The Choice of Sampling Frequency and Product Acceptance Criteria to Assure Content Uniformity for Continuous Manufacturing Processes

Transcription

1 The Choice of Sampling Frequency and Product Acceptance Criteria to Assure Content Uniformity for Continuous Manufacturing Processes

2 Authors Tim Kramer Sal Garcia Jeff Hofer Xiaoyu Zhang Ian Leavesley Wyatt Roth Leo Manley Ahmad Almaya 15Jan2016 Kramer et al, IFPAC

3 Outline Lilly continuous manufacturing Measure of closeness for content uniformity Implications for acceptance criteria at the feed frame Sampling frequency at the feed frame Sampling frequency and acceptance criteria of core tablets measured by NIR Summary 15Jan2016 Kramer et al, IFPAC

4 Continuous Drug Product Manufacturing Process at Lilly Frequency: continuous Loss-in-weight feeders Frequency: continuous Rapid real-time measure of API content in blend Residence-time distribution (RTD) model Feed frame Frequency: 2~3x per ~3-5 min NIR tablet assay 15Jan2016 Kramer et al, IFPAC

5 Predicting Concentrations Output from loss-in-weight feeders combined with residence time distribution model provides concentration estimates at feed frame May be used to reject tablets having extreme concentrations NIR scans at feed frame provide alternative estimates of concentration May also be used to reject tablets having extreme concentrations 15Jan2016 Kramer et al, IFPAC

6 Assuring Content Uniformity Want majority of individual dosage units to be close to target Use 85% to115% label claim as interval that represents closeness Internal sampling and batch acceptance criteria relate to these intervals Use ASTM 2810 with 50% confidence that 80% of samples will pass USP<905> for routine batches Use ASTM 2810 with 50% confidence that 95% of samples will pass USP<905> for process validation batches 15Jan2016 Kramer et al, IFPAC

7 Example OC Curves when True Mean, µ= Percentage of Time Pass Criteria % 99% 98% 97% 96% 95% 94% 93% 92% 91% 90% Percentage of Individual Dosage Units Within % LC 15Jan2016 Kramer et al, IFPAC 2016

8 Assuring Dose Uniformity Criteria % of Individual Dosage Units Between 85% and 115% Label Claim (with 95% Confidence) ASTM % Confidence of 95% Passing (Process 98% Validation Criteria) ASTM % Confidence of 80% Passing (Routine 94% Release Criteria) USP<905> 86% 15Jan2016 Kramer et al, IFPAC

9 Assuring Content Uniformity Acceptance criteria are guided by the desire to ensure product is between 85% and 115% label claim With the understanding That the process is targeting 100% label claim There are process and measurement variabilities That there are potential biases between NIR and HPLC measurements 15Jan2016 Kramer et al, IFPAC

10 Potential Feed Frame Criteria Having some dosage units outside 85% to 115% does not imply that you will fail content uniformity However, having vast majority within 85% to 115% does imply that you will pass content uniformity requirements A proposed option is to set feed frame criteria to ensure that underlying concentration is between 85% and 115% 15Jan2016 Kramer et al, IFPAC

11 Hypothetical Feed Frame Observations 110 True Concentration and NIR Observed (1 Spectra and Average of 5) 105 Concentration (% of Nominal) Observation Blue: True Concentration Red: NIR, Individual Spectra Green: NIR, Average of 5 15Jan2016 Kramer et al, IFPAC

12 How to Assure True Concentration is > 85% Label Claim Assuming NIR independence, no measurement bias and a constant true concentration: 85% + 3 σσ NNNNNN / nn σσ NNNNNN Number of Signals Averaged Jan2016 Kramer et al, IFPAC

13 Adding Underlying Process Variability To assure underlying concentration is 85% (assuming NIR independence, no measurement bias and an independent concentration process): 85% + 3 (σσ NNNNNN 2 + σσpppppppppppppp 2 )/ nn σσ NNNNNN Number of NIR Signals Averaged Standard Deviation of Underlying Concentration (% Label Claim) Jan2016 Kramer et al, IFPAC

14 Adding potential bias (NIR relative to HPLC) To assure underlying concentration is 85% (assuming NIR independence, systematic bias and an independent concentration process): 85% + bbbbbbbb + 3 (σσ NNNNNN 2 + σσpppppppppppppp 2 )/ nn 15Jan2016 Kramer et al, IFPAC

