Trends in Excipient Safety Evaluation

Abstract

Excipients are used in all drug products and in most food products. New technologies are being tested to increase the amount or rate of absorption of drugs and new and novel excipients may be included among them. New physical approaches such as nanoparticles of drug and excipients or lysosomes may offer better drug delivery especially of hard to absorb or difficult to formulate oral drugs. New excipients may improve or mask the flavor of foods, drugs, and dietary supplements. Recently, impurities in drug products have become subject to greater scrutiny and various international and national guidelines, guidances, and regulations have been proposed and accepted for use; excipient evaluation is included in these efforts. This symposium discussed new developmental concepts, guidelines/guidances and regulations involving impurities in excipients, new drug delivery systems involving excipients, and thoughts for possible improvement to these guidelines to promote faster regulatory acceptance of these substances.

This symposium, chaired by Christopher C. DeMerlis and Robert E. Osterberg, was part of the 30th annual meeting of the American College of Toxicology (ACT). It highlighted new technologies regarding excipient manufacturing that could improve the utility of drug products regarding difficulties with physical drug delivery problems and how they could be overcome. Some presentations discussed national and international regulatory concerns regarding impurities in excipients and explained current approaches to set their safe limits. Thoughts to improve current regulatory guidelines/guidances were presented to perhaps accelerate the emergence of new and novel excipients for use in drug development.

Current and Future Methods for the Safety Assessment of Excipients (Robert E. Osterberg)

Excipients are chemical substances that are used in drug products or in foods as additives that are deemed necessary for their manufacture. They are substances that bring little or no therapeutic value to the product because they are designed to be therapeutically inert, inactive, and engender no pharmacological activity. Historically, they have been called “pharmaceutical necessities” because of their value in producing drug products that could not be made without them.

The use of excipients goes back to ancient times. The Bible tells of several substances such as honey, wine, various gums, and leaves that were used to make drugs and mask the unpleasant taste of the drug component. ¹ In 1820, the US Pharmacopeia (USP) placed acacia gum in a monograph in its first edition. ² Over the past decades, the USP has added more excipients to its pharmacopeias.

There are several functional categories of excipients for use in drug products. The list is large but involves examples such as

antioxidants, that is, butylated hydroxyanisole (BHA), ascorbic acid (vitamin C), and butylated hydroxytoluene (BHT),

preservatives, that is, benzalkonium chloride, thimerosal, and benzyl alcohol,

colors, that is, Red 40 and FD&C Green,

flavorings, that is, cherry syrup, monosodium glutamate (MSG), and lactose,

solubilizing agents, that is, ethanol, dimethyl sulfoxide (DMSO), and water,

suspending agents, that is, acacia and carboxymethylcellulose, and

thickening agents, that is, waxes and petroleum jelly.

There are many uses for these and other excipients and they can be found in products such as tablets, capsules, solutions, suspensions, creams, ointments, suppositories, injectables, inhalants, and so on.

Toxicity

A question often arises when excipients are discussed regarding their inert nature. Are excipients toxic? If they are inert, how can they be toxic? Paracelsus, the often recognized father of toxicology, in the 16th century said “Poison is in everything and no thing is without poison. The dosage makes it either a poison or a remedy.” ³ However, not much thought was given to the potential toxicity of excipients until around 1937. A chemical company wanted to produce an elixir of a relatively insoluble and bad tasting sulfonamide antibacterial drug. One of its chemists found that he could make a solution of this antibacterial that had a pleasant blue color and a sweet taste by adding a toxicologically untested diethylene glycol (DEG) as the excipient. The product was called Elixir of Sulfanilamide and was subsequently marketed and prescribed by physicians until a disaster occurred among the children who ingested this product. It was discovered that over 100 children died and several hundred became ill with kidney failure as a result of the DEG that was consumed. Public outrage eventually forced the Congress to pass the Copeland-Lea Act of 1938, also known as the US Food, Drug and Cosmetic Act (FD&C Act), that among other laws placed the safety burden of drugs on their manufacturer rather than on the federal government. In 1958, Congress passed the Food Additive Amendments that also placed the burden of safety of food additives on US food manufacturers. It is of great interest to learn that the word excipient or any specific concern for their potential toxicities are “not” mentioned in the FD&C Act, since it was an excipient that was responsible for the genesis of this powerful law.

Several different toxicities have been ascribed to excipients both from topical administration and systemic administration. Regarding topical application of some excipients, dermal toxicities—such as hypersensitivity from lanolin, benzoic acid, para-aminobenzoic acid (PABA), and local anesthetics; phototoxicity from cinnamon oil, Bergamot oil (used in perfumes), and 8-methoxypsoralen with Ultraviolet A light (PUVA) as therapy for psoriatic lesions; and contact dermatitis from propylene glycol, polyethylene glycol, and oleic acid—have been observed.

