Evaluation of the Warning Letters issued by the FDA for the Fiscal Year 2010 with regard to Risk Management

The finalisation of the ICH Guidance Q9 "Quality Risk Management" has led to an integration process into the national pharmaceutical regulations of the Triad (USA, EU and Japan). Because of this integration the Quality Risk Management has become a significant topic for inspections.

What do inspectors have to object to in regard to Quality Risk Management?

There is sporadic advice on what inspectors pay attention to. A WHO paper about Risk Management provides a checklist on inspections for such systems (see our GMP News from 23 September 2010). In a Question and Answer document of the MHRA you can also find some information (see our GMP News from 15 September 2010). You can also use the FDA Warning Letters as an information source. In the following, you will find some excerpts taken from the Warning Letters issued during the fiscal year 2010 (October 2009 - September 2010), see also our GMP News from 17 February 2011.

"Your firm has not thoroughly investigated the failure of a batch or any of its components to meet its specifications whether or not the batch has already been distributed, nor has your firm extended investigations to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy [21 C.F.R. § 211.192]. For example:
a. Your firm did not thoroughly investigate particulate contamination found in lot […] of […] injection. This particulate contamination ranged in size from less than 0.5 to 5 mm for vials and less than 0.2 to 8 mm for syringes. During a second inspection, particulate contamination was discovered in a syringe sample. Despite this finding, your firm did not re-inspect the remainder of the syringe sub-lot or the vial sub-lot. In addition, your firm did not conduct a formal risk assessment of the particulate contamination found in the drug product and its possible impact on product quality."

"Your firm has not rejected drug products failing to meet established standards or specifications and any other relevant quality control criteria [21 CFR 211.165(f)] For example...In addition, we note that the dissolution results using the new method are approximately […] higher than previous results or the same lots using the inappropriate method. You have … not provided your risk analysis of the lots that were analyzed with the current method, or your determination of the acceptability of product analyzed using the former apparently inappropriate method."

"Your firm has not established separate or defined areas or such other control systems as necessary to prevent contamination or mix-ups during aseptic processing. [21 C.F.R. § 211.42(c)]. For example,
a) Your firm lacked an adequate assessment of the cross-contamination risks posed by the manufacture of several potentially hazardous compounds (e.g., beta lactam antibiotic and steroid products) at your facility. Deficiencies were observed in the shared manufacturing areas where you manufacture potentially hazardous compounds and sterile ophthalmic drug products intended for the U.S. market. You should ensure that a documented justification and a well-designed contamination prevention strategy has been put in place to minimize the possibility of contamination. FDA encourages sound risk assessment approaches to address hazard identification, exposure consequences, and implement controls designed to prevent and detect cross-contamination. To achieve an acceptable level of risk requires sound and risk-based assurance that one drug does not contaminate another drug."

Conclusion: The Risk Management topic has become more present in the FDA Warning Letters. But we can notice that the Warning Letters of fiscal year 2010 mainly focused on Risk Analysis/Observation. However, the topics focused on in the cases of Risk Analysis/Observation are not only concentrated on Validation/Qualification anymore, like in the past.   

Sven Pommeranz
CONCEPT HEIDELBERG (a service provider entrusted by the ECA Foundation)

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