Stable Liposomes as Drug Carriers

October 18, 2019 Attachment 3 has been added. The document contains questions and answers related to the Challenge. ******************** October 1, 2019 Attachment 2 has been added. The document contains a question and an answer related to the Challenge. ******************** September 13, 2019 Attachment 1 has been added. The document contains a question and an answer related to the Challenge. ******************** This Challenge Notice is issued under the Innovative Solutions Canada Program (ISC) Call for Proposals 002 (EN578-170003/C). For general ISC information, Bidders can visit the ISC website. Please refer to the Solicitation Documents which contain the process for submitting a proposal. Steps to apply: Step 1: read this challenge Step 2: read the Call for Proposals Step 3: propose your solution here CHALLENGE TITLE: Stable Liposomes as Drug Carriers CHALLENGE SPONSOR: National Research Council of Canada (NRC) Funding Mechanism: Contract MAXIMUM CONTRACT VALUE: 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 (2) 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. Problem Summary Statement The National Research Council (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. 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:  at least three different sizes (60±10 nm, 100±10 nm, 200±20 nm); with a polydispersity index (PDI) of <0.15 in Dynamic Light Scattering (DLS) measurement; and 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; and 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 1; produce 2,000 units for one selected size before the end of Phase 2 (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.

Additional Outcomes N/A 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. ENQUIRIES All enquiries must be submitted in writing to TPSGC.SIC-ISC.PWGSC@tpsgc-pwgsc.gc.ca no later than ten calendar days before the Challenge Notice closing date. Enquiries received after that time may not be answered.