Advances in analytical methodology and increased sensitivity have facilitated detection by pharmaceutical manufacturers of low levels of previously undetected components in well-established, widely used excipients. Unfortunately, this increased awareness has led to potential concerns that excipients and pharmaceutical products containing these excipients with previously undeclared additives, processing aids, and/or concomitant components could now be considered adulterated and/or misbranded.
This is, in part, due to these new identified components being considered erroneously by some as impurities in excipients. In addition, compendial excipients having United States Pharmacopeia–National Formulary (USP–NF) monographs could face further issues because USP General Notices 5.20 (1) specifically prohibits the presence of such non-disclosed components.
Many additives, processing aids, and concomitant components have always been present and have had a long precedence of acceptable use in excipients. In addition, excipients containing these additives and processing aids have been safely used in pharmaceutical products for many years (sometimes decades) without incident. However, the identity of these additives and processing aids, as well as their presence, was often not disclosed in excipient composition profiles. In certain cases, excipient manufacturers have not been willing to disclose the identity of such components due to the proprietary nature of their use. As a result, there are a large number of excipients in approved medicines that contain undeclared additives, processing aids, and/or concomitant components.
There is typically a justifiable technical need for additive and processing aid inclusion in excipients. Additives and processing aids should not be reduced or eliminated, or considered as impurities, nor should excipients containing additives or processing aids be avoided without understanding the impact to pharmaceutical product safety or efficacy.
This article expands on a previous publication (2) and a US Pharmacopeial Convention (USP) stimuli article (3) and addresses:
- History and use of additives and processing aids in excipients
- Current regulatory position including acceptance of concomitant components as part of excipient composition
- Recommendations to ensure pharmaceutical products are not being deemed adulterated and/or misbranded.
This article focuses on the use of additives and processing aids in excipients with established safety profiles and precedence of use and the concerns with compliance to US Food and Drug Administration (FDA) labelling and USP General Notices requirements. The presence of additives, processing aids, and concomitant components has not been well understood by regulators and pharmaceutical manufacturers. A follow up article will address concomitant components which, based on USP’s stimuli article (3), are now recognized as a natural part of excipient composition and not as impurities. Table I provides the International Pharmaceutical Excipients Council (IPEC) definitions of common terms (4).
Most excipients are not pure substances, but rather, multi-component ingredients that likely would not perform the same if any of the components were removed. Inherent residual and trace components present in excipients are important and can impact key excipient functional characteristics when used in pharmaceutical formulations. These components in excipients are not considered impurities by excipient manufacturers and could vary from supplier to supplier due to different raw materials and manufacturing processes. Although for APIs high purity is deemed a superior product, for excipients high purity is not necessarily better and may lead to decreased functional performance.
Examples of excipient components can be found in Figure 1.
Additives and processing aids in excipients
Additives are important components commonly used at low concentrations in excipients. Additives provide certain functions such as enhancing stability, modifying pH, preventing microbial growth, etc. For many excipients currently containing additives, the absence of additives could adversely impact excipient performance and/or stability.
Processing aids are used by excipient manufacturers to support excipient manufacturing processes. Examples of processing aid functions might include reducing excipient adherence to manufacturing equipment, increasing powder flow through piping and hoppers/bins, and decreasing viscosity to facilitate pumping.
The benefits from process aid inclusion in excipient composition realized by excipient manufacturers might also be advantageous to pharmaceutical manufacturers. Often, the relationship between excipient composition, physical form, and performance is not fully understood. Removal of undeclared additives and/or residual processing aids could have unintended negative consequences, and the impact of the removal would have to be evaluated in all pharmaceutical products containing excipients with additives and/or processing aids. For example, switching from butylated hydroxytoluene (BHT) stabilized polyethylene glycol (PEG) to an additive-free PEG could compromise pharmaceutical product stability if the pharmaceutical product is unknowingly stabilized by the undeclared antioxidant contained in the excipient. Fully understanding excipient composition profiles, including potential undeclared additives or residual processing aids, via early dialog with excipient manufacturer, would avoid such problems. Additionally, having this information could help to avoid similar future problems should a new excipient and/or supplier be qualified where the substituted excipient comprises different additive or processing aid types or levels or is free of additives or processing aids altogether.
