Guest Column | March 22, 2024

Navigating Grades And Sources Of Materials In Drug Manufacturing

By Allison Radwick, RPh, Ph.D., senior regulatory and policy communications manager, U.S. Pharmacopeia

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From raw materials to finished dosage forms (FDF), understanding material quality is essential in drug manufacturing. However, with complex supply chains that extend worldwide, lack of global harmonization of standards, and practical challenges to ensure functional suitability, material specifications and sourcing are confusing to navigate for both procurement and quality control. This article examines how material grades and sources guide selection for optimal safety and functionality to strengthen supply chain integrity and fully harness quality standards to protect patients.

Understanding The Significance Of Material Grades And Sourcing Is Crucial

Raw materials like excipients are crucial for pharmaceutical formulations, influencing critical quality attributes and process parameters like stability and bioavailability. Though inactive, these ingredients constitute up to 90% of a drug's composition enabling precise drug delivery.1 Despite their importance, active ingredient quality often overshadows inactive ingredient quality within the complex pharmaceutical supply chain.

While regulations universally mandate drug quality, there is greater uncertainty around material selection. Shifting economic, regulatory, and demographic landscapes have enabled an environment enabling shortcuts and adulteration, requiring standards to guide decision-making. Controlling consistency and quality and minimizing risk necessitate even more diligence across material selection, with material grades and their sources providing crucial indicators.

Cost pressures have led some manufacturers to use inappropriate material suppliers such as chemical, industrial, technical, food, cosmetic, or feed grades where no mandated production monitoring or good manufacturing practices (GMP) exists. For example, the American Chemical Society sets impurity limits that are often less stringent than those required for pharmaceutical use.2 Without proper verification, full traceability, and GMP, material grades meeting only these standards may risk patient harm if used in drug manufacturing.

The U.S. Pharmacopeia (USP) classifies a material based on suitability as ingredients in FDFs versus manufacturing intermediates. Raw materials can be exclusively used in formulating active drug substances and do not appear in the FDF, whereas raw materials added during processing may remain in trace amounts. USP monographs provide the quality expectations for a material, including its identity, strength, purity, and performance.3 They also describe the tests to validate that the material meets these criteria. A unique functional category is assigned to a material, correlating with its specific function or utility in an approved formulation.4 USP general chapter <1059> Excipient Performance provides an overview of the key functional categories of materials and suggested test methods that can be used to help monitor and control critical material attributes.5

Pharmacopeial monograph standards may address multiple grades and types of materials. These are considered umbrella monographs that could differ by measurable properties such as particle size, density, and polymer molecular weights. Examples include polyethylene glycol (PEG) for multiple grades based on viscosity or sodium starch glycolate based on sodium types. In both cases, the umbrella monographs address a single excipient but require different labeling depending on the grade or type. USP has an excipient nomenclature guideline that provides examples of compendial grades and types.6

USP General Notices and Requirements 4.10 Applicability also addresses differences that occur in chemicals based on different grades: "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.”4 To assure substitutability in such instances, users may wish to ascertain functional equivalence or determine such characteristics before use.

Global Regulations Vary For Pharmaceutical Material Standards

While regulations for materials of drug products vary worldwide, most countries govern use through pharmacopeial standards. For U.S. drug approvals, USP General Notices and Recommendations 3.10 Applicability of Standards requires official substances to be manufactured according to appropriate current GMP and from ingredients complying with specifications designed to ensure that the resultant substances meet the requirements of the compendial monographs.4 The compendial grade for pharmaceutical use denotes meeting pharmacopeia monograph specifications and current GMP — the highest material benchmark.

In situations where multiple pharmacopeias are in place, a material meeting all pharmacopeia standards is designated as multi-compendial grade, simplifying international trade. However, when there is no specific standard or monograph, supply grade materials must still ensure traceability in the supply chain under quality protocols, though data is less comprehensive. If these materials pose higher risks, they may require closer scrutiny before acceptance.2

Supplier Qualification Mitigates Risk For Material Quality And Safety

With common excipients now at heightened risk for economically motivated adulteration, quality cannot be assured by certificates of analysis (COAs) alone. Even batches labeled as GMP-grade can exhibit variations between different sites and production runs, impacting performance. While maintaining compliance with pharmacopeial standards, these discrepancies may cast doubt on the authenticity of chain of custody documentation or appropriate GMP. Complexity across today’s material supply chain requires careful supplier qualification practices beyond routine testing or COAs. Protecting patient safety means direct responsibility for material verification lies with finished product manufacturers.

