What were the trends in excipient use in the past?
VD: Pharmaceutical excipients are broadly defined as, ‘"Any component other than the active principle added intentionally to the medicinal formulation." Thus, although by definition excipients are required to be pharmacologically inert, their use in drug products is ubiquitous. Excipients are used in virtually all pharmaceutical formulations and serve valuable function in one or more domains of drug product development. In a pharmaceutical formulation excipients are used mainly to improve processing (eg, improving powder flow), enhance aesthetics (eg, identification, branding, etc), optimize product performance (eg, modified drug-release), and/or to facilitate patient compliance (eg, taste masking). Over the years, the use of excipients has been driven by preformulation characteristics of the API, drugexcipient compatibility, processability, excipient cost, and marketing. Excipients find their origin in a variety of sources including plant, animal, mineral, biotechnology, and chemical synthesis. Hence, a majority of pharmaceutical excipients are supplied by food and chemical industries. The USFDA maintains a database of inactive ingredients (excipients) present in approved drug products. This database assists formulation scientists involved in the drug product development in a rational selection and use of excipients. A new excipient to be used in a drug product requires undergoing an extensive review process by the FDA to ensure safety in humans.
CM:
- Largely traditional uses for immediate release and controlled release, etc, for small molecules, and some of this will continue.
- Changes caused by the move into peptide and protein drugs.
- Changes caused by the increased number of BCS II and IV drugs (a consequence of combinatorial chemistry and high throughput screening).
- Changes with the introduction of ICH Q3B because we now have to look more closely at even minor degradants.
JZ: Traditionally, excipients have been used in combination with processing, such as granulation (wet and dry), to overcome the difficulties of developing and manufacturing drug products. The obstacles ranged from developing solid dosage forms having high API loading to establishing content uniformity for low dose drug compositions, regardless of delivery form, whether solid, semi-solid, topical, or liquid. That focus began to change several years ago with a shift toward relying more on excipient performance and less on processing toward developing and commercializing robust products. This became apparent in the shift to direct compression from more complex processes for the development and manufacture of solid dosage forms. As a result, more attention was given to investigating excipient performance by industry and academia, and in particular, institutions with industrial pharmacy programs. Unfortunately, many colleges and universities have scaled back or abandoned excipient research in favor of focusing attention of APIs given the glamour that accompanies the latter.
TD: There has been greater recognition of the role excipients play in drug delivery, leading to the focus on functional excipients such as controlled-release matrix formers or solubilizers. There has also been recognition that excipients often constitute a major part of a drug product and can therefore have a significant impact on final drug product manufacturing, quality, and patient outcomes. The development of the QbD process and the significant part that excipients play in QbD is an indication of increased understanding of the impact excipients have on the final product performance.
SC: Over the last 2 or 3 decades the compendial (USP, NF, EP, JP) excipients used in Pharmaceutical industry has remained somewhat static. One of the main reasons for this is the cost and time involved in testing and proving the safety and efficacy of any new excipient moiety. Most of the major excipient companies have focused their R&D efforts on line extensions and co-processing existing excipients to improve functionality.
What are some challenges in finding or working with excipients?
VD: All excipients are required to fulfill a plethora of safety, quality, and functionality criteria—and rightfully so. There exists limited data on the safety of newer excipients. Ideally, excipients should have a GRAS (Generally Regarded As Safe–a term mainly used for food additives) status. Commercial manufacture of excipients is required to follow stringent cGMP guidelines and meet specifications regarding residuals (eg, ethylene glycol in glycerin), degradation products (eg, 5-hydroxymethyl furfural in lactose), etc. In addition, due to the inherent variability in the sources of most excipients, their manufacture requires strict control over lot-to-lot variability. Also, to ensure control of the overall quality, excipient manufacturers are required to have built-in traceability through supply chain. Moreover, in recent years, it has become increasingly important to clearly define the function of an excipient in a formulation, along with the knowledge of factors influencing its functionality.
Other challenges include cost and awareness. Newly developed excipients typically tend to be costlier than traditionally used excipients. Formulators may not be aware of newly developed excipients with improved functionalities. Additionally, limited manufacturing history (QbD type studies) of new excipients presents an inherent risk of sourcing and variability to the formulators.
Thus, there exists development and regulatory risks that may act as a barrier to the use of an excipient, particularly newer excipients.
CM:
- The biggest challenge is to have adequate understanding; finding where the knowledge resides, and being able to apply it.
- Being able to move away from just developing a formulation, to being able to develop robust formulations. This will require a greater understanding and adoption of Quality by Design.
- Being able to adopt alternate sourcing strategies; again QbD will be important.
- Ensuring that all our excipients remain available despite increasing regulation.
WPW: A large challenge in finding new excipients is simply addressing safety/toxicology risks. Many chemicals exist which have fabulous properties, however, excipients which have been proven safe and yet also have desired properties are much more scarce. Proving safety is an expensive, time-consuming process so as an end user, I always appreciated supportive toxicology data from an excipient producer when I was evaluating. Supply train of a key excipient, particularly if novel, is also always a key concern. One counts on a reproducible and steady supply to carry out operations.
JZ: Because many excipients are derived from natural products, there seems to be growing concern regarding variability in supply. Additionally, there seems to be increased fear related to excipient impurities. This is evident in the introduction of USP general chapters <232> and <233> as well as the work being done by ICH. Both are understandable given the challenges created by many of the APIs in today’s pharmaceutical development pipeline, particularly as drug candidates, once shelved, are being revisited in an attempt to fill development pipelines. These fears, while understandable, are somewhat misplaced. The most often used excipients have been used by pharmaceutical companies for decades and are produced by reputable excipient manufacturers having equally long experience in excipient production. It is up to the pharmaceutical companies to determine whether an excipient supplier is reliable and offers consistent, quality materials for use in development, and manufacture of their products.
