A Rational Approach for Setting and Maintaining Specifications for Biological and Biotechnology–Derived Products—Part 3 - 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 3
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 8


Figure 4. An example of how to set final product release specifications for an attribute that shows loss over time, taking into account all stability losses during handling and storage (solid line)and release assay variability
The loss rates determined in stability studies can be used in conjunction with preclinical or clinically derived specifications, as well as release assay variability, to calculate release limits that provide assurance that product released to market is safe and effective and will remain so throughout its shelf life. Figure 4 shows an example of how to set release specifications for an attribute that shows loss over time. The lower specification limit corresponds to the mean of a lot that showed satisfactory performance in clinical trials. (Note that this represents the reportable value from release testing of the clinical lot, together with either additional information about the lot or a compendial or consensus limit for the quality attribute.) The product is earmarked for a 24-month shelf life to allow adequate time for product distribution and consumption. The total loss from release through expiry (solid line) is combined with uncertainties in the release assay and loss estimates to derive the lower release limit (LRL) for the lot. The total loss value may be determined from the sum of individual losses under various storage and handling conditions (e.g., room temperature handling during packaging, labeling, and inspection of a refrigerated product, long-term storage at the labeled temperature, loss after reconstitution and storage in a physician's office).

The fundamental concept behind the strategy of release limits is represented by the equations that follow:

URL = USL – 1.64 x σassay







in which:

URL = upper release limit

LRL = lower release limit

USL = upper specification limit

LSL = lower specification limit

1.64 = statistical factor associated with 95% confidence

σassay = release assay variability expressed in the form of SD

bi = loss rate associated with ith

storage and handling conditions

ti = time at ith storage and handling conditions

σbi = variability of loss rate associated with ith storage and handling conditions

and

i indexes multiple storage and handling conditions.

Finally, development data can be used to forecast process capability for manufactured product. Quality by design (QbD) tools can be used to mimic the ranges of normal operating conditions for the product, leading to a preliminary estimate of process capability. Those forecasts should be verified through early manufacturing experience, and updated as necessary to formulate control or process capability limits (LCL, UCL) for the process. Standards of practice for establishing control limits vary throughout the industry. The application of standard tools for quality assessment can help mitigate risk and facilitate the implementation of a strategic quality system.16


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