SOLICITATION NOTICE
A -- Liposomal Drug Products: Quality by Design Studies and Guidance Development for Rapid Consistent Drug Product Approval
- Notice Date
- 8/17/2008
- Notice Type
- Combined Synopsis/Solicitation
- NAICS
- 541712
— Research and Development in the Physical, Engineering, and Life Sciences (except Biotechnology)
- Contracting Office
- Department of Health and Human Services, Food and Drug Administration, Office of Acquisitions and Grants Services, 5630 Fishers Lane, Room 2129, Rockville, Maryland, 20857-0001
- ZIP Code
- 20857-0001
- Solicitation Number
- REQ1044477
- Point of Contact
- Monifa N Coleman, Phone: 301-827-7164
- E-Mail Address
-
monifa.coleman@fda.hhs.gov
- Small Business Set-Aside
- N/A
- Description
- This is a combined synopsis/solicitation for commercial items prepared in accordance with the format in FAR 12.6, simplified acquisition procedures and the resultant purchase order will include all applicable provisions and clauses in effect through the Federal Acquisition Circular 05-26. This announcement constitutes the only solicitation and a written solicitation will not be issued. This synopsis, NAICS code 541712, is to notify contractors that the government intends to issue a Purchase Order in accordance with FAR Part 13.106 for the following statement of work, under the simplified acquisition procedures. The Food and Drug Administration intends to award a purchase order on a sole source basis to: University of Connecticut, Dianne Burgess. Not withstanding, any firm that believes it is capable of providing the required service as stated herein may submit a capability statement to document its ability to provide the required services, which will be considered if received by the third (3rd) calendar day following the appearance of this announcement. A determination to compete this procurement based on a response to this notice is solely within the discretion of the Government. The Government reserves the right to award a contract without discussions if the Contracting Officer determines that the initial offer(s) is/are providing the Best Value and discussions are not necessary. This solicitation is issued as a Request for Quote(RFQ) The Government’s period of performance is for one (1) year effective ARO. The Food and Drug Administration (FDA) intends to award a purchase order. The purpose of this project is to extend Quality by Design concepts to liposome products in order to: i) facilitate regulation of liposomal preparations; ii) facilitate determination of generic equivalency of liposomal preparations; and iii) assist with the completion of FDA draft guidance for industry on liposome drug products. The Statement of Work is as follows: Project Title: Liposomal Drug Products: Quality by Design Studies and Guidance Development for Rapid and Consistent Drug Product Approval Purpose: The purpose of this project is to extend Quality by Design concepts to liposome products in order to: i) facilitate regulation of liposomal preparations; ii) facilitate determination of generic equivalency of liposomal preparations; and iii) assist with the completion of FDA draft guidance for industry on liposome drug products. Description of Work: The specifics aims of this research are: 1.Development of liposome formulations with different release characteristics and development of appropriate analytical methods. 2.Application of Quality by Design principles to liposome products to characterize liposome design space at a lab scale. 3.Development of a workshop where government, industry and academic scientists can discuss and debate Quality by Design and in vitro testing methods for liposome products. To achieve the above Specific Aims the following Tasks will be conducted: 1.Selection of appropriate API. 2.Development of analytical methods. 3.Formulation design. 4.Risk analysis for liposome products. 5.Screening of liposome formulations. 6.Optimization of formulation. 7.Establishment of Design Space at a lab scale for the selected liposome formulation(s). 8.Evaluation of Design Space. 9.Presentation and discussion of Quality by Design and in vitro testing methods for liposome products at a workshop attended by regulatory, industrial, and academic scientists in this area. Experimental Design Task 1. Selection of appropriate API The API will be selected first. An appropriate choice would be a poorly soluble small molecule drug such as cyclosporine-A, which is an immunosuppressant drug. Selection will be made based on availability of appropriate analytical methods and ease of adaptation/modification of these methods to suite needs when formulated in a liposome delivery vector. Depending upon FDA’s interest, either cyclosporine or tenofovir or another appropriate drug will be selected. Task 2. Development of analytical methods The analysis of tenofovir fumarate will be performed using reverse-phase high-performance liquid chromatographic (RP-HPLC) method as described by Kandagal, et al. Piroxicam (PRX) can be used as an internal standard. The assay of the drug