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Cross Contamination Control in Shared Facilities and Equipment. Reflection on common deficiencies and expectations as seen in recent PIC/S guidance.

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During this period where MHRA has been conducting predominantly remote inspections, we have reflected on some of the common factors in critical deficiencies we have been seeing in control strategies for cross contamination between products in shared facilities. Requirements and expectations have been refreshed with Inspectors with a particular focus of attention on sites handling products with lower level Health Based Exposure Levels (HBELs), those with products around the red area of the continuum seen in the PIC/S Q&A document,

Question Mark

As a result, we would make Industry aware of the following elements of their control strategy that they should ensure they are addressing:

Health Based Exposure Limits (HBELs) completed for all products by experienced professional Toxicologists

So what is going wrong?

HBELs are being generated by company personnel without adequate and appropriate experience in developing HBELs. Q4 in the PIC/S Q&A document explains the expectations. It is important that HBEL values are of the appropriate magnitude to ensure cross contamination control strategies are establish based on the relevant hazard level, this can only be achieved by personnel with extensive relevant toxicology knowledge and experience.

The HBEL value and hazard knowledge should be used to set the context and the reference for conducting Quality Risk Management development of Organisational and Technical controls

So what is going wrong?

Many companies are conducting risk assessments without any reference to the HBEL level they are required to control to. Risk assessments are thus conducted without consideration of the magnitude and nature of the hazards they are trying to control so are unlikely to be effective. The only use that some companies are making of HBEL is to set cleaning validation acceptance criteria.

As described in Q3 in the above PIC/S Q&A, input to a Quality Risk Management study to develop Organisational and Technical controls (or critically assess existing controls) is a key use of the Health Based Exposure Limit studies. Risk Management requires a focus and a perspective as well as knowledge and data. QRM is a team activity and all team members should be clear on what level of residue they are trying to control at both batch and unit dose levels – the HBEL allows this context to be established. Pictorial representation of these critical HBEL values may be helpful, and patient safety should be a core focus to control risks of failure through design of controls and minimisation of human error. Critical control points should be established, these may include key parts of equipment to dismantle, retention points of contamination, primary control/containment systems. QRM team members may have inherently different risk perception and acceptance so expectations of how the risk is assessed and controlled should be clearly defined in a documented process.

Sole reliance on visual inspection for cleanliness at changeover between products following cleaning validation should only be made when there is clear and safe evidence that residues can be consistently and readily seen at the acceptance criteria level.

So what is going wrong?

Having completed basic cleaning validation many companies are ceasing analytical testing at product changeover and applying a visual inspection only. In some cases, the allowable residue limits that safely meet HBEL cannot be seen at the visual threshold of the product contaminant. As a result, there is no discerning test of success of the cleaning activity post validation. Where manual cleaning is used, this is a high-risk strategy that has been found to be unjustifiable in some manufacturers. Visual inspection is always regarded as a minimum requirement for confirmation of cleaning but Q7 and Q8 in the PIC/S Q&A describe circumstances where sole reliance may be placed on visual inspection.

Manufacturers should ensure compliance with cross contamination control requirements and consult the PIC/S Q&A for further clarification of expectations. Manufacturers should also consider if their cleaning validation can truly be considered reproducible and consistent, particularly where manual cleaning is conducted.

Regulatory action has been required as a result of failures at several sites in the last year, so don’t be caught out and reassess your controls.


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1 comment

  1. Comment by Vijay Patil posted on

    Nicely explained the problems in Cleaning validation with solutions!