Opportunity Information: Apply for RFA FD 14 023
Apply for RFA FD 14 023
- The Food Drug Administration in the health science and technology and other research and development sector is offering a public funding opportunity titled "The Effect of Different Preparation Methods on the In Vitro and In Vivo Performance of Solid Dispersion Formulations (U01)" and is now available to receive applicants.
- Interested and eligible applicants and submit their applications by referencing the CFDA number(s): 93.103 Food and Drug AdministrationResearch.
- This funding opportunity was created on Apr 18, 2014 and posted on Apr 18, 2014.
- Applicants must submit their applications by Jun 19, 2014. (Agency may still review applications by suitable applicants for the remaining/unused allocated funding in 2026.)
- The funding agency has allocated a total of $1,500,000.00 to eligible and selected applicants.
- Each selected applicant is eligible to receive up to $500,000.00 in funding.
- The number of recipients for this funding is limited to 1 candidate(s).
- Eligible applicants include: Nonprofits that do not have a 501(c)(3) status with the IRS, other than institutions of higher education Private institutions of higher education City or township governments Native American tribal organizations (other than Federally recognized tribal governments) Public and State controlled institutions of higher education Independent school districts County governments Native American tribal governments (Federally recognized) Others (see text field entitled Additional Information on Eligibility for clarification) Nonprofits having a 501(c)(3) status with the IRS, other than institutions of higher education Public housing authorities/Indian housing authorities Small businesses For profit organizations other than small businesses Special district governments State governments.
- Foreign
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Opportunity Summary:
The FDA cooperative agreement opportunity (U01) titled "The Effect of Different Preparation Methods on the In Vitro and In Vivo Performance of Solid Dispersion Formulations" focuses on a practical problem in modern drug development and generic drug approval: many active pharmaceutical ingredients have poor water solubility, and solid dispersion technologies are widely used to improve dissolution and, in turn, bioavailability. Even though solid dispersions are heavily studied and can be very effective, only a limited number of commercial products have reached the market, with examples including Prograf (tacrolimus), Sporanox (itraconazole), and Kaletra (lopinavir/ritonavir). At the same time, the number of approved and pending ANDAs referencing these types of products is increasing, which raises regulatory and scientific questions about how differences in formulation and manufacturing translate into real clinical performance, especially as products age on the shelf and as batches vary over time.
A key scientific motivation behind the grant is that amorphous solid dispersions can be fragile systems. The core strategy is converting a drug from a crystalline form (typically lower solubility) to an amorphous form (typically higher apparent solubility and faster dissolution). That conversion can be achieved through different manufacturing routes, broadly grouped into solvent-based methods and melting-based methods. The problem is that amorphous materials tend to be thermodynamically unstable: they can crystallize during storage, and they can also precipitate out of supersaturated solutions during dissolution in the gastrointestinal tract. On top of that, polymer carriers used in solid dispersions are not passive ingredients; they can strongly influence stability, drug-polymer miscibility, dissolution behavior, and potentially permeability in the GI tract. The FDA is essentially pointing out that two products can look similar on paper yet differ in subtle, process-driven ways that might change crystallinity, dissolution, precipitation tendency, and ultimately pharmacokinetics.
The overall objective is to systematically compare in vitro and in vivo performance of solid dispersion drug products made using different preparation methods and/or different polymer carriers, and to evaluate how consistent that performance remains across batches and over storage time. The agency is looking for research that identifies critical process parameters (the controllable manufacturing conditions that matter most) and critical quality attributes (the measurable product properties that are linked to performance). A major deliverable is the development or optimization of discriminating analytical methods that can actually detect meaningful changes in solid dispersion quality, rather than relying on tests that may be too blunt to pick up early crystallization or performance-relevant shifts.
The work plan described in the announcement lays out several linked studies. First, the project should choose appropriate model drugs and prepare amorphous solid dispersions using multiple preparation methods, explicitly including (but not limited to) solvent and melting approaches. Importantly, applicants are expected to design manufacturing processes with drug-polymer miscibility in mind, since miscibility affects whether the drug remains molecularly dispersed (desirable) or phase separates and crystallizes (undesirable). Second, the project should determine which process parameters and quality attributes are most critical for each preparation method, and pair those with analytical tools capable of detecting changes such as increasing crystalline content, shifts in dissolution profiles, and evidence of precipitation during dissolution under GI-relevant conditions. The announcement references common crystallinity and solid-state tools like PXRD, IR, and DSC, but also highlights a persistent gap: quantifying amorphous content is hard because it is often inferred indirectly by measuring crystalline content, so the FDA is signaling interest in more sensitive or better-validated ways to monitor these systems during manufacturing and storage.
Third, the project should include quality characterization of both brand-name (RLD) and generic solid dispersion products, including assay, related substances (impurities/degradants), and dissolution testing according to USP standards when available, and otherwise in consultation with FDA as the sponsor. Fourth, the project should define stressed storage conditions that reliably produce significant quality changes, particularly changes tied to dissolution and precipitation behavior. A specific relationship the FDA wants explored is how moisture content and crystalline content interact to affect dissolution rate, both under stress and under long-term storage, since moisture uptake is a common trigger for amorphous-to-crystalline transitions and can also plasticize polymers, accelerating physical instability.