TD: Finding a quality supplier to work with from the beginning of the development process is a key to success. Identifying which excipient to use to optimize a formulation can require a significant amount of experimentation if you are not working with an excipient supplier that has pharmaceutical formulation expertise.
SC: From formulator’s perspective, one of the challenges in finding or working with excipients may relate to limited choice. For example, in Inhaler application lactose still remains the only true “tried and tested” choice as the carrier, even though there has been several white paper and efficacy data relating to the use of mannitol in inhalers. This is to be expected, since there are no available toxicology data with regard to the use of mannitol in this application. So, formulators generally are forced to take a conservative route and stick to the “tried and tested” excipient.
What do you expect to see in the future regarding excipient development or use?
VD: The future of excipient development/applications is optimistic at the least. Although the likelihood of developing a new chemical entity as a pharmaceutical excipient is rare, innovations in recent years in this area are nonetheless promising. Increasingly, the research is being focused on one or more of these areas:
Newer grades of existing excipients: Excipient manufacturers frequently introduce newer grades of existing excipients with one or more improved characteristics, eg, Benecel™ PH DC or HPMC K100M DC, hydroxypropyl methyl cellulose products with larger particle size and improved flow for direct compression.
Co-processed excipients: Excipients with similar or different functionalities have been synergistically combined to achieve significantly improved performance, eg, Prosolv® (MCC + silicon dioxide, for improved flow).
Processing aids for newer techniques: Excipients have been developed to be used in specific pharmaceutical techniques such as roller-compaction, hot-melt extrusion, etc. For example, Avicel® DG was specifically designed to optimize roller-compaction process and Soluplus® was designed for solid solutions via hot-melt extraction.
Nanotechnology: Innovations in nano-pharmaceutical research have led to parallel growth in the application of excipients (nano-excipients) as drug delivery aids. These excipients play a critical role in product performance, eg, DL-distearoylphosphatidylcholine and cholesterol are used to prepare a liposomal delivery system for daunorubicin-citrate in DaunoXome®.
Innovations such as these will lend themselves to newer and promising applications of excipients in future.
CM:
- If the IQ Consortium can get their proposals for the FDA to review and approve new excipients ahead of a product NDA, that will be of tremendous importance.
- In the absence of such an approval, it is likely that the majority of new developments will concern co-processed excipients. However, we will need new excipients for use with eg, protein drugs to facilitate oral administration, solubilization of very poorly soluble drugs, etc.
- Better understanding of the link between excipient performance and excipient composition and structure.
- Better understanding of excipient variability—necessary for the effective application of continuous processing methods.
- Pressure to increase the security of supply chains; however, the methods being proposed for finished product may not be suitable for excipients due to their diverse nature and the types and sizes of packaging that are used.
WPW: With drug solubility dropping significantly over the past 15 years (ie, increased BCS class II and IV compounds) excipients, in some cases, have become integral to formulation design to improve in vivo solubility. This can be seen in approaches such as liquid filled capsules with surfactants, oils, and co-solvents as solubilizing agents as well as in amorphous dispersions where polymers with specific characteristics are required. New excipients that can help in the pursuit to improve solubility and therefore bioavailability are clearly desirable and will be key in the future to effectively deliver drug. Further, any new excipients which can aid in compound solubilization may also have use in preclinical pharmacological and toxicology studies. There is also more rigor around characterization of excipients which has been highlighted in many book chapters, conference proceedings, and peer-reviewed journals and I expect this will continue.
JZ: While not impossible to develop new chemical entities as excipients, there are many more obstacles to overcome before pharmaceutical companies and regulatory authorities will accept their use in finished dosage forms. For this reason, there will be continued focus and development in the area of co-processed excipients, particularly for solid dosage forms, which remain the preferred drug delivery format. Co-processing excipients offer numerous benefits beyond the synergistic enhancement of functional performance. Co-processed excipients are generally more likely accepted by pharmaceutical companies and regulatory authorities given that most are comprised of existing, accepted materials. Co-processed excipients, if properly designed, can meet many of the challenges faced by formulators while containing development costs. Their use in solid dosage form development and manufacture often permit direct compression where granulation would otherwise be used. And through the co-processing of intelligent combinations, other challenges, such as limited solubility and permeability, may be addressed as well. There also will be greater collaboration between pharmaceutical and excipient manufacturers in the development of new excipients. This will be critical to the success of both. Open communication will lead to significant advances in excipient technology, enhancing drug development and allowing patients greater access to better medicines.
TD: Novel excipients for bioavailability enhancement, novel uses of excipients in continuous processing and excipients for improved delivery of biopharmaceuticals (proteins/peptides) will be developed. There will be increased regulatory accountability on the part of excipient suppliers and we foresee innovation-based excipient suppliers becoming a more integral part of the drug development and regulatory approval process.
SC: We expect to see more and more research and development activities in the use of co-processed compendial excipients to achieve synergistic boost in functionality. There are several examples of this currently used in Pharma applications (eg, Pharmaburst, Prosolv, Fujimelt, etc). Given the risk-reward profile of a new discovery in excipient space, we will continue to see novel and innovative excipient systems and platforms that focus on delivering superior functionality and ease-of-use by combining proven excipients.