News about GMP/cGMP


MHRA inspections: Deficiencies and expectations on HBELs and cross contaminations – PIC/S AiM and Q&A provide answers

On its Inspectorate Blog, the UK MHRA (Medicines and Healthcare products Regulatory Agency) has critically reviewed the implementation of the requirements on HBELs and the prevention of cross contamination in shared facilities. What are the expectations to be met and what deficiencies have been identified in recent inspections?

According to the MHRA Inspectorate Blog, answers can be found in these two PIC/S documents:

The two documents were published in June 2020 (we reported).  They address the requirements for setting health-based exposure limits (HBELs) and quality risk assessment to control cross contamination. Through this blog, pharmaceutical manufacturers are now to be made aware of critical deficiencies that arose during recent remote inspections. These are directly linked to the expectations described in the PIC/S documents.  

Here are some shortcomings that occurred during MHRA inspections:

Reference: PIC/S Q&A 3:
It was noticed that companies conducted risk assessments without reference to the required HBEL levels, required to control. Often the HBELs are only used to establish acceptance criteria for cleaning validation. However, HBELs reflect the relationship between residue levels at both batch and unit dose level needing to be controlled. The MHRA proposes a pictorial representation of critical HBELs as well as a clearly defined documented process.  

Reference: PIC/S Q&A 4:
It is noticeable that although all HBELs have been completed within the company, they were generated by employees without the necessary experience and without toxicological expertise. The PIC/S Q&A question 4 clarifies the expectations on the qualification of the personnel.

Reference: PIC/S Q&A 7 and 8:
It was noticed that with product changeover in a shared facility, analytical testing is often omitted. Instead, only visual checks are carried out. This visual control during product change is usually not sufficient to detect product contamination and to safely maintain the HBEL. Especially in case of manual cleaning, this is a high-risk procedure. The PIC/S HBEL Q&A describes situations where a visual control is sufficient in questions 7 and 8.

The MHRA refers pharmaceutical manufacturers to the PIC/S documents in order to clarify the requirements to control cross contamination.  It should be critically examined whether the current cleaning validation used in a company is really reproducible and consistent, especially when performing manual cleaning. In the past year there have been violations in several companies which required actions.


MHRA: Inspectorate Blog