RGA 6234: Drug and Device Supplier Risk Management: Compliance and Processes. Winter 2023 Term Final Project Paper Assignment Case Scenario: A marketed product ABC1 [antihemophilic factor (recombinant), Fc-VWF-XTEN fusion protein-ehtl] is a recombinant DNA-derived, Factor VIII concentrate indicated for use in adults and children with hemophilia A (congenital factor VIII deficiency) for: Routine prophylaxis to reduce the frequency of bleeding episodes. On-demand treatment & control of bleeding episodes. Perioperative management of bleeding. The ABC product is not indicated for the treatment of von Willebrand disease. This ABC product requires specific production process which involves extremely stringent purification and development process. The manufacturer is facing the following product-related situations. A. Due to the adjustment of dosage for this new indication, it would require supporting 150 patients' clinical data with new treatment regimen for 3-months and the clinical team has proposed that the product should be supplied as an investigational product2 to the registered clinical sites prior to 6-months from October 1, 2023. The expected quantity to be supplied is 42000 I.V. vials. B. Additionally, due to a raw material supplier issue, the manufacturer is already planning to seek a new Tier-1 raw material supplier. Technically, such raw material changes could impact the in-process material, active formulation constitution, that may not conform to the predetermined specification to one or more processing steps that are different from the established manufacturing process in order to obtain acceptable quality in-process material. Further, a batch supplied by this new raw material supplier to another manufacturer for a marketed product is under review due potential ingredient which could be contaminated and could potentially cause public health concerns. 1 The case scenario product is named hypothetically as "Product ABC", for the purpose of this project assignment, however, the first hypothetical product described with its indication represents an actual marketed product. 2 The investigational product is hypothetical, and not a marketed product.

C. Currently, the manufacturer is also planning to scale-up the commercial production of this marketed product, and establish a validated cGMP program in partnership with a contract manufacturer outside the US, and this transfer would allow to start production in the next 6-months. Based upon the assessment of the raw materials team, the current stock would only allow production of 35,000 I.V. vials. Therefore, the manufacturing team is facing a dilemma of whether to focus on the reformulation and supply of investigational drug batches to the clinical sites or to use the raw materials to meet the market supply and demand. The ABC product costs $202.00 (USD) per vial in actual production, and sells at the market price of $1895 (USD) per vial. Each vial filling (including formulation) takes 36 hours (i.e., per unit/vial) due to an additional purification step prior to lyophilization and to allow the finished product to be packaged. The market price for US and EU will remain the same at $1895 per vial, though the price for foreign developing markets would be reduced to $995 per vial to factor in the currency change and market price fluctuations. However, the US and EU markets may need the demand, though may not be able to exhaust the inventory which could lead to fewer orders in future. Whereas, the foreign markets have higher demand and potential for more orders. Strategy for supply chain: Based upon this case scenario create a strategy for the manufacturer taking into consideration both tasks: 1) supply to clinical sites; 2) supply to US and foreign markets. Add to this assessment the impact of raw materials supplies (as described earlier). Then present as a logical pathway to a resolution. Take an approach of this presentation pitch as am internal supply chain and risk management team to the manufacture's executive management. Estimate the time, raw materials, and calculate how much it will take to create the inventory. Evaluate if there is any option for introducing any contract manufacturing work which could add up or scale-up production. If so, how should the manufacturer strategize meeting the demand. NOTE: This would add as a third option (apart from the two options/path) Develop the RPN calculation for the raw material supplier change (i.e., B). Assess and create a product severity, occurrence, and detection scores. Create an assessment of new raw material supplier and implementation into quality system. Include additional review that may be needed due to their recent history of ingredient contamination issue with potential to cause public health concerns, for another manufacturer. Apply general risk management process and develop a cause-and-effect assessment, as applicable for all options (two options and additional if added for contract manufacturing). Calculate and present the decision path for both options and how the limited supply of raw materials and estimate of potential 35,000 I.V., production meets as best strategy for the two options and market demands of 42,000 I.V. How should the deficit of 7,000 I.V. be justified? Provide a comparative of both options strategies and the decision path to the best and final decision. Additional criterion should be additionally included based upon your team's viewpoint and research. o Identify the subject product from FDA website (database). Review what was its regulatory pathway to market (NDA, BLA). o Rationale for the analysis presentation and supportive for all criterion applicable to this plan. o Create and add exhibits as tabular, or flow chart illustrations as needed to present the strategies for both options (including third option), and their comparative assessment. o Explain, any limitations or challenging factors, if applicable. o Conclusion (must be included) o Comprehensive write-up - the analysis and strategic plan should be written in a manner that represents a high-quality comprehensive plan which could be applied to a real-world scenario. INSTRUCTIONS NOTE: This paper is a team assignment and a graded deliverable. The grade will be shared by all team members. The paper must be written as an original write-up text (no copy n paste using articles or web), as an analysis. FINAL PROJECT PRESENTATION - In Week 10 Class (March 13th) Note: Team Presentations must be uploaded via CANVAS prior to the class in Week 10. FINAL PAPER SUBMISSION - In Week 11 via CANVAS (March 20th by 11:59 pm ET) REFERENCES: Modules material readings, weekly reading materials, and web research. https://www.fda.gov/drugs/pharmaceutical-quality-resources/current-good- manufacturing-practice-cgmp-regulations ICH Q9 (FDA document) ICH Q10 (FDA document) CITATIONS: Formal AMA Style PAGE LIMIT: 20 Pages, plus exhibits. FONT Style: Times New Roman FONT Size: 12 Fonts. LINE SPACING: Double line spacing. EXHIBITS allowed: 3 to 5 allowed. [End of document]