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

Specifications can be divided into two categories, product-specific specifications and compendial or regulatory specifications:

  • Product-specific specifications are those for which components of quality attributes, methods, and limits are unique to the product (e.g., molecular weight by SEC, potency, charge distribution by ion exchange, pH, color).
  • Compendial or regulatory specifications are those for which attributes and limits are well defined by regulatory agencies2 (e.g., DNA, endotoxins, particles). For these specifications, the application of an evolutionary approach will be limited.

Although the focus of most discussions about specifications is about acceptance criteria, a certain clarification about types of specifications, quality attributes, and methods would benefit the industry.

ICH guidelines specify quality attributes for DS and DP, acknowledging that in some cases in-process testing may be more appropriate than DS or DP specifications. Nevertheless, the guidelines specify desirable quality attributes for DS and DP, including the following:

  • DS: appearance and description, identity, purity and impurities, potency, and quantity.
  • DP: appearance and description, identity, purity and impurities, potency, quantity, general tests, and additional testing unique to the dosage form.

For the most part, the quality attributes for DS and DP are similar. Additional testing specified for DP is associated with changes related to the formulation, vials, or devices. At early stages of development (corresponding to Phase 1–2 clinical trails), many manufacturers do not use the final commercial formulation; instead, they may use a frozen liquid DS or other simple dosage form. Therefore, at this early stage of development, many tests performed on DS and DP may be redundant without adding value for patients or the manufacturer.

Another difference between conformance testing for DS and DP is the treatment of impurities. In testing the DS, the term impurities refers to product and process impurities, whereas in testing the DP, the focus of impurity testing is on degradation products. The purpose of testing for process-related impurities (e.g., DNA, host cell proteins, solvent and buffer components) may not change during drug development. Whether or not expectations regarding impurity testing are well defined in a given regulation, such testing should not be relaxed at any stage of development because impurities are directly related to patient safety. However, robust process validation that demonstrates the removal of impurities (e.g., adventitious agents) may alleviate the need for such stringency. The issue of product-related impurities and product-related substances may merit different considerations. At early stages of development, understanding the presence and chemical structure of product-related impurities may be limited, making a distinction between product-related impurities and product-related substances difficult. Frequently, we refer to them as isoforms, structural variants, or posttranslational modifications. Many of these "modifications" are well known to scientists, but their quantification and physiological significance sometimes remains elusive. In addition, existing literature does not provide unequivocal or uniform evidence about their physiological relevance.3–4 This category includes several well known posttranslational modifications, such as methionine oxidation, deamidation of asparagine residues, and N- and O-glycosylation. Therefore, at the early stage of product development, specifications may not need to focus on product-related impurities. At the later stages, when the understanding of the product increases, and the clinical relevance of product-related impurities and substances can be elucidated, the specifications can be amended to include additional testing for product-related impurities and degradants.

Analytical Methods

Analytical methods associated with specifications define how a particular attribute will be tested. Therefore, any change in an analytical method may affect the numerical limits and statistical considerations applied in establishing this limit. Because of the continuous progression of analytical technologies, the industry and regulators will need to continuously develop strategies to address the issue of the difference between old and new methods. Modern, more efficient technologies will appear on the market, while old technologies (instruments and consumables) will no longer be supported by current vendors. For example, an evaluation of the history of separation methods suggests that separation technologies have doubled in capabilities in approximately 11 years.5

As analytical methods evolve over time, these new methods frequently provide additional information that was not previously available. In such cases, the relevance of this new information to specifications needs to be evaluated including attributes, methods, and limits.


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