Total Excipient Control: A Pathway to Increased Patient Safety

Excipients are used in almost all approved drug products in some way and are essential to the performance of the product. Most excipients used in pharmaceutical products are manufactured to comply with pharmacopeial standards and are used in multiple products. Excipients vary from active pharmaceutical ingredients (APIs) because they are used in many drug products and have different functional characteristics depending on the particular formulation.

Current IPEC guidelines and excipient controls

The International Pharmaceutical Excipients Council of the Americas (IPEC-Americas) is an organization representing makers, distributors, and users of pharmaceutical excipients. IPEC–Americas is a member of the recently established IPEC Federation. The federation was formed in 2010 to coordinate IPEC's global activities in the areas of compendial harmonization, excipient guideline/standard development, and coordination of excipient supply-chain security initiatives with regulatory agencies throughout the world. The federation's current membership is made up of IPEC–Americas, IPEC–Europe, IPEC–Japan, and IPEC China.

IPEC–Americas has also formed two partnerships in Latin America to allow that region's growing pharmaceutical and excipient industry to participate in IPEC activities. The partnerships also allow the Latin American pharma and excipient industry to use IPEC guidelines to improve drug quality and protect patients.

IPEC has developed guidelines, programs, and proposals on various aspects of excipient control during the past 20 years. Each guideline fills a specific need related to an area of excipient control (see Table I). These guidelines and whitepapers have been used by many companies and regulators to establish appropriate standards for excipient control throughout the world.

Table I: IPEC Excipient guidelines and whitepapers available on ipecamericas.org.

IPEC's efforts to assist the Pharamcopeial Discussion Group (PDG) with monograph harmonization has also helped to establish scientifically justified test methods and specifications for pharmacopeial excipients that can be used globally. Many IPEC proposals have resulted in providing the key excipient information and expertise needed to modernize and harmonize existing monographs in the United States Pharmacopeia–National Formulary (USP–NF), European Pharmacopeia (PhEur), and the Japanese Pharmacopeia (JP) to meet today's standards of quality.

IPEC developed an Excipient Safety Guideline (FDA participated on the committee as an advisor) that was published in 1996 in Regulatory Toxicology and Pharmacology (1) to provide guidance on how the safety of new excipients should be evaluated. FDA then published its own guidance document in 2005 titled, Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients, which was based on much of the work done to develop the IPEC guideline and is now the standard for how FDA assesses the safety of new excipients when used in a dosage form (2).

IPEC also recently collaborated with FDA to implement a New Excipient Safety Evaluation Procedure. The procedure provides a mechanism for independently assessing a new excipient for safety and to establish an initial precedence of use (3).

IPEA third-party auditing and certification

Recognizing the importance of supplier qualification and auditing to improve supply-chain security, IPEC established the International Pharmaceutical Excipients Auditing (IPEA) in 2001 to perform qualified third-party audits of excipient manufacturers for which the audit reports can be shared with user companies throughout industry. In 2010, IPEA went through an intensive ANSI qualification program that resulted in IPEA becoming the first independent, ANSI-accredited organization that can perform qualified third-party audits and certifications of excipient manufacturers and distributors.

The formation of IPEA and its recent ANSI accreditation represent a major step forward in providing the industry with an alternative for obtaining GMP audit information from suppliers. Some excipient users find that suppliers are not willing to let them perform an audit if they purchase a small amount of the excipient. In other situations, the supplier may not be willing or have the capabilities to host an audit for every customer. That same supplier may, however, be willing to host an IPEA audit or become certified by IPEA as a means of providing qualified GMP audit information to multiple customers at a reduced cost.

Utilizing the full excipient control toolkit

In recent years, IPEC worked to pull together its various guidelines to create an Excipient Qualification guideline. The 2008 guideline provides overall guidance on how to use a number of related IPEC guidelines to build a credible excipient qualification program from both the maker's and the user's perspective.

