Stable Liposomes as Drug Carriers

From: Innovation, Science and Economic Development Canada

NRC is seeking a solution to develop stable liposome formulations, with narrow size distributions at nanoscale and sub-micron scales, to support the development of drug product submissions, streamline the regulatory approval process and improve the manufacturability of drug delivery formulations.

Sponsoring department: National Research Council of Canada (NRC)

Funding mechanism: Contract

Opening date: September 3, 2019
Closing date: October 29, 2019 14:00 Eastern Daylight Time

Please refer to the tender notice for this challenge on Buy and Sell.

Challenge

Problem statement

Liposomes are used as drug delivery vehicles in indications such as cancer, pain management and vaccines. Each liposome can be uniquely produced to match the drug to be delivered and the target tissue. Among others, the physical properties of liposomes such as stability, storage, sterilization, size and charge are factors in determining their applicability and suitability for drug delivery. However, maintaining the physical properties of liposomal formulations can be difficult. For example, stability is impacted by chemical degradation, which results in phospholipid structure changes. Physical agglomeration or aggregation can change the uniformity of size distribution and encapsulation efficiency, which has an impact on the shelf-life of liposomes. Changes in the size distribution and stability problems due to the hydrolytic and oxidative degradation are general problems upon storage. NRC's certified reference material program provides reference standards and methods to confirm the physical characteristics and quality of a particle. The lack of a stable liposome formulation prevents the development of certified reference material. NRC is seeking a solution to develop stable drug carrier formulations with narrow size distributions at nanoscale and sub-micron scales, to enable the development of certified reference material to support drug product submissions, streamline the regulatory approval process and improve the manufacturability of drug delivery formulations.

Desired outcomes and considerations

Essential (Mandatory) outcomes

Proposed solutions must:

enable the development of drug loaded liposomes, with stable sizes, in three (3) formulations, with the following physical properties:
1. at least three different sizes (60±10 nm, 100±10 nm, 200±20 nm);
2. with a polydispersity index (PDI) of <0.15 in Dynamic Light Scattering (DLS) measurement; and,
3. positive, neutral and negative charges (e.g. one charge per size is reasonable)
demonstrate the development of lipid nanoparticle products based on new formulations (including, but not limited to, lipidoids) targeted for gene or cell therapies
demonstrate that the potency of the carrier is better than or similar to the lipid particle for the United States Food and Drug Administration (FDA) approved RNAi (Ribonucleic acid interference) patisiran drug by Alnylam.
if using cationic, neutral or anionic lipid compositions to prepare the three particle sizes as described above, ensure that the oxidation and hydrolysis issues are addressed clearly.
ensure that the liposome particle size and PDIs are maintained during storage, for a minimum period of three (3) years. Note: long-term storage of liposomes in frozen state is acceptable as long as the target specifications are maintained.
develop liposomes that are non-toxic and therefore suitable for use in drug delivery.

Bidders must demonstrate the ability to:

produce 200 units of each size and deliver to NRC for verification in a lab environment in Phase One;
produce 2,000 units for one selected size before the end of Phase Two (selected bidders may be required to provide to NRC as part of a resulting contract); and,
demonstrate Good Manufacturing Practice (GMP) level of large scale production drug/oligonucleotide carriers.

Background and Context

Liposomes are complex formulations. Liposome drug products consist of the liposome and the drug molecule. A liposome is made up of lipids, each of which has a head region, tail region and a linker that connects both regions. Tail length, tail unsaturation, linker type and head group structure all contribute to the performance characteristics of a liposome drug product. It is the unique combination of differing characteristics of these regions that determines their stability. For example, low degrees of tail unsaturation and ether increase biodegradation. The size and charge of the lipid head group can influence drug permeation. The selection of a lipid to formulate the liposome is important, and will depend on desired factors which determine safety, stability, efficiency. Because liposomes are complex, small changes in formulation may significantly affect clinical results. Pharmaceutical companies develop in-house standards to verify the results of their research and validate the manufacturability and production quality of a liposome drug product. A summary of the product characteristics and the test results forms part of the regulatory submission. However, the submission does not include the necessary information to enable the regulatory agency to verify the product characteristics or test results. The quality and performance of a liposome drug product can be impacted by many factors, including drug loading and drug leakage. However, the method by which the liposome drug product is developed is considered a trade secret, owned by the producer. Therefore, the unique characteristics of each drug/carrier combination can only be verified by the producer. Certified reference materials are a measurement standard used to confirm the physical characteristics and quality of a particle with a given uncertainty or traceability, to validate methods of measurement, and/or to calibrate instruments. Certified reference materials for liposomes do not exist. There is currently no ability for the scientific community, regulatory agencies, third-party laboratories or liposome producers to confirm the characteristics of a liposome against a known sample. The lack of a stable liposome product prevents the development of certified reference material for liposomes. This challenge seeks a solution to develop stable drug carrier formulations to support the NRC development of certified reference material. The lack of commercially available reference standards for liposomes slows the regulatory review process, and creates inefficiencies and quality control issues in the drug production process. Certified reference materials for liposomes create a publicly available measurement standard which can expedite the market adoption of liposome-assisted drug delivery by supporting the development of drug product submissions, streamlining the regulatory approval process and improving the manufacturability of drug delivery formulations.

