Multi-Compendial Compliance for Pharmaceutical Excipients–Part 1: A Practical Application of Specification Equivalence

In an earlier series of articles by Wiggins and Albanese addressing the challenges of pharmacopoeia compliance, consideration was given to the global regulatory expectations and requirements, with guidance provided on how to address the potential misalignment of compendial monographs and drug product registrations (1). A subsequent article in that series provided a case study detailing the specific challenges for excipients (2). That article listed several strategies to ensure multi-compendial compliance for excipients and included a brief discussion on internal or in-house harmonization. Previous articles in this current series have introduced the concepts and provided the tools for establishing specification equivalence (3,4). The present article details a practical application of specification equivalence to excipients testing to achieve in-house harmonization.

Excipients are present in essentially every pharmaceutical product currently approved and marketed around the world. For most of these drug products, excipients comprise the vast majority of the dosage form content. Oftentimes, a small number of different excipients are used in a wide variety of products in a company’s portfolio. For example, many solid oral dosage forms combine the active drug substance with common excipients, including lactose, starch, microcrystalline cellulose, magnesium stearate, and titanium dioxide, among other ingredients. Pharmacopoeia monographs exist for most common excipients, and regulatory agencies require conformance with these monograph requirements.

Compliance with the quality requirements for excipients as published by pharmacopoeias around the world is a significant challenge in global registration and distribution of medicinal products (pharmaceuticals, biologics, and vaccines). Establishing appropriate specifications through in-house harmonization can help ensure compliance with excipient monographs in multiple pharmacopoeias to provide meaningful benefits. These include minimizing the testing needed to ensure compliance with pharmacopoeia requirements and health authority expectations while also enabling flexibility in filing strategies. The approach is based on the principles of specification equivalence presented in the earlier articles in this series and addresses regulatory expectations and requirements at a global level, while reducing redundant testing of multi-compendial excipients by a bio/pharmaceutical company.

As indicated in the General Notices of the European Pharmacopoeia (Ph. Eur.), and the United States Pharmacopeia–National Formulary (USP–NF), compendial compliance can be summarized as follows: an excipient would pass if tested by the compendial methods; however, alternative methods can be used to demonstrate conformance. A similar statement is included in the General Notices of the Japanese Pharmacopoeia (JP) and applies not only to materials listed in the JP, but also those included in the Japanese Pharmaceutical Excipients (JPE), whose General Notices refer to those in the JP. It is emphasized that the Ph. Eur. General Notices contains an additional expectation that the use of alternative methods requires agreement of the competent regulatory authority, stating in the event of doubt or dispute, the analytical procedures of the applicable pharmacopoeia are alone authoritative in determining compliance (5). The determination of specification equivalence as detailed in previous articles by the authors established that acceptance criteria must also be considered when ensuring overall compliance with quality requirements. Once appropriately harmonized specifications have been established for a given excipient, ongoing compliance must be maintained when compendial revisions occur, with appropriate change control documented through the company’s quality management system.

Establishing Excipient Specifications–Consideration of the Pharmacopoeias

The goal of determining specification equivalence for excipients is to ensure compliance with the requirements contained in all applicable pharmacopoeias for that material. Still, common sense also comes into play when determining whether and when to evaluate specification equivalence for the excipients in a drug product. For example, if a product is only approved in one country, the excipients used in that product only need to meet the pharmacopoeia requirements in that country. If a product is approved in multiple countries but a specific excipient batch will be used in product batches going only to one country, then compliance with the pharmacopoeia in that single country is necessary for that excipient batch. However, most excipients and specific batches may be used in multiple products for distribution in many countries, and it may be beneficial for a company to follow a risk-based approach to testing by performing in-house harmonization of the multiple pharmacopoeia monographs, through specification equivalence, to reduce redundant testing.

In considering the compendial scope for the equivalence evaluation, it is useful to remember there are currently as many as 40 pharmacopoeias that may be applicable around the world (6). It is also helpful to consider the suggestion that three pharmacopoeias in particular—Ph. Eur., USP–NF, and the British Pharmacopoeia (BP)—may be considered “global pharmacopoeias”, meaning they are acceptable to regulators well beyond the boundaries of the country or region in which they are established (7). However, other applicable national pharmacopoeias must be considered for products that are approved and marketed in many other major markets.

