Editor’s Note: This article was published in Pharmaceutical Technology Europe’s April 2021 print issue.
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Editor of Pharmaceutical Technology Europe
Accelerated formulation strategies are a useful tool to reduce development timelines and cost, but key priorities must be considered early on to ensure success.
Although approximations vary considerably in the literature (1–3), it is widely accepted that the costs associated with bringing a drug to market are substantial. Drug development can be made more cost-efficient by accelerating the development timeline, so that the speed-to-market is shortened, an aspect that can be aided with accelerated formulation strategies.
“An accelerated formulation strategy offers many benefits,” says Andreas Seidl, chief operating officer, Leukocare. “Formulation development often can be taken off the critical path, allowing for better process development and project management. Furthermore, the overall project timelines from development until approval and commercial manufacturing can be accelerated.”
Editor’s Note: This article was published in Pharmaceutical Technology Europe’s April 2021 print issue.
For Alexander Faude, director Process Science, Downstream Processing, Rentschler Biopharma, being able to take formulation development off the critical path provides the biggest benefit of accelerated formulation strategies. “Moreover, efficient processes that implement all the components discussed earlier will save time. This in turn will translate to a faster time-to-clinic which ultimately leads to a faster time-to-market,” he adds.
Although in agreement that the time efficiencies are the greatest potential benefit, Jeffrey Zonderman, chief commercial officer, RedShiftBio, also specifies that faster formulation studies provide opportunities for developers to gain a more complete understanding of the drug. “With the right technology in place, formulators can screen more drug candidates, assess a wider range of excipients and buffers, and rigorously apply quality‑by‑design (QbD) principles to develop a more robust product,” he notes. “So, acceleration can lead directly to an improved drug product with better stability and a higher chance of successful commercialization. Investing in information gathering at this stage can pay dividends in terms of a lower risk of product failure and a narrower field of higher quality candidates for further development.”
Seidl concurs that a successful accelerated formulation strategy can reduce the risks related to stability and adds that by closely interacting with other areas of the manufacturing process, such as downstream processing (DSP), it is possible to gain synergies across the whole process (e.g., integration of the formulation development results into DSP development). “Hence, risk reduction and yield increase are some advantages that result from this integration,” he says.
Formulation is clearly becoming more of a bottleneck in the biopharmaceutical drug development pipeline, explains Zonderman. “Strategies for accelerated formulation are consequently a growing focus for the industry and include the adoption of a QbD, knowledge-led approach, the greater use of computational modelling, and the identification of an optimal suite of orthogonal analytics,” he says. “The challenge is to enable more predictive formulation by combining the most appropriate analytical techniques with state-of-the-art modelling, to bring molecules through formulation more rapidly while at the same time driving down the risk of poorly formulated drugs proceeding further down the pipeline.”
A broad range of assays can be used to characterize therapeutic proteins, Zonderman continues. “Against a backdrop of accelerating formulation, identifying a suite of biophysical tools that work effectively together to generate the information required is therefore a vital and shared goal for many biopharmaceutical companies,” he emphasizes.
Some techniques that can provide valuable formulation insight, such as nuclear magnetic resonance and X-ray crystallography, are not necessarily compatible with accelerated strategies due to the amount of manual input required, particularly for data processing, Zonderman confirms. “Here, automation is a defining priority because it typically delivers rapid measurement, reduced manual input, and high throughput—all of which are crucial,” he says. “And it is important to note that the requirement for automation extends right through from sample preparation to data processing and handling.”
Using in-silico tools to narrow down the suitable excipients can greatly improve prediction of formulation strategies, asserts Marvin Kadisch, director Process Science, Upstream Processing, Rentschler Biopharma. “The application of in-silico tools is gaining increasing importance and will continue to do so in the near future,” he states. “This application will facilitate the efficient examination of excipient libraries (prior to design of experiment [DoE]) and overall prediction.”
Of high priority when approaching accelerated formulation strategies is the early availability of materials, notes Faude. “In addition to that, the process implemented for product development should be kept in mind, as this can greatly influence the final product, which in turn affects formulation development strategies,” he says.
Zonderman agrees that material availability and amount of material required for robust analysis early on are practical concerns, but he underlines that not everything is about practicality and speed. “The relevance and value of the information generated is critical,” he highlights. “Companies are looking to invest in complementary, orthogonal assays that slot together to generate understanding of the factors that influence formulation performance, notably drug activity and stability. The aim is to establish correlations that facilitate an efficient QbD approach.”
“Structural characterization is a vital aspect of this drive for fundamental knowledge, and an important analytical focus with secondary structure offers increased insight into the development of a robust understanding of protein behaviour, conformational stability, and aggregation pathways,” Zonderman asserts.
Identifying key degradation pathways and weaknesses of the molecule early on is certainly recommended, confirms Seidl. “With this information in hand, one can tailor formulation candidates with excipients that best address these weaknesses,” he adds. “Classically, several formulation candidates are tested at increased temperature in a short period of time to check for the impact of formulation on stability behaviour (aggregation, de-amidation, etc.) of the molecule. Components such as mechanical or freeze/thaw parameters can be included.”
Sequential testing (i.e., by applying clever DoE matrices) help to swiftly identify best performing excipients and combinations thereof, Seidl explains. “Using a confirmatory stability study as a last step, with the possibility to still be able to fine-tune formulations, further helps to reduce the risks and surprises at a later point in time,” he says. “With a proper data-set combining the accelerated aging and the confirmatory stability study, prediction quality of long-term storage is enabled and allows decisions on final formulation candidates already after only one month’s data of the formulations being tested in a confirmatory stability study.”
A lack of available material is challenging, according to Faude, who highlights the use of a staggered approach to accelerate the formulation process when early material is not available. “One should start formulation development early with available material and continue sequentially with material received at later time points (representative of clinical material),” he says.
