A 2006 Georgetown University Report on Pharmaceutical Manufacturing stated, “If the FDA could change the way it regulated . . . the industry could save 10% to 50% of the cost of goods sold.” Well, the FDA has changed, most recently with its revised Process Validation guidance, which embodies modern concepts such as product lifecycle, Quality by Design, risk-based approaches and statistical process control.

Most impressive is how FDA has clearly defined the three major production lifecycle areas and integrated current risk- and science-based approaches. The three stages focus on:

1. designing the process itself
2. proving the process works
3. monitoring the process, to verify that it is well understood and that one can continually learn from it via “continued process verification.”

The major difference from previous guidance (circa 1987) is that the technical expectations for Stages 1, 2 and 3 are now more clearly delineated—there is far less ambiguity in what the Agency expects. There are other significant differences as well. Two of the most important are that worst-case testing during the qualification lots is not necessarily expected, and the term revalidation is not used.

Fit for Everyone

How much does the new guidance raise the bar? And just as importantly, does it raise it out of reach for small companies?

The expectation for Stage 1, Process Design, is to employ principles of Quality by Design and the Design Space—that is, to use lab- and pilot-scale testing to gather data, and set the permissible operating ranges for the process.

Every quality manufacturer wants to know why its process runs where it does. This requires that scientists document their work, following good documentation practices. It requires solid technical reports describing why the process operates where documents say it should, and also provides a way of keeping track of these reports. These are basic, fundamental expectations, and well within reach of even the smallest company that wants to manufacture drugs.

Stage 2, Process Qualification, is largely the same as practiced today, and perhaps less cumbersome than before since it formally removes the need for commercial-scale worst-case testing if sufficient process data are available. A key change is that while industry largely relies on three qualification lots to prove the process, the FDA is focusing on the data, not the number of lots. For a robust, well characterized process with a good clinical manufacturing history, this could mean fewer than three lots. Conversely, if the data is less compelling, more than three lots will be needed to prove its performance.

With Stage 3, Continued Process Verification, a firm should identify what to monitor, and why it’s being monitored—for example, it’s a high risk or critical process parameter. The firm then tracks and statistically analyzes the data in a formal program for monitoring the process. Other industries call this Statistical Process Control. It will require identifying what you need to monitor, gathering the data and analyzing it. SPC methods are well within reach of any manufacturing company.

Dealing with Risk

The concepts outlined in the revised guidance embrace a risk-based approach, which is not surprising, given what we have been hearing from the FDA in recent years (e.g. FDA Guidance for Industry - Q9 Quality Risk Management). Yet it’s been said that doing an in-depth risk-analysis might take longer than just doing all the work in the first place.

The beauty of risk analysis is that it forces one to employ structured thinking. Identify what could go wrong, how it can go wrong and what the impact is to product quality and patient safety. Once risk analysis is well understood, and done properly (for example, with process experts), it’s really not difficult. ICH Q9 lists several structured risk analysis methods, and the guidance spells out clearly what to work on and why, focusing attention on the more important issues. As the saying goes, “Anything is possible, but not everything is equally probable.” Risk analysis allows one to spend your resources on the likely problems.

True risk analysis was formally introduced to our industry just a couple of years ago, so this is still relatively new territory for pharma. A period of confusion and adjustment is to be expected, but the best preparation is to study simple risk assessment methods such as Preliminary Hazard Analysis and Fail Modes and Effects Analysis.

Statistical Challenges

The guidance makes a point of clearly referencing a number of CFR’s which require statistics. For example, the revision states, “The data should be statistically trended and reviewed by trained personnel.” Such statements requiring a knowledge of statistical process control are consistent with employing better science. Will the increased emphasis on statistics be too much for some companies?

When the FDA makes statements such as, “Procedures should guard against overreaction,” it indicates that they have a solid understanding of the realities of SPC—that firms should avoid the temptation to overadjust processes. Most engineering and many life science degree programs have statistics as a core course, so there is already a good knowledge base in industry. Some firms may supplement that training with additional in-house statistics courses. While not every company can afford that, there are many continuing education courses as well as service providers available to bolster the use of statistics. The American Association for Quality (ASQ.org) is an excellent resource.

Hence, it really shouldn’t be a challenge.

Process Monitoring