Case Scenario:

A marketed product ABC¹is a recombinant DNA-derived coagulation Factor IX concentrate indicated in children and adults with hemophilia B (congenital Factor IX deficiency) and intended for:

1) On-demand control and prevention of bleeding episodes; 2) Perioperative management of bleeding;

3) Routine prophylaxis to prevent or reduce the frequency of bleeding episodes. It is not indicated (contraindication) for immune tolerance induction in patients with Hemophilia B.

The ABC product is supplied as a lyophilized powder in single-dose vials. The product is packaged with 2.5 mL (for reconstitution of 250, 500, or 1000 IU vials) or 5 mL (for reconstitution of 2000 or 3500 IU vials) of Sterile Water for Injection, USP. The finished product package is required to be protected from light. The package can be stored in a refrigerator or at room temperature 225C (36 to 77F). It should not be frozen.

Currently, the manufacturer is working towards submitting a clinical data package for obtaining a new indication of routine prophylaxis to reduce the frequency of bleeding episodes in varied populations for new dosage forms and to add special population subgroups. This ABC product requires a specific production process that involves extremely stringent purification steps.

Currently, the manufacturer is facing the following product-related situations:

• Due to the adjustment of dosage for this new indication, it would require supporting 3200 patients' clinical data with a new treatment regimen for 6-months and the clinical team has proposed that the product should be supplied as an investigational product²to the registered clinical sites prior to 6-months from September 1, The expected quantity to be supplied is 48000 I.V. vials.
• Additionally, due to a raw material supply (and supplier) issue, the manufacturer is already planning and seeking replacement with a new Tier-1 raw material Technically, such raw material changes could impact the in-process material, active formulation constitution, which 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, the manufacturer has learned that a batch supplied by this new Tier-1 raw material supplier to another manufacturer for their marketed product is under investigation due to potential ingredients that could be contaminated and could potentially cause public health concerns.
• Currently, the manufacturer is also planning to scale up the commercial production of this currently marketed product (i.e. original dosage), and establish a validated cGMP plan 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 materials stock would only allow the production of 40,000 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 clinical sites or to use the raw materials to meet the market supply and demand.

The ABC product costs $167.50 (USD) per vial in actual production and sells at the market price of $945 (USD) per vial. Each vial filling (including formulation) takes 36 hours (i.e., per unit/vial) due to an additional purification step prior to the composition of the final filled formulation and to allow the finished product to be packaged. The market price for both the US and EU will remain the same at $945(USD) per vial, though the price for foreign markets (i.e., other international markets, global geographies) would be reduced to $499 per vial to factor in the currency change and market price fluctuations. However, the US and EU markets may need the demand, though they may not be able to exhaust the inventory which could lead to fewer orders in the future. Whereas, the foreign markets have higher demand and potential for more orders.

Strategy for Supply Chain and Business Decision:

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 a logical pathway to a resolution. Take an approach of presenting a business decision pitch with the best suitable option, as the manufacturer's supply chain and risk management (RM) team to the executive management.

Estimate the time, and raw materials, and calculate how much it will take to create the

Evaluate if there is any option for introducing any contract manufacturing work that could add up or scale up If so, how should the manufacturer strategize to meet the demand? Note: This would add as a third option (apart from the two options, i.e. strategic pathways)

Develop the RPN calculation for the raw material supplier change (i.e., B). Assess and create a product severity, occurrence, and detection

Create an assessment of new raw material suppliers and implementation into quality Include additional review that may be needed due to their recent history of ingredient contamination issues with the 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).