Many pharmaceutical excipients are also manufactured for non-pharmaceutical applications. These applications do not always require identification of additives and/or processing aids. Due to the multitude of industries that excipient manufacturers support, historically, they may not have understood how important it is for pharmaceutical manufacturers to know if additives and processing aids exist in their ingredients. In addition, intellectual property confidentiality concerns may be a factor in non-disclosure of these components. As a result, unlike APIs, which are typically single entities, excipients are often complex substances that may contain components not appearing on labelling or in monographs. Differences in additives and/or processing aids due to raw material sourcing or manufacturing processes can result in different excipient composition profiles for seemingly identical excipients that meet the same pharmacopeial specifications. For pharmaceutical products, excipient substitutions from one supplier to another supplier could have an adverse impact on product performance and could pose potential risks by compromising safety, stability, or efficacy.
Additives and processing aids can serve a variety of functions. These include, but are not limited to:
- Anti-adherent agents. Additives such as silica or talc may be used as anti-caking agents.
- Antioxidants. Antioxidants are agents that prevent the oxidation process, thus avoiding its deterioration.
- Potential antioxidants found in excipients might include ascorbic acid, butylated hydroxyanisole (BHA), and BHT.
- Buffering agents. Designed to control the pH drift. Examples of buffering agents might include sodium bicarbonate and calcium biphosphate.
- Diluents/fillers. Some excipients may contain diluents or fillers such as calcium carbonate and lactose.
- Emulsifying agents. Emulsifying agents might be added to an excipient (e.g., simethicone emulsion) to enhance the emulsion stability, thus avoiding separation between two phases. Examples include sodium lauryl sulfate and polysorbate 60
- Glidants. Glidants may be added to powders or granules to enhance their flowability. Examples of glidants might include silica and/or silica derivatives.
- Preservatives. Preservatives may be added to excipients in order to prolong their shelf life by protecting them from micro-organism deterioration. Examples of preservatives might include benzoic acid and butylparaben.
Based on excipient good manufacturing practices (GMPs) (5), IPEC-Americas believes that additive and processing aid use should be controlled. The USP stimuli article (3) supports IPEC-Americas’ position, as stated in their conclusion: “A distinction must be made between excipient impurities that detract from the quality of the excipient (including safety), and those components which can be present, have always been present, and which may need to be present to achieve the necessary performance in the application.”
Therefore, it should be clearly understood that additives and processing aids are not impurities.
The pharmaceutical industry is currently facing a dilemma where FDA and USP expect more detailed composition information in monographs and labelling.
Current regulatory situation
Due to excipient sourcing globalization and increased need to detect and prevent supply of adulterated ingredients, many new and modernized test methods are now finding previously undetected components in excipients. Historically, excipient manufacturers have used common techniques that measure single-variable characteristics, like solution pH, to confirm desired endpoints. These techniques do not detect the presence of multiple components of a product. With the concern for adulterated ingredients, more sophisticated methods, such as high-performance liquid chromatography (HPLC), are employed and can detect the presence of multiple components within a given sample. Although they are now being detected, these components have always been present but undetectable by older, less sophisticated methods.
Further, preclinical toxicology studies conducted on excipients containing additives and processing aids have not exposed any health or safety issues or any other adverse impact due to the presence of these excipient components.
FDA expects pharmaceutical manufacturers to have a thorough understanding of composition and impurities in pharmaceutical products. As a result, because these components had not been disclosed in the past, and because pharmaceutical manufacturers are analyzing for and finding these components due to advances in analytical techniques, it is not well understood if these components have been added intentionally or in the case of concomitant components, are inherent to excipient composition and are not impurities.
