Prevention of Cross Contamination in Pharmaceutical Industry.
Normally, the production of non-medicinal products should be avoided in areas and with equipment destined for the production of medicinal products but, where justified, could be allowed where the measures to prevent cross-contamination with medicinal products described in Eudralex Volume 4 (Chapter 3 & 5) can be applied. The production and/or storage of technical poisons, such as pesticides (except where these are used for manufacture of medicinal products) and herbicides, should not be allowed in areas used for the manufacture and / or storage of medicinal products.
- Contamination of a starting material or of a product by another material or product should be prevented.
- This risk of accidental cross-contamination resulting from the uncontrolled release of dust, gases, vapours, aerosols, genetic material or organisms from active substances, other starting materials, and products in process, from residues on equipment, and from operators’ clothing should be assessed.
- The significance of this risk varies with the nature of the contaminant and that of the product being contaminated.
- Products in which cross-contamination is likely to be most significant are those administered by injection and those given over a long time.
- However, contamination of all products poses a risk to patient safety dependent on the nature and extent of contamination.
Cross-contamination should be prevented by attention to design of the premises and equipment as described in Eudralex Volume 4 (Chapter 3) .
This should be supported by attention to process design and implementation of any relevant technical or organizational measures, including effective and reproducible cleaning processes to control risk of cross-contamination.
A Quality Risk Management process, which includes a potency and toxicological evaluation, should be used to assess and control the cross-contamination risks presented by the products manufactured.
-Factors including;
facility/equipment design and use, personnel and material flow, microbiological controls, physico-chemical characteristics of the active substance, process characteristics, cleaning processes and analytical capabilities relative to the relevant limits established from the evaluation of the products should also be taken into account.
The outcome of the Quality Risk Management process should be the basis for determining the necessity for and extent to which premises and equipment should be dedicated to a particular product or product family. This may include dedicating specific product contact parts or dedication of the entire manufacturing facility.
It may be acceptable to confine manufacturing activities to a segregated, self contained production area within a multi-product facility, where justified.
The outcome of the Quality Risk Management process should be the basis for determining the extent of technical and organisational measures required to control risks for cross-contamination.
These could include, but are not limited to, the following:
Technical Measures
- Dedicated manufacturing facility (premises and equipment);
- Self-contained production areas having separate processing equipment and separate heating, ventilation and air-conditioning (HVAC) systems. It may also be desirable to isolate certain utilities from those used in other areas;
- Design of manufacturing process, premises and equipment to minimize opportunities for cross-contamination during processing, maintenance and cleaning;
- Use of “closed systems” for processing and material/product transfer between equipment;
- Use of physical barrier systems, including isolators, as containment measures;
- Controlled removal of dust close to source of the contaminant e.g. through localised extraction;
- Dedication of equipment, dedication of product contact parts or dedication of selected parts which are harder to clean (e.g. filters), dedication of maintenance tools; viii. Use of single use disposable technologies;
- Use of equipment designed for ease of cleaning;
- Appropriate use of air-locks and pressure cascade to confine potential airborne contaminant within a specified area;
- Minimising the risk of contamination caused by recirculation or re-entry of untreated or insufficiently treated air;
- Use of automatic clean in place systems of validated effectiveness;
- For common general wash areas, separation of equipment washing, drying and storage areas.
Organisational Measures
- Dedicating the whole manufacturing facility or a self contained production area on a campaign basis (dedicated by separation in time) followed by a cleaning process of validated effectiveness;
- Keeping specific protective clothing inside areas where products with high risk of cross-contamination are processed;
- Cleaning verification after each product campaign should be considered as a detectability tool to support effectiveness of the Quality Risk Management approach for products deemed to present higher risk;
- Depending on the contamination risk, verification of cleaning of non product contact surfaces and monitoring of air within the manufacturing area and/or adjoining areas in order to demonstrate effectiveness of control measures against airborne contamination or contamination by mechanical transfer;
- Specific measures for waste handling, contaminated rinsing water and soiled gowning;
- Recording of spills, accidental events or deviations from procedures;
- Design of cleaning processes for premises and equipment such that the cleaning processes in themselves do not present a cross-contamination risk;
- Design of detailed records for cleaning processes to assure completion of cleaning in accordance with approved procedures and use of cleaning status labels on equipment and manufacturing areas;
- Use of common general wash areas on a campaign basis;
- Supervision of working behaviour to ensure training effectiveness and compliance with the relevant procedural controls.
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Measures to prevent cross-contamination and their effectiveness should be reviewed periodically according to set procedures.