Although this article focuses on establishing specification equivalence through in-house harmonization of excipients for compliance to requirements in the Ph. Eur., USP–NF, and JP—the original members of the Pharmacopoeial Discussion Group (PDG)—the approach may be extended to other national pharmacopoeias as needed, including the Indian Pharmacopoeia, Chinese Pharmacopoeia, Brazilian Pharmacopoeia, Korean Pharmacopoeia, and Russian Pharmacopoeia. Similarly, the approach can be extended to excipients listed in the BP. However, the BP is required to publish all the same monographs as contained in the Ph. Eur., according to the European Pharmacopoeia Convention to which the BP was one of the initial signatories. There are only a handful of excipients that are listed in the BP alone and otherwise not included in the Ph. Eur.

Establishing Excipient Specifications–Approach

The International Council for Harmonisation (ICH) Q6A and Q6B guidelines define a specification as a list of tests, references to analytical procedures, and appropriate acceptance criteria used to demonstrate that a material is acceptable for its intended use (8,9). The specification for an excipient establishes the identity, purity, and quality of the material. For a given excipient, the specifications in the compendial monographs of various pharmacopoeias are often generally consistent in terms of the types of tests required for conformance (e.g., assay, impurities, pH, loss on drying, etc.). The methods in the various compendia are sometimes identical but may have differences that generally do not impact the ability to assess a particular quality attribute for the material. The acceptance criteria in the various compendia for the same test, however, may be different; nevertheless, compliance with all appropriate compendial acceptance criteria is required.

The process for selecting a particular method and acceptance criteria to ensure compliance with multi-compendial requirements calls for a thorough, scientific evaluation of the different monographs and general chapters in each of the pharmacopoeias, with appropriate documentation of the decisions reached. The detailed technical assessment of the monograph requirements is intended to justify the final in-house harmonized specification. In comparing compendial tests, it is understood that the methods have been validated and/or demonstrated to be suitable for the analysis of the particular material to which the test is applied. The compendial acceptance criteria are similarly considered appropriate for ensuring the purity and quality of the excipient. Standardizing on the Ph. Eur. method, when appropriate, addresses the expectation in Europe that the use of alternative methods requires agreement of the competent regulatory authority.

Method evaluation. A comparison of two or more compendial methods for a particular quality attribute may enable the use of a single method to ensure compliance, thereby minimizing redundant testing. Differences between the methods are evaluated to establish their suitability to assure the identity, purity, and quality of the excipient. The selected method must provide the same result, to the extent this is practical, and the same accept/reject decision must be reached for the material tested. The recommendations generally apply to a paper-based assessment of the methods, but may also include an evaluation of existing data, or a laboratory study. The following terms are used to define the possible types of evaluation (See also Figure 1, reproduced from an earlier article [4]):

• Paper-based method assessment–A method review (paper evaluation only) to determine whether two (or more) methods are equivalent
• Existing data comparison–An analytical evaluation of historical test data to determine whether two (or more) methods are equivalent

• Assessment of data from laboratory studies–An analytical laboratory evaluation carried out to determine whether two (or more) methods are equivalent.

The following terms are used to define the outcome of method evaluation:

• Equivalent–Based on an equivalency study, two (or more) methods that provide the same analytical results and the same accept/reject decision is reached
• Not equivalent–Two (or more) methods determined to be non-equivalent based on a paper-based method assessment, comparison of existing data, and/or assessment of data from laboratory studies
• Superior–A method that is determined to provide advantages over another method, in terms of increased accuracy, precision, sensitivity, and/or selectivity, etc., based on a paper-based method assessment, comparison of existing data, and/or assessment of data from laboratory studies. Note that appropriate sensitivity should be used when an evaluation concludes a method in one pharmacopoeia is superior to a method in another pharmacopoeia. The technical justification should be written with the understanding that the document may be reviewed during an inspection by the regulatory agency from the country with the inferior pharmacopoeia method. It may also be appropriate to consider submitting a revision request to that pharmacopoeia to adopt the superior method.

