Excipients consists of  a large ingredients segment which the  common public is unaware of. Though drug products give life to humans due to active ingredients they contain,  the excipients are the ones who aid that product for efficient delivery to particular site of action. Excipients are major contributory ingredients in pharmaceutical dosage forms, sometimes accounting more than 90 per cent of the weight. These are of different types and grades. The whole fundamentals of drug delivery systems rely on their effective use in appropriate concentrations. This article focuses on excipient market with development of novel excipient along with regulatory guidelines for development of these ingredients.

Excipient is generally a pharmacologically inactive substance used as carrier for active ingredients of medication. They serve different purposes such as bulking, carriers, disintegrants, solubility modifiers and many more. According to European Medicines Agency (EMA earlier EMEA), excipients may be defined as “the constituents of a pharmaceutical form that are not the active substance. According to their function, these constituents can be classified as technological, applicatory, stabilizing or biopharmaceutical excipients.”

Till 90’s decade, excipients were the most neglected sector in pharmaceutical industry. Only a few novel excipients were launched in market in this period. In the current decade, excipient market has shown pronounced growth. In 2011, global pharmaceutical excipients market was $4.9 billion and is expected to grow to $6.7 billion by 2016. In terms of volume approximately 5 billion kg of excipients were used in year 2011. Compound annual growth rate for this market segment is expected to be 6.5 per cent.

The major producing areas for excipients in world are North America and Europe. These regions consume around 70 per cent of the output whereas Japan is having around 15 per cent. Recent market research suggests that emerging markets for pharmaceuticals such as India, China and Brazil are also becoming major markets for excipients. Many foreign companies have recently set up offices in India as part of expansion of business. The reason behind growing of excipients segment is that many patented drugs will go off patent by end of 2012. Therefore, for developing new generic versions, it becomes essential to use new excipient in formulation development.

In general, excipients are used for following purposes:

• Aids processing of the system during manufacture
• Protect, support, or enhance stability,
• Bioavailability, or patient acceptability
• Assist in product identification
• Enhance any other attribute of the overall safety and effectiveness of the drug delivery system during storage and use.

The novel excipient
Novel excipient is a new chemical entity, a new innovation that has not been used in any drug approved by regulatory authorities or it is a combination of excipients containing new chemical entity/entities (not in approved drugs) and excipients that are already in approved drugs in a mixed or co-processed scenario.

Developing novel excipients
Karl Kotler states that developing novel excipients is not of choice for excipients manufacturers and suppliers because long development timelines, high costs incurred during safety studies and other studies and risks of failure.

Market trends suggest that pharma companies are not eager to use novel excipients because they don’t want to add additional risks to product being developed as regulatory authority might not approve drug product because of new excipient. Apart from this, pharma companies are also worried about reliable supply from GMP production facilities while using novel excipients.

Development of novel excipients can be carried out in two different ways:
Modification of already known excipient
This type of development is done by modification of already existing excipient by developing its derivative or successor. Chemical modification in structure of excipient is done by changing or introducing new functional groups to existing excipient. Classical example of it may be development of different cellulose derivatives, cyclodextrins etc.

Completely new excipient with no predecessor
This is the most challenging task that researchers have to face. It starts from thinking about base moiety for excipient. Once target is identified, different chemical structure classes are screened and selected structure is optimized for particular characteristics. After that scale up and pilot scales batches were taken. At each step, quality control testing and characterization different parameters such as viscosity, rheology, spectroscopy testing etc. is done. Along with this, toxicological testing in animals is carried out which generally takes three years to complete. Subsequently, production scales batches are manufactured and drug master file (DMF) application is submitted. In all, novel excipient development takes 6-8 years to complete.

Examples of novel excipients developed recently are as follows:
Characterization of novel excipients
Generally novel excipients are characterized for three important properties domains:

Functionality
This involves pharmaceutical assessment and investigation of drug delivery properties. For this study, different formulations containing novel excipient along with already existing approved excipients are prepared and are assessed for different tests such as dissolution testing. In vitro dissolution testing provides prediction of in vivo bioavailability.

Physicochemical properties
It involves assessment of physicochemical properties of excipients, impurities profiling, and stability assessment. This characterization involves spectroscopic, chromatographic, thermal methods of analysis. During this analysis, viscosity, rheology, melting point, specific gravity, refractive index, acid and ester values, loss on heating and drying, pH value, heavy metals, residual solvents and monomers were determined.