Examples of systemic administration associated with some excipients include renal tubular necrosis caused by intravenous (IV) or subcutaneous (SC) administration of β-cyclodextran, respiratory toxicities in young children caused by inhalation of solutions containing benzyl alcohol, digestive problems caused by ingestion of lactose, allergic responses caused by ingestion of sulfites, and diarrhea caused by ingestion of mannitol-containing solutions have been reported. It is important to recall a toxicological truth that “The dose makes the poison.”

In the ensuing years from 1938 to 1990s, not very much occurred in the further regulation of excipients and concern for their specific toxicities. They were tested for toxicity either independently or in their drug products, but there was little guidance regarding a plan for testing them. However, Weiner ⁴ and, later in 1996, the Safety Committee of the International Pharmaceutical Excipients Council ([IPEC]-Americas) ⁵ published guidelines for the safety testing of excipients. This guideline described the different toxicology tests that should be performed to uncover excipient toxicities according to the therapeutic route of administration in which they would be used. In 2003, Osterberg and See published an article that laid the foundation for the formal development of a US Food and Drug Administration/Center for Drug Evaluation and Research (FDA/CDER) guidance. ⁶ During that time, the FDA/CDER’s Inactive Ingredients Subcommittee of the Pharmacology/Toxicology Coordinating Committee was working on an excipient guidance that was published for public comment in 2002 and finalized in 2005. This guidance is entitled “Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients” and is available on the FDA/CDER Web site. ⁷ It was a product of the International Conference on Harmonization (ICH) M3 guidance ⁸ and the IPEC Safety Committee’s guideline for the testing of excipients. ⁵

As previously mentioned, the USP has monographed many excipients over the years. So has the Japanese Pharmacopeia and the European Pharmacopeia. However, it should be understood that the inclusion of an excipient in an USP/National Formulary (NF) monograph or other non-FDA document is not an indication that the substance has been reviewed by the FDA and found safe for use. Without FDA’s declaration of safety, an excipient may not be used in a drug product.

Regulatory Toxicology

Since FDA has no specific regulatory process to review excipients independently, how can a drug sponsor legally add an excipient to a drug product? It should be recalled that an excipient used in previously approved drug products or having generally recognized as safe (GRAS) status as a direct food additive or having a similar route of administration or level of exposure in an approved drug product or a similar duration of exposure associated with a prior approved use could qualify the new excipient. However, it may be necessary for the excipient’s safety database to be brought up to current standards as described in FDA/CDER’s excipient guidance.

The FDA’s guidance recommends the acquisition of toxicology data from the following types of studies

safety pharmacology with an emphasis on cardiovascular, respiratory, and central nervous systems,

pharmacokinetic/absorption, distribution, metabolism, and excretion (ADME) studies,

ICH S2B genetic toxicology battery,

reproduction toxicology,

appropriate duration repeat dose studies in 2 species (rodent and nonrodent mammal), and

carcinogenicity studies, if warranted.

The excipient must be tested using the anticipated clinical route of administration. It is recommended that before any studies are begun, the appropriate FDA/CDER review division be contacted to discuss the appropriate tests. Specific guidance regarding routes of administration can be found in the FDA/CDER Excipient Guidance ⁷ and in the IPEC publication. ⁵

It was mentioned above that data from carcinogenicity studies may be necessary, “if warranted.” A review of the FDA/CDER guidance indicates that one of the following approaches could be used, but it must be emphasized that any of the approaches chosen should be discussed with the FDA review division before studies are begun. Either two 2-year bioassays in rodents or a 2-year assay in a rodent (usually rat) and an alternative assay such as a neonatal or a transgenic assay in a different rodent species (usually mouse). However, there is a third possibility that is implied in the ICH Guidance S1A, which is “The need for long-term rodent carcinogenicity studies of pharmaceuticals,” ⁹ and in the FDA Excipient Guidance. ⁷ A “weight-of-evidence or WOE” approach has been discussed. If the excipient

has no structural alerts,

has no pharmacological activity in the ICH safety pharmacology studies and in other pharmacological assays,

is not genotoxic,

is not a reproductive toxicant,

shows no severe toxicities in a 90-day or 180-day repeat dose tests in rodent and nonrodent mammalian species,

has a very large margin of safety in the repeat dose tests, and

perhaps has negative data from a transgenic assay, maybe carcinogenic assay/assays can be waived.

It should be understood that if a request for a waiver is accepted by the CDER review division, the excipient may be capable of producing tumors in rodents if tested in the 2-year bioassays. There are at least 2 excipients that were shown to be nontoxic in these specific shorter-term toxicology studies; but when tested in carcinogenicity studies, they produced tumors in either the rat or the mouse. These excipients were laurocapram and hydroxypropyl-β-cyclodextran, but because of their potential mechanisms that could be rodent specific, they were allowed to be used in some prescription products.

