Potential problems related to excipients

Excipient and vendor selections can greatly influence development time, performance, quality, and acceptance of final products. Consequently, quality excipient suppliers should:

• maintain drug master files with FDA for noncompendial items;
• consistently conform to monograph requirements;
• manufacture in ISO 9000–certified facilities;
• pass FDA inspection and auditing by either pharmaceutical companies or International Pharmaceutical Excipient Audit (IPEA, http://www.ipeainc.com/).

Inattention to excipients, excipient suppliers, and regulations may lead to product development failure. Quality-by-design concepts, which have recently been initiated by FDA, emphasize the need for characterizing material properties (e.g., micromeritic, chemical, thermal, rheological, and mechanical properties) and elucidate their vital role in formulation and manufacturing processes (5–8).

Currently available excipients are sufficient to support typical formulation development. A significant number of drug entities under development, however, have physicochemical, permeation, and pharmacokinetic properties that are less than ideal. These drugs present formulation challenges and may require either the discovery of new excipients or new applications of existing excipients. Regulatory agencies require new excipients to undergo a series of toxicology tests, which may be costly.

Few new excipients of new chemical entity have been introduced into the market, primarily because of the economic hurdles associated with toxicology testing. Instead, excipient manufacturers have improved excipient performance and have expanded product lines by modifying already approved products (see Table I). Excipients undergoing these approaches may be advantageous in their formulation, manufacture, and marketing. In formulation, these excipients may decrease strain rate sensitivity, increase rework potential, increase dilution potential, decrease lubricant sensitivity, enhance flow properties, enhance the blending process, optimize content uniformity, increase compression ratio, facilitate material handling, require smaller quantities, decrease environmental concerns, and improve stability. These formulation benefits can lead to manufacturing advantages such as enable direct compaction to avoid time-consuming wet granulation, increase production capacity using excipients with enhanced flow and compaction behavior, reduce tablet tooling and machine wear, and eliminate the facility need of solvent recovery. Benefits such as rapid formulation development, smaller tablet size, better quality products, and no solvent residues may be possible by using these excipients with proven functionality.

Table I: Examples of modified excipients.