Method harmonization. Some analytical methods have undergone harmonization by PDG and may have been subjected to further evaluation of interchangeability by the regulatory agencies through the ICH Q4B process (10). This harmonization process (PDG and/or Q4B) enables the use of any of the compendial methods to ensure multi-compendial compliance. PDG has also harmonized several excipient monographs in the Ph. Eur., USP–NF, and JP, and this outcome may be used as justification to perform testing according to one pharmacopoeia to meet the requirements of all three. For those monographs where PDG has harmonized by attribute, meaning some of the specific tests have not been aligned across the pharmacopoeias, the approach detailed in this article may be applied to those non-harmonized attributes, to further reduce redundant testing. Additional detailed information on harmonization approaches and progress may be found in previously published articles that were focused on pharmacopoeia compliance (11,12).

Acceptance criteria evaluation. To achieve multi-compendial compliance, the tightest acceptance criteria will generally be applied. However, it is recognized that analytical methods and acceptance criteria are necessarily interrelated. In cases where the underlying chemical or analytical principles are essentially the same, the tighter limits from one of the compendia may be applied to ensure compliance with all of the compendial requirements. For acceptance criteria with overlapping ranges, the appropriate upper and lower limits may be used to create the tightest range. In cases where the test result is affected by dependent variables (e.g., temperature or concentration), the association of the method and acceptance criteria will be maintained.

Establishing excipient specifications–Recommendations

The following principles may be generally applied in establishing appropriate specifications to ensure multi-compendial compliance for excipients. Consideration is given to the list of tests, the analytical procedures for these tests, and the associated acceptance criteria for a given excipient.

Tests. All tests from all of the compendia (Ph. Eur., USP–NF, and JP, as applicable) are included in the specification for the excipient. However, not all of the methods associated with these tests necessarily need to be performed, as detailed below, and in Figure 2.

Analytical procedures. Two or more compendial methods for a particular test or quality attribute may be compared, and redundant testing minimized through the following selection process for the excipient:

• All Ph. Eur. methods are selected.
• Only the Ph. Eur. method is necessary if it is determined to be equivalent or superior to the USP–NF and/or JP method(s), based on a paper-based method assessment.
• If the outcome of the paper-based method comparison is not conclusive, then assessment of existing data or data generated in a laboratory study may be performed to assist in the evaluation. If the assessment is still not conclusive, and in the absence of additional information, the compared methods should be considered not equivalent.
• If the Ph. Eur. method is not equivalent to the USP–NF and/or JP method(s), then the additional USP–NF and/or JP method(s) must also be selected.
• If no Ph. Eur. method exists, the USP–NF method is selected if it is determined to be equivalent or superior to the JP method.
• If the USP–NF method is not equivalent to the JP method, then the additional JP method must also be selected.
• Additional methods for tests appearing only in the USP–NF and/or JP are selected.

Acceptance criteria. Where two or more compendial methods for a particular quality attribute for a given excipient have been compared, and a single method has been selected, the appropriate acceptance criteria are selected according to the following process:

• Generally, the tightest/most stringent acceptance criteria are selected. In some instances, it may be necessary to modify the selected method (e.g., sample and/or standard concentration) to allow assessment of compliance with the tightest acceptance criteria.
• Generally, for acceptance criteria ranges, the limits from different compendia may be combined to provide the tightest/most stringent acceptance criteria.
• In cases where the acceptance criteria are inherently linked to the methodology (e.g., temperature- or concentration-dependent tests), the association between method and acceptance criteria will be maintained and a single method may be utilized, provided the acceptance criteria shift is consistent with chemical and/or physical principles for the material and method.
• Where compendial methods have not been compared, have been determined to be not equivalent, or are unique, the acceptance criteria associated with the method are selected.

A detailed listing of compendial tests commonly found in the Ph. Eur., USP–NF, and JP, an assessment of differences between the methods and acceptance criteria, and the potential impact of these differences on multi-compendial compliance is provided in the next paper in this series (13).The details for the specific methods are intended to provide guidance in the assessment of the different tests in compendial monographs and provide selection recommendations to ensure multi-compendial compliance. These detailed method assessments may be applied to tests for drug substances and drug products, in addition to excipients.

