How to develop an ATP.... and verify it has been met. Melissa Hanna-Brown Analytical R & D; Pfizer Global R+D, Sandwich UK.

Transcription

1 How to develop an ATP... and verify it has been met Melissa Hanna-Brown Analytical R & D; Pfizer Global R+D, Sandwich UK. 06 May 2014

2 Overview Some context accuracy, precision and risk What is an ATP? What are the elements of an ATP? an example: ATP for assay an example: ATP for purity An overview of ATP verification steps 5/27/2014 2:44 PM 2

3 Some context accuracy, precision and risk 5/27/2014 2:44 PM 3

4 Back to basics some context Purpose of a method? to provide a number with an associated confidence which describes the level of an analyte (e.g. in a starting material/process intermediate/api/dp etc) Why do we need this number? to understand how the level of the analyte corresponds to pre-defined threshold(s) (specifications) How do we determine the associated confidence? by understanding the total contributions to variability How do we improve our associated confidence? by minimising variability (through in depth understanding ) 5/27/2014 2:44 PM 4

5 QbD, ICH Q8-10 quality and methods... LSL USL In broad terms, QUALITY encompasses the TOTALITY of features of a process or product (w.r.t. properties, attributes, capabilities). To be able to understand the TOTALITY of features an in-depth understanding must be achieved. LSL Analytical variation Process variation USL σ 2 (measured) = σ 2 (process) + σ 2 (method) Process variation Analytical variation 5/27/2014 2:44 PM 5

6 The importance of Accuracy and Precision criteria in context to other method performance criteria *Modified from a slide presented by Oliver Grosche, Pittcon Mar-2013 Analytical Change Control Result ATP Decision Results: Accuracy and Precision Method Performance Method Performance Data: Method Range Specificity/Peak Resolution Linearity Limit of Detection Instrument Repeatability 5/27/2014 2:44 PM 6

7 Method Performance: Bias and Precision The figure represents the distribution of 95% of the measurements given by four different hypothetical procedures having each a true bias and a true precision. If acceptance criteria is: µ(true) - µ(measured) 15% From Hubert, et al. J Pharm. Biomed. Anal. 36 (2004) 579 Which procedures fulfill this objective and which ones will the analyst retain as valid? 5/27/2014 2:44 PM 7

8 What is an ATP? 5/27/2014 2:44 PM 8

9 ATP? The ATP describes the performance characteristics of the method... such that the data the method produces will be fit for purpose...for e.g. making decisions on about whether a batch of drug substance or drug product meets the specification criteria for assay or purity. 5/27/2014 2:44 PM 9

10 elements to incorporate in an ATP The total uncertainty, expressed in terms of systematic (accuracy) and random (precision) uncertainty (variability) components. A statement which links to the level of risk associated with making incorrect decisions (probability statement). The range for which the analytical method is expected to quantify the analyte. A description of the analyte to be tested, including the sample or matrix in which it will be tested. 5/27/2014 2:44 PM 10

11 An example...atp for assay Example ATP for Drug Product Assay The procedure must be able to accurately quantify PF-1234 in film coated tablets over the range of % of the nominal concentration with accuracy, and precision such that measurements fall within ± 3.0% of the true value with 95% probability. 5/27/2014 2:44 PM 11

12 An example...atp for assay Example ATP for API Assay The procedure must be able to accurately quantify PF-1234 Hydrochloride Drug Substance over a range of 90% to 110% of the nominal concentration with accuracy, and precision such that measurements fall within ± 2.0% of the true value with at least a 95% probability. 5/27/2014 2:44 PM 12

13 Graphical Representation of Traditional Method Validation Criteria Accuracy and Precision with Independent limits/criterion At boundaries: no trade-off between increasing method bias and/or variability It is possible to accept a method with both high bias and high variability Criteria: Bias: NMT 2.0% Variability: NMT 1.25% 5/27/2014 2:44 PM 13

14 Justification of Assay ATP ATP Criterion vs unconstrained {u,sigma} The procedure must be able to accurately quantify PF-1234 Hydrochloride Drug Substance over a range of 90% to 110% of the nominal concentration with accuracy, and precision such that measurements fall within ± 2.0% of the true value at least a 95% probability. 5/27/2014 2:44 PM 14

