SESSION 11 Stability Data Evaluate, Set Specifications and Prepare Reports

Transcription

1 SESSION 11 Stability Data Evaluate, Set Specifications and Prepare Reports Dan Willingmyre, Neha Frantz, Philip Pue-Gilchrist, Donnie Pulliam, Ketan Shah, and Brian K Nunnally

2 Agenda Introduction Inputs and Outputs Case Study: Laboratory Variability The specification process Case Study: Setting Stability Specifications 2

3 Purpose of Stability Studies Evaluate Quality of DS and DP under Environmental Influences: Temperature Humidity (if applicable) Light Outcome: Establishment of recommended storage conditions, retest or expiry periods for DS and shelf life for DP. Evaluate Quality based on Product-related factors: Interaction of DS with excipients Product in container closure systems and packaging materials 3 3

4 Inputs The goal is to set a DP expiration date on the label Many inputs are needed to set the DP expiration date Within each input are many more inputs Considering each one of these inputs will allow for a comprehensive stability strategy to be developed. 4

5 Drug Substance 5

6 Drug Substance: General Assumptions Detail the assumptions being made What is the final formulation for the DS? What storage temperature(s) will be used? What shelf life is desired? What container closure(s) will be used? 6

7 Development Studies Protocol-driven Accelerated Stability Assessment Program (ASAP) Studies 1,2 Does not replace real-time stability Provides insight into stability-indicating attributes Forced degradation / characterization Impurities Real-time stability on feasibility 6M / accelerated condition on development material to support clinical DP shelf-life. 1: Waterman, K.C., et al (2007), Pharmaceutical Research, Vol. 24, No. 4 April : Waterman, K.C. (2010), AAPS Short Course on Stability Testing in Pharmaceutical Development.

8 Phase Specific Stability Protocol Considerations (Small Molecule) Phase I Phase II Phase III/Reg PVR/ PostApp # of Batches a 0-3 b Storage Conditions per ICH Q1A (R2) Target Retest/Expiry Minimum Data at submission Initial Retest Claim (ICH Q1E) Development data (as applicable) and 3M, minimum 25 C (Zone II) or 2-8 C Globally 30 C (Intermediate) 40 C (Accelerated) 60 Months 12M real time 6M, minimum 24M, minimum N/A (Post-approval updates) Extensions with realtime data Storage label Claim CRT (20-25 C) or 2-8 C CRT (20-25 C) or 2-8 C a: at least 1 batch at commercial scale from intended site of mfg b: depending on # of full scale registration batches, a total of 3 batches at commercial scale.

9 Phase Specific Stability Special Studies (Small Molecule) Phase I Phase II Phase III / Reg PVR/ PostApp Special Study Description Photostability (ICH Q1B) Evaluate at Ph1 for DS handling / pack (1 batch) Conduct in PhIII if process / packaging changes (1 batch) Temperature cycling/ Short-term excursion studies Stability of RSM and Process Intermediates N/A support handling / TE with stability data up to 40 C (accelerated) N/A unless required or need determined during early phase. Conduct to support supply chain and handling of drug substance (1 batch) Temp range = -20 o C to up to 70 o C Conduct prior to registration or during PVRs (1 batch) 9

10 Phase Specific Stability Protocol Considerations (Large Molecule) Phase I Phase II Phase III/PV PostApp # of Batches / Storage Conditions per ICH Q1A (R2) Target Expiry Frozen or 2-8 C 25 C (Accelerated) 24 Months (minimum) Minimum Data at submission Development data (as applicable) and 6M (min) 12M real time N/A (Post-approval updates) Initial Expiry Claim (ICH Q1E) 12M, minimum 24M, minimum Extensions with realtime data Storage label Claim Frozen or 2-8 C Frozen or 2-8 C

11 Methods 11

12 Phase Specific Stability Tests (Small Molecule DS) * * Phase I Phase II Phase III/Reg PVR/ PostApp Test List (ICH Q6A) Appearance XRPD Chiral Assay Impurities Water Content Verify consistency and free from foreign matter Evaluate as applicable per ICH Q6A decision trees 4 and 5 Required: ICH Q6A Specifications as applicable Evaluate from development studies and ICH Q6A Decision Tree 2; Report, Identify, Qualify per thresholds stated in ICH Q3A (R2) Required: ICH Q6A unless otherwise justified MLT N/A due to rationale* * PAD control strategy for Phase 1 TBD per ICH Q6A Decision Tree 6 * * Methods validation Specs Proposal/SRB

