Excipients and the effect they have on the quality of small molecules is a complex subject. Sally Turner speaks to Dr David Elder, former director of CMC due diligence at GSK, about some of the common challenges that occur during excipient selection, including labelling and safety, alignment of risk-based guidance, biowaivers, the inactive ingredient list, and the diffi culties around novel excipients and safety collaborations.
Typically made from a variety of components, including active pharmaceutical ingredients (APIs), drugs are becoming increasingly complex. Therefore, an expert understanding of pharmaceutical excipients is essential for achieving the optimum delivery of drug formulations and the most effective manufacturing process.
An excipient is defined as any component other than the active drug that is included in the production process or contained in the final pharmaceutical product. Excipients fall into two categories: compendial and non-compendial, and it is the former, standardised type that is the preferred option for pharmaceutical manufacturing. Compendial excipients provide a broad range of functions; they act as binders, lubricants, emulsifiers, sweeteners, preservatives and coating agents. They may also add a specific function to the final product, such as modifying drug delivery. Excipients need to be relatively non-reactive, chemically stable, inert in the human body and viable to work with during the rigorous manufacturing process. Developing excipients that meet these requirements (and that pass regulatory inspection) can be a challenge, meaning that only a limited number make it into the marketplace.
Dr David Elder, an independent management consultant, points out that given the high percentage of poorly soluble drugs in today’s global portfolio, optimising formulation is crucial to improving their viability. “The current portfolio of poorly soluble drugs is 90% based on some estimates, and formulation needs to play an increasing role in improving the biopharmaceutical properties of these molecules,” he says. “The Developability Classification System (DCS) developed by Buttler and Dressman provides useful guidance to the formulator in identifying the optimal formulation approach for these poorly soluble molecules. Obviously, as part of this strategy, excipients play a key role in enhancing bioavailability and stabilising the product.”
Alignment of risk-based guidance
A large amount of risk-based guidance impacts upon excipient selection, which creates challenges for the industry. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) brings together the regulatory authorities and pharmaceutical industry to discuss scientific and technical aspects of drug registration. However, in practice, different risk assessments may contradict one another, or be in conflict with a product’s remit and market profile.
Elder believes it is crucial to make ‘holistic-based decisions’, where risk can be intentionally increased in one area in order to mitigate it in another. “ICH Q9 says you need to manage risks, not avoid them,” he explains. “These different risk assessments can drive very different outcomes, and what is good for one could have adverse outcomes for another. For example, if you were developing a biopharmaceutics classification system (BCS) Class I compound where a simple formulation and a low cost of goods were appropriate, then you might select a mined diluent such as Emcompress.
“This might be perfectly acceptable from a mutagenic impurity risk assessment (MRA), such as ICH M7, or a microbial risk assessment, such as USP Bioburden Control of Non-sterile Drug Substances and Products, perspective, but obviously mined excipients would flag up as high risk from a residual metals risk perspective. Alternatively, if you were to change that selection to lactose, the residual metals risk assessment (ICH Q3D) and potentially the MRA (ICH M7) risk assessments would be OK, but you would need to manage a higher microbial risk as well as a TSE/BSE risk from bovine sourced lactose,” he adds.
Labelling and safety
The European Medicines Agency (EMA) is developing a definitive excipient-labelling initiative to optimise safety standards, with a particular focus on preservatives. Elder is keen to point out that the overarching drive for the safety of common excipients – particularly preservatives – can’t be to the detriment of patient safety when viewed from the product’s perspective.
“If the patient population requires a multi-use oral/semisolid formulation, then there is an increased risk of microbial contamination,” says Elder. “If this formulation cannot be adequately preserved because of general safety considerations, then you are exposing the patient to a bigger issue arising from microbiological contamination.”
With the increased focus on parabens, there are no obvious preservatives that can be used in the product pH range 7–8. “All of the other common preservatives work best at pH 4.5. So, if you need to formulate at a pH of 7–8 because of API solubility or stability considerations, what can you do?”
