Defining Product Quality Using Analytical Methods. Reed Harris Senior Staff Scientist, Pharma Technical Development

Transcription

1 Defining Product Quality Using Analytical Methods Reed Harris Senior Staff Scientist, Pharma Technical Development CE Pharm 2015, Brooklyn NY, 21-Sep-2015

2 How to Define Suitable Product Quality? 2 What s the basis for any development target or specification limit, especially for new clinical products?

3 How to Define Something 3 US Supreme Court I shall not today attempt further to define the kinds of material I understand to be embraced within that shorthand [obsencity] description, and perhaps I could never succeed in intelligibly doing so but I know it when I see it. - US Supreme Court Justice Potter Stewart, 1964, Jacobellis vs. Ohio

4 Types of Product Quality Ranges or Limits 4 Brain: science-based USP, EP, WHO etc. Gut know it when I see it precedents (un)familiar risks brain gut

5 Types of Product Quality Ranges or Limits 5 1. Clinical specifications 2. Critical Quality Attribute assessments 3. Comparability assessments 4. Development targets

6 Specifications for Early Stage Clinical Products Specifications define a range of test results to ensure suitable quality includes tests and acceptance criteria We used to have report the value criteria for early clinical programs In practice, we had rejected lots that gave unexpected results Health authorities wanted to see limits, even if wide What s the basis for any limits? (FDA Phase I guidance) FDA Guidance for Industry: CGMP for Phase 1 Investigational Drugs (July 2008). The manufacturer should establish acceptance criteria for specified attributes on each material. For some materials, all relevant attributes or acceptance criteria may not be known at the phase 1 stage of product development. However, attributes and acceptance criteria selected for assessment should be based on scientific knowledge and experience for use in the specific phase 1 investigational drug. The material attributes and acceptance criteria will be reviewed in the IND application...

7 Specification Acceptance Criteria IND-enabling toxicology studies help establish safety for new products The clinical lots should resemble the Tox material Tox lot is the first reference material, and assigned 100% potency Some Phase I mab specifications have default acceptance criteria SEC 95% main peak, seems to be an industry standard CE-SDS 85% main peak, based on a threshold for detection of mab reduction host cell proteins, endotoxin, strength, osmolality etc. have standard limits Tox material profile forms the basis for some product-specific Phase I criteria 60% 140% potency at Phase I (with <75% and >125% alert limits) Acceptance criteria for IEC/IEF (charge) profile: % main peak for Tox lot ±10% 20%, sometimes with intermediate alert limits, for standard mabs Plus careful QC analyst review of chromatographic or CE profiles to look for new peaks or unexpected peak shapes

8 Phase 1 SEC Profile for a Rejected Lot Quantitative results met the >95% main peak criterion Profile assessment showed unexpected very high MW species (peak 1) Batch was not accepted

9 Phase 1 IEC Profiles for Accepted Lots: three Phase I lots vs. Reference acidic forms basic forms Quantitative results met the main peak criterion Profile assessment showed higher levels of basic forms for two lots Variability due to the inconsistent proline amidation at heavy chain C-termini Pro amidation variability unlikely to affect patients All batches were accepted Cell culture studies determined that the origin of this variability was copper addition (Kaschak et al., mabs 3, , 2011)

10 Four Ways to Define Product Quality Type Basis Purpose and Guidance Clinical specification acceptance criteria Critical Quality Attributes Test results for Tox or early clinical batches, or platform criteria, plus profile comparisons. Range of acceptable results that ensure suitable product quality. ICH Q6B Comparability assessments Development targets

11 Critical Quality Attribute Challenge Critical Quality Attribute: 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 R1] Based on patient impacts, not process capability or historical values How to convert this concept into an empirical assessment? - what molecular properties to assess? - how to quantify low, medium, high, very high risks? Combine impact type and level, and an uncertainty level Perform a preliminary CQA assessment early in development to identify control system gaps, then perform the full assessment when the project approaches licensing

