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Chris Moreton is principal, FinnBrit Associates
Priscilla Zawislak is global regulatory affairs advocacy manager, DuPont
Katherine L. Ulman is principal, KLU Consulting
Luke Grocholl is regulatory affairs expertâpharma food materials, MilliporeSigma
With ingredients sold to multiple markets, excipient manufacturers must understand the different regulatory requirements for pharma vs. food.
Manufacturers of pharmaceutical excipients often serve other markets in addition to the pharmaceutical industry. The excipient qualification process, quality systems supporting excipient manufacture, and regulatory scrutiny associated with pharmaceutical excipients offer confidence to potential customers in other regulated industries that the pharmaceutical excipient grade material could be qualified to meet their needs. The reality, however, is that significant differences often exist between regulated industry requirements, and neither suppliers nor customers can assume a single material qualification can meet every markets’ requirements.
Many ingredients used as pharmaceutical excipients have applications in dietary supplement or food ingredient markets. The common sugar alcohol, mannitol (HOCH2(CHOH)4CH2OH), for example, can be used as a pharmaceutical excipient, a non-dietary ingredient in dietary supplements, or a food additive. Mannitol monographs are accessible in the United States Pharmacopeia’s National Formulary (USP–NF), European Pharmacopoeia (Ph.Eur.), and Japanese Pharmacopoeia (JP), as well as the Food Chemicals Codex (FCC) and the European Union (EU) Food Additive regulations (Reg. (EU) 231/2012). Mannitol, with its sweet taste and pleasant mouthfeel, may serve the same purpose in confectionaries, chewable dietary supplements, or oral medications.
Each market application, whether food, dietary supplement, or pharmaceutical, has its own requirements, and although some of the requirements may overlap, pharmaceutical excipient manufacturers must understand and implement the requirements relevant to the intended uses before supplying into the aforementioned applications. Similarly, manufacturers of food additives and/or non-dietary ingredients need to understand and implement pharmaceutical requirements prior to supplying mannitol for drug product use. It is incorrect to assume that materials meeting food additive and/or non-dietary ingredient standards will also meet pharmaceutical excipient requirements. Likewise, it is also incorrect to assume that product approved for use as a pharmaceutical excipient will automatically comply with food or dietary supplement requirements.
FDA’s food additive definition (1) does not include generally recognized as safe (GRAS) substances; however, all food ingredients (including food additives, GRAS substances, and non-dietary ingredients for dietary supplements) are held to the same good manufacturing practice (GMP) requirements. For the sake of brevity, in this article, food additives, GRAS substances, and non-dietary ingredients for dietary supplements will be referred to collectively as food ingredients. Pharmaceutical excipients will be referred to as excipients.
Excipient, dietary supplement, and food ingredient markets are regulated, having requirements for quality management systems with material specifications and qualifications. Some markets have voluntary GMPs and other certification programs as discussed in the following. While there is considerable overlap in requirements for the different markets, there are also significant differences. No single quality management system or certification scheme satisfies the demands or requirements for all three markets, and some applications may have market-driven requirements not considered for the other applications. Table I lists pertinent guidelines and certification programs mentioned in this article.
Table I: Sources for guidelines and certification programs, food and pharmaceutical excipients.
NSF/IPEC/ANSI 363–2016 Good Manufacturing Practices for Pharmaceutical Excipients
EXCiPACT Certification Standards for Pharmaceutical Excipient Suppliers: Good Manufacturing Practices, Good Distribution Practices
Joint International Pharmaceutical Excipient Council–Pharmaceutical Quality Group Good Manufacturing Practices Guide for Pharmaceutical Excipients
Food Chemicals Codex
International Food Additives Council
The Global Food Safety Initiative
Food Safety Systems Certification 22000
Safe Quality Food Institute
International Featured Standards
ISO 22000 Food Safety Management
World Anti-Doping Agency
International Council for Harmonization
There are well-established GMP standards for regulated markets. For excipients, the NSF/IPEC/ANSI-363 and EXCiPACT excipient GMP standards, or the Joint International Pharmaceutical Excipient Council–Pharmaceutical Quality Group GMP guide for pharmaceutical excipients should be followed. In contrast to food ingredients, pharmaceutical products are not limited to the oral route of administration. For non-oral routes of administration, additional GMP requirements are based on intended uses.
Food GMP conditions are mandatory for food ingredients. In Current Good Manufacturing Practice, Hazard Analysis, and Risk Based Preventative Controls for Human Food (2), FDA requires that all food must be manufactured in compliance with food GMP requirements. Finished dietary supplements are subject to Current Good Manufacturing Practice in Manufacturing, Packaging, Labeling or Holding Operations for Dietary Supplements (3) dietary supplement GMP requirements; non-dietary ingredients are subject to 21 Code of Federal Regulations (CFR) 117 Part B (2) like all food ingredients.