Finally, the opportunity includes a human in vivo component designed to connect lab findings to real pharmacokinetic outcomes. The announcement calls for a randomized, single-dose, four-treatment, four-period crossover bioequivalence-style study in 24 healthy adult volunteers (male and female, non-pregnant). The four treatments are structured to isolate the effects of product identity (RLD versus a generic) and aging-related dissolution changes: (1) RLD fresh, (2) RLD aged with slower dissolution than fresh, (3) Generic A fresh with slower dissolution than the RLD, and (4) Generic A aged with much slower dissolution. Safety monitoring and adverse event collection are required. Pharmacokinetic statistical analysis is expected to compare peak exposure and both partial and total exposure measures, with the aim of determining whether differences in dissolution behavior and storage-driven quality changes translate into significant differences in systemic exposure.
From a regulatory science standpoint, the value of the project is that it aims to bridge a common gap: in vitro tests can be good at detecting some differences, but not always the differences that matter for in vivo performance, especially for complex systems like amorphous solid dispersions where precipitation, crystallization, and polymer effects can dominate. The FDA is looking for evidence that supports better, more predictive in vitro batch quality controls and stability monitoring approaches, so that both brand and generic manufacturers can demonstrate consistent in vivo performance batch to batch and over the labeled shelf life.
Administratively, this was an FDA discretionary funding opportunity using a cooperative agreement mechanism (U01), meaning the FDA expects substantial scientific involvement and coordination rather than a fully hands-off grant. The funding opportunity number is RFA-FD-14-023, posted April 18, 2014, with an original and final closing date of June 19, 2014, and an archive date of July 19, 2014. The program is associated with CFDA 93.103 (FDA research). The announcement anticipated a single award, with an estimated total funding level of $1,500,000 and a stated award range of roughly $450,000 to $500,000 (no cost sharing required). Eligibility was broad across higher education institutions, nonprofits (including 501(c)(3) and some non-501(c)(3) categories), small businesses, certain for-profit entities, and various government and tribal organizations; foreign eligibility is explicitly referenced in the listing. The sponsoring agency is the Food and Drug Administration, and the listed grants management contact was Gladys Melendez Bohler (phone 240-402-7565).
Frequently Asked Questions (FAQs)
What is the title of this FDA cooperative agreement opportunity?
The opportunity is titled "The Effect of Different Preparation Methods on the In Vitro and In Vivo Performance of Solid Dispersion Formulations."
What kind of funding mechanism is this (and what does U01 mean)?
This is an FDA cooperative agreement using the U01 mechanism. A cooperative agreement means the FDA expects substantial scientific involvement and coordination during the project, rather than a fully hands-off approach.
What is the funding opportunity number?
The funding opportunity number is RFA-FD-14-023.
Which agency is sponsoring this opportunity?
The sponsoring agency is the U.S. Food and Drug Administration (FDA).
What is the CFDA number associated with this program?
The program is associated with CFDA 93.103 (FDA research).
When was it posted and what were the deadlines?
It was posted on April 18, 2014. The original and final closing date was June 19, 2014. The archive date was July 19, 2014.
How many awards did FDA anticipate making?
The announcement anticipated a single award.
How much total funding was FDA estimating for this project?
The estimated total funding level was $1,500,000.
What was the expected award size (award range)?
The stated award range was roughly $450,000 to $500,000.
Is cost sharing required?
No cost sharing was required.
Who was the listed grants management contact?
The listed grants management contact was Gladys Melendez Bohler (phone 240-402-7565).
What problem in drug development and generic approval is this project trying to address?
The focus is on poorly water-soluble active pharmaceutical ingredients and the use of solid dispersion technologies to improve dissolution and bioavailability. The opportunity highlights regulatory and scientific questions about how formulation and manufacturing differences (and changes during storage) can affect real clinical performance, especially as the number of approved and pending ANDAs referencing solid dispersion products increases.
What are solid dispersions and why are they important here?
Solid dispersions are formulation approaches often used to increase drug dissolution by converting a drug from a crystalline form (typically lower solubility) to an amorphous form (typically higher apparent solubility and faster dissolution). This opportunity is concerned with how different ways of making solid dispersions and selecting polymer carriers affect product performance in vitro and in vivo.
Why does FDA describe amorphous solid dispersions as "fragile" systems?
Amorphous materials are thermodynamically unstable. They can crystallize during storage, and drugs can also precipitate from supersaturated solutions during dissolution in the gastrointestinal tract. These behaviors can change dissolution and potentially pharmacokinetics over time or across batches.
Why do polymer carriers matter in this grant topic?