Excipient Regulatory Information From Europe and Japan

The European Medicines Agency (EMA) guideline on excipients in the Dossier for Application for Marketing Authorisation of a Medicinal Product (June 2007) ¹⁰ mentions a full safety evaluation without specifying details. It does state that excipients are to be reviewed only in context with an active pharmaceutical ingredient (API). The Japanese Pharmaceutical Excipients Directory ¹¹ contains chemical standards for more than 1000 published excipients but no specific safety information is given. However, in 1999, a Japanese article discussed the safety evaluation of excipients based on toxicity studies in use today. As in the United States, Japan, and Europe, new excipient use is only allowed as part of an approved new drug product.

General Excipient Information

Sources of additional excipient information can be obtained from the IPEC-Americas and its New Excipient Evaluation Procedure, ¹² the Japanese Excipients Council (JPEC), IPEC-Europe, IPEC-China, and IPEC-India (in development).

While discussions were occurring during IPEC-Americas meetings of its toxicology committee, its chairperson Dr Marshall Steinberg made a cogent remark regarding excipient testing. He said that the development of an excipient that shows toxicity at low exposure levels or shows certain types of toxicity such as carcinogenicity, mutagenicity, or teratogenicity would not be practical or economically feasible. Any excipient development program should pay particular attention to this remark.

The Need for New Excipients in Oral Solid Dosage Form Development (Christopher C. DeMerlis)

Excipients have various functions and applications in oral solid dosage forms. The USP/NF ¹³ contains a category listing of excipients by function. The Handbook of Pharmaceutical Excipients also contains useful information regarding excipient functionality. ¹⁴

The USP published General Chapter <1059>, which provides an overview of the key functional categories of excipients—tests that may assess excipient performance and test procedures that may not be presented in compendial monographs.

Various factors in oral solid dosage form development influence and create the need for new excipients such as

the increased need for an ideal tablet binder for direct compression as a tablet manufacturing process,

the need for excipients to have a superior compressibility to handle increased tablet press speed, and

the need to formulate drug substances with solubility and permeability problems. ¹⁵

There are specific unmet needs for polymers for extended release hydrophilic matrices that also create the need for new excipients such as

• polymers needed when drug solubility is pH dependent,

• matrices needed that do not exhibit initial burst release rate for very soluble drugs, and

• matrix formulations needed for high-dose drug substances. ¹⁶

Currently, combinations of polymers are used to handle these formulation challenges. For example, different molecular weight grades of hydroxypropylmethylcellulose (HPMC) are used. Hydroxypropylmethylcellulose is also used in combination with ionic hydrophilic polymers, fatty acids, alcohols, waxes, or nonionic hydrophilic polymers.

Types of New Excipients

Generally, excipients not listed in the FDA’s Inactive Ingredients Database (IID) are considered new excipients. New routes of administration or higher use levels for existing excipients than those listed in the IID are also considered new excipients. Types of new excipients include

simple physical mixtures containing a new excipient,

coprocessed mixtures of existing excipients,

physical or chemical modification of existing excipients, and

new chemical entity (NCE).

A simple physical mixture is an admixture of 2 or more excipients produced by a manufacturing process of short duration such as low-shear processing. The individual components are isolated, distinct, and intact. The simple physical mixture becomes a new excipient if one or more of the components are not listed in the IID. The mixture is not considered new or novel if the components are listed in the IID. Examples of simple physical mixtures include color and flavor blends or immediate release film-coating powders. These simple physical mixtures are not appropriate for consideration of a monograph in the USP/NF.

There is a significant trend to develop and market coprocessed excipients. Coprocessed excipients are an intimate mixture of established excipients that possess performance advantages and improvements that cannot be achieved through simple mixing. The improvements include increased surface area, improved flow, or improved compaction. Covalent bonds are usually not formed. The specialized manufacturing processes used for coprocessed excipients include spray drying, melt extrusion, high shear dispersion, or granulation. One or more components may be formed in situ. Coprocessed excipients are appropriate for consideration of a monograph in the USP/NF. Several coprocessed excipients are listed in the IID. Various publications discuss the development and formulation with coprocessed excipients and are listed in the reference section of this article. ¹⁷

The IPEC Composition Guide defines a coprocessed excipient as follows.

A coprocessed excipient is a combination of two or more compendial or non-compendial excipients designed to physically modify their properties in a manner not achievable by simple physical mixing, and without significant chemical change. However in some instances, formation of necessary components may occur, such as in situ salt formation. Many different co-processing methods may be used, including standard unit operations such as granulation, spray drying, melt extrusion, milling, etc. The choice for a specific application will depend on the materials used, their form (e.g. whether dry powders or liquid) and the specific physical properties desired. Likewise the ratios of the components may vary depending on the desired performance. ¹⁶

The USP published a stimuli article titled “Co-Processed Excipients” which is included in the Pharmacopeial Forum. ¹⁸ The USP is developing an approach for monographs for coprocessed excipients. This family of excipients is expected to grow dramatically in the future as more and more companies develop these materials for unique pharmaceutical applications, where standard excipients do not provide appropriate performance or consistency. These types of excipients are engineered to meet the needs of the Quality by Design (QbD) initiatives, which are driving new pharmaceutical development and improvement of existing pharmaceutical manufacturing processes.

