Multi-Compendial Compliance for Pharmaceutical Excipients–Part 2: A Detailed Assessment for Specification Equivalence

The previous article in this series (1) detailed a practical approach to establish specification equivalence for in-house harmonization to ensure multi-compendial compliance for excipients. Application of this approach allows a manufacturer to minimize testing for the material while remaining compliant with regulatory requirements in different regions of the world. This paper provides a technical assessment of compendial tests commonly found in the European Pharmacopoeia (Ph. Eur.), the United States Pharmacopeia–National Formulary (USP–NF), and the Japanese Pharmacopoeia (JP), detailing differences between the methods and acceptance criteria, and the potential impact of these differences on multi-compendial compliance. Recommendations are also provided to facilitate a paper-based determination of specification equivalency. The assessments may be applied for in-house harmonization of drug substances and drug products, in addition to excipients.

Establishing Excipient Specifications–Considerations for Specific Tests

The following is a detailed assessment for many of the compendial tests typically used for excipients with a recommendation of which method may be most appropriate to select in an evaluation of specification equivalence. In general, minor differences between compendial methods are not expected to impact the fundamental pass/fail decision for a particular test and are not expected to necessitate the use of multiple compendial methods to assess multi-compendial compliance. Detailed considerations for the appropriate selection of specific test methods and acceptance criteria are provided below. The selection recommendations generally apply to a paper-based assessment of the methods, but may also include an evaluation of existing data, or a laboratory study. A monograph for a particular excipient may include tests in addition to these, and similar principles should be applied in evaluating any other compendial tests.The authors caution the readers that the conclusions suggested below are applicable to general tests/monographs as of June 2025, and users should confirm that there have been no subsequent updates to the pharmacopoeias.