Maximum value and travel

Multiple contracts could result from this Challenge.

The maximum funding available for any Phase 1 Contract resulting from this Challenge is $150,000.00 CAD (plus tax) including shipping, travel and living expenses, as applicable, for up to 6 months.

The maximum funding available for any Phase 2 Contract resulting from this Challenge is $1,000,000.00 CAD (plus tax) including shipping, travel and living expenses, as applicable, for up to 24 months. Only eligible businesses that have completed Phase 1 could be considered for Phase 2.

This disclosure is made in good faith and does not commit Canada to contract for the total approximate funding.

Travel

For Phase 1 it is anticipated that two meetings will require the successful bidder(s) to travel to the location identified below:

Kick-off meeting

Ottawa, ON

Final Review Meeting

Ottawa, ON

All other communication can take place by telephone.

Eligibility

Solution proposals can only be submitted by a small business that meets all of the following criteria:

for profit
incorporated in Canada (federally or provincially)
499 or fewer full-time equivalent (FTE) employees^{Footnote *}
research and development activities that take place in Canada
50% or more of its annual wages, salaries and fees are currently paid to employees and contractors who spend the majority of their time working in Canada^{Footnote *}
50% or more of its FTE employees have Canada as their ordinary place of work^{Footnote *}
50% or more of its senior executives (Vice President and above) have Canada as their principal residence^{Footnote *}

Application guide

Evaluation Criteria

The official source of the Evaluation Criteria for this challenge is the Government Electronic Tendering System (Buy and Sell) (https://buyandsell.gc.ca/procurement-data/tender-notice/PW-18-00846769)

In the event of a discrepancy between the information below and the information published on Buy and Sell, Buy and Sell will take precedence.

Part 1: Mandatory and Minimum Pass Mark Criteria

Proposals must meet all mandatory criteria (Questions 1a and 2) and achieve the minimum pass mark for Question 3 in order to be deemed responsive and proceed to Part 2.

Mandatory and Minimum Pass Mark Criteria (Applicant/Bidder's proposal must address)
Question	Evaluation Schema
1 a. Scope Describe your proposed solution and how it responds to the challenge. Include in your description the scientific and technological basis upon which your solution is proposed and clearly identify how your solution meets all of the Essential Outcomes (if identified) in the Desired Outcomes and Considerations section in the Challenge Notice.	Mandatory — Pass/Fail Pass The Applicant/Bidder's proposed solution is clearly articulated, within the scope for the challenge and addresses all Essential Outcomes (if identified) in the Challenge Notice. Fail There is little or no evidence that the proposed solution is likely to meet the challenge. OR The proposed solution is articulated as out of scope for the challenge. OR The proposed solution does not address all Essential Outcomes listed in the challenge. OR The proposed solution is poorly described and does not permit concrete analysis.
2. Current Technology Readiness Level (TRL) Indicate the current TRL of your proposed solution. (Drop Down Menu of the Application/Bid Submission Form) Describe the research and development activities that have taken place to bring the proposed solution to the stated TRL.	Mandatory — Pass/Fail Pass: The Applicant/Bidder has demonstrated that the proposed solution is currently between TRLs 1 and 4 (inclusive), and provided justification by explaining the research and development (R&D) that has taken place to bring the solution to the stated TRL. Fail: The Applicant/Bidder has not provided sufficient evidence to demonstrate that the current TRL is between 1 to 4 (inclusive) including: There is insufficient/no evidence provided for TRL judgment. The solution involves the development of basic or fundamental research. The solution is at TRL 5 or higher. Insufficient/unclear/no justification explaining the R&D that took place to bring the solution to the stated TRL. The explanation simply paraphrases the description of a given TRL level.
3. Innovation Describe the novelty of your solution and how it advances the state-of-the-art over existing technologies, including competing solutions.	Point Rated with Minimum Pass Mark The minimum pass mark for this criteria is 4 points. 0 points/Fail: The Applicant/Bidder has not demonstrated that the proposed solution advances the state-of-the-art over existing technologies, including available competing solutions; OR The stated advancements are described in general terms but are not substantiated with specific, measurable evidence. 4 points: The Applicant/Bidder has demonstrated that the proposed solution offers one or two minor improvements to existing technologies, including available competing solutions, that have potential to create competitive advantages in existing market niches. 6 points: The Applicant/Bidder has demonstrated that the proposed solution offers three or more minor improvements to existing technologies, including available competing solutions, that together are likely to create competitive advantages in existing market niches; OR The Applicant/Bidder has demonstrated that the proposed solution offers one significant improvement to existing technologies that is likely to create competitive advantages in existing market niches 8 points: The Applicant/Bidder has demonstrated that the proposed solution offers two or more significant improvements to existing technologies, including available competing solutions that are likely to create competitive advantages in existing market niches and could define new market spaces; OR The Applicant/Bidder has demonstrated that the proposed solution can be considered a new benchmark of state of the art that is clearly ahead of competitors and that is likely to define new market spaces

