Cross Contamination –1: the Rules
Definition - The contamination of a product by materials that are not part of the formulation, from another product.
Changes in EU guidelines are setting quantifiable rules to guard against the risk of product cross contamination.
The requirement is that the risks are formally assessed and periodic measurements taken to validate the assumptions made in the assessment.
The key sections of the regulations are:
- Chapter 3 sets out the general objectives and requirements
- Chapter 5 sets out some measures that can be used to mitigate the risk.
- Guideline for setting health based exposure limits for use in risk identification in the manufacture of different products in shared facilities, sets out a methodology for assessing the ‘accepted’ levels of cross contamination.[1 ]
The guideline attempts to quantify the contamination that would have no observable effect on a person if taken for a lifetime. In the guideline this is referenced as the Permitted Daily Exposure [PDE], or in other sources an Accepted Daily Acceptable. [ADE]
The data necessary to make these calculations is not always available, so there are some proposed ‘work around’ approaches in the industry.[2,3]
What to do about it in design and operational terms in dealt with in the next article.
For each contaminant toxicology tests will establish the highest dose at which no ‘critical’ effect is observed. This level is called the No Observed Adverse Effect Level.[NOAEL].
As above the permitted daily exposure [PDE] is established for each contaminant.
The PDE = NOAEL divided by a number of factors, F1 through F5. These factors vary and not all maybe applied.
Once you have this data you can work backwards to ensure that the facility design and the operations can deliver this attenuation [reduction of] of any release, or transfer of active material.
Exceptions - Beta Lactams, Genotoxic
- Some products such as beta lactams have no safe lower limit and therefore cannot be made in the same facility as other non-beta lactams.
- Some products have a genotoxic risk [cancer forming]. Again no safe level is established, but the European Medicines Agency [EMA] accepts a cross-contamination level of <1.5µg/ person/ day.
Extracts of the relevant regulations and guidelines
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2 Joel Bercu, How OELs & ADEs Develop Over the Life Cycle of a Drug, presentation, Gilead Sciences.
3 EMA Guideline on Setting Health-Based Exposure Limits, The results of an industry workgroup’s examination of EMA’s guide on shared facilities are presented, Dec 02, 2015, By Andrew Teasdale, Bruce D. Naumann, Gretchen Allison, Wendy Luo, Courtney M. Callis, Bryan K. Shipp, Laura Rutter, Christopher Seaman. Pharmaceutical Technology, Volume 40, Issue 1