But even validation, now accepted as a basic requirement, was once a new concept. When validation was first expected of companies,
a number of articles were published that argued against it.2 Interestingly, despite all the skepticism about QbD today, we have yet to see an article challenging it. Instead, the doubts
seems to be expressed more quietly, perhaps out of fear of contradicting the regulators who support it. But there must be
a discussion of the pros and cons of QbD. We must be able to justify QbD in real terms of reduced risk to the patient and
money and time savings. Without a vigorous discussion, it will quietly fade away and the tremendous benefits will be lost.
Design of Experiments (DOE)
Concerns About the Concept
The skeptics have valid concerns that must be answered clearly. During the webcast of "Pharmaceutical Quality by Design: The
Road Ahead," the participants were polled for their concerns about QbD.3 According to the responses, 39% were concerned about lack of clarity on what the concept means; 15% had time constraints
(it takes too long) and 13% had budget constraints (it costs too much) for QbD implementation; 13% were concerned about the
lack of management support and 11% about the inability of quantifying potential benefits; and 9% had concerns about lack of
skilled personal. These concerns are expected and timeless. Every new endeavor faces similar comments.
Addressing the Concerns
The lack of clarity is being addressed by the FDA and industry organizations by presenting conferences, seminars, training,
and publications. The FDA has been very proactive in giving talks and being available for discussions. Participants must continue
to read, reread, and discuss the available information until the concepts and ideas become clear enough for implementation.
Time is money, and thus the concerns about time and cost can be discussed together. Any new activity is awkward, slow, and
inefficient. A student just learning to use a keyboard is frustrated. But with determination and practice the student gains
proficiency and speed. Eventually, the keyboard becomes second nature and the attention is on the contents of the document
and not the skill of typing. So it is with QbD. At first, it is strange and uncomfortable. The old approach seems faster with
fewer trial runs. In the short term, the old ways seem better. But QbD takes a lifecycle approach. The goal is to minimize
total costs and time from initial development to product retirement. "Pay me now or pay me later," was once a jingle for motor
oil, meaning you could pay to change the engine oil as needed or replace the engine later. The same applies to development.
If you short change the development stage, you may pay later for more rejected lots, stability failures, 483 citations, warning
letters, and recalls.
Management's support is essential; without it few initiatives prosper and succeed. As W. Edwards Deming so forcibly told us,
"It is management's job to work on the system so the employees can work within the system." For example, management needs
to make QbD easy to implement. Anything less than full support is worthless.
The inability to quantify potential benefits is a management issue. Cost of quality systems have been used for many decades
in the field of quality control.4 Modifications to these systems can potentially be an easy way to initially carry out a cost–benefit analysis. A paper published
in the year 2000 titled "The Cost of Non-Conformance: The Linkage Between Quality Performance and Business Results" also proposed
an approach to be considered.5 The authors developed the "Cost of Non-Conformance Model" to capture the business impact of non-conformance with quality
standards and regulations.
Management should start with the employees that are eager to participate, and encourage, support, and reward them in public.
Others will join in as they see the rewards and benefits of participating. Formal and informal training is needed for topics
such as statistics and DOE, and the related software.6