21 CFR 211.192 Production Record Review

“The USP has established that the acceptable range of most compounded preparations is typically ±10%; however, it can be as great as ±20% (as with some proteins) or as tight as ±5% (as with potent analgesics). For some raw powders, potency is required to be within ±2%”, (Kupiec, 2005, p. 136; Rooney & Heuvel, 2004).

In addition 211.192 requires review and approval of all production records prior to batch release/distribution and any unexplained discrepancy (including a percentage of theoretical yield exceeding the maximum or minimum percentages established in master production and control records) or the failure of a batch or any of its components to meet any of its specifications shall be thoroughly investigated.  211.192 is included in the Draft FDA Guidance for Industry, cGMPs – Interim guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act.

However, USFDA inspection results from a recent compounding laboratory identified an example of 37 lots of products that were released prior to receiving potency results.  When the potency results were obtained, as identified in the Form 483, the potencies ranged from a low of 0% potency (Epinephrine) to a high of 207.9% for (Morphine Sulfate).

Potency variation also existed within a specific product.  For example, in the Form 483 9-lots of Midazolam were released with potency variations of 7.1, 27.6, 33.8, 34.7, 37.7, 44.2, 55.7, 68.4, and 120.9%.  Given the observed variation in potency, it does not seem probable that this can be assigned to a common cause (a chance, or natural pattern) variation, but rather a special cause (assignable to one or more specific causes).  Per the USP monograph, Midazolam injection is required to have a potency of not less than 90.0 nor more than 110.0% of the labeled amount of Midazolam (United States Pharmacopeial Convention, 2015).

As reported in the Form 483 the compounding facility did not conduct an investigation into the out of specification test results.  With no investigation performed, we can assume the root cause for the variation was not identified and no corrective action was implemented.  Thus, the facility may continue to compound products that are out of specification for potency.

This is a great example to illustrate how a commonly used quality tool, the Ishakawa or Fishbone diagram and the 6M practices may be used to help identify the cause of the variation, and thus allow implementation of controls to mitigate these special causes of variation and place the compounding process in a better state of control.  The 6M methods provides a starting point for the user to evaluate the cause-and-effect.  6M addresses issues such as manpower, machinery, materials, methods, mother nature (the manufacturing /storage environment), and measurement.  Guidance on how to conduct root cause analysis is available from many sources for example the American Society for Quality, Rooney and Heuvel (2004) , or Juran and Godfrey (1999).

Example Ishakawa Diagram with the 6M categories and a few primary causes identified:

Ishawaka Diagram 503B

Using the Ishakawa diagram and the 6M principles the special cause(s) of variation, the root causes can be identified, and mitigations can be implemented to correct or control the variation.  The end result that there are fewer instances of out of specification product in the market place.  Reducing special cause variation will:

  • Reduce cost, fewer product recalls, less waste, less replacement product, minimize litigation
  • Improve sustainability, better utilization of raw materials, and organizational resources
  • Improve brand perception

Does your organization use root cause analysis? If not/ why not?

Juran, J. M., & Godfrey, A. B. (1999). Juran’s quality handbook (5th ed.). London: McGraw-Hill.
Kupiec, T. (2005). Quality-Control Analytical Methods: Checmical Testing Aspects of USP Chapter <797> for Compounded Sterile Preparations. International Journal of Pharmaceutical Compounding, 9(2), 136-138.
Rooney, J. J., & Heuvel, L. N. V. (2004). Root cause analysis for beginners. Quality Progress, 37(7), 45-56.
United States Pharmacopeial Convention. (2015). USP 38-NF33. Rockville, Md: United States Pharmacopeial.

Previous 21 CFR 211.42 – Buildings and Facilities
Next Data Integrity Warning Letter Summary – August 2018