15 Observed NIR Averages to Assure True Concentration is 85% Label Claim With 2% assumed bias: σσ NNNNNN Number of NIR Signals Averaged Standard Deviation of Underlying Concentration (% Label Claim) Observed averages of 5 NIR signals between 93.0% and 107.0% assure underlying concentrations are between 85% and 115% for σσ NNNNNN = 4%, σσ PPPPPPPPPPPPPP = 2% and bias = 2%. 15Jan2016 Kramer et al, IFPAC

16 Feed Frame Sampling Frequency Potential goal is not just to monitor the process but to react to deviations Have limited time between feed frame signal and ejection of tablets Want to reject anomalies (transients) that occur downstream of feeders (Feeder issues are handled separately not considered in this talk) 15Jan2016 Kramer et al, IFPAC

17 Hypothetical Transient Seen at the Feed Frame True Concentration and NIR Observed (1 Spectra and Average of 5) Concentration (% of Nominal) Excluded from tableting Observation 15Jan2016 Kramer et al, IFPAC

18 Hypothetical Downstream Concentrations When Product Is Rejected at Feed Frame True Concentration and NIR Observed (1 Spectra and Average of 5) Concentration (% of Nominal) Observation 15Jan2016 Kramer et al, IFPAC

19 What s the Worst That Could Happen? Picking limits of 100 ± x% with averages of n signals will effectively catch short-term transients of nx% from target ± 7% limits with n=5 will catch short-term transients of 35% from target For example, average of five signals {100, 100, 100, 100, 65} is 93 15Jan2016 Kramer et al, IFPAC

20 Feed Frame Sampling Frequency Sample as fast as system allows Each spectra is available every 1.2 seconds (one spectra is average of 20 scans) Number used in average is limited by reaction time Want to be able to reject all material that comprises average In addition to reaction time, actual number of spectra used in average will depend on process standard deviation, NIR standard deviation, and importance of quick detection 15Jan2016 Kramer et al, IFPAC

21 Core Tablet Sampling Frequency and Acceptance Criteria Purpose is to confirm that upstream processes have delivered as expected and measured Does not need to be any more stringent than for batch processing Use same sampling frequency and acceptance criteria as for HPLC-measured batches 15Jan2016 Kramer et al, IFPAC

22 Acceptance Criteria for NIR Determinations (Core Tablets) For core tablets, treat NIR and HPLC determinations equivalently (once NIR method is qualified) Potentially use ASTM 2810 with 50% confidence that 80% of samples will pass USP<905> for routine batches Potentially use ASTM 2810 with 50% confidence that 95% of samples will pass USP<905> for process validation batches 15Jan2016 Kramer et al, IFPAC

23 Potential Routine Release Sampling Frequency and Acceptance Criteria Tier 1 Sample 10 locations throughout the batch with 1 sample per location (10x1 plan) Test against ASTM E2810 criteria for 50% confidence of passing the USP <905> test 80% of the time using Sample Plan 1 for the 10x1 plan Tier 2 Sample 20 additional locations throughout the batch with 1 sample per location for a total of 30 locations (30x1 plan) Test against ASTM E2810 criteria for 50% confidence of passing the USP <905> test 80% of the time using Sample Plan 1 for the 30x1 plan 15Jan2016 Kramer et al, IFPAC

24 Potential Process Validation Sampling Frequency and Acceptance Criteria Tier 1 Sample 20 locations throughout the batch with 2 samples per location (20x2 plan) Test against ASTM E2810 criteria for 50% confidence of passing the USP <905> test 95% of the time using Sample Plan 2 for the 20x2 plan Tier 2 Sample 20 additional locations throughout the batch with 2 samples per location for a total of 40 locations (40x2 plan) Test against ASTM E2810 criteria for 50% confidence of passing the USP <905> test 95% of the time using Sample Plan 2 for the 40x2 plan 15Jan2016 Kramer et al, IFPAC

25 Summary Feed frame acceptance criteria can be guided by goal of ensuring concentrations between 85% and 115% Number of spectra used at feed frame should consider reaction time, process standard deviation, NIR standard deviation, potential bias and resulting rejection limits Acceptance criteria and sampling frequency of core tablets measured by NIR can be identical to batch processes measured by HPLC 15Jan2016 Kramer et al, IFPAC

26 Thank you for your attention! Questions??? 15Jan2016 Kramer et al, IFPAC

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