The FDA emphasizes that polymer carriers are not passive. They can influence stability, drug-polymer miscibility, dissolution behavior, and potentially permeability in the GI tract. Because of this, two products may appear similar but behave differently due to process-driven or polymer-driven effects.
What is the overall objective of the research?
The overall objective is to systematically compare in vitro and in vivo performance of solid dispersion drug products made using different preparation methods and/or different polymer carriers, and to evaluate how consistent that performance remains across batches and over storage time.
What does the FDA want researchers to identify in the manufacturing process?
The FDA is looking for research that identifies critical process parameters (controllable manufacturing conditions that matter most) and critical quality attributes (measurable product properties linked to performance).
What are "discriminating analytical methods" in the context of this opportunity?
These are analytical methods that can detect meaningful changes in solid dispersion quality that relate to performance, rather than tests that are too insensitive to pick up early crystallization or subtle shifts that may later affect dissolution, precipitation, or pharmacokinetics.
Which preparation methods should be compared?
The work plan calls for preparing amorphous solid dispersions using multiple preparation methods, explicitly including (but not limited to) solvent-based methods and melting-based methods.
What role does drug-polymer miscibility play in the planned work?
Applicants are expected to design manufacturing processes with drug-polymer miscibility in mind, because miscibility affects whether the drug remains molecularly dispersed (desirable) or phase separates and crystallizes (undesirable).
What types of analytical tools are referenced for solid-state characterization?
The announcement references common tools such as PXRD, IR, and DSC for crystallinity and solid-state assessment, while also noting a need for more sensitive or better-validated approaches for quantifying amorphous content.
Why is quantifying amorphous content highlighted as a challenge?
The FDA notes that amorphous content is often inferred indirectly by measuring crystalline content, which can be a limitation. The opportunity signals interest in improved methods to monitor these systems during manufacturing and storage.
Does the project include testing of both brand-name and generic products?
Yes. The work plan includes quality characterization of both brand-name (RLD) and generic solid dispersion products.
What kinds of quality tests are expected for the product characterization work?
The announcement describes characterization including assay, related substances (impurities/degradants), and dissolution testing according to USP standards when available, and otherwise in consultation with FDA as the sponsor.
What does FDA mean by defining "stressed storage conditions"?
The project is expected to define stressed storage conditions that reliably produce significant quality changes, especially changes tied to dissolution and precipitation behavior, so that performance-relevant degradation or physical changes can be studied systematically.
What specific storage-related relationship does FDA want explored?
The FDA specifically wants exploration of how moisture content and crystalline content interact to affect dissolution rate, under both stress conditions and long-term storage.
Why is moisture considered important for amorphous solid dispersions?
Moisture uptake is described as a common trigger for amorphous-to-crystalline transitions and can plasticize polymers, which can accelerate physical instability and affect dissolution behavior.
Is there an in vivo human study component?
Yes. The opportunity includes a human in vivo component designed to connect laboratory findings to pharmacokinetic outcomes.
What is the design of the in vivo study described?
The announcement calls for a randomized, single-dose, four-treatment, four-period crossover bioequivalence-style study.
How many participants are expected in the in vivo study, and who are they?
The study is described as enrolling 24 healthy adult volunteers (male and female, non-pregnant).
What are the four treatments in the crossover study?
The four treatments are: (1) RLD fresh, (2) RLD aged with slower dissolution than fresh, (3) Generic A fresh with slower dissolution than the RLD, and (4) Generic A aged with much slower dissolution.
What is the point of comparing "fresh" versus "aged" products in the study?
The study structure is intended to isolate how aging-related dissolution changes (and more broadly, storage-driven quality changes) may affect in vivo exposure, both for the RLD and for a generic product.
What safety expectations are included for the human study?
Safety monitoring and adverse event collection are required.
What pharmacokinetic comparisons are expected?
Pharmacokinetic statistical analysis is expected to compare peak exposure and both partial and total exposure measures, to determine whether dissolution and storage-driven quality changes translate into significant differences in systemic exposure.
What is the regulatory science value FDA is aiming for?
The project is intended to bridge the gap between in vitro tests and in vivo performance for complex amorphous solid dispersion systems. FDA is looking for evidence that supports better, more predictive in vitro batch quality controls and stability monitoring approaches to help demonstrate consistent in vivo performance batch to batch and over labeled shelf life.
Are there example commercial products mentioned that use solid dispersion approaches?
Yes. Examples mentioned include Prograf (tacrolimus), Sporanox (itraconazole), and Kaletra (lopinavir/ritonavir).
What types of applicants were considered eligible?
Eligibility was described as broad, including higher education institutions, nonprofits (including 501(c)(3) and certain non-501(c)(3) categories), small businesses, certain for-profit entities, and various government and tribal organizations. Foreign eligibility is explicitly referenced in the listing.
Does the opportunity explicitly mention ANDAs and generics?
Yes. The announcement notes that the number of approved and pending ANDAs referencing solid dispersion-type products is increasing, and that this raises questions about how formulation and manufacturing differences translate into clinical performance, especially over shelf life and across batches.
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