Part 2: Point-Rated Criteria

Proposals that do not achieve the overall minimum score of at least 55 points out of a possible 110 points (50%) will be declared non-responsive and given no further consideration.

The overall minimum score is determined by adding the Applicant/Bidder's scores from the following questions together (1b, 3, 4-13).

Point-Rated Criteria (Applicant/Bidder's proposal to address)
Question	Evaluation Schema
1b. Scope Describe how your proposed solution addresses the Additional Outcomes (if identified) in the Desired Outcomes and Considerations section in the Challenge Notice. If no Additional Outcomes are identified in the Challenge Notice, text entered in this section will not be considered. If no Additional Outcomes are identified in the Challenge Notice, Bidders/Applicants will receive 10 points	Insufficient or no information provided to demonstrate that the solution will address any of the Additional Outcomes. 0 points Information provided clearly demonstrates that the solution will address some (<50%) of the Additional Outcomes. 5 points Information provided clearly demonstrates that the solution will address most (50% or more) of the Additional Outcomes. 8 points Information provided clearly demonstrates that the solution will address all (100%) of the Additional Outcomes. 10 points
4. Phase 1 Science and Technology Risks Identify potential scientific and/or technological risks to the successful development of the proof of concept and how they will be mitigated in Phase 1?	Insufficient or no information provided to demonstrate that the Applicant/Bidder has considered potential risks and mitigation strategies and/or information provided contains significant gaps. 0 points Information provided demonstrates that the Applicant/Bidder has considered some potential risks and associated mitigation strategies but there are minor gaps in risks and/or associated mitigation strategies. 5 points Information provided clearly demonstrates that the Applicant/Bidder has sufficiently considered the risks and defined associated mitigation strategies. 10 points
5. Benefits to Canada Describe the benefits that could result from the successful development of your solution. Applicants/Bidders should consider the potential benefits using the following three categories: Innovation Benefits: Expected contribution towards the enhancement or development of new industrial or technological innovation within your firm. Assessment factors could include: potential spillover benefits, creation of intellectual property, impact on productivity of the new technology, etc. Economic Benefits: Forecasted impact on the growth of Canadian firms, clusters and supply chains, as well as its expected benefits for Canada's workforce. Assessment factors could include: number of jobs created, number of high-paying jobs, project-related revenue growth, etc. Public Benefits: Expected contribution to the broader public, including inclusive business and hiring practices (e.g., gender balance), investment in skills and training and environmental best practices. Assessment would consider the degree to which the Applicant/Bidder demonstrates that the solution is expected to generate social, environmental, health, security or other benefits to Canada. Assessment factors could include: solution-related environmental benefits, investment in local communities and solution-related impact on Indigenous communities.	Innovation Benefits Benefit not identified or insufficient claim of benefit. 0 points Benefit has marginal increment or limited justification. 1.5 points Benefit is significant and well justified. 3 points Economic Benefits Benefit not identified or insufficient claim of benefit. 0 points Benefit has marginal increment or limited justification. 1.5 points Benefit is significant and well justified. 3 points Public Benefits. Benefit not identified or insufficient claim of benefit. 0 points Benefit has marginal increment or limited justification. 1.5 points Benefit is significant and well justified. 3 points
6. Phase 1 Project Plan Demonstrate a feasible Phase 1 project plan by completing the table. Include: Project milestones; project activities under each milestone; time required to complete each milestone (e.g., days, weeks and/or months); (Indicate if any milestones and activities will be completed concurrently) total time required to complete the project; and key success criteria. Note: Phase 1 cannot exceed 6 months and TRL 4.	Insufficient or no information provided to demonstrate a feasible project plan for Phase 1 and/or the project plan exceeds the maximum duration indicated in the Challenge Notice. 0 points Project plan for Phase 1 is conceivably feasible but not clearly demonstrated and/or includes gaps. 5 points Information provided clearly demonstrates a feasible project plan for Phase 1. 10 points
