TOWARDS A RISK BASED METHODOLOGY TO ASSESS THE ACCEPTABILITY OF AN ANALYTICAL METHOD TRANSFER:...
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TOWARDS A RISK BASED METHODOLOGY TO ASSESS THE ACCEPTABILITY OF AN ANALYTICAL METHOD TRANSFER: COMPARISON OF DIFFERENT APPROACHES. E. Rozet 1 , W. Dewe², B. Govaerts³, B. Boulanger², A. Ceccato 2 , P. Chiap 4 , J. Crommen 4 and Ph. Hubert 1 1 Laboratory of Analytical Chemistry and 4 Laboratory of Analytical Pharmaceutical Chemistry, Bioanalytical Chemistry Research Unit, ULg, B 36, B-4000 Liège, Belgium. 2 Lilly Development Centre, rue Granbompre, 11, B-1348 Mont-Saint-Guibert, Belgium. 3 Institute of Statistics, Université Catholique de Louvain, 20, voie du Roman Pays, B-1348 Louvain-la-Neuve, Belgium. ANALYTICAL METHOD TRANSFER: DEFINITION AND OBJECTIVE The Objective of a transfer is therefore: To provide users the guarantee that each measurement (x i ) on unknown sample is close enough to the true value ( T ). Enough, means for example less than 15% away from sample true unknown value ( acceptance limits, e.g. 5% (dosage form), 10% (impurities) or 15% (bio-analysis)). Guarantee, means that it is very likely that whatever the measurements, it will be close enough from the unknown true value β risk), e.g. 5%, 20% or 33%. T i µ x Pr CLASSICAL APPROACHES The classical approaches assess separately two criterion: trueness (systematic error) and precision (random error). Table 1 shows the risks controlled by each approach. CONCLUSIONS The objective of an analytical method transfer is to provide users guarantee in order to minimize the risks to have future results out of specifications. The total error approach achieves this by computing the risk of having future individual results outside the acceptance limits. It gives the guarantee that the receiver masters the analytical method and furthermore allow to manage the risks of having results out of specifications during routine use [3]. The classical approaches should be avoided to evaluate the acceptability of an analytical transfer. Table 1. The classical approaches used to accept/reject a method transfer. Definition: An analytical method transfer consists in transferring a previously validated analytical method from a sending laboratory (called “sender”) mastering this method, to a receiving laboratory (called “receiver”). Experiments are made in both laboratory in order to demonstrate the acceptability of the transfer. EXAMPLES Research grant from the Walloon Region and the European Social Fund to one of the author (E. Rozet) is gratefully acknowledged (First Europe Objective 3 project n°215269). AKNOWLEDGMENTS Example 1: Transfer of a LC-UV method for the quantitation of Fenofibrate and Fenofibric acid in Lidoses [2] Results of transfer are shown in Table 2. The acceptance limits (λ) for Fenofibrate and Fenofibric acid were set at 5 and 10% respectively. The maximum risk (1-β), was set at 10% for both analytes. As the maximum risk of 10% is not exceeded, the transfer is accepted. Indeed, the effective risk of having results out of specifications during routine use, i.e. Risk C, at the receiver is of 1.9% for Fenofibrate and 6.6% for Fenofibric acid. Fig. 3. Risk profile for example 2. [1]. Dewé, W. and al. Chemom. Intell. Lab. Syst. Accepted for publication [2]. Rozet E. and al. J. Pharm. Biomed. Anal. In press. [3]. FDA, Process Analytical Technology (PAT) Initiative, 2004. 0 1 2 3 4 5 6 0 100 200 300 400 500 600 C oncentration (µg/l) Risk (% ) Norepinephrine M axim um Risk Epinephrine Dopam ine T i µ x REFERENCES TOTAL ERROR BASED APPROACHES A novel total error based approach is proposed [1]: the Risk approach Compute the β-expected tolerance interval of the receiver results: [L R ;U R ], i.e. the interval in which one can expect that at least a proportion β (e.g. 90%) of future individual results will lay. Set a priori acceptance limits: ±λ. The ideal acceptance region is: [1- λ;1+ λ] Take into account that the sender gives results with more or less uncertainty: compute the confidence interval of the mean of the sender results: [L S ;U S ]. This penalize the acceptance region: [(1- λ)U S ;(1+ λ)L S ] Compare the β-expected tolerance interval of the receiver results: [L R ;U R ] to the acceptance region: [(1- λ)U S ;(1+ λ)L S ]: Compute the probability P of having results falling outside the acceptance limits and compare it with the maximum tolerated risk 1- β. If P 1- β the transfer is accepted If P > 1- β the transfer is rejected WHAT RISKS DURING ANALYTICAL METHOD TRANSFER ? 