12 CQA Assessment Tool: Impact Scales Impact & Rating Biological Activity PK / PD Incremental Immunogenicity Risk Safety Very High (20) >100% change >40% change on PK ATA detected and confers limits on safety Irreversible AEs High (16) % change 20-40% change with impact on PD ATA detected and confers limits on efficacy Reversible AEs Moderate (12) 20-40% change 20-40% change with no impact on PD ATA detected with effects that can be managed Manageable AEs Low (4) <20% change <20% change with no impact on PD ATA detected with minimal effect Minor, transient AEs None (2) No change No impact on PK or PD Anti-Therapeutic Antibodies not detected or detected with no relevant in vivo effect No Adverse Events Developed in 2008 with Paul Motchnik and Ron Taticek! Incorporated into the Amab Case Study, v2.1 Oct 2009 (CaSSS website)

13 CQA Assessment Tool: Bioactivity Impact Scale Impact & Rating Very High (20) High (16) Moderate (12) Low (4) None (2) Biological Activity >100% change % change 20-40% change <20% change No change Can be >2X potent is some cases e.g., afucosylation 40% is 2X the 20% threshold 20% threshold based on presumed commercial 80%-120% potency acceptance criteria

14 CQA Assessment Tool: PK/PD Impact Scale Impact & Rating Very High (20) High (16) Moderate (12) Low (4) None (2) PK / PD >40% change on PK 20-40% change with impact on PD 20-40% change with no impact on PD <20% change with no impact on PD No impact on PK or PD More than 2X the 20% threshold Double the 20%, with PD changes - example: Xolair (free IgE)* Double the 20% - example: rituximab (saturated B cell depletion) 20% threshold based on 80% 125% bioequivalence criterion (FDA 2001 guidance*). PK: pharmacokinetic assessment of the AUC (area under the curve for a concentration / time plot). Use relative FcRn binding if PK data are not available. PD: pharmacodynamic assessment, if a biomarker is available * FDA, Statistical Approaches to Establishing Bioequivalence, Jan ** Hochhaus et al., Pharmacodynamics of omalizumab: implications for optimised dosing strategies and clinical efficacy in the treatment of allergic asthma. Curr Med Res Opinion 19(6) (2003)

15 CQA Assessment Tool: Immunogenicity Impact Scale Impact & Rating Very High (20) High (16) Moderate (12) Low (4) None (2) Incremental Immunogenicity Risk ATA detected and confers limits on safety ATA detected and confers limits on efficacy ATA detected with effects that can be managed ATA detected with minimal effect Anti-Therapeutic Antibodies not detected or detected with no relevant in vivo effect Applied a 5-level risk assessment system developed by Valerie Quarmby et al. Assume immune tolerance for variants found on plasma-derived IgG Safety issues due to ATAs are assessed on this scale

16 CQA Assessment Tool: Safety Impact Scale Impact & Rating Very High (20) High (16) Moderate (12) Low (4) Safety Irreversible AEs Reversible AEs Manageable AEs Minor, transient AEs Anaphylaxis e.g., anti-gal(α1-3)gal- [Chung et al.] Manageable e.g., rituximab infusion reactions managed by pre-dosing with steroids Minor transient e.g., injection site reactions None (2) No Adverse Events Based on FDA s Adverse Event Reporting requirements: GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/ucm pdf Chung CH et al., Cetuximab-Induced Anaphylaxis and IgE Specific for Galactose-Alpha-1-3-Galactose. New England J Medicine 2008: 358;

17 Uncertainty Scale Rank Uncertainty Product Variants & Process-Related Impurities 7 Very High No information (new variant or attribute) 5 High External literature for variant or attribute in a related molecule 3 Moderate Non-clinical or in vitro data with this molecule. Non-clinical, in vitro or clinical data from a similar class of molecule 2 Low Variant has been present in clinical trial materials 1 Very Low Impact of specific variant established in clinical studies Low (2) uncertainty is aligned with ICH Q6B (specifications): If a consistent pattern of product heterogeneity is demonstrated, an evaluation of the activity, efficacy and safety (including immunogenicity) of individual forms may not be necessary.