IPEC-Americas survey. IPEC-Americas is concerned that discovery of additives or processing aids present in excipients could result in undue alarm and potentially trigger consequences that could negatively impact availability of pharmaceutical products when there is no safety concern. As a result, IPEC-Americas completed a survey to identify additives and/or processing aids that are integral to excipient composition. The survey identified a list of more than 70 additives currently undeclared in commonly used excipients with all but five of the additives currently listed as excipients in the FDA Inactive Ingredient Database (IID). Examples include, but are not limited to, silica, BHT, and propyl gallate.
Based on the survey results, IPEC-Americas developed a backgrounder document (6) that includes a list of additives and processing aids used in excipients, submitted a formal request to FDA in July 2017 (7) for a meeting to develop a strategy for handling undeclared additives and processing aids in excipients, and continues to look forward to dialoging with them.
Concerns with current USP policy. The excipient manufacturers have concerns about USP General Notices 5.60, which states, “the presence of an unlabelled other impurity in an official substance is a variance from the standard if the content is 0.1% or greater” (8). This is further complicated by USP General Notices 5.20 requirements that state, “Official substances may contain only the specific added substances that are permitted by the individual monograph. Such added substances shall not exceed the quantity required for providing their intended effect. Where such addition is permitted, the label shall indicate the name(s) and amount(s) of any added substance(s)” (1).
Therefore, based on USP General Notices 5.60 and 5.20, presence of undeclared additives or processing aids, at or above 0.1%, is not allowed. This is a major concern to excipient manufacturers because undeclared additives or processing aids are present in many USP- or NF-grade excipients currently used in pharmaceutical products and typically this has been the case for many years.
Ensuring drugs are not being deemed adulterated and/or misbranded
The pharmaceutical industry is currently facing a dilemma where FDA and USP expect more detailed composition information in monographs and labelling. In addition, pharmaceutical manufacturers need a better understanding of excipient composition. However, excipient manufacturers may need to keep certain additive and processing aid information confidential for intellectual property or trade secret reasons. Resolving this issue will require collaboration by all impacted stakeholders.
Historically, there has not been a consistent approach to disclosure of additives and processing aids in excipients, even though they have been used for many years without adversely impacting product safety. Given the large number of excipients currently in approved medicines containing undeclared additives or processing aids, and the much greater number of pharmaceutical products potentially affected, there is an urgent need for the pharmaceutical and excipient industries, FDA, and USP to collaborate in developing a strategy for addressing additives and processing aids in excipients. This approach should allow excipient suppliers to share confidential information with FDA without direct disclosure of the identity and level of additives and/or processing aids to pharmaceutical manufacturers.
Specific recommendations from IPEC–Americas include:
1. To avoid restricting current, safe excipient use, FDA should review and acknowledge additives and processing aids not listed in the IID, but which have historically been present in and demonstrated to be safely used in excipients.
2. FDA should exercise enforcement discretion to allow additives and processing aids, listed in the IID and present in excipients, as well as individually in pharmaceutical product formulations to exceed IID maximum potency limits in final pharmaceutical products, if it can be shown that there is a precedence of use in excipients having been used in the route of administration being reviewed.
3. FDA, USP, and industry stakeholders should collaborate to develop a strategy that addresses how intellectual property and labelling issues related to additives and processing aids might be handled. One such approach could include a bridging justification, reference to use in food, or generally recognized as safe (GRAS) position to justify the safety.
4. USP should include identified excipient additives and processing aids in the exclusion list for compliance with USP General Notices 5.60.10 impurity labelling requirements. Current list of exclusions includes:
- Fermentation products and semi-synthetics derived therefrom
- Biotechnology-derived products
- Crude products of animal or plant origin.
