It has now been 10 years since the last revision of Chapters 3 and 5 of the GMP Guidelines came into force. One of the main objectives of that update was to align its content with the “Guideline on setting health-based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities” published by the EMA. This revision marked a shift in the approach to cross-contamination control, moving towards a strategy based on the toxicological evaluation of active substances and the application of risk management principles. As a result, it became necessary to implement a Cross-Contamination Risk Assessment (CCRA) supported by Permitted Daily Exposure (PDE) values, as well as to adapt cleaning validation strategies to align them with toxicologically justified limits.
A living document, not a one-time requirement
The CCRA should be understood as a living process. GMP guidelines state that it must be updated whenever relevant changes occur, such as:
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Introduction of new products or active pharmaceutical ingredients.
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Modifications to facilities or equipment.
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Changes in the manufacturing process.
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Review of toxicological data or replacement of PDE reports.
According to Chapter 5 of the GMP guidelines, the risk management process must consider the pharmacological and toxicological activity of the products, along with key aspects such as facility design, personnel and material flows, product and active substance characteristics, cleaning processes, and the analytical capability to detect residues.
Is it necessary to dedicate facilities for the manufacture of sensitizing or highly toxic products?
One of the key advantages of the risk-based approach is that the use of dedicated facilities is not mandatory by default. It should only be required when the risk of cross-contamination cannot be adequately controlled through technical and organizational measures.
These measures may include, among others:
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Physical containment and segregation procedures (physical and/or temporal).
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Segregated personnel and material flows.
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Validated cleaning procedures with PDE-based limits.
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Evaluation of equipment design and HVAC systems.
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Specific training and qualification of personnel.
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Sampling and inspection strategies.
In fact, both the GMP guidelines and the EMA guidance emphasize that when such measures are robust, well-implemented, and properly documented, operating in shared facilities is possible without compromising product or patient safety.
The Link Between CCRA and Cleaning Validation: A Common Strategy Based on PDE
One of the key elements derived from the implementation of the CCRA is the need to adapt the cleaning validation strategy to the principles of the risk-based approach. In this regard, residue acceptance limits should be established using the PDE values defined for each active substance, rather than traditional, less precise (and scientifically unsupported) methods, such as 1/1000 of the therapeutic dose or 10 ppm.
This methodological change allows for:
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A more realistic and safer evaluation of the exposure risk to the patient.
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Alignment between the results of the CCRA and the cleaning validation criteria.
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The possibility to design more efficient, justified, and scientifically grounded cleaning strategies.
Moreover, a robust and well-documented cleaning validation is one of the key technical measures that can be used to demonstrate that the risk of cross-contamination is controlled, and thus, justify the non-need for dedicated facilities.
Applying the PDE value both in the CCRA and cleaning validation allows cross-contamination to be addressed with a single risk management strategy. This makes it easier to make more consistent, efficient, and justifiable decisions when dealing with regulatory authorities.
Safety measures must be proportionate to the risk: an active substance with high toxicity will require stricter controls—such as the use of isolators or specialized containment—while products with lower toxicity may only require less complex, but still effective, measures.
Maintaining Compliance and Operational Efficiency
With a well-managed approach, cross-contamination prevention does not have to lead to excessive restrictions. On the contrary, it presents an opportunity to implement more efficient, safer strategies that are tailored to the operational realities of each plant.
In this context, keeping the CCRA updated not only ensures compliance with regulatory requirements, but also becomes a strategic tool to optimize the use of multiproduct facilities, avoid unnecessary investments in dedicated areas, and make decisions based on objective data—fundamental principles in the continuous improvement of pharmaceutical plants.