Novel Approaches to Predicting Physical Stability of Drugs in Amorphous Solid Dispersions

OVERVIEW

Novartis, the Seeker for this Wazoku Crowd Challenge, is looking for reliable methods to predict physical stability upon storage of small molecule drug products formulated as amorphous solid dispersions.

The chemical and physical stability of therapeutic drug products is of paramount importance. Traditionally, however, the bulk of attention has been paid to chemical stability of drugs, while assessing their physical stability remains relatively less developed.

This Challenge focuses on the physical stability of one of the small drug formulations, that is rapidly growing in popularity: amorphous solid dispersions (ASD)

The purpose of the Challenge is two-fold. First, the Solvers are expected to identify and analyze factors affecting the physical stability of ASD formulations. Among the given critical parameters to consider, one may encompass the time of storage, temperature, and moisture ingress from packaging material.

Second, they’re required to design a protocol/workflow to anticipate the ASD formulations’ changes upon storage. As an example, a stress test and a set of analytical techniques could be designed that would allow the prediction and a rapid assessment of the rate and extent of the changes of the physical properties of ASD formulations under long-term storage.

This Prize Challenge has a special award structure.

By taking part, you are granting to Novartis a royalty-free, perpetual, and sublicensable, non-exclusive license to use (but not own unless the Option stated below is exercised) any information included in your proposal, including for promotional purposes. 

Novartis must determine award winners within 45 days from the start of evaluation.

A Guaranteed Award of $30,000 will be paid out for this Challenge.
Please note the best solution has the opportunity to win the award of $30,000 USD for meeting all solution requirements, otherwise if there are solutions that partially meet the requirements, there will be at least one award of $10,000 or larger with no award being smaller than $5,000.

The Challenge requires a written proposal to be submitted and award decisions will be determined after the theoretical evaluation of the proposals by Novartis against the solution requirements.

The Option: Awarded Solvers shall agree to grant Novartis an exclusive 90-day option to acquire ownership with respect to all intellectual property rights in their proposal with the commitment by Novartis to pay a consideration of a maximum of $20,000 for the transfer of the ownership. This one-time payment is in addition to the aforementioned Award.

Novartis can exercise this option within 90 days subsequent to the notification to Solvers that they have been selected for an Award.

 

WIN Scouts are very much invited to participate, this being any Solver who can propose a potentially suitable partner (startup or expert) for this Challenge from your network. As a WIN Scout, by referring a relevant partner you will be recognized with a share of a separate $1,000 recognition award, if your referral meets certain minimum criteria of detail, relevance, and format.

The input required is guided during the submission process for WIN Scouts below.

 

Submissions to this Challenge must be received by 11:59 PM (US Eastern Time) on December 03rd, 2024.

- Login or register your interest to start solving and scouting!

 

ABOUT THE SEEKER & ELIGIBILITY

Novartis is an innovative medicines company. Every day, we work to reimagine medicine to improve and extend people’s lives so that patients, healthcare professionals and societies are empowered in the face of serious disease. In a world where many diseases don’t have a treatment option, our research and development teams push the boundaries of scientific discovery and turn breakthroughs into medicines that change lives. We focus on four core therapeutic areas with high unmet patient needs and five technology platforms that enable cutting-edge innovative therapies. Our medicines reach more than 250 million people worldwide.

Reimagine medicine with us: Visit us at https://www.novartis.com and connect with us on LinkedIn, Facebook, X/Twitte and Instagram.

Employees of ­­­­Novartis are ineligible to receive an award for this Challenge.
 

WIN Scouts are invited to participate, this being any Solver who can propose a potentially suitable partner (startup or expert) for this Challenge from your network.

Find out more about participation in Wazoku Crowd Challenges.

 

THE CHALLENGE

Background

The long-term stability of therapeutic drugs is of paramount importance. Even a minor change in the composition of a drug, be it a chemical compound or a complex biological molecule, can lead to dramatic negative consequences, such as the loss of the drug efficacy or, worse, harmful side effects.