13 Methods: Large Molecule DS Type of tests Assay Attribute Color Appearance Clarity General ph ph Osmolality Osmolality Quantity Protein Concentration Total protein concentration Identity Binding Assay Identity icief Identity Biological Activity Binding Assay Potency SEC Aggregate Non Reducing CE- Total Purity Purity and SDS Single Highest Impurity Impurities Lower pi Isoforms icief Main Peak Endotoxin (USP,EP) Endotoxin level Safety TAMC Bioburden TYMC Additional methods for process impurities (e.g. HCP, DNA, Leachate(s), Viral inactivation surfactants, etc) may be added 13

14 Phase Specific Stability Tests (Small Molecule Drug Product) * * Phase I Phase II Phase III/Reg PVR/ PostApp Test List (ICH Q6A) Appearance Verify Product Appearance Conforms to Specification Dissolution / Disintegration Assay Impurities Water Content Evaluate per ICH Q6A Decision Tree 7 Specifications as applicable Required: ICH Q6A Evaluate from development studies and ICH Q6A Decision Trees 2 and 5; Report, Identify, Qualify per thresholds stated in ICH Q3B (R2) Required: ICH Q6A unless otherwise justified MLT N/A due to rationale* Per ICH Q6A Decision Tree 6 Per ICH Q6A Decision Tree 6 and also required in some markets (minimally on limited number of batches) *PAD control strategy for Phase 1 * Methods validation * Specs Proposal/SRB

15 Methods: Large Molecule DP Type of tests Assay Component General Appearance Color Clarity Particulates ph ph Osmolality Osmolality Quantity Protein Concentration Total protein concentration Extractable Volume Volume in container Identity Binding Assay Identity icief Identity Biological Activity Binding Assay Potency SEC Aggregation Non Reducing CE- Total Purity Purity and SDS Single Highest Impurity Impurities Lower pi Isoforms icief Main Peak Endotoxin Endotoxin level Sterility Sterility Safety CCI Container closure integrity Particulates 10µm Particles 25µm Particles CCI is only tested on stability 15

16 Accuracy or Precision? Problem statement Yield for the material was outside the 2σ Processing Limits. 120 Yield was above 100%. Analytical and manufacturing investigation revealed the problem was likely to due to an assay issue. 1-Point Average Solution The problem was the variability (not the accuracy, per se) of the quantity assay, so there was a need to reduce the variability of the quantity assay Range

17 Accuracy versus Precision

18 What do you do? Run more samples! Run more replicate injections! Are these the right answers? Maybe, maybe not? How do you know????

19 Step 1: Determine your precision Four common methods Use of validation data Stability data Control data Blind control data 19

20 Use of validation data to determine precision Advantages Easy to acquire Provides variance component analysis (even if only for a moment in time ) Best accepted method Disadvantages Rarely gives accurate assessment of true variability Spotlight effect Underestimation of variability due to intense concentration and the use of highly skilled analysts during special studies such as validations Lack of long term variability

21 Example of using validation data Analyst Day/Assay Instrument Capillary Result 1 1/ / / / / / / / / / / / / / / / / / / / / /5 7.1 Mean 7.2 Std 0.55 %RSD 7.7% Response Result Summary of Fit RSquare RSquare Adj Root Mean Square Error Mean of Response Observations (or Sum Wgts) 22 Analysis of Variance Source DF Sum of Squares Mean Square F Ratio Model Error C. Total Prob > F * Parameter Estimates Term Estimate Std Error t Ratio Prob> t Intercept Instrument Capillary Day <.0001 * * *

22 Use of stability data to determine precision Advantages Provides long term variability Relatively immune to Spotlight effect Minimal contribution of sampling variability No contribution due to manufacturing variability Disadvantages Material must be unchanging or have a predictable rate of change Can take a long time to acquire the data set Lacks ability to show day to day variability Periodicity can be invisible

23 Example of using stability data Timepoint Potency Lot A A A B B B B B C C C C C C D D D Lot A B C D Mean Standard Deviation RSD (%) Estimated Method RSD (%) 5.0

24 Use of control data to determine precision Advantages Easy to do, if control data is available Provides variance component analysis Provides long term variability Disadvantages Spotlight effect Especially when there are acceptance criteria or system suitability criteria associated with the control Control must be run identically to sample

25 Example of using control data Individuals s = s = s = Moving Range

26 Use of blind control data to determine precision Advantages Best way to understand true analytical variability Eliminates the Spotlight effect Provides variance component analysis Disadvantages Takes more organization than other means Usually does not show long term variability

