Excipients are components of a finished drug product other than the active pharmaceutical ingredient and are added during formulation for a specific purpose. Excipient functionality is one of the latest buzz phrase heard in pharmaceutical industry now-a-days. Excipients are not active pharmaceutical ingredients and they do not treat medical conditions. But without them, the therapeutic revolution of the past 50–60 years could not have occurred.

The International Pharmaceutical Excipients Council (IPEC) defines excipients as “substances, other than the active drug substance of finished dosage form, which have been appropriately 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; enhance stability, bioavailability, or patient acceptability; assist in product identification; or enhance any other attributes of the overall safety and effectiveness of the drug delivery system during storage or use”.

Due to the USFDA initiatives such as Quality by Design (QbD), excipient selection is now being considered earlier in the drug development process, especially since new candidates today are often less soluble. Exploring excipient functionality in the pre-formulation stage can help advance promising candidates that might otherwise be abandoned due to inadequate dissolution or bioavailability. In a post-blockbuster era when the number of new compounds being launched is ever diminishing, novel excipients can help increase New Drug Application (NDA).

In recent years there have been several excipient quality disasters that have heightened awareness for the need to better regulate the excipients industry. In 2006, 46 people died in Panama after taking cough syrup also contaminated with DEG. In 2008, 84 children died in Nigeria after consuming teething formula containing glycerine contaminated with diethylene glycol (DEG). Several similar incidents have occurred, most often due to intentional misuse or neglectful mislabelling. With several deadly accidents related to excipients, no one can deny that there is a real need for better regulations to reduce confusion, ensure quality and prevent such tragedies. While various guidelines and certifications exist in the excipients industry, there is no universal standard.

Because excipient manufacturers are not required to register as drug manufacturers, it remains relatively easy for an ingredient not intended or suited for pharmaceutical use to be introduced into the supply chain. Since the excipient user bears ultimate responsibility for an excipient’s quality, many pharmaceutical manufacturers have embarked on supply chain security initiatives or an excipient pedigree verification practice to mitigate risks. However, these measures only guarantee the source of the excipient, not necessarily the quality of the excipient as it is manufactured.

Regulatory requirement for excipients
Parties involved in the supply chain should be aware that an excipient can only be pharmaceutical grade when it is in compliance with pharmacopoeial specification and/or appropriate regulatory requirements (if existing for the specific excipient) and is manufactured, repackaged, and handled in accordance with excipient GMPs (e.g. IPEC PQG GMP, WHO Excipient GMP). Customers can be assured that excipients manufactured according to the Joint IPEC – PQG Good Manufacturing Practices Guide for Pharmaceutical excipients 2006 will meet internationally accepted Good manufacturing practice (GMP) principles. Unlike active pharmaceutical ingredients, there is a lack of regulatory procedures for a new excipient and no appropriate regulatory protection of ‘know-how’ or of any other intellectual property rights.

Good Manufacturing Practice is a requirement for nearly every component of a drug – from the packaging to the active pharmaceutical ingredient. However, a global regulatory standard does not exist for excipients. The path to accredited certification for excipients began in 2008, when the USFDA stated that excipient GMP conformance certification could benefit the excipient and pharmaceutical industry beyond the existing International Pharmaceutical Excipient Auditing (IPEA) program.

By August 2009, IPEA and ANSI had developed an accreditation plan and process. In February 2010, the first ever ANSI accredited excipient GMP certification of a quality management system was performed at W. R. Grace & Co.’s facility in Baltimore, Maryland, USA, where their Silicon Dioxide NF – Syloid® FP excipient is manufactured. This certification has multiple benefits since it assures the pharmaceutical company of GMP compliance by the excipient manufacturer and also reduces the inconvenience and expense associated with individual company audits at the excipient site.

Control of excipients:
Some experts believes that the pharmacopeia monographs should include the tests that establish the safety of the excipient and include the tests that are necessary to differentiate between available pharmaceutical grades, but in a labelling section or an alternate section, which will allow the necessary flexibility, to include all different pharmaceutical grades in the monograph. Another trend is for excipient users to demand tighter specifications from their suppliers and lower prices.

But concerns exist about whether we are getting to the stage at which users’ demands are exceeding manufacturers’ capabilities to deliver a product routinely that meets the tighter specifications. Another supplementary question that bears consideration is how far the excipient manufacturers can or should go to overcome the problems associated with poorly formulated products. Excipients frequently are manufactured in dedicated plants on a continuous basis. In part because of the size of the plants, variability is an inherent part of any production process. For example, a temperature difference exists between the fluid coming into a pipe and the environment outside the pipe. Therefore, there will be a temperature variation across and along the pipe. Some plants produce tens of thousands of tonnes of excipients each year for various industries. There will be some inevitable differences between batches, but it is vital that this variability is kept within acceptable limits.

Because the pharmaceutical market may only represent a small percentage of a manufacturer’s total production volume, it can be difficult to persuade a company to work with unnecessary tight controls for a small part of its output.

If these demands become unreasonable, the manufacturer may simply decide to withdraw from the pharmaceutical market, or to drop its pharmacopeia designation. This scenario recently occurred in the United States with a supplier of Liquid Glucose NF, although for reasons other than tighter specifications. Whenever this situation occurs and for whatever reason, the excipient user is put in a difficult position, particularly if no alternative source of pharmaceutical-grade material is available.

Excipients filing strategy
Many drug manufacturers are understandably wary of jeopardizing their application if a new excipient is deemed unsafe, or they are unwilling to extend the time required to approve a new drug due to use of a novel excipient. There is widespread discussion and debate about the need to develop novel excipients for improved drug delivery solutions. In many ways novel excipients may seem the ultimate solution. But they are still a gamble most are unwilling to undertake, given that the current regulatory environment has historically discouraged their use, which often ends up limiting excipient choices to those already approved.

Exploiting the multi-functional benefits of existing approved excipients can be an easy and safe alternative route compared to the more time consuming and risky path of pursuing novel excipients. By working directly with the excipient manufacturer, pharmaceutical companies can learn about an excipient’s full beneficial properties and have more confidence about its quality, origin, and performance. Drug manufacturers are starting to appreciate the truly vital role excipients can play in the success of their formulation. As a result, they are turning to excipient manufacturers and contract formulators to support R&D innovation, improve manufacturing, and accelerate time to market.

Excipients have never shared the limelight with active pharmaceutical ingredients, nor have they historically been given the credit that they deserve in drug development, manufacturing, and delivery. An excipient’s role has traditionally been viewed as merely a filler or binder contributing to the stability of the end product. The full value that a formulation can bring to a final dosage form; or the real importance of ensuring an excipient’s quality and performance; are often underestimated, overlooked, misunderstood or disregarded. In reality, the functionality of the excipient can help determine whether or not a drug succeeds or fails.