Excipient Evolution: Past and Future Innovations Spur the Field, but Potential Regulations Loom Large

Introduction 

Excipients are one of the anomalies of the pharmaceutical sciences. They are inactive; they are not intended to treat a disease or medical condition; yet, without excipients, the therapeutic advances of the last 100 years or so would not have happened. Excipients are a vital part of modern medicine. They help convert bulk active drugs (APIs) into medicinal products that the patient can benefit from because, unformulated, most APIs are not particularly convenient for patients. 

In the past 25 years there have been developments and innovations in drug formulation and in excipients, particularly relating to Quality-by-Design (QbD), continuous manufacturing and safety/toxicology.

Impact of Quality-by-Design on Excipients 

QbD has arguably been the most significant change in pharmaceutical formulation development in the past 25 years. It has forced us to look at excipients in far more detail than previously. While QbD is not compulsory, if the principles of QbD have not been followed during drug product development, the reviewers at regulatory agencies may ask questions that can only be answered through a QdD Design of Experiments (DoE). The formulation development report is now required to demonstrate that the applicant has enhanced understanding of the impact of Critical Material Attributes (CMAs) of their API and excipients on the Critical Quality Attributes (CPAs) of the finished product. The excipient CMAs frequently are not those attributes controlled by the tests in the pharmacopeia monograph or manufacturer’s specification. This has led to a significant increase in requests for information and samples at the limits of specification by the excipient users from the excipient manufacturers. Unfortunately, due to the nature of the manufacturing process for many excipients (large scale continuous manufacturing), the provision of samples at the limits of specification is most generally not possible. In recognition of this, IPEC-Americas has developed a QbD Sampling Guide, which explains the reasons and also provides suggestions for simulating excipients at the limits of specifi cation.¹ 

Trends in design and delivery 

The past 25 years have seen several different trends in the properties of new drug molecules. There has been a significant increase in the number of biologic drug products introduced into the market, including biosimilars. Biologic drug products still require excipients, but since they are almost all administered by injection, there are other constraints such as microbiological quality and endotoxins, which are highly relevant. There are parallel trends in small molecule drug candidate design. With the introduction of combinatorial chemistry and high-throughput screening, and beyond, the number of poorly water-soluble drug candidates in development (possibly as many as 90% of new drug candidates are poorly water-soluble) has risen. This increase has led to the development of more bioavailability-enhancing drug delivery technologies, all of which rely on excipients. Finally, advances in the oral delivery of peptide drugs for systemic absorption have been achieved through the use of excipients, some of which are novel (see below). These developments in drug candidate properties have impacted excipients, since there have been developments in drug delivery technologies for poorly water-soluble drugs. These have required that some excipients be used in novel ways.

Continuous Manufacturing 

The move to continuous manufacturing of medicinal products (CM) will place even more demands on excipients (see Page 18). Excipient variability must be acknowledged, and CM will require more consistency of performance and a much better understanding of the potential impact of variability on the CQAs of the medicinal product because there will be less opportunity for operator intervention to compensate for such variability. In addition, the parameters that will need to be controlled most likely will not be those included in the pharmacopeia monograph or manufacturer’s specification. In time, as more data and understanding are accumulated for a particular product, it may be possible to compensate for such excipient variability using some form of feed forward control. However, the details of such controls will be formulation-specific. Innovation in excipients 

With the necessary innovations in drug delivery and the interest in continuous manufacturing discussed above, the question has to be asked, “Will the existing range of excipients continue to adequately address current and future needs?” in this author’s opinion, the answer is “No!” This has been borne out by some of the reasons that new excipients have been introduced – generally, to meet an unmet technical need, i.e., there was no other way to create the medicinal product. 

The number of new chemical excipients ‘approved’ in recent years is small. Between 1995 and 2015, only four new chemical excipients were included in drug products approved by the US FDA:

•  Hydroxypropyl Betadex Sodium (Captisol® - Cydex) 
• Polyoxyl 15 Hydroxystearate (Solutol® - BASF) 
• Fumaryl diketopiperazine (Mannkind) 
• Salcaprozate Sodium (SNAC – Emisphere Technologies) 
• In addition, BASF also launched Soluplus® (Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer); however, as yet, no approved products in the US contain this excipient, although there are products undergoing clinical evaluation containing Soluplus®. It is believed that the mRNA vaccines against the Sars-Cov-2 virus also contain novel excipients that are required for delivery of the mRNA to the cell. 

In large measure, the paucity of new chemical excipients stems from the lack of an independent regulatory approval process for new excipients. Traditionally, new excipients have only been ‘approved’ as part of a new drug application (NDA). This is still the case, although in September 2021 the US FDA announced a pilot program to assess new chemical excipients, which would last for two years; companies were invited to submit applications for consideration. During 2022 and 2023, the US FDA would select two applications for review. At the end of the pilot program, a decision will be made as to whether to continue the program. If the pilot program is successful, the new excipient evaluation program will become permanent, and we do need new excipients! 

Innovation in excipients has come in the development of new grades of existing excipients and in co-processed combinations of excipients. The development of new grades of existing excipients is very much influenced by demands from excipient users (customers). However, there is a limit to the number of new grades that can be commercialized. The development of new co-processed excipients is also influenced by customer needs. However, the number of combinations of excipients that could be co-processed is broad, and this is an area of active development. New co-processed excipients will likely be of benefit in continuous manufacturing, particularly of oral solid dosage forms. However, the acceptance of co-processed excipients in parts of Europe has been called into question due to an erroneous belief that co-processed excipients somehow compromise cGMP. This will need to be resolved. One further point to remember with co-processing is that any potential excipient incompatibilities will not be overcome since they are not new chemical entities. 