27 Example of using blind control data Individuals Moving Range Laboratory expanded

28 Step 2: Reduce variability So now you know your precision, what s next (Ruthlessly) reduce variability!!! The exercise will give an example of the effects of reducing variability Steps Identify sources of variation (e.g. reagents, equipment, techniques, practices, knob twisting, etc.) For reagents and equipment take the randomness out of the process and standardize For techniques and practices decide on one-way of doing things Implement changes 28

29 Case Study: Variability reduction project Purpose Reduction of controllable variability within all critical assays. Provide data that is irrefutable within the inherent variability of the method. Build a relationship of trust between the laboratory and the customers. Execution Scientist driven [CRITICAL] Step by step review of each method Identification of agreed upon best practices Published minutes documenting best practices Training Syllabus Present Future 29

30 Concentration DOE Data Summary Preproject DOE Postproject DOE % Drop in s Assay Control (Intermediate) Total Analyst/ Assay Drug Substance Total Analyst % 47% 50% 72% Scientist portion of the total variability dropped over 72% for the drug substance and 47% for the intermediate Overall variability dropped 50% for the drug substance No drop for the intermediate This is due to variability in dilutions Intermediate Before = 5.1%; After = 5.6% Drug Substance Before = 6.3%; After = 3.2%

31 Proposed replication strategy Two scientists run the assay independently Keep n = 4 replicates, but they must be independent draws from the sample. This will also help if there is any homogeneity variability. Averages across scientist Averages across two standard curves (key component of variability) No acceptance criterion for agreement between replicates or between scientists The point of the replication strategy is to average out variability A Sample Concentration Sample Analyst Replicates Result Result Result Result Analyst Replicates A Concentration Result Result Result Result 31

32 Does it work? Point Average RSD pre-improvement = 10.3% RSD post-improvement = 1.9% Range

33 Formulation 33

34 Formulation: Studies The various buffer combinations are studied to determine the impact on quality attributes: DOEs to optimize the formulation. Short term stability to justify selection. Formulation lock Research different formulations leading to the selection of a lead candidate Confirming final concentration 6 months of stability data will be collected to confirm stability 34

35 Drug Product 35

36 Drug Product: General Assumptions Detail the assumptions being made What is the final formulation for the DP? Is it the same as DS? What storage temperature(s) will be used? What shelf life is desired? What container closure(s) will be used? Are there multiple presentations? 36

37 Phase Specific Stability Protocol Considerations (Small Molecule) Phase I Phase II Phase III/Reg PVR/ PostApp # of Batches 1 / strength 1 / strength 3 a 0-3 b Storage Condition per ICH Q1A (R2) Target Shelf-life 30 C (Zone IV) Globally 25 C (Zone II) Back-up condition to 30 C (Zone IV) 40 C (Accelerated) 36M, minimum Minimum Data at submission Initial shelf-life Storage label Claim Development data (as applicable) and 1 month 40 C (min) 6M, min (with 6M development data, initial shelf-life 12M) Store below 30 C (Store below 25 C, if applicable) 12M LT + 6M Acc. N/A (Post-approval updates) 24M, minimum Extensions with realtime data Store below 30 C (Store below 25 C, if applicable) a: at least 1 batch at commercial scale b: depending on # of full scale registration batches, a total of 3 batches at commercial scale.

38 Phase Specific Stability Special Studies (Small Molecule) Phase I Phase II Phase III / Reg PVR/ PostApp Special Study Description Photostability (ICH Q1B) Temperature cycling Short-term excursion studies If DS photosensitive, evaluate at Ph1 (1 batch) N/A support handling / TE with stability data Conduct in Ph3 / final commercial image in open dish and commercial package (as applicable) Conduct to support supply chain and handling of drug product, and unmonitored shipping of drug (1 batch) Bulk Hold Studies N/A through phase 2 In-use stability (for multidose containers) EU Guidance: CPMP/QWP/2934/99 N/A through phase 2 Conduct on 1 batch per ICH conditions in bulk container (or smaller, comparable container). Conduct on 2 batches in worstcase commercial multidose container; with one batch at end of shelf-life.

39 Phase Specific Stability Protocol Considerations (Large Molecule) Phase I Phase II Phase III/PV PostApp # of Batches a 0-3 b Storage Condition per ICH Q1A (R2) 2-8 C 25 C (Accelerated) 40 C (Stressed) Target Shelf-life 36M, min Minimum Data at submission Development data (as applicable) and 6M (min) 12M LT + 6M Acc. N/A (Post-approval updates) Initial shelf-life 12M, min 24M, min Extensions with realtime data Storage label Claim Store at 2-8 C Store at 2-8 C (X months outside of refrigeration, if applicable)