As IPEC moves into its third decade, the council is taking this concept further to develop a system of Total Excipient Control (TEC). The system will use all existing IPEC guidelines, programs, and proposals to build an overall control system from the time an excipient manufacturer thinks of marketing a chemical as an excipient to the pharmaceutical manufacturing industry's use of that excipient to the time the patient takes the drug product containing the excipient.

The TEC system involves three areas of control: excipient design, excipient safety, and excipient manufacturing process control and distribution (see Figure 1). Excipient design controls address setting design criteria in a way that meets the perfromance requirements for the intended use. The controls also take into account quality-by-design (QbD) principles.

Figure 1: Total Excipient Control (TEC) involves control in three main areas to maximize patient safety. QA is quality assurance.

Ensuring excipient safety involves using information that has been developed to support the safe use of the excipient in the intended application at the levels of use expected to be experienced by the patient. Excipient manufacturing process control and distribution is the area of control traditionally covered by GMPs, auditing, quality-control testing, information-sharing, and supply-chain security.

As part of developing the TEC process, IPEC has identified some areas that are not fully covered by current IPEC guidelines and programs. The following sections of this article provide some details related to IPEC's plans in this regard.

Validation versus process capability. Validation is one of the most commonly misunderstood issues that comes up during pharmaceutical company audits of their supplier's excipient manufacturing facilities. Pharmaceutical company auditors often ask excipient manufacturers for their validation data on the manufacturing or cleaning process and do not always get the information they are looking for because excipient manufacturers do not always have formal validation studies compiled in the manner typical of the pharmaceutical industry. In many cases, the problem is tied to the terminology rather than an actual issue of control.

Excipient manufacturers typically have a huge amount of process-capability data that is essentially the same type of data that a pharmaceutical company would call "validation data," but it is often stored in sophisticated large-scale computerized process-control systems in a different format from that usually used by the pharmaceutical industry. Sometimes, due to terminology differences during the audit, the excipient company doesn't realize that this information is what the pharmaceutical auditor needs. Process-capability data can, however, provide appropriate excipient control and, in many cases, can provide information far beyond what is typically obtained in pharmaceutical validation studies.

To address this common misunderstanding, IPEC is drafting an Excipient Validation Guide which will clarify how validation studies should be handled for excipients. This guide will help excipient manufacturers convert their process capability data into useable information that will provide pharmaceutical users with a better understanding of how the excipient processes are controlled. Ideally, this guideline will lead to fewer unnecessary observations during audits of excipient manufacturing operations and help excipient manufacturers better understand what type of validation or process-capability information they should have in place.

Excipient composition: additives and processing aides.As noted above, IPEC published an Excipient Composition Guide that provides details about the types of components which are typically part of an excipient's composition and how to go about developing an appropriate excipient composition profile. However, there is still much confusion in the industry and regulatory community related to the presence of additives and residual processing aids. These components have always been part of various excipients' composition but have not been routinely discussed.

It is crucial in a QbD environment that information concerning the additives and residual processing aids which may be present in an excipient be shared with the users so that adequate developmental work can be done to understand any interactions that may occur between the additive or processing aid and the other components of a drug product. There have been many reports of instances where the presence of a small level of an antioxidant or other additive in an excipient has affected drug-product stability or other performance properties.

The difficulty for industry lies in how regulators may respond when they find out that an existing excipient has always had an additive or residual processing aid in it and that this information had not been disclosed in the past. Companies are concerned about compendia and regulatory complications if this information is brought out. Therefore, companies are currently struggling to have appropriate discussions concerning the presence of additives and residual processing aids.

To address this situation, IPEC–Americas is compiling a list of additives and processing aids that are known to be commonly used in a number of excipients. The actual excipients which contain these additives and processing aids are not being identified at this point due to concerns the manufacturers have for confidentiality and unknown regulator reaction. IPEC–Americas plans to submit this list of well-known additives and processing aids (typically GRAS or excipient materials on their own right) to FDA. The organization also will request a meeting with FDA to discuss how best IPEC can work with the agency to find a mechanism (possibly grandfathering) that could be used to provide a way for excipient manufacturers to provide specific additive and processing aid information to FDA in a manner such that the presence of these materials can be considered to be acceptable in specific excipients in the future. Ultimately, this information could then be placed into the USP–NF monographs to show that there is no problem with these materials being present as long as they are identified. In some cases, due to confidentiality, there may need to be disclosure of this information to FDA through the use of a drug master file.

