Regulatory insight
FDA has recognized the additional risk for excipients used in drug products. 21 CFR 314.94(a)(9) includes a requirement that new drug applications (NDAs) show that inactive ingredients (i.e., excipients) are
safe. In addition, drug manufacturers must provide information in the NDA demonstrating that the inactive ingredients do not
affect the safety or efficacy of the drug product. Over-the-counter drug-product manufacturers as defined in 21 CFR 330.1(e) must demonstrate that suitable inactive ingredients are safe and do not interfere with the effectiveness or quality
of the drug product.
Food GMPs and HACCP do not address all the potential risks excipients pose in drug-product formulations. The use of excipients
may cause failed quality release testing of a finished drug product, but may not necessarily pose a safety risk when used
in a food product. In addition, a patient can suffer harm if the excipient has an adverse effect on the drug's quality after
it is released onto the market. For instance, an excipient can have a slow interaction with the drug's active pharmaceutical
ingredient (API), reduce the product's shelf life, or alter the API release during the digestive process.
ICH Q9 defines risk as "a combination of the probability of occurrence of harm and the severity of that harm," and defines
harm as "damage to health, including the damage that can occur from the loss of product quality or availability" (1). Excipients
have the potential to harm patients in two ways:
• Introduction of a hazard (i.e., common to many uses)
–Microbiological (pathogen)
–Chemical (toxicity, physiological effect)
–Physical (choking, irritation)
• Adversely affecting drug product availability or performance (unique to excipients)
–Finished drug product manufacturing failure (e.g., friability of tablets, dissolution, blending)
–Stability of finished drug product
–Dosage of API (e.g., bioavailability, potency, changes in modified release).
Figure 1: Dividing the process diagram into the realization, transfer, and use of the excipient product yields three categories
useful for excipient risk assessment.
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The risk-assessment model recommended in ICH Q9 identifies three steps: risk identification (define the potential harm), risk
analysis (probability and severity of the potential harm), and risk evaluation (combine the two together). The output enables
relative ranking by criteria used in decisions to accept or mitigate the risk. Excipient risk assessments for harm resulting
from microbiological, chemical, or physical hazards parallel those for food ingredients and additives. These hazards typically
result from failures during excipient manufacture and distribution. There is potential for harm to the patient in all formulations,
but the risk may be heightened by the route of administration of the drug product. The potential for an excipient to adversely
affect the drug product's availability or performance depends on the formulation and is a function of both the characteristic
of the API and the role of the excipient in the formulation. There is no comparable risk in the food realm.
Figure 1 defines the steps to consider in performing a risk assessment for an excipient used in a drug product. At each step,
the processes and characteristics specific to both the excipient and practices of the makers or users influence the risk-assessment
outcome. For example:
- Excipients sourced from animal products have an inherent risk not found in synthetic excipients and vice versa
- Manufacturing processing, types of catalyst, or equipment may result in varied risk
- Certain excipients are at risk for microbial contamination while others by their chemical nature or process are not subject
to such contamination
- Some excipients have a complex composition that is crucial to their performance
- Some excipients are susceptible to degradation or modification during storage and handling while others remain stable
- Certain excipients are crucial to the efficacy of the drug product
- Excipients used in dosage forms that bypass the body's natural defense systems have increased potential to cause harm.
Adequately identifying and analyzing risk across the steps in this process diagram require a depth of understanding and breadth
of knowledge beyond that of a single stakeholder (i.e., excipient maker or user alone).
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