The quality of excipients in medicines – which make up every part of a drug other than the active pharmaceutical ingredient (API) – is critical to a resilient medicines supply chain, panelists agreed at an April 25 session of the Asia-Pacific Economic Cooperation (APEC) forum’s Medical Product Supply Chain Dialogue, co-hosted by the U.S. FDA and USP in Rockville, Maryland. The session was titled "Mitigating and Managing Risks in Excipient Quality." By consensus, the panel emphasized the importance of implementing crucial measures, such as appropriate excipient testing, supplier qualification, and risk management through harmonized standards and regulations.
Despite being called “inactive” ingredients, excipients in medicines play a vital role in drug development, delivery, effectiveness, and stability. Comprising up to 90% of individual drug products, excipients function as binders, disintegrants, solubilizers, coatings, preservatives, colors, and flavorings. That means they can be essential not just for helping to deliver the API to the body, but for ensuring a medicine will work as intended to achieve its therapeutic effect.
Sourced from suppliers around the world, excipients are relied on by developers of finished medications everywhere. The complexities of the excipient supply chain, however, can present unique risks related to quality, regulatory oversight, and overall supply chain resiliency. Related issues include the need to evaluate and qualify current and new suppliers. In addition, as novel excipients and uses emerge, the relationship between quality, testing, performance, and compliance can become more complicated. An overview of potential risks and regulatory challenges for pharmaceutical excipients in the upstream supply chain is outlined in Figure 1 below.
Figure 1. An overview of potential risks and regulatory challenges in the complex upstream supply chain for pharmaceutical excipients.
The potential risks posed by excipients were thrust into the spotlight once again in recent months, following identification of substandard medicines in The Gambia, Indonesia and Uzbekistan impacted by confirmed or suspected contamination of excipients with diethylene glycol (DEG) and ethylene glycol (EG). The issue led to the deaths of numerous children who received the impacted cold syrups. While USP has developed a toolkit to help address potential DEG and EG contamination, it is clear that the possibility for such issues to arise requires stakeholders to think differently about excipients quality than they have in the past. Earlier this year, the World Health Organization (WHO) issued a global call to action to prevent, detect and respond to incidents of substandard and falsified medicines.
Risk-based approach
History has shown that high-risk excipients including glycerin, propylene glycol, and solutions of maltitol or sorbitol, can be contaminated with DEG and EG, leading to deadly incidents. Using a risk-based approach to quality, tools and resources can be allocated more efficiently, and high-risk excipients can be more rigorously evaluated to safeguard the quality of the final drug product. The risks associated with excipients also should be considered based on specific manufacturing operations and product formulations. Nevertheless, it is clear that monitoring, controlling, and testing the quality of all excipients in the medicines supply chain is necessary to protect patient safety.
As the complexity of excipients continues to evolve, the potential risks are multifactorial, so it is essential to identify, assess and control risk from different perspectives. In particular, “understanding the physiochemical properties of novel and complex excipients is important in determining their functional use, because excipient functionality is a critical quality attribute,” stressed panelist Yognandan Pandya, USP director, Industry Programs, Excipients and Special Projects.
Supplier qualification
Supplier qualification is also an essential part of the solution to ensuring excipient quality, said panelist Milind Ganjawala, director of FDA’s Division of Drug Quality 2, Office of Manufacturing and Product Quality, Office of Compliance, Center for Drug Evaluation and Research. He emphasized that “to understand the excipient supply chain, drug manufacturers should know their excipient suppliers and have knowledge of the source from which they procure the excipients.” Furthermore “supplier qualification should involve a comprehensive evaluation of the supplier’s quality management system, manufacturing process, and analytical testing methods,” Ganjawala said.
To help ensure suppliers meet the necessary standards for producing high-quality excipients, such evaluations should also include an assessment of the supplier's facilities, personnel, documentation, and quality control procedures. In addition, ongoing monitoring and auditing of the vendor's performance is essential to maintain the quality of excipients over time. Appropriate supplier qualification can help ensure that excipients used in drug products meet the necessary quality regulatory requirements; reduce the risk of substandard and falsified medicines, product recalls, and drug shortages; and help ensure safe drug products for patients.
To facilitate a risk-based approach to supplier qualification, USP developed General Chapter <1083> Supplier Qualification, which includes excipients and will be effective in August 2023. This critical resource provides a quality risk-based approach on how to select, assess, approve, and monitor suppliers of ingredients, including excipients, packaging materials, and other components and services.
Excipient testing
Drug manufacturers should not just presume that excipient certificates of analysis (COAs) provided by suppliers are authentic. Drug makers receiving the excipients need to ensure appropriate testing for impurities, including excipient identity and composition, and such testing should be conducted immediately upon receipt and each time before use in drug product manufacturing. Quality testing of excipients should include all specific identity testing for impurities such as DEG and EG, with testing of representative samples of each lot. Each final drug product lot should also be collected and tested to verify potency and dissolution to help ensure the excipients are functioning as designed.
Furthermore, accurate traceability on sourcing is needed. “Traceability is a particular challenge with excipients, adding to risks,” stated panelist Rutendo Kuwana, WHO team lead, Incidents and Substandard/Falsified Medical Products. In most alert cases reported by WHO, it turned out that the identified excipient manufacturer never supplied excipients to the particular finished-dosage form manufacturer found to have a contaminated drug product. “There are so many hands involved, and when you try to follow up on the hands at some point, the traceability stops in finding the source of contamination or falsification,“ Kuwana said.
Standards and harmonization
Limitations of existing quality standards including limited harmonization across borders continue to exist, adding to the challenges of ensuring excipient quality across a globalized supply chain, suggested panelist Hikoichiro Maegawa, director of Japan’s Division of Pharmacopoeia and Standards for Drugs, Office of Review Management, Pharmaceuticals and Medical Devices Agency. The USP Pharmacopeial Discussion Group (PDG) is working together with Europe, Japan, and India to harmonize general chapters and monographs for excipients. The U.S. Pharmacopeia–National Formulary (USP–NF) includes documentary standards for excipients that provide validated test procedures, acceptance criteria and other requirements to establish identity, purity, and quality. Meanwhile, USP physical Reference Standards for excipients have been tested and approved as suitable for use as comparison standards in USP–NF tests and assays.
Regulation and guidance
In addition to the key role for public quality standards in ensuring and strengthening excipient quality, the panel agreed on the need for a holistic, risk-based approach to improved regulation of excipients across borders. This should include:
- International cooperation among all stakeholders;
- Collaborative efforts between regulators and industry in particular to understand and define risks in the upstream excipient supply chain (which includes excipient suppliers, distributors, brokers, traders, and agents) as well as in the downstream supply chain (drug manufacturers);
- Testing for DEG and EG (FDA has issued related guidance, and USP offers related resources);
- Compliance, accountability and enforcement of regulations and guidelines (including for supplier qualification programs);
- Advanced technologies to track and monitor excipient quality throughout the supply chain;
- Post-marketing surveillance and rapid reporting; and
- Development of new analytical methods, if needed.
Taken together, such actions will go a long way toward effectively mitigating and managing risks in excipient quality for the benefit of patients and global health, the panel concluded.
