Op Ex & Lean Six Sigma / QRM Process

Therapeutic Dose: Ready, Aim, Aim, Aim…

Risk management in the 21st century: We have the tools, but do we have the will?

By Emil W. Ciurczak, Contributing Editor

I have a dear friend who has been out of the pharmaceutical industry for over five years. While in the industry, she had done remarkable things with NIR spectroscopy. She recently saw a major company whose representative was quoted in this very magazine, discussing plans to begin using NIR for raw materials. Her comment? “And I thought I was out of the loop.”

I am fond of pointing out that NIR was being used for 100% of incoming raw materials by Sandoz in 1985! And that included “quality” (particle size, moisture, etc.) in a container-wise fashion, as per EMEA guidelines. Now 23 years later, numerous U.S. and foreign-based companies are just “considering” using NIR for raw materials.

That reminds me of a quote: “Nothing is ever done until everyone is convinced it ought to be done and has been convinced for so long that now it is time to do something else.” [1] This either harkens back to my earliest columns in this magazine about communication failures or is the ultimate tribute to inertia in the industry. My Lord, even FDA has been publishing work using NIR for years now. How much more hidebound can you get? When the very regulators we are afraid of offending are already using a technique, it should be a clear signal.

I have also heard that whatever can be misunderstood already has been misunderstood. You see, I was listening to some table conversations at the last IFPAC meeting. A couple of the people were discussing “risk management,” and they didn’t think their managers would allow them to participate in anything with the word “risk” attached. I don’t think they read the document published by FDA, or understand what risk analysis is in their daily lives.

So what does the document really mean? It simply states that all processes have a risk of failing the product. Any part of a pharmaceutical production process can cause a product to be ineffectual. There could be too much moisture, leading to an early stability recall. There could be an incorrect polymorph, causing an improper dissolution pattern. What about the physical and chemical characteristics of all the raw materials (see the first paragraph) as well as the API? Whoa! Not too much knowledge all at once!

While I am putting a well-written document into simple words, I think I will capture its essence (as well as Q8 and Q10). The three steps are simply:

  1. What might go wrong?
  2. What is the likelihood (probability) that it will go wrong?
  3. What are the consequences (severity)?

More formally, these steps are named risk identification, risk analysis, and risk evaluation. The identification process might include a Design of Experiment (DoE), showing what actually affects the production of some product. This multivariate approach is made easier by the plethora of software now available.

Risk analysis involves estimating the risk associated with the DoE-identified hazards. “It is the qualitative or quantitative process of linking the likelihood of occurrence and severity of harms. In some risk management tools, the ability to detect the harm (detectability) also factors in the estimation of risk.” [2]

Risk evaluation means assessing the consequence of something happening. If an aspirin tablet is made too hard, what is the consequence? [Aspirin with 99+ % pure API will immediately disintegrate, no matter how hard it is made.] Too much pressure, however, could mean heat and possible degradation. Therefore, checking for produced salicylic acid is better than the traditional hardness check, unless some verified multivariate work of hardness versus API breakdown has been performed.

Thus, using PAT techniques to monitor the Critical-to-Quality parameters becomes the best way to mitigate risk to the product, and hence to the patient. Monitoring many of the dosage units and having a science-based program of feedback and feed forward (hmm, PAT leading to QbD, what a notion) will minimize the risk of a bad product. Now, how many years will it take before this little bit of information is accepted? Me? I have a firm grasp of the painfully obvious. The others? I’m not so sure.

References
  1. F.M. Cornford, in Microcosmographia Academica, 1 (1908).
  2. Q9 Quality Risk Management, USFDA Guidance for Industry, June 2006

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