Excipients for biologic drugs 

The development and introduction of biologic drug products, particularly protein drugs and monoclonal antibodies, has also impacted excipients. These drugs, by their very nature, must be administered by injection, very often subcutaneously. Due to the small volume that can be administered subcutaneously, the concentration of the drug is high and this can lead to stability issues, e.g., agglomeration and particulate formation, from which there is an increased risk of immunogenicity. One means of stabilizing such formulations is to include a surfactant, e.g., a polysorbate. However, stability issues have been reported with the use of polysorbates whereby the polysorbate has hydrolyzed, giving rise to free fatty acids. This and the reduced surfactant concentration can cause agglomerates to form, and increased potential for immunogenicity. It is clear that more stable surfactants are required for the formulation of biologic drugs. However, there is a further consideration; since these products are administered by injection, they are required to be sterile and endotoxin-free. This places further constraints on excipients intended to be used in such formulations. 

Impact of the application of newer analytical technologies on excipients 

Traditionally, excipient pharmacopeia monographs, for the most part, have not had specific and/or stability-indicating analytical methods for excipients. Indeed, we will perhaps never have such methods for some excipients, e.g., Powdered Cellulose. However, this is changing. Where possible, older non-specific analytical methods, such as titration, are being phased out and replaced by more specific methods such as chromatography. In other instances, the traditional residue on the ignition test is being replaced by elemental impurities tests. These two trends have impacted excipients in that heretofore undetected excipient components have since been detected. The important point is that these materials have always been present, but undetected due to the inadequacy of the older, traditional analytical methodology. As new analytical techniques are introduced, inevitably and if appropriate, they will be applied to excipients. An important point to remember is that, before panicking, older samples should also be tested using the new method to provide some context to the new findings. 

Nanomaterials 

There is currently considerable concern about the future of several excipients due to an initiative from the French Agence Nationale de Sécurité Sanitaire de l’Alimentation, de l’Environnement et du Travail (ANSES). ANSES have developed two lists of food additive materials.² The first list contains materials proven to contain manufactured nanomaterials, as assessed by ANSES. The second list contains materials suspected of containing manufactured nanomaterials. Included in the first list is titanium dioxide (TiO2), which is used in many oral solid dosage forms and also in sunscreen products. This initiative has been taken up by the European Food Safety Authority (EFSA), and the use of TiO2 in food is now banned in the European Union (EU). This ban is based on the application of the precautionary principle; there is no credible evidence that TiO2 causes cancer, but there was no data specifically showing that TiO2 nanoparticles did not cause cancer. Since the pharmaceutical use of TiO2 is based on its approval for food use, this ban also affects its pharmaceutical use. If the ban is extended to pharmaceuticals, literally thousands of products will need to be reformulated across the EU; including both innovator and generic products. EFSA is now asking for information on the safety of iron oxides, which are also included in the first ANSES list. 

The ANSES lists contain many materials that are commonly used as excipients, including magnesium stearate, which, after water, is probably the most commonly used pharmaceutical excipient. The ANSES lists also include excipients such as microcrystalline cellulose and silica. If the ban of all the materials on the two lists were to be extended to pharmaceuticals, few pharmaceutical products on the market today would be allowed to remain. Admittedly, it would take some years for all this to happen. However, it must be a concern because many small volume products, including those for orphan indications, would simply be withdrawn; it would be uneconomic to reformulate them. Such a situation would not benefit patients relying upon those medicines! 

Microparticles 

Another European proposal could impact excipients and also certain medicinal products. This concerns proposed reporting requirements about the release of microparticles into the environment. A microparticle is defined under the proposed rule as a synthetic particle having no dimension >5 mm. Natural, soluble and biodegradable materials are exempt. The definitions of these properties are taken from the REACH regulations. The concern for excipients and medicinal products is that certain excipients and medicinal products will be excreted from the body as microparticles. Medicinal products that could fall within the scope of the proposed regulations include multi-particulate modified release products (for more on microparticles and excipients, see Page 68). There is also an exemption for so-called secondary microplastics (materials that change their form and are then reformed and excreted as microparticles). A major reason for concern is that some of the assumptions included in the proposals are incorrect. In addition, based on the reporting results, regulations will be promulgated restricting the emission of microparticles. There is concern that certain excipients and medicinal products containing them will be restricted, and possibly banned, to the detriment of patients. Microparticles are a serious environmental concern, but the amount of microparticles released from pharmaceutical products is very small compared to the amount released due to wear on motor vehicle tires and synthetic textiles. 

Summary/Conclusions 

The excipients field continues to evolve. QbD has caused us to re-examine excipients, and to delve deeper into their characteristics and variability. At the same time, the future looks bright with the FDA Pilot Scheme for novel excipient review. Innovation in the area of co-processed excipients promises to bring new functionalities, particularly to continuous manufacturing of medicinal products and also for the formulation of biological drugs. At the same time, the application of newer analytical technologies to excipients can help to develop understanding of excipient composition. However, recent regulatory developments in Europe suggest that the range of excipients available could be curtailed, to the detriment of patients. 

References 

1. The IPEC-Americas Quality by Design (QbD) Sampling Guide (2016), IPEC Americas, Arlington, VA. 

2. Nanomatériaux dans les produits destinés à l’alimentation, Avis de l’Anses, Rapport d’expertise collective, (Mai 2020), Agence nationale de sécurité sanitaire de l’alimentation, de l’environnement et du travail, Maisons-Alfort, France.

Subscribe to our e-Newsletters