Section 1. Tests/information included in monographs

• Appearance (characters)
  • Assessment: as stipulated in the General Notices of the Ph. Eur., USP–NF, and JP, the appearance, characters, and/or description provided in a monograph for an excipient are not considered compendial requirements but are provided for information. These tests typically employ a simple visual assessment.
  • Selection: the specification may include a requirement for appearance that is appropriate for the material used, but the appearance is not considered a compendial requirement.
• Appearance of solution (color and clarity/degree of opalescence)
  • Assessment: these tests in the Ph. Eur. are usually limit tests using standard solutions of color and opalescence for comparison to the sample (or sample solution) to evaluate conformance. Method differences may include sample preparation and solvent. The comparison is usually visual, although instrumental methods are also possible. By contrast, the tests in the USP–NF and JP are generally more qualitative, employing a simple visual assessment of color and clarity without comparison to specific reference solutions.
  • Selection: the Ph. Eur. method, with associated acceptance criteria, is considered superior due to the comparison to standards, and therefore is the method of choice to ensure compliance with similar tests in the USP–NF and JP.
• Assay (titration)
  • Assessment: differences between compendial titration methods may include the use of visual or potentiometric endpoints, different titrants and indicators, and different concentrations of the sample, titrant, or indicator. In comparing compendial titration methods, these differences are not expected to have a significant impact on the analytical results or the pass/fail decision.
  • Selection: if the outcome of the method comparison is conclusive, standardizing to the Ph. Eur. titration method will generally ensure compliance with USP–NF and JP titration methods. The tightest acceptance criteria will be applied to ensure multi-compendial compliance.
• Assay (chromatography)
  • Assessment: differences between chromatographic assay methods in the various compendia may include column packing, column dimensions, system temperatures, mobile phase, gradient or isocratic systems, injection volume, flow rate, detector type, detector wavelength, sample and standard concentrations and preparations, and system suitability requirements. Allowable variations for several of the chromatographic parameters are detailed in the corresponding Ph. Eur. and USP–NF General Chapters. In considering chromatographic methods, many of these potential differences are not significant since the compendial methods have been validated for linearity, accuracy, repeatability, etc. and the results are expected to yield the same pass/fail decision.
  • Selection: if the outcome of the method comparison is conclusive, standardizing on a chromatographic assay method from the Ph. Eur. will generally ensure compliance with USP–NF or JP chromatographic requirements. The tightest acceptance criteria will be selected to ensure multi-compendial compliance, with consideration given to whether the method has sufficient precision to allow application of the tighter limits.
• Assay (titration versus chromatography)
  • Assessment: it is difficult to compare different assays where one test is performed by titration and another by chromatography. Titration procedures are generally more precise, but chromatographic methods are generally more selective. The acceptance criteria may also be different to reflect the precision of the particular method.
  • Selection: in many cases, it may be necessary to carry out analysis using both the chromatographic and titration assay method to ensure multi-compendial compliance for the excipient. There may be cases where the Ph. Eur. titration assay method and acceptance criteria may provide assurance of conformance to the chromatographic assay methods in the USP–NF and/or JP. To help address potential issues with selectivity, the Ph. Eur. titration method must be coupled with a chromatographic method for determination of impurities. There may also be cases where the Ph. Eur. chromatographic assay method and acceptance criteria may provide assurance of conformance to the titration assay methods in the USP–NF and/or JP. Any such determination must be documented as part of the assessment carried out for the specific excipient.
• Boiling point/distillation range
  • Assessment: differences in compendial specifications for boiling point/distillation range may include the apparatus, rate of heating, and the acceptance criteria.
  • Selection: because there is minimal potential for the apparatus and heating to impact the result, the use of the Ph. Eur. method to determine the boiling point or distillation range will be used, with the tightest acceptance criteria applied.
• Identity (general)
  • Assessment: current good manufacturing practices (CGMPs) require that at least one specific identity test must be performed for all excipients. The underlying goal of identity testing is the confirmation, with an acceptable degree of assurance, of the material’s identity. Compendial monographs may include several different identity tests for the same material. Some of these tests are intended to identify the entire chemical or molecule (e.g., IR) while others are intended to identify a particular moiety (e.g., a selective chemical test for a specific counter ion). Specific identity tests are preferred to non-specific chemical tests. The Ph. Eur. monographs may provide subdivisions entitled “First identification” and “Second identification”. The test or tests that constitute the “First identification” may be used for identification in all circumstances, as stated in the Ph. Eur. General Notices. If the “First identification” tests are performed, the “Second identification” tests do not need to be performed.
  • Selection: the Ph. Eur. “First identification” tests will be selected to establish the identity of the excipient. If the Ph. Eur. monograph does not include divisions for “First identification” and “Second identification” tests, then all of the Ph. Eur. identity tests will be included in the compendial release requirements, with the expectation that an excipient so identified would pass any other compendial identity tests. In the event that the USP–NF or JP monograph includes an identity test for a specific characteristic of the excipient (e.g., a test for a particular counter ion or physical characteristic), which is not otherwise addressed by a comparable Ph. Eur. identity test, then the additional USP–NF or JP test should also be performed to ensure compliance with the appropriate compendia. If there is no Ph. Eur. monograph for the excipient, appropriate USP–NF and/or JP identity tests will be included, based on a similar principle.
• Identity (infrared spectroscopy, [IR])
