FAQs regarding Cross Contamination

Following you will find some questions frequently asked in ECA training courses and conferences - and the respective answers.

1. Is it acceptable to refer to scientific papers for the Contamination Control Risk Assessment in addition to the general guidelines?
Yes. Both WHO and EMA in the EU GMP Guideline Part 3 QRM principles (ICH Q9) encourage the industry to include scientific data from literature after evaluation of being applicable to the specific case as well as toxicological evaluations from external sources in risk assessments, particularly for setting health-based exposure limits (HBELs) to decide which level of segregation is needed to avoid cross-contamination.

2. How and to what extent should surfaces that do not come into contact with the product be taken into account when considering the measures in avoiding cross contamination?
Surfaces such as walls, floors, equipment exteriors and HVAC systems may be involved in cross contamination and should therefore be evaluated in a cross contamination control strategy. However, for cleaning validation EMA Annex 15 explicitly requires consideration of product contact surfaces.

3. Is a roughness of 0.8 µm a general requirement for good cleanability? Can you say a roughness of e.g. 1.6 is half as good?
Yes and no. 0.8 µm Ra is the widely accepted limit for cleanable GMP-grade stainless steel surfaces and can be considered as industrial standard. Cleanability is not linear; a surface of 1.6 µm is not "half as clean" -  but it may trap significantly more residue. Also, cleanability is heavily dependent on the types of residues. 

4. For OSD production in a shared facility: when is a clean corridor principle acceptable without an airlock for each production room and when is an airlock typically required?
Only under strict conditions. The clean corridor concept is acceptable if:

• clear unidirectional flow of personnel and materials exists
• differential pressures are maintained
• robust cleaning and containment (if applicable) are demonstrated

For potent APIs or highly sensitizing agents, dedicated airlocks are typically required per EU GMP Annex 3, PIC/S and ISPE Baseline® Guide for OSD.

5. Which parameters does a "state of the art" cleaning verification measure?
Typically:

• Total organic carbon (TOC)
• Specific active ingredient (API) residues
• Bioburden / endotoxins (if applicable)
• Conductivity/pH for cleaning agent residues
• Visual inspection

7. How often does the periodical cleaning validation verification have to be performed?
According to a risk-based schedule. EU GMP Annex 15 and PIC/S PE009 recommend periodic requalification of cleaning processes. The frequency must be justified (e.g. every 1-3 years) and triggered by changes in:

• product type
• cleaning SOP
• equipment
• campaign duration
• deviations or failures