Consequently, all critical attributes of the drug product need to be specified in advance and then controlled to ensure its efficacy, safety, and performance across the product shelf life.

Traditionally, the bulk of attention has been paid to chemical stability of the drugs aiming to anticipate and assess their integrity at the end of the shelf life under chosen storage conditions. Conceptually, this approach is simple: to apply intentional treatment that would mimic the conditions of the long storage and then adjust, if necessary, the composition of the drug product, properties of packaging material, and/or storage conditions themselves.

A set of sophisticated models, such as Roger Testing, have been developed to predict chemical stability of drugs either as bulk or in solution. These approaches primarily consider storage temperature and humidity (for bulk) while accounting for moisture ingress through packaging materials.

Not only did these efforts improved the chemical stability of new therapeutic entities; quite often, the stability studies helped guide the development of more efficient drugs by minimizing the discoveries of deficiencies in drug formulations late in development and addressing the use of combinations of multiple excipients.

More recently, these approaches were even used to replace long-term storage and related accelerated storage testing in order to speed up the start of clinical trials aiming to provide faster access of medicine to patients.

At the same time, the field of physical stability of drugs has remained relatively undeveloped due to additional level of complexity.

This shortage of knowledge of the fundamental principles underlying physical stability of drugs has become especially apparent with the growing popularity of one specific drug formulation: amorphous solid dispersion (ASD).

The introduction of ASD is a response to the increasing level of complexity of molecular structure of active pharmaceutical ingredients (APIs), which often translates into their decreased solubility.  

To improve a drug’s solubility in a relevant biocompatible medium, the drug is brought to the amorphous state. This amorphous state is then stabilized by polymeric excipients, such as polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose (HPMC), to create a polymer matrix (amorphous glass). Three characteristics of ASD: amorphicity, miscibility (mixability), and absence of molecular mobility—then become its critical attributes [1].

(Incidentally, ASD technology has been successfully applied in other fields: i) in food preparation—ASDs can be used to improve stability and bioavailability of poorly soluble food additives, such as flavors and colors; ii) in plastics manufacturing—by dispersing additives like flame retardants or antimicrobials uniformly throughout a plastic matrix in an amorphous state, ASDs can help create new materials with specific properties; iii) in tire production—ASDs can be used to incorporate desired functionalities, such as enhanced traction and reduced rolling resistance.)

Reliable, data-driven approaches to designing long-term storage conditions that would preserve amorphicity of ASD-formulated drugs—and prevent their re-crystallization—have only started to emerge.

Three major parameters have been found to affect this process: i) type of API/polymeric excipient; ii) API load; iii) storage conditions (relative humidity and temperature) [2].

Complicating the advancement in this field is a limitation of currently available stability tests that require a long time, literally months and years, to be conducted, making confirmation of the results operationally unsustainable. There is therefore an urgent need to develop the so-called stress tests, experimental protocols in which drugs compounds are intentionally exposed to extreme conditions to identify potential weaknesses that might later lead to their breakdown under normal storage conditions.

Of the extreme conditions that are routinely used in stress tests, temperature and relative humidity are the most common, although often not the only ones. Of course, to be predictive, these conditions must not impose stresses on the molecular structure of the drug that would not occur during conventional storage conditions.

A recent study shows a possible approach to predicting the shelf life (crystallization onset) for two specific API/polymeric excipient combinations [3]. The study proposes a method and experimental framework for a given API/polymer combination and manufacturing method that are valid for any API load, temperature, and relative humidity. As a result, the proposed approach allows predicting the shelf life (crystallization onset) of a potential ASD in early stages of development within a few days.

There are certain limitations to the applicability of the above study to predicting the shelf life in many real-life situations: it doesn’t consider the impact on the crystallization kinetics of water ingress from packaging material or water introduced by other excipients present in the ASD that takes place over long-term storage

Besides, the stress conditions used in the study were chosen in such a way that 100% recrystallization of the API in question was achieved after just a couple days, whereas in real-life situations, it takes a few months to see the API losing its amorphicity; moreover, full API recrystallization almost never happens.

