cGMPs and Statistics

FDA’s Rick Friedman and Karthik Iyer explain why some manufacturers need to get a better grip on GMP-related statistics.

By Agnes Shanley, Editor in Chief

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Statistics are critical to the pharmaceutical industry, from clinical operations through manufacturing. However, clinical and manufacturing statistics represent entirely different worlds. Where they might be well staffed on the clinical side, some pharmaceutical companies today aren’t hiring qualified staff to analyze operations data, resulting in misapplied tools, inadequate CAPAs and superficial root cause analysis, all of which lead to financial loss and noncompliance.

Few people have analyzed these trends more closely than staffers at FDA’s Office of Compliance, which must examine problem cases where inspectors have found inadequate compliance with CGMP. 

Rick Friedman FDA
Rick Friedman

In a recent interview, Rick Friedman, Associate Director, and Karthik Iyer, statistician and Senior Policy Advisor at CDER’s Office of Manufacturing and Product Quality, now part of FDA’s Compliance super office, discussed problem areas and areas where pharma might learn from the way other industries use statistics.

Representative of a new breed of regulatory professional at FDA, Iyer, who has been with the Agency for two years, has a B.S. in chemical engineering and an MBA, is certified by the American Society of Quality as a Quality Engineer and Six Sigma Black Belt, and spent over 11 years in the chemicals, refining and consumer products industries. 

These industries, he says, use standardized methods to analyze root cause and have an understanding of the cost of poor quality. Below is an excerpt from that interview.

PhM: Looking at 483s and inspection notes of the past few years, we continue to see inadequate CAPA and root cause analysis. How can this situation be improved?

R.F.: Companies should assess the effectiveness of their CAPA systems. The C in CAPA (Corrective and Preventative Action) means that the company is reacting to a problem, the P means that it has seen signals of an emerging problem and has acted in a preventive way to avoid the risk.

In pharmaceutical manufacturing today, there is still a lot more C going on than P. For a CAPA program to be truly mature, the company involved must have implemented a system that really does look at the root causes of problems, and does not assume that the root cause is restricted to the product that may have failed on the line that day. Other products may share the common root cause problem. 

Even though industry professionals know what CAPA is, generally its practitioners within individual companies are not always the more experienced quality and production people, and in some cases, they’re not always scientifically qualified to get to the true root cause of failures. As a result, some investigations end up being superficial and problems remain there, latently, until they show up later as causes of excessive variability, further batch failures, unexpected delays or shortages, and all these can lead to financial losses. 

[Philip B.] Crosby is famous for saying that quality is free. This is because a QA-oriented system allows an organization to prevent problems that are often very costly. If you’re merely reacting, you can’t assure the two essential objectives of any manufacturing operation: consistent product quality and customer supply.

PhM: Are there any lessons in determining root cause that pharma could learn from the petroleum and chemicals industries?

K.I.: Basic unit operations in the refining and chemicals industries have remained virtually unchanged since the 1920s and 1930s. In these industries, which use and produce dangerous chemicals, improvements have focused primarily on worker safety, with OSHA putting a microscope on chemical and refinery workplace safety practices, and EPA looking closely at environmental safety practices. Because they are also highly competitive commodity markets, product quality also became a key differentiator.

Karthik Iyer FDA
Karthik Iyer

In petrochemicals and chemicals, safety concepts combined with the quality concepts advanced by Deming and Juran and merged into one, so the concept of CAPA is more robust in those industries. When chemical and petrochemical companies do an investigation, they use the same approach to determine the root causes of safety and quality problems, resulting in fairly robust processes. No matter what type of incident is reported to EPA and  OSHA, regulators look to see whether a formal process has been set up or whether a proven methodology is being used. For example, two companies that I used to work for used a detailed investigative methodology that a third party private company created but a lot of chemical and petroleum companies use. The software package  included a system to analyze root cause, offering structured methodology that is consistent, standardized, and calibrated across industries. So proven standardized root cause analysis methods do exist for manufacturing. 

R.F.: In this case, regulatory attention from EPA and OSHA helped accelerate the realization by petrochemical and chemical companies that improving root cause analysis was important for both safety and business reasons.  For the drug industry today, a credible surveillance and enforcement presence that focuses on the effectiveness of a company’s systems to analyze and resolve manufacturing problems has never been more critical to effectively regulate in a complex global environment.

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