Tablet and DDSs

Coprocessed excipients are used to design oral solid dosage form systems to improve bioavailability or to release a drug at a target site in the gastrointestinal tract. The development of drug delivery systems (DDSs) creates a need for new and novel excipients for use by formulation scientists when working with formulation challenges.

The need for excipient functionality has been discussed at various forums such as the Product Quality Research Institute (PQRI). Professional organizations such as the Controlled Release Society (CRS) and American Association of Pharmaceutical Scientists (AAPS) serve as a forum for scientists to discuss the use of new excipients in the field of pharmaceutics and drug delivery. Many publications discuss the recent trends and development of novel platforms for oral drug delivery. ^{19 ,20}

Risk Assessment of Coprocessed Excipients (Combination Excipients)

Quantitative structure–activity relationships (QSARs) can be used to assess complex mixtures of structurally related compounds. It is critical that analytical testing of the coprocessed excipient be conducted to prove the absence of chemical change and to confirm whether any new impurities are formed. Toxicological data may be limited for the whole mixture; therefore, abbreviated studies may sometimes be necessary. Mixture concepts such as additivity should be evaluated for the component combination for any types of interaction. ²¹ Data must be extrapolated from the individual components and the dose ratio of the components should be considered. An NCE will require a full toxicology testing program and detailed chemistry, manufacturing, and controls information.

A new or novel excipient should be properly described and its specifications and supporting information included in the Common Technical Document (CTD) Section P4 of Excipients in a drug application. Section P4.6 Novel Excipients of the CTD is specifically designated for the information on novel excipients. In the United States, supporting toxicological information for a new excipient can be provided in the drug application or in appropriately referenced Type IV or V Drug Master File (DMF). International Pharmaceutical Excipients Council developed the Excipient Master File Guide to assist in the development of supporting information for new excipients for regulatory submissions.

In conclusion, very few NCEs will be introduced as new excipients. The trend is for the introduction of coprocessed excipients and physical/chemical modifications of existing excipients. Risk assessment should be conducted on a case-by-case basis for coprocessed excipients. The IPEC New Excipient Evaluation Procedure can be used to evaluate the safety of new coprocessed excipients. The IPEC Procedure will minimize the risk of the use of a new excipient for a drug product sponsor. Several articles have been recently published discussing the IPEC Procedure. ^22,23

Excipients in New and Specialized Areas of Drug Delivery (David W. Hobson)

New and specialized areas of drug delivery as related to the use and development of excipients may be described as follows.

New Area. A relatively new or emerging drug delivery technique, technology, or application that is not in routine use and may be applied to improve a routine mode of delivery or to facilitate a completely novel mode of delivery.

Specialized Area. A mode of drug delivery that is currently in routine use and requires the application of specialized techniques and/or technologies including formulation with specialized excipients to accomplish that which is novel but not relatively new.

There are many specialized areas that often require the use of excipients for various purposes including improving the stability of the active agent as well as its delivery into or on the target tissue. New areas emerge with new innovations in pharmaceutical technology, and this can include new delivery technologies and new excipient formulation technologies that are improvements over previously available excipients. With respect to various types of products, examples of new and specialized areas of drug delivery that might require the use of excipients include the following examples.

New

• Drug impregnated adhesives and coatings,

• microneedles,

• nanoparticles (NPs), and

• nanoparticle-based delivery systems.

Specialized

• Coated stents and catheters,

• transdermal delivery devices,

• wound healing and tissue repair products,

• therapeutic imaging agents,

• implants, and

• autoinjectors and inhalers.

New and specialized delivery systems can necessitate or drive excipient development to achieve different goals or purposes including

controlled release,

targeted release,

preserving from microbial degradation,

stabilizing drug substances to maintain potency,

increasing shelf life,

binding or adherence of API to a particle or device, and

permitting optimal shipping, storage, and use conditions.

for example, drug-incorporated NPs may have particle surface charge characteristics that are measured as zeta (ζ) potentials that must be maintained within specified limits for optimal drug configuration during stability and a coated cardiovascular stent could require the use of specialized bioerodable polymer systems that provide controlled release of drugs into the bloodstream at a defined rate.

