By Gus Bassani, PharmD, PCCA Chief Scientific Officer

One of the most important, if not the most important, aspects of making a compounded preparation is the quality of the raw materials used to make it. The quality and functional attributes of pharmaceutical chemicals can vary greatly, but these variances may not always be fully appreciated.

Pharmacists have been taught to view AB-rated generic finished products as bioequivalent to the brand-name products, and thus substitutable in most cases. This perspective has also carried over into the world of raw materials in pharmacy compounding, which has led many pharmacists to the conclusion that pharmaceutical ingredients of the same grade, but which are made by different manufacturers, can be substituted without any risk of safety, performance or functional issues. Some would say, “A chemical is a chemical is a chemical,” or, “If it is labeled with the ‘USP’ or ‘NF’ designation, it is interchangeable, right?” Well, maybe or maybe not.

What the FDA Says about Raw Material Substitutions

Recently, the FDA issued a statement urging compounders to “Know Your Bulks Supplier ,” reinforcing the importance of bulk raw material quality and due diligence when it comes to the supply chain. I think we can all understand that purchasing a chemical from an obscure entity that has come onto the scene overnight, or that does not test the products they make or repackage, carries some risk. That is obvious. But the agency is also worried about the not-so-obvious aspects of raw materials that don’t appear on a certificate of analysis, such as undesirable impurities.

The message is simple: Purchase your ingredients from reputable repackagers and manufacturers of active ingredients that are registered with the FDA and that thoroughly test the products they handle. Doing so will mitigate a lot of risk. How an active pharmaceutical ingredient (API) or excipient is made, the facilities where it is made and the conditions under which it is made all affect the quality and function of the ingredient in the formulations that your patients ultimately need. Trusting a repackager simply because they are well known and registered with the FDA is not enough, either. It is crucial to really know suppliers and their quality processes to ensure that they provide high-quality ingredients.

This is an important message, but what about the question of substitutability? If we look at conventionally manufactured and approved drugs, we know that finished generic drugs are approved by the FDA and determined to be bioequivalent to the branded drug product (AB rated). The raw materials used in those products, and their manufacturers, are all included in the abbreviated new drug application (ANDA) that was reviewed and approved by the agency. Pharmaceutical manufacturers cannot substitute ingredients used in the manufacturing of these products without extensive vendor audits, testing and regulatory filings. Why? The chemistry, manufacturing and controls section of a new drug application is quite extensive and delves into every detail associated with how and where the ingredients are made. So any deviation may impact the quality and performance of the finished product.

What USP Says about Raw Material Substitutions

In the pharmacy compounding world, an easy place to look for a quick answer to the question of substitutability is theUnited States Pharmacopeia (USP) and the National Formulary (NF). In the General Notices, Section 4.1, it states, “Because monographs may not provide standards for all relevant characteristics, some official substances may conform to the USP or NF standard but differ with regard to nonstandardized properties that are relevant to their use in specific preparations. To assure substitutability in such instances, users may wish to ascertain functional equivalence or determine such characteristics before use.”¹ In other words, USP specifications may not cover every important aspect of a raw material. Examples of characteristics that play an important role in functionality but are not typically included in monograph standards, and which may be specific to a manufacturer, are solubility and particle size — just to call out a couple of “biggies.” The passage above is especially important, too, because the General Notices in USP form the foundation for basic assumptions and definitions applied in the more detailed chapters and monographs. Having a standard such as USP/NF, is vitally important for quality and safety, but there are other specifications beyond the monograph that determine how chemicals perform in formulations for patients.

In the opening paragraph of USP General Chapter <1059>, Excipient Performance, it states, “Excipients used in drug products typically are manufactured and supplied in compliance with compendial standards. However, the effects of excipient properties on the critical quality attributes (CQAs) of a drug product are unique for each formulation and process and may depend on properties of excipients that are not evaluated in USP or NF monographs.”² Again, this describes a high degree of functional specificity that may be associated with a unique chemical or manufacturer, and why one cannot substitute ingredients in a formulation in a cavalier fashion. The bioequivalence line of thinking does not necessarily translate to raw material selections, as USP indicates in the previous quotes.

What PCCA Does to Mitigate Risk for Compounders

Many of our PCCA formulas have a “Blue Box Warning” on them, which states that the PCCA products specified in the formula must be used in order for the beyond-use date (BUD) to apply. There are scientifically valid reasons why this statement is placed on the formulas, as evidenced by the information above. In chemistry and in pharmaceutics, the “little things” matter a lot, and they can be the difference between stable and unstable, or between safe or unsafe. At PCCA, we know how we source, process, handle, test, store and assess the substances in the preparations, and we know how they perform. These attributes cannot be blindly transferred to ingredients from other sources without appropriate testing.

Additionally, where the drug substance or excipient comes from, where it is made and under what conditions is critical. If a USP-grade drug substance is not prepared in a clean environment that complies with current good manufacturing practices (CGMPs) by an FDA-registered manufacturer that has been recently inspected, it can possess undesirable impurities or attributes that negatively affect the quality of a finished compounded medication.

Why It Matters

Functional equivalence of raw materials depends on many factors, as discussed above. In large industries, raw materials are not substituted on a whim, and pharmacists should exercise caution when selecting a supplier and when seeking to substitute ingredients in a formulation. Various types of finished-preparation testing may be warranted, depending on the formula, to qualify a raw material.

At PCCA, we have a standard that we call The PCCA Standard ^™, which is our commitment to the highest level of due diligence in the industry to mitigate risk. We are dedicated to importing, distributing and manufacturing quality products that make a difference in patient’s lives. The steps we take matter because patient lives depend on a job well done. They matter because they help ensure that compounders can produce products that are consistently high quality, are reproducible and perform as expected.

You can also hear Gus Bassani discuss “ Understanding the Importance of Your Bulk Substance Provider ” on PCCA’s podcast, The Mortar & Pestle.

Gus Bassani, PharmD, PCCA Chief Scientific Officer, has been with PCCA since September 2002. Prior to that, he was a formulation pharmacist in the product development lab of a veterinary pharmaceutical company. He has worked in multiple pharmacy practice settings in Alaska, Iowa and Kansas, and has taught extemporaneous compounding principles to pharmacy students in Drake University's Pharmaceutics Laboratory course. Gus earned his Doctor of Pharmacy degree from the Drake University College of Pharmacy and Health Sciences. He is a member of the 2015–2020 United States Pharmacopeia Council of Experts – Compounding Expert Committee, and served on the 2012–2014 Drake University College of Pharmacy and Health Sciences National Advisory Council. He is a member of the American Pharmacists Association (APhA), Alliance for Pharmacy Compounding (APC), and American Association of Pharmaceutical Scientists (AAPS).

References

1. United States Pharmacopeial Convention. (2019). General notices and requirements. In United States pharmacopeia and national formulary (USP 42nd ed. & NF 37th ed.). https://www.uspnf.com/

2. United States Pharmacopeial Convention. (2019). General chapter <1059> excipient performance. In United States pharmacopeia and national formulary (USP 42nd ed. & NF 37th ed.). https://www.uspnf.com/