Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions

II. Types of Excipients

III. Regulatory Perspective

Based on available safety testing information, the International Pharmaceutical Excipients Council (IPEC) has classified excipients into four classes (67):

1. New chemical excipients: These excipients require a full safety evaluation program. It is estimated that the cost of safety studies for a new chemical excipient is about $35 million over 4–5 years. E.U. directive 75/318/EEC states that new chemical excipients will be treated in the same way as new actives. In the U.S. a new excipient requires a Drug Master File (DMF) to be filed with the FDA. Similarly, in Europe a dossier needs to be established. Both the DMF and dossier contain relevant safety information. IPEC Europe has issued a guideline (Compilation of Excipient Master Files Guidelines) providing guidance to excipient producers on constructing a dossier to support MAA (Marketing Authorization Application) while maintaining confidentiality of the data.

2. Existing chemical excipient—first use in man: This class implies that animal safety data exists and that the excipient may have been used in some other application. Additional safety information may be necessary to justify use in humans.

3. Existing chemical excipient: This class designates that the excipient has been used in humans but change in route of administration (e.g., from oral to parenteral), new dosage form, higher dose, etc. may require additional safety information.

4. New modifications or combinations of existing excipients: These excipients indicate a physical interaction, not a chemical reaction. No safety evaluation is necessary in this case.

Simply because an excipient is listed as GRAS (Generally Recognized As Safe), does not mean it can be used in a parenteral dosage form. The GRAS list may include materials proven safe for food (oral administration) but not deemed safe for use in an injectable product, making it difficult for a formulation development scientist to choose additives during dosage form development.

Many pharmacopeial monographs for identical excipients differ considerably regarding specifications, test criteria, and analytical methods. When a pharmaceutical manufacturer plans to supply a product throughout the world, repeat testing on the same excipient will be needed to meet USP, JP, Ph. Eur., BP, and other pharmacopoeias. There is ongoing harmonization of excipient monographs under the auspices of the Pharmacopoeial Discussion Group (PDG). The PDG has been working on several of the commonly used excipients in order to achieve a single monograph for each excipient. At present, 26 general chapters and 40 excipient monographs have been harmonized (Stage 6 of the process). For example, benzyl alcohol undergoes degradation by a free radical mechanism to form benzaldehyde and hydrogen peroxide. The degradation products are much more toxic than the parent molecule. The USP, JP and Ph. Eur. require three different chromatographic systems to test for organic impurity (mainly benzaldehyde). The harmonized monograph of benzyl alcohol has eliminated unnecessary repetition, which does not contribute to the overall quality of the product (68). The following 11 pharmacopoeial tests can be substituted by a single gas chromatography (GC) method:

Regulatory bodies are focusing their attention on the manufacturing process used to produce excipients. Major initiatives by the IPEC to improve the quality of additives has resulted in a publication guide titled Good Manufacturing Practices Guide for Bulk Pharmaceutical Excipients (69). Excipients may be manufactured for food, cosmetic, chemical, agriculture, or pharmaceutical industry; the requirements differ for each area. This guide proposes to develop a quality system framework to be used for suppliers of excipients, one that is acceptable to the pharmaceutical industry and will harmonize the requirements in the U.S., Europe, and Japan.

The United States and Europe require all excipients to be declared, along with their quantity, on the label (what is put on the immediate container) if the product is an injectable preparation. In Japan only the excipient names are required in the labeling (information that is included with the product, such as a package insert); E.U. Article 54(c) requires that all excipients must be declared on the labeling if the medicinal product is an injectable, a topical, or an eye preparation. The European guide for the label and package leaflet also lists excipients with special issues and are addressed in an Annex (70). Table XIII is a summary of some of these ingredients commonly used as parenteral excipients and the corresponding safety information that should be included in a leaflet. A package leaflet must include a list of information on those excipients, knowledge of which is important for the safe and effective use of the medicinal product. Similarly, 21 CFR 201.22 requires prescription drugs containing sulfites to be labeled with a warning statement about possible hypersensitivity. An informational chapter in USP, 〈1091〉 Labeling of Inactive Ingredients, provides guidelines for labeling of inactive ingredients present in dosage forms.

According to the Notes for Guidance on Pharmaceutical Development (CHMP/ICH/167068/04), the choice of excipients, their grade, compatibility, concentration, and function should be described in the P2 section of the Common Technical Document. It is necessary to justify inclusion of all ingredients in the drug product and describe their intended function. A specification of ±10% at the end of shelf-life is acceptable except for antioxidants and preservatives where performance data from PET or stability data may justify broader limits.