One popular stent coating strategy is to apply different excipient polymers as a matrix to the stent surface and add biologically active substances geared to effectively manage thrombosis and intimal hyperplasia to this matrix. Unfortunately, many polymers exhibit undesirable characteristics such as being prothrombotic and creating an intense inflammatory response in the artery. Naturally occurring polymers like phosphorylcholine are rare exceptions and inert coatings such as silicon carbide, perilitic carbon, and the so-called diamond-like coatings appear potentially useful. ^24,25 Nakano et al ²⁶ developed and demonstrated an NP-mediated DDS as a bioabsorbable polymeric NP-eluting stent using poly(d,l-lactide-co-glycolide) that provides better and more prolonged delivery compared with current polymer dipcoated stent technology.

Excipient use of a novel and specialized nature can necessitate the need to obtain toxicologic data for establishing and demonstrating their safety for practical and regulatory purposes. Osterberg and See ⁶ described this need from a regulatory perspective and indicated clearly that until substantial data are available showing otherwise, new excipients and those used for specialized purposes would, like all chemicals, be viewed as potential toxicants and not inert substances. Therefore, when developing new excipients or using an existing excipient for a specialized purpose, careful consideration must be given to establishing the safety of the excipient with the collection of adequate safety data using procedures and methods acceptable to the regulatory agency responsible for excipient review and acceptance for use. New and specialized use excipients that have not been previously marketed may require the collection of extensive toxicity information. Osterberg and See have described the general guidance approach currently employed by the FDA for the collection of adequate safety pharmacology and toxicology information for new and specialized use excipients. ⁶

Some of the practical reasons for conducting adequate safety testing on new and specialized use excipients would be

to identify, understand, and eliminate/avoid any potential adverse effects in use relevant areas,

to support “go”/“no go” pharmaceutical or medical device development decisions, and

to provide documentation and assurance of adequate and responsible safety characterization for corporate needs including liability and investor confidence purposes.

Using the FDA as an example, some of the more significant reasons for conducting safety tests on new and specialized excipients would include

• providing FDA with the information necessary for regulatory review and approvals,

• demonstrating safety for investigational new drug (IND) approval,

• providing adequate safety data for inclusion in the clinical trial investigator’s brochure, and

• establishing safety for new drug approval (NDA).

Historically, it is always important to keep the following in mind when considering the use or development of any excipient in a drug product especially those that are new or are being developed for a new purpose. The Federal Food, Drug and Cosmetic Act (FFD&C) of 1938 (The Act) was enacted after the tragedy of the elixir of sulfanilamide ingestions in 1937, in which an untested excipient was responsible for the death of many children who consumed the pharmaceutical as noted above and this established that excipients cannot be assumed to be without toxicity. The FDA and other similar regulatory agencies worldwide clearly have many other historical experiences with excipient toxicology issues such that they consider excipient safety along with that of the API. In the case of some new excipient forms, the need for this information can be on equal footing with the need to have relevant and complete toxicologic characterization and safety evaluation of the API itself.

The FDA currently defines new excipients as follows. “New excipient means any inactive ingredients that are intentionally added to therapeutic and diagnostic products, but that:

we believe are not intended to exert therapeutic effects at the intended dosage, although they may act to improve product delivery (e.g., enhance absorption or control release of the drug substance); and

are not fully qualified by existing safety data with respect to the currently proposed level of exposure, duration of exposure, or route of administration.”

Factors that typically drive the need for obtaining toxicology data for excipients in new and specialized drug products include the following for new, modified, and new uses of allowed excipients.

• New excipient

• Modified excipient

• New use of an approved excipient

New excipients are being developed and patented on a regular basis and the use of previously allowed excipients in specialized products also occurs with substantial regularity. Typical uses of excipients in new and specialized products may be summarized as follows

• preservatives,

• colorants,

• binding agents,

• thickening agents,

• stabilizers,

• pH adjustment,

• fillers,

• extenders,

• diluents,

• wetting agents,

• solvents,

• emulsifiers,

• flavors,

• absorption enhancers, and

• sustained release matrices.

Sometimes excipients are developed for novel uses that would also be considered substantially specialized examples of areas where novel excipient technologies are required to enable a specialized product and include the following

• penetration enhancement by physical means,

• novel combination drug binding/adhesive/controlled release polymers,

• particle matrix/construct for drug delivery/presentation to target tissues,

• bioerosion/biodegradation matrix/enhancers, and

• tissue, cellular, or molecular targeting agents.

The use of NPs as excipients incorporated in new materials for current uses or as novel materials for specialized uses is possible and increasingly being considered for many different products. This approach is currently a viable and useful means for creating new forms of excipients with properties that heretofore have not been possible, developing new intellectual property, and extending patent protection for excipient manufacturers.

Nanocoatings can be used to protect and improve small tablet product quality during manufacturing and may assist with the ingestion of large therapeutic doses (600-800 mg). One large international company is reported to have an ibuprofen formulation with a “nanolayer” coating that protects against temperature effects during manufacturing and speeds production. ²⁷ Nanocoatings also appear to have potential for reducing or eliminating the lubricants needed in manufacturing and reducing or eliminating the need for wet granulation and compacting.

