Specification Equivalence—A Practical Approach

A specification is defined by the International Council for Harmonisation (ICH) documents Q6A and Q6B (1,2) as a list of tests, references to analytical procedures, and appropriate acceptance criteria, which are numerical limits, ranges, or other criteria for the tests described. A specification establishes the set of attributes and their associated criteria to which an excipient, drug substance or drug product should conform to be considered acceptable for its intended use. Conformance to specifications means that the excipient, drug substance, and/or drug product, when tested according to the listed analytical procedures, will meet the listed acceptance criteria. The guidance documents go on to indicate that specifications are critical quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities as conditions of approval. Specifications are foundational to a robust control strategy for all components of a finished dosage form.

Many bio/pharmaceutical companies find themselves trying to meet specifications for an excipient, drug substance and drug product that may have different tests and acceptance criteria in different regions or countries around the world. Companies can establish scientific rationale that methods are equivalent for a specific attribute (test) on the material’s specification, and then when tested, the material will comply with the acceptance criteria for all applicable regions. This risk-based approach is often used by companies to reduce the testing burden for release and stability laboratories. However, companies struggle with establishing equivalence for different methods used for the same attribute on the specification. Oftentimes, the acceptance criteria for the methods are not suitably considered in the evaluation.

As an example, pharmaceutical manufacturers often try to determine specification equivalence for materials that come from different sources. The different sources could be the “same” material produced at two or more sites or made by two or more suppliers. While the comparison of specifications may appear to be a straightforward exercise, the details of the differences for both the analytical procedures and the acceptance criteria make the determination far more complicated. Specification equivalence is essential to determining if two different analytical procedures produce the same results for a given substance or product regardless of the manufacturing site. Specification equivalence is the first step in assessing the potential differences for materials from different sources. Once the analytical assessment is completed; a manufacturing assessment may also be required.

This series of papers intends to offer a practical approach to the concept of specification equivalence, first defining key terms used in the specification evaluation process in this paper. Subsequent papers will take a deeper dive into method equivalence and acceptance criteria equivalence which results in a process leading to a scientific decision on specification equivalence for a given attribute on a material specification. The last paper of the series will focus on the steps needed to perform specification equivalence for compendial materials where the respective monographs in the world’s pharmacopeia may not be harmonized.

Specification equivalence: concepts

Advances in technology, new regulatory requirements, and manufacturing processing changes are some of the potential reasons that there is a change to an analytical procedure or to the associated acceptance criteria. It is recognized by the health authorities that changes will occur in the lifetime of a material/product and there are pathways to make these changes with the impacted regulatory agencies. These pathways require suitable documentation to demonstrate that the changes being made continue to ensure suitable quality pharmaceutical substances and products for the patients. It also can provide a business opportunity to “harmonize specifications” and minimize redundant testing especially for multi-market products.

Specification equivalence can be defined in a way that is generally consistent with that of method equivalence published by Chambers (3) but is more fundamentally based upon the Pharmacopoeial Discussion Group (PDG) definition for harmonization, which is when a pharmaceutical substance or product tested by the harmonized procedure yields the same results and the same accept/reject decision is reached (4). The authors believe that adapting the PDG definition to include non-compendial methods provides for the most straightforward approach to determine specification equivalence. Additionally, specification equivalence draws on the concept of “harmonization by attribute”, which is an approach established by the PDG when an entire monograph (i.e., specification for a material) could not be harmonized. The PDG focused on the individual attributes that could be harmonized. The same is true for specification equivalence. Companies can go attribute by attribute to do a risk assessment of the methods and their acceptance criteria to ensure the same accept/reject decision is reached. Specification Equivalence is illustrated in Figure 1. The benefit of re-defining this approach for specification equivalence is to minimize the use of cumbersome statistical techniques that can confound the analysis and to bring more emphasis to the acceptance criteria for the specific attribute.

The challenge of determining equivalency lies in the components of the specification, namely the analytical procedures and the acceptance criterion for the method. The differences encountered in both analytical procedures and the acceptance criterion can rapidly confound a straightforward approach to determine equivalency. In this series of papers, the authors examine all the parts of a specification and the role each plays in determining specification equivalence. The authors will offer a streamlined process to achieve a decision on specification equivalence, including a simple flow chart assessment for both the analytical procedure and its associated acceptance criteria. These flow charts could be used in a manufacturer’s Standard Operating Procedure (SOP) or Guidance for Specification Equivalence established by a bio/pharmaceutical manufacturer.

Both small-molecule and biotherapeutic drug products are in scope of the paper, and the approach applies to release and shelf-life (where applicable) specifications for excipients, drug substances, drug products, and primary packaging containers used by pharmaceutical manufacturers. Microbiological methods are out of scope for this series of papers.

