Regulations and requirements
According to Catherine Sheehan, Senior Director at the US Pharmacopeia (USP) and Otilia Koo, Chair, USP Complex Excipients Expert Committee and Executive Director, BMS, ensuring the safety of excipients is extremely important. Excipients often make up the majority of a drug’s composition, Sheehan and Koo reveal, and perform a variety of functions such as maintaining pH and stability and making the drug palatable via tastemasking, coating, and coloring. Sheehan and Koo also point to the complex supply chain of excipients that lacks regulatory oversight.
“Unlike APIs, there are times when the quality of excipients is not given the necessary level of importance because excipients are inactive ingredients. Unfortunately, the impact of this can be devastating, for example, the recent deaths of reportedly 300 children in as many as seven countries due to diethylene glycol (DEG) and ethylene glycol (EG) contamination in cough syrups and oral analgesics for children,” say Sheehan and Koo.
Pharmaceutical Technology® spoke with Sheehan and Koo to find out more about the regulations involved in excipient quality. In addition, Sheehan and Koo will be discussing these topics at the 2023 AAPS PharmSci 360 event.
PharmTech: What are the USP requirements for excipients?
Sheehan (USP) and Koo (BMS): Pharmacopeias worldwide contain standards and test methods to test for several excipients required for determining their quality. The USP-NF [United States Pharmacopeia–National Formulary] General Notices 3.10. Applicability of Standards requires excipients recognized in USP–NF to be prepared according to recognized principles of GMP [good manufacturing practice] and from ingredients complying with specifications designed to ensure that the resultant substances meet the requirements of the compendial monographs. In addition, USP contains general information chapters on GMP requirements for bulk pharmaceutical excipients <1078>, Good distribution practices for bulk pharmaceutical excipients <1197>, and Significant change guide for bulk pharmaceutical excipients <1195>.
USP is a member of the Pharmacopeial Discussion Group (PDG) with representatives from the European Pharmacopoeia and the Japanese Pharmacopoeia (including the very recent addition of a pilot membership for the Indian Pharmacopeia as it prepares for global expansion), with WHO [World Health Organization] as an observer, to retrospectively harmonize standards for excipients monographs, general chapters, ICH [International Council for Harmonisation] Q4B chapters, and biotechnology chapters. The USP–NF has over 500 documentary standards for excipients, including high-risk for adulteration (e.g., EG/DEG) excipients such as Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, and Sorbitol Solution.
According to General Notices 3.10. Applicability of Standards, standards for excipients recognized in the USP–NF are expressed in the excipient’s monograph, applicable general chapters, and General Notices. The identity, quality, and purity of excipient standards are determined by the official tests, procedures and acceptance criteria, and other requirements incorporated in the monograph, in applicable general chapters, or in the General Notices.In addition, USP–NF excipient monograph standards have over 320 reference standards to support the test methods included in excipient monograph standards.
PharmTech: What are the requirements for complex excipients such as polysorbates?
Sheehan (USP) and Koo (BMS): USP-NF excipient standards contain standards that include test methods and acceptance criteria required for determining their quality. Excipients can be small molecules with a very well-defined chemical structure that can be characterized well analytically. Many are mixture-based products (e.g., fats and oils). Some may come in multiple grades that can be natural or synthetic or semisynthetic. Some are more complex, like polysorbates and some may vary in degree of characterization.
Polysorbates (PS) are considered complex excipients and are amongst the most versatile surfactants in pharmaceutical use used across almost all routes of administration and dosage forms. [These complex excipients] are also used as emulsifiers, solubilizers, and stabilizers. Some of the PS are well characterized in traditional routes of application in terms of their chemistry. However, they need additional characterization in some of the newer applications, such as when used in therapeutic biological drugs (e.g., in preventing protein aggregation and denaturation and stabilizing therapeutic proteins formulations).
One of the main challenges with complex excipients such as PS is identifying appropriate test methods for analyzing their complex composition and setting appropriate and meaningful specifications. The composition of such excipients can vary by inherent variations in the source of the raw materials used to manufacture the excipient and the manufacturing process. Further, their performance is highly dependent on their composition. Thus, these excipients should have standards for not only their identification, and levels on impurities, but also their composition.
One such example is the use of the fatty acid composition tests and specific tests on fats and fixed oil content in current USP-NF monographs of PS 20, 40, 60, 80. USP is also considering strengthening the quality control of PS by adding a direct assay testing procedure to determine the content of intact PS. Another example of a complex polymeric type of excipient is Lactide and Glycolide polymer for which a new monograph proposal was published in USP Pharmacopeial Forum and includes tests for monomer ratio and terminated group.
—Susan Haigney