The quality of excipients is critical to assure the safety, quality and efficacy of drug products. Excipients impart cosmetic appearance, stability and delivery of the active substanceto formulated drug products.

To have a controlled drug product, appropriate specifications and test methods must be established and applied for identification, purity, impurities and physical characteristics. In addition to this for excipients, functionality test must be included in the specification to support the function for which it is selected.

Ideal excipients should be inert towards active ingredients, other excipients, machinery and packaging materials.

Excipients are defined as any substances other than the active drug substance which have been evaluated for safety and are included in a drug delivery system to either aid the processing of the drug delivery system during its manufacture, protect, support or enhance stability, patient acceptability and bioavailability.

Excipients are used as the vehicle that carries the few milligrams of drug to the body.

Drug products consist of Active Pharmaceutical Ingredients and excipients. Excipients will have one or more of the following functions in a drug formulation.

Solvent Binder Coating agent
Emulsifier Disintegrant Colorant
Antifoaming agent Filler Taste agent
Thickener Lubricant
Antioxidant Solubilizer
Preservative Wetting agent
Buffer

These functions are vital for the quality, safety and efficacy of drug products. During the development of the drug product a careful study and selection of excipients influence these performance parameters.

The function of an excipient in a drug formulation should be straight forward. It should serve a physical, chemical or biological function by acting for example as a tablet filler, a lubricant, an antimicrobial agent, a surfactant or as an agent added to improve the performance or manufacturability of the formulation. Therefore specifications for excipients must be finalized after verification of the drug product after development. Test methods must be described in detail by which the quality is tested. As already discussed, excipients are essential constituents of drug formulation. Excipients contribute unique functionalities to drug products, thereby determining the drug products quality, safety and efficacy. Since excipients play such an important role, it is obvious that the drug manufacturer have to require from excipients manufacturer's adherence to adequate GMPs.

As required for drug substances, these GMP practices also required for excipients. The most important control parameter for GMP is Change control system.

The excipient manufacturer therefore should establish and maintain an adequate system for controlling changes within production process. So drug manufactures must have a policy to audit the excipient manufacturer's facilities. Since process changes might also have regulatory impact, the manufacturer must file the variation to the health authorities. In order to fulfill this requirement, drug manufacturers must have continuous communication system with excipient manufacturers.

An important requirement for functionality related tests is that they should provide information that facilitates the optimum choice of the excipient. The customer requirements can be expressed in terms as good mixing properties, should contribute to a good content uniformity, compatible with other components, should have good binding properties, should yield good tablets.

To meet these requirement manufacturer must consider the following properties for excipients as required for production, particle size distribution.

Specific area:
Rugosity
Hausner ratio
Angle of repose

To have a better control on excipients well defined quality systems must be followed.

Antioxidants and antimicrobial preservatives are substances which are used to extend the shelf - life of medicines by respectively retarding the oxidation of active substances and excipients and by reducing microbial proliferation.

Justification of specifications must be addressed.

Drug product manufacturers should know the process followed to make the excipients its process flow and solvents used in the process. The same set of rules followed for APIs must be applied for excipients.

Chemically transformed excipients include excipients which have undergone a special chemical treatment in order to confer certain technological characteristics. The name and quality of such excipients should be defined in such a way as to avoid confusion with an unmodified excipient.

Excipients are generally manufactured on a large scale, which means that the use of automated process controls and continuous stream processing are more likely to be utilized.

Many excipients have applications other than for pharmaceutical uses and are used in food, cosmetics or industrial products. Therefore drug formulators must identify and set appropriate limits for impurities based on the process.

The formulator of finished dosage forms is highly dependant on the excipient manufacturer to provide bulk pharmaceutical excipients that are uniform in chemical and physical characteristics. This is particularly important in the context of the product approval process where bioequivalency comparisons are made between pivotal clinical biobatch production and commercial scale-up batches. For this reason drug formulators should have a control mechanism for controlling the quality parameters of excipients.

Since excipients are used as purchased, so impurities present in it will present in the finished dosage form, while manufacturers of dosage forms may have limited control over excipient quality through specifications, the excipient manufacturer has greater control over physical characteristics, quality and the presence of impurities in the excipients.

Since excipients are used in different types of dosage forms where physical characteristics such as particle size, bulk density, flow ability are important, the manufacturer of dosage form must have control for these properties.

Since residual solvents control is required as per the GMP, the manufacturer of drug product must have full control on its limits in excipients.

In view of the increasing globalization of the pharmaceutical industry and harmonization of pharmaceutical registration requirements the following cGMP requirements for excipients are required.

The formal release of every batch based on validated methods or compendial methods.

Close monitoring of suppliers and manufacturing processes.

Assurance of the traceability and execution of comprehensive change control agreements along with the entire supply chain.
Assurance of hygiene excipients manufacture.
Minimization of the known quality risk of the substances.
Control over residual monomers in synthetic polymer excipients.

The author is Executive Vice President for Corporate QC and QA, Natco Pharma Ltd, Hyderabad.