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Future Directions – Formulation In The Drug Development Process

Well-Planned Formulation Strategies Save Millions

Discovering and developing new treatments is a complicated, lengthy and expensive exercise, resulting in high attrition rates for new chemical or biological entities (NCEs, NBEs). A frequently quoted attrition rate for all molecules entering the clinic is 90% – only 10% ever get to the marketplace. Furthermore, a significant proportion of the therapies that are approved actually do not deliver a profitable return on the research budget invested. The key question industry needs to answer: is there a better way to develop these molecules that can shift the economics of R&D to a more productive path?

In a recent webinar, Future Directions – Formulation in the Drug Development Process, key findings of the 2018 survey on formulation were reviewed, which made clear that about 60% of the survey respondents had seen formulation issues lead to the failure of drug development projects or to significant delays (Fig. 1a).

Of these projects, 10% experienced complete failure and 52% encountered a delay of more than 12 months (Fig. 1b). The survey was conducted by Informa Engage on behalf of Informa Pharma Intelligence, Rentschler Biopharma SE and LEUKOCARE AG, and its findings were published in November 2018. The webinar brought together about 100 participants from the worldwide drug development industry to listen to the findings and engage in a meaningful discussion.

Fig. 1: Results of the survey to the questions a) Have you ever experienced a project failure or a significant delay, because of formulation challenges? b) How long was the project delayed because of the formulation challenges?

“The survey interviewed 150 qualified senior personnel from all over the world with a very relevant spread across the industry and geographies,” said Michael Scholl, CEO of LEUKOCARE. “The purpose of this survey was to evaluate the status quo of the drug development industry, particularly in drug substance and drug product development, where formulation plays a vital role. Moreover, we wanted to learn about the needs, requirements and constrictions that are currently active in the drug development industry.” Additionally, the survey confirmed that the importance of early-stage formulation is currently underestimated in the biopharma industry.

“Given this obvious and significant impact on the success of drug development, we were surprised to see that about half of all respondents thought the deployment of a ‘commercially viable’ formulation should take place only during or after Phase IIa clinical trials or as late as the start of Phase III trials,” noted Scholl. “So, according to many respondents, the pre-IND or Phase I studies initially were not considered to be the correct time to develop a commercially viable formulation,” he added.

“There are many opportunities that can be realized if formulation is properly considered in early drug product development and an optimized formulation is developed from the get-go. For example, amendments such as longer shelf life, advantages in intellectual property, accelerated market entry and most certainly reduced costs are vital considerations to the success of a drug,” stated Federico Pollano, SVP, Business Development of Rentschler Biopharma.

When asked about important aspects of formulation, 83% of respondents attributed “competitive advantage” as “very important” or “important” on a 5-point scale and 75% found a “reduced time to market” “very important” or “important.” (Fig. 2)

Fig. 2: Results of the survey to the question about important decision criteria in formulation: on a scale from 1 to 5, please rate the importance of the following aspects of formulation.

“The competitive advantages to be gained from strategic formulation planning are potentially vast. For instance, a vaccine that must be transported in cold store or frozen becomes expensive and bulky to transport, while a vaccine that can simply be transported at 4°C or room temperature is relatively inexpensive and the potential geographic markets are much greater,” said Scholl.

Another important area of formulation is increased shelf life and stability, and ease of use. Intravenous (IV) administration is good for use in hospitals with trained staff, yet, expensive and inconvenient both for patients and physicians. Subcutaneous (SC) administration gives enormous flexibility and the potential for self-administration, especially in treatment of chronic diseases.

“Last but not least,” added Scholl, “a potentially improved safety profile of a biologic via IV to SC switch may add enormous value to patients and pharma. In general, these competitive advantages increase the probability of success of a product and reduce time to market. It is always very important to have the final product in mind, so we have to increase the probability of success for a drug product. A very important aspect in the drug product is the formulation.”

Investment In Early-Stage Formulation Set To Increase

In terms of early-stage formulation, which is currently underestimated, the survey responses show a willingness to invest more funds in early-stage formulation within the next five years, as indicated by a three-fold increase of companies planning to spend between $1 million and $5+ million on formulation per project over the next five years.

“We found that the industry is expecting an approximate mean average doubling of investments. This does indicate that companies are beginning to understand the real potential of drug product formulation. However, the question remains if the current spending on formulation is adequate given the importance that respondents allocate to formulation,” Pollano said. “The indicated raise could also be related to the growth of biosimilar and generic drugs, which our clients expect and where they feel a higher investment will put them in a much better competitive position in terms of early market entry, competitive pricing and ease-of-use, for instance.”

This view is backed by the survey where IP, time to market and development time topped the respondents’ formulation priorities in response to the question: “How important are the following considerations in evaluation of your formulation strategies?”

Following the discussion, it became clear that commercial aspects need to be considered when evaluating a formulation strategy, but, surprisingly, this is not reflected in the departments included in the formulation decision-making process. Looking at the data, commercialization specialists such as business development and management, along with marketing and sales, seem to be involved to a much lesser extent at the earlier stages of decision-making. Whereas, formulation development, bioprocess, drug product development and clinical development are the main decision-making departments at the earlier stages of drug product development.

“It appears there are many different understandings of formulation and the potential it delivers in overcoming drug development challenges. For instance, the costs of putting clinical trials on hold for reasons of formulation are significant and often put massive pressure and risk on R&D budgets,” noted Scholl. “Beyond this, to know the final market positioning of approved products from an early stage can help companies in business development and licensing deals, as well as IP positioning. This study has raised several vital points for the formulation and drug manufacturing industries, and we are ready to take these lessons forward in our business,” Pollano added.

Questions Asked By The Participants

Several questions were raised by the participants during the discussion at the end of the webinar. Following is a list of the key questions:

“When should companies begin thinking that their molecule is not just a candidate but a potential product?”
Scholl replied: “You should have your drug product in mind right from the beginning. If you only think about the drug substance, you are making a mistake from the start. The drug product and the target product profile must be in your plans right from the start. This also means you should decide on the requirement of your formulation. The correct time to consider your commercially viable formulation is day one.” “We still see companies going into clinical development with frozen material; you can imagine what this means in the clinical set-up,” added Pollano. “So, the earlier a company begins to focus on formulation the better for clinical development. It is important that companies understand that formulation is one of the key success factors.”
“Do supply chain issues, especially tracking and maintaining the integrity of the product also factor into commercial viability?”
“Yes, most definitely,” Scholl stated. “Supply chain issues starting from the sourcing of excipients throughout the entire process of drug substance, drug product fill and finish, plus storage obviously have an impact on the success of a product. We only source excipients that are easily attainable in the correct quality and long-term safeguarding of ‘sourceability.’”
“How well do you need to know your API before proposing excipients for stabilization?”
“It is critical to know the API and more importantly to know the degradation pathways for tailor-made superior formulation,” said Scholl. “One of the very first steps in our development approach is a work package called ‘basic characterization’ and through this we learn as much about the API as possible and this enables us to preselect a set of excipients from our database. Then we screen these through our algorithm-based statistical software approach and eventually start to combine them.”

About Rentschler Biopharma and LEUKOCARE

The Rentschler Biopharma and LEUKOCARE alliance offers a whole range of services for the drug product development industry and specialist formulation expertise. The alliance aims to incorporate formulation development at every step throughout biopharmaceutical development and manufacturing, especially during the early stages. Working closely with the client, this ensures the end products will – from the very beginning – have a best-in-class formulation and administration mode. This innovative approach provides clients with significant competitive advantages, enabling them to exploit the full commercial potential of their products and markets.

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