Understanding the Value of Excipient Grade

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Excipients commonly make up the largest proportion of many drug dosage forms, performing specific functions, such as modifying API release, enhancing drug stability, or masking the taste of the active ingredients, among others. However, despite the wide use of excipients within finished drug products, the importance of their grade and quality is not always clearly or fully comprehended, which can lead to potentially serious patient safety issues.

Defining an excipient

“FDA defines an excipient as a drug as it is part of the drug product, and for that, you need two things,” asserted Nigel Langley, global technical director, Gaylord Chemical Company and immediate past-chair of IPEC-Americas, in a panel discussion with Pharmaceutical Technology® (1). “You need to manufacture under good manufacturing practice (GMP) and also the material needs to comply with the relevant pharmacopeia and regulatory requirements.”

Pharmacopeial compliance for excipients depends upon the country where the drug product is being manufactured and distributed, for example, the United States Pharmacopeia (USP) is followed in the United States and the European Pharmacopoeia (Ph.Eur.) in Europe. For global products, multi-compendia are often required, Langley added. Local regulatory requirements that apply to the excipient must also be complied with, and this can create additional complexity.

Additionally, while excipients are traditionally used for pharmaceutical applications, some of the same chemicals can also be used in different applications, such as in personal care, in industrial applications, or as food ingredients, Langley explained. As a result of the broad applications of these chemicals, grades are employed to allow for differentiation. These grades can indicate different levels of purity, physical forms, or particle size distributions for the same material, Langley specified.

Traceability of supply

“A lot of people have historically tended to treat excipients like they are commodities,” added David Schoneker, president/owner, Black Diamond Regulatory Consulting, and Executive Committee member and QbD/Composition Committee chair, IPEC-Americas, in the panel discussion (1). Generally-speaking, companies search for a supplier that they believe has the correct grade of materials they need and then start using the materials without even discussing, or having the right conversation with the supplier, about the grade, Schoneker stated.

“Too many times, excipient [suppliers] never even find out what their customers are doing with their product until there’s an actual problem,” Schoneker continued. The supplier may have been able to avert the problem from ever happening had they been consulted beforehand because of the supplier’s knowledge of the material and ability to provide a recommendation for the right grade, he explained.

So, communication is an important first step, Schoneker specified, but how does a company make sure that their excipient supply chain is appropriate? “Well, that really does come down to properly qualifying each and every excipient supplier for your particular intended use,” he said. “The user of the excipient is ultimately the one responsible to make sure they are using the right grade from both a regulatory and technical perspective in their application.”

“[There have been a lot of incidents], like the cough syrup deaths, [that] really emphasize the importance of understanding [the] supply chain (2),” added Priscilla Zawislak, Global Regulatory Affairs Advocacy manager, IFF, vice-president of IPEC Federation, and vice chair, Science and Regulatory Policy, IPEC-Americas, in the panel discussion (1). “The fact is that sometimes companies do source [materials] and don’t really understand the full supply chain, and some of the recent incidents have actually involved excipients.”

Collaborative work undertaken by IPEC and the World Health Organization that looked at these incidents found that it is not always a case of a bad quality excipient being used, but that sometimes it is the incorrect grade of material or even counterfeit material being used, Zawislak confirmed. “And these are the kinds of things that you have to look at very carefully in your supply chain to make sure that you know exactly where [the excipient] was from the time it left the manufacturer till it got to your door,” she said.

“That’s where traceability comes in,” remarked Joseph Zeleznik, director, Technical Service, North America IMCD, and current chair, IPEC-Americas, in the panel discussion (1). “You need to be able to trace the entire supply chain back to the origin, so that if there was any adulteration, or if there was any repackaging of a material, an ingredient didn’t end up in a wrong container, whether it was intentional or inadvertent. If you don’t have traceability of your supply chain, you can run into risk of having issues later on.”

Therefore, a qualification process needs to be formalized and performed for every single excipient supplier that will be used, Schoneker asserted. Guides are available to help companies through these processes, he pointed out. At IPEC, a whole suite of guides are available to help companies properly qualify and control their supply chain, suppliers, and excipients. A key umbrella guide for companies would be IPEC’s guide and checklist, Qualification of Excipients for Use in Pharmaceuticals, which references a lot of other guides and how those guides can be used (3), Schoneker pointed out.

It is also important to note, Schoneker stressed, that it is not simply a one-to-one situation. There can be many distributors involved in the supply chain, and an understanding of each link in the chain is vital. There may have been someone in the distribution chain, for example, that has taken an industrial-grade material and up-tested it to meet USP requirements and sold it as pharmaceutical grade, Schoneker added. “Unfortunately, you can’t just up-test something to pharmaceutical grade,” he warned. “It doesn’t matter whether [the material] meets the specifications in the pharmacopeia; if it hasn’t been made under appropriate GMPs with appropriate controls, then that’s where you have problems.”

Testing-up?

First of all, the definition of excipient, as outlined earlier, should be remembered, stated Katherine Ulman, owner and primary for KLU Consulting, and member/consultant for IPEC-Americas, in the panel discussion (1). “So, what that means is that [the excipient] manufacturer has to follow appropriate GMPs when producing the excipient, and also, if there’s a compendial grade of the excipient, then it needs to meet the compendial requirements, which means that it needs to follow the test procedures and meet the specifications limits of the applicable monograph,” she confirmed.

“When you test-up a material, you’re testing it up from a different grade, such as industrial, food, or cosmetic grade, and you’re testing it to meet pharmacopeial specifications using their test methods,” Ulman continued. “But what’s missing is that you’re not following the excipient GMP practices required for the manufacture of that material. So, to test-up is to just perform the physical and chemical testing, not to ensure that the material is pure, safe, and has the quality that is required for the excipient grade of material.”

