Regulatory Aspect For Excipient

Pharmaceutical excipients are ingredients in drug formulations and are generally considered pharmacologically inert. Regulation of excipient manufacturing and distribution is now considered a top priority by pharmaceutical manufacturers, as adulteration of pharmaceutical excipients can cause adverse effects in patients. As innovative excipients and delivery systems emerge, improved quality and supply control of pharmaceutical excipients become increasingly important for in vivo performance. Since excipients play a crucial role in pharmaceutical dosage forms, excipients suppliers must meet pharmaceutical industry quality standards, and the pharmaceutical industry as a whole must work to ensure the integrity of the supply chain.

Apart from the active pharmaceutical ingredient (API), the finished medicinal product generally contains inactive ingredients, known as excipients, e.g., co-solvents, preservatives, colourants, surfactants or sweeteners. The US Food and Drug Administration (FDA) defines an inactive ingredient as "any component of a drug product that isn't the active ingredient". This definition of a pharmaceutical excipient is now considered an essential component of the drug formulation. Excipients are necessary for several purposes, including facilitating product manufacturing, aiding identification, modulating stability, preservation and delivery, and increasing product acceptability. Excipients can be derived from natural sources or synthesized chemically or by other means, such as fermentation. They range from basic, well-defined organic or inorganic molecules to complex materials that are hard to understand fully. However, most excipients are not explicitly manufactured for pharmaceutical products; they have other uses in the chemical and food industries. Complex supply chains and increased dependence on outsourced manufacturing create the potential for counterfeit or substandard excipients to enter the supply chain, causing problems in manufacturability, alteration of bioavailability and shelf life with consequent adverse effects on patients. Therefore, carefully testing excipients and auditing their supply chains is necessary to ensure their safety in the final medicinal product. Although the pharmaceutical industry has been strictly regulated for years, excipients have been generally less so. The importance of excipient quality is gaining recognition in the pharmaceutical industry and regulatory agencies across the globe. Many governments are developing legislation and regulations impacting how excipients are sourced and controlled. This review discusses the quality, functionality and novelty-related aspects of pharmaceutical excipients together with the regulatory efforts by the pharmaceutical industry and various regulatory agencies across the globe.

Quality Aspects

The quality of excipients is critical to assure the safety and efficacy of medicines. The volumes of excipients used in pharmaceutical products make up only a tiny percentage of the total volume of bulk chemicals manufactured. In this context, not all excipient manufacturers and distributors know or recognize the specific quality requirements for excipients. Pharmaceutical manufacturers must ensure that excipients are suitable for use in their products by specification, sampling and testing, for which there are detailed regulatory requirements, and that they are manufactured to an appropriate standard of Good Manufacturing Practices (GMP). The supply chain for a pharmaceutical excipient starts at the source of the raw or starting material of the excipient and continues through until used by the finished product manufacturer. Parties involved in the supply chain should recognize that an excipient needs to meet pharmaceutical quality standards and be manufactured, repackaged, and managed in alignment with those rules and regulations.

Many challenges are associated with excipient quality management, managing extended supply chains and developing certification schemes for producing and supplying excipients. Not satisfactorily meeting these challenges creates the potential for counterfeit or substandard excipients to enter the supply chain. Several incidents where pharmaceutical excipients have caused harm to patients have led to stricter regulations to ensure that the required characteristics for pharmaceutical excipients are monitored and met. A recent drug contamination incident reported in March 2012 involved the discovery of 77 million medicinal gelatin capsules made from industrial-grade gelatin that contained chromium, a carcinogenic heavy metal. China's State Food and Drug Administration (SFDA) has published a list of 28 high-risk excipients that require a manufacturing license before they can be used in pharmaceutical products. The US FDA Center for Drug Evaluation and Research (CDER) has limited the use of certain phthalates as excipients in CDER-regulated products due to potential human health risks associated with dibutyl phthalate (DBP) and di(2-ethylhexyl) phthalate (DEHP). The absence of rigorous global regulation for excipients and inadequate scrutiny of the supply chains can and has resulted in the deliberate adulteration of excipients, which could potentially cause and have caused life-threatening harm to patients. Therefore, auditing and monitoring excipient manufacturing and supply chains is essential to demonstrate a commitment to producing high-quality excipients. This has been recognized by the regulatory agencies and the excipient and pharmaceutical industries, resulting in the establishment of regional International Pharmaceutical Excipients Councils (IPECs) beginning in 1991. The objective of the councils is to formulate regulations that can provide a basis for improving excipient quality and patient safety. Regional IPECs and their affiliate organizations around the world have also established the IPEC Federation to allow the excipient industry to speak with one voice and promote the best use of excipients in medicines resulting in the improvement of patient treatment and safety. The IPEC Federation represents the four existing regional IPECs, i.e., IPEC-Americas, IPEC Europe, IPEC Japan and IPEC China. In addition, the IPEC Federation has been collaborating with a group of companies in India to assist them in developing an IPEC organization in the Indian Subcontinent. IPEC-India is expected to become registered as a formal trade association in 2013. IPEC has published many guidelines, programs and proposals on various aspects of excipient control. These IPEC initiatives are designed to address specific needs related to excipient quality control.

Excipient GMP

In 1995, the first voluntary standards for good manufacturing practice for pharmaceutical excipients were published jointly by IPEC Americas, IPEC Europe, and their member companies. The World Health Organization (WHO) adapted it for use by its national member states. Following the release of an updated IPEC guidance in 2001, the United States Pharmacopoeia (USP) used it as the basis for General Chapter <1078> in the USP -NF.

Pharmaceutical Excipient GDP
To provide a guide for companies involved in the pharmaceutical excipient supply chain, a joint document by IPEC-Americas and IPEC Europe, entitled the "Good Distribution Practice Guide for Pharmaceutical Excipients", was published in 2006

Pharmaceutical Excipients Supplier Qualification

Implementation of supplier assessment and audit programs assures the integrity of the supply chain and authenticates the 'pedigree' of the excipient. Suppliers of excipients, distributors, and the pharmaceutical sector are wholly dedicated to overseeing excipient quality across the supply chain and ensure this by self-regulation and through accredited auditing bodies.

Functional Aspects

Pharmaceutical excipients contribute unique functionalities to formulations, determining their clinical performance. A greater understanding of the functional benefits of excipients has led manufacturers to turn to excipients to improve pharmaceutical formulations. An excipient may have several intended uses depending on the formulation, manufacturing process, and dosage form, and consequently, there are many applications for a particular excipient.

Novel Excipients

Novel excipients are required to improve the performance, solubility and membrane permeability of new drug moieties and aid modern manufacturing processes. A novel excipient may include a new chemical entity, an innovation that has not been utilized in any drug approved by regulatory authorities or 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 state.
At Clyzo, excipients and raw materials have different application ranges that fulfil the quality and regulatory requirements.