Introduction
This installment of the column is a little different. I hope to address some of the issues with new excipients. In general, it appears in recent years that small molecule drug candidates have become more sophisticated and chemically complex. There has been an increase in molecular weight, with a commensurate reduction in solubility, and newer drug molecules maybe less stable (more prodrugs). We continue to need new excipients. I think all formulation scientists would agree that, despite the number of excipients available (perhaps 1500 or so by current estimates), there are still gaps in the range of excipients available. We need new excipients to cope with the increasing number of poorly soluble and more labile compounds, and also to allow manufacturing and filling equipment to operate at high speed. There are also existing deficiencies, such as a vehicle for oral solutions that is not cariogenic and does not have a laxative effect, and a soluble tablet/ capsule lubricant that is as effective as magnesium stearate, but is non-irritant to mucosal tissues and the eyes. These gaps have been known for many years, and perhaps one should ask if they are still worth pursuing, or if they are in fact impossible dreams. (Contrary to the traditional definition of excipients as ‘inert carriers’, excipients can have physiological effects, some more obvious than others, and perhaps we are coming up against a physiological barrier.)
Some years ago I gave a series of presentations and wrote a paper on the future for new Excipients [1], which suggested we were unlikely to see very many new chemical excipients because it was a difficult economic proposition. It seems appropriate to revisit this topic, in part to see whether much has changed, and in part to reflect on the needs of formulation scientists and manufacturing scientists as we embrace Quality-by-Design (QbD) and accommodate the trends in drug candidates. In general, as I shall explain, QbD may provide more impetus to the introduction of new excipients and/or new grades of excipients.
Before we consider the progress that has been made, we need to take a step back and look at the definition of new. For excipients, ‘new’ can be defined in several ways, according to the context, including:
- A new chemical material, never before used in man or animals, e.g. β-cyclodextrin sulfobutyl ether.
- New semi-synthetic derivatives of existing types of materials, e.g. different semi-synthetic fatty acid triglyceride esters such as the polyethylene glycol ester of hydroxystearic acid.
- An excipient that has been used in animals (veterinary medicines) and now being proposed for use in humans.
- An existing excipient that has been used in man, but is now proposed for a new route of administration, e.g. β-cyclodextrin sulfobutyl ether for oral use.
- A food material that is now proposed as an excipient for oral use, e.g. ceratonia (locust bean gum).
- New chemistry, e.g. degree of substitution, for an existing semi-synthetic or synthetic excipient.
- A new botanical source for an existing excipient, e.g. hardwood-derived vs. softwood-derived microcrystalline cellulose.
- A new physical grade of an existing excipient, same route of administration, same botanical source, e.g. large particle size grades of microcrystalline cellulose, low density grades of microcrystalline cellulose.
- New co-processed combinations of existing excipients, e.g. silicified microcrystalline cellulose, mannitolized microcrystalline cellulose, combinations of lactose with powedered cellulose, microcrystalline cellulose, or corn starch, etc.
- An alternate manufacturing source for an existing excipient, e.g. the alternative sources of microcrystalline cellulose, etc.
As we can see, there have been examples of many of these categories in the past 25 years.
We use excipients, along with appropriate processing, to convert active pharmaceutical ingredients (APIs) into medicines that then patient can use. Unformulated APIs are mostly quite inappropriate for use by the patient. We formulate APIs into drug products to make them acceptable to the patient or care giver, and much more convenient to use. From a QbD perspective, what we are looking for is consistency, both in chemical and physical attributes, and in performance.
If we consider the list of definitions of ‘new’ given above, and look at the number of ‘new’ excipients that have reached the market in the past 25 years, we can see that most effort has been concentrated in a few areas. In particular, new grades of existing excipients have emerged, and also new co-processed combinations of excipients have been introduced. There are good reasons for this. The introduction of a new chemical excipient is expensive and uncertain, and there must be a compelling unmet technical need that overrides the natural conservatism of most pharmaceutical companies when it comes to innovation outside API molecules. However, there have been some limited successes in introducing new chemical excipients such as β-cyclodextrin sulfobutyl ether and the polyethylene glycol ester of hydroxystearic acid.
New Chemical Excipients
New chemical excipients will continue to be needed. New grades of existing materials and new co-processed combinations of existing excipients will still have the same drawbacks, e.g. incompatibilities, they have always had. One of the few ways to reduce incompatibilities is to change the chemistry, i.e. develop a new chemical excipient.
It is worth considering briefly how both β-cyclodextrin sulfobutyl ether and the polyethylene glycol ester of hydroxystearic acid. gained acceptance. They did not achieve acceptance in the US market in quite the same way.
