Establishing and Applying Critical Quality …

1 1 ISCT Liaison Meeting October 19, 2016 Tom Finn, Product Reviewer Office of Tissues and Advanced Therapies FDA/CBER Establishing and Applying Critical Quality Attributes During the Product Development Lifecycle 2 Topics Product terminology CQA and CPP and how they are developed and used during the product lifecycle Considerations for demonstrating product comparability after a manufacturing change 3 A CQA is a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product Quality . -ICH Q8 (R2) (Pharmaceutical Development) Product Quality is defined in terms of Specifications and Critical Quality Standards and Attributes Definition: Parameter/test Assay Criterion Sterility 14 day culture, aerobic and anaerobic No growth Specification: 4 Definition: specifications Full product characterization Specifications are Critical Quality standards (CQAs) that are proposed and justified by the manufacturer and approved by regulatory Specifications are chosen to confirm the Quality of the DS and DP rather than to establish full characterization, and should focus on those characteristics found to be useful in ensuring the safety and efficacy of the DS and DP.

2 - ICH Q6B and Q11 CQA 5 BLA Phase III Phase II Phase I Preclinical Research Clinical efficacy Potency Preclinical efficacy But efficacy data is not usually obtained until late in product development, long after CQAs have been established You should make use of preclinical and clinical data whenever available to adjust CQA and CPP parameters. This is easier to do if two phase 3 studies are done- revise CQA prior to conducting confirmatory trial. Although not required until phase 3, we recommend you develop a potency assay as early as possible. The more reflective CQA are of clinical safety and efficacy, the easier it is to evaluate the consequences of a manufacturing change Sterility Endotoxin Mycoplasma Viability Identity Purity Visual appearance Potency Lots that don t meet these cut-offs should not be distributed and used Lot release tests exist to set expectations for adequate product safety and Quality 6 It is important to choose them carefully and apply them where needed Lot release specifications are at the center of many product areas and are interrelated.

3 7 8 CQA are also fundamental to Critical process parameters (CPP) Critical Process Parameters (CPP) are independent process parameters most likely to affect the Quality attributes of a product CPPs are determined by sound scientific research or manufacturing experience CPPs are controlled and monitored to confirm that the Quality attributes of the product are maintained or improved CPP 9 CQA and CPP are used together to help ensure Quality and manufacturing consistency In-process criteria Process limits Acceptance criteria for source material FP Release criteria Equipment performance Action limits for specific steps Criteria for intermediates Process Parameters have boundaries within which a given process yields an expected result that is defined in terms of CQAs Early product development and preclinical data are used to justify safety and Quality of the product for use in clinical studies FDA encourages continual improvements to product Quality .

4 But that must be balanced with maintaining product consistency Need to be sure that preclinical testing is representative of actual clinical lots Typical early product development approach Initial product characterization Initial specifications & manufacturing process Conduct pivotal animal safety and POC studies Manufacture lots for clinical trial Further refinement of specifications during trials Adjustments to specifications based on preclinical data Tumorigencity Proof of concept Toxicity Biodistribution Manufacture lots for clinical trial Conduct pivotal animal safety and POC studies GMP or GLP GMP GMP 10 11 Proposed mechanism of action What properties or characteristics of the product ( , Quality attributes) are likely to achieve the intended action in the patient? What manufacturing steps are Critical and how would you measure and ensure they were successful? -identify process parameters What safety concerns are associated with this type of product What undesirable properties do you want to minimize?

5 What labeling claims do you want to make based on identified attributes and/or process parameters? Assay suitability & qualification Factors important for Establishing CQA and CPP CD3 Too little? Too much? Perform the right level of product characterization to ensure product Quality Determining the right level is not easy! CD3 CD8 CD3 CD45 Th1 Treg CD4 CD4 NK Th2 Th9 CTL CD8 Treg Th3 Th17 Tr1 TEM TCM Th9 Th22 iTrg Tc9 CD25 CD69 12 Impractical Too much emphasis on a single attribute Appropriate attributes, criteria too low Appropriate attributes, appropriate criteria Focus on Critical Quality attributes 13 Common issues with choosing product release specifications Specifications not capturing key product attributes Criteria inconsistent with manufacturing experience Lack of supportive data or rationale Product characterization that does not take into account cellular impurities that might interfere with the activity of the product, or present a safety concern Criteria set for a very wide range could add variability to clinical trial outcomes Misinterpretation or over-interpretation of data 14 15 Assays are sometimes qualified/validated under ideal or best case conditions.