It is also important to not rely exclusively on the ASD composition itself but also track down potential manufacturing issues leading to inhomogeneity at the molecular level, such as hot spots or even phase separation. This focuses the problem also on changes in manufacturing process or even in manufacturing technologies which were not implicitly identified when examining typical key quality attributes. This may appear as an example of an apparent identical composition with potential hot and cold spots if one is considering local concentration of API as an example.

Finally, the experimental parameters needed to predict crystallization onset of an ASD are specific for a particular ASD/polymer excipient combination with prevents their application to a wider set of cases.

References:

[1]. Chasse et al., Industry White Paper: Contemporary Opportunities and

Challenges in Characterizing Crystallinity in Amorphous Solid Dispersions. J. Pharm. Sci., 111 (2022): 1543-1555.

[2]. Wolbert et al., The Shelf Life of ASDs: 1. Measuring the Crystallization Kinetics at Humid Conditions. Mol. Pharm. 19 (2022): 2483-2494.

[3]. Wolbert et al., The Shelf Life of ASDs: 2. Predicting the shelf life at storage conditions. Int. J. Pharm. 6 (2023): 100207.

The Challenge

The goal of this Challenge is to design a general approach to predicting crystallization onset of ASDs that would overcome the limitations of the previous approaches.

We want to design a model that would apply to any ASD/polymer excipient combination and, even more importantly, account for water ingress from packaging material or water introduced by other excipients that takes place over long-term storage. In particular, the approach is expected to be nailed down beyond the composition itself, aiming to address potential batch to batch variability.

Besides, we want to predict the impact on ASD properties upon storage of potential microscopic composition variations even if the macroscopic composition remains the same—or any other type of relevant impact on quality attributes.

We also want to replace existing long-term stability tests with a stress test where monitoring of parameters and mathematical treatment of the data would allow the anticipation of the formulation’s behavior upon storage.

The objective of this Challenge is therefore two-fold: 

1. To identify factors driving the re-crystallization of drugs from amorphous dispersion under long-term storage—and to better understand the risk and opportunities during the drug formulation process.
2. To develop a protocol for a stress test and analytical strategy that would allow predicting the dispersion’s shelf life (crystallization onset) and the extent its amorphous status might be affected by storage conditions.

We envision that by using conventional laboratory equipment capable of monitoring the extent of drug recrystallization, we can apply this stress condition program to predict the long-term shelf life of the formulation under chosen conditions.

We also envision that this stress test could be conducted within weeks, not months or years, and could also be used potentially as a performance test.

Finally, we hope that the design of the proposed stress test and the scientific modeling of the collected data will help identifying factors and/or storage conditions that could increase long-term ASD stability.
 

SOLUTION REQUIREMENTS

We’re open to any innovative approach for as long as the proposed solution will meet the following Solution Requirements:

1. The proposed solution will identify factors driving re-crystallization of small molecule drugs in ASDs.
2. The proposed solution will design a stress-test protocol to predict long-term stability of ASDs:
   a. The proposed stress test will allow predicting the stability of ASD formulations for two (2) years under different conditions.
   b. The proposed stress test could be conducted in 3-4 months and, ideally, in 3-4 weeks.
   c. The proposed stress test will require equipment and experimental set up easily transferable from R&D labs to quality control (QC) operations.
   d. The results of the proposed stress test will provide data allowing us to fine-tune the original ASD formulation.

Important! We welcome solutions based on the experience borrowed from other industries where ASDs are widely used (food preparation, plastic manufacturing, etc.). However, if this is the case, the Solvers need to clearly explain (using appropriate references and case studies) how the proposed solution can be applied to the specific case of ASD-based drug formulations.  