Bioburden and endotoxin limits of excipients used in the manufacture of sterile medical products shall be stated. Individual testing of excipients may be omitted if bioburden and endotoxin testing of the solution is checked prior to sterilization.

If an excipient is present in Ph. Eur or other major pharmacopoeia, the monograph specifications are usually acceptable in the registration file. For excipients not described in any pharmacopoeia, specifications should include physical characterization, identification tests, purity test, assay, and impurity tests. A certification must be included to confirm that excipients are of non-animal (specifically non-ruminate) origin. If this is not the case, a regulatory agency will require documentation to demonstrate freedom from viral and transmissible spongiform encephalopathies (TSE) risks (71).

IV. Criteria for the Selection of Excipient and Supplier

During the development of parenteral dosage forms, a formulator selects excipients to provide a stable, efficacious, and functional product. The choice and the characteristics of excipients should be appropriate for the intended purpose.

“An explanation should be provided with regard to the function of all constituents in the formulation, with justification for their inclusion. In some cases, experimental data may be necessary to justify such inclusion, e.g., preservatives. The choice of the quality of the excipient should be guided by its role in the formulation and by the proposed manufacturing process. In some cases it may be necessary to address and justify the quality of certain excipients in the formulation” (72).

Normally in the U.S. a pharmaceutical development report is written and should be available at the time of a pre-approval inspection. A development report captures the choice of excipients; their purpose and level in the drug product; their compatibility with other excipients, drug, or package system; and how they may influence the stability and efficacy of the finished product.

The following key points should be considered in selecting an excipient and its supplier for parenteral products:

1. Influence of excipient on overall quality, stability, and effectiveness of drug product.

2. Physical, chemical, and biological compatibility of excipient with drug and packaging system (73).

3. Compatibility of excipient with manufacturing process. For example, preservatives may be adsorbed by rubber tubes or filters; acetate buffers will be lost during lyophilization process, etc.

4. Amount or percentage of excipients that can be added to drug product. Table VI summarizes the maximum amounts of preservatives and antioxidants allowed by various pharmacopoeias.

5. Route of administration. USP, Ph. Eur., and BP do not allow preservatives to be present in injections intended to come in contact with brain tissues or cerebrospinal fluid. Accordingly, intracisternal, epidural, and intradural injections should be preservative free. It is preferred for an intravenously administered drug product to be a solution. If the size of the particle is well controlled, and below a certain maximum size (e.g., in a fat emulsion or a colloidal albumin or amphotericin B dispersion) then the drug can be administered by intravenous route.

6. Dose volume. All large volume parenterals (LVPs) and those vmall volume parenterals (SVPs) in which a single dose injection volume can be greater than 15 mL are required by Ph. Eur./BP to be preservative-free unless otherwise justified. The USP recommends that added substances are carefully chosen for use in injections that are administered in volumes exceeding 5 mL (34).

7. Whether a product is intended for single or multiple dose use. According to the USP, single dose injections should be preservative-free. The FDA's position for single dose injections, which have to be aseptically processed, is that manufacturers should not use a preservative to prevent microbial growth. European agencies have taken a less stringent stance on this subject.

8. The length or duration of time that a drug product will be used once the multi-dose injection is opened.

9. How safe is the excipient? Does it cause tissue irritation, hemolysis, or other toxic effects on cells, tissues, or organs?

10. Does the parenteral excipient contain very low levels of lead, aluminum, or other heavy metals?

11. Does a dossier or DMF exist for the excipient?

12. Has the excipient been used in humans? Has it been used via a parenteral route and in the amount and concentration that is being planned?

13. Has the drug product containing this excipient been approved throughout the world?

14. What is the cost of the excipient; is it readily available?

15. Is the excipient vendor following the GMP guide? Is the vendor ISO 9000 certified?

16. Will the excipient supplier certify the excipient to meet USP, BP, Ph. Eur., JP and other pharmacopoeias?

17. Has the supplier been audited by the FDA or the company's audit group? How did they fare?

Impurities in excipients can have a dramatic influence on the safety, efficacy, or stability of a drug product. Monomers or metal catalysts used during a polymerization process are toxic and also destabilize a drug product if present in trace amounts. Due to safety concerns, the limit of vinyl chloride (monomer) in polyvinyl pyrrolidone is ≤10 ppm and for hydrazine (a side product of polymerization reaction) ≤1ppm. Monomeric ethylene oxide is highly toxic and can be present in ethoxylated excipients like PEGs, ethoxylated fatty acids, etc.