Excipient safety is paramount in the manufacture of paediatric medicines; those used in adult formulations, such as ethanol, may have the potential to cause adverse side effects in children. Neonates and infants are particularly at risk due to the immaturity of their hepatic and renal systems, which are less able to metabolise and eliminate excipients effectively. Identifying the excipients in a particular medicine is relatively straightforward – manufacturers’ summaries of product characteristics can be accessed via the electronic medicines compendium – but it is rare to find amounts specified. This issue is pertinent when paediatric patients are taking multiple drug formulations, particularly liquid medications. Exposure to certain excipients should be minimised, and safety limits and clear information provided to pharmacists and health professionals in order to carry out a risk assessment.
The Safety and Toxicity of Excipients for Paediatrics database, being developed by the Eu–US PFI, compiles safety and toxicity data of excipients that is scattered over various sources and presents it in one freely accessible space. It presents preclinical, clinical and regulatory information and toxicological reviews, with references and source links.
The BCS has issued guidance on biowaivers and dissolution that highlights the effects of certain excipients on bioavailability. Elder comments that most of the excipient focus has centred on BCS Class III compounds, which offer good solubility, but poor permeability: “In this instance, excipients can open up tight junctions to enhance absorption, like surfactants such as tween. Or they can increase intestinal transit times; for example, sugars such as sorbitol, sucrose and so on can reduce absorption (less time in the main absorptive organ, the small intestine). More research is required on the effect of these types of excipients on BCS Class III compounds, such as ranitidine and altenol.”
The US FDA has issued a recommended Inactive Ingredients List for manufacturers, which has received mixed responses from industry commentators, but Elder believes it is a useful and laudable initiative.
“Users can search the FDA database to support the use of a ‘new’ excipient,” says Elder. “If it is present in another product it is likely ‘qualified’, if not the company is faced with extra costs to demonstrate the safety of this novel excipient.”
Novel excipients and safety collaborations
There are major issues regarding the approval process for new excipients (with regard to safety considerations), which has limited manufacturers’ investment in this area. However, Elder cites an ongoing initiative being explored by the industry and the IQ consortium that may offer a positive way forward.
“The aim is to unlock safety data that is currently available within big pharma. This data, however, can’t be easily shared because of intellectual property considerations. Within certain fields, such as inhaled biologics where the cost of goods is already high, there is an appetite to evaluate new excipients, but in those areas where reducing costs is important there is less.”
Although recently developed excipients may offer better functionality, they can be more costly than their traditional counterparts. There is often limited data available on the safety of new versions and a sense of nervousness within the industry regarding possible supply chain issues with a new product of this nature. With a limited manufacturing history, drug formulators may be wary of risks in the ongoing sourcing of a new product and the potential for variability across batches. To optimise overall quality, manufacturers of excipients need to operate full traceability throughout the supply chain. Over the past ten to 20 years, the market for new excipients within the pharmaceutical industry has stalled, largely because formulators of drug products prefer to invest in tried-and-tested versions. There is a tendency for excipient companies to focus on the efficacy of their current lines and improve functionality by adding an improved characteristic, rather than investing in potentially challenging and costly novel excipients.
Undoubtedly, excipient selection remains a challenging area of expertise, but Elder thinks that, eventually, the science will win through. “Common issues such as stability, solubility and so on will remain important, but in the future excipient selection will be driven by biopharmaceutical considerations initially – it will become more science-based.”
Certainly, innovations in this area are promising. As well as improving existing excipients, co-processing is a growing field of research, whereby functionalities have been synergised to enhance performance. By combining two excipients with similar or different functions, the overall effect is optimised; for example, Prosolv is a combination of microcrystalline cellulose and silicon dioxide for improved flow.
Nano-pharmaceutical research may also have positive implications for excipient production and drug delivery. Ultimately, it is the holistic selection and manipulation of a broad range of ingredients that determines a drug’s success, of which excipients are an increasingly important part.