A Rational Approach for Setting and Maintaining Specifications for Biological and Biotechnology–Derived Products—Part 1 - Currently, there is no industry-wide guideline about the process f

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A Rational Approach for Setting and Maintaining Specifications for Biological and Biotechnology–Derived Products—Part 1
Currently, there is no industry-wide guideline about the process for establishing specifications for biologicals at different stages of the product lifecycle. The Working Group on Specifications and Formulations of the PhRMA Biologics and Biotechnology Leadership Committee set out to help fill this gap. The first of a three-part article.


BioPharm International
Volume 21, Issue 6

TERMINOLOGY

A quality attribute is a property that is either demonstrated or predicted to be related to the clinical safety or efficacy of the final product. Among these are purity and potency, which are linked to preclinical and clinical experience during product development. Other properties such as pH and osmolality might be measured to demonstrate the consistency of the manufacturing process.

The reportable value of a quality attribute is the result that is held to appropriate limits. For release testing, this is the value that is reported in the certificate of analysis (COA) for the lot, and may be the average from replicate independent determinations of multiple samples from a lot.

For the purpose of this paper, specification limits will refer to the limits on a quality attribute that predict that the product is fit for use. This is the same as the acceptance criteria set forth in ICH Q6B. Product that does not meet a specification limit for a quality attribute is said to be out-of-specification (OOS).

Control limits, sometimes called process capability limits or alert limits, are limits on a parameter that have been empirically derived from measurements made on product produced in the manufacturing facility, and are used by the manufacturer to monitor a process for shifts or trends during routine manufacture. Product that does not meet its control limits for a parameter is said to be out-of-expectation (OOE) or out-of-trend (OOT). The specification limits for a quality attribute need not be the same as the control limits for that attribute, as the purposes and risks associated with each are different.

It is important to distinguish characterization testing from conformance testing. A significant level of physicochemical product characterization must be performed before establishing specification or control limits. Detailed product characterization may take several years of investigation. Some of these characterization tests will become conformance tests with specification limits, once it has been established that the test measures a property that is related to product quality. Primary among these are tests that may be associated with product safety and efficacy, while others may forecast performance throughout product shelf life. Other characterization tests will be eliminated or reserved for characterization after a process change.

Limits used at release may be different from those used throughout the shelf life of the product. Release limits on a quality attribute are internal or registered limits that forecast that a lot will be fit for use throughout its labeled shelf life. An expiry limit is a limit on the predicted or measured value of the quality attribute beyond which a lot is no longer fit for use.

Preclinical studies are performed in animals or in cell culture, and are undertaken to predict outcomes in the target clinical population. Nonclinical studies are performed to investigate the factors that affect product performance and quality. These include process and product optimization studies, assay development and validation studies, and process intermediate and final product stability studies. Some studies are performed to provide information that guide company business decisions, whereas other studies are used to help ensure quality and support regulatory requirements.

STAGES OF THE LIFECYCLE OF A PRODUCT

An evolutionary approach to specification setting should reflect the fact that at early stages of development, manufacturers have limited knowledge of the product and limited clinical experience. During late stage development, there is limited manufacturing information to develop meaningful monitoring tools. Therefore, a staged approach to establishing limits should be considered.


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