18 CQAs Are Assigned Based on Their Severity Score Low Uncertainty High High Impact Low Critical Quality Attribute Not a CQA

19 Quality by Design (QbD) Control Strategy: concept c CQA Control by testing Specifications: In-Process, Release, Stability Quality Quality attributes CQA Assessment Process control Process characterization, Process validation, PALM plan Not a CQA Extended characterization, Comparability assessments, PALM plan Consistency * PALM: post-approval lifecycle management

20 QbD Control Strategy Development: current CQA RRF CQA-AC definition Process impact/ stability impact Residual risk to be outside CQA-TR ATS RRF Testing Quality QAs High impact Low impact Low risk to be outside CQA-TR Lowest risk to be outside CQA-TR Additional Monitoring Attributes No Testing Robustness assessment Process CQAs are defined Acceptable levels determined Evaluation of residual risk of process and stability to stay in AC defines testing strategy Attribute Testing Strategy confirmed 20 Roche QbD Control Strategy teams

21 Four Ways to Define Product Quality Type Basis Purpose and Guidance Clinical specification acceptance criteria Critical Quality Attributes Test results for Tox or early clinical batches, or platform criteria, plus profile comparisons. Bioactivity, PK/PD, Immunogenicity, Safety Range of acceptable results that ensure suitable product quality. ICH Q6B Establish a control system: tests, validation, monitoring. ICH Q Comparability assessments Development targets

22 Comparability ICH Q5E (Comparability): The goal of the comparability exercise is to ascertain that pre- and post-change drug product is comparable in terms of quality, safety, and efficacy. - Material can be different, but the quality may be considered comparable The goal of the comparability exercise is to ensure the quality, safety and efficacy of drug product produced by a changed manufacturing process, through collection and evaluation of the relevant data to determine whether there might be any adverse impact on the drug product due to the manufacturing process changes. The demonstration of comparability does not necessarily mean that the quality attributes of the prechange and post-change product are identical, but that they are highly similar and that the existing knowledge is sufficiently predictive to ensure that any differences in quality attributes have no adverse impact upon safety or efficacy of the drug product. A determination of comparability can be based on a combination of analytical testing, biological assays, and, in some cases, nonclinical and clinical data. If a manufacturer can provide assurance of comparability through analytical studies alone, nonclinical or clinical studies with the post-change product are not warranted. However, where the relationship between specific quality attributes and safety and efficacy has not been established, and differences between quality attributes of the preand post-change product are observed, it might be appropriate to include a combination of quality, nonclinical, and/or clinical studies in the comparability exercise.

23 Comparability: Two Questions 1. Same or different? - objective criteria needed Same Conclusion: comparable product quality Different No No impact Maybe Further studies (PK, PD, in vitro) 2. Adverse patient impacts due to differences? Adverse impact Yes Quality is not comparable

24 Comparability and Specifications are Different Comparability assessments ask: is the new material different? Specifications define ranges to ensure suitable quality: is it good enough?

25 Profile Comparison Acceptance Criteria Control 1 Control 2 Control 3 Qual 1 Qual 2 Qual 3 Reference Acceptance criteria for profile comparisons: - no new peaks in the full-scale profiles for post-change lots - same general peak shape in the expanded-view profiles for post-change lots - alternate: rank order of forms is maintained Objective acceptance criteria are pre-defined - avoid no significant new peaks

26 mab Cation Exchange Chromatography Before CpB Treatment 0K, pe Ref Std After CpB Treatment Ref Std 1K, pe New clone 0K, pe New clone 2K, pe AV2 0K, 1Q AV1 0K, 2Q 0K, 1Q Acidic variant differences can be eliminated with neuraminidase treatment AV1 and AV2 contain some sialylated forms Two types of basic variants are observed: due to HC C-term Lys, and partially cyclized HC N-term Gln to pyroglu Jennifer Wang 26

