Preventing cross-contamination in the pharmaceutical industry

Often on projects in the pharmaceutical industry, we are asked various questions regarding cross-contamination prevention. It could be a greenfield project for a multi-products and multi-purpose manufacturing facility, an NPI (New Product Introduction) project in an existing facility, or a compliance remediation project. 

There’s no simple answer to questions like, “Can the two products share the same facility and equipment?”, “How to plan material and personnel flow” or “Can these two operations share the same process suite?”, and different facilities will address the problem differently. 

The answer will need to consider a holistic assessment of: 

• Material (including raw materials and finished material) 
• Premises (production suite extended to QC and other ancillary facilities) 
• Equipment 
• Manufacturing processes, and  
• Procedures (including quality system) 

A few simple examples of how the equipment type could affect the control strategy: 

In two different facilities you handle the same materials, but in the first facility unit operations are using open process (the product is in contact with the room environment) and in the second, more modern facility, you are using closed process equipment. This will dramatically impact your contamination control strategy and the two facilities will have different AHU/Procedures/work sequences.  

For the second modern facility, it may be acceptable to locate two unit operations in the same process suite with the same AHU, while in the facility with open operation you may need to segregate them temporally, or better physically meaning in 2 separate process suites and potentially with separate AHUs. 

The guidance you could obtain from regulation requirements is only the basics. Eventually, what type or level of segregation/separation is required is specifically assessed for your situation. Some cGMP citations on this topic are: 

• EudraLex Vol. 4 

3.6 Cross-contamination should be prevented for all products by appropriate design and operation of manufacturing facilities. The measures to prevent cross-contamination should be commensurate with the risks. Quality Risk Management principles should be used to assess and control the risks.  

Depending on the level of risk, it may be necessary to dedicate premises and equipment for manufacturing and/or packaging operations to control the risk presented by some medicinal products.  

Dedicated facilities are required for manufacturing when a medicinal product presents a risk because:  

1. the risk cannot be adequately controlled by operational and/or technical measures,  

1. scientific data from the toxicological evaluation does not support a controllable risk (e.g., allergenic potential from highly sensitising materials such as beta-lactams) or  

1. relevant residue limits, derived from the toxicological evaluation, cannot be satisfactorily determined by a validated analytical method.
    

• EudraLex Vol. 4 Annex 2 

57. In cases where a virus inactivation or removal process is performed during

manufacture, measures should be taken to avoid the risk of recontamination of treated products by non-treated products.
 

• EudraLex Vol. 4 Annex 14 

6.13 A system for clearly segregating/distinguishing between products or intermediates which have undergone a process of virus reduction, from those which have not, should be in place.
 

• EudraLex Vol. 4 Part IV 

4.16 Special precautions should be taken in the case of manufacturing activities involving infectious viral vectors (e.g., oncolytic viruses): these activities should take place in a segregated area. 

The above specifically concerned allergenic materials, biologics products, plasma/blood-derived products, as well as ATMP. But it does not mean other materials are exempt from such assessment/requirements. For example, certain materials with extremely low toxicity may still require dedicated equipment as it’s very difficult to be cleaned to an acceptable residual level.  

Though there’s no standard answer for all the questions, the approach is simple – an assessment based on science and risk. Also, there are various guidelines of assistance, for example: 

• The ISPE Baseline Guide Vol. 7 Risk-Based Manufacture of Pharmaceutical Products introduced the risk-based approach based on ICH Q9 to manage the risk of cross-contamination.  
• FDA recently published a draft guidance, Non-Penicillin Beta-Lactam Drugs: A cGMP Framework for Preventing Cross-Contamination (download a copy here). Though the guidance document is specifically focused on materials containing a beta-lactam ring, some concepts and principles are widely applicable. E.g., the Guidance defined “complete and comprehensive separation” as consisting of the complete physical separation (including separate air handling system) and additional design and procedural controls. Its Appendix B Design Features and Controls to Prevent Cross-Contamination could also be a good reference for facilities other than beta-lactam manufacturers.  

The last point, always worth stressing, is that the cross-contamination prevention strategy is a multi-disciplinary effort, which is a shared principle for risk assessment.  

Any doubt about your prevention strategy, or simply need assistance on establishing such assessment? Please feel free to drop a line to hello@nodeviation.com. Our Process, Facility and Quality & Compliance expert will reach out to you.  

You can also visit our website for more information about No deviation and its services.