In early November 2003, Wyeth BioPharma, headquartered in Andover, MA, hosted the quarterly meeting of the BioPharma Operations
Excellence Consortium. Approximately 50 people representing over 15 companies attended this first meeting of the consortium's
newly established East Coast chapter.
The day's agenda included key industry topics such as the future of biogenerics, successful process transfer, supply-chain
cycle-time reduction, and highlights from the Tefen-led "BioBenchmark Study."
The Future of Biogenerics
In the first session, John Dingerdissen, vice president of worldwide manufacturing for Centocor, discussed follow-on biologics,
or biogenerics. As patent protection expires for the first wave of biopharmaceutical products, generic substitutes offer
a potential multibillion dollar market but are a threat to current innovator companies. It is believed that most of these
biopharmaceuticals are already under development by generic producers. There are a few key factors, however, complicating
the biogenerics issue: a lack of clear regulatory guidelines, the potential shortage of bulk active biopharmaceuticals obtained
through non-patent-infringing routes, and, most critically, the widespread belief that for biopharmaceuticals "the process
makes the product" - meaning that even minor modifications of the bioprocess may lead to variation in product quality or safety.1
Figure 1. Batch Record Review Process
Dingerdissen focused on the processing issue, emphasizing that FDA must ensure that follow-on products will not risk patient
safety. He also discussed the differences between internal process changes (moving to a new site, for example) and generics.
Innovator companies have years of experience with their products, large amounts of clinical data verifying safety, and full
transparency of any process being transferred. Generics manufacturers will be implementing processes without that depth of
knowledge. Dingerdissen's key message was that although biogenerics are inevitable, the question remains: How much safety
data will be required for their approval?
Successful Process Transfer
Blair Okita, Sr., vice president of therapeutics manufacturing and development at Genzyme, discussed elements of process transfer.
He addressed the risks and rewards of standardizing on a single platform the development of products, and making the products
fit within that platform. He also explored how human capital supports process transfer. Genzyme uses a structure that includes
a technical support role, focusing on the management of communications and scheduling of process transfers. A final, important
component of process transfer is data collection, in the form of statistical process controls. By continuously tracking the
process parameters in production, troublesome trends and out-of-specification conditions can be quickly observed and appropriate
action taken to drive overall process improvement.
Reducing Cycle Time
Allen Jacques, director of production control for Wyeth BioPharma, discussed his company's effort to compress the overall
cycle time of its product supply chain. Wyeth BioPharma has a highly complex biopharmaceutical product supply chain because
the company deals with a large number of customers and contract sites all over the world. The biggest challenge Wyeth faces
is maintaining an effective and efficient flow of information. By the time demand figures work their way up the communication
chain and product moves down the supply route, market needs may have changed. To battle these challenges, Wyeth has focused
on improving the quality and frequency of communication and coordination with all supply and demand points, providing much
more responsive manufacturing. The company has accomplished this by implementing a corporate data warehouse, accessed and
populated by all affected parties. The effort has been supplemented by activities - conducted by cycle-time reduction teams
- focusing on improvements at relevant sites. The main objective of these teams is the reduction of overall disposition times
through more efficient batch record review and deviation investigations.
As demonstrated through Wyeth's case study - and validated by Tefen's own industry experience - batch record review and deviation
management typically are the business processes with the greatest contribution (and improvement potential) to a company's
cycle-time performance. Although deviation management is starting to receive the operations-focused attention it deserves
(for example, business process reengineering efforts, automated deviation management, and corrective and preventive action
[CAPA] information systems), the batch record review process still lacks the required operations-centric focus, usually resulting
in poor performance.
Tefen's practice shows that the following elements must be in place in order to implement and maintain an efficient and effective
batch record review process:
- scheduling and management of the release process by dedicated resources
- quality resources co-located with production or on the production floor
- accurate resource modeling of disposition staff, and retention of review staff
- key performance indicators to control disposition time, variability, and backlog and provide visibility to management
- focused coordination and reduction of document errors by production and laboratory staff with QA functioning in a mentoring
- use of an electronic system to track lots in disposition process, including the status of release components.
Figure 1 illustrates these main elements and their interdependencies.
A comprehensive cycle-time reduction study conducted by a large biopharmaceutical manufacturing company concluded that the
most significant contributing factor to lengthy cycle times is the extremely long batch record review process due primarily
to frequent documentation errors. The company's executive team accepted the diagnosis and the recommended improvement roadmap
and formed a 12-month improvement program targeting significant enhancement in the organization's "right first time" documentation
metrics. The results of the program were impressive with a more than 60% reduction in errors and a 35% reduction in overall
disposition cycle time.