Imagine a group of pharmaceutical manufacturing experts who convene to discuss the FDA’s Process Analytical Technology (PAT) initiative and over the course of two days never once delve into near infrared spectroscopy (NIR) — or virtually any other on-line technology. That’s exactly what happened at a recent PAT symposium comprising pharmaceutical executives, industry consultants, academics, and one of the initial leaders of the FDA’s PAT effort, Ajaz Hussain. Far from being a glaring omission, however, the relative absence of such discussion provided a striking confirmation of the real opportunity that PAT offers pharmaceutical companies: a chance to achieve systematic improvement in manufacturability through application of a holistic, strategic implementation framework designed to generate significant business benefits.
As Figure 1 (below) suggests, the most effective PAT programs begin by putting PAT in a strategic context, including an appreciation of the value it can generate and a prioritization of the products and processes to which PAT can be applied to realize that value. Nevertheless, few companies launch their PAT initiatives in this organized and logical fashion. Most companies “doing PAT” today continue to be focused on the search for applications of technology such as NIR.
|Figure 1. The most effective PAT programs put PAT in a strategic context.
After establishing the PAT value proposition and prioritizing products and processes, attention should turn next to improving process understanding for those products and processes where there is value to be gained. The three elements for achieving that all-important process understanding include:
- quality by design (QbD) techniques and identifying critical process parameters (CPPs)
- drivers of variation and of interactions in critical processes
- process control strategies.
Again, as Figure 1 depicts, analytical technology is not the central focus of the effort, but an enabler of the real goal: the understanding, variation reduction, and control of critical process parameters in the business context of maximizing value.
Understanding the Value
The value to be gained from improved manufacturing through superior process understanding is enormous. Although the scale and precise distribution of savings will differ for each pharmaceutical company, a strategic PAT program can yield millions of dollars in savings in four key areas: reduced cost of quality, reduced capital investment, reduced inventory, and increased speed to market (see Figure 2, below).
In the pharmaceutical industry the first pass defect rate, which is an expression of lack of process understanding, is estimated to be approximately 15% (2.5 sigma). For that reason, the largest contributor to overall savings arising from an extensive PAT program will generally be reduced cost of quality. Fortunately, inspection regimens prevent these first-pass defects from reaching the marketplace, increasing quality to 5.5 sigma or 0.003% defects; however, improved process understanding can greatly reduce those defects in the first place and thereby greatly lower the cost of quality.
|Figure 2. A strategic PAT program can yield millions of dollars in savings in reduced cost of quality, reduced capital investment, reduced inventory and increased speed to market.
It is currently estimated that for most pharmaceutical companies, the total cost of quality is, on average, about 25% of sales, with much of that cost resulting from poor process understanding, which a PAT initiative could dramatically reduce. In fact, one estimate puts the potential savings from PAT-driven reduced cost of quality at over $1 billion for each of the top 10 pharma companies.
Similarly, savings from reduced capital investment can also be significant. Consider that for each of the top ten pharmaceutical companies, 2005 capital expenditure (CAPEX) is forecasted to be 11% of sales on average, or about $3.2 billion. (Interestingly, in 2004, CAPEX spending was only 5.3% of sales.) PAT technology could become a key enabler to move from batch to continuous manufacturing, in which materials are modified and tested continuously to minimize delays in movement from start to finish during the process. Assuming no change in production volumes, continuous manufacturing requires significantly less square footage and equipment.
Continuous manufacturing would therefore enable companies to manufacture the same amount of product in smaller factories, or manufacture far more product in existing facilities. Because CAPEX is correlated with square footage, CAPEX would also be expected to go down. For each of the top ten pharmaceutical companies a 50% reduction in CAPEX would translate into an average savings range of $0.8 to $1.6 billion per year.
On-line and at-line testing could also reduce production cycle time. Reduced production cycle times would, in turn, decrease inventory in the system and save inventory carrying costs, which average $76 million for each of the top ten pharmaceutical companies. In addition, breakthrough improvements in drug development that improved process understanding can greatly reduce time to market, resulting in far greater return on investment through longer patent protection and first-to-market advantage.