The handling and examination of nonconformances and deviations is becoming more and more important to the pharmaceutical industry,
primarily for two reasons. Firstly, the ongoing modernisation of pharmaceutical quality management systems has made the industry
recognise the value and benefit of "failure" detection and CAPA (Corrective and Preventive Action). Continuous process improvement
tools have a long and successful history, especially in the automotive industry, and these are now being adopted and implemented
in the pharmaceutical industry. Applied properly, nonconformances can be prevented and processes can be continuously improved.
Secondly, the regulatory requirements and expectations of government agencies worldwide have continued to increase in recent
years. In November 2009, for example, the UK Medicines and Healthcare Products Regulatory Agency (MHRA) published a "Deficiency
Data Review"1 for the period April 2008 to March 2009, in which it cited "anomalies" as their most frequent observation of regulatory
deviations, with nonconformances and deviations in conjunction with CAPA being the third most common observation. This is
similar to the findings of the recently published FDA Warning Letters Report from the European Compliance Academy (ECA).2 Here, the deficiencies in the "Production Record Review" (21 CFR 211.192) are among the most frequently reported GMP deviations.
According to the report, more production record review deviations were observed in 2009 than in any other years and, on closer
examination, most of the objections applied to the poor handling of deviations and incorrect CAPAs. In most cases, the companies
did actually detect the deviations themselves, but did not properly examine them and did not define appropriate corrective
and preventive actions. So what went wrong?
Industry's common failings
It seems that one of the biggest challenges for companies is to complete investigations and actions in a timely manner. In
many cases, incorrect assumptions are made that everything is an isolated incident. In other instances, problems are not corrected
and everything is blamed on a single employee or a simple laboratory error, or the system fails to ensure that a problem does
not extend to other lots, and the incident recurs. The ultimate criterion for adequate correction is to ensure that it doesn't
CAPA was adopted as a new quality management tool following the introduction of the ICH Q10 guideline. According to the ICH
Q10 document, which was adopted by the FDA in April 2009 as an industry guideline, a pharmaceutical Quality Management System
(QMS) consists of four central elements:
- process performance and product quality monitoring
- corrective action and preventive actions
- management review of process performance and product quality.
The guideline states that a pharmaceutical company should have a system in place to detect and evaluate nonconformances to
take respective corrective and preventive actions. Among other things, the information regarding nonconformances can result
from complaints, deviations, recalls, observations at audits and inspections, or from monitoring findings. The examinations
within the system must have the objective of determining the actual root cause. As a result, the process and product should
be better understood so that improvements can be derived from it.
The EU Commission has now published a suggestion for the revision of chapter 1 of the EU GMP Guide to incorporate the recommendations
of ICH Q10. Now, specific requirements for a CAPA system shall be included. A comprehensive description can be found in section
1.8 items 7, 8 and 9, in conjunction with the requirements for quality risk management systems according to ICH Q9 (identical
to annex 20 of the EU GMP Guide). Accordingly, the extent of the actions, technical complexity and documentation of the necessary
CAPA actions have to be managed according to a risk assessment. In doing so, it will become more and more important to fulfil
these requirements and expectations quickly and smoothly, whilst keeping an eye on the economical and operational situation.
However, neither of the above documents provides precise instructions on how to operate an efficient CAPA system. In this
scenario, a 2009 proposed guidance on the Global Harmonisation Task Force (GHTF), titled "Quality management system — Medical
Devices — Guidance on corrective action and preventive action and related QMS processes", might offer assistance. Within this
guidance, the CAPA system is described as an integral part of a QMS and is divided into four phases (Figure 1). Although suggested for medical device manufacturers, this document also provides comprehensive guidance on how a pharmaceutical
company could implement a functioning CAPA system.