40 Phase Specific Stability Special Studies (Large Molecule) Phase I Phase II Phase III / PV PostApp Special Study Description Photostability (ICH Q1B) Conduct in final commercial package Temperature cycling Short-term excursion studies Conduct to support supply chain and handling of drug product (1 batch) Secondary CCS End to End Conduct many of the same studies needed for the original CCS (omit photostability, End to End, Cycling studies) Conduct on 1 batch; Need DS at expiry and then longterm, accelerated, stress DP studies

41 Drug Product: Needs Final packaging for Photostability studies Pstab data for Cycle 2 and Cycle 3 concentrations Final formulation Specifications Confirmation of no method changes # vial sizes (assumption is 3) and fill volumes Worst case justification Ask agencies for the ability to use statistics (CMC question) Patient convenience needs? In use stability data Will excipient to protein ratio be the same across all strengths Agency agreement on stability strategy 41

42 Packaging and Device 42

43 Detail the assumptions being made Packaging and Device: General Assumptions Is the container the same or is a switch needed for the device? What shelf life is desired? What container closure(s) will be used? Are there multiple presentations? 43

44 Phase Specific Stability Protocol Considerations (Devices) Phase I Phase II Phase III/PV PostApp # of Batches N/A N/A 3 0 Storage Condition per ICH Q1A (R2) Target Shelf-life 2-8 C 25 C (Accelerated) 40 C (Stressed) 36M, min Minimum Data at submission 12M LT + 6M Acc. N/A Initial shelf-life 24M, min Extensions with realtime data Storage label Claim Store at 2-8 C (X months outside of refrigeration, if applicable)

45 Phase Specific Stability Special Studies (Devices) Phase I Phase II Phase III / PV PostApp Special Study Description Photostability (ICH Q1B) Conduct in final commercial package Temperature cycling Short-term excursion studies Conduct to support supply chain and handling of drug product (1 batch) End to End Conduct on 1 batch; Need DS at expiry and then longterm, accelerated, stress DP studies

46 Specifications 46

47 The Specification Process Specifications are reviewed by a committee with a chairperson as the lead Committee is a standing cross-functional team with other ad-hoc members brought in as needed Additional Executive committee is available for new modalities, specification strategy, and higher level discussions. Intent is to infuse and maintain consistency of approach for specification setting and rationale The Specification report is the internal technical report supporting the proposed specifications/strategy; intended to be a more detailed version of the 32S45 and 32P56 filing documents (e.g. extensive explanation of stats where applicable) 47

48 The Specification Process: Scope Specification review process applies to all stages, but is phaseappropriate Platform specifications have been developed for early stage compounds based on standardization Action limits have been added at release while we are still learning about the molecule Inquiries impact specs, this is also in scope of SRB review and endorsement 48

49 Specifications: Assumptions Clinical specifications are the maximum ever submitted (likely lower) Best support for any specification is clinical data Manufacturing capability will drive final specifications as well Japan only allows one specification; so stability specification is licensed specification 49

50 Specifications: Drug Substance Type of test General Assay Component Release Limit Stability Limit Appearance Color <YX Same as Release Clarity < A NTU Same as Release ph N/A TBD (equal tail tolerance) Same as Release Osmolality N/A TBD (equal tail tolerance) N/A Quantity Concentration N/A TBD (equal tail tolerance) N/A Identity Biological Activity Safety Binding Assay icief Binding Assay Endotoxin (USP,EP) Bioburden N/A N/A N/A Meets Biological Activity Specification Comparable to reference standard TBD (equal tail tolerance) + clinical experience N/A N/A Same as Release N/A Z EU/mL N/A TAMC Y CFU/10mL N/A TYMC Y CFU/10mL N/A 50

51 Specifications: Drug Substance (cont d) Type of tests Biological Activity Purity and Impurities Assay Component Release Limit Stability Limit Binding Assay SEC Purity pi N/A TBD (equal tail tolerance) + clinical experience N/A TBD (equal tail tolerance) + clinical experience Total Purity TBD (equal tail tolerance) + clinical experience TBD (equal tail tolerance) + Single Highest Impurity clinical experience Lower pi Isoforms TBD (equal tail tolerance) + clinical experience Main Peak TBD (equal tail tolerance) + clinical experience Same as Release = DS release spec + D X mos = DS release spec + D X mos = DS release spec + D X mos = DS release spec + D X mos = DS release spec + D X mos For highlighted parameters, if DS is stored frozen, there is no need for a different stability limit as there are no trends over time for frozen material. X months is the shelf life of DS 51

