Every now and then, a drug developer will get extremely lucky and stumble upon an active pharmaceutical ingredient (API) that is entirely free from problems. Its bioavailability is excellent, it’s safe and presents no challenges to patient compliance, it’s easy to manufacture and shelf-stable, and while it’s innovative enough to be commercially successful, it doesn’t pose any challenges for regulators.

These APIs certainly exist, but they are outnumbered by many APIs that come with hidden challenges that can be overcome — that is, if they’re identified early. In fact, many of these imperfect APIs may actually represent some of the most significant economic opportunities in the market moving forward, despite what the following statistics say.

The Alarming Failure Rates of Recent Drug Development Programs

According to recently published statistics, more drug developers are choosing to roll the dice instead of identifying and solving potential problems:

• 90% of clinical trials fail
• 40-50% fail due to a lack of clinical efficacy
• 30% fail due to unmanageable toxicity 
• 10-15% fail due to poor drug-like properties
• 10% fail due to poor strategic planning or a lack of commercial viability 

Most of these problems could and should have been caught long before the clinical trial stage, where fixing them could have been cheaper and less time-consuming. 

Takeaways: While investments in pharmaceutical research and development hit all-time highs in 2021, and incredible opportunities are certainly still out there,  the vast majority of biotech companies are either hoping to conserve resources early on in drug development, aren’t sure how to attract investors early in the process, or are unaware of the benefits a skilled formulator can bring to a project.

The Benefits of Thorough Pharmaceutical Development

While every drug development journey is different — and so is every biotech company’s level of risk tolerance — here are the most common benefits that a formulator can offer:

• Reducing risk throughout drug development 
• Increasing commercial viability 
• Helping attract investors to your project
• Clarifying budget and timeline expectations
• Avoiding regulatory setbacks 
• Simplifying the manufacturing process

While many leaders of biotech companies have extensive backgrounds in chemistry or medicine — and are, therefore, experts in how chemicals interact or how the body operates — many are unfamiliar with how chemicals behave within the body. So before we delve further into formulation, let’s explore the science behind it.

1. Pharmaceutics

Pharmaceutics is the study of how different drug formulations affect how a drug is delivered to its targeted location within the body. 

2. Physical Chemistry

In our line of work, physical chemistry experts focus on understanding the properties of drug substances and excipients — often referred to as inactive ingredients — in formulation development.

The Role of Excipients

Excipients are an often overlooked component of a pill, but the term “inactive ingredients” is a bit misleading. To be fair, the excipients that we often use today were typically not designed for the purpose they are now serving, and scientific advancement in this area is yet another undervalued but potentially lucrative opportunity, but they alone can be the key to solving each of the four main pharmaceutical challenges: efficacy, safety, viability, and regulatory compliance.

Excipients can be used by formulation experts in order to: 

• Improve bioavailability 
• Increase stability 
• Prevent dissociation or aggregation 
• Cause a tablet to fizz when it comes in contact with water
• Maintain the osmolarity and/or pH of liquid formulations 
• Control the release of the drug inside the body
• Improve the flavor or mouth-feel of a pill
• Act as fillers or binders
• Alter the pill’s appearance

3. Biopharmaceutics

Biopharmaceutics studies the relationship between the physicochemical properties of the drug and its biological effects, and how a drug’s formulation will influence absorption, distribution, metabolism, and excretion (ADME).

4. Biotechnology and Molecular Biology

As biologic drugs (medicines made from organisms or their products) have unique formulation challenges, these areas of focus are key to helping these treatments remain stable and avoid triggering an immune response, as well as delivering them to very specific cells. 

5. Material Science and Nanotechnology

Nanotechnology — which allows one to manipulate matter at the nanoscale — isn’t entirely new, but its practical use in the pharmaceutical industry dates from the ‘80s and ‘90s. Certainly, not every drug development project will require these types of advanced skills, but if your API is known to cause unpleasant side effects — as is the case with many cancer treatments — nanotechnology has proven itself to be effective at reducing them. 

In fact, Doxil, which was first approved by the FDA in 1995, uses nanotechnology to facilitate the release of the drug precisely at the site of a tumor.

6. Regulatory Science

Many biotech companies that don’t work as closely with regulators mistake their approvals for endorsements. In an era where regulations are evolving quickly and where regulatory setbacks and delays can jeopardize the financial viability of an entire project — let alone an entire company — it’s vital to have team members who understand what regulators are looking for, what methods may require additional scrutiny, and the like.

7. Pharmacodynamics and Toxicology

Pharmacodynamic studies are primarily aimed at identifying the mechanisms behind both the therapeutic and toxic effects of therapeutic agents.

8. Clinical and Patient-Centered Considerations

A lack of sufficient patient compliance at clinical trials  — which can result from a failure to match your clinical supplies with your protocol, among other things — can undermine your data significantly. However, even if your drug is eventually approved, failing to consider your patient population’s needs and challenges may mean that your approved drug, while commercially available, will not be prescribed at a sufficient rate to recoup the costs of its development. 