15 ATP criterion vs Traditional {µ,sigma} sets 25% 10% 5% 5% 5% 5% 5/27/2014 2:44 PM 15

16 Justification of Assay ATP ATP Equation The expression for defining the acceptance region is the following: where, µ = true mean / accuracy; a parameter σ = true sigma / precision; a parameter e = allowable analytical window, a fixed constant y = individual assay value; a random variable with mean µ and standard deviation σ T = true analytical content, fixed target p = minimum probability for individual assay to reside within error bound e, fixed constant Φ(.)= normal density function centered at µ, with standard deviation σ 5/27/2014 2:44 PM 16

17 Interactive ATP Tool - Modeling the Trade-off between Accuracy and Precision API Specification % Process Mean = 100.0% Process std dev = 0.2% ATP criteria: ± 2.0 from the true value with a 95% probability If method bias = 0 then the method standard deviation should be 1.0% (area under the curve that is OOS is ~ 5%) 5/27/2014 2:44 PM 17

18 Interactive ATP Tool Modeling the Trade-off between Accuracy and Precision API Specification % Process Mean = 100.0% Process std dev = 0.2% ATP criteria: ± 2.0 from the true value with a 95% probability If method bias = 1.0% then the method standard deviation should be 0.6% (area under the curve that is OOS is ~ 6%) 5/27/2014 2:44 PM 18

19 Interactive ATP Tool Modeling the Trade-off between Accuracy and Precision - with Replicates API Specification % Process Mean = 100.0% Process std dev = 0.2% ATP criteria: ± 2.0 from the true value with a 95% probability Adding another replicate (n=2) reduces the probability of an OOS result from ~ 6% to 1%. 5/27/2014 2:44 PM 19

20 An example - ATP for Quantitation of Impurities Specifications: Impurity A NMT 0.15% Impurity B NMT 0.15% The procedure must be able to accurately quantify Impurity A and Impurity B relative to PF-1234 Hydrochloride in the presence of drug substance and other impurities over a range from the reporting threshold through twice the specification limit. The accuracy and precision of the procedure must be such that the measurements fall within ± 15% of the true value for impurity levels 0.15% with at least 90% probability, and within ±10% of the true value for impurity levels > 0.15% with at least 90% probability. 5/27/2014 2:44 PM 20

21 Graphical representation of the Purity ATP statement Impurities > 0.15% Impurities 0.15% 5/27/2014 2:44 PM 21

22 An overview of ATP verification steps 5/27/2014 2:44 PM 22

23 Verification Strategy Sampling Sample Preparation = Method Verification Measurement Method ATP 5/27/2014 2:44 PM 23

24 Chromatographic Performance Verification DoEs The first DoE experiment(s) are run during the method evaluation part of the method development lifecycle the important focus of these experiments are parameter interactions and parameter criticality. Driven by outcome of risk assessment Desired outcome = draft MODR (method operable design region) 5/27/2014 2:44 PM 24

25 Chromatographic Method Verification Strategy 1 Screening DoE s Chromatographic Performance Criteria Draft MODR + 2 Verification DoE (s) ATP Verified MODR = Chromatographic Verification 5/27/2014 2:44 PM 25

26 ATP Verification DoEs Following proposal of the MODR ATP verification must be considered. Here the resulting MODR from the screening DoEs is used and multiple verification conditions selected across this MODR using samples representing the range over which the method needs to be able to perform all tested against the ATP criteria. Method parameters not deemed critical from the screening DoEs can be left out of the verification DoE (s). An important consideration during this verification is intermediate precision i.e. performing the verification on different instruments/columns, on different days with different operators. These experiments can result in further refinement of the MODR each time the MODR is refined experimental verification of ATP compliance is required. 5/27/2014 2:44 PM 26