The FDA has issued a guidance suggesting that animal-derived materials (e.g., egg yolk lecithin, egg phospholipid) used in drug products, originating from Belgium, France, and the Netherlands between January and June 1999 should be investigated for the presence of dioxin and polychlorinated biphenyls. Contamination of the animal-derived product was probably caused by consumption of contaminated animal feed.

Excipients manufactured by fermentation processes, such as dextrose, citric acid, mannitol, and trehalose, should be specially controlled for endotoxin levels. Mycotoxins (highly toxic metabolic products of certain fungi species) contamination of an excipient derived from natural material has not been specifically addressed by regulatory authorities. The German health authority issued a draft guideline in 1997 wherein a limit was specified for Aflotoxins M₁, B₁, and the sum of B₁, B₂, G₁, and G₂ in the starting material for pharmaceutical products.

Heavy metal contamination of an excipient is a concern, especially for sugars, phosphate, and citrate. Several rules have been proposed or established. For example, Ph. Eur. sets a limit of ≤1 ppm of nickel in polyols. California Proposition 65 specifies a limit of ≤0.5 μg of lead per day per product (74). Similarly, the USP and FDA limit aluminum content for all LVPs used in TPN therapy to 25 μg per liter (75). Further, it would require that the maximum level of aluminum in SVPs intended to be added to LVPs and pharmacy bulk packages, at expiration date, be stated on the immediate container label.

Physical and chemical stability of an excipient should be considered in assigning a re-evaluation date. Many drug products have a small amount of active drug and a comparatively high amount of excipients. Degradation of even a small percentage of excipient can lead to levels of impurities sufficient to react with or degrade a large percentage of active material. For example, benzyl alcohol decomposes via a free radical mechanism, in the presence of light and oxygen, to form benzaldehyde (x% of benzaldehyde is approximately equivalent to 1/3 x% of hydrogen peroxide). Hydrogen peroxide can rapidly oxidize sulfhydryl groups of amino acids like cysteine present in peptides or proteins.

Adequate research and thought is essential in the selection of a pharmaceutical excipient supplier. It is not uncommon for a supplier to change its manufacturing process to make it more efficient (less costly). Frequently, excipients are commodity (high volume/low value) products which are used by several industries. The pharmaceutical industry is often not a major customer in terms of volume of material purchased. For example, the pharmaceutical industry uses approximately 20% of gelatin produced. Of this 20%, most is used for production of oral dosage forms. The parenteral portion is approximately 5% of the 20%. It is extremely important that a drug manufacturer has a contract with an excipient supplier, prohibiting the supplier from making any change in the process or quality of the material without informing their customer well in advance. Pharmaceutical manufacturers should investigate all alternate sources that could be used in an emergency. A change in supplier should not be made without consulting the pertinent regulatory bodies because such an event may require prior regulatory approval.

A pharmaceutical manufacturer should have an active Vendor Certification Program. It should assure that vendor is ISO 9000 certified. An audit of an excipient manufacturer is essential because the pharmaceutical manufacturer is ultimately responsible for the quality of the drug product that includes the excipient(s) as one of its components. The IPEC GMP guide may be used as an audit tool because it is written in an ISO 9000 format using identical nomenclature and paragraph numbering. An audit ensures that quality is being built into the excipient, which may be difficult to measure later by quality control upon receiving the material. This is especially true for parenteral excipients where not only chemical but also microbiological attributes are critical. Bioburden and endotoxin limits may be required for each of the excipients and several guidelines are available to establish specifications (76, 77).

There are no legal requirements for excipient GMPs in Europe (78). A qualified person is responsible to assure that excipient quality is appropriate based on pharmacopeial specifications or a company's quality systems.

