Excipients are the ingredients of a therapeutic that change an API into a medicine and perform roles such as preservatives, diluents, buffers, binders, and drug release controllers. These excipients work in combination with the API to ensure the benefit of the drug product, according to the International Pharmaceutical Excipient Council of the Americas (IPEC-Americas). The high levels of excipients in drugs, compared to the API, mean the quality of these substances are just as important as the active ingredient. “Such excipient performance expectations as enhancing drug bioavailability, enhancing drug stability, providing controlled and sustained-release characteristics, enabling dosage form processability are but a few of the crucial roles excipients provide to ensure the drug performs as intended over its shelf life,” says IPEC-Americas.
“Excipients used in drug products may be compendial (i.e., there is a monograph for the excipient in a recognized pharmacopeia) or non-compendial.For blended excipient mixtures and co-processed excipients, unless there is a monograph for that exact blend or co-processed mixture, they are classed as non-compendial, even if all the components individually have pharmacopeial monographs,” says IPEC-Americas.
Low-quality excipients may be unsafe and present risks to the patient, including exposure to toxic substances such as benzene and diethylene glycol.“Any low-quality ingredient or adulteration that could compromise drug product quality, safety, or performance could lead to undesirable consequences, such as adverse events, lack of efficacy of the drug, hospitalizations, or at worst, death,” stresses IPEC-Americas.
According to Subba Reddy Inta, vice president and head-Quality, Dr. Reddy’s Laboratories, North America Generics, excipients may interact with the API and, therefore, lower the titer or assay. Impurities may also be generated, or the absorption, distribution, metabolism, and excretion (ADME) may be altered.
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
“In comparison to APIs, the repercussions of low-quality excipients can be equally significant. While APIs are the active components responsible for the therapeutic effect of a drug, excipients act as essential delivery vehicles and support structures. Substandard excipients can adversely affect the API’s stability, safety, and performance, rendering even a high-quality active ingredient less effective or potentially harmful,” caution Aryo Nikopour, VP, Global Market-Pharmaceuticals, and Shiri Hechter, senior manager, Scientific and Technical Services, both with Nelson Labs. Nikopour and Hechter also point to the business risks of poor-quality excipients, such as recall of products, legations, and damage to the company or brand reputation. But IPEC-Americas states the finished drug may be impacted regardless of the API.
Steps for ensuring quality
Excipients are usually sourced by either the sponsor company or the contract manufacturing organization (CMO) from ingredient manufacturers and then used in the final product. The sponsor company and the CMO are responsible for ensuring the quality of the final pharmaceutical product. So, how may a sponsor company and/or a CMO ensure that the excipients purchased from third-party vendors are safe and best suited for the dosage form they are creating?
According to Catherine Sheehan, senior director at the US Pharmacopeia (USP) and Otilia Koo Chair, USP Complex Excipients Expert Committee and Executive Director, BMS, excipients should be sourced from qualified suppliers and sponsors should also evaluate those suppliers. Additionally, sponsors should check that the supplier has a testing program in place. Sponsors should also know who the original manufacturer of the ingredient is if it is not the supplier and an original manufacturer’s certificate of analysis should be obtained. Furthermore, each shipment of incoming raw materials should be tested for applicable standards and regulations.
According to IPEC-Americas, it is important to make sure the manufacturer of the excipient is producing the excipient under good manufacturing practices (GMPs) appropriate for excipients with the intent of that ingredient being used in pharmaceuticals. “Finally, for excipients not purchased directly from the manufacturer or a manufacturer authorized distributor, it is important for sponsors to understand the full supply chain back to the manufacturer,” says IPEC-Americas.
A comprehensive risk assessment that begins with a questionnaire is also imperative. “Ingredient samples are requested and received for assessment against specification acceptance criteria. Excipient manufacturers whose products are used for the first time should be audited either directly or by an accredited third party acquainted with pharmaceutical and excipient manufacturing requirements such [as] the appropriate level of GMP,” according to IPEC-Americas. Assessment of the manufacturer’s standard operating procedures (SOPs), batch records, and other procedures and documents should also be performed.
Quality management program
In addition to GMPs, according to IPEC-Americas, “Compendial excipients conform to the appropriate monograph using the compendial methods or validated equivalents. Non-compendial excipients should
be adequately characterized and properly vetted through a risk assessment to ensure the excipient meets specified quality requirements,” says IPEC-Americas.
Key elements of a quality management program, according to Nikopour and Hechter, include supplier qualification and auditing, quality agreements with suppliers, risk assessments, testing of raw materials, and change control management. In addition, stability testing, documentation, and quality matrices should be performed. “By implementing a robust quality management program encompassing the above elements, pharmaceutical manufacturers can ensure that the excipients used in their products are of high quality and safe for patients,” say Nikopour and Hechter.
Testing excipient quality
Received excipient materials should go through testing and analysis, says Nikopour and Hechter. Samples should be tested regularly to determine that they meet quality specifications.The US Pharmacopeia–National Formulary (USP–NF) provides methods for testing compendial excipients.
To test non-compendial excipients, IPEC-Americas says that suppliers should develop validation methods that show that the quality and composition of their products are consistent from batch to batch. Inta points out that additional test methods may be needed based on the functional requirements of the sponsor. “Sometimes the supplier develops the different grades of a material to meet the formulation development requirement,” he says.
Manufacturers can use many of the analytical techniques used in chemical analysis for testing excipients, according to IPEC-Americas. These include infrared spectroscopic techniques (FTIR, NIR), atomic absorption (AA), inductively coupled plasma (ICP), mass spectrometry, X-ray crystallography, pH, conductance, Karl Fischer water determination, as well as the many compendial test methods (LOD, ROI, etc.). “In addition to chemical analysis, functional performance can be assessed by a variety of methods; however, functionally related characteristics (FRCs) can pose some challenges if not considering context of use.Not all FRCs will be applicable to all materials or cases,” says IPEC-Americas.
“When a compendial monograph does not exist, excipient users should determine if other regulations, compendia, or guidelines can be used to characterize suitable quality,” say Nikopour and Hechter.
According to IPEC-Americas, no formal regulatory process exists for evaluation a novel excipient outside of the drug product. However, for novel excipients that have yet to be used in a drug formulation, Nikopour and Hechter suggest following IPEC recommendations for safety evaluation of a novel excipient (1). FDA also provides guidance on safety testing for novel excipients (2).
Conclusion
According to IPEC-Americas, “often, sponsors don’t do all they should to qualify an excipient. However, because they don’t, that means they may accept low quality materials without knowing it ... low quality excipients may be the wrong grade of product (not intended for use in pharma), adulterated, the result of supply chain failures or from manufacturers who intentionally do not follow GMPs or regulations.”
Low-quality excipients present as much of a risk to patients as low-quality APIs, especially because they may impact the efficacy of the API. They are the support system and play a significant role in ensuring drugs are safe and work as intended. It is imperative that both sponsor companies and ingredient manufacturers have the appropriate management plan in place to perform the vital risk assessments, testing, and
verification of excipients.
References
- IPEC. The International Pharmaceutical Council Excipient Safety Guide for Pharmaceutical Excipients (IPEC, 2021).
- FDA. Guidance for Industry, Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients (2005).
About the author
Susan Haigney is managing editor of Pharmaceutical Technology®.
Article details
Pharmaceutical Technology
Vol. 47, No. 9
September 2023
Pages: 12–16
Citation
When referring to this article, please cite it as Haigney, S. In Equal Measures: The Importance of Excipient Quality. Pharmaceutical Technology 2023 47 (9).