  • Assessment: differences in IR identity methods typically involve sample preparation (Attenuated Total Reflectance [ATR], Potassium Bromide [KBr], mull, film, or solution) and are not considered significant when evaluating the fundamental properties of the chemical bonds through IR analysis. In most cases, the spectrum from a sample is compared to that of a reference standard or reference spectrum similarly prepared, which provides unequivocal information regarding the identity of the material. The specific wavelength ranges used for the test may also vary, but this is also not considered significant in making an appropriate identification determination.
  • Selection: standardizing on the Ph. Eur. IR method will ensure compliance with USP–NF and JP IR tests.
• Identity (ultraviolet spectroscopy [UV])
  • Assessment: differences in UV identity methods may involve sample concentration, solvent, temperature, path length, and the particular wavelength used for the evaluation. Because most methods involve comparison to a reference standard or reference spectrum similarly prepared, these potential differences are not considered significant.
  • Selection: standardizing on the Ph. Eur. UV method will generally ensure compliance with USP–NF and JP UV tests.
• Identity (chromatography)
  • Assessment: different chromatographic identity procedures are capable of confirming the identity of the particular material. Differences between chromatographic method types (high-performance liquid chromatography [HPLC], gas chromatography [GC], or thin layer chromatography [TLC]) or differences between similar method types (see assay [chromatography] above) are not expected to have a significant impact on the ability of a particular method to establish the material's identity.
  • Selection: standardizing on the Ph. Eur. chromatographic identity method will generally ensure compliance with USP–NF and JP chromatographic identity tests.
• Identity (chemical, other)
  • Assessment: chemical identity methods may employ color change, precipitate formation, and/or solution formation based on a specific reaction of the excipient to provide assurance of the identity. Different tests may be necessary to ensure the identity for each moiety in a given excipient. Because an excipient may undergo a wide variety of reactions, there may be a large number of different chemical identity methods in compendial monographs for a material. These chemical methods are not typically specific to a particular excipient and therefore may not provide unequivocal identity. In addition to differences in the fundamental reactions utilized, these identification methods may also vary in the sample concentration and reagents used. Differences in chemical identity tests are not considered significant if the reactions are intended to evaluate the same chemical property of the material (such as presence of chloride). Multiple identification methods are usually unnecessary if one selective and specific method is available. Multiple tests may be necessary to demonstrate the identity of different moieties in the excipient.
  • Selection: Ph. Eur. chemical identity methods will be included in the compendial specification, if they are among the "First identification" tests. If the Ph. Eur. monograph does not include divisions for “First identification” and “Second identification” tests, then all of the Ph. Eur. chemical identity methods will be included in the compendial specification. No additional Ph. Eur., USP–NF, or JP chemical identity methods will typically be needed to ensure multi-compendial compliance.
• Impurities–organic/related substances (chromatography)
  • Assessment: as with chromatographic assays, the differences between chromatographic impurities/related substances methods in the various compendia using HPLC may include column packing, column dimensions, system temperatures, mobile phase, gradient or isocratic systems, injection volume, flow rate, detector type, detector wavelength, sample and standard concentrations and preparations, and system suitability requirements. Another typical difference for impurities methods lies in the procedures used for calculating results (e.g., weight percent, volume percent, area percent, use of an internal standard, use of an external standard, or use of a diluted sample as standard). Allowable variations for several of the chromatographic parameters are detailed in the Ph. Eur. General Chapter. In considering chromatographic methods, many of the potential differences are not significant because the individual methods are validated for linearity, accuracy, repeatability, etc. and the results should yield the same pass/fail decision. TLC may also be used as a suitable compendial method for control of impurities, although an HPLC method would generally be considered superior to TLC for quantitation, and this should be taken into account when selecting the test or tests required to ensure multi-compendial compliance for the excipient.
  • Selection: standardizing on a chromatographic method for impurities/related substances from the Ph. Eur. will generally also ensure compliance with USP–NF or JP requirements. The tightest acceptance criteria for each specified impurity should be selected to ensure multi-compendial compliance. The Ph. Eur. General Monograph–Substances for Pharmaceutical Use and General Chapter 5.10 Control of Impurities in Substances for Pharmaceutical Use should also be considered when establishing the appropriate limits.
• Impurities–inorganic
  • Assessment: There are a number of compendial tests which are intended to limit the amount of various inorganic impurities that may be present in excipients. These tests usually include wet chemical methods but may also employ instrumental methods. The test may be qualitative (i.e., pass/fail), semi-quantitative, or quantitative. These tests are not broadly applied to all excipients but are usually included in specific monographs as appropriate.
    • Examples of this type of test are aluminum, ammonium, arsenic, calcium, chlorides, iodides, iron, lead, magnesium, mercury, nickel, sodium, and sulfates. Wet chemical procedures generally rely on a chemical reaction to provide a visual change, such as color, turbidity, or formation of a precipitate, which enables a determination of the presence of the particular impurity at or below the acceptance criteria. Differences in compendial wet chemistry approaches for a specific inorganic impurity would typically involve different chemical reactions intended to detect the same impurity. Instrumental techniques may also be used for lower-level impurities or where greater sensitivity may be required. Instrumental methods are generally considered superior to wet chemical methods for determination and quantitation of inorganic impurities, as in the evaluation of an excipient for elemental impurities. Other than as listed in specific excipient monographs, a test for an inorganic impurity would only be included if the elemental impurities assessment determines there is a need to employ a control strategy for a specific inorganic impurity in the particular excipient.
