Risk Assessment for Excipients for Enhanced Patient Safety

The primary focus of risk assessment for the use of excipients in any drug product is patient safety. According to the International Conference on Harmonization (ICH) Q9 guideline on quality risk management, "Quality risk management is a process that supports science based and practical decisions when integrated into quality systems" (1).

Twenty years ago, excipient manufacturers, distributors, and users established the International Pharmaceutical Excipients Council of the Americas (IPEC–Americas) to apply the concept of science-based and practical decision-making to the evaluation, qualification, and control of excipients. Since its inception, IPEC has developed and promoted the implementation of appropriate and scientifically valid, voluntary industry guidance documents for the excipient industry.

IPEC's mission has been and continues to be to ensure that excipients meet the highest appropriate standards for quality, safety, and functionality throughout their manufacturing process and supply chain. The use of risk-management principles furthers this cause.

The need for risk assessment

In a recent article, J. Orloff aptly noted "the potential for quality risk-management to degenerate into a non-value added exercise of identifying noncritical, improbable, low-risk scenarios indefinitely" (2). Equally detrimental to effective application of risk-management principles is the blinding self-deception emerging from group-think or tunnel vision that reasons away all possibility of risk. Effective risk assessment should identify the proper balance of risk for which control is necessary to ensure the quality, safety, and functionality of excipients. Focusing too much on controls aimed at low-risk hazards only diverts resources and attention from high risk hazards, and can ultimately lead to an unsustainable control system and unrecognized noncompliance.

At the other extreme, failing to acknowledge vital risk can lead to unknowingly accepting failure. Orloff explained that "risk assessment and control fundamentally rely on hypothesis, judgment, and expert opinion." He clarified that this judgment call is "to be made by experts backed with an in-depth understanding of the underlying science and a common covenant to work on what is vital."

Manufacturers typically produce a material that is sold into diverse markets (e.g., excipients, food, cosmetics, and industrial) and their knowledge base tends to tilt toward their primary market. However, the risk assessment for excipients is unique because of their use in drug products. Risk assessment for use in food or chemical applications do not properly account for the risk unique to drug-product components.

Many industry manufacturers and users of excipients rely on good manufacturing practices (GMPs) coupled with hazard analysis critical control point (HACCP) plans for food-ingredient manufacturers or failure mode effect analysis (FMEA) for chemical manufacturers. These tools may provide adequate controls to ensure that food is safe for human consumption or that an ingredient quality is sufficient for household products. Implementing these tools for excipients used in drug products, however, may not be adequate to ensure patient safety.

Excipients share some similar hazards to food, but they also have a risk associated with their function in drug-product formulations and manufacturing. The act of a physician prescribing a medicine for a patient is the result of a risk assessment that concluded the benefit of taking this medication is greater than the consequence from lack of treatment. Under these conditions, a patient suffers harm when the drug product does not function as intended or is not available in the market. A patient may be harmed not only as a result of the excipient's composition, but also by potential variation in an excipient's characteristics. This variation can result in erratic performance in the drug-product formulation.

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).

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: Dividing the process diagram into the realization, transfer, and use of the excipient product yields three categories useful for excipient risk assessment.

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).

An excipient-product risk assessment is performed by the excipient manufacturer that has expertise and knowledge in excipient manufacture and inherent characteristics. For raw materials:

• Physical and chemical characteristics are typically unique to an excipient regardless of the manufacturing location

• Type, source, and history of supply for raw materials used in excipient manufacturing may be common to a given excipient

• Excipients can be made from different sources and/or materials sourced from different regions with associated risk.

Risk-assessment outcomes may differ for a specific excipient based upon manufacturer and location. The differences in outcomes increase exponentially when the variables associated with excipient manufacturing are considered (see Figure 2). The same excipient made by the same process methodology can have different risk-assessment outcomes depending on variables, such as:

• Type of equipment used

• Facility floor plan

• Physical location of the manufacturing plant

• Dedicated versus multiple use operations

• Conveying methodology

• Open versus closed systems

• Choice of processing aids

• Recycle and recovery in process

• Robustness of the engineering design

• Process cleaning operations

Effective implementation of excipient GMPs helps equalize these differences to an acceptable level of potential risk. However, a true and complete risk assessment for the realization of an excipient must be unique to a given manufacturing location.

Figure 2: Excipient risk-assessment categories.

Supply-chain concerns

Risk-assessment outcomes can also change over time due to changes in GMP expectations and to the manufacture of the excipient. For example, risk assessment for excipient storage and distribution can be generalized, but also depends on the particular circumstances. An excipient that is susceptible to degradation or modification during storage or transport, for example, has more potential for failure in than a stable excipient. Good distribution practices (GDP) require adequate control and monitoring of storage conditions for excipients susceptible to environmental conditions. While GDP conformance lowers risk during storage and distribution of an excipient, poor storage practices or distribution methods may heighten the risk associated with an excipient. For example:

• Using dedicated vessels or single-use containers versus allowing back hauls or reusable containers

• Short-direct distribution paths minimize the risk of tampering or contamination during transfer versus a longer route that may offer greater opportunity

• Trace contaminants introduced from packaging, storage, or transfer may react slowly over time with the excipient

• Changes in ownership, repackaging, and relabeling operations bring unique opportunities to adversely affect the quality or the reported characteristics and increases the risk of mislabeling.

