Establishing and Applying Critical Quality Attributes During the Product Development Lifecycle ISCT Liaison Meeting October 19, 2016 Tom Finn, Ph.D. Product Reviewer Office of Tissues and Advanced Therapies FDA/CBER 1 www.fda.gov
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 2
Definition: “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 Specification: Parameter/test Assay Criterion 14 day culture, aerobic and Sterility No growth anaerobic 3
Definition: “ Specifications are critical quality standards (CQAs) that are proposed and justified by the manufacturer and approved by regulatory authorities… 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.” - ICH Q6B and Q11 CQA specifications Full product characterization 4
The more reflective CQA are of clinical safety and efficacy, the easier it is to evaluate the consequences of a manufacturing change But efficacy data is not usually obtained until late in product development, long after CQAs have been established Research Preclinical Phase I Phase II Phase III BLA Preclinical efficacy Potency Clinical efficacy • 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. 5
Lot release tests exist to set expectations for adequate product safety and quality Lots that don’t meet these cut -offs should not be distributed and used Viability Sterility Identity Endotoxin Purity Mycoplasma Visual Potency appearance 6
Lot release specifications are at the center of many product areas and are interrelated. It is important to choose them carefully and apply them where needed 7
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 CPP • CPPs are controlled and monitored to confirm that the quality attributes of the product are maintained or improved 8
CQA and CPP are used together to help ensure quality and manufacturing consistency Acceptance criteria for Action limits source for specific material steps Criteria for intermediates Equipment performance In-process criteria FP Release Process criteria limits Process Parameters have boundaries within which a given process yields an expected result that is defined in terms of CQAs 9
Typical early product development approach Initial product characterization Adjustments to specifications based on preclinical data GMP or GLP Conduct pivotal animal Manufacture lots safety and POC for clinical trial studies GMP • Tumorigencity Further refinement • Proof of concept of specifications • Toxicity during trials • Biodistribution Conduct pivotal animal Manufacture lots safety and POC for clinical trial studies Initial specifications & GMP manufacturing process • 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, but that must be balanced with maintaining product consistency • Need to be sure that preclinical testing is representative of actual clinical lots 10
Factors important for establishing CQA and CPP • Proposed mechanism of action • What properties or characteristics of the product (i.e., 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? • What labeling claims do you want to make based on identified attributes and/or process parameters? • Assay suitability & qualification 11
Perform the right level of product characterization to ensure product quality Too much? Tc9 Th9 Th22 Th3 CD8 CD69 CD8 Treg Too little? iTrg CD3 CTL CD3 CD4 Th1 CD25 CD3 Th17 CD45 Th2 T EM CD4 Th9 NK T CM Treg Tr1 Determining the right level is not easy! 12
Focus on critical quality attributes Too much emphasis on a single attribute Impractical Appropriate attributes, Appropriate attributes, criteria too low appropriate criteria 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
Consider assay variability and “worst case” in designing assays and setting criteria Assays are sometimes qualified/validated under ideal or best case conditions, and may factor only one variable at a time. This can lead to overconfidence of an assay. Real world use may involve: • • Different QC analysts Different interpretation of • Different batches of reagents procedures due to vague • Different equipment SOPs • • Samples held for different Subjective parameters (such lengths of time as flow cytometry gates, background cut offs, dilutions, etc.) Assay variability can confound efforts to demonstrate manufacturing consistency, comparability, or stability. 15
CQA and CPP are not meant to be static- they should be continually evaluated and revised as needed • 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 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! 16
Major manufacturing changes 17
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
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. 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” 19
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 20
As important as lot release specifications are, they alone only provide a partial assessment of quality Depending on the It is important to issue or the study, understand where there may be the the gaps exist so need to extend an that an analysis to appropriate product properties characterization beyond lot release can be done values 21
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