A Rational Approach for Setting and Maintaining Specifications for Biological and Biotechnology–Derived Products—Part 2 - The Biologics and Biotechnology Working Group on specifications of

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A Rational Approach for Setting and Maintaining Specifications for Biological and Biotechnology–Derived Products—Part 2
The Biologics and Biotechnology Working Group on specifications of the Pharmaceutical Research and Manufacturers of America presents new approaches to analyzing development and manufacturing data.


BioPharm International
Volume 21, Issue 7

Reportable value versus individual measurements

Currently, there are conflicts in thinking and in regulatory guidances regarding whether specifications are applied to individual samples, individual measurements on the same sample, or the average of multiple samples. The International Conference on Harmonization's (ICH) Q1E guideline, Evaluation of Stability Data 12 instructs that shelf life be determined from a lower 95% confidence interval on the mean regression line from the analysis of a quality attribute over time, whereas ICH Q6A, Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances 13 stipulates that individual measurements be held to shelf-life specifications. The recently issued US Food and Drug Administration Guidance for Industry on Investigating Out-of-Specification (OOS) Results for Pharmaceutical Production 14 states in one section,

"It may be appropriate to specify in the test method that the average of these multiple assays is considered one test and represents one reportable result," and in another section,

"In cases where a series of assay results (to produce a single reportable result) are required by the test procedure and some of the individual results are OOS, some are within specification, and all are within the known variability of the method, the passing results are no more likely to represent the true value for the sample than the OOS results. For this reason, a firm should err on the side of caution and treat the reportable average of these values as an OOS result, even if that average is within specification." 14

These incongruities create undue concern on the part of manufacturers and regulators alike. Although manufacturers strive to obtain reliable information on products through strategic study design and adequate replication, they are likely to be penalized when a single measurement is OOS. This situation creates a disincentive for collecting data.15 The regulator, faced with the question of whether or not to question an OOS measurement, will likely deem a satisfactory result OOS in accordance with the more restrictive of these rules.

Quality control measures should guarantee that the product on the market conforms to the attributes of materials tested during development. In development, clinical lots are tested and described by the average of measurements made on the lot. The average may be obtained from a single dosage unit or multiple dosage units. In this way, quality attributes of the lot are mapped to clinical response in the population of patients receiving the lot.


Figure 1
Figure 1 illustrates this relationship for a bioassay. A sample of dosage units is taken from each of three clinical lots and then tested in a bioassay. The reportable value for each lot is the average of the measurements on these dosage units, and these reportable values are used to set the specifications for the product (represented as a normal curve). Another sample of dosage units is administered to patients in the clinical trial, and the clinical response to these is reported as the clinical outcome (here, 95% response). Post-licensure, samples are taken from a commercial lot and compared to the specifications derived during development. When the reportable value for the commercial lot falls within the specifications, it is inferred that patients receiving this lot will experience the same clinical benefit as those studied in the clinical trial (i.e., 95% response).

Holding commercial product to the same standard as development materials will help guarantee that the clinical response will be similar to that observed during development. However, measurements on individual dosage units or individual measurements on the same dosage unit should not be held to specifications established during development, because clinical doses were not tested prior to clinical administration, and thus there is no link between measurements made on individual doses and clinical outcome.


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