7. Phase 1 Project Risks Identify potential project risks (eg. Human resources, financial, project management, etc) to the successful development of the proof of concept and how they will be mitigated?	Insufficient or no information provided to demonstrate that the Applicant/Bidder has considered potential risks and mitigation strategies and/or information provided contains significant gaps. 0 points Information provided demonstrates that the Applicant/Bidder has considered some potential risks and associated mitigation strategies but there are minor gaps in risks and/or associated mitigation strategies. 5 points Information provided clearly demonstrates that the Applicant/Bidder has sufficiently considered the risks and defined associated mitigation strategies. 10 points
8. Phase 1 Implementation Team Demonstrate how your project implementation team has the required management and technological skill sets and experience to deliver the project plan for Phase 1 by completing the table. A member of the implementation team can have more than one role. Include the labour rates and level of effort for each member. A day is defined as 7.5 hours of work, exclusive of meal breaks. The labour rates and level of effort will be reviewed as part of the evaluation for Question 10.	Insufficient or no information provided to demonstrate that the project team has the required management and technological skill sets and experience to deliver the Phase 1 project plan. 0 points Information is provided but there are minor gaps in required management and/or technological skill sets and/or experience to deliver the Phase 1 project plan. 5 points Information provided clearly demonstrates that the project team has the required management and technological skill sets and experience to deliver the Phase 1 project plan. 10 points
9. Inclusivity If your business were to receive funding from Innovative Solutions Canada, describe what actions (e.g., recruitment strategy, internships, co-op placements, etc.) might be taken in Phase 1 to support the participation of under-represented groups (e.g., women, youth, persons with disabilities, Indigenous people, visible minorities) in the research and development of the proposed solution. Each bidder/applicant in their response to this question must focus only on describing relevant programs, policies, or initiatives that it currently has in place or would put in place to support the R&D effort in Phase 1. Do not provide any personal information of individuals employed by your company or that of your subcontractors in the response below.	No description and/or concrete examples of actions provided that would be taken to encourage greater participation of under-represented groups. 0 points A description and concrete examples of actions to encourage greater participation of under-represented groups provided. 3 points
10. Phase 1 Financial Proposal Demonstrate a realistic financial proposal for the Phase 1 project plan by completing the table.	Insufficient information provided and/or information provided significantly lack credibility. Does not demonstrate a realistic financial proposal for the Phase 1 project plan. 0 points Information is provided but some costs appear to be either over or under estimated for the Phase 1 project plan. 5 points Information provided contains credible elements to clearly demonstrate a realistic financial proposal for the Phase 1 project plan. 10 points
11. Phase 1 Financial Controls, Tracking and Oversight Describe the financial controls, tracking and oversight that will be used to manage the public funds throughout Phase 1.	Insufficient or no information provided to demonstrate the Applicant/Bidder's ability to manage public funds in Phase 1. 0 points Information provided is vague and/or contains gaps. The Applicant/Bidder has some controls, tracking and/or oversight in place to manage the public funds in Phase 1. 5 points Information provided clearly demonstrates that the Applicant/Bidder has strong financial controls, tracking and oversight to manage public funds in Phase 1. 10 points
12. Phase 2 Strategy Describe a realistic strategy for the prototype development if selected to participate in Phase 2. Responses should include: anticipated barriers key tasks estimated cost	Insufficient or no information provided to demonstrate that the Applicant/Bidder has contemplated a realistic strategy for the Phase 2 prototype development. 0 points Information provided demonstrates a conceivably realistic strategy for Phase 2 prototype development, however there are gaps and/or the strategy is vague. 5 points Information provided demonstrates that the Applicant/Bidder has a clear and realistic strategy. 10 points
13. Commercialization Approach Describe your overall commercialization approach for the proposed solution. Responses should include: Target markets (excluding Government of Canada) Non-ISC funding sources Transition to a commercially-ready product or service Any other indicators of commercial potential and commercial feasibility	Insufficient or no information provided to demonstrate that the proposed solution has commercial potential. 0 points Some information provided to demonstrate that the proposed solution has commercial potential, however there are gaps in the commercialization approach. 5 points A realistic commercialization approach is provided that demonstrates that the proposed solution has commercial potential. 10 points

Questions and answers