β-cyclodextrin sulfobutyl ether was developed some years ago now, specifically to address drug solubility issues, and to overcome some of the issues relating to the existing β-cyclodextrin materials. But how did it get into two marketed products? There are several things that must come together for a new excipient to be used/ approved for use in a pharmaceutical product. We have already mentioned the unmet technical need. In addition, there must be sufficient confidence in the safety of the excipient, and there needs to be someone in the company developing the new drug to act as ‘champion’ for the new excipient, i.e. sufficiently senior and sufficiently convinced of its potential to promote its use for the project. All this happened with β-cyclodextrin sulfobutyl ether. In addition, both the drug developer and excipient manufacturer worked closely together to obtain the requisite safety data.
The polyethylene glycol ester of hydroxystearic acid is a more recent introduction to the US market, and its use in a medicinal product and approval took advantage of recent developments in the regulatory area for excipients. Since β-cyclodextrin sulfobutyl ether was included in the formulation of an approved medicinal product, there have been some developments that have helped clarify the FDA’s expectations and also to provide support to both developers and users of new excipients.
The International Pharmaceutical Excipients Council of the Americas (IPEC-Americas) produced a guideline on the safety studies required for new chemical excipients that was published in 1996 [2]. (The United States Pharmacopeia also has General Information Chapter <1074> Excipient Biological Safety Evaluation Guidelines which is similar to the IPEC-Americas recommendations.) The FDA then issued their Guidance for Industry: Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients, initially as a draft, which became final in May 2005 [3], the requirements of which were very similar to the IPEC-Americas recommendations published earlier. However, the FDA Guidance Document rightly carries much more weight. The important point was that we now had a defined set of studies that was required to be carried out on the new excipient. Prior to the publication of the IPEC-Americas recommendations and the FDA Guidance there was nothing established for the evaluation of new chemical excipients.
However, it was still a big leap of faith on the part of a pharmaceutical company to accept a brand new chemical excipient for use in a potential new drug. There are many things that can go wrong during the development of a new drug candidate, and many of the same issues can arise during the development of a new excipient candidate. However, the real issue was not how well the new excipient would perform in the formulation, but its safety. There was the question of how the FDA reviewer would regard the data, particularly the safety data, and whether or not the safety package would be accepted. There is now a scheme set up by IPEC-Americas whereby excipient safety packages can be reviewed by an independent panel of toxicologists to assess whether or not the safety package would, in the opinion of the independent experts, be likely to be accepted by the FDA review staff. The first materials to be assessed using this scheme was the polyethylene glycol ester of hydroxystearic acid. In this particular instance, the FDA agreed to review the findings of the expert panel to provide a further independent assessment of the scheme. The expert panel review of the polyethylene glycol ester of hydroxystearic acid was well received by the Agency.
Co-processed Excipients
One major area of innovation in excipient technology has been in the development of co-processed excipients. The regulatory hurdles are much reduced, although other hurdles remain such as the very conservative nature of the pharmaceutical industry, and its reluctance to accept anything ‘new’. Co-processed excipients are not new. Some have been available for many years. What may be changing is the general attitude to co-processing on the part of the pharmaceutical industry. There appears to have been more acceptance of co-processed materials in recent years. In the past the perception was that there was little no benefit in co-processed excipients for the innovator companies. This seems to be changing, in large measure because of examples of co-processed excipients whereby the same performance cannot be achieved by combining the components using unit processes typically of the manufacture of pharmaceutical finished product.
Acceptance still requires that there be an unmet technical need, but the height of the regulatory and safety barrier is much lower (but not absent). The key distinction between new chemical excipients and new co-processed excipients is that the primary components of co-processed excipients should not be combined using covalent bonding. However, there still needs to be a safety assessment, but this assessment may be more of an analytical investigation to confirm the absence of significant covalent bonding, thus allowing bridging to the safety studies and data for the individual component excipients. Tobyn and co-workers published an example of the types of such analytical bridging studies [4]. In summary, using a range of different spectroscopic analytical techniques, the authors were able to demonstrate that the combination of microcrystalline cellulose and colloidal silicon dioxide in silicified microcrystalline cellulose was not covalently bonded, thus confirming the link to the safety data for the component excipients.
Economic Considerations
The economic factor is also important. It can cost USD20 – 30 million to undertake all the safety studies required for a new chemical excipient, depending on the route of administration, and then there is the cost of the CMC (Chemistry, Manufacturing and Controls) part of the project. This will all be reflected in the commercial cost of the excipient. There is a further economic component that is sometimes forgotten; for new drug products there is the possibility of an extension of patent exclusivity under the Hatch-Waxman rules because of long development times. No such extensions are available for new excipients. Without some form of combination safety evaluation (‘piggy-back’ study), as was done for β-cyclodextrin sulfobutyl ether, the patent of the excipient may well have expired before commercial approval of the first drug product [1].