Recognizing the importance of excipient supplier qualification, the International Pharmaceutical Excipients Council of the Americas (IPEC-Americas) and USP have each developed guidance for drug manufacturers. IPEC developed a Qualification of Excipients for Use in Pharmaceuticals Guide & Checklist (Second Version, 2020).7 USP published general chapter <1083> Supplier Qualification in August of 2023 that complements current USP excipient GMP chapters detailing additional bulk pharmaceutical excipient manufacturing information (<1078> GMPs for Bulk Pharmaceutical Excipients, <1080> Bulk Pharmaceutical Excipients — Certificate of Analysis, <1197> Good Distribution Practices for Bulk Pharmaceutical Excipients and <1195> Significant Change Guide for Bulk Pharmaceutical Excipients).8-13

Both IPEC and USP share best practices for rigorously vetting and monitoring material, packaging, and contract service vendors. Core elements include auditing facilities, agreements delineating quality responsibilities, assessing supply chain risks, and robust change management procedures. This is especially important for high-risk materials like glycerin and propylene glycol where the U.S. FDA advised identity tests on samples from all containers of all lots for impurities like ethylene glycol and diethylene glycol, strengthening protection against lapses upstream.13

Ensuring Material Quality Is Vital For Safeguarding Patient Health

Market complexity means material quality can no longer be assumed — it must be validated. Through robust material selection protocols, GMP, traceability measures, testing programs, and supplier qualification processes, drug manufacturers can make informed material sourcing choices while safeguarding patient health. Through unified standards and cooperative efforts, we can advance the security and resilience of the supply chain.

This information was previously presented in a prerecorded prologue video prior to the 2023 AAPS PharmSci 360 event.

References

  1. Giannone J. Thinking Differently about Excipient Quality to Ensure Medicines Supply Chain Resilience. Quality Matters, U.S. Pharmacopeia, 6 June 2023. Accessed 11 March 2024.
  2. Wiggins JW and Albanese JA. A Case Study in Pharmacopeia Compliance: Excipients and Raw Materials. BioPharm International, 15 March 2020. Accessed 11 March 2024.
  3. U.S Pharmacopeia. An Overview of USP Monographs. Accessed 11 March 2024.
  4. U.S Pharmacopeia. USP General Notices and Requirements. Accessed 11 March 2024.
  5. U.S Pharmacopeia. <1059> Excipient Performance (PDF). Accessed 11 March 2024.
  6. U.S Pharmacopeia. Compendial Nomenclature. Accessed 11 March 2024.
  7. International Pharmaceutical Excipients Council Federation. Qualification of Excipients for Use in Pharmaceuticals: Guide & Checklist. Second Version 2020; https://www.ipec-europe.org/uploads/publications/20201026-eq-guide-revision-final-1615800052.pdf. Accessed 11 March 2024.
  8. U.S Pharmacopeia. <1083> Supplier Qualification (PDF). Accessed 11 March 2024.
  9. U.S Pharmacopeia. <1078> Good Manufacturing Practices for Bulk Pharmaceutical Excipients (PDF). Accessed 11 March 2024.
  10. U.S Pharmacopeia. <1080> Bulk Pharmaceutical Excipients—Certificate of Analysis (PDF). Accessed 11 March 2024.
  11. U.S Pharmacopeia. <1195> Significant Change for Bulk Pharmaceutical Excipients (PDF). Accessed 11 March 2024.
  12. U.S Pharmacopeia. <1197> Good Distribution Practices for Bulk Pharmaceutical Excipients (PDF). Accessed 11 March 2024.
  13. U.S. Food and Drug Administration. May 2023. Testing of Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol Solution, and Other High-Risk Drug Components for Diethylene Glycol and Ethylene Glycol. Accessed 11 March 2024.

About The Author:

Allison Radwick has more 20 years of experience in pharmacy and the pharmaceutical industry and currently serves as a senior regulatory and policy communications manager at the U.S. Pharmacopeia (USP). With a B.S. in pharmacy/minor in psychology from the Philadelphia College of Pharmacy and a Ph.D. in pharmaceutical sciences from the University of Connecticut, she has a unique blend of expertise in technical support, formulation, study oversight, and program management. Throughout her career, she has demonstrated a commitment to fostering education, collaboration, engagement, and support across the drug development lifecycle. In addition to her work at USP, Radwick is an active participant in several professional organizations, including the American Pharmacists Association (APhA), the American Association of Pharmaceutical Scientists (AAPS), the Regulatory Affairs Professionals Society (RAPS), and the Drug Information Association (DIA).