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Providing regulators with a holistic approach to addressing deficiencies is the best response to an inspection, says Siegfried Schmitt, PhD, vice-president, technical, Parexel Consulting.
Q. A recent inspection of our facility resulted in several observations, including insufficient hand sanitization by personnel in the sterile filling area, deficient gowning in the microbiology laboratory, and use of wooden pallets in the cold storage area. Before concluding, the inspectors told us that they want us to address these deficiencies holistically. Can you give some advice on how to do this?
A. It is correct that all too often, companies address each and every inspection observation individually, rather than address fundamental flaws or gaps in the systems, processes, or organizations. The regulators want the industry to find the true root causes for their compliance lapses. This is why your inspectors want to see the issues they identified addressed holistically. For example, they want you to clearly identify the functional relationship between the parts that lead up to a compliant operation and the whole.
Looking at the examples you cite, it seems that you would be best served by preparing a contamination control strategy (CCS). Control strategies are an increasing requirement in the European Union good manufacturing practice regulations (EU GMPs) and expected to be referenced in the next revision of EU GMP Annex 1 (1). The draft text, which is likely to be adopted in the final version, reads:
‘Quality assurance is particularly important, and manufacture of sterile products must strictly follow carefully established and validated methods of manufacture and control. A contamination control strategy should be implemented across the facility in order to assess the effectiveness of all the control and monitoring measures employed. This assessment should lead to corrective and preventative actions being taken as necessary. The strategy should consider all aspects of contamination control and its life cycle with ongoing and periodic review and update of the strategy as appropriate.’
In your case, the CCS should consider all the integral elements of sterile product manufacturing, including quality risk management (QRM) principles and supporting risk assessments for contamination control and monitoring (detectability of contamination event) (2). How should or could you develop this CCS? First, you need a complete process flow description of all materials and personnel. This will allow you to identify points of critical risk of contamination and points of inherent risk of contamination.
If we take the examples provided by your inspectors, you will need to identify where there is a risk for contamination (e.g., the operators) and how you control this risk of contamination (e.g., gowning and barriers, such as isolators and disinfection). Next, you need to determine whether these control measures (individually and as a whole) are sufficient to reduce the risk to an acceptable level. For example, is hand sanitization performed often and sufficiently, and is the procedure following industry best practices (3)? Are your personnel suitably trained and are they following the prescribed procedure? Have you collected sufficient data (e.g., from swabs and dabs) that prove the efficiency of the sanitizing regime? Once you have performed this risk assessment, you will have sufficient information and data to understand, whether:
If not, you should be able to immediately identify corrective action and preventive action (CAPA) measures to reduce the risks to an acceptable level.
The CCS will bring all these assessments together and provide a holistic view of your approach to contamination control. The CCS is not only needed for responding to the inspection observations, it is an essential document for any pharmaceutical operation and, in particular, for sterile manufacturing ones.
1. EC, Annex 1, Manufacture of Sterile Medicinal Products, December 2017,
2. PHSS, Control Strategy in Manufacture of Sterile Pharmaceutical/
Drug Products, Whitepaper.
3. CDC, Morbidity and Mortality Weekly Report, 51 (RR-16), Oct. 25, 2002.
Vol. 4,2 No. 9
Pages: 50, 49
When referring to this article, please cite it as S. Schmitt, "Developing an Effective Contamination Control Strategy," BioPharm International 43 (9) 2019.