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Wyeth BioPharma has identified cycle-time reduction as critical to customer responsiveness and the success of commercial and pipeline products. In formulating a plan of attack, the company focused on two aspects of cycle time: the global planning process and disposition cycle times.
Wyeth BioPharma has identified cycle-time reduction as critical to customer responsiveness and the success of commercial and pipeline products. In formulating a plan of attack, the company focused on two aspects of cycle time: the global planning process and disposition cycle times. While the latter is a traditional concern of cycle-time reduction efforts, the former is a little out of the ordinary because it deals with data flow and timeliness of capacity scheduling. The benefits of Wyeth's cycle-time reduction efforts include inventory reduction, increased bioreactor capacity, improved responsiveness to customer demand, significant improvement in product launch timelines, a shorter feedback loop from downstream processes to upstream quality, and reduced inventory exposure in the event of quality non-compliance.
BeneFIX is a recombinant Factor IX used for the treatment of hemophilia B, a hereditary blood clotting disorder. Wyeth is the only manufacturer of a commercial recombinant Factor IX; all other products on the market are derived from human plasma, with its associated infectious risks. FDA approved BeneFIX in 1997 and EMEA approved it for Europe in 1999. It has attained a market share of more than 80% in the US and more than 45% in Europe. The active ingredient (drug substance) of BeneFIX is manufactured in two of Wyeth's five cell culture and purification suites in Andover, Massachusetts, and contract manufactured in one cell culture and purification suite in Glaxo Smith Kline's Conshohocken, Pennsylvania, facility. All drug product is contract manufactured by Hospira (formerly Abbott) in McPherson, Kansas. Hospira also performs packaging for the US, Canadian, Asia-Pacific, and Latin American markets. Baxter BioScience markets BeneFIX in Europe and performs all European packaging at their Lessines, Belgium facility.
Some of the challenges presented by the BeneFIX supply chain include the following:
1. The supply chain crosses many geographies, companies, and IT platforms.
2. The corporation has limited supply chain data visibility and validation, and a longer-term, global solution enabling total supply chain visibility is years away.
3. Supply chain management has historically been based primarily on internal and external communication via purchase orders.
4. Manufacturing site planning is conducted strictly within the local enterprise resources planning (ERP) environment, focused on local optimization.
5. Global supply chain planning is conducted in an Excel-based environment.
6. Excessive cycle times and cycle time variability add to uncertainty at decision making points.
7. Regulatory filings can create capacity and material-sourcing constraints, necessitating characteristic-based planning when there are two plants making the same protein but one is approved globally and one is approved only in the US.
Historicially, the lack of data availability and total supply chain visibility has meant that demand signals are communicated through the supply chain via internal and external purchase orders. For example, imagine that events in a country result in a significant positive or negative change to that country's forecast. The country's purchasing process typically takes a six to 12 month view of their own requirements to meet market demand and their on-hand and in-transit inventory before placing a purchase order with their packaging supplier. The packaging site then performs a manufacturing resources planning (MRP) process: consolidating purchase orders for all the countries they supply with this product, accounting for on-hand and in-transit inventory, and placing a purchase order with the drug product manufacturer. Again, following an MRP process, the fill and lyophilization site calculates net requirements for protein and places a purchase order with the drug substance manufacturer. Although the distribution requirements planning (DRP) and MRP logic may be sound as the demand signal makes it way through the supply chain, it is not uncommon to see monthly execution frequency result in a four to five month delay before the demand signal reaches the drug substance facility.
Supply Chain Overview
The following are some of the measures Wyeth has taken over the last 18 months to address supply chain visibility and the resultant cycle time:
1. Focusing supply chain planning on drug substance and drug product simplifies data collection and event tracking.
2. The company implemented a global process to collect forecasts, inventory, and in-transit inventory into a corporate data warehouse on a monthly basis. This process is partially dependant on manual data entry; a more-automated, longer-term solution is still years away.
3. Wyeth developed a roadmap for improving the planning process. The main features of the roadmap include central planning of the entire supply chain aligned with demand forecast, migration to more advanced database software and solutions, inclusion of characteristics as constraints, and limited optimization.
The current planning process captures beginning-of-month inventory throughout the supply chain, from drug substance manufacturing through packaging, fill and lyophilization to the customer holding the finished product. We then consolidate updated 36-month forecasts from our affiliates and use DRP/MRP logic for each manufacturing site, with inventory re-balancing as necessary. The fundamental improvement to our process is not using DRP/MRP logic but that improved inventory and forecast visibility allows us to plan the entire supply chain simultaneously and eliminates our dependence on monthly purchase orders for information.
Overview of the Process
The next factor Wyeth addressed was the time it takes to perform batch disposition at each step of the manufacturing process. It is not unusual to see disposition cycle times approaching or exceeding 90 days for drug substance and drug product in the biopharmaceutical world, and this was previously the case with BeneFIX.
A pilot cycle-time reduction project was conducted for our Factor VIII product and involved a longer term, lower level commitment of representatives from two US and three European manufacturing sites, one of which is a contract manufacturer. This effort consisted of four phases:
1. Assessment of current state
2. Identification of target opportunity
4. Implementation and monthly monitoring of key metrics
The following recommendations were implemented as a result of this project:
1. Batch records are sent for QA review before all QC results are finished, allowing some activities to occur in parallel rather than sequentially.
2. Location of a QA reviewer in the manufacturing suite for real-time batch record review, reducing batch record errors.
3. Several steps to expedite sample shipment and mycoplasma testing minimized a critical bottleneck.
4. Wall charts are used to monitor batch record review activities and due dates.
The result of this effort was a 47% cycle-time reduction at the company's contract manufacturer and a 10% reduction at a European site that was already performing at a very impressive level. Based on this effort, Wyeth recently gained organizational support for a more intensive project.
An interesting event took place during the pilot project. Halfway through the project, the corporation launched a process change critical to the survival of this product. Historical cycle-time performance indicated a mid to end of fourth quarter launch, and Wyeth's team was challenged to make this happen sooner. As a result of the improvements already in place, the team was able to facilitate this process change four months earlier than expected and to implement changes to ensure the sustainability of this improvement.
The success and timeliness of this pilot initiative convinced the organization that allocating resources to cycle-time reduction is crucial and made the BeneFIX cycle-time reduction project possible. We have also seen cycle time awareness begin to permeate the manufacturing and quality organizations, with reduction efforts springing up at lower levels without prodding by upper management.
Allen Jacques is senior director, networking planning for Wyeth BioPharma, 181 Ballardvale Street, Bloomington, MA 01877, 978.247.4664, Ajacques@wyeth.com.