AN EXAMPLE OF COSTS BEYOND API LOSSES
The experience of a major pharmaceutical manufacturer vividly answers these questions. The manufacturer was experiencing problems
with a product capsule consisting of three components: immediate release pellets, sustained release pellets, and enteric release
pellets. The dissolution performance of both the immediate release pellets and the sustained release pellets was poor. Although
recent production batches had met specifications, they were trending out of spec, requiring investigation and justification
for release. The shift in performance of the pellets appeared to coincide with a change in the API supplier, which resulted
in a change in particle size distribution. The organization took some stopgap measures to mitigate the problem, but making
those measures permanent would have resulted in significant and costly yield loss and would have required an amended filing
to be submitted to FDA.
Prior to the change in the API supplier, the process capability was such that the probability of failure was less than one
batch in 2500. Following the change, failures were occurring at a rate of approximately one batch in 25. To avoid a stock-out
situation, it was crucial to determine the root cause of the problem, remediate it, and release the out-of-trend finished
product. The problem was already costing approximately $250,000 per month in lost batches and yield. A stock-out of greater
than 21 days had the potential to cause losses in excess of $400,000 per day and a serious loss in market share.
To solve the problem, the company turned to QbD tools that enabled them to identify a relationship between process parameters,
API particle size distribution, and dissolution profile. They were then able to reduce the probability of failure to less
than one batch in 5000. Further, the change in the process parameter was within the spec ranges that had been originally filed
and, therefore, did not require a filing change. By significantly reducing the risk of failure, QbD tools had essentially
eliminated the stock-out risk and costs of poor quality.
DEFINING THE GENERAL COMPETITIVE ADVANTAGES OF QBD
As the experience of the manufacturer demonstrates, QbD is not just a tactic for reducing costs but a strategy for increasing
competitiveness that cuts across all functions of the enterprise. In considering QbD, it is important to adopt a strategic
perspective in order to understand the full value that QbD can generate within and across functions and in the marketplace.
In making the case to leadership for adopting QbD, it's worth dwelling on some of the following key business benefits and
Greater Speed to Market
Every day that a product makes it later rather than sooner to market means lost or deferred revenue. QbD can greatly reduce
time to market and speed up return on investment because it maximizes the probability that a product in development will make
it smoothly and effectively through scale-up, technology transfer, and validation. It is, however, exceedingly important that
one doesn't just take some arbitrary cost per day by dividing the total R&D budget and multiplying it times an arbitrary number
of days which might be saved. This invariably rings hollow and, it should. An analysis of the organization's historical performance,
delays in product commercialization and failure modes will not only generate a better estimate, it will enhance credibility.
Lower Cost of Quality
When quality is produced through extensive control, as it is in the traditional approach, the result is high cost. By contrast,
QbD's science-based understanding of processes frees manufacturers to focus their control efforts on the factors that are
critical to quality. Greater process understanding also enables more accurate and thorough validation than the three-batch
standard and more robust processes that can accommodate inevitable variations in raw materials.
Better Allocation of Resources
The best-laid plans in the allocation of resources can be waylaid by unpredictable and costly quality problems. But with QbD,
companies can have greater confidence in their ability to maintain in-specification operations, freeing resources for more
productive and predictable investment.
Improved Manufacturing Performance
The more processes that QbD permeates, the more the organization will realize bottom-line benefits through improved yield,
increased equipment uptime and plant and capacity utilization, capital cost avoidance, and reduced rework and fewer rejected
Reduced Regulatory Burden and Continuous Improvement
Once an organization understands the design space, the manufacturing processes within that design space can be continuously
improved without further regulatory review. FDA can use risk assessment and management approaches to reviews and inspections,
and continuous improvement of processes can lead to greater cost reduction and reliability of products and processes.
QBD IN THE COMPLEX PHARMACEUTICAL WORLD
In addition to these key business benefits, QbD can be a key enabler for companies that want to get ahead of one of today's
biggest challenges in the development of drugs, diagnostics, and therapies: their sheer complexity. The days have long passed
when medications were taken briefly to treat relatively straightforward conditions. Whole new classes of drugs have appeared
to treat chronic diseases and address extremely complicated therapeutic areas like oncology, AIDS, Alzheimer's, and Parkinson's.
QbD is particularly well suited for these complex contexts, because it has the ability to scientifically establish the complicated
multi-dimensional interactions of the input variables and process parameters that determine the quality of a product. In the
increasingly complex world of the life sciences and therapeutic needs, companies that have adopted QbD are likely to have
a strategic advantage.
James P. Catania is a managing consultant at Tunnell Consulting, firstname.lastname@example.org