While it is absolutely not acceptable to test-up a material to move from one grade to another without fully understanding the GMPs used to manufacture the material, it is possible to test-up a pharmaceutical grade material to meet other pharmacopeial requirements, Schoneker added. For example, if a pharmaceutical-grade excipient has been bought that meets USP requirements but the product will also be used in Europe and the Ph.Eur. specifications are a little tighter, then it could be possible to do some additional testing or show compliance to the tighter limits to meet the other pharmacopeial requirements as the material has been manufactured under appropriate GMP conditions, he explained.

The pharmacopeial tests and monographs were designed with the assumption that the materials being tested had been manufactured under appropriate GMP conditions, asserted Schoneker. “So, you could have an industrial-grade [material] that has some other contaminant [in it] because of the manufacturing processes [used], which is something nobody ever dreamed to test for in a pharmaceutical-grade [excipient],” he said.

This is an important issue, Langley stressed, because if there are impurities in the material being used because it has not been manufactured under GMP conditions, then these may not be identified, which could lead to potential degradation of the active ingredients and ultimately toxicity to the patient. “So, why take that risk when you don’t need to? If you use the appropriate excipient grade, which is manufactured under GMP, then you know you have some guarantee that it’s going to work every time,” he specified.

“There actually isn’t a compendial monograph for every excipient. So, there actually are non-compendial excipients out there, [that have] been used very safely for many years,” said Zawislak. “In the absence of having a monograph, though, you still have to demonstrate the safety of [the excipient] being used in a pharmaceutical (its quality), as it also has to be suitable for its intended use.”

Additionally, a company may encounter a scenario where a compendial monograph does exist but there is no commercially available pharmaceutical grade of that material to purchase that is certified by the supplier to meet the requirements of the compendia, Zawislak continued. In these instances, companies would need to do a risk assessment for the intended use of the excipient, which goes beyond the testing-up and GMP assessment as mentioned earlier, she added.

Functionality-related characteristics

“Functionality-related characteristics (FRCS) are not universal,” stressed Zeleznik. “There is no requirement in, say USP, for FRCS, but there are some general chapters that can help. Whereas, in Europe, there are actually non-mandatory tests for FRCS for some ingredients [listed in the Ph.Eur. monographs].”

Commonly, the physical and chemical form of the ingredient is what drives the functional performance; however, while the chemistries may be the same and the compendial standards may be met, one grade of an ingredient may be appropriate for a formulation and another may not, Zeleznik explained. “What may be appropriate for a liquid formulation or topical may not be appropriate for an oral, solid dosage form,” he added. “So, FRCS may be important in order to establish [whether] you have the right material for the right application, and that’s going to depend solely on the context of use.”

The characteristics of an excipient, as reported on a certificate of analysis, really are just the tip of the iceberg, Zeleznik remarked. “You need to do a deep dive sometimes to understand what are the functional characteristics and how are they going to impact my formulation and, more importantly, drug delivery,” he said. “If you don’t choose the right excipient grade for that application, it may fail.”

Where does responsibility lie?

“Ultimately, the [drug developer] is totally responsible for the use of the appropriate grade for their intended use,” remarked Schoneker. “So, from a legal perspective, and this is how regulators tend to look at it, [the drug developer] made the decision to put [a specific] grade of material into a drug product that now patients are going to be exposed to […] that is the overriding responsibility.”

For excipient manufacturers, their responsibility is making sure they have correctly graded and promoted the material for the appropriate applications, Schoneker explained. “If the manufacturer says, ‘I made this as a food grade’, that’s all they need to demonstrate,” he confirmed.

There are, of course, many instances where scenarios are not that simple, Schoneker continued. For example, a company may be selling a compendial grade of an excipient, but the supplier’s intended market for the material is for oral drug applications; however, a customer purchases the excipient and, without the supplier’s knowledge, uses the material for a parenteral product that needs to be sterile. Now, Schoneker asserted, in such a case the liability would be attributed to the user of the material rather than the manufacturer.

Another potentially controversial topic is that of atypical actives, which is where a material has been designed and manufactured as an excipient but has been used as an active by pharmaceutical companies. “It’s always important to recognize that the maker’s intended use is really what the overall basis is [for the material]. If I don’t intend to make an API and somebody’s using it as one, then that’s their responsibility,” Zawislak confirmed.

“Collaboration is critical,” emphasized Langley. If a drug company sees the value in an excipient supplier being part of the drug development process, many issues with regards to inappropriate materials being used will go away. This need for greater collaboration is also true for academics, who tend to buy materials from catalogues and don’t necessarily think about the grade of the materials being used in development studies, he said.

“So, the communication not only rides between the excipient supplier and the pharmaceutical company, but there should be a stronger understanding between academia and where they’re sourcing excipients from in the first place, because the outcome of their research could be a lot better,” Langley summarized.

References

1. Thomas, F. Drug Digest: Making the Grade: The Importance of Using the Correct Excipient Grade in Drug Products. Pharmaceutical Technology, Jan. 31, 2024.
2. IPEC Federation. Latest Fatal Incidents with Contaminated Medicinal Syrup during 2022/2023, an Updated IPEC Federations Position Paper. August 2023.
3. IPEC Federation. Qualification of Excipients for Use in Pharmaceuticals. Guide and Checklist, Second Version, 2020.

About the author

Felicity Thomas is associate editorial director for Pharmaceutical Technology®.

Article details

Pharmaceutical Technology®
Vol. 48, No. 9
September 2024
Pages: 12–14

Citation

When referring to this article, please cite it as Thomas, F. Understanding the Value of Excipient Grade. Pharmaceutical Technology 2024 48 (9) 12–14.