Three Warning Letters reference products contaminated by metal particles. This problem was definitely caused by the equipment. The question is how this could have happened.

Manufacturing equipment should be qualified, thus proving its suitability for the intended purpose. Just because time and again deficiencies are found in the equipment, special focus is placed on validation and qualification within the framework of pharmaceutical manufacture. National and international regulations as well as GMP inspectors consider qualified equipment and validated processes to be an important prerequisite for attaining and maintaining pharmaceutical quality.

If one looks at the equipment before and also after qualification, a variety of points can have caused the deficiencies.

Before the equipment is qualified, there is the construction according to the pharmaceutical regulations. Next to the regulations concerning production itself and quality control, the construction has to create the conditions for reproducible operation. In this respect, GMP/FDA-compliant engineering has a pivotal role in the initial stages.

After qualification, two integral parts of quality assurance are regular and preventive maintenance in pharmaceutical production as well as the documentation of changes.

The complaints regarding metal contamination were discussed in detail within FDA Warning Letters and 483s. In this context, the FDA stresses the fact that a systematic analysis/investigation has to be carried out in case of such an 'unexpected contamination.' Moreover, the FDA demands that not only the batch in which the 'unexpected contamination' was found has to be analysed, but also all other batches that could potentially be affected. 

If the analysis shows that the contamination with metal particles was caused by faulty engineering, this can at worst result in the closure of the facility.

The following complaints can be found in inspection reports and even in Warning Letters:

• Rust was observed in various parts of the equipment, transport carts and furniture used in cleanrooms and in critical parts of the filling section
• Rust was also observed in the active air sampler used to monitor the cleanrooms
• There were no controls for metal in the areas where rust was observed
• There was no SOP describing the investigations to be carried out when unexpected contamination (e.g. metal particles) is detected
• Due to the use of a wrong equipment part, mechanical problems occurred resulting in metal abrasion. As a consequence, metal particles were found in the product.
• etc.