The manufacture of chemical and mineral food ingredients may vary considerably from production requirements for agricultural food ingredients. Similar to excipients, food ingredients are often manufactured in chemical or mineral manufacturing facilities.
As such, it is not always clear to these manufacturers how to apply food GMP requirements to food ingredients. For this reason, the International Food Additives Council (IFAC) developed a GMP guide (4) for the food ingredient industry. Similarly, the Global Food Safety Initiative (GFSI) recommends the Food Safety Systems Certification FFSC 22000, Safe Quality Food Institute, or International Featured Standards as applicable food safety schemes for the manufacture of (bio)chemicals. The FSSC 22000 is based on ISO 22000 Food Safety Management requirements and adds additional elements appropriate to food ingredient manufacturers. Regardless of the certification standard used, application of food ingredient GMPs is sometimes quite different than for finished foods. Appropriate controls for food ingredients are based on identified and potential material hazards.
Although some quality management systems (i.e., GMPs) for excipients may exceed requirements needed to meet food ingredient GMPs, it is incorrect to assume excipient GMPs meet all food ingredient requirements. It is often easier to obtain acceptance of a food-grade material for use as a pharmaceutical excipient than for an excipient to comply with food regulatory requirements. Like excipients, food ingredients must undergo rigorous toxicological and safety evaluation prior to being approved for use in food; however, excipients, unlike food ingredients, may be evaluated based on their intended route of administration. In addition, whereas direct contact equipment and packaging supplies for excipients must be qualified based on the excipient being handled-including verification activities and identification of potential risks-food contact materials must follow FDA rules limiting the types of materials that can be used.
Table II illustrates some of the differences between food ingredient and excipient GMP requirements.
In addition to GMPs, food ingredients and excipients are subject to other regulatory requirements including the following:
Excipients and food ingredients require analytical testing, often described in published monographs. Although there may be some overlap in attributes, test methods, and specifications described in the monographs, significant differences often exist.
For instance, food and food ingredients’ heavy metal requirements typically focus on arsenic, cadmium, mercury, and lead. For pharmaceutical products, elemental impurities (7) are emphasized, which does not apply directly to excipients, but rather, to the final dosage form of which the excipient is a component. As of Jan. 1, 2018, heavy metals specifications were no longer required for excipients in the United States and European markets unless specific metals are included in the excipient’s monograph. Excipients have requirements for residual solvents (8); however, in the United States, no specific residual solvent requirement for food ingredients exists. This is not to say that there is no consideration for solvents in food ingredients. When appropriate, food safety risk due to potential residual solvent should be evaluated.
Regulatory agencies, such as FDA, sometimes inspect excipient and food ingredients facilities for cause; however, only food ingredient manufacturing facilities are required to register with FDA under the Bioterrorism Act of 2002 (9). Under the Food Safety Modernization Act (FSMA), food ingredient facilities are subject to additional FDA requirements intended to protect against intentional adulteration (10). FSMA requirements include implementing a food defense plan targeted at preventing intentional adulteration intended to do mass harm to the public and food fraud mitigation programs targeted at protecting against economically motivated adulteration. Although similar intentional adulteration concerns may exist for excipients, a written plan to address intentional excipient adulteration is not explicitly required.
Importers of food ingredients must confirm foreign suppliers comply with US food requirements per the Foreign Supplier Verification Program (FSVP) (11). FSVP requires food ingredient importers to verify that their suppliers have controls in place for meeting US food safety requirements, including implementing supplier verification activities to mitigate risks identified for each imported food. There is no corresponding regulatory requirement to verify GMP of foreign manufacturers of excipients. Pharmaceutical customers should evaluate the risks associated with imported excipients.
Because ingredients used in any of these markets could be derived from raw materials of natural origin, additional restrictions to prevent exploitation of endangered species (12,13) need to be considered. There are also more specialized requirements to address illegal logging (14) intended to protect vulnerable environments (15). In addition to controls on flora- and fauna-derived materials, conflict mineral concerns require supply chain control on some inorganic materials (16,17). These conventions and regulations are impacted by material origin and harvesting for excipients and food ingredients.
Consumers also may want food ingredients to have attributes that are not defined by safety or quality. Despite the lack of scientific evidence, “natural,” “organic,” and “genetically modified organism (GMO)-free” are all perceived as “healthier” and verification can add significant consumer-recognized value to food ingredients. Although there is no regulatory definition of “natural” for most food ingredients, flavors have a clear regulatory definition (18). The United States Department of Agriculture (USDA) regulates organic claims, labeling, and practices (19). Furthermore, USDA defines the requirements on labeling bioengineered foods: food containing bioengineered genetic material, which consumers commonly associate with GMO (20).
