Notice: Clarification of bioanalytical method validation procedures

An addendum has been added to this notice.

October 8, 2015
Our file number: 15-110985-741

The purpose of this notice is to clarify Health Canada’s interpretation and expectations for all matrix-based stability experiments [that is (i.e.) Long term, Freeze-thaw and Bench top] conducted during bioanalytical method validation.

It has come to the attention of Health Canada that some companies conducting the analysis of bioanalytical samples have used unacceptable procedures during the validation of the analytical method. Specifically, during tests of the stability of drug in biological matrix, some companies have employed the procedure of subjecting only one bulk Quality Control (QC) sample at each concentration to the stability conditions and taking multiple aliquots from that sample. This practice produces repeated measurements from a single replicate, but does not produce multiple replicates of the storage conditions. Therefore, it provides limited (i.e., N = 1) information regarding the effects of the storage conditions on accuracy and no information on the effects of the conditions on the variability of the drug concentration. Any variability in the repeated measurements of a single sample results not from the storage conditions, but from observational error (i.e., variability inherent to the analytical method). This is not considered to be sufficient evidence of stability.

Any scientific study of the effects of an independent variable on a given outcome requires appropriate replication to determine a precise estimate of the effect. In analytical method validation, the purpose of stability studies is to evaluate the effect of storage conditions on the accuracy and variability of the drug concentrations in biological samples. This assessment requires multiple replicates of the storage conditions (i.e., separate tubes each containing a pre-specified concentration of drug in relevant biological matrix). Therefore, in the case of stability experiments, sets of low and high QC samples, consisting of multiple replicates at each concentration, should be aliquoted prior to the stability experiment and a minimum of three samples should be subjected independently to the stability conditions that are to be evaluated.

The Health Canada Guidance for Industry Conduct and Analysis of Comparative Bioavailability Studies (2012) stipulates that the principles and procedures for bioanalytical method validation and analysis of study samples described in the European Medicines Agency Guideline on bioanalytical method validation should be followed. While guidance documents such as these are not intended to and cannot enumerate all important aspects of good scientific practices, Health Canada nevertheless expects sound scientific practices and experimental design to be applied in studies submitted in support of drug submissions.

For all method validations where only one tube of test QC samples at each concentration was subjected to the stability conditions, the validation is considered deficient. In these cases, an amendment to the validation report will be requested that includes stability experiments conducted using sets of low and high QC samples aliquoted prior to the stability experiment and all samples subjected to the given stability conditions independently prior to processing.

For questions on bioanalytical method validation, please contact:

Bureau of Pharmaceutical Sciences
Therapeutic Products Directorate
Health Canada
Finance Building
Address Locator 0202A2
Ottawa, Ontario
K1A 1B9

Telephone: 613-941-3184
Facsimile: 613-957-3989
Email: bps_enquiries@hc-sc.gc.ca

Addendum to Notice: Clarification of bioanalytical method validation procedures

March 9, 2016

This addendum to the Notice: Clarification of bioanalytical method validation procedures (posted on October 8, 2015) serves to provide additional information to clarify how the Therapeutic Products Directorate (TPD) will manage drug submissions with respect to the issues raised in the Notice.

In the time since the preparation and posting of this notice the TPD has continued to interact with sponsors of submissions affected by this issue and has received new information concerning this issue on an a continuous basis. This new information shows that a significantly greater number of drug submissions are impacted than was originally evident. This includes both submissions in review and those awaiting issuance of a Notice of Compliance subsequent to the operation of the Patented Medicines (Notice of Compliance) Regulations. As a result, Health Canada is updating the approach to the handling of bioanalytical method validation concerns in drug submissions.

Submissions filed after October 8, 2015 are expected to be in compliance with the expectations outlined in the Notice: Clarification of bioanalytical method validation procedures. Submissions filed prior to this date will not be evaluated against this standard. Where regulatory letters, including Notices of Deficiency and Notices of Non-compliance, have been issued containing comments related to the bioanalytical method validation concerns outlined in the October 8, 2015 Notice, those letters  will be revised and reissued without these comments. If the only comments in the regulatory letter referred to bioanalytical method validation, and the letter has not yet been responded to, the letter will be rescinded and the submission returned to the same status it was in prior to issuance of the letter. All submissions filed prior to October 8, 2015 and which received a regulatory letter concerning only bioanalytical method validation issues will be scheduled for review based upon the target date assigned prior to the issuance of the regulatory letter.

The Notice and this addendum are considered to be part of Health Canada’s Guidance for Industry Conduct and Analysis of Comparative Bioavailability Studies (2012) and other applicable guidance documents.

As noted in the forward to the above guidance document, ”Guidance documents are administrative instruments not having force of law and, as such, allow for flexibility in approach. Alternate approaches to the principles and practices described in this document may be acceptable provided they are supported by adequate justification. Alternate approaches should be discussed in advance with the relevant program area to avoid the possible finding that applicable statutory or regulatory requirements have not been met.”

Health Canada is taking this updated approach in order to maintain timely access to generic drugs for Canadians and to provide a consistent and transparent approach for stakeholders.
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