Development and Testing of a Multi-dose Vial for Scopolamine Hydrobromide Trihydrate Formulation for Intramuscular Injection

KEY TECHNOLOGY AREAS: Chemical/Biological Defense, Biomedical OBJECTIVE: To develop a multi-dose, scopolamine hydrobromide trihydrate vial containing a formulation that is stable, injectable, and suitable for GMP manufacture. DESCRIPTION: The Joint Project Manager for Chemical, Biological, Radiological, and Nuclear Medical (JPM CBRN Medical) is developing scopolamine hydrobromide trihydrate (Scop-HBT) under the Improved Nerve Agent Treatment System - Centrally Acting (INATS CA) program. Scop-HBT is an anticholinergic medical countermeasure (MCM) that temporarily blocks severe or life-threatening muscarinic effects caused by organophosphorus nerve agent (OPNA) poisoning. The improved OPNA treatment regime will consists of the Scop-HBT intramuscular (IM) injection as an adjunct to the standard of care autoinjectors containing atropine and 2-PAM (2-pyridine aldoxime methyl chloride (Pralidoxime). The combined therapeutic action will help to decrease morbidity and mortality of military personnel and civilians exposed to OPNAs. Currently, the JPM CBRN Medical is developing Scop-HBT in an autoinjector format; the concentration is not yet final, but a concentration between 0.8 mg/ml and 2.0 mg/ml is anticipated. The autoinjector in development is suitable for use by an individual to deliver immediate treatment. However, the use of single dose devices and/or vials represents a significant logistical burden to military first responders that will need to deliver multiple injections during a mass casualty event. A multi-dose vial with Scop-HBT for IM injection, 20 ml total volume containing 10-20 doses, will significantly decrease logistical burden associated with having to use multiple single dose vials to treat during mass casualty OPNA exposure incidents, as well as for treating single OPNA exposure casualties over a prolonged period of time. PHASE I: Establish preliminary specifications for a multi-dose formulation under International Conference on Harmonization (ICH) Pharmaceutical Development Guidelines. The active drug substance to be employed will be Scop-HBT (United States Pharmacopeia (USP) grade or Department of Defense (DoD) supplied). Initial test vials will contain a total of 20 ml of drug solution volume, containing a concentration range of 0.8 mg to 2.0 mg of Scop-HBT per ml in an appropriately sealed, pharmaceutical grade light-restricting glass vials, as designed for injectable drug formulations. Based on the single dose formulation ranging from 0.8 mg/ml to 2.0 mg/ml, the target pH of the formulation is approximately 3.00 0.10 in pharmaceutical grade buffer, and tonicity adjusted to approximate isotonicity (270 to 310 mOsm (milliosmole). The test formulations will evaluate added U. S. Food and Drug Administration (FDA) approved, effective antimicrobial preservatives (e.g., 0.9% benzyl alcohol or 0.5% chlorobutanol) against analytical parameters established for the DoD single dose formulation (currently in development). Stability assessments could employ forced degradation and initial real time testing for the scopolamine drug substance, and development of degradants at targeted temperatures and relative humidity conditions: refrigerated (2-8 C), room temperature (25 2 C / 60% 5% RH), and stressed (40 2 C / 75% 5% RH). PHASE II: Conduct further evaluation, improvements, and stability enhancements of selected candidate. Subsequent analytical testing is to be performed to determine the presence and concentrations of extractables and leachables. Real-time stability is to be evaluated to achieve a targeted shelf-life of two years at 25 2 C / 60% 5% RH. Subsequent studies may determine the effects of potential stability enhancement techniques as needed, such as utilization of head-space nitrogen purge, vacuum seal, or other to promote extended stability to two years. A syringe needle puncture study is to be performed to evaluate required 28 day drug stability (28 days at 2-8 C and 25 2 C / 60% 5% RH (relative humidity)). The performer may evaluate the use of lyophilization as a dry powder stability enhancer after reconstitution, with bacteriostatic saline or sterile water for injection. This may be accomplished with variable addition of the antimicrobial agent as needed. The performer may determine the shelf-life stability of the lyophilized powder as needed under vacuum seal or nitrogen purge. A 28 day stability study will be evaluated to determine shelflife after reconstitution. The last developmental step is analytical analysis to demonstrate equivalence to the single dose IM Scop-HBT formulation currently being developed by the DoD (final concentration and comparator to be provided at time of contract award). PHASE III: Develop scale-up processes and technology transfer protocol for the pilot lot and good manufacturing practice (GMP) production. Develop regulatory strategy, and initiate interactions with the FDA. PHASE III DUAL USE APPLICATIONS: The Department of Health and Human Services (HHS) has a similar need for improved anticholinergic therapeutics, including multi-use vialed Scop-HBT for use in civilian casualty situations. Successful completion of all three phases under this solicitation will support small business valuation by confirming technical merit that invites further investment. This award mechanism will bridge the gap between laboratory-scale innovation and entry into a recognized FDA regulatory pathway leading to commercialization. REFERENCES: 1. Selection of the Appropriate Package Type Terms and Recommendations for Labeling Injectable Medical Products Packaged in Multiple-Dose, Single-Dose, and Single-Patient-Use Containers for Human Use. Guidance for Industry. Division of Drug Information, Center for Drug Evaluation and Research, FDA. FDA-2015-D-3438. 2018. 2. Allowable Excess Volume and Labeled Vial Fill Size in Injectable Drug and Biological Products. Guidance for Industry. Division of Drug Information, Center for Drug Evaluation and Research, FDA. June 2015 Pharmaceutical Quality/CMC. 2015. 3. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonized Tripartite Guideline. Pharmaceutical Development Q8 (R2). 2009.