6 And may factor only one variable at a time. This can lead to overconfidence of an assay. Real world use may involve: Consider assay variability and worst case in designing assays and setting criteria Different QC analysts Different batches of reagents Different equipment Samples held for different lengths of time Different interpretation of procedures due to vague SOPs Subjective parameters (such as flow cytometry gates, background cut offs, dilutions, etc.) Assay variability can confound efforts to demonstrate manufacturing consistency, comparability, or stability. 16 CQA and CPP are not meant to be static- they should be continually evaluated and revised as needed Carved in stone Continually upgrading Changes to CQA could include either revising existing criteria, or adding or removing a specification (as supported by product characterization data) But since these have tremendous impact, revise cautiously!

7 Additional product characterization data may indicate a better way of ensuring Quality Clinical outcome data may provide clues as to what product properties are the most important Additional manufacturing experience may guide CPP and CQA 17 Major manufacturing changes A little planning up front can help avoid problems later Think in advance about: Donor eligibility of source material Cell bank qualification Cell bank capacity Logistical issues for products with short shelf lives Scale up needs Second source for custom or Critical materials Qualification & validation 18 19 It is easier to accommodate manufacturing changes at earlier developmental stages Product knowledge should increase with stage of development (identity, stability, potency, manufacturing, consistency/product comparability, etc.) Consider manufacturing changes that might be needed to accommodate larger trials and commercial production Manufacturing changes can be implemented at any stage, but the potential impact of a manufacturing change can increase the farther you are along in the product lifecycle.

8 Phase 1 & 2 may be a good time to implement a major manufacturing change prior to conducting pivotal phase 3 studies. However, for these phases manufacturing is often on autopilot 20 Phase 3 is a little like commercial manufacturing on training wheels Should be using as close to the commercial process as is feasible for registration studies Potency should be in place Critical Quality Attributes (CQA) should be identified and appropriate assays in place Additional stability data should be collected Well defined CPPs should be in place: Phase 3 is Critical for demonstrating manufacturing consistency But some details are still being worked out to prepare for commercial production Depending on the issue or the study, there may be the need to extend an analysis to product properties beyond lot release values It is important to understand where the gaps exist so that an appropriate characterization can be done As important as lot release specifications are, they alone only provide a partial assessment of Quality 21 Situations where additional product characterization and analysis may be needed Process qualification and validation studies (to demonstrate manufacturing consistency) Additional in-process and final product attributes, yield Comparability studies after a major manufacturing change ( new process step, new facility, new Critical reagent, etc.)

9 Additional measures of identity, potency, purity, etc. Yield Stability studies (not all lot release tests are stability indicating- you need to evaluate each one) Genetic stability and identity of cell lines Evaluate apoptosis in addition to viability Additional measures of potency 22 23 Goalpost CQA are often used as goalposts Applications for lot release Establish a lower limit for key attribute Maximum limit of an impurity Establish an allowable range 24 There are advantages to targeting narrow versus wide tolerances for specifications Narrower tolerances make it easier to assess comparability Size matters Goalpost Narrow tolerances Wide tolerances Need to have a very good understanding of your process and product, with sufficient control points Difficult to rely on just lot release specifications to show consistency and comparability 25 You should aim like CQA as a goalpost Not When a product has substantial inherent variability you need to consider what you are targeting 26 Each CPP should have it s own target If CPP are appropriate and the process is consistent, then the same target will be hit each time Source material Intermediate Intermediate Final product Designing meaningful comparability studies Perform risk assessment to establish scope- what is most likely to be affected and to what degree?

10 Consider what are the most sensitive parameters to test What assumptions are you making? Leverage what you already know from product development Where does known variability exist and how will you try to control for that? Justify # of samples, types of samples, number of tests, and type of analysis What limits does the study design place on interpretation? How will you analyze the data? 27 28 First show the current process is consistent Where possible use a split manufacturing approach to factor out source material variability- this allows for a head-to-head comparison of the new method compared to the existing method Criteria should be predetermined Understand and incorporate worst case Additional thoughts What to include in a manufacturing change IND amendment Clear description of what you are changing and why Change control- what is the scope of the change and what was impacted A summary of your risk assessment Whether this is intended to be a temporary fix or a long-term solution Comparability study, including.