• Selection: if the outcome of the method comparison is conclusive, standardizing on a wet chemical procedure from the Ph. Eur. for these types of inorganic impurities will generally also ensure compliance with USP–NF and JP wet chemistry requirements for the particular impurity. An instrumental compendial method is generally superior to a wet chemical method and this should be taken into account when selecting the test or tests required to ensure multi-compendial compliance for the excipient. Standardizing on an instrumental procedure from the Ph. Eur. for inorganic impurities will generally also ensure compliance with USP–NF or JP wet chemical or instrumental requirements. The tightest acceptance criteria for the particular impurity should be selected to ensure multi-compendial compliance. Consideration should also be given to the superior, International Council for Harmonisation (ICH)/ Pharmaco-poeial Discussion Group (PDG) risk-based approach for control of elemental impurities (including appropriate test methods and acceptance criteria).
• Loss on drying (LOD)
  • Assessment: Differences in LOD methods typically involve sample size, temperature, time, vacuum, and desiccants in the procedure for drying. The differences may have an impact on the result obtained and should be considered in selecting the method to be used. If the method specifies that the test is performed until constant weight is achieved, the differences in the methods are not expected to impact the final result, and the identical pass/fail decision should be reached.
  • Selection: If the outcome of the method comparison is conclusive, standardizing on the Ph. Eur. method for LOD will generally ensure compliance with USP–NF and JP requirements. The tightest acceptance criteria should be applied to ensure multi-compendial compliance. In establishing the acceptance criteria, the impact of time and temperature on the result should be considered (i.e., the longer the time and the higher the temperature, the higher the expected LOD result) to ensure the tightest acceptance criteria are applied.
• Melting point/melting range
  • Assessment: Differences in compendial methods for these tests may include the apparatus, heating rate and the acceptance criteria.
  • Selection: Because there is minimal potential for the apparatus and heating to impact the result, the use of the Ph. Eur. method to determine the melting point or range will be used, with the tightest criteria applied.
• Microbiological tests (microbial limits, bacterial endotoxins, sterility)
  • Assessment: The microbiological tests in the Ph. Eur., USP–NF, and JP have been harmonized by PDG and assessed by ICH Q4B. Based on this assessment, the tests in the individual compendia are equivalent.
  • Selection: Typically, the microbiological procedures from the Ph. Eur. will be selected with appropriate consideration of sample qualification requirements.
• pH/acidity or alkalinity
  • Assessment: Differences in pH methods typically include instrumentation, indicators, sample concentration, and measurement temperature. These differences may impact the result obtained and should be considered when selecting the method to use. The impact of sample concentration on the result may be considered in terms of the Henderson-Hasselbalch equation. Acidity or alkalinity of a sample is determined by assessing the occurrence or absence of a color change upon adding an acidic or basic reagent in the presence of an appropriate indicator. Differences in acidity or alkalinity tests may include sample concentration, solvent, titrant, and/or indicator.
  • Selection: Tests for pH and acidity/alkalinity evaluate the same fundamental attribute for the material related to its inherent acidic or basic functional groups, or those of residual materials present along with the excipient itself. If the outcome of the method comparison is conclusive, standardizing on the Ph. Eur. method for pH or acidity/ alkalinity will generally ensure compliance with the corresponding USP–NF and JP methods. For pH, the tightest acceptance criteria may generally be applied to ensure multi-compendial compliance. For acidity/alkalinity, the acceptance criteria associated with the selected method should be applied.
• Refractive index
  • Assessment: The primary difference in refractive index methods for liquid excipients is the measurement temperature. The expected trend for the effect of temperature on the result is difficult to predict. Despite temperature differences in methods, the refractive index result, as a fundamental physical property, is expected to comply with the corresponding, appropriately established acceptance criteria.
  • Selection: If the outcome of the method comparison is conclusive, standardizing on the Ph. Eur. method for refractive index will generally ensure compliance with USP–NF and JP requirements. The specific acceptance criteria associated with the selected method should be used.
• Specific gravity/density
  • Assessment: Differences in specific gravity/density methods typically involve sample preparation (neat liquid or solution), solvent, and the measurement temperature. The general trends expected are that the higher the sample concentration, the higher the result, while the higher the temperature for the test, the lower the specific gravity/density result. Despite differences in methods, the specific gravity/density result, as a fundamental physical property, is expected to comply with the corresponding, appropriately established acceptance criteria.
  • Selection: If the outcome of the method comparison is conclusive, standardizing on the Ph. Eur. method for specific gravity/density will generally also ensure compliance with USP–NF and JP requirements. The acceptance criteria associated with the selected method should be applied.
• Specific rotation/optical rotation
  • Assessment: Differences in specific rotation/optical rotation methods typically involve sample preparation, solvent, measurement temperature, path length, and detection wavelength. The general trends expected are that the higher the concentration and the longer the path length for the test, the higher the expected rotation result. Despite differences in methods, the specific rotation/optical rotation result, as a fundamental physical property, is expected to comply with the corresponding, appropriately established acceptance criteria.
  • Selection: If the outcome of the method comparison is conclusive, standardizing on the Ph. Eur. method for specific rotation/optical rotation will generally also ensure compliance with USP–NF and JP requirements. The acceptance criteria associated with the selected method should be applied.

