Although multiple factors can compromise the drug-like properties of biological molecules, we are still at a very early stage in learning how to assess them. This is despite — or perhaps more correctly, because of — the pharmaceutical industry’s accelerating drive to develop biological molecules as therapeutic agents. And I say “we” because this applies not only to the biopharmaceutical industry itself and the analytical instrument companies that serve it, but also those charged with regulating it. We are all to some extent running to keep up with the unprecedented pace of change as large-molecule drugs attract increasing attention and investment and begin to influence the prognosis for many diseases.

For those of us who want to stay ahead in delivering the necessary analytical methods, this is proving to be a strong catalyst for change in the way we identify and test technology and develop and deliver new instruments. At Malvern Instruments, a dedicated Bioscience Development Initiative (BDI) is the embodiment of a new approach that sees us letting go of some established practices and partnering at the highest level with technology inventors — and ultimately, end users — with the goal of providing the most appropriate tools as rapidly as possible. With shared learning at the heart of this enterprise, biotechnology and biopharmaceutical companies are enthusiastically embracing what for them is a low-risk opportunity to influence analytical technology development.

PRODUCT FOCUS: BIOLOGICS

PROCESS FOCUS: CHARACTERIZATION, VALIDATION, QUALITY

WHO SHOULD READ: PROCESS DEVELOPMENT, FORMULATION, MANUFACTURING

KEYWORDS: QA/QC, LABORATORY ANALYSIS, INSTRUMENTATION

LEVEL: INTERMEDIATE

The Prompt for Change

Traditional small-molecule discovery, development, formulation, and production enjoy a well-trodden route from identification of a candidate molecule through to taking a pharmaceutical preparation (quite often a solid dosage form) to market. Parameters for success are well established, and key attributes of purity and potency tend to be confirmed, measured, and controlled using proven analytical techniques.

That process is less straightforward when dealing with biological molecules, which by their nature are inherently variable. The analytical technology needed for quality assurance and quality control and to generate the biophysical and biochemical data needed for preformulation and formulation of biologics differs greatly from the pharmaceutical industry’s traditional practices. Couple that with a situation in which novelty is the norm and regulation is evolving, and you are constantly leaping into the unknown. We seek solutions not only for today’s analytical problems, but also for what tomorrow might bring.

Some analysts might argue that until you know exactly what it is you want to measure, you can’t develop the tools for measurement — a real “chicken and egg” conundrum. Do you compromise by measuring a parameter simply because the methodology exists? Or for expediency, do you cobble together a set of data using nonideal techniques that give you roughly (but not wholly) what you want? How will regulators view that? And (perhaps the biggest concern) what are the economic implications associated with analytical bottlenecks that hold back progress at key points during development? Those are all challenging questions for an industry in which “fast-moving” hardly begins to convey the reality of operating in an environment undergoing such enormous changes in development, manufacturing, and regulatory criteria.

What’s Driving Analytical Development?

The cost of getting a biological molecule through discovery and into development tends to be significantly greater than for small molecular entities. In addition, this process involves complex R&D and production. So manufacturers face enormous pressures to ensure that further investment goes into only those molecules with a high chance of making it through to a stable, manufacturable product. “Fail fast” is probably not “fail cheap” in this environment, but putting the brakes on a molecule that may cause problems farther down the line is certainly important. That means a lot of screening as molecules move from discovery into preformulation and formulation — and all at a stage where usually only a very small amount of material is available.

Fundamentally, we’re talking about analyzing proteins. Before exploring the implications for those researchers charged with coming up with the analytical tools needed for that task, it is worth a reminder of what makes a biological molecule such a different development prospect than a small-molecule drug.

Other than the fact that both proteins and small-molecule drugs are used to treat specific conditions, superficially there appears to be little similarity. I have seen the disparity in size between aspirin and an antibody, for example, likened to the difference in weight between a bicycle and a business jet. But it’s not just size that’s the issue. Proteins are quite different from traditional small-molecule drugs. They are not produced by precisely controlled synthesis or crystallization methods, but rather are grown and harvested from sometimes variable biological systems and growth media. They are heterogeneous, complex, and inherently unstable molecules that are subject to structural change and may become misfolded, aggregated, or denatured. They cannot be delivered in traditional solid dosage formats but instead are usually administered in solution by injection (although other delivery mechanisms are of significant interest and are under investigation). What this all adds up to is a level of complexity in development processes that is absent when developing small-molecule drugs.

Ultimately, ensuring the safety and efficacy of a final drug product is the overriding factor, and up until now that is largely what has been driving analytical requirements. Issues of protein aggregation — potentially giving rise to unpredictable and negative immune responses in patients as well as seriously compromising the activity of the drug — are of great concern. As the industry grows, however, manufacturers face mounting pressure for more sophisticated analysis throughout the development cycle to better understand and predict stability and behavior. Right now, major challenges exist not only in what can be measured, but also in what will provide meaningful predictive information about quality. Continual debate remains about what measurements will be needed in the future.

Tackling It from the Top

It’s pretty fair to conclude that there’s a high degree of uncertainty and risk for everyone involved in trying to pin down the rapidly evolving analytical needs of this industry. But getting the technology right is critically important to the industry’s future — or at least getting the technology development and delivery model right is important. It may well be that for quite some time, the technology itself has to change with great rapidity simply to keep pace. That demands a highly collaborative and agile approach to developm
ent and commercialization of that technology. And that is the founding principle of Malvern’s global Bioscience Development Initiative.

BDI was set up in 2012 (operating from facilities in Columbia, MD) and is now incorporated in the United States. We have a well-resourced, dedicated group that engages in high-level partnering for technology development and is focused solely on serving the biopharmaceutical market with the analytical tools that it needs. BDI is independent from but closely linked with the main Malvern Instruments organization. That frees it to have a very distinct purpose while retaining ready access to the expertise that exists within a company that has 40 years’ experience of producing analytical instruments.

