Drug Product Comparability: Using Process and Product Knowledge for Successful Comparability Exercises

Transcription

1 Drug Product Comparability: Using Process and Product Knowledge for Successful Comparability Exercises Jamie Moore Head, Late Stage Pharmaceutical Development CMC Strategy Forum July 18-19, 2016

2 Many Reasons Tech Transfers are Necessary Increase Capacity Global market demand Natural disasters Equipment failures Demand variability Dual Sourcing Enable Facility Closure Older technologies Facility design

3 Goals of Tech Transfers Process Product Same Process Comparable product quality Modifications only for facility/ equipment fit Same Expiration Dating assigned for material produced at each site Comparability established at the point of change, ie if a Drug Substance process is tech transferred to a new manufacturing site, comparability is established for Drug Substance

4 Building Blocks of Comparability Process Analytical Control System C of A testing Comparison to Historical Trends Product Quality/ Analytical Comparability Extended Characterization Chemical & biological characterization Non-clinical and Clinical Studies (if necessary): Pharmacokinetic Pharmacodynamic Stability Stressed and real time Stress studies establish degradation pathways, provide direct pre-to-post comparison, and probe potential 4

5 Assessing the Process: Foundation of Overall Comparability Exercise Process Goal is to minimize process changes during tech transfer Perform Gap Assessment and Risk Assessment What are the gaps between process A and process B? What risk are associated with gaps? What equipment changes are necessary? What process changes are necessary? Type and extent of change? What is the criticality of the process step, location, and downstream impact? What is the rationale for change? What is the potential impact to product quality? What product knowledge and prior knowledge is available? Design Process Characterization, Validation and Qualification Studies Selection of CQAs sensitive to process changes Design Analytical Comparability 5

6 Assessing the Process: Small-Scale Product Quality Impact Assessment from Extended Mixing 6

7 Product Quality and Analytical Comparability: Analytical Control System Established using entire historical data by 95/99 tolerance interval approach (EBE: Concept Paper Considerations in Setting Specifications, 2013) Cannot exceed specification limits All test results must meet these acceptance criteria comparability acceptance criteria specification acceptance criteria % SEC main peak Specification acceptance criteria xxx xxx Comparability acceptance criteria = Tolerance interval range Series Sample size 7

8 Product Quality and Analytical Comparability: Analytical Control System What do we need to measure? AC=Report Do we have reliable methods? What s an acceptable result? AC=Specification

9 Product Quality and Analytical Comparability: Analytical Control System with Process Knowledge Site A Site B DP % 0.8%+0.4%=1.2% < 95/99TI upper limit=1.1% A B ΔFree drug between two sites TotalΔ Acceptance Criteria 2-8C 1 day 2 day 0-0.1% % < 1.1%+0.17%(Δ DP ambient hrs % process) hrs Demonstrate understanding of processes differences between the two sites prospectively Minimize process holding 2-8 and ambient Assess the safety / efficacy impact based on existing clinical data and product knowledge Positive feedback received from HA regarding the strategy prior to execution 9

10 Product Quality and Analytical Comparability: Extended Characterization Assessing the impact of VHP on Product Quality 10

11 Product Quality and Analytical Comparability: Stability Assessment RO W EMA FDA Slower approval Registration style stability package for changes Up to 24 months real time + 6 months accelerated at time of submission No statistics No flexibility/ acceleration Stress Comparability used Statistics not always required but observed/ common Product Knowledge Faster Approval Stress Comparability used Statistics expected Product Knowledge HA Authority Expectations for Stability Package to License New Manufacturing Site: Evolving 11

12 Stress Studies Provide a Sensitive Analysis to Assess Potential Differences Overall Behavior Mode of Degradation Rate of Degradation 12

13 Stress Studies: Probe for Differences for a Faster Assurance of Comparability How are stressed studies performed? Storage under a stressed condition Typically higher temperature (eg 40 C) Relatively short time (eg 1 month) At least 4 time points, including initial Side by side comparison of 3 lots each produced from current site and new site Advantages of stressed studies More sensitive and faster ability to detect potential differences in degradation rates and modes of degradation compared to real time storage Demonstration of comparability under stressed conditions provides high assurance of comparability at recommended storage temperature Qualitative and Quantitative comparison of all attributes Statistical comparison of select attributes 13

14 Stress Stability Provides a Sensitive Analysis to Assess Potential Changes Overall Behavior Qualitative and Quantitative comparison of stress test results for all test attributes to assess the overall behavior and extent of degradation under stress conditions. Any change is monitored and compared over the course of the stress study. 14

15 Stress Stability Provides a Sensitive Analysis to Assess Potential Changes Mode of Degradation Qualitative profile comparison at each time point for chromatographic and electrophoretic methods to assess the mode of degradation. The profiles are assessed for the appearance of new peaks overall peak shapes the same rank order with respect to peak height AU Control: Lot , T61, 40C/75%RH Site 2 Control: Lot , T61, 40C/75%RH Control: Lot , T61, 40C/75%RH Qual: Lot , T61, 40C/75%RH Site 1 Qual: Lot , T61, 40C/75%RH Qual: Lot , T61, 40C/75%RH Minutes 15

16 Stress Stability Provides a Sensitive Analysis to Assess Potential Changes Rate of Degradation Statistical evaluation of stress data to quantitatively assess the rate of degradation for designated stability indicating parameters Two-stage approach to assess if rates are the same for typically one to two attributes Homogeneity of slopes: Is there any evidence the rates are different? Ratio of rates: Are the rates the same? 16