Whenever we assist clients in the formulation of an oral solid dosage (OSD) project at Corealis, we think through each drugs intended patient population, the condition it’s intended to treat, and its eventually commercial viability from day one. 

Takeaways: formulation services are not a single science, but will require a team that understands each foundational science involved, and knows enough to know where they may have skill gaps. Not every drug development project will require all of these skills, but a basic understanding of which advanced skills may be necessary and when for each project could save quite a few biotech companies from quite a bit of heartache.

Skill gaps are fairly common, and will likely become far more common in the next few years. According to recent statistics, The pharmaceutical and life sciences industry will face a 35% talent deficit by 2030.

Many biotech companies have an understandable preference to attempt to keep formulation development in-house, with the hope that it will save them money. However, they often aren’t sure exactly where their skill gaps are, and in formulation development, not knowing what you don’t know can be very expensive. 

At Corealis, while we can assist clients with creating clinical trial supplies, we often find that those who reach out much earlier have a much smoother and less expensive journey overall. 

However, all CDMOs are definitely not the same. Click the link below to get our guide to finding the best pharmaceutical outsourcing partner for your next project. 

Read How To Find the Best CDMO

We touched on this earlier — not all APIs are ideal. Some will only be druggable with the help of a skilled formulator, while others may lack critical attributes that would ultimately affect their safety, efficacy, stability, or commercial viability.

No one wants to hear bad news, but it’s always better if that bad news comes earlier rather than later. Therefore, the first step in formulation development is to fully understand an API so that problems can be anticipated and addressed without a significant investment of time and resources. 

API Analytics

Before you proceed with creating a prototype, you should have a thorough understanding of your APIs: 

• Particle morphology
• Particle size and size distribution 
• Hygroscopicity 
• Bulk and tap density/flow properties
• Crystal forms (if applicable)
• Suitability for your proposed treatment
• Behavior when subjected to extreme conditions 
• Solubility

Depending on the characteristics of your API, you can make some informed decisions about how your active ingredient would best be delivered in the body, and what special manufacturing or packaging requirements your final product might have.

Getting a Second Opinion for OSD Projects

At Corealis, we put a lot of emphasis and value into assessing your drug product for “druggability.” This can help you make decisions in selecting the best of multiple drug candidates, help us to design the most appropriate formulation plan, and most importantly, give you the opportunity to assess our scientific expertise and potential working relationship with a nominal commitment and investment.

Request a Druggability Assessment

Once you have a thorough understanding of your API and have a sense of how it may best be delivered and what problems you may have to overcome, the formulation development process can start taking shape. 

Essentially, the ultimate goal of formulation development is to create a promising prototype that can then be used as a model for producing clinical trial materials.  Creating an optimized prototype of a drug can be very exciting, and even with a thorough understanding of the solid science that is required to formulate a challenging API, it can be tempting to rush this phase. And sometimes you can!

Depending on your API and your company’s tolerance for risk, some of these steps can be streamlined to save time and money: 

1. Manufacturing between 1-6 optimized prototype formulations   
2. Evaluating manufacturing reproducibility
3. Evaluating dissolution profiles in conditions that resemble a human GI tract (biorelevant dissolution)
4. Performing stability studies in different environmental conditions on the most promising prototypes
5. Conducting further stability tests in animal models to select the formulation with the optimum absorption profile
6. Selecting the most suitable prototype for the manufacture of clinical trial supplies
7. Scaling up your manufacturing processes
8. Packaging, labeling, analytical method validation, release testing, and further stability testing of your clinical trial materials (CTM)

Takeaways: More testing isn’t always better, and a skilled formulation development team will understand where you can gain speed and reduce costs without adding unnecessary risk.

Our scientists have recently produced a white paper on how you can adjust your formulation services process according to your risk tolerance. Click the link below to download your copy! 

Read Reducing Risk at Every Stage of Drug Formulation

One of the biggest challenges in our industry is the fact that regulations are constantly evolving. However, some things have changed very little since we were founded in 2005. 

Before regulators will approve an OSD drug substance for phase I clinical trials, they expect a comprehensive set of documents to ensure the product's safety, quality, and potential for success. If the data is clean, well-organized, and makes a compelling case that the drug is safe, regulatory approvals can happen quicker. And if your formulation development was thorough, you should already have all of the data that you need. 

Here’s a list of key documents that regulators typically expect to see as part of an investigational new drug (IND) application or clinical trial application (CTA) for a phase I clinical trial involving an OSD:

1. Preclinical Studies

Here, regulators will be hoping to see data that your drug is expected to behave as predicted in the human body. More specifically, they will be hoping to get a thorough understanding of your prototype in these areas: 

Pharmacology

Regulators will need to understand your drug’s mechanism of action, its therapeutic targets, and biological effects in preclinical (animal) models. 

Toxicology 

Your data should make it clear to regulators that your drug substance has been rigorously tested for safety and it shows no signs of organ toxicity, carcinogenicity, genotoxicity, reproductive toxicity, and the like. 

Pharmacokinetics (PK) Data

You should provide thorough information on how your drug is absorbed, distributed, metabolized, and excreted. 

