When addressing the requirements of analytical test procedures, 21 CFR 211.160 states:
“Laboratory controls shall include the establishment of scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity.”
21 CFR 211.194(a)(2) states:
“The suitability of all testing methods used shall be verified under actual conditions of use.”
In addition, Analytical Procedures and Method Validation for Drugs and Biologics: Guidance for Industry (July 2015) states:
“Data must be available to establish that the analytical procedures used in testing meet proper standards of accuracy, sensitivity, specificity, and reproducibility and are suitable for their intended purpose.”
A natural question from this is: How do I determine whether my analytical methods are appropriate/suitable and fit for purpose? This is linked to the requirement of the test procedure, which should be embedded within the methods Analytical Target Profile (ATP), which as per USP <1220>:
“For quantitative procedures, the ATP describes the required quality of the reportable value since the reportable value generated using a qualified analytical procedure provides the basis for key decisions regarding compliance of a test article with regulatory, compendial, and manufacturing limits.”
The ATP is a key component of the lifecycle of the analytical procedure and has been discussed in previous blog articles. The ATP can be considered analogous to an instrument’s User Requirement Specification or a product’s Quality Target Product Profile. Within ICH Q14 annexures, examples of ATP are provided. For example, when giving an example of analytical procedure to quantify stereoisomers A-F in Sakuratinib Maleate API, ICH Q14 refers to the rationale for the accuracy and precision ATP requirements based on:
“At a specification level of 0.1%, 20% bias would lead to a variation of the analytical result of 0.02%, which was found acceptable for a release decision. In a similar fashion, values for precision were derived.”
This raises an important concept for a method’s ATP in that, for quantitative analytical methods, the basis for determining whether the method is appropriate/suitable and then fit for purpose can only be made with an understanding of the error for the method (recognizing that all analytical methods are associated with a certain level of error of measurement). This concept is illustrated with another example within ICH Q14 annexures where there is reference to Total Analytical Error (TAE), which under USP <1210> provides statistical tools and guidance for deriving an understanding of the combined impact of the method bias and precision (primary components of TAE) on the reported result. However, once I understand the level of error of my method (across the proposed reporting range) how would I know whether the level of risk associated with the TAE for that method is acceptable? An approach that can be taken is comparing the method’s TAE to the associated specification which that method’s reported result will be considered against.
The MHRA “Technical Review of MHRA Analytical Quality by Design Project,” issued in June 2019, assessed four different ATPs for an Oral Solid Dosage analytical method where one of them – ATP 4 – was based upon the associated product specification where the following formula was used:
For the example that was given within the MHRA Technical Review, the target TUR ratio was 4:1, which for a 10% product release specification range would result in a 1.25% for u. It should be noted that the MHRA technical review document focused on errors due to precision and made assumptions on bias that must also be factored in when determining the method’s TAE.
Ultimately, the goal for a firm is to understand the error associated with the method of measurement and consider this when establishing the test procedure’s ATP, which defines the required quality of the reported result, which in turn should reference the associated “guard rails” – the material specification when evaluating whether the method is fit for purpose.
If you have any questions relating to the above topic, Lachman Consultants can help you! Please contact LCS@lachmanconsultants.com for support with this critical undertaking.