In essence, the authors provide an approach to perform “in-house harmonization” of specifications, or introduction of new methodology, assessing each method and associated acceptance criteria to provide scientific justification that will allow a company to comply with health authority regulations. Therein lies the connection with the PDG concept of harmonization, namely, the same accept/reject decision would be reached regardless of the analytical method employed for that material.

Specification equivalence: practical

The detailed impacted analytical procedures, associated acceptance criteria, relevant validation packages or method verification packages, method transfers as well as any other generally known information about the methods and then the impacted materials or products must be collected. Each of the two or more methods must first be suitably validated to the current standards described by regulators. It is crucial that the validation package is reviewed for any gaps to current standards; this becomes especially relevant for analytical procedures that were not recently validated or gap assessed. Additionally, if one method was developed and validated by a different laboratory, it is required that the receiving laboratory properly demonstrate it has implemented the method as it was intended to be run (i.e., method verification or transfer). With the two methods suitably validated and verified in a laboratory, it is possible to determine if the methods are comparable or equivalent. Layering in the acceptance criteria associated with each method, it is possible to determine specification equivalence.

As the paper expands on these concepts for assessing specification equivalence, it is important to keep in mind the terms used for analytical methods and their relationship to specification equivalence: method validation, method verification, method comparability and method equivalence. These terms can be confused and have been wrongly used by manufacturers to describe work they have completed. Method validation and method verification have been the subject of confusion. With the adoption of ICH Q2(R2) (5), ICH Q14 (6), and several general chapters in the pharmacopeia (e.g., European Pharmacopoeia [Ph. Eur.] 5.26, United States Pharmacopeia [USP] <1225> and <1226>) some clarity has been provided to industry. The ICH guidance documents will be addressed in a subsequent paper in the series.

Specification equivalence: regulatory guidance

There is not a lot of regulatory guidance provided on the topic of specification equivalence. For analytical procedures, the first part of a specification, there is some guidance provided by the pharmacopoeia. All pharmacopoeias allow, via their General Notices, for the use of “alternative methods” when testing a substance or product by an existing monograph. Use of an alternative method entails risk because of the associated regulatory restrictions of using an alternative method. Specifically in Europe, the Ph. Eur. General Notices clearly indicate that approval of the competent authority is needed prior to using an alternative method for routine testing. Not receiving this approval places a bio/pharmaceutical manufacturer in a position of non-compliance. Additionally, most global pharmacopoeia General Notices sections include a disclaimer “that in event of doubt or dispute, the analytical procedures of the pharmacopoeia are alone authoritative.” This means that if the alternative method provides a different result than the pharmacopoeia method, the result obtained by the pharmacopoeia method is viewed as the official result.

More recently, the Ph. Eur. has published a first of its kind general chapter, 5.27 Comparability of Alternative Analytical Procedures, which is an informational chapter that became official July 2024. (7) This general chapter’s intent is to provide information to help manufacturers demonstrate that an alternative method is comparable to a pharmacopoeial method. It is stressed in the preamble of the chapter that, “The use of an alternative procedure is subject to authorization by the competent authority. The final responsibility for the demonstration of comparability lies with the user and the successful outcome of the process needs to be demonstrated and documented to the satisfaction of the competent authority” (7). The burden (or risk) of demonstrating comparability is on the manufacturer. However, these requirements are mainly focused on the validation state of the alternative method because pharmacopoeial methods are considered validated to current requirements. After the methods are determined to be of suitable validation status, the chapter indicates that a study where the same samples are tested by both methods should show that the results of the alternative procedure lead to the same unequivocal decision that would be made with the pharmacopoeial procedure. The chapter provides a visual reference of statistical assumptions that should be considered in the data analysis.

FDA issued a draft guidance in July 2015 entitled Analytical Procedures and Methods Validation for Drugs and Biologics–Guidance for Industry (8). This guidance is mostly focused on validation parameters of a method and there is a section focused on the use of alternative methods. The information is consistent with the requirements provided by the pharmacopoeia to demonstrate that one method is comparable to another. However, there is no specific guidance provided on method equivalence (i.e., that the same accept/reject decision would result when tested by either method).

Specifications component: analytical procedures

Looking first at the analytical procedures included in the specifications; there are clear requirements from regulators and pharmacopoeias that the analytical procedures are validated and/or verified.

Method validation. Method validation is the evaluation of the analytical procedure performance characteristics (APPCs) such as specificity/selectivity, sensitivity (at the lower range limit), accuracy, linearity, and range. All these characteristics should be assessed to ensure the method meets the requirements expressed in ICH Q2 (5). These same requirements are also clearly described in section VI B of the FDA guidance referenced previously, which provides more detail on verification activities for non-compendial methods in the same section (8).