Although dissolution testing technology is evolving, and regulators are starting to signal their openness to using GI-simulation methods in certain cases, if you’ve been strategic about how you’ve compensated for the differences in animal vs. human GI tracts, your in-vivo testing data can still be a decent early predictor of how a drug is likely to behave in the human body. 

Pharmacodynamics (PD) Data

Regulators are also hoping to see clear data on how your drug substance may affect the body at different doses, and how it may interact with different biological systems.

2. Formulation and Manufacturing Information

Before you can expect an OSD project to be approved for a phase I trial, regulators will also need to know exactly how it was formulated and manufactured and why. 

Your materials should include robust information regarding: 

• Formulation development data, including the composition of your drug substance and its final dosage form
• Robust process development and manufacturing information indicating how your product has scaled up from the laboratory to production scale — including any cGMP documentation
• Batch records and process validation information that indicates that your manufacturing process produces consistent batches that are in line with quality standards 
• Analytic methods and validation data that speak to your drug substances quality, purity, identity, strength, and potency

3. Stability Data

Here, regulators are hoping to see robust data that indicates your product will maintain its intended quality throughout the clinical trial process and expected shelf life, including any storage requirements.

4. Good Manufacturing Practice (GMP) Certification

Your certification should make it clear that your drug was manufactured according to GMP guidelines and include details — not only of the manufacturing facility but also of the quality control measures used and the validation of equipment and processes during production.

5. Your Clinical Trial Protocol (Phase I)

Regulators will need to see a detailed clinical trial protocol outlining the following: 

• Study design
• Objectives
• Methodologies
• Inclusion/exclusion criteria 
• Dosing regimen
• Duration of treatment
• Safety monitoring procedures 
• Safety and efficacy endpoints
• How results will be measured and reported 
• How you will gather informed consent of trial participants

6. A Comprehensive Risk Management Plan

In addition to identifying any risks associated with your drug — such as possible adverse reactions, toxicity, and other safety concerns — your risk management plan (RMP) should outline your strategies to minimize any risks during clinical trials. 
It should also specify procedures for ongoing safety monitoring and the reporting of any adverse events.

7. Clinical Trial Material (CTM) Documentation

You’ll need to confirm that your clinical trial materials are appropriately labeled and have been manufactured in accordance with regulations and your protocol.

8. Toxicology and Safety Summary

Regulators will also expect an overall safety profile that summarizes all preclinical toxicology studies, including the No Observable Adverse Effect Level (NOAEL) and other safety data.

9. Environmental Impact Assessment (if applicable)

In some regions, like the European Union, you’ll also need to add an environmental risk assessment for certain drug formulations, especially for new chemical entities (NCEs).

Takeaways: Regulators expect OSD drug developers to provide a comprehensive set of data that demonstrates the safety, efficacy, quality, and manufacturability of the drug product before clinical trials. If you choose to work with a contract development manufacturing organization (CDMO) as opposed to doing formulation development entirely in-house, they should also be experts in providing full dossier support for investigational new drug and clinical trial applications.

While formulation development is often rushed and underrated, when done well, it can help drug developers reduce risk and save money throughout the course of their project. 

See Our Drug Development Roadmap

We are in an era of swift pharmaceutical innovation, but that also means the ICH — an international organization that seeks to harmonize pharmaceutical regulations worldwide — has had to issue a series of updated guidelines. Especially for smaller biotechs and startups, staying on top of rapidly changing regulations can be challenging.

Top 10 Dont's for Drug Developers Regarding the ICH and Other Regulatory Bodies

While most of these may seem obvious, many promising biotech companies have made one or more of these mistakes, which can lead to non-compliance, inefficiencies, or missed opportunities.

1. Don’t ignore updates or revisions
2. Don’t rely on a single source of information 
3. Don’t underestimate the complexity of ICH guidelines
4. Don’t skip engagement with regulatory authorities — make time for Pre-IND/Pre-CTA meetings
5. Don’t overlook local regulatory differences
6. Don’t fail to incorporate ICH guidelines into your internal procedures
7. Don’t disregard the importance of documentation
8. Don’t wait too long to adapt to new guidelines
9. Don’t neglect risk management and quality systems
10. Don’t overlook the need for expert guidance

While there are many ways that proper formulation development can help minimize risk and cost throughout your project, cutting corners with regulators isn’t one of them.

Outsourcing your formulation development to a specialist is often the better choice in these circumstances: 

• The API you’re working with has challenging properties 
• Your organization needs to reduce risk 
• Your team may have critical skill gaps 
• You lack the equipment or space your project will need
• You’d like to bring your drug to market faster
• Staying on top of ICH guidelines is a challenge 

Outsourcing your formulation development will come with a price tag, but a highly skilled CDMO can also help you attract additional investment and bring your product to market faster. 

That said, all CDMOs are not the same! While you may spot us at upcoming industry events, in order to get a better understanding of how we work and what we bring to the table, feel free to request a one-on-one meeting using the link below.

Request a Meeting