3 risks to take into account: A. Type I error: rejecting an acceptable method transfer B. Type II error: not rejecting an unacceptable method transfer C. Risk of having measurements out of specifications during routine use of the method at the receiving site As can be seen in Table 1, no risks are managed by both descriptive approaches. The difference and equivalence approaches partially manage risks A or B. However, risk C, that is the risk of having measurements out of specifications, is not managed by any of the classical approaches. Furthermore when combining back those two criterion there is a non negligible risk to obtain a high proportion of unacceptable results at the receiving site as illustrated in Fig. 1. Fig. 1. Risk in routine with classical approaches. Example 2: Transfer of an on-line SPE-LC-ECD method for the quantitation of 3 catecholamines in human urine Results of the transfer are shown in Fig. 3 as risk profiles for norepinpehrine (NE), epinephrine (E) and dopamine (DA) at each concentration level evaluated during method transfer. The acceptance limits λ were set at ±15%. The transfer is rejected if the observed risk is above the maximum risk accepted. As can be seen, the risk is smaller than the maximum risk of 5% for all the catecholamines studied irrespective of the concentration levels. Therefore, the risk of having results out of specification during routine use of the method for the receiver is of maximum 2.5%, 3.4% and 3.1% for NE, E, DA respectively. M e a n V a r i a b i l i y % Bias< x% % CV< x% Routine Table 2. Results of the transfer for example 1. A B C Descriptive Estim ated bias com pared to acceptance lim it No No No D ifference C onfidence interval contains 0% relative bias Y es No No Equivalence Confidence intervalcom pared to acceptance lim it No Y es No Descriptive Interm ediate precision com pared to acceptance lim it No No No Equivalence U pperconfidence lim itofinterm ediate precision com pared to acceptance lim it No Y es No Trueness P recision M anaged risks C riterion Approach D escription Fenofibrate Fenofibric Acid M axim um risk (1-β)in % 10 10 R isk C orE ffective risk (% ) 1.9 6.6
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Transcript of TOWARDS A RISK BASED METHODOLOGY TO ASSESS THE ACCEPTABILITY OF AN ANALYTICAL METHOD TRANSFER:...
TOWARDS A RISK BASED METHODOLOGY TO ASSESS THE ACCEPTABILITY OF AN ANALYTICAL METHOD TRANSFER: COMPARISON OF DIFFERENT
APPROACHES.
E. Rozet1, W. Dewe², B. Govaerts³, B. Boulanger², A. Ceccato2, P. Chiap4, J. Crommen4 and Ph. Hubert1
1 Laboratory of Analytical Chemistry and 4 Laboratory of Analytical Pharmaceutical Chemistry, Bioanalytical Chemistry Research Unit, ULg, B 36, B-4000 Liège, Belgium.
2 Lilly Development Centre, rue Granbompre, 11, B-1348 Mont-Saint-Guibert, Belgium.3 Institute of Statistics, Université Catholique de Louvain, 20, voie du Roman Pays,
B-1348 Louvain-la-Neuve, Belgium.
ANALYTICAL METHOD TRANSFER: DEFINITION AND OBJECTIVE
The Objective of a transfer is therefore:To provide users the guarantee that each measurement (xi) on unknown sample is close enough to the true value (T). Enough, means for example less than 15% away from sample true unknown value (acceptance limits, e.g. 5% (dosage form), 10% (impurities) or 15% (bio-analysis)). Guarantee, means that it is very likely that whatever the measurements, it will be close enough from the unknown true value βrisk), e.g. 5%, 20% or 33%.
Ti µxPr
CLASSICAL APPROACHES
The classical approaches assess separately two criterion: trueness (systematic error) and precision (random error). Table 1 shows the risks controlled by each approach.
CONCLUSIONS
The objective of an analytical method transfer is to provide users guarantee in order to minimize the risks to have future results out of specifications. The total error approach achieves this by computing the risk of having future individual results outside the acceptance limits. It gives the guarantee that the receiver masters the analytical method and furthermore allow to manage the risks of having results out of specifications during routine use [3]. The classical approaches should be avoided to evaluate the acceptability of an analytical transfer.
Table 1. The classical approaches used to accept/reject a method transfer.
