How does one manage the apparent conflict between the regulatory and safety goals of zero tolerance for pharmaceutical product metal contamination when most manufacturing equipment is constructed of metal? Is it even possible to completely prevent the presence of minute quantities of metal in our products? Product contamination with metal particles is unacceptable from both regulatory and safety perspectives. So, how do we address this challenge?
It is essential that any metal contamination management approach be comprehensive. One simply cannot rely alone on removal of rogue contaminants or safety screening of raw materials. This discussion aims to outline an approach to metal contamination prevention that should achieve a level of control acceptable to all stakeholders. A three-tiered approach to prevent metal contamination is described. The approach includes prevention measures as a key means for avoiding contamination, application of in-process controls to remove the presence of metal particles, and systems for detection of metal contamination and monitoring controls.
This paper also discusses the application of engineering and procedural controls in pharmaceutical manufacturing. Practical examples to cover a variety of pharmaceutical dosage forms are included to illustrate this comprehensive approach.Regulatory basis for zero tolerance on metal contamination
The regulatory requirement to control manufacturing processes to avoid contamination with extraneous materials is clear. In Chapter 21 of the Code of Federal Regulations (CFR) Section 211.67 (a) under "Equipment, Cleaning, and Maintenance," the following is observed:
"Equipment and utensils shall be cleaned, maintained, and, as appropriate for the nature of the drug, sanitized and/or sterilized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product..." (1).
In Chapter 21 of the CFR Section 211.84 (d)(5), the following is included under "Testing and approval or rejection of components, drug product containers and closures:" "Each lot of a component... that is liable to contamination with filth, insect infestation, or other extraneous adulterant shall be examined against established specifications for such contamination" (2).
For API manufacturing, International Conference on Harmonization (ICH) Q7 V. A. (5.1) states: "Closed or contained equipment should be used whenever appropriate. Where open equipment is used, or equipment is opened, appropriate precautions should be taken to minimize the risk of contamination" (3).
Additionally, the FDA's Compliance Program Guidance Manual (CPGM 7356.002), the manual used to direct facilities inspections by FDA, lists "controls to prevent contamination" as an element of the inspections for facilities and equipment systems (4).
Many firms have been cited in FDA-483 observations or Warning Letters for failing to prevent the contamination of drug products with foreign material. These citations have impacted oral solid dosage products, parenterals, and nearly every other product type. The bottom line expectation for industry is that current good manufacturing practices (CGMP) and all associated guidance documents require that all necessary measures be applied to ensure contamination is prevented. These measures include control or inspection of raw materials and packaging components, protection of exposed product, proper selection and maintenance of equipment, cleaning of equipment, proper facility and flow design, precautions during product sampling and testing, and proper storage and shipment of drug products.
Failure to prevent product contamination renders affected product adulterated under the Food, Drug and Cosmetics Act. The bar is high regarding product protection. There is no allowed tolerance for product contamination, and systems must be established to prevent it.