5. USP should create a new General Notice section 5.20.15 that exempts excipients from declaring specific additive and processing aid types and levels on labelling unless the excipient manufacturer desires to do so. This information, when considered confidential by the excipient manufacturer, can be shared with FDA using a Type IV drug master file (DMF) and referenced in drug applications using a letter of authorization. The excipient manufacturer, however, would need to identify that an additive or processing aid was present.
Many excipients contain additives and/or processing aids to enhance performance or facilitate manufacture. While additives can be used for such purposes as pH buffering, controlling microbial contamination, preservation, etc., processing aids are used to improve manufacturing processing and efficiency. Many additives and processing aids contained in excipients may not be found on labelling or in monographs, and additive and processing aid concentrations and types may differ among excipient manufacturers. Generally, additives and processing aids are themselves excipients or food additives and have been used safely in pharmaceutical products for years and sometimes decades. As a result, their presence in pharmaceutical products poses no risk to patient safety. However, while additive and processing aid use pose no safety risk, absence of these components could compromise pharmaceutical product stability and efficacy.
USP General Notices 5.20 and 5.60, in their current language, require additives and processing aids to be on labels and reported when used at levels >0.1% (based on International Council for Harmonization Q3B). Such a requirement(s) may present challenges for excipient manufacturers due to confidentiality concerns and for pharmaceutical manufacturers who may not understand the complete excipient composition profile. IPEC-Americas recommends changes to USP General Notices 5.20 and 5.60 regarding labelling requirements for additives and processing aids.
IPEC-Americas takes the position that excipient and pharmaceutical manufacturers should have open communication regarding the potential for the presence of additives and processing aids (9–11). This can include use of confidentiality disclosure agreements during excipient/supplier qualification. Details for accessing information regarding additive and processing aid use also may be via DMF, when appropriate. However, in other regions (e.g., Europe) where excipient DMFs are not applicable, the need for further discussion with regulators may be required.
Lastly, stakeholders, USP, and FDA, need to collaborate and develop a path forward that would affect the following:
- Ensure that identification of low levels of additives and processing aids in established excipients does not lead to pharmaceutical products being deemed adulterated and/or misbranded.
- Ensure that excipients containing additives and/or processing aids comply with revised USP requirements (as proposed).
- Create a means to share the above information in a manner that does not compromise excipient manufacturer’s intellectual property.
1. USP, USP 40-NF 35 [Official May 1, 2017], p. 5.20.10 (USP, Rockville, MD, 2015).
2. Carlin et. al, Pharm Tech 41 (10) 54-63 (October 2017).
3. USP, “The Complexity of Setting Compendial Specifications for Excipient Composition and Impurities,” USP Pharmaceutical Forum 44 (3) 1 May 2018
4. IPEC, “General Glossary of Terms and Acronyms,” (Arlington, VA, 2014).
5. NSF/IPEC/ANSI 363–2016 Good Manufacturing Practices (GMP) for Pharmaceutical Excipients.
6. IPEC-Americas backgrounder document for “Additives in Pharmaceutical Excipients.”
7. IPEC-Americas letter to Dr. Lawrence Yu, Deputy Director OPQ, FDA, July 25, 2017.
8. USP, USP 40-NF 35 [Official 1 May 2017], p. 5.60.10 (USP, Rockville, MD, 2015.
9. IPEC, The IPEC Excipient Composition Guide (2009).
10. J. Zeleznik and G. Collins, “Additives & Concomitant Components vs Impurities in Pharmaceutical Excipients,” IPEC-Americas Webinar, March 2018.
11. B. Carlin and R.C. Moreton, “ The Importance of Excipient Composition and Complexity,” IPEC-Americas Webinar, November 2018.
Supplement: APIs, Excipients, and Manufacturing
When referring to this article, please cite it as G. Collins et al., “Additives and Processing Aids in Pharmaceutical Excipients," Pharmaceutical Technology APIs, Excipients, and Manufacturing Supplement (October 2019).