IDBS Blog | 4th July 2019

Excipients Take Center Stage: The Impact on Formulations and Compliance

When you think of a medication, is the active ingredient the first thing that pops into your head, or perhaps the name of the drug?

You’re not alone. The active ingredient of a medicine gets all the attention, which is fair, considering it’s what gives the medicine its therapeutic properties. But it forms a tiny percentage of a medication – sometimes as little as 0.1%! The remaining 99.9% is excipients.

Formulations, including the choice of excipients, is often overlooked, but shouldn’t be. It has a role in every research and development sector, whether it’s new and exciting biotherapeutics, industrial goods such as paints and solvents, or even your run-of-the-mill paracetamol tablets from your local pharmacy.

Why is the spotlight on excipients?

In the drug development world, what makes a medication is split into two parts: the active ingredient or substance and the rest, a concoction of supporting ingredients called excipients. The ultimate goal is determining which additional ingredients to include into a tablet or biological, how much of it, and navigating the complex interactions to form a winning recipe. Excipients normally don’t act directly on the patient, they simply facilitate the active ingredient’s release in the body.

What makes a successful formulation? Manufacturers are looking for a stable formula that works with its active ingredient, designed to behave in a specific way – does it have a good shelf life? Is it convenient to take? It should comply with regulations and be safe for patients to take. Crucially, patients should want to take it as a treatment.

Patient acceptability is a key consideration

Compliance can take two meanings in a pharma context: regulatory compliance and patient compliance. While regulations certainly have an impact on formulations, the right formula can improve the patient experience and, in extension, influence patient compliance or acceptability. A huge number of patients need regular doses of medications to support their daily lives but are either unable to (think dysphagia) or refuse to take their medicine.

In pharma, this can be for any number of reasons: ‘the tablet is difficult to swallow’ is often cited as an explanation, perhaps due to its shape or size, as is ‘it tastes foul’. These are all elements controlled during formulation, and scientists have now tweaked formulas to best suit the market as well as regulatory compliance and reducing operating costs.

Regulatory bodies are increasingly encouraging production of medications for young children. Pediatric versions of treatments need to consider the palatability and size of the tablet, given the age and weight of the young patient. For example, medicines with fillers and disintegrants ensure good ‘mouth feel’ for tablets that disintegrate in the mouth, and the right coating material can mask any unpleasant tastes by delaying the drug’s release in the saliva. Characteristics such as these make a patient more likely to take their medication.

Today, new technology and techniques, modelled on pioneers such as the first orally dispersible tablet Zydis, attempt to create formulations that cater to all patients.

Introducing novel technologies calls for change

With the rise of innovative technologies such as 3D printing and continuous manufacturing, more and more active ingredients are insoluble. Without clear regulations on excipients, there is no guarantee that the chosen one compliments the main ingredient. This creates problems, as regulatory bodies including the FDA assess the entire drug, and never the excipients on their own. Oftentimes, countless drugs are rejected because they are not available in the right dosage forms needed to be effectively delivered in the body.

So, companies could invest millions in creating a novel excipient to add to their formulation, only to have it scrapped along with the treatment. Unfortunately, this means no manufacturing company is jumping to be the first to create a new ingredient. Consequently, the industry is stagnating, and patients don’t receive the treatments they so desperately need.

While there is limited regulation around the safety of excipients at present, as technologies change, so must the excipients that form part of the formulation. They balance out the insolubility of the active ingredients, but manufacturers should also work to optimize the formulations to account for new technologies and techniques.

To affect change, regulators must work with manufacturers to spotlight excipients and their role in a successful formulation.

Confusion around regulations has choked innovation

As you can imagine, making sure all these components are compatible and form a stable structure requires strict procedures and monitoring. Regulators expect excipients to be selected carefully, and for formulators to justify their choice, as well as the amounts used.

But unclear regulation for excipient operations before it enters the pharma sphere has caused confusion regarding the specifications and controls needed. This is a challenge, because excipients are primarily manufactured by chemical companies, who create the same set of excipients for a wide variety of their customers, of which pharma organizations are just a small fraction. The products used in medications are often the same sold to food and beverage companies, paint and plastics industrials, and many more.

Yet, pharma companies have specific GMP regulations in place to ensure safe medication use in patients. Other sectors do not have the same level of control, just as the consequences of incompatible ingredients aren’t as drastic. Having the correct procedures in place, using the right technology and opening channels of communication to ensure consistency are vital to remove these bottlenecks.

There are software technologies on the market that support formulations from the get go, such as the IDBS E-WorkBook.

How software fits into the formulation picture

There is no denying that formulations is a complex part of therapeutics development, made all the more difficult to navigate when data is not available to access as required. Ideally, formulators avoid repeating work as they have a comprehensive knowledge base from past experiments to hand and can built upon it, saving both man hours and operating costs.

This idyllic scenario is not something that paper-based reporting practices can realize. This is where software can benefit a formulations lab; capturing all relevant information in a single platform, eliminating the need to coordinate multiple Excel spreadsheets, searching through archived data, and deciphering easily-corrupted paper notebooks.

Formulators can trace their items back to their origins and create a searchable genealogy – not just for the final product but also the individual ingredients. For formulations especially, this approach is increasingly important as the meta data must be consistent, good quality, and should be shared in full with colleagues in analytical labs among others.

All these features rolled into a single platform ensures speedy production in a safe and regulatory compliant environment. Scientists can draw insight from a pool of knowledge and make informed decisions about any novel excipients they propose to add to a formulation.

Most important of all, innovative technologies such as E-WorkBook help get medications to market sooner to treat patients, and isn’t that what the drug development industry is all about?