Excipients incorporated into nano-sized liposomes are also resulting in potential new uses particularly in vaccine production where lyophilized NP formulations suspend small amounts of excipients (sucrose and mannitol or dioctyl sodium sulfosuccinate with trehalose and mannitol) in polyvinyl alcohol with the antigen being adsorbed to the surface of the NP. However, the influence of nano-sized liposomes on the biodistribution of drug substances and potential immune system effects must be studied to support safety and efficacy decisions. ²⁸ Calcium phosphate nanotechnology is being developed as an effective and safe replacement for aluminum salts as an FDA-approved adjuvant for vaccines. ²⁹

With some of the first nanomaterial forms such as metal oxides of titanium and zinc that have been used for many years as whitening agents and the blocking agent for some sunscreens, it was not known for certain if toxicological characteristics would be significantly altered when the material was nano-sized. Subsequently, this has led to much debate and study with the current practical recognition that an excipient particle, which historically has been micron sized, is nano-sized. The substantial increased surface area alone is enough to warrant a determination as to whether any significant toxicological differences occur. Furthermore, increasing recognition among toxicologists that traditional safety testing protocols may need to be modified or changed to accommodate the evaluation of nanomaterials is resulting in consideration within the United States and Europe to increase regulatory oversight of nanomaterials intended for human consumption including their use in food, cosmetics, and pharmaceuticals as excipients. At present, there appears to be a trend toward evaluating nanomaterials whether new or nano-sized forms of historically used materials potentially having new toxicologic characteristics requiring a demonstration of potential toxicity and safety by the submission of appropriate safety study data.

New and specialized areas of drug delivery clearly provide opportunity and necessitate the novel use of excipients and/or the development and use of novel excipients. With the advent of molecular medicine and the need to continually provide new, safe, and effective pharmaceutical products to address current and emerging health issues worldwide, medical and pharmaceutical science will no doubt continue to create new and specialized areas of drug delivery. As a result, we can expect that excipient development will advance in response to these needs and continue to provide the foundation for safe and effective drug delivery for many years to come.

Excipients: Toxicological Concern for Impurity Safety (Timothy J. McGovern)

Excipients often comprise the majority of the composition of an administered pharmaceutical. However, the expectations regarding the characterization and safety evaluation of pharmaceutical excipients, especially in regard to excipient-related impurities, are not as clearly defined as those for the API. The goals of this presentation were to define impurities in the context of pharmaceutical excipients and to discuss issues related to the setting of impurity specifications for excipients, the safety evaluation of impurities in excipients in comparison to those in drug substances and products, and current issues surrounding genotoxic impurities and how they may relate to pharmaceutical excipients.

What Are Impurities?

Impurities can be defined differently depending on the context in which they are discussed. The ICH, a joint initiative of both regulators and research-based industry representatives with the goal of promoting international harmonization by establishing common guidelines, defines impurities in guidances Q3A(R2) ³⁰ and Q3B(R2) ³¹ in relation to drug substances and products, respectively. For a drug substance, an impurity is any component of the new drug substance that is not the chemical entity defined as a new drug substance. For the drug product, an impurity is any component of the new drug product that is not the drug substance or an excipient in the drug product.

Defining and characterizing impurities in pharmaceutical excipients can be more complicated. As described in the 2009 IPEC Excipient Composition Guide, ³² excipients are often composed of multiple components and the functionality of excipients may be dependent on the presence of components other than the labeled entity. Therefore, there must be recognition of, and a distinction made between, “concomitant” components and true impurities. The composition profile of a pharmaceutical excipient may be defined as a description of the components present in a typical lot produced by a given manufacturing process. The main components of an excipient can include nominal components, concomitant components, additives, and processing aids. Other components can include unreacted starting materials, by-products, degradants, and residual solvents.

Basis for Setting Impurity Specifications in Excipients

The Code of Federal Regulations [21 US CFR 211.84(6)(d)(2)] indicates that each excipient component shall be tested for conformity with all appropriate specifications for purity, strength, and quality. The FFD&C recognizes the USP/NF ¹³ as official compendia. A drug product in the US market must conform to the standards in the USP/NF to avoid possible charges of adulteration and misbranding. The USP describes drug substances and dosage forms, while the NF describes excipients. These compendia are the most commonly recognized resources for determining the identity, strength, purity, and quality of excipients. When an article differs from the standards of the NF monograph, the differences should be plainly stated. The FDA’s CDER Office of New Drug Quality and Assurance (ONDQA) issued a Manual of Policies and Procedures (MaPP) ³³ in 2007 that provides some allowance for the use of alternate compendia if the standards are equal to or better than those listed in the USP/NF.

The USP creates and continually revises USP/NF standards through a public/private collaborative process, which involves the pharmaceutical industry as well as government and other interested parties. The committee is composed of volunteer scientists elected on the basis of their knowledge and expertise and makes the final decisions to publish standards in the USP/NF. However, the actual criteria for setting impurity standards are not clearly defined.