52 Specifications: Drug Product Type of test General Assay Component Release Limit Stability Limit Color <YX Same as Release Appearance Clarity < A NTU Same as Release Particulates Essentially Free of Particles Same as Release ph N/A TBD (equal tail tolerance) Same as Release Osmolality N/A TBD (equal tail tolerance) N/A Quantity Identity Biological Activity Safety Concentration N/A TBD (equal tail tolerance) N/A Extractable Volume N/A X ml N/A Binding Assay N/A Meets Biological Activity Specification N/A icief N/A Comparable to Reference Standard N/A Binding Assay N/A TBD (equal tail tolerance) + clinical experience Same as Release Endotoxin N/A Z EU/mL N/A Sterility N/A No Growth N/A CCI N/A N/A Pass Particulates 10µm Particles 6000 Particles/Container Same as Release 25µm Particles 600 Particles/Container Same as Release 52

53 Specifications: Drug Product (cont d) Type of test Assay Component Release Limit Stability Limit SEC N/A TBD (equal tail tolerance) + clinical experience = DS release spec + D Y mos + DP Mfg Purity and Impurities Purity Total Purity Single Highest Impurity TBD (equal tail tolerance) + clinical experience TBD (equal tail tolerance) + clinical experience = DS release spec + D Y mos + DP Mfg = DS release spec + D Y mos + DP Mfg icief Lower pi Isoforms Main Peak TBD (equal tail tolerance) + clinical experience TBD (equal tail tolerance) + clinical experience = DS release spec + D Y mos + DP Mfg = DS release spec + D Y mos + DP Mfg For highlighted parameters, if DS is stored frozen, the formula will be DP release specification + D Y months + DP Mfg 53

54 Label 54

55 Label Label will include expiry and storage temperature Package insert will include patient convenience details 55

56 Setting Specifications for Stability: Case Study

57 Approach Product quality attributes for this compound demonstrate significant change as a function of storage time and temperature: Global Stability collaborated with several groups to set release and stability specifications. DS stability specification calculation = (DS release specification) + (maximum predicted change over storage) DP stability specification calculation = (DS release specification) + (change predicted during DP manufacturing) + (maximum predicted change over DP storage) 57

58 Widening Stability Specifications: Case Study

59 Case Study: Specification Widening A new manufacturer for the DP was being added for a biotech product As part of the submission, a specification was widened. At the 5±3 C long-term storage condition, a biphasic trend exists Appropriate statistical model was applied to fit the data set The change was then calculated between the intercept of the common slope line at T=0 and the plateau of the upper 99.9% confidence interval at shelf life. The resulting value represents the worst case on stability. The widening was supported by a tox/safety assessment. The proposed widening was accepted! 59

60 A word about the Regulatory filing

61 CTD Structure Module 1 Regional Administrative Information 1.0 CTD Table of Contents 2.1 Not Part of the CTD CTD Introduction 2.2 Module 2 Quality Overall Summary 2.3 Nonclinical Overview 2.4 Nonclinical Written and Tabulated Summaries 2.6 Clinical Overview 2.5 Clinical Summary 2.7 CTD Module 3 Quality 3.0 Module 4 Nonclinical Study Reports 4.0 Module 5 Clinical Study Reports 5.0

62 CMC Granularity Granularity depends on the product and life cycle decisions Defines how the completed document is broken down, tagged and stored for reuse Determines smallest piece of information that is reusable Changing granularity during lifecycle is difficult, therefore must be planned at the beginning. More complex products, such as biotech, typically benefit from greater granularity Granularity beyond the ICHM4 granularity annex can be used, such as sub-sections or attached reports; these are separate documents/leaves 62

63 Stability Information (32S7 and 32P8) Summary and Conclusions (32S71 and 32P81) This includes a summary and analysis of the stability data, including figures Post-approval Stability Protocol and Commitment (32S72 and 32P82) This includes the post-approval stability protocol, with analytical methods, specifications, and timepoints tested Stability data (32S73 and 32P83) This includes the stability data tables Additional stability documents (e.g. in-use stability, clinical stability, stress testing, etc.) may be included as separate documents (e.g. additional granularity) Legacy programs may have slightly different set-ups 63

64 Specification Information DS Specifications are listed in 3.2.S.4.1; DP Specifications in 3.2.P.5.1 Justification of these specifications are presented in 3.2.S.4.5 (DS) and 3.2.P.5.6 (DP) Justification for method stability indicating behavior can be put in several places in the dossier pick one and put hyperlinks in the other places 64

65 Managing Multiple Versions Ideally, there is only one version of the filing used for all markets In practice it is difficult to have a single version (if not impossible) Japan requires more detail in the manufacturing and testing sections than any other market Specifications between markets can be difficult to align For 32S7 and 32P8, it is often easy to have one version of the stability data and stability conclusion sections 65