These acts may result in the same excipient having different risk levels based on the differences in distribution. Excipient manufactures whose primary sales outlet for excipients is through distribution companies do not always have a sufficient view of the supply chain necessary to perform adequate risk assessments and likewise the excipient users may not have a clear view of the supply chain beyond their immediate supplier. This lack of clarity in the supply chain creates a knowledge gap that in and of itself increases risk in terms of potential adulteration or contamination. Product testing is an impractical remediation for unknown gaps in the supply chain because one often does not know what tests to perform. It's crucial to know and understand the excipient's full supply and distribution chain.

Formulation challenges

The risk assessment for excipients associated with their use in drug-product formulation and use can only be adequately performed by the drug-product manufacturers. Generalizations around the route of administration, the function of the excipient in the formulation, and the characteristics of the type of API can be useful in identifying potentially high-risk excipients. However, many excipients can have multiple functions, in multiple formulations, and are used with different types of APIs. Just because an excipient manufacturer can point to a drug-product formulation where their excipient presents a lower risk does not mean the excipient will be of lower risk in other formulations.

It's crucial that the excipient manufacturer clearly communicate its expectations for the route of administration for the final drug product using its excipient to avoid additional risks. In most cases, excipient manufacturers do not have adequate experience and knowledge of the use and function of their excipients in all user formulation and drug-product manufacturing processes. Certain assumptions are necessary for the excipient manufacturer to design appropriate controls into their processes, but these assumptions should be transparent and clearly open for the user's evaluation.

Conclusion

Excipient makers and users should each use risk-management principles to prevent failures in the final drug product. Risk assessment will not identify the extent of GMP required for a particular excipient but will serve to strengthen the processes. The engineering design, process control, and GMPs form the prerequisite controls necessary to reduce the infinite possibility for failures to a smaller and more manageable number from whence risk assessment can serve to focus our attention toward the few opportunities for failure in the absence of heightened control. Well-functioning GMPs have layers of checks and balances built into the procedures and processes to ensure that a single lapse at one point will likely not result in failure or necessitate a withdrawal of product.

Overall, risk assessment provides a tool to evaluate the status quo and find the opportunities to make the good better. Risk assessment brings an obligation for action to protect the patient because once a significant risk is identified, it cannot be ignored.

Regulatory bodies and excipient users may benefit from focusing their limited resources on higher-risk excipients as determined from a risk assessment based on available information. Assigning a higher risk to an excipient that in reality has a lower risk when sourced from a specific manufacturing facility due to advanced engineering and the unique processes utilized carries little consequence to the patient or drug manufacturer.

The opposite result of designating an excipient a lower risk when in actuality significant risk exists due to the particulars of its manufacturing process or facility introduces potential to harm the patient and drug maker. In the interest of patient safety, excipient risk characterizations must come from a proper and complete risk assessment, including consideration of the specific manufacturing locations and supply chains.

Pending IPEC guideline.IPEC–Americas is developing a guideline for excipient risk management in conjunction with the global IPEC Federation. This guide will explore risk management from both the makers' and users' perspective. The guide will outline the process, structure, and documentation necessary to demonstrate the effective application of risk management principles. The current ANSI NSF 363 stand-alone excipient GMP draft standard, and EXCIPACT ISO 9001 Annex Certification Standard for Excipient GMP, require documented risk assessments at several points to justify the application of certain GMP controls (3, 4). These standards are scheduled to become publically available in 2011 and the IPEC Excipient Risk Management guideline will be a helpful reference for companies seeking GMP certification to either of these proposed standards.

Acknowledgments

W. Busch, DowWolff Cellulosics; L. Calhoun, King Pharmaceutical/Pfizer; G. Collins Jr., RT Vanderbilt; D. Fillar, Perrigo; F. Flynn, RT Vanderbilt; J. Garofalo, Avantor Performance Materials; R. Green, CP Kelco; S. Hernadez, Ashland Aqualon; L, Herzog, Asahi Kasei; D. Klug, sanofi-aventis; F. Murphy, Dow Chemical; B. McCarter, EMD Chemicals; P. Merrell, Jost Chemical; L. Milano, Genentech; RC Moreton, FinnBrit Consulting; C. Perini, ISP; D. Schoneker, Colorcon; I. Silverstien, IBS Consulting in Quality; R. Sulouff III, Ashland Aqualon; A. Van Meter, Dow Chemical; P. Zawislak, Ashland Aqualon.

W. Dale Carter is chair of the International Pharmaceutical Excipients Council of the Americas (IPEC–Americas) and director of global quality-silica with Huber Engineered Materials in Atlanta, GA, tel. 678.247.2735.

References

1. ICH, Q9 Quality Risk Management (Geneva, November 2005).

2. J. Orloff, Pharm. Technol. 35 (2) 38–40 (2011).

3. ANSI NSF 363 (September 2009).

4. EXCIPACT ISO 9001 (in development). EXCIPACT is a consortium of industry bodies including IPEC-Americas, IPEC–Europe, PQG, EFCG, and FECC.