Kadish underscores the fact that a lack of material affects analytical method development. “With limited availability of material, one often has to begin with generic methods and refine these along the way as more information becomes available,” he notes.
Kadisch underscores the fact that a lack of material also affects analytical method development. “With limited availability of material, one often has to begin with generic methods and refine these along the way as more information becomes available,” he notes.
“Close collaboration with clients on accelerated formulation development is both a key factor and a potential challenge,” adds Seidl. “In general, the client knows the molecule best, and the information exchange with the client can be crucial when tailoring formulations for the specific molecule, for example, when based on previous findings of the client on aspects such as stability.”
Representative measurement at each stage of development is a major challenge raised by companies seeking to employ accelerated formulation strategies, Zonderman continues. “In early formulation this means measuring a parameter that is relevant to formulation behaviour with minimal amounts of sample, while in later formulation the problem may be the ‘dirtiness’ of the sample, including protein concentration and complexity,” he says. “Add to this requirement the need for precision/high sensitivity and you have a significant ask for instrumentation that is optimally suited to an accelerated formulation environment.”
When measuring structure, specifically protein higher-order structure—secondary, tertiary, and quaternary—drug activity can be defined, continues Zonderman. “Structural measurements also provide a sensitive indication of instability and insight into aggregation mechanisms,” he says. “Measuring structure is therefore extremely useful when it comes to building a robust, fundamental understanding of the drug product for accelerated formulation.”
However, this type of structural measurement demands technology that is capable of quantifying structure with sufficient sensitivity to generate useful information for a wide range of sample types, Zonderman asserts. “Unfortunately, techniques for secondary structure, including circular dichroism and conventional Fourier Transform infrared, have limitations when it comes to automated measurement in the presence of excipients, at high concentrations or, conversely at low concentrations,” he notes.
Additionally, sample preparation for measurement purposes can compromise data, Zonderman highlights. If the sample is diluted, then the protein is no longer in the native environment of interest, the structure may be affected, and the resultant data jeopardized, he adds. “Switching between techniques, because, for example, one can be used at low concentration while the other is better for more clinically representative formulations, raises the issue that any differences observed may be related to artefacts of the techniques, rather than the drug,” Zonderman states.
“Alignment of project goals at the start is vital for pragmatic risk assessment and to align on how much risk one is willing to undertake in accelerated strategies,” emphasizes Faude. “A good strategy with defined goals and target achievement measures goes a long way in implementing a successful strategy. In addition, QbD plays a significant role, [and] an efficient analytical control strategy that is needed for approval is also equally important.”
Consultation between an outsourcing partner and sponsor company is key when establishing project goals and a successful strategy, continues Faude. “It is essential to approach the project as a partnership, as a collaboration where the client and outsourcing partner are equally invested in project success,” he explains.
Early alignment between the client and the formulation developer to determine the target product profile greatly facilitates the design of formulations to be applied, agrees Seidl. “Also, one should aim to know the molecule, as platform buffer systems may risk unwanted surprises at later stages of development,” he says.
Therefore, an outsourcing partner’s experience in formulation development settings, strategies, and execution is vital for predefined targets by the client to be met, Seidl stresses. “Clear communication and consultation of the formulation development expert prior to project start enables smooth project execution,” he says. “Furthermore, the outsourcing partner should lead the client in the project but should also listen to clients’ needs.”
To assure success in accelerated formulation strategies, the chosen strategy must be fit-for-purpose and suit the client’s needs to save time, confirms Kadisch. “Hence, early-stage material that matches stability requirements for clinical material must be utilized to ensure optimal time-to-clinic,” he says.
For Zonderman, it is important to think hard about what sort of information will be helpful when accelerating formulation. “For example, when it comes to stability studies, aggregate detection via a sizing technique, such as size exclusion chromatography (SEC), is routine practice. However, to deploy SEC, the study needs to continue until aggregates are detectable,” he asserts. However, SEC only sizes aggregates and does not measure structure, providing only limited insight.
Secondary structure measurements can provide a rewarding and complementary way of detecting instability, Zonderman underscores. “Changes in elements of secondary structure, notably beta sheet content, are a reliable indicator of instability and incipient aggregation,” he adds. “By measuring secondary structure, it is therefore possible to accelerate stability studies by detecting instability much earlier, before aggregates form. At the same time, structural information provides insight into the aggregation pathway, facilitating mechanistic understanding and a QbD approach.”
Furthermore, it is imperative to understand the value of sensitivity—the ability to detect difference—affirms Zonderman. “A technique with high sensitivity will differentiate samples that a less sensitive technique classifies as identical. Higher sensitivity will therefore bring your understanding into sharper focus, enabling more precise structure-functionality relationships and more effective formulation optimization,” he states.
“One final point to make is that the analytical offering for biopharma is evolving fast, with many companies recognizing that it remains a work in progress,” Zonderman summarizes. “Keeping an open mind as to what might now be possible is vital when it comes to putting in place accelerated formulation strategies.”
1. J.A. DiMasi, H.G. Grabowski, and R.W. Hansen, J. Health Econ., 47 (May) 20–33 (2016).
2. V. Prasad and S. Mailankody, JAMA Intern. Med., 177 (11) 1569–1575 (2017).
3. O.J. Wouters, M. McKee, and J. Luyten, JAMA, 323 (9) 844–853 (2020).
Felicity Thomas is the European editor for Pharmaceutical Technology Group.
Pharmaceutical Technology Europe
Vol. 33, No. 4
When referring to this article, please cite it as F. Thomas, “Focusing on Accelerated Formulation Strategies,” Pharmaceutical Technology Europe 33 (4) 2021.