeline perspectives for implementing transferred methods at the labs (readiness)? Are they different based on type of method? 3) Are there any lessons learned from having completed analytical method transfers?

MANUFACTURING SITE TRANSFERS 1) What are the considerations prior to manufacturing site transfers as part of planning? 2) What are some of the timeline perspectives for transferred process at the site (readiness)? Are they different based on complexity of the process? 3) Are there any lessons learned from having completed site transfers?

CHANGE MANAGEMENT PLANS & RISK ASSESSMENTS 1) Where are risk assessments done as part of your change management process? 2) What is your approach for method and site transfers? 3) What functional area drives the program or responsibility?