Strategic Considerations for Manufacturing Process Development

Transcription

1 Strategic Considerations for Manufacturing Process Development PDA Israel Key areas for strategic drug development planning Ramat Gan, 24th Oct 2018 Oren Hesrhkovitz GM, Opko Biologics

2 Presentation Overview Biological Drug Manufacturing Overview General Strategic Considerations Process and Product Development Considerations 2

3 Biological Drug Manufacturing Overveiw The goal of manufacturing process development for the drug substance is to establish a commercial manufacturing process capable of consistently producing drug substance of the intended quality ICH Q11 3

4 Biological Manufacturing - General Scheme Cell Line UPSTREAM DOWNSTREAM RELEASE SPECIFICATIONS Clone 4

5 Where to Start??? CQA Regulation Cost and Budget Scale Quality and Control TPP Timelines CMO Project Management /team Clone QbD 5

6 ALWAYS START BY LOOKING AT THE END 6

7 Biological Manufacturing - Initial Strategic Considerations Many Business and Development Strategy Decisions Where do I develop?? Business Decision In-House Development vs CMO Development Who do I need on my team to make it work? How much will it cost and how much product do I need for different stages?? Defining early demand vs commercial How long will it take me? How can I do it faster? Alignment with the development plan as CMC is usually the rate limiting step What is the Process profile? Process early development vs late stage development - What is the Target Product Profile?? The path from initial TPP to commercial TPP in the regulatory environment 7

8 Biological Manufacturing - Initial Strategic Considerations The Bridging Strategy Balancing your budget early expanses until clinical POC while meeting the necessary process development requirements Regulation IND consideration Clinical Study Conduct region Reasonable specification and scale Big Pharma do it right from the beginning, Biotech companies must accelerate the time to clinical POC while keeping the basic regulatory requirements and allowing reasonable optimization to bridge early process to late process 8

9 Where to Develop your Process - In House Development capabilities Where to Develop? Pros Provide process knowledge and understanding which are a huge advantage in regards to timelines and managing CMO following TT. Allows the sponsor to conduct house studies following TT to accelerate process development Cons Require relatively early investments and constant costs (Labs, equipment and dedicated team). Support by the Israeli Innovation Institute? CMO are usually better facilitated and experienced 9

10 Selecting and Managing a CMO Eventually you will most probably use a CMO to manufacture your drug, this is a key vendor and there are so many options. How to select to right one for you? 10

11 Selecting and Managing a CMO Criteria Size of CMO Capability and facility fit to your process Range of Services Reputation and Reliability Geographic location and accessibility Regulatory track record Quality Control Experience and Expertise Commitment and Considerations Big CMOs are much less flexible but more experienced from a regulatory perspective, only consider for late stage processes Does the CMO have the infrastructure and equipment you need (e.g. BR scale, disposable vs reusable buffer capacity, columns size and skids and more) Does the CMO have the range of services you need or many services are provided by a third party. Can he meet your short term and long term needs, will you need to TT down the road Collect at least 2 relevant client references to understand the quality of their service and potential issues Time zone difference and distance Regulatory audits track records, when? and outcomes (483?). Compliance with ICH Evaluation by an audit of the quality system and GMP compliance - Key! Have the CMO manufactured a product similar to yours. For complex proteins, it could be essential. Are you heading to process qualification, 11 does he have PPQ and submission experience? Are they responsive, adhere to timelines, can work with you to develop

12 Selecting and Managing a CMO Criteria Scheduling and availability Mentality/Cultural fit Cost Financial stability Other considerations Considerations How booked are they? Sense the water in terms of responsiveness and availability/flexibility at early stage, can work with you to develop aggressive timelines? Evaluate the mentality /cultural fit that can make the difference between partnership and battleship Apple to apple comparison to alternative CMOs pricing, should fi your budget Make sure that you assess the financial stability of your CMO before you start the work Meet the team, don t be dazzled by the BDs, Phase distribution, turnover rate, meet the PM, ask for CV, he/she is a key executioner of the program Look at the CMO as your key partner, build a relationship, insist where you should and be flexible where you can 12

13 Biological Manufacturing - Initial Strategic Considerations Who do I need on my team to make it work? Development in house requires USP/DSP/QC/RA/QA experienced CMC integrated team Managing a CMO requires also an experienced PM that knows how to manage a CMO and that can apply effective management tools(trackers, Gantt, Budget) Consultants Don t think you know it all, it is recommended to identify key consultants in different relevant areas (RA/QA and CMC) with the proper experience and expertise it could become critical Successful team comprises of experienced members but also young enthusiastic members 13