will be performed on a CLC C18 (5 μm, 25 cm×4.6 mm i.d.) with UV detection at 259 nm. The mobile phase will be acetonitrile-water mixture in the ratio of 75:25, and a flow rate of 1 ml/min. Cyclosporine-A will be analyzed using RP-HPLC with ultraviolet detection at 205 nm. Naproxen will be used as an internal standard. Samples will be pretreated by liquid-liquid extraction with diethyl ether. The ether extract will be evaporated and the residue be reconstituted in acetonitrile-0.04 M monobasic potassium phosphate buffer (pH 2.5) solvent mixture. After washing with n-hexane, 30 micro liter of the reconstituted solution will be injected into HPLC system for analysis. The above methods, or other suitable methods available in the literature, will be modified as necessary since there may be interference from other components of the liposome formulations, (e.g. possible interactions between drug and lipids). The following in vitro release test method will be used for the liposome formulations (refer to Method section): 1)Flow thorough cell method 2)Dialysis sac method 3)Reverse dialysis sac method 4)In vitro cell culture method Task 3. Formulation design A wide variety of lipids are available for liposome preparation for example phosphatidylcholines (PC), phosphatidylethanolamines (PE), phosphatidylglycerols (PG), sphingomyelines, etc. The lipids can be cationic, anionic, zwitterionic or modified phospholipids (such as lipids capped with polyethylene glycol called PEGylated lipids/stealth liposomes). Using these different lipids, formulations can be prepared to release: 1) immediately; 2) in controlled manner; or 3) following uptake by phagocyte cells such as macrophages. To increase the physical stability of the formulation, an appropriate amount of cholesterol should be selected, as usually the higher the concentration of the cholesterol, the less fluid the membrane and thus the faster the release rate. Use of different combinations of lipids will change the in vivo performance, for example inclusion of fusogenic lipids such as di-oleoyl phosphatidyl ethanolamine (DOPE) will facilitate membrane fusion thus enabling endosomal escape. Three formulations will be selected to represent three different types of liposomes as described above. For example, lipid containing DPPC and cholesterol (8:2 molar ratio) will be used to prepare the controlled release liposomes and PEGylated DPPC and cholesterol (8:2 molar ratio) will be used to prepare the liposome that release only following cellular uptake. Briefly, the liposomes will be formed by first dissolving lipid in chloroform followed by evaporation, after which sonication and extrusion will be used to control the particle size (refer to Methods section). Task 4. Risk analysis for liposome products According to the quality by design concept, quality cannot be tested into products, but should be built-in through appropriate formulation design (refer to ICH-Q8&Q9). Therefore, it is necessary to identify sources of potential harm to the quality of the final product, assessing the likelihood that harm will occur and the consequences if harm does occur. An Ishikawa diagram will be constructed to identify the potential risks and corresponding causes. Specifically, several major risk categories will be defined and these will be further delineated to identify all potential risks. The major categories for liposomes will be formulation composition, environment conditions, manufacturing process. Under each category, all possible factors will be identified. A few examples are illustrated below. 1)Change in the lipid type and amount will significantly alter the stability of the liposome membrane and this will impact functionality (fusogenic or controlled release); 2) Hydrolysis of the lipid in the liposome membrane will depend on the pH and temperature conditions the liposome product experiences, and this will also impact the functionality with possible faster release and reduced stability; 3)The phase transition temperature of the lipid will impact the liposome stability with lower phase transition temperature lipid expected to result in liposome products with low stability and faster release. For example, the DPPC liposome has a phase transition temperature of 41°C, it is expected to exhibit slow release upon administration into the body (37°C) as it will remain in the lamellar gel phase and the membrane will be less flexible and thus less permeable; 4)The particle size and the size distribution of the final liposome product will largely depend on the processing steps where usually extrusion, homogenization and sonication are employed. A complete risk analysis, in accordance with the ICH-Q8 and ICH-Q9 documents, will allow quality control of the production process through analysis of the particle size, zeta-potential, and rheology. Task 5. Screening of liposome formulations Based on our previous experience with liposome formulations and knowledge gained from the literature, it will be possible to narrow down the factors that may alter product