Extending excipient specification equivalence to additional pharmacopoeias–example

This article has focused on specification equivalence to achieve in-house harmonization for excipients listed in the Ph. Eur., USP–NF, and JP. The principles, however, may be extended to include other pharmacopoeia requirements.

For example, sodium hydroxide may be used as an excipient in a drug product distributed to the European Union, United States, and Chinese markets. Therefore, sodium hydroxide will have to comply with the pharmacopoeial monographs (current as of June 2025) in the Ph. Eur., USP–NF, and Chinese Pharmacopoeia (ChP). Table I captures the methods and acceptance criteria for the sodium hydroxide monographs in each of the pharmacopoeia for the reader's understanding. To minimize the redundant testing needed to comply with all the monographs, a specification equivalence report may be generated evaluating each quality attribute. Some of the test attributes are straightforward to determine but others are not. For the sake of brevity, this article will focus on only four attributes: pH; chlorides; potassium; and the test for aluminum and iron:

• For the pH test, each monograph requires a dilution of the sodium hydroxide, and the resultant solution pH is measured. The same acceptance criteria for all three monographs is “not less than 11”. Following the recommendation in this article, use of the test method listed in the Ph. Eur. may be used to ensure compliance with all three pharmacopoeia monographs.
• For the chlorides test, which is only present in the Ph. Eur., and ChP, the Ph. Eur. and ChP tests are chemical reactions where the test sample is compared to the standard solution to ensure the same or less opalescence. The limit of the Ph. Eur. test is 200 ppm, while the ChP monograph limit is 50 ppm. In this case, some lab work needs to be performed to determine if the Ph. Eur. method can demonstrate the change at 50 ppm. If it does, the Ph. Eur. method should be run. If it does not, then the methods are not equivalent, and each method should be run.
• For the potassium test, the USP use of atomic absorption spectroscopy is superior to the ChP chemical reaction test. Also, the company would need to determine the potassium concentration that produces opalescence in the ChP method to ensure the USP limit of 0.5% (5000 ppm) is appropriate.
• The test for aluminum and iron appears only in the ChP monograph. Specification equivalency is not applicable for this attribute so the ChP test must be run for any sodium hydroxide batch released.

A similar approach would be conducted for each remaining attribute and documented in a report that would be approved by the technical group and quality assurance. The specification document would also reflect what testing would be necessary to comply with all three monographs.

Conclusion

This article provides practical guidance to establish appropriate specifications that can help ensure multi-compendial compliance with excipient monographs in multiple pharmacopoeias through in-house harmonization, based on the principles of specification equivalence presented in the earlier articles in this series. A detailed look at specific tests, methods, and acceptance criteria in the pharmacopoeia to supplement this approach will be provided in the next article in this series (13).

Acknowledgment

The authors gratefully acknowledge the significant contributions of G. A. Duff and R. A. Fitzgerald at Merck & Co., Inc. for valuable discussions that helped shape the concepts and processes described in this paper. Without their technical expertise and practical suggestions, this article would not have been possible.

References

1. Wiggins, J.M. and Albanese, J.A. A Practical Approach to Pharmacopoeia Compliance. Pharmaceutical Technology Regulatory Sourcebook eBook, 2020 March, pp 24–32.
2. Wiggins, J.M. and Albanese, J.A. A Case Study in Pharmacopoeia Compliance: Excipients and Raw Materials. PharmTech.com, March 15, 2020.
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10. ICH. Section 3–Glossary. Q4B(R1) Evaluation And Recommendation of Pharmacopoeial Texts For Use In The ICH Regions (ICH, July, 2024). https://database.ich.org/sites/default/files/ICH_Q4B%28R1%29_Guideline_2024_0605.pdf (accessed Aug. 28, 2024).
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13. Wiggins, J.M.; Albanese, J.A.; Reed, G.; and Ionova, Y. Multi-Compendial Compliance for Pharmaceutical Excipients–Part 2: A Detailed Assessment for Specification Equivalence. PharmTech.com (in production. publication date to be determined).

About the authors

J. Mark Wiggins is owner and compendial consultant with Global Pharmacopoeia Solutions, LLC. 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.