At the same time, we will not accept solutions that:

• Involve experimental approaches at the very early stages of development, that is, that have not yet been validated for drug formulation studies.
• Require equipment that is not routinely available to pharmaceutical quality control (QC) labs to conduct the proposed stress test.

 

Solutions with Technology Readiness Levels (TRLs) 3-6 are invited.

This Prize Challenge has the following features:

• By taking part you are granting Novartis a royalty-free, perpetual, and sublicensable, non-exclusive license to use (but not own unless the option is exercised) your submitted information; Novartis must determine the award winners within 45 days from the start of evaluation. You will receive notification.
• There will be a guaranteed award of $30,000, with at least one award being no smaller than $10,000 and no award being smaller than $5,000 for partially meeting the Solution Requirements. Please note the best solution has the opportunity to win the award of $30,000 USD for meeting all solution requirements.
• Awards will be contingent upon the theoretical evaluation of the proposal by Novartis, as solely determined by Novartis.
• Awarded Solvers will also agree to grant Novartis an exclusive 90-day option to acquire ownership with respect to all intellectual property rights in their proposal with the commitment by Novartis to pay a consideration of a maximum of $20,000 for the transfer of the ownership. This one-time payment is in addition to the aforementioned Award.
• Novartis can exercise this option within 90 days subsequent to the notification to Solvers that they have been selected for an Award.
• WIN Scouts are invited to participate, this being any Solver who can propose a potentially suitable partner (startup or expert) for this Challenge from your network. As a WIN Scout, by referring a relevant partner you will be recognized with a share of a separate $1,000 recognition award, if your referral meets certain minimum criteria of detail, relevance, and format. The input required is guided during the submission process for WIN Scouts below.
• Novartis may also issue “Honourable Mentions” for notable submissions that are not selected for monetary awards.

Novartis may wish to partner with the Solver at the conclusion of the Challenge. Please indicate your interest in partnering. 

 

YOUR SUBMISSION

Please login and register your interest, to complete the submission form.

The submitted proposals must be written in English and can include:

1. Participation type – you will first be asked to inform us how you are participating in this challenge, as a Solver (Individual), Solver (Organization) or WIN Scout (submission uses an alternative form).
2. Solution Level - the Technology Readiness Level (TRL) of your solution.
3. Partnering - there may be an opportunity to partner with Novartis at the conclusion of this Challenge. Please indicate if partnering is of interest to you.
4. Problem & Opportunity - highlight the innovation in your approach to the Problem, its point of difference, and the specific advantages/benefits this brings (up to 500 words).
5. Solution Overview - detail the features of your solution and how they address the SOLUTION REQUIREMENTS (500 words, there is space to add more in the summary field, and attach supporting data, diagrams, etc.).
6. Solution Feasibility – Supporting Information and Rationale, such as references and precedents, that will help Novartis evaluate and validate the feasibility of the solution (up to 500 words).
7. Experience - Expertise, use cases and skills you or your organization have in relation to your proposed solution (up to 500 words).
8. Solution Risks - any risks you see with your solution and how you would plan for this (up to 500 words).
9. Timeline, capability, and costs - describe what you think is required to deliver the solution, estimated time and cost (up to 500 words).
10. Online References - provide links to any publications, articles or press releases of relevance (up to 500 words).

Wazoku encourages the use by Solvers of AI approaches to help develop their submissions, though any produced solely with generative AI are not of interest.

Find out more about participation in Wazoku Crowd Challenges.

Submissions to this Challenge must be received by 11:59 PM (US Eastern Time) December 03rd, 2024.

Late submissions will not be considered.

Your submission will be evaluated by the evaluation team first reviewing the information and content you have submitted at the submission form, with attachments used as additional context to your form submission. Submissions relying solely on attachments will receive less attention from the evaluation team.

After the closing date for Challenge submissions, Novartis will complete the review process and make a decision with regards to the winning solution(s) according to the timeline in the Challenge header. All Solvers who submit a proposal will be notified about the status of their submissions.