17 Selection of Test Attribute and Test Conditions for Stress Stability The objective is to observe relevant stress behavior and significant change within a reasonable time frame The degradation observed over the course of the study should be significant enough to achieve these objectives without over-degrading the molecule to a point at which analysis is no longer meaningful 17

18 Selection Test Conditions: Duration 18

19 Selection of Test Condition for a Lyo DP: Different Degradation Profiles in DS and DP Stress Stability 7 % Free Drug Plateaued Drug Substance Comparability@40C Time (days) % Free Drug Time (days) No plateau _ _ QC stability data provided by Heather Power (816981) Drug Product Comparability@50C lyo

20 Dependency of Free Drug Formation on Moisture and Temperature Free drug (% ) Time (months) 40 C 4% moisture 3% 2%, 1% T-DM1 40 C 1% moisture T-DM1 40 C 2% moisture T-DM1 40 C 3% moisture T-DM1 40 C 4% moisture Tg vs. Moisture Free drug (%) C 2% moisture 1% Time (months) T-DM1 50 C 1% moisture T-DM1 50 C 2% moisture ~ 8 C decrease in Tg per 1% increase in moisture content

21 Selection of Temperature with Predictable Behavior: Rate of Free Drug Formation vs. Moisture and Tg Rate (µm/hr) Formation of free drug as a function of T-Tg T-Tg Free drug% Compare the free drug formation of the samples from the same batch Δ moisture 0.5% Tg=49 C Tg=56 C As the incubation temperature approaches the glass transition temperature (affected by moisture), the degradation rate accelerates. Small difference in moisture results in variation of degradation C

22 Comparability is Demonstrated by Meeting Stage 1 or Stage 2 Homogeneity of Slopes Test the hypothesis Meet if no statistically significant difference between slopes (a=0.05 level) Detects small differences between slopes Can be applied to data with high variability and/or low degradation rates Ratio of Rates Evaluate the 90% confidence interval (CI) for Meet if CI lies entirely within [0.80, 1.25] CI gives high degree of assurance that difference is small enough to be acceptable Data generated with high assay variability and/or low degradation rate may fail due to width of CI 22

23 Case Study 1: Liquid Drug Product Transfer Process previously transferred successfully All comparability acceptance criteria met Attribute 1 Site 2 Site 1 Attribute 2 Site 2 Site 1 Passed homogeneity of slopes criteria for comparability p = 0.62 p=0.11 Material produced at Site 2 is comparable to material produced at Site 1

24 Case Study 2: Lyophilized Drug Product Transfer Previously had successfully transferred this process twice Drug Product batches met all release acceptance criteria Stress stability comparability assessment: Qualification lots and Control lots peak profiles for selected assays comparable with no new peaks (Qualitative assessment) Degradation rates of Qualification lots and Control lots were not comparable using two-stage model

25 Case Study 2: Lyophilized Drug Product Transfer Site 1 Site 2 Site 1: T0: 74-75% Up to 8% change (183 days) Site 2: T0: 67-72% Up to 7% change (183 days) Time (days) 61 days 183 days 90% Confidence Interval for Ratio Lower Upper [0.80] [1.25] P-Value for Homogeneity Ratio Test Does not meet Does not meet Results Homogeneity Test Does not meet Does not meet Overall Results for Rate Comparison Does not meet Does not meet

26 Case Study 2: Lyophilized Drug Product Transfer Slope (Square Root of Time) Intercept (Surrogate for T0) Development batches showed no difference from control and passed both tests for comparability Observed rate differences in qualification batches were determined to be related to the starting level of the variant, not production site Comparability was ultimately demonstrated Real time stability demonstrated that the lots were within specification Rates of degradation for other attributes assessed by stressed study met the acceptance criteria Scientific understanding enabled us to attribute differences in starting material and not the site of production

27 Case Study 2: Lyophilized Drug Product Transfer Failed Comparability Older process that showed high variability with respect to moisture content Decision was made to employ more conservative drying cycles at new site based on experience with similar product Full-scale development runs and process characterization runs showed excellent initial results Early indication of stress degradation comparability issues (engineering runs) Process qualification batches runs showed excellent initial results Stress study failed

28 Case Study 3: Lyophilized Drug Product Transfer Site 1 Site 2 Step 1 (homogeneity of slopes) p = = reject homogeneity Step 2 (ratio) Ratio = % confidence interval of ratio = Far Outside the acceptance Chromatography showed differences Site 2 lot 6M 60 C Site 1 lot 6M 60 C

29 Case Study 3: Lyophilized Drug Product Transfer Investigation into causes of differences indicated product quality changes related to the adjusted drying parameters used Differences in rates were also observed at lower storage temperatures Potential to impact shelf-life Further development work required to proceed

30 Summary: Key Attributes for DP Comparability Process Understanding Critical process parameters Link between process parameters and product quality attributes Sources of variability Product Knowledge Critical attributes Structure-function understanding Product stability profile Historical ranges Analytical Capability Use of specific and sensitive physicochemical and biological assays to detect any structural and functional changes Suitable assays to detect purity/impurities Validated or qualified Non-clinical and clinical studies may be required

31 Doing now what patients need next

32 ICH Q5E Guidance Comparability is a well established global regulatory mechanism based on ICH Q5E Comparability of Biotechnological / Biological Products Subject to Changes in Their Manufacturing Process No adverse impact on safety and efficacy post-change Product quality attributes need not be identical Highly similar Sufficient product knowledge to predict differences have no impact Compare results to pre-defined acceptance criteria Objective assessment of comparability Stress Studies establish degradation pathways and provide direct comparison pre-change to post-change Stress Studies can detect potential differences that May be subtle and undetected by characterization studies Warrant additional evaluation Require additional control 32