Improving Understanding

BDI has been established to encourage leaders in the biopharmaceutical industry to partner with us and share their challenges; to provide a vehicle for us to identify and target emerging technologies; and to provide agile, fast-moving technology development. When we talk to senior executives in biopharmaceutical and biotechnology companies, our very well-received approach is that “You need to understand the problems and meet the needs of the regulators. We have to understand how to better serve you. Let’s join forces and do this at a high level in our respective organizations.”

The key to success, however, is being the pivotal link. You must be the enabler who seeks out those who have emerging technology and works with those who may want to use it. You should understand how those two may or may not fit together and then engineer the necessary access to try out the technology, learn from it, and either improve it or set it aside.

Figure 1 shows the structure of BDI. In the middle is my company’s team of scientists, engineers, and project managers. They reach out to universities and technology start-ups to assess opportunitie sand determine whether we can invest in and provide support to bring a technology through development quickly. We will push some very early stage technologies straight to our biopharmaceutical partners, disclosing ideas at a much earlier stage than would be the norm. Once a technology has been fully tried, evaluated, and proven worthy of further development, it is passed through to our established engineering and product management teams.

Figure 1:  ()

Fundamentally, we don’t believe that Malvern has to come up with all the good ideas for technology and instrumentation. Whereas some products will come about as the result of organic development, our remit allows us to look at technology acquisition or enter into licensing agreements, perhaps with small companies or academia. The main point is our recognition that traditional product development is too lengthy a process to meet the needs of the biopharmaceutical industry.

The BDI model brings inventor and potential end users together in the development cycle. It provides partners with very early access to new technologies to evaluate and improve in an iterative process of shared learning and to quickly produce a usable instrument. The starting point may simply be an idea for discussion, or it could be a concept or possibly a prototype. But it’s the important feedback provides an opportunity to integrate improvements to build something that is useful and immediately adds value. The last thing we want to do is take two years to develop a new product only to find that market needs have moved on (an ever-present risk in the current environment).

With so much fluidity in biopharmaceutical testing, it is hardly a safe bet to pursue just one technological avenue. Partnering provides great opportunity for all parties to explore in parallel many different potential solutions, which may be at different stages of development. It helps spread business risk. It also means we can take a long-term view of some technologies and put effort into areas that might be regarded as “too early stage” to be interesting in a more traditional analytical instrument environment.

A Focus on Technology

Horror stories abound in the biopharmaceutical industry wherein the ability to measure certain parameters early in a development cycle might have saved millions of dollars of wasted investment in a molecule that fails farther down the line. Selecting the right candidate in preformulation is critical. It is here that bottlenecks in analytical testing are often reported. Many traditional measurement techniques fail to stand up to the need to test multiple parameters in exceptionally small sample volumes.

One example is formulation viscosity. Drug efficacy and patient experience are significant drivers. With most biological drugs being delivered intravenously, or by intramuscular or subcutaneous injection, injection volume, drug concentration, and viscosity are crucial parameters.

Developing high-concentration formulations that can be injectable at low volume can be a big challenge. For biopharmaceuticals, high concentration very often also means high viscosity, which can lead to problems with drug delivery. Early viscosity screening of proteins in preformulation is therefore critical, but conventional techniques based upon mechanical rheology are less than ideal. One of the first commercial products to emerge through the BDI route is an instrument that automates viscosity measurement and molecular sizing using only a few microliters of sample. It has been developed in cooperation with both technology providers and end users.

Another area of focus is measurement of protein aggregation. The tendency of a monomeric protein to aggregate within a formulation is a serious challenge for both drug formulators and regulators. Formation of protein aggregates large enough to be immunogenic may pose significant dangers to human health, so formulation stability is crucially important. Some debate remains, however, about what size particles or aggregates are the most important, and regulatory requirements continue to evolve. Various particle sizing technologies are used at different stages of biopharmaceutical development and quality control. But the crucially important preformulation stage is one where gaining reliable results will pay dividends downstream.

The ability to quantify as well as size particles is now very important. Regulators have identified potential immunogenicity concerns surrounding protein aggregates from 0.2 µm to 2 µm in diameter. But standard optical particle-measurement techniques cannot deliver quantitative data throughout this size range. Addressing this need is the technique of resonant mass measurement (RMM), which is being applied in the Archimedes system, brought into Malvern’s portfolio through a partnership managed through BDI.

Closing the Gap

There is no doubt that biopharmaceuticals represent a paradigm shift in the development, manufacture, storage, testing, and delivery of formulated medicines. The bioindustry is therefore in a state of rapid developmental, manufacturing, and regulatory change. At a time when the sector is in its greatest need of new product characterization technologies, analytical instrument companies have only scant information available on which to base large investment decisions. The result is delayed introduction and deployment
of new and validated measurement tools that can help alleviate screening and testing bottlenecks.

The Bioscience Development Initiative is set to recognize and tackle the “mismatch” between rapid technology deployment and established engineering and volume manufacturing practices in place for mature analytical technologies that serve well-established analytical testing requirements. Its mission is to seek out technologies, add them to the toolbox, and (with the help of end-user partners) evaluate them quickly for market suitability. Early successes bode well for the future development of all parties involved

About the Author

Author Details
E. Neil Lewis, PhD, is chief technology officer at Malvern Instruments Ltd., Enigma Business Park, Grovewood Road, Malvern, Worcestershire, WR14 1XZ, UK; 44-1684 892456; fax 44-1684 892789; www.malvern.com.

REFERENCES

1.) 2013. World Biological Drugs Market 2013-2023, Visiongain.