Preventing Cross-Contamination During Lyophilization. GMP and Occupational Cleaning Requirements for Nonproduct and Indirect Product Contact Parts

Abstract

A detailed overview is provided for the possible patient exposure to highly-potent API (HPAPI) from potential cross-contamination through the lyophilization process. The intent of this paper is to raise awareness of the risk(s) to patients and stimulate the implementation of adequate risk-based controls such as containment process(es), use of adequate surrogates in cleaning validation/verification, and test method-sensitivity-based cleaning validation acceptance conditions. Although lyophilizers are considered to be non-product contact surfaces or indirect product contact surfaces because their surfaces and fixtures usually do not come into direct contact with the product, product contamination can occur at critical locations within a lyophilizer and/or during the unloading process. Contamination of the air due to released product particles can also create a risk. Special attention should therefore be paid to high-potency active pharmaceutical ingredients (HPAPIs) as the permitted daily exposures (PDEs) for patients are particularly low. During a lyophilizer cycle, areas of concern are;- spreading of the lyophilizer HPAPI powder due to air turbulence, contaminated plates, mechanical transfer systems, and spreading due to damaged vials or contaminated surfaces (stainless steel or polymer). Specific considerations for contamination containment for the lyophilizer unloading process are presented. Suggestions are provided for the prevention of patient exposure through cross-contamination via non-direct contact areas. Risk-based cleaning validation/verification strategies are discussed, with specific consideration of the QC test method sensitivity expectations and use of suitable surrogates for lyophilized products in the cleaning verification studies.