Events in Haiti highlight the importance of assuring excipient quality to the same degree that one normally does for active ingredients. From November 1995 through June 1996, acute anuric renal failure was diagnosed in 86 children. This was associated with the use of diethylene glycol contaminated glycerin used to manufacture acetaminophen syrup (79). The FDA is advising pharmaceutical companies to test for melamine down to a 2.5 ppm level in certain nitrogen-rich drug ingredients (raw materials that contain more than 2.5% nitrogen and those for which purity or strength is determined on the basis of nitrogen content) (80). The list of excipients includes albumin, amino acids derived from casein protein hydrolysates, ammonium salts, protamine sulfate, povidone, lactose, gelatin, etc. This guidance is in response to the incidents of pet food and Chinese milk doped with melamine.

The FDA recognizes the importance of excipients in a drug product for performance and safety. An injectable generic product should have identical non-exceptional excipients (qualitatively and quantitatively) as that of reference listed drug if the generic drug product is to follow the simplest path of registration; otherwise additional data must be submitted to demonstrate that the differences do not affect safety or performance (81). For parenteral products, non-exceptional excipients are ingredients other than preservatives, pH adjuster, antioxidant, and buffers.

V. Safety Issues

Handbook of Excipients edited by Bernstein (82) is an excellent reference on the safety and adverse reaction to several excipients. Sensitization reactions have been reported for parabens, thimerosal, and propyl gallate. Sorbitol, which metabolizes to fructose, can be dangerous when administered to fructose-intolerant patients. Table XIII lists safety concerns that must be included in labeling.

Progress in drug delivery systems and new proteins/peptides being developed for parenteral administration has created a need to expand the list of excipients that can be safely used. An informational chapter in the USP presents a scientifically based approach for safety assessment of new pharmaceutical excipients (83). A new or novel excipient is defined as one not previously used in a pharmaceutical preparation or not fully qualified by existing safety data with respect to the proposed level and duration of exposure or route of administration (84). Table XIV summarizes the approach in developing a new excipient. Besides the baseline toxicity data (either through literature or experimentation), if the drug (excipient) will be administered short-term (<14 days of consecutive days per treatment episode), intermediate-term (14–90 days), or long-term (>3 months) then additional safety information on the excipient is needed (84).

Currently, there are concerns regarding TSE via animal-derived excipients such as gelatin (85). TSEs are caused by prions that are extremely resistant to heat and normal sterilization processes. TSEs have a very long incubation time with no cure and include diseases such as

• Scrapies in sheep and goat

• Bovine spongiform encephalopathy (BSE), otherwise known as Mad Cow Disease, in cattle

• Kuru disease in humans

• Creutzfeldt-Jacob disease in humans, which has been attributed to repeated parenteral administration of growth hormone and gonadotropin derived from human pituitary glands

Several guidelines have been issued that address the issue of animal-derived excipients and scientific principles to minimize the possible transmission of TSE via medicinal products (86, ). The current situation indicates that there are negligible concerns for lactose, glycerol, fatty acids and their esters, but the situation is less clear for gelatin. Gelatin is still a necessary ingredient for some medicinal products and EMA (European Medicine Agency, formerly known as EMEA) has updated its guidance to allow gelatin from Category I and II countries if gelatin is produced by the acid process and Category I, II, and III countries if produced by the alkali process (88). Additional information on risk assessment of ruminate materials originating from USA, Canada, and other countries can be found in the references (87, 89, 90).

In the current regulatory environment, if given a choice, it is beneficial to select non-animal-derived excipient. Concerns about bovine serum albumin or human serum albumin (HSA) because of possible derivation from virus-contaminated blood remain. Recombinant human erythropoietin and darbepoetin alfa formulations were changed to replace albumin with polysorbate 80. Presently, recombinant HSA is available from several companies; this reduces probability of TSE (91). The risk of TSE from excipients can be greatly reduced by controlling the following parameters:

1. Sourcing of animal from countries where BSE has not been reported.

2. Using young animals

3. Category III or IV animal tissue used in manufacture (86)

4. Production process which is likely to destroy TSE agents

European Commission directive EMEA/410/01/rev 2 requires manufacturers to provide a “Certificate of Suitability” or the underlying “scientific information” to attest that their pharmaceuticals are free of TSEs.

Vegetable origin polysorbate should be used. If older products contain animal-sourced polysorbate then a switch should be made. EMA has stated that a change of a polysorbate 80 source will not result in re-performing viral inactivation studies (92). The vegetable source (e.g., trehalose from corn or tapioca) must be known as well as if any processing aids (e.g., enzymes during production of lactose) used during manufacturing of the excipient are derived from an animal source.