Sulphated ash/residue on ignition

• Assessment: The tests for sulphated ash/residue on ignition in the Ph. Eur., USP–NF, and JP have been harmonized by PDG and assessed by ICH Q4B. Based on this assessment, the tests in the individual compendia are equivalent.
• Selection: Standardizing on the Ph. Eur. method for sulphated ash will also ensure compliance with USP–NF and JP requirements. The tightest acceptance criteria should be applied to ensure multi-compendial compliance.
• Total ash/loss on ignition (LOI)
  • Assessment: Differences in total ash/LOI methods typically involve sample size, ignition temperature, and ignition time used in the procedure. The Ph. Eur. and USP–NF carry out the test to constant weight, which should provide the highest loss on ignition result (i.e., a more stringent assessment).
  • Selection: If the outcome of the method comparison is conclusive, standardizing on the Ph. Eur. method for total ash/LOI will generally ensure compliance with USP–NF and JP requirements. The tightest acceptance criteria should be applied to ensure multi-compendial compliance.
• Viscosity
  • Assessment: Differences in rotational viscometer (e.g., Brookfield) methods typically involve sample concentration, measurement temperature, spindle, speed, and instrumentation. Use of capillary viscometers (e.g., Ubbelohde-Type and Ostwald-Type) is also very common in excipient monographs and methods may differ in sample concentration and temperature. The expected trends are that the higher the sample concentration, the higher the resulting viscosity, and the higher the temperature, the lower the resulting viscosity. It is difficult to compare rotational and capillary viscosity methods. Despite differences in methods, the viscosity result, as a fundamental physical property, is expected to comply with the corresponding, appropriately established acceptance criteria.
  • Selection: If the outcome of the method comparison is conclusive, standardizing on the Ph. Eur. method for rotational or capillary viscosity will generally ensure compliance with the corresponding USP–NF and JP methods. The acceptance criteria associated with the selected method should be applied.