Method verification. Method verification is the assessment of whether the analytical procedure can be used for its intended purpose, under the actual conditions for use for a specified material. Methods must be demonstrated to be suitable for use and applicable under actual conditions of use in the implementing laboratory. A US regulation in the Federal Food, Drug, and Cosmetic Act (FD&C Act) code speaks directly to method verification, namely 21 Code of Federal Regulations (CFR) 211.194(a)(2), which states, “suitability of all testing methods used shall be verified under actual conditions of use” (9). The FDA guidance on Analytical Procedures and Methods Validation provides more detail on verification activities for a compendial method in Section VI, C. (8).

General Chapter 5.26, Implementation of Pharmacopoeial Procedures in the Ph. Eur. (10) indicates that the implementation of a compendial procedure in a laboratory is a combination of the implementation assessment and the verification assessment. The implementation assessment evaluates if there are any factors associated with the complexity of the procedure and the actual conditions of its use in the implementing laboratory that may affect the performance of the procedure. If any factors are determined to potentially affect the successful implementation, then a verification assessment must be completed. The verification assessment is laboratory work performed to ensure that the procedure is suitable for examination of the article under test, under the actual conditions of use. If the implementation assessment identifies the need for verification experiments, relevant analytical procedure performance characteristics (APPCs) are assessed and verified depending on the intended use of the analytical procedure. A convenient guide is provided for manufacturers to consider when performing verification experiments. Lastly, the general chapter states that these activities should be captured in an appropriate quality system. The requirements to document this activity will be discussed in a subsequent paper in this series.

It should be noted that method validation and method verification activities are carried out for a specific analytical procedure. If multiple analytical procedures are under consideration, the user must ensure that each procedure is validated and verified (if needed). Method validation and method verification are scientific and compliance activities that need to be completed for each of the separate analytical procedures under evaluation as shown in Figure 2. The completion of these two activities for each analytical procedure is necessary before an equivalence study can be undertaken. On the other hand, method comparability and equivalence involve the evaluation of the method validation work completed across multiple analytical procedures as shown in Figure 3.

Method comparability. Chambers, et al., (3) define method comparability as studies to evaluate similarities and differences in method performance characteristics between two analytical methods (i.e., accuracy, precision, specificity, detection limit, and quantitation limit). In other words, comparability is an evaluation of the method validation results for each method. The comparison of their performance characteristics allows a determination as to whether there are any method limitations or lack of sufficient capability (e.g., limit of quantitation [LOQ] is too high for one method; critical pairs of impurities are not separated, etc.). Determination of differences in the performance characteristics of the methods is important to help identify whether one method is superior to another method but does not allow one to say whether or not the methods can generate equivalent results. That can only be accomplished with a method equivalence evaluation.

Method equivalence. Chambers, et al., (3) define method equivalence as studies to evaluate similarities between two analytical procedures regarding generating results for the same sample. In other words, analytical method equivalency evaluates whether the new method can generate equivalent results to those from an existing method. The concepts of comparability and equivalence between analytical methods are illustrated in Figure 3, which shows the applicability across multiple procedures, rather than for one specific procedure. Method equivalence is used to identify the level of risk for not running every method for every test required by every country. In performing method equivalence, understanding the acceptance criteria in relation to the different procedure’s capability is an important consideration to reaching a sound scientific conclusion.

Specifications component: acceptance criteria

Appropriate acceptance criteria are established for a specific pharmaceutical substance or product based on manufacturing capabilities and quality considerations. The acceptance criteria are applicable to the specific analytical procedure used in the determination of material acceptability and within regulatory commitments. When considering different acceptance criteria for different methods, a well-accepted practice is to apply the tightest limits. Choosing the tightest acceptance criteria is a straightforward choice, ensuring that if the result obtained from an analysis meets the criterion, it will comply with all acceptance criteria established for all markets. Readers should be cautioned to ensure that the tightest acceptance criteria make scientific sense and are consistent with the manufacturing process capability for the substance or product and are within the analytical method capability for the substance or product.

However, choosing the tightest limits may not always be possible. If an analytical procedure has a one-sided limit and the second analytical procedure that will be compared to the first procedure has a two-sided limit, using the upper or lower boundary of the one-sided limit may not be practical or scientifically sound.

Compliance implications

Method equivalence helps assess the risk of not performing every method for every test required by every country. By trying to do this risk assessment, as mentioned earlier, it is a prerequisite that the user of the analytical procedure ensure that both methods are suitably validated and verified before any method equivalence study is conducted.