Once IPEC–Americas discusses this issue with the FDA and determines a process for handling the situation, IPEC will pursue similar discussions with other regulatory agencies globally to try to obtain similar flexibility. It is crucial that these discussions occur because additives and residual processing aids exist in numerous excipients and always will. It is important that global regulators find a way to effectively deal with this issue. The alternative, regulators saying these excipients can no longer be used, for example, would have a significant negative impact on the availability of many drugs. This issue has caused problems in Japan already, and IPEC hopes its efforts to obtain some type of grandfathering of these materials will lead Japanese regulators to make certain changes in its laws and guidelines to allow for these additives and processing aids in excipients. Japanese regulators may also need to determine the appropriate levels of use for particular applications.

Visible particles. Another hot topic concerning excipient composition is the presence of visible particles (not contaminants) in excipients that may typically exist and how users should deal with their presence. These particles may be off-color, charred particles from heat in the manufacturing process, small amounts of metal particles which typically occur from normal manufacturing process-equipment wear, or other types of particles that are visibly different from the main excipient particles but may be present as a part of the normal process that cannot be easily removed. Typically, these particles have no safety implications.

IPEC has established a subcommittee of its Composition Committee to develop a guideline on how to determine when the presence of these particles is acceptable depending on their type, number, and size. This guideline will also discuss appropriate testing methodologies for assessing these visible particles and what may be necessary to characterize the particles' identity.

Elemental impurities. The ICH Q3D guideline and the USP general chapters on elemental impurities currently under development will head toward implementation in the next few years. These guidelines and chapters will have a significant impact on the pharmaceutical and excipient industry going forward. Many excipients contain small amounts of elemental impurities and these amounts may cause some drug products to exceed the limits proposed. As a result, some drug products may need to be reformulated. It is the opinion of IPEC that the official implementation timeline of these guidelines and chapters be delayed until appropriate characterization studies can be carried out by excipient manufacturers to fully understand what levels of these elemental impurities may exist in their excipients.

In the past, excipient users had to perform a heavy-metals limit test. This test did not provide much useful information about the actual impurity levels were in the excipients. IPEC plans to work with the industry to encourage appropriate analytical studies once the ICH Q3D limits are known so that this information can be shared with pharmaceutical users. Pharma-excipient users can then establish the appropriate calculations to determine what levels of elemental impurities may exist in the finished dosage form and whether their drug products comply with the established limits.

Other areas of focus. IPEC has identified and is working on several other excipient-control areas that need further guidance. These include:

• QbD: excipient variability in chemical and physical properties and the effect of this variability on drug product manufacturability and performance

• Coprocessed excipients: supporting analytical data to build safety bridging arguments to component safety data

• Atypical actives: excipients being used as APIs that are not manufactured using ICH Q7 (4).

Conclusion

There are still many gaps in IPEC-Americas' TEC system. However, the organization is dedicated to continue to develop appropriate guidelines and whitepapers to fill these gaps and find ways of combining all of IPEC's tools into a workable system of controls that begin with excipient design and ends with patient consumption. If IPEC can do this, patient safety will surely be improved.

David R. Schoneker is vice-chair for Scientific and Regulatory Policy at the International Pharmaceutical Excipients Council of the Americas (IPEC–Americas). He is a member of Pharmaceutical Technology's editorial advisory board.

References

1. M. Steinberg et al., Regul. Toxicol. and Pharmacol. 24, 149–154 (1006).

2. FDA, Guidance for Industry: Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients (Rockville, MD, May 2005).

3. C. DeMerlis et al., Pharm. Technol. 33 (11) 72–82 (2009).

4. ICH, Q7 Good Manufacturing Guide for Active Pharmaceutical Ingredients (Geneva. November 2000) Nov. 10, 2000.