performance. For example, lipid type and drug lipid ratio might be the most important factors in determining the stability and functionality of the product, while the pH and temperature conditions are the most important environmental conditions. With respect to processing conditions, factors that affect particle size may be more significant since liposome particle size is an important quality attribute, as it can affect both release characteristics and targeting. Critical quality attributes are: stability, release rates and target ability as well as sterility. Accordingly the ten most influential variables will be identified for screening, and out of these 2 to 3 key variables will be selected for formulation optimization. Task 6. Optimization of formulation Upon selection of the 2 to 3 key variables, the formulation will be optimized using the experimental design method where for each of the selected variable 3 levels (low, medium, high) will be tested. After evaluating the in vitro release profile of the different types of liposome products, optimized formulations (depending on different end-points set for immediate release, controlled release, and release after cellular uptake) will be obtained followed by a statistical analysis. Task 7. Establishment of Design Space at a lab scale for the selected liposome formulation. Key parameters from all three categories (formulation, environmental condition, and process parameters) that have been demonstrated to affect quality will be used to construct the design space. Selected variables will be changed and mapped against each other to determine the design space within which the critical quality attributes are maintained. Task 8. Evaluation of Design Space After completion of the mapping of the design space, key variables will be changed to give different formulations with various performances (both qualified and non-qualified formulations). These formulations will be then subjected to in vitro release testing to confirm the constructed design space. Task 9. Proposal submission for presentation and discussion of Quality by Design and in vitro testing methods for liposome products at a workshop attended by regulatory, industrial, and academic scientists in this area. A proposal will be submitted to either the American Association of Pharmaceutical Scientists (AAPS) or the Controlled Release Society (CRS) to conduct a workshop on Quality by Design of liposome products. Due to the time required to submit a workshop proposal to these associations, this task may not be completed within 1 year timeframe. Deliverables: 1. Monthly teleconferences with the project officer and key study personnel will be on the first day of the month in the afternoons. 2. Quarterly reports in Word document are to be submitted to the project officer and key study personnel by the first day of the month (Q1: Tasks 1-3, Q2: Tasks 4&5, Q3: Task 6, Q4: Task 7-9). 3. A final report in Word document is to be submitted to the project officer and key study personnel two weeks prior to the end of the 12-month time period of the study. 4. Presentation in PowerPoint format at the FDA on the final results will be two weeks after the 12-month time period of the study. 5. A manuscript draft in Word document is to be submitted to the project officer and key study personnel two weeks prior to the end of the 12-month time period of the study. Period of Performance: One (1) year effective ARO. PAYMENT SCHEDULE: Payment will be made in monthly installments based on level of effort (hours worked). CCR: Vendors must be registered in the Central Contractor Register (CCR) prior to the award of a contract. You may register by going to www.ccr.gov. You will need your Dun & Bradstreet number and banking information. QUESTIONS DEADLINE: All questions are to be submitted via email to Monifa.Coleman@fda.hhs.gov no later than August 20, 2008, 2:00pm EST. QUOTATIONS DUE: All quotations are due, via email to: Monifa.Coleman@fda.hhs.gov, no later than 12:00pm, EST on August 25, 2008. PROVISIONS and CLAUSES: The provision at FAR 52.212-1, Instructions to Offerors Commercial Items applies to this solicitation. The following agenda has been attached to this provision: None. Offerors shall include a completed copy of the provision at FAR 52.212-3, Offeror Representations and Certifications Commercial Items. The clause at FAR 52.212-4, Contract Terms and Conditions, Commercial Items applies to this acquisition. The following agenda has been attached to the clause: None. The clause at FAR 52.212-5 Contract Terms and Conditions Required to Implement Statues or Executive Orders, Commercial Items applies to this acquisition. The following FAR clauses cited are applicable: FAR 52.217-8, FAR 52.222-26, FAR 52.222-35, FAR 52.222-36, and FAR 52.232-33. Clauses and provisions are incorporated by reference and apply to this acquisition. Responses to this notice must be sent via email to Monifa.Coleman@fda.hhs.gov. No phone calls will be accepted.
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