Water determination

• Assessment: Differences in water determination using titrimetric methods include sample amount, solvent, titrant, titrant concentration, and end-point determination (potentiometric or coulometric). These differences are not expected to have a substantial impact on the result obtained using a suitably qualified and calibrated instrument that is appropriate for the expected amount of water in the sample. For determination of low levels of water, a coulometric/micro procedure is preferred.
• Selection: If the outcome of the method comparison is conclusive, standardizing on the Ph. Eur. method for water will generally ensure compliance with USP–NF and JP requirements. The tightest acceptance criteria should be applied to ensure multi-compendial compliance. Appropriate consideration for the method, sample amount, and acceptance criteria should be given for low-level water determinations.

Waxes, fats, and fixed oils—typical properties (e.g., acid value, hydroxyl value, iodine value, saponification value)

• Assessment: Differences in the wet chemical procedures used to determine particular properties of waxes, fats, and fixed oils may include the sample preparation, reagents, indicators, titrants, and test conditions. However, for a particular procedure, differences in the compendial methods would not typically be expected to produce a different result. The acceptance criteria may be different in the different compendial monographs.
• Selection: If the outcome of the method comparison is conclusive, standardizing on the Ph. Eur. method for a particular procedure, (e.g., saponification value) will generally ensure compliance with the USP–NF and JP requirements for the same procedure (e.g., saponification value). The tightest acceptance criteria should be applied to ensure multi-compendial compliance.

