Top 10 problems encountered in IND or BLA submissions

24th October 2013

Category: Bioanalytical / Regulatory

Tags: , ,

By: Dr Daniel Galbraith, CSO,

During the Well Characterised Biological Congress an FDA reviewer gave us an insight into some of the common problems encountered in IND or BLA submissions with a list of the Top 10 inadequacies.

Number 1 – The lack of procedural details contained within the submission. What was clear was that the FDA requires a working SOP to be submitted with the dossier, with enough detail for someone within the agency to be able to recreate the assay and derive data.

Number 2 – The lack of system suitability controls. It seems that some submissions do not describe or use the correct controls for the assay to be able to trend data adequately; standards should be described.

Number 3 – The lack of representative outputs. The FDA expects to see actual chromatograms or other output data which has been appropriately labelled so this would be interpretable for the reviewer.

Number 4 – The inappropriate use of Validation Characterisation. Here the agency indicated the over use of limit test criteria for assays which should be either a characterisation or quantitation assay. Limit tests only require limit of detection and precision as part of the validation, whereas characterisation or quantitative tests need a full ICH validation package costing more and taking more time. The FDA is discouraging the use of limit tests pushing for more tests to be quantitative.

Number 5 – As part of the validation the determination of linearity should be performed in matrix; it appears many submissions assess linearity in buffer. Linearity requires to be shown at a minimum of 5 concentrations using the correct matrix, plus r, r-squared, y intercept, slope of regression and residuals.

Number 6 – An interesting inadequacy especially for the European companies introducing products into the USA. The inadequacy was that Pharmacopoeia methods are submitted without verification or validation. The FDA reviewer pointed out that pharmacopoeia methods are only able to be used without validation for compendia described products and as most biologics are not compendia described products there is an issue with using these assay methods without validation. He also pointed out that the European pharmacopoeia is not recognised as compendia for the USA. The minimum requirements would be specificity in matrix, precision and stability.

Number 7 – The lack of evidence of robustness of the assay, either the robustness was not addressed at all or there is a limited amount of robustness attempted which is insufficient for the agency to accept. The guidelines for robustness are detailed in ICH Q2 (R1) and it is recommended that it should be reviewed closely. Particular issues were the stability of reagents, standards but in particular the robustness should be performed using DoE to assess multiple factors.

Number 8 – The inadequacies of accuracy calculations, accuracy should be assessed at 3 levels between 80-120% in matrix and known recovery should be assessed.

Number 9 – The evaluation of range, this should be assessed over a concentration where the precision, accuracy and linearity have been determined.

Number 10 – The choice of factors to evaluate for intermediate precision. The lack of different pieces of equipment, different analysts or laboratories was cited as an inadequacy.

Overall many of the inadequacies can be rectified by some simple additions to the validation procedure, however many of these methods lend themselves to the chromatographic methods where many parameters are easily evaluated. In contrast cell based potency or characterisation assays are much more complex and involved and ensuring the validation criteria are completely assessed is a significant undertaking.

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