Consumer demands for natural, organic, and GMO (bioengineered food) are less likely for dietary supplements and currently are very limited for excipients. Although sustainable and fair-trade supply chain verification may be very important for foods, similar concerns for dietary supplements or pharmaceuticals are less likely.
Some consumers desire vegan or vegetarian ingredients, and certain regions such as India (21) require vegetarian labeling on food products. These same consumers typically do not hold pharmaceuticals to the same requirement.
Religious requirements for food are very clear to the extent that in some countries these requirements are written into law. Kosher and halal are the most common religious requirements, and recognized religious agencies provide detailed requirements on meeting these standards. Many religious scholars recognize kosher/halal alternatives are not available for all pharmaceuticals; however, the pharmaceutical’s benefits are medically necessary and may have no suitable alternatives. As such, although halal or kosher ingredients may be desirable for pharmaceutical excipients, acceptance by patients is not a strict requirement, particularly when there is no suitable halal or kosher alternative. There may be other religious dietary requirements, and the degree to which they ascribe those to dietary supplements or drug products may vary.
Although there may be considerable overlap in quality management systems and material specifications/requirements for substances sold for use as food ingredients, non-dietary ingredients, and excipients, many significant differences remain. No single quality management system or certification scheme satisfies ingredient requirements for the three markets. Therefore, manufacturers who supply into two or more of these markets need to understand and implement quality management system requirements to meet each of the markets they serve.
1. FDA, “Substances Generally Recognized as Safe,” Final Rule, Federal Register, 81 FR 54960, 54960-55055.
2. 21 CFR Part 117, Current Good Manufacturing Practice, Hazard Analysis, and Risk Based Preventative Controls for Human Food.
3. 21 CFR Part 111 (Government Printing Office, Washington, DC) 275–305.
4. IFAC, Quality Systems, Food Safety and Good Manufacturing Practices Guide for Food Additives and GRAS Substances, Revision 1 (2019).
5. IPEC, Significant Change Guide for Pharmaceutical Excipients, 2014.
6. FDA, “Use of Materials Derived from Cattle in Human Food and Cosmetics,” Rule, Federal Register, 81 FR 14718, 14718-14732.
7. ICH, Q3D, Guideline for Elemental Impurities, Step 4 version (December 2014).
8. ICH, Q3A, Impurities in New Drug Substances (R2), Step 4 version (October 2006).
9. 21 CFR Part 1, Subpart H, (Government Printing Office, Washington, DC) 5.
10. FDA, “Food Safety Modernization Act (FSMA),” www.fda.gov.
11. 21 CFR Part 1, Subpart L (Government Printing Office, Washington, DC) 6–7.
12. US Fish and Wildlife Service, “Endangered Species Act Overview”, www.fws.gov.
13. Convention on International Trade in Endangered Species, “How CITES Works,” cites.org.
14. US Fish and Wildlife Service, “Lacey Act,” www.fws.gov.
15. Roundtable on Sustainable Palm Oil, “RSPO Certification,” rspo.org.
16. US GPO, Dodd Frank Wall Street Reform and Consumer Protection Act of 2010, Section 1502, Conflict Minerals (July 10, 2010).
17. EU, Regulation (EU) 2017/821 of the European Parliament and of the Council of 17 May 2017 Laying Down Supply Chain Due Diligence Obligations for Union Importers of Tin, Tantalum and Tungsten, Their Ores, and Gold Originating from Conflict-Affected and High-Risk Areas (May 17, 2017).
18. 21 CFR Part 101 (Government Printing Office, Washington, DC) 10–199.
19. 7 CFR Part 205 (Government Printing Office, Washington, DC) 400–456.
20. 7 CFR Part 66, (Government Printing Office, Washington, DC) 200–210.
21. Food Safety and Standards Authority of India, “Draft Regulation on Labelling (Claims)” File Number 1-94/FSSAI/SP/(Labelling) 2009 (Dec. 27, 2012).
Luke Grocholl is regulatory affairs expert–pharma food materials, MilliporeSigma; Priscilla Zawislak is global regulatory affairs advocacy manager, DuPont; R. Christian Moreton is principal, FinnBrit Consulting; and Katherine L. Ulman is principal, KLU Consulting.
Vol. 44, No. 4
When referring to this article, please cite it as L. Grocholl, et. al, “Comparison of Pharmaceutical Excipients and Food Ingredient Requirements" Pharmaceutical Technology 44 (4) 2020.