Environmental contamination results from the ingress of contaminants from the surrounding production areas or even from outside environments
Cross-contamination is defined as contamination of a starting material, intermediate product or finished product with another starting material or product during production.
Whether performing risk assessments or impact assessments there are six factors to consider in order to determine environmental impact and to inform contamination control.
Amenability of equipment and surfaces to cleaning and sanitization
Personnel presence and flow
Material flow
Proximity to open product or exposed direct product-contact material
Interventions/operations by personnel and their complexity
Maybe you’ve been there too, you need to take a risk-based approach to determine environmental monitoring, so you go to a HAACP or FMEA and realize those tools just do not work to provide information to determine how to distribute monitoring to best verify that processes are operating under control.
What you want to do is build a heat map showing the relative probability of contamination in a defined area or room| covering six areas:
Amenability of equipment and surfaces to cleaning and sanitization
Personnel presence and flow
Material flow
Proximity to open product or exposed direct product-contact material
Interventions/operations by personnel and their complexity
Frequency of interventions/process operations.
This approach builds off of the design activities and is part of a set of living risk assessments that inform the environmental monitoring part of your contamination control strategy.
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U.S. Food & Drug Administration, Code of Federal Regulation Title 21, part 211 current good manufacturing practice for finished pharmaceuticals, Subpart D – Equipment, sec.211.67 Equipment cleaning and maintenance (a)
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The FDA recently released a Form 483 it handed to Catalent Belgium following an inspection of its 265,000 square-foot facility in Brussels in October 2021. Catalent is a pretty sizable entity, so it is very valuable to see what we can learn from their observations.
Failure to adequately assess an unexplained discrepancy or deviation
“Standard Operating Procedure STB-QA-0010, Deviation Management, v21 classifies deviations as minor, major or critical based on the calculation of a risk priority number, with a HEPA filter failure within a Grade A environment often classified as minor. Specifically, Deviation 327567 (Date of occurrence 04 March 2021) was for a HEPA filter failure on the <redacted> fill line, with a breach at the HEPA filter frame.”
This one is more common than it should be. I’ve recently written about categorization and criticality of events. I want to stress the term potential when addressing impact in the classification of events.
Control barriers exist for a reason. You breach that control barrier in any way, you have the potential to impact product or environment. It is really easy for experienced SMEs to say “But this has never had any real impact before” and then downgrade the deviation classification. Before long it becomes the norm that HEPA filter failures are minor because they never have impact. And then one does. Then there are shortages or worse.
It is important to avoid that complacency and treat each and every control barrier failure to the same level of investigation based on their potentiality to impact.
The other problem here is failure to identify trends and deal with them. I can honestly say that the last thing I ever want anyone, especially an inspector, to write about something where I have quality oversight is a failure to investigate multiple control barrier events.
“Other GMP manufacturing areas have a similar elevated level of HEPA filter failures, with the root cause of the HEPA filter failures unknown. There is no CAPA in support of correction action. Your firm failed to ensure your investigations identify appropriate root causes and you failed to implement sustainable corrective action and preventive action (CAPA).“
Contamination Control function
Observation 2 and 3 are doozies, but there is probably a lack of expertise involved here. The site is using out-of-date and inadequate methods in their validation. Hire a strong contamination control expert and leverage them. Build expertise in the organization through a robust training program. Connect this to all relevant quality systems/processes.
Corrective Maintenance and Troubleshooting
“Equipment and facilities used in the manufacture of drug product are not adequately maintained or appropriately designed to facilitate operations for their intended use.“
This is starting to feel a lot like my upcoming presentation at the 2022 ISPE Aseptic Conference where I will be speaking on “Contamination Control, Risk and the Quality Management System”
“Contamination Control is a fairly wide term used to mean “getting microbiologists out of the lab” and involved in risk management and the quality management system. This presentation will evaluate best practices in building a contamination control strategy and ensuring its use throughout the quality system. Leveraging a House of Quality approach, participants will learn how to: Create targeted/ risk based measures of contamination avoidance; Implement Key performance indicators to assess status of contamination control; and ensure a defined strategy for deviation management (investigations), CAPA and change management.”
Microbiologists won’t be sequestered in the laboratory, running samples and conducting environmental testing, once the revisions proposed for Annex 1 of the EU and Pharmaceutical Inspection Cooperation Scheme (PIC/S) GMP guides take effect, Annex 1 rapporteur Andrew Hopkins said Oct. 15.
They will have a broader role that includes conducting risk assessments to ensure that sterile products are made as contamination-free as possible, said Hopkins, who is an inspector for the UK Medicines and Healthcare products Regulatory Agency.
Contamination Control is a fairly wide term used to mean “getting microbiologists out of the lab” and involved in risk management and compliance. Our organization splits that function off from the QC Microbiology organization but there are many models for making it work.
Risk Management is a major part of the new Annex 1, and what they are driving at are good risk assessments with good risk mitigation that involve the microbiologists.
Targeted/ risk based measures of contamination avoidance
Key performance indicators to assess status of contamination control
A defined strategy for deviation management (investigations) and CAPA
When it comes to change management, one of the easiest places to go wrong is to forget to bring the microbiologist in to changes. Based on your strategy you can determine change changes require their assessment and include it in the tool utilized to determine SMEs, for example:
Department
Required if the change meets any of the following criteria:
Contamination Control
The change impacts environment integrity, conditions or monitoring, including:
Changes to a controlled room or area that impact integrity
Changes in sampling methodology
Construction activities
Changes in personnel or material flow
The change will result in or modify exposure of product to the environment.
The change can impact microbiological control within a process stream, raw material or process equipment
Investigations of a Dog 