14 Start with modeling what would be your material demand to support your development, toxicological studies and Phase 1 and 2 demands. Consider the following : Clinical design and doses ; o o o What is your expected therapeutic window? What would be your formulation concentration to accommodate the required doses and volume constrains use vials/cartridge base calculation Is it a single/multi center site, blinded? Many countries? All of this will lead to calculating your clinical margins (20-100%). For complex studies, use forecasting tools! Non-Clinical : o o Biological Manufacturing - Initial Strategic Considerations How much and How many At early phase, tox will be more demanding then clinical demand Consider the required exposure margins, if possible, it could be helpful to conduct non-glp study to determine the MTD and reduce doses in the GLP study o Demand for additional PK/PD and pharmacological studies CMC : o Consider stability requirements, release and retain (X2), 15-20% loses in DS and DP, required material for further development of process and formulation, product characterization and other activities 14

15 Biological Manufacturing - Initial Strategic Considerations Once you know your short term demand, simulate what could be your commercial need. Yes, it is too early, but essential to understand what scale of a process you might need to get to eventually. Consider the following : o o How much and How many Demand - Therapeutic range, dose frequency, market size and share Process Clone productivity, process yield gr/l purified DS Short term demand Commercial demand Regulatory Considerations 15

16 Biological Manufacturing - Initial Strategic Considerations Regulatory considerations for process scale up and general process changes during development COMPARABILITY OF BIOTECHNOLOGICAL/BIOLOGICAL PRODUCTS SUBJECT TO CHANGES IN THEIR MANUFACTURING PROCESS ICH Q5E Although process changes are integrated part of drug development, your initial process should reflect and set the basis for reasonable changes implemented during development. ICH Q5E provide the regulatory frame work for comparability exercise. Scope is dependent on the clinical stage Some regulatory authorities are more sensitive to process changes. Even within the FDA (CBER vs CDER) there are different approaches. Manage your predicted changes wisely to tie it with the overall development plan 16

17 ANALYTICAL FORMULATI ON DOWNSTRE AM UPSTREAM RESEARCH How Long? Drug Candidate Screening and Transfer Phase 1 Phase 2 Phase 3 Cell Line Developme nt Cell Line Selection Initial Process Development Transfer to MFG (GMP Manufacturing) Process Characterization Risk assessment and Process Lock PPQ Process Development Process Characterization Risk assessment and Process Lock PPQ Developability/Pre-formulation Formulation Process Development and Tech Transfer Formulation Robustness Test Development and qualification Testing Support Methods Validation Year 1 Year 2 Year 3 Year 4 Year X 17

18 How to accelerate your process development? Cloning Always on the critical path. huge variability in time to clone between different vendors. Start your process development from stable pool, then RCB and only then with MCB Select CMOs with aggressive timelines Use Internal/CMO with high throughput tools (Amber, Robocolumn, analytical tools) Start your process development using a platform where possible (e.g.abs),and experience with similar protein (glycosylation ) 18

19 Once you defined your business wise process development strategy, you need to start to get into the details of your target drug and process profiles 19

20 Relevant ICH Guidlines for of Process Development and Manufacturing of Biological Prodcuts 20

21 Quality by Design QbD is a systematic approach to drug development that begins with predefined objectives and emphasizes product and process understanding and process control, all based on sound science and quality risk management. QbD is a systematic approach to drug development that begins with predefined objectives and emphasizes product and process understanding and process control, all based on sound science and quality risk management. 21

22 Quality by Design 22

23 ALWAYS START BY LOOKING AT THE END 23

24 Target Product Profile and Quality Target Prduct Profile Target Product Profile (TPP) It is a more business perspective of the final characteristics of your drug that should consider commercial landscape. Important parameters will include the following: Formulation liquid vs lyo handling Storage conditions cold vs RT storage convenience and supply chain Storage duration Shelf life at least 1y at desired storage temp Delivery system Syringe/device patients convenience Quality Target Product Profile (QTPP) - A prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure desired quality, taking into account safety and efficacy of a drug product 24

25 Target Product Profile and Quality Target Prduct Profile QTPP is essential for understanding how your final commercial drug will look at the end You should define the QTPP with that in mind, and determine based on a risk assessment, what is your QTPP for Phase 1 and 2, and can you bridge the gap during development to your Phase3/commercial QTPP You need to assess the criticality of each quality attribute Critical Quality Attribute (CQA): A quality attribute that must be controlled within predefined limits to ensure that a product meets its intended safety, efficacy, stability, and performance 25