The Basis for Setting Impurity Specifications in ICH Guidelines

In contrast to excipients, the criteria for setting impurity specifications in drug substances and products are well defined. The ICH Guidances Q3A(R2) and Q3B(R2) describe specific qualification thresholds or levels below which no safety information is needed, for drug-related impurities that use a sliding scale based on the total daily intake of the API. In cases where the maximum daily dose of the API is less than or equal to 2 g/d, the qualification threshold for the drug substance is 0.15% or 1.0 mg/d, whichever is less. When the maximum daily dose of the API is greater than 2 g/d, the qualification threshold for the drug substance is 0.05%.

The ICH Guidance Q3B(R2) addresses only those impurities in new drug products classified as degradation products of the drug substance or reaction products of the drug substance with an excipient but not excipients themselves. The guidance specifically excludes impurities arising from excipients present in a new drug product. The qualification thresholds are categorized again based on the daily dose of the API at levels less than 10 mg, 10 to 100 mg, greater than 100 mg to 2 g, and greater than 2 g. The associated qualification thresholds are 1% or 50 µg, 0.5% or 200 µg, 0.2% or 3 mg, and 0.15%, respectively.

For cases where the thresholds listed above are exceeded, the guidances provide recommendations to provide appropriate safety information to support higher specifications. The recommended studies when desired include a general toxicity study (1 species) of 14 to 90 days duration. The duration should be based on available relevant information and conducted in a species most likely to maximize the potential to detect toxicity. Genotoxicity studies, including in vitro point mutation and chromosome aberration assays, are also recommended and other end points may be selected as appropriate.

The FDA Guidance on Safety Testing of Excipients

The FDA issued guidance on the safety evaluation of excipients (Guidance for Industry: Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients), ⁷ which was finalized in May 2005. The guidance describes the types of toxicity data that the FDA recommends to determine whether a potential new excipient is safe for use in human pharmaceuticals and testing strategies for pharmaceuticals proposed for short-term, intermediate, and long-term use. It also indicates that available information supporting prior use will also be considered in light of any new use.

Importantly and as mentioned earlier, the FDA guidance states that the inclusion of an excipient in an USP/NF monograph or other non-FDA document is not an indication that the substance has been reviewed by the FDA and found safe for use. It is important that a new or inadequately qualified inactive ingredient proposed for use in any product to be marketed pursuant to a New Drug Application (NDA), Biologics License Application (BLA), or Abbreviated New Drug Application (ANDA) be supported by adequate data. The FDA guidance does not specifically address the issues of impurities in an excipient and, therefore, there is no formal FDA guidance on excipient-related impurities.

The Toxicological Basis for Impurity Control in Excipients

Impurity specifications in USP monographs for excipients have traditionally been based on manufacture capabilities and expert review. The listed attributes are considered adequate, but the safety evaluation appears to be limited relative to that conducted for APIs and drug products. In addition, the basis for determinations of accepted specifications are not publicly formalized. The 2009 IPEC Excipient Composition Guide recommends that any undesirable components should be identified when they are present at levels equal to or greater than 0.1% to determine the need, if any, for quantitative limits. However, there are generally no formal safety assessments conducted on the impurities based upon their eventual use in drug products. One exception may be when degradants are formed from the combination of the API and the excipient; as noted previously, this situation would be covered under the ICH Guidance Q3B(R2).

As stated previously, there is currently no formal guidance regarding the assessment of excipient-related impurities. Based on the FDA guidance on excipient safety, however, novel excipients, or those proposed for use by a novel route of administration, would generally require a more stringent assessment. Excipients may in fact be treated similarly to an API with submission of a DMF, if desired, and the evaluation may include the safety evaluation of impurities. Given the lack of specific guidance related to impurities, the recommendations provided in the ICH Q3 guidances may serve as an initial starting point for consideration.

Some informative text is provided in a 1998 draft FDA Guidance for Industry-Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products. ³⁴ The draft guidance states that excipients can have a substantial effect on the safety, quality, stability, performance, and effectiveness of such drug products and that the source of each excipient should be identified in the application. Adequate DMFs with appropriate authorization should be submitted to the FDA for major (eg, propellant and carriers) and noncompendial excipients. The draft guidance goes on to state that a full description of the acceptance criteria and the test methods used to ensure the identity, assay, functionality, quality, and purity of each excipient should also be submitted.

When USP or NF monograph materials are used and the associated specifications do not provide adequate assurance for inhalation use with regard to the assay, quality, performance, and purity; monograph specifications should be supplemented with additional acceptance criteria and tests to ensure lot-to-lot reproducibility of the components. Switching the route of administration from oral dosing to inhalation can require additional work and accepted purity standards for the new route can differ from those in the accepted monograph. The purity standards may be impacted by the specific impurities identified and by the proposed use and total daily intake.