Co-processed excipients, by contrast, are less expensive to develop, and can be introduced without having to undertake an expensive and long safety evaluation. Thus, a much longer proportion of the patent exclusivity will be available at commercial launch. Co-processed excipients are thus a more attractive proposition for excipient companies, and this is reflected in the relative numbers new excipients introduced compared to the number of co-processed excipients introduced commercially since 1995.
Implications of Pharmaceutical Formulation QbD for New Excipients
The principles of QbD can be applied to any development project, including the development of new excipients. However, the objective of this paper is to consider the implications of pharmaceutical formulation QbD for new excipients. As has been stated many times and by many authors, we use excipients to help convert active pharmaceutical ingredients (APIs) into medicines that the patient is able to use conveniently. Pharmaceutical formulation QbD requires that we have better understanding of our materials (including APIs) and processes. In a QbD development program it is likely that information on the API will be more important than ever, particularly the information concerning potential degradation pathways and incompatibilities. This suggests that formulation development groups will focus sooner on the short comings of the available range of excipients. Might this lead to requests for the development of new excipients or new grades of excipients?
It seems logical to suggest that there may be opportunities out there for new materials. However, there will need to be a balance between what the user is willing to pay, and the cost of manufacture and economic viability. If the excipient cannot be manufactured at a price that the market can support, then it is not a viable project.
New grades of existing materials may be a further opportunity. This is where our understanding of our excipients becomes important. The mantra “Know your excipients!” cannot be emphasized enough; we can never know too much about our excipients. Most excipients for non-parenteral applications (and even some for parenteral applications) function because they are not single compounds, but are de facto combinations of materials. They will contain the nominal component, but they will also contain other components that are necessary to achieve the requisite performance. Sometimes it is these minor (concommitant) components that are responsible for drug excipient interactions and eventual stability problems. Is there a way to remove the offending minor component(s) without compromising the performance of the excipient in the particular formulation? This could create a new grade of an excipient; perhaps specific to a particular customer; a ‘designer excipient’ if you will. Such an approach may not work for every excipient, but it may be possible for some.
Again, the economics will be an important factor in the success of such a project. However, there are also a couple of other factors that must be taken into account; the willingness of the formulator company and the excipient manufacturer to communicate effectively, and the willingness of the excipient manufacturer to look at such projects. In the past the excipient manufacturers have been willing to look at changes to particle size distribution, for example, but what is suggested here concerns extra processing steps, and perhaps different processing in part. Looking forward, there may be intellectual property benefits for both the product manufacturer and the excipient manufacturer.
Pharmaceutical formulation QbD is a great opportunity for the formulation scientists carry out projects in a more scientific manner. There may also be opportunities for excipient manufacturers to become more involved and develop better, more lasting relationships with their customers by providing a more individual service.
I hope this paper has provided some food for thought. It is a departure from the main stream QbD, but I think it is a topic that needs to be considered in the context of new pharmaceutical product development and QbD. The next, and final, installment of this series of articles will address the issue of continuous manufacture of pharmaceutical products.
References
1. Moreton, R.C., Tablet excipients to the year 2001: A look into the crystal ball, Drug Dev. Ind. Pharm., (1996), 22, (1), 11 - 23.
2. Steinberg, M., Borzelleca, J.F., Enters, E.K., Kinoshota, F.K., Loper, A, Mitchell, D.B., Tamulinas, C.B., and Weiner, M.L., A new approach to the safety of pharmaceutical excipients, Reg. Toxicol. Pharmacol., (1996), 24, 149 - 154.
3. Guidance for Industry: Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER), May 2005.
4. Tobyn M.J., McCarthy G.P., Staniforth J.M. and Edge S., Physicochemical comparison between microcrystalline cellulose and silicified microcrystalline cellulose, Int. J. Pharm., (1998), 269, 182 – 194.
Dr Moreton has over thirty years’ experience in the pharmaceutical industry. He has worked as a formulation scientist developing a variety of different dosage forms, and has experience in the design, development, scale-up, technical transfer and validation of drug products and associated analytical methods, both during clinical development and eventual transfer into commercial manufacture, and working with licensing partners and contractors. He has also worked in QA/QC, Regulatory Affairs and Technical Support in excipients and drug delivery.
He is a past Chair of the AAPS Excipients Focus Group, and of IPECAmericas. He is a member of the International Steering Committee of the Handbook of Pharmaceutical Excipients, and of the USP Expert Committee—Excipient Monograph Content 2. He has authored and coauthored scientific papers and book chapters, and lectured extensively in the areas of excipients, drug delivery and formulation at universities, training courses and symposia in the U.S. and Europe.