Specification Equivalence: A Practical Approach to Method and Acceptance Criteria Equivalence

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A specification as previously defined is a list of tests, references to analytical procedures, and appropriate acceptance criteria (1). The specification establishes the methodology to be applied and the corresponding acceptance criteria to which a drug substance or drug product must conform to be considered acceptable for its intended use. Conformance to specifications means that the drug substance and/or drug product meets the specified acceptance criteria when tested following the test procedure contained within the specification. Specifications are critical quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities as conditions of market authorization. Specifications are foundational to a robust control strategy for all components of a finished dosage form. In this article, the authors consider both the method and acceptance criteria components of the specification.

Methods included in the specification must be validated and/or verified as described in current regulatory and compendial guidance documents. Methods are either used for release testing purposes or to detect changes in quality attributes over time (i.e., for stability testing). Also, as noted in the previous paper (1), if compendial methods for compendial articles are not used, the in-house method is defined as an alternate method to the official method per the regulations.

Various regulations are applicable when establishing method equivalency, including those from health authorities, compendial standards, and the International Council for Harmonisation (ICH) standards. The ICH Q2 document (2) describes the specifics regarding analytical method validation requirements, and the complementary ICH Q14 (3) describes the scientific and risk-based approaches for analytical procedure development and maintenance. It is critical to develop and validate an analytical method that is fit for purpose, which makes it vital to understand the intended use of the method prior to initiating any work. The intended use of a method is typically described in an analytical target profile (ATP). The ATP provides the basis for the required method development and subsequent method validation parameters per ICH Q2.

An option during method development is to define the method operable design regions (MODRs), which is a type of quality by design (QbD) for methods. Defining a MODR provides flexibility in an individual method, such that the operating ranges provided in the method are larger than the standard single points. Methods compared with a MODR cannot be theoretically compared unless there is overlap in their MODR design space. If there is no overlap in design space, an experimental equivalence study must be performed.

Methods may be developed internally or obtained from external sources, such as compendial monographs or other vendors/suppliers. During the lifecycle of a material, there will be method changes for any number of reasons, such as manufacturing changes, discontinuation of technology, automation introduction, and method modernization. The significance of the changes to the method and a review of the approved marketing authorization filing by the relevant health authorities must be considered. A change that impacts the method in the approved marketing dossier must be submitted to the health authorities for some level of approval prior to implementation.

Any changes to internal documents, whether or not they impact the filed dossier, must be managed under a change control process, required of each company as part of good manufacturing practices (GMPs). The change control process must include a step for the company’s regulatory department to review the changes and determine the impact, if any, to the filed dossier(s). If there is an impact to the filed dossier(s), the company’s regulatory department must submit the method to the relevant health authorities, and there must be a hold on implementation of the new method until the required filings are completed and approvals granted. During this process, the change(s) to the method will be reviewed and approved by the relevant health authorities. As part of this review, the reviewers may evaluate how the equivalency or superiority of the new method was established relative to the originally approved method.

Equivalency studies are performed to demonstrate that results generated using either the original analytical method or the proposed modified method, alternative method, or fully new method, yield insignificant differences in accuracy and precision, meaning that equivalent results are produced using either analytical procedure, and the same accept or reject decision is reached. United States Pharmacopeia (USP) <1010> (4) presents numerous methods and statistical tools to design, execute, and evaluate equivalency protocols and data generated in these protocols. While the chapter is a valuable educational tool, it requires a proficient understanding of statistics to apply it well and, in many cases, may be more than is required in typical pharmaceutical analytical laboratories. With a deep knowledge of the methods being evaluated and the material or product being tested, basic statistical tools (e.g., mean, standard deviation, pooled standard deviation, evaluation of data generated against historical data, and comparison of data against approved specifications) may be sufficient to determine method equivalency or lack thereof. Equivalence of more complicated methods, such as methods that require the use of modeling will most likely require more sophisticated evaluation. Ultimately, the value in determining specification equivalence is the ability for a bio/pharmaceutical company to reduce analytical testing by choosing to perform one method to ensure compliance with other equivalent methods. If the methods under consideration are compendial, the outcome may be considered an internal or in-house harmonization of the various pharmacopoeial test methods.

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About the authors

Gail Reed is senior scientist with Johnson & Johnson; Joseph A. Albanese is the managing director and consultant with Albanese Consulting, LLC; Yelena Ionova is senior manager, Data Strategy and Analytics with Redica Systems; and J. Mark Wiggins is owner and compendial consultant with Global Pharmacopoeia Solutions, LLC.

Article details

BioPharm International®/Pharmaceutical Technology®/Pharmaceutical Technology® Europe
Quality and Regulations 2025 eBook
August 2025
Pages: 20–31

Citation

When referring to this article, please cite it as Reed, G.; Albanese, J.A.; Ionova, Y.; and Wiggins, J. M. Specification Equivalence: A Practical Approach to Method and Acceptance Criteria Equivalence. Pharmaceutical Technology Quality and Regulations eBook, 2025 August, 20-31.