VI. Future Directions

Several new excipients, such as cyclodextrins, are being evaluated to improve solubility or stability of parenteral drugs. Currently, there are two FDA-approved parenteral products that utilize alpha and gamma cyclodextrins. Beta-cyclodextrin is unsuitable for parenteral administration because it causes necrosis of the proximal kidney tubules upon intravenous and subcutaneous administration (93). Hydroxypropyl beta-cyclodextrin (HPβCD) and sulfobutylether β-cyclodextrin (SBE-7-β-CD) have shown the most promise. Captisol™, the trade name of SBE-7-β-CD, is anionic. Currently, three Captisol™-based drug formulations have been approved in the U.S. One parenteral formulation is in Phase II/III clinical trials that utilize HPβCD (Cavitron®), and another (Sporanox) has been approved by the FDA. Manufacturers of HPβCD and SBE-7-β-CD have established a DMF with the FDA. Detailed reviews of cyclodextrins have been recently published (94, 95). One caution in using cyclodextrin is that they can (in rare cases) accelerate drug product degradation (96) and can sequester preservatives, rendering them ineffective (97).

Chitosan, β-1,4-linked glucosamine, a naturally occurring, biodegradable, nontoxic polycationic biopolymer, is being investigated for its potential as a cross-linked microsphere matrix to deliver antineoplastic drugs. Because of its charge, it can trap several drugs and can bind strongly with cancer cells, minimizing drug toxicity and enhancing therapeutic efficacy (98). Chitosan has also been shown to stabilize liposomes.

Biodegradable polymeric materials (polylactic acid, polyglycolic acid, and other poly-alpha-hydroxy acids) have been used as medical devices and as biodegradable sutures since the 1960s (99). Currently, the FDA has approved for marketing only devices made from homopolymers or co-polymers of glycolide, lactide, caprolactone, p-dioxanone, and trimethylene carbonate (100). Such bio-polymers are finding increased application as a matrix to deliver parenteral drugs for prolonged delivery (101). At least four drug products—Lupron Depot®, Decapeptyl®, Nutropin Depot®, and Zoladex®—have been approved. All four drug products are microspheres in Polyglycolic acid (PGA), Polylactic acid (PLA), or Polylacic-glycolic acid (PLGA) matrix. PGA is highly crystalline (approximately 50%) with a high melting point (220–225 °C). PLA can be produced by polymerization of L-lactic acid (LPLA), D-lactic acid (DPLA), or a blend of D&L-lactic acid (DLPLA). LPLA is 37% crystalline while DLPLA is amorphous. The degradation time of LPLA is much slower than that of DPLA. By copolymerizing lactic and glycolic acid polymeric matrices, a wide range of properties (tensile strength, crystallinity, and degradation rate) can be obtained. Decapeptyl®, a microsphere for intramuscular administration, is approved in France. It contains drug in a matrix of PLGA and Carboxymethyl cellulose with mannitol and polysorbate 80.

Polyanhydrides degrade primarily by surface erosion and possess excellent in vivo compatibility. In 1996 the FDA approved a polyanhydride-based drug implantable delivery system to the brain for the chemotherapeutic agent 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU).

Several phospholipid-based excipients are finding increased application as solubilizing agents, emulsifying agents, or as components of liposomal formulations. The phospholipids occur naturally and are biocompatible and biodegradable, for example, egg phosphatidylcholine, soybean phosphatidylcholine, hydrogenated soybean phosphatidylcholine (HSPC), dimyristoyl phosphatidylcholine (DMPC), distearoyl phosphatidylcholine (DSPC), 1,2 dioleoyl-sn-glycero-3-phosphocholine (DOPC), distearoyl phosphoethanolamine (DSPE), L-alpha-dimyristoylphosphatidylglycerol (DMPG), 1,2-dipalmitoyl-sn-glycero-3-phosho-rac-(1-glycerol) (DPPG), and distearoylphosphatidylglycerol (DSPG). Spartaject™ technology uses a mixture of phospholipids to encapsulate poorly water-soluble drug, forming a micro-suspension that can be injected intravenously. Busulfan drug product uses this technology and is currently undergoing Phase I clinical trials. Many liposomal and liposomal-like formulations (DepoFoam®) are either approved (DepoCyt®) or are undergoing clinical trials to reduce drug toxicity, improve drug stability, prolong the duration of action, or to deliver drug to the central nervous system (102). Two amphotericin formulations, a liposomal, or lipid complex between the antifungal drug and the positively charged lipid, have been approved in the U.S. Amphotec® is a 1:1 molar ratio complex of amphotericin B and cholesteryl sulfate while Abelcet® is a 1:1 molar complex of amphotericin B with phospholipids (7 parts of L-α-dimyristoylphosphatidylcholine and L-α-dimyristoylphosphatidyl glycerol).