27 mab Phase IIb / III Process Differences Phase I / IIa Phase IIb / III Cell line NS0 CHO Sialic acid 0.05 mol/mol NGNA 0.13 mol/mol NANA C-terminal Lys ~40% trace levels Gln / pyroglu on heavy chain 0% / 100% ~5% / ~95% Consider both individual and cumulative impacts Conducted a rat PK comparability bridging study - 20/group, subcutaneous administration - AUC and Cmax within 80%-125% ratio between groups Conclusion: material is different, but with comparable product quality Srikanth Chary et al. 27

28 Four Ways to Define Product Quality Type Basis Purpose and Guidance Clinical specification acceptance criteria Critical Quality Attributes Test results for Tox or early clinical batches, or platform criteria, plus profile comparisons. Bioactivity, PK/PD, Immunogenicity, Safety Range of acceptable results that ensure suitable product quality. ICH Q6B Establish a control system: tests, validation, monitoring. ICH Q Comparability assessments Development targets Prior product characteristics. Use statistics for postapproval changes. Justify process or mfg facility changes. ICH Q5E

29 Product Quality Task Force 29 We have product quality targets during development for attributes including: Host cell proteins Sequence variants Color / colored impurities We extended this concept to standard format mab quality attributes that historically had been more product- and process-specific, including: Charge variants Size variants (e.g., high molecular weight aggregated forms) Data mining by Nattu Vijayasankaran et al. Team included CMC and non-cmc experts Intent was to make it easier for teams to develop processes by providing targets, and to enable timely feedback regarding tradeoffs Escalation by exception to reduce oversight burden Core team notification of unusual quality issues ( risks understood) Can t replace judgment 2012, Genentech / Proprietary information Please do not copy, distribute or use without prior written consent

30 Setting Product Quality Targets during Process Development Based on historical analytical results from clinical development and related licensed therapeutic antibody products Quality attributes in ranges seen for similar clinical development molecules are viewed as being lower risk for patients Standard (Green, lowest risk) Average ± 2SD Teams are asked to product material in this range Borderline (Yellow, medium risk) Values at limits of individual lots Teams need to discuss risks of higher levels with non-cmc experts Outside (Red, higher risk) Outside limits of historical experience Teams need to escalate to management review can they improve purity with more time and resources?

31 % SEC HMWS 2% 3% Key Historical Limit Historical Mean excluded

32 % Acidic Charge Variants 35% 40%

33 Four Ways to Define Product Quality Type Basis Purpose and Guidance Clinical specification acceptance criteria Critical Quality Attributes Test results for Tox or early clinical batches, or platform criteria, plus profile comparisons. Bioactivity, PK/PD, Immunogenicity, Safety Range of acceptable results that ensure suitable product quality. ICH Q6B Establish a control system: tests, validation, monitoring. ICH Q Comparability assessments Development targets Prior product characteristics. Use statistics for postapproval changes. Historical results for similar molecule type Justify process or mfg facility changes. ICH Q5E Guide development teams

34 Closing thoughts 34 Don t ask what will FDA/EMA require? product quality is our responsibility patients trust that we re providing them with material that gives them the best chance of a successful treatment product quality limits are not based on process capability CMC experts aren t safety experts make sure non-clinical experts are included in product quality discussions 2012, Genentech / Proprietary information Please do not copy, distribute or use without prior written consent

35 Thank you! 35 Clinical Specifications Christof Finkler Sarah Du Hélène Gazzano-Santoro CQA Assessments & Control Strategy Paul Motchnik Ron Taticek Valerie Quarmby Mary Cromwell Nadja Alt Felix Kepert Comparability Kathy Francissen Sabine Wöller Jennifer Wang Matt Kalo Product Quality Targets Nattu Vijayasankaran Yung-Hsiang Kao Chris Yu 2012, Genentech / Proprietary information Please do not copy, distribute or use without prior written consent