Safety / toxicology
During this study, ICH M4S (R2) guideline is followed for generation of safety data. Chronic and sub-chronic toxicity, genotoxicity (including mutagenicity), reproductive toxicity, carcinogenicity, primary irritation and skin sensitization testing, bioavailability, pharmacokinetics (ADME) and characterization of impurities and their toxicity are done in this study domain.

Regulatory provisions
Question arises in minds whether  excipients are actually inert? Historically, Sulfanilamide tragedy 1937 happened due to lack of knowledge about excipients’ use. This gave us regulatory reforms leading to development of regulatory guidelines regarding excipients.

Currently, there is no special provision for approval of new excipients. Excipients are approved along with the dosage forms. Excipient is regarded as “approved” when the new drug formulation containing  novel excipient received regulatory approval. Existing guidelines do not provide guidance on potentially useful excipients from food / beverage industries or for excipient with a new application such as changing dose route.  But still pharmaceutical excipient companies are investing in evaluation of new materials and application of new uses for existing excipients.

In 3.2.P.4.6 Section of International Conference on Harmonization (ICH) M4 Q (R1) step 4 guideline following is mentioned:

For excipient(s) used for the first time in a drug product or by a new route of administration, full details of manufacture, characterization, and controls, with cross references to supporting safety data (nonclinical and/or clinical) should be provided according to the drug substance format.

Similarly European Medicines Agency has given following guidelines in Section 4.5 with following details :

For novel excipients, a dossier should be established containing the same data as required for new active substances:

• A strict definition of the excipient, its function and its conditions of use. If the excipient is complex or is made of a mixture of compounds, the composition should be specified in qualitative and quantitative terms.
• For novel excipients and for excipients presented as a mixture of compounds the following should be taken into consideration:
• Any bibliographical data on the chemistry and on the toxicology and the field in which the product is already used.
• The community provisions concerning additives in foodstuffs: any criteria which are based on the toxicological data, with cross-references to these data.
• The quality specifications which have been laid down in the directives are satisfactory as long as the routine control tests used are validated.
• The international specifications (FAO/ WHO/ JECFA), and other publications such as the Food Chemical Codex.
• For medicinal products for cutaneous use, data on the starting material in cosmetic products.
• Data concerning the toxicology of the novel excipient should be presented according to the dosage form and the route of administration of the medicinal product (if applicable).
• Documentation on chemistry of excipients is required for all new excipients, taking as its basis the CPMP Guideline on the Chemistry of New Active Substances
• The origin of the excipient, including the name and address of manufacturer.
• A general outline of the synthesis (manufacture and purification).
• Structure.
• Physical, chemical properties, identification and purity tests.
• Validated methods of analysis with a presentation of batch results.
• Miscellaneous information (microbiological tests, etc).
• Contamination, presence of foreign substances, residual solvents etc.
• In the case of an excipient obtained from a mixture of several components, the quality of each component and the physiochemical tests for the mixture should be described.
• Stability data should be provided as required for the active substances in the ICH Q1A
• The routine test procedures and limits should be established on the basis of the documentation given in the dossier.

International Pharmaceutical Excipients Council (IPEC) is working for harmonization and setting up guidelines for novel excipients. IPEC has set up excipient master file guide for novel excipients as Type IV Drug master file (DMF). This guide has been divided into administrative information and technical document portion. Technical document is similar to ICH Common technical document (CTD) portion with 15 points.

Novel excipient monograph
Once the excipient has been used in formulations and  has been approved by regulatory authorities, monograph making process starts. Proposed monograph data package is sent to pharmacopoeial expert committee on excipients for review. If it is accepted, it is released for public comment. If no comments are received for monograph, it will be approved for inclusion which takes 60- 90 days. If comments are received, revision is made and again public consultation is done. In general, for an excipient monograph to get official status, 6 to 15 months are required.

Future prospects
In short it can be said that challenges in formulation and drug delivery of active ingredients are impossible to solve with old excipients. Therefore, more research will be focused on development of novel excipients for efficient drug delivery at targeted site. Individual approval of excipient by separate registration process from finished product registration will provide guide to pharma companies for effective use of novel excipient in safe dosage. Due to this, research on novel excipient will also foster leading to their use in different dosage forms and routes. All these activities will promote innovation in novel excipients by providing ease of market approach and penetration to excipient companies. Final outcome of this will be effective, safe and reliable medicine to patient leading to betterment of mankind.