Definition:
An analytical method transfer consists in transferring a previously validated analytical method from a sending laboratory (called “sender”) mastering this method, to a receiving laboratory (called “receiver”). Experiments are made in both laboratory in order to demonstrate the acceptability of the transfer. EXAMPLES
Research grant from the Walloon Region and the European Social Fund to one of the author (E. Rozet) is gratefully acknowledged (First Europe Objective 3 project n°215269).
AKNOWLEDGMENTS
Example 1: Transfer of a LC-UV method for the quantitation of Fenofibrate and Fenofibric acid in Lidoses [2]
Results of transfer are shown in Table 2. The acceptance limits (λ) for Fenofibrate and Fenofibric acid were set at 5 and 10% respectively. The maximum risk (1-β), was set at 10% for both analytes. As the maximum risk of 10% is not exceeded, the transfer is accepted. Indeed, the effective risk of having results out of specifications during routine use, i.e. Risk C, at the receiver is of 1.9% for Fenofibrate and 6.6% for Fenofibric acid.
Fig. 3. Risk profile for example 2.
[1]. Dewé, W. and al. Chemom. Intell. Lab. Syst. Accepted for publication.[2]. Rozet E. and al. J. Pharm. Biomed. Anal. In press. [3]. FDA, Process Analytical Technology (PAT) Initiative, 2004.
0
1
2
3
4
5
6
0 100 200 300 400 500 600
Concentration (µg/l)
Ris
k (%
)
Norepinephrine Maximum Risk Epinephrine Dopamine
Ti µx
REFERENCES
TOTAL ERROR BASED APPROACHES
A novel total error based approach is proposed [1]: the Risk approach
Compute the β-expected tolerance interval of the receiver results: [LR;UR], i.e. the interval in which one can expect that at least a proportion β (e.g. 90%) of future individual results will lay.
Set a priori acceptance limits: ±λ. The ideal acceptance region is: [1- λ;1+ λ]
Take into account that the sender gives results with more or less uncertainty: compute the confidence interval of the mean of the sender results: [LS;US]. This penalize the acceptance region: [(1- λ)US;(1+ λ)LS]
Compare the β-expected tolerance interval of the receiver results: [LR;UR] to the acceptance region: [(1- λ)US;(1+ λ)LS]:
Compute the probability P of having results falling outside the acceptance limits and compare it with the maximum tolerated risk 1- β.
If P 1- β the transfer is accepted
If P > 1- β the transfer is rejected
WHAT RISKS DURING ANALYTICAL METHOD TRANSFER ?
3 risks to take into account:
A. Type I error: rejecting an acceptable method transfer
B. Type II error: not rejecting an unacceptable method transfer
C. Risk of having measurements out of specifications during routine use of the method at the receiving site
As can be seen in Table 1, no risks are managed by both descriptive approaches. The difference and equivalence approaches partially manage risks A or B. However, risk C, that is the risk of having measurements out of specifications, is not managed by any of the classical approaches. Furthermore when combining back those two criterion there is a non negligible risk to obtain a high proportion of unacceptable results at the receiving site as illustrated in Fig. 1.
Fig. 1. Risk in routine with classical approaches.
Example 2: Transfer of an on-line SPE-LC-ECD method for the quantitation of 3 catecholamines in human urine
Results of the transfer are shown in Fig. 3 as risk profiles for norepinpehrine (NE), epinephrine (E) and dopamine (DA) at each concentration level evaluated during method transfer. The acceptance limits λ were set at ±15%. The transfer is rejected if the observed risk is above the maximum risk accepted. As can be seen, the risk is smaller than the maximum risk of 5% for all the catecholamines studied irrespective of the concentration levels. Therefore, the risk of having results out of specification during routine use of the method for the receiver is of maximum 2.5%, 3.4% and 3.1% for NE, E, DA respectively.
Mea
nV
aria
biliy
% Bias< x%
% CV< x%
Routine
Table 2. Results of the transfer for example 1.
A B C
Descriptive Estimated bias compared to acceptance limit No No No
Difference Confidence interval contains 0% relative bias Yes No No
Equivalence Confidence interval compared to acceptance limit No Yes No
Descriptive Intermediate precision compared to acceptance limit No No No
Equivalence Upper confidence limit of intermediate precision compared to acceptance limit No Yes No
Trueness
Precision
Managed risksCriterion Approach Description
Fenofibrate Fenofibric Acid
Maximum risk (1-β) in % 10 10
Risk C or Effective risk (%) 1.9 6.6