Section 2. Additional tests to be considered

• Residual solvents
  • Assessment: Residual solvents in pharmaceuticals are defined in the International Council for Harmonisation (ICH) Q3C guideline (2) as organic volatile chemicals that are used or produced in the manufacture of drug substances or excipients, or in the preparation of drug products. The guideline recommends acceptable amounts for residual solvents in pharmaceuticals for the safety of the patient. The approach to limit residual solvents as specified in the ICH guideline is also included in the Ph. Eur, USP, and JP general notices, general monographs, and general chapters. A manufacturer needs to demonstrate that the levels of residual solvents comply with the limits established in ICH Q3C, and that solvent levels are maintained using an appropriate control strategy that encompasses the drug product and all of its components. As such, residual solvents in excipients must be controlled to comply with the ICH and pharmacopoeia requirements.
  • Selection: The harmonized approach to residual solvent control listed in the pharmacopoeias should be used for an excipient, including the appropriate test method and acceptance criteria.
• Elemental impurities
  • Assessment: The ICH Q3D guideline (3) presents a process to assess and control elemental impurities in the drug product using the principles of risk management as described in ICH Q9 (4). Although focused on the drug product, the guideline recognizes that, among other potential contributors, elemental impurities may be present in the excipients used in the preparation of the product and must therefore be considered in the overall risk assessment. The ICH Q3D guideline is also being incorporated into the pharmacopoeias, and consideration of elemental impurities is required by the pharmacopoeial general notices. The harmonized general chapter by PDG is being implemented, with the Indian Pharmacopoeia being the last to make it official in July 2026 (5). For pharmaceutical manufacturers, adoption of the harmonized approach to elemental impurities is recommended for acceptance into major markets. Whenever the elemental impurities risk assessment for a drug product requires testing a particular excipient for a specific element, or if a test for a specific metal impurity is listed in the excipient monograph, the test method from the pharmacopoeia should be used whenever possible and appropriate.
  • Selection: The test method recommendations listed in the harmonized chapter “Elemental Impurities” as published in the pharmacopoeias should be used in the determination of elemental impurities, as needed for an excipient. Acceptance criteria listed in the harmonized pharmacopoeia chapter for a specific elemental impurity should be applied to the excipient being tested, ensuring the limit is appropriate for the overall drug product risk assessment.
• Heavy metals
  • Assessment: The test for heavy metals is a wet-chemistry limit test that has long been included in pharmacopoeia monographs. The test is intended to detect the presence of metal impurities that form insoluble precipitates with sulfide ion. The metals that respond to this test typically include lead, mercury, bismuth, arsenic, antimony, tin, cadmium, silver, copper, and molybdenum. Long-standing questions about the test’s usefulness to accurately detect these metals contributed to the introduction of the ICH/PDG risk-based assessment of elemental impurities that are likely to be present. (See above.)
  • Selection: It is possible that a test for heavy metals may still be listed in the pharmacopoeia monograph for a particular excipient, especially in national pharmacopoeias that are not currently part of PDG; although, this should become increasingly rare. Applying the superior, risk-based approach for control of elemental impurities (including appropriate test methods and acceptance criteria) and testing particular excipients to limit specific metals that may be present, should in all cases be considered an acceptable alternative to the wet-chemistry test for heavy metals.
• Nitrosamines
  • Assessment: The Ph. Eur. and USP have introduced controls for a risk-based N-nitrosamine evaluation for drug substances and excipients. Many N-nitrosamines are classified as probable human carcinogens and regulators are taking action to ensure these impurities are minimized or eliminated from substances and final drug products. The requirements for control of N-nitrosamines are being captured in pharmacopoeial general chapters. Ph. Eur. General Monograph 2034 Substances for Pharmaceutical Use includes a requirement to establish a control strategy for N-nitrosamines. The control strategy is listed in Ph. Eur. general chapter 2.5.42 N-Nitrosamines in Active Substances. USP General Chapter <1469> Nitrosamine Impurities provides recommendations regarding: a) the establishment of controls of nitrosamine levels in order to ensure their elimination or reduction; and b) analytical procedure performance characteristics for procedures used to monitor nitrosamine levels. Many health authorities have also issued guidance documents that are applicable for the evaluation of nitrosamine levels.
  • Selection: Manufacturers should consider whether control of nitrosamines is necessary for the excipients used in their drug products, including the selection of appropriate test methods and acceptance criteria. Manufacturers should also remain vigilant to current nitrosamine requirements, given the dynamic state of regulatory expectations and the lack of harmonization to date among the pharmacopoeias.
• Tests for ethylene glycol (EG), diethylene glycol (DEG) and triethylene glycol (TEG)
  • Assessment: The Ph. Eur., USP, JP, and Chinese Pharmacopoeia have all introduced testing to control EG, DEG, or TEG in several high-risk monographs in response to the public health concerns posed by the potential presence of these contaminants in medicinal products (6-11). Regulatory agencies around the world are also issuing guidance for control of these toxic impurities. To date, the pharmacopoeia and regulatory approaches have not been harmonized.
  • Selection: Manufacturers need to be aware of these monograph changes as well as the regulatory guidance documents for controlling EG, DEG, and TEG that are being issued directly by global health authorities to combat adulteration of drug products. For example, FDA has issued a guidance document (12) that targets several high-risk excipients and requires that each drum of the material be sampled and tested to comply. Companies will need to execute testing required in individual monographs to ensure compliance with the testing for these contaminants. Given the intense focus of pharmacopoeias and regulators on this area, companies should ensure compliance with country or regional requirements as they continue to evolve.

Conclusion

This article has provided a detailed assessment of compendial tests commonly found in the pharmacopoeias, highlighting differences between the methods and acceptance criteria, and the potential impact of these differences on multi-compendial compliance. This information serves to supplement the previous article (1), which detailed a practical approach for establishing specification equivalence for in-house harmonization to ensure multi-compendial compliance for excipients. The first two articles (13,14) in this series introduced the concepts and provided a streamlined, step-by-step process for establishing specification equivalence. Taken together, these four articles provide the opportunity to gain efficiency by minimizing redundant testing for drug products and their ingredients, while also enabling flexibility in filing strategies.

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.

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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.