For inhalation use, cases exist where additional tests and specifications were requested to better define quality and purity attributes. The need for these additional tests is based at least partly on the potential use in a population with an already compromised respiratory system. In some cases, no toxicity evaluation is needed; the observed impurity may not be of concern if it is present at very low levels, based on experience with similar types of compounds, or if a DMF is available (not always the case for those with an USP monograph for oral use).

In cases where an USP monograph is not available, the accepted specifications may be based on supporting nonclinical toxicity studies conducted with the excipient and the amount of impurity present in tested batches. It can therefore be important to consider testing “dirty batches,” or drug batches with high levels of impurity, in order to generate supporting toxicity data. In the absence of supporting nonclinical data, there is no clear guidance available, but an approach along the lines recommended in the ICH Q3 guidances can be considered.

Excipients and Genotoxic Impurities

The issue of genotoxic impurities in drug products has been of increasing concern among regulators as evidenced by the release of a final guideline by the EMA in 2006 entitled Guideline on the Limits of Genotoxic Impurities ³⁵ and an FDA-issued draft guidance entitled Genotoxic and Carcinogenic Impurities in Drug Substances and Products: Recommended Approaches ³⁶ that was released in 2008.

The scope of the EMA guideline includes new active substances and existing active substances with new routes of synthesis resulting in a change in the impurity profile such that new or higher levels of genotoxic impurities are introduced. In general, there is no need for retrospective analysis of authorized products unless a specific cause for concern is identified. Although excipients are not mentioned in the guideline, based on discussions at various public meetings, new excipients could be included in the evaluation. Similar to the EMA guideline, the FDA draft guidance does not address excipients. The guidance addresses synthetic impurities and degradants in drug substances but does not otherwise address the genotoxicity or carcinogenicity of actual drug substances or intended drug product ingredients.

The EMA guideline distinguishes between genotoxic impurities with different mechanisms with the focus on DNA-reactive substances that have the potential for direct DNA damage. The guideline discriminates between genotoxic compounds with sufficient experimental evidence for a threshold-related mechanism (to be handled like “normal” toxic impurities according to ICH Q3 guidances) and genotoxic compounds without sufficient experimental evidence for a threshold-related mechanism.

In cases where a threshold-related mechanism is not available, a substance-specific calculation of an acceptable limit is possible if carcinogenicity data are available. An acceptable exposure is one associated with a calculated risk level of less than or equal to 1, with additional cancer death in 100 000 persons exposed over the course of a lifetime.

When carcinogenicity data are not available, a substance-specific calculation of the acceptable limit is not possible. However, a threshold-driven approach is considered acceptable and the guideline refers to a Threshold of Toxicological Concern (TTC). The TTC represents an acceptable exposure level in most cases and the guideline states that a “… 1.5 µg/day intake of a genotoxic impurity is considered to be associated with an acceptable risk … for most pharmaceuticals”; the TTC corresponds to a 1 in 100 000 cancer risk levels for even unknown compounds. Some special class compounds including nitrosamines are not included in the TTC approach due to increased cancer potency. The FDA draft guidance follows a very similar approach to the EMA guideline.

Views on the issue of genotoxic impurities in excipients vary and have been published in the literature. Humfrey ³⁷ suggests that if the concern of regulators is based on human safety, there is no rational reason why the available regulatory guidances should not be applied to excipients and APIs. The author contends that it is difficult to rationalize a requirement for control of genotoxic impurities in an API with no such requirement for other components of a drug product. A potential result of this approach may be that certain excipients may be unacceptable for use in some drug products.

An alternate view is offered by Brusick ³⁸ and suggests that excipients are less likely than an API to have residues that are biologically active. Older excipients have been used safely and are essential components, while newer excipients are tested in an extensive battery of studies that include genetic toxicology. Others are still food materials or other natural products with no complex chemical synthesis. The author counters that human populations are continuously exposed to a wide range of genotoxins with considerable risk and concludes that exposure to genotoxic impurities in excipient products would not likely pose serious adverse health consequences, especially when balanced against benefits derived from drug excipients and that there is no gain in scientific knowledge or public health from an expansion of the approach to excipient products.

In conclusion, there are currently no formal regulations in place regarding the presence of impurities in excipients although IPEC provides recommendations for controlling impurities. The USP/NF standards provide some measure of comfort in regard to older excipients and novel excipients are likely to be held to increased standards. One approach to consider in setting acceptance criteria for a new excipient is to base the initial criteria on current manufacturing capabilities. The criteria could be considered reasonable if impurities are within the ICH Guidance Q3 qualification thresholds. If they are in excess of the thresholds, the safety of the proposed use could be determined based on the availability of safety information from published literature, human experience, or toxicology studies with the excipients. If a known genotoxin is identified, the potential human risk in the context of the proposed product use should be considered. The guidances currently available can be used as a framework to address potential safety concerns.