Poloxamer or pluronic are block copolymers comprised of polyoxyethylene and polyoxypropylene segments. They exhibit reverse thermal gelation and are being tried as solubilizing, emulsifying, and stabilizing agents. A depot drug delivery system can be created using pluronics whereby the product is a viscous injection that gels upon intramuscular injection (103). Pluronics can prevent protein aggregation or ad/absorption and help in the reconstitution of lyophilized products. Pluronic F68 (Polaxamer-188), F38 (Poloxamer-108), and F127 (Poloxamer-407) are the most commonly used pluronics. For example, a liquid formulation of human growth hormone and Factor VIII can be stabilized using pluronics. Fluosol® is a complex mixture of perfluorocarbons with a high oxygen carrying capacity emulsified with Pluronic F-68 and various lipids. It was recently approved by the FDA for adjuvant therapy to reduce myocardial ischemia during coronary angioplasty. A highly purified form of Ploxamer 188 (Flocor™), intended for intravenous administration, is undergoing Phase III clinical trials for various cardiovascular diseases. Purification of Poloxamer 188 reduces nephrotoxicity. Another non-ionic surfactant, Solutol HS 15 (Macrogol-15-Hydroxystearate), has been approved by the Health Canada in a vitamin K1 formulation for human application.

Poloxamer and other polymeric materials like albumin may coat micro- or nanoparticles, alter their surface characteristics, and reduce their phagocytosis and opsonization by reticulo-endothelial system following intravenous injection. Such surface modifications often result in prolongation in the circulation time of intravenously injected colloidal dispersions (104). Poloxamers have also been used to stabilize suspensions (105).

The first successful development of an injectable perfluorocarbons-based commercial product was achieved by the Green Cross Corporation in Japan. They made Fluosol-DA®, a dilute (20% w/v) emulsion based on perfluorodecalin and perflurotripropylamine emulsified with potassium oleate, Pluronic F-68, and egg yolk lecithin. These perfluorocarbons are inert and can also be used to formulate non-aqueous preparations of insoluble proteins and small molecules (106). Perfluorocarbons have been approved by the FDA in one ultrasound contrast agent, Optison®, administered via the intravenous route. Optison® is a suspension of microspheres of human serum albumin with octafluoropropane. Heat treatment and sonication of appropriately diluted human albumin, in the presence of octafluoropropane gas, is used to manufacture microspheres in Optison® injection. The protein in the microsphere shell makes up approximately 5–7% (w/w) of the total protein in the liquid. The microspheres have a mean diameter range of 2.0–4.5 μm with 93% of the microspheres being less than 10 μm.

Sucrose acetate isobutyrate (SAIB), a high viscosity liquid system, converts into free flowing liquid when mixed with 10–15% ethanol (107). Upon subcutaneous or intramuscular injection, the matrix rapidly converts to a water-insoluble semi-solid capable of delivering proteins and small molecules for a prolonged period. SAIB is biocompatible, and it biodegrades to natural metabolites.

Several other biodegradable, biocompatible, injectable polymers are being investigated for drug delivery systems. They include polyvinyl alcohol, block copolymer of PLA-PEG, polycyanoacrylate, polyanhydrides, cellulose, alginate, collagen, modified HSA, albumin, starches, dextrans, hyaluronic acid and its derivatives, and hydroxyapatite (108). Efficient parenteral delivery of genes, immunomodulators, RNAi, anti-sense, aptamers, and other novel therapeutic agents will invariably require new excipients, with several excipients in early pre-clinical or clinical use (109).

Recent concerns about swine flu and other infectious diseases have regenerated interest in new vaccines and adjuvants to improve immune response. Some of the adjuvants included in marketed vaccines in Europe but still being evaluated include AS03 and AS04 (GSK) and MF-59 (Novartis). AS04 is composed of 3-O-desacyl-4′-monophosphoryl lipid A. It is present in Cervarix, which was approved in 2010. Newer adjuvants being tested include saponin-based (QS-21, Quil A, ISCOM) or emulsion-based (SA03).