27 Visualisation - ATP Verification Lab 2 Lab 1 5/27/2014 2:44 PM 27 27

28 Conclusions ATPs should direct the design, development and continuous verification of methods throughout the lifecycle of a method. The principle of ATPs are aligned with QbD for process - akin to a QTTP ATPs are also aligned with other industries with respect to the growing recognition of the need to understand the confidence associated with a number describing a sample attribute which has been derived from a measurement method. This is especially important when this number drives a pass/fail decision. There are currently no regulatory or industry guidances on ATPs (It s challenging to prosecute AQbD in the current global regulatory environment where requirements differ across multiple markets a paradigm change via global guidance in this area would really facilitate continuous improvement in method lifecycles). The prospective setting of an ATP allows for the total acceptable variability of the method to be defined up front. Verification of the whole method as complying with the ATP requires a depth of method understanding to be generated. 5/27/2014 2:44 PM 28

29 Thank-you for your attention 5/27/2014 2:44 PM 29

30 Acknowledgements a team effort Dave de Antonis Graham Cook Loren Wrisley Kimber Barnett Brent Harrington Tim Graul Jim Morgado Steve Colgan Debbie Kraus Chuck Melucci Neil Clayton 5/27/2014 2:44 PM 30

31 References BIPM, JICM 100: Guide to the expression of uncertainty in measurement (GUM), ISO/IEC (2008). ISO 21748:2010, Guidance for the use of repeatability, reproducibility and trueness estimates in measurement uncertainty estimation (2010). S.L.R. Ellison, M.Rosslein, A. Williams. Quantifying Uncertainty in Analytical Measurement in EURACHEM/CITAC Guide*, (2 nd ed., QUAM 2000.P1). V.R. Meyer. Measurement Uncertainty. J Chromatogr. A. 1158, (2007). ISO/IEC 17025:2005, General requirements for the competence of testing and calibration laboratories (2010). W. Horwitz, R. Albert. Quality IssuesThe Concept of Uncertainty as Applied to ChemicalMeasurements Analyst. 122, (1997). M. Feinberg, B. Boulanger, W. Dewe, P. Hubert. New advances in method validation and measurement uncertainty aimed at improving the quality of chemical data Anal Bioanal Chem. 380, (2004). J. Wallace. Ten methods for calculating the uncertainty of measurement. Science & Justice. 50, (2010). 5/27/2014 2:44 PM 31

32 A case study why ATPs matter 5/27/2014 2:44 PM 32

33 Case Study : Product X What if?... Drug Product X successfully validated and transferred per ICH Q2a principles. Method globally registered and accepted. Actual Method Performance per retrospective review of validation report Method was NOT fit for purpose was found to be ROOT 1 cause of type 1 commercial batch failure. (Potency < 95.0% of claim). Method falls outside of a more restrictive ATP acceptance criterion of within 3% of the true value with 95% probability. 5/27/2014 2:44 PM 33

34 0.3 Case Study : Product X What if?... Using the described Analytical Target Profile (ATP) evaluation tool and model scenarios based on method (combined accuracy/precision) and process performance - predicts a 3-5% OOS rate with the legacy Product X method Distribution of Results Including Analytical Method Variation % LC Individual Results Mean of 1 Reps 5/27/2014 2:44 PM 34

35 Case Study : Product X What if?... A simple change to add replicate analyses (even with the existing method), would decrease risk to < 0.1% according to modeling. QbD method design principles would have foreseen the method problem and help drive continuous improvement. 0.3 Distribution of Results Including Analytical Method Variation % LC Individual Results Mean of 3 Reps 5/27/2014 2:44 PM 35

36 New Method Developed with AQbD Principles Sample Preparation Target Profile Simple straightforward sample preparation process to quantitatively extract active The extraction solvent, extraction technique, sonication, and shaking time were studied to optimize extraction. The extraction development had 2 primary targets, which were: (1) intermediate precision of less than 1% RSD (2) spiking recovery of 100%. Additionally, the working sample solvent composition/strength choice was geared to obtain symmetric peaks for all components under the chosen separation conditions. For degradation analysis, the working sample concentration was to be optimized in order to gain additional sensitivity. 5/27/2014 2:44 PM 36

37 New Method for Product X Developed with QbD Principles Combined accuracy and precision estimate lies within this ATP acceptance criterion Method continues to run well in commercial setting. Old Method New Method 5/27/2014 2:44 PM 37