The importance of performing method verification, method comparability, and method equivalence cannot be overstated. Failure to adhere to the regulations outlined in 21 CFR part 211 has resulted in numerous citations by the regulatory authorities. Since 2010, 21 CFR 211.194(a)(2), which mandates the verification of all testing methods under actual condition of use, has been cited in 155 distinct inspections. Of these, 45 led to Official Action Indicated (OAI) classifications (29%), and 20 escalated to warning letters (12.9%). US 21 CFR 211.165(e), which requires that the accuracy, sensitivity, specificity, and reproducibility of test methods be established and documented in accordance with 211.194(a)(2), has been cited more frequently during the same time frame, appearing in 488 inspections, leading to 131 OAI classifications (26.8%) and 69 warning letters (14.1%) (see Table I) (11). Since 2010, the average rates of OAI and Warning Letter issuance associated with any 21 CFR Part 211 citation have been 26% and 13.9%, respectively, indicating that inspections citing 21 CFR 211.194(a)(2) are slightly more likely to result in an OAI classification compared to the overall average for 21 CFR part 211 citations (9).

Deficiencies outlined in these warning letters signal critical compliance failures. For instance, DuPont Nutrition USA received a warning letter from FDA (12) in December 2022 after failing to validate and verify its compendial and non-compendial methods for conductivity testing of Avicel, a widely used microcrystalline cellulose excipient. The third deficiency cited in the warning letter underscores the failure to ensure that the test methods used for in-process and release testing were suitable for their intended use. Specifically, the company did not adequately verify its compendial conductivity test method or validate its non-compendial method. Notable deficiencies included the absence of an approved verification protocol, failure to evaluate the accuracy of the method, and a lack of scientific rationale to support the range evaluated during the method verification (i.e., the acceptance criteria were not considered during the company’s evaluation). Additionally, the non-compendial method used for in-process and packaging testing showed a low correlation with the compendial method. Despite this, DuPont released the excipient that failed to meet USP conductivity standards.

In July 2023, Intas Pharmaceuticals Limited received a warning letter from FDA (13) citing critical violations that directly relate to 21 CFR 211.165(e). One of the key deficiencies noted was the company’s failure to establish the accuracy, sensitivity, specificity, and reproducibility of its test methods. Specifically, Intas did not perform necessary method validation or verification for multiple in-house and compendial methods used in testing of critical raw materials.

Analytical laboratories that perform testing for drug manufacturing facilities are subject to similar regulatory oversight as drug manufacturers. For example, Valisure, a contract analytical lab facility, received a Form 483 from FDA (14) in 2021 for failing to adequately validate and verify several analytical methods used in the testing of pharmaceutical products. Specifically, the firm was cited for failing to document the validation and verification process, establish acceptance criteria, or evaluate the validity of the methods for their intended use. The observation also noted that “the firm failed to verify equivalency” between methods. Following the issuance of the Form 483, Valisure received an untitled letter from FDA in December 2022 (15), which further underscored deficiencies in method validation processes. While Valisure’s testing may not be used for regulatory purposes, FDA expressed concern that the drug manufacturing facilities would use their test results for current good manufacturing practice (CGMP) purposes. This highlights the broader regulatory expectation that both drug manufacturers and contract laboratories must adhere to the validation and verification standards to ensure drug quality.

Similar deficiencies were identified in a FDA Form 483 issued to Hikma Pharmaceuticals USA in June 2024 (16), highlighting issues related to method comparability under 21 CFR 211.160(b). This regulation requires that laboratory controls include scientifically sound and appropriate test procedures to ensure that drug products conform to established standards of identity, strength, quality, and purity. Regulators cited Hikma for failing to include established key characteristics of method validation, such as accuracy and instrument comparability, in their co-validation process. In addition, the co-validation of the analytical procedure was conducted at Hikma’s Research and Development laboratory, while the original validation was performed by their contracted testing laboratory. Neither validation included justification for excluding key characteristics beyond precision.

Conclusion

Demonstrating specification equivalency appears to be a straightforward task but can be quite complex for bio/pharmaceutical companies to consistently complete. In this paper, several important terms were defined that will be the foundation of additional papers to follow providing a practical approach to specification equivalence. The regulatory risk of not doing appropriate specification equivalency was also demonstrated with recent trending of FDA inspection data. The rate of these observations indicates that more direction for the regulatory expectations is needed for industry. There are some regulatory and pharmacopeial guidance documents available, but the documents remain at a high level in their detail and their approaches. The coming papers will provide an in-depth breakdown on analytical method equivalence, acceptance criteria equivalence, and a process for completing in-house specification equivalence to help eliminate duplicate or redundant testing in laboratories. The next paper in this series will give the bio/pharmaceutical companies decision trees to help determine method equivalence and acceptance criteria equivalence and a process for in-house specification equivalence that could serve as a basis for company’s SOPs.

References

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9. Code of Federal Regulations 21 CFR 211.194(a)(2)
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About the authors

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