26 Target Product Profile and Quality Target Prduct Profile Consider adding an achievable specifications for early Phases that will bridge to your commercial QTPP 26

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28 Key Consideration During Process Development

29 Process Development Stages Cell Culture Upstream Development GOAL: Productivity and Quality Purification Downstream Development GOAL: Purity and CQA Drug Product Formulation & Fill/Finish Development GOAL: Stability, Minimize stress conditions All of development shares the goals of: Safety Efficacy Consistency 29

30 Cell Line Development Cell Line (Clone) Development Protein DNA Clone Pool Created Clone Performance Evaluated Robot picks clones *Clonality confirmed Cell Line (Clone) Selection Clones scaled-up Clones evaluated in Amber Productivity Product Quality Top clones confirmed in larger BRs 30

31 Cell Line Development Productivity Counts!!! Yield per gram will define your scale/development costs and your COGs Timelines diversity among CMOs Questions you must ask: Expression system less copies is better Well characterized parent cell line Proven document for no animal derived components Monoclonality take a picture, not just statistic MCB/WCB meet the regulatory requirement (ICH Q5D, EU Pharmacopeia) 31

32 Upstream Development The objective of the upstream development is to select the conditions which will maximize the cells productivity while maintaining a cost effective process (raw material cost, process duration), meeting your desired target product quality (glycosylation, other PTMs, contaminants) and have a consistent process 32

33 Upstream Development Vitamins Amino Acids Temperature Oxygen Osmolality Sugars CELL Product (mab) ph Lipids Waste Host Cell Proteins (HCPs) How many cells? Which Media and Feed? How long is the process? 33 What is the target Product Quality profile??

34 Upstream Development Small-Scale 5L Glass BRX Pilot Scale ~ L BRX Full Scale 2,000-18,000L BRX Scale-up Scale-up Scale-up data should build confidence that the process we are running in MFG is the same as the process we developed on the bench (and changes we make on the bench will have the same impact in MFG!) Must-haves: Consistent performance between scales Independent and dependent variables same between scales 34

35 Upstream Development Productivity Counts!!! Yield per gram will define your scale/development costs and your COGs Use high throughput systems such as Amber to screening a wide range of conditions using Design of Experiment (DoE) tools to optimize your development scope, process knowledge and timelines No animal origin components Early assessment of BR mode (fed batch, perfusion) Scalability of your (or CMO) model -Tech Transfer Development of tools to assess product quality Early assessment of consistency 35

36 Downstream Development The objective of the downstream development is to select the conditions which will meet your product QTPP while maintaining a cost effective process (raw material cost, process duration and complexity ), and consistency 36

37 Downstream Development Screening of chromatography media Optimize yield while meeting your QTPP Determination of unit operations, sequence and unit Parameters Identify potential Critical Process Parameters (CPP) Optimize process efficiencies 37

38 Downstream Development Impurity (internal to process) Product related impurities (aggregate, related forms) Process related forms o o o Host Cell Proteins (HCP) DNA USP/DSP components/additives Contaminant (external to process) Viruses Bacteria, endotoxin

39 Viral Clearance for Phase 1 Demonstration of viral clearance may be required. Exceptions: certain source materials (e.g., E. coli, yeast) or in the event of unmet medical need Perform small scale clearance study that mimics the clinical purification process Spike Drug Substance with a model virus to demonstrate viral removal by several logs beyond the potential load CHO cell substrate demonstrate retroviral clearance Human cell substrate - demonstrate clearance of enveloped and non-enveloped viruses (e.g., parvoviruses) Design the process upfront to adequately assess potential risks Two orthogonal robust steps (e.g., low ph, nano-filtration, solvent/detergent treatment, heat) typically included in the purification process 39

40 Downstream Development The endless battle between yield and purity Using standard resins Cost driver Buffer consumption Cost and CMO fit Viral Inactivation steps Ambient Process product is stable throughout the process in ambient conditions Process complexity and duration (step duration and holding times) Development of tools to assess product quality Early assessment for consistency YIELD PURITY Balance Yield versus Purity 40

41 Conclusions and Final Remarks Define your business development strategy Define your product and process target profiles Define your early vs late stage development cost till clinical POC using a risk based bridging strategy 41