Test Method Validation for Cleaning Validation SamplesTest Method Validation for Cleaning Validation Samples

ASEPTIC

Richard J. Forsyth Associate Director in Worldwide GMP Quality Merck & Co., Inc,

Abstract

Testing of cleaning validation samples requires a validated method. The extent of validation is dependent upon the type of method employed, the capabilities of the method, the scientific
and regulatory needs of the resulting data, and the anticipated outcome of the testing. A number of test method options are reviewed for their analytical capabilities along with their method validation parameters.

Introduction

Cleaning validation is a critical function in pharmaceutical manufacturing. Regulatory agencies have placed great emphasis on demonstrating that a cleaning process prevents cross-contamination [1, 2]. Manufacturing equipment cleanliness does not merely impact
the subsequent formulation, but every formulation processed in the equipment and the overall manufacturing program in a facility. A cleaning process is validated and monitored through testing of the equipment. Testing ranges from visual inspection to swab sampling or rinse sampling.

For any test method to be suitable for its intended purpose, it must be appropriate for measuring analytes at and below the acceptable residue limit (ARL). An ARL can be based on available toxicological data, such as an allowable daily intake or ADI, an adulteration limit such as 10 ppm; and visual cleanliness. The ARL has a direct bearing on the validation parameters of the test method.

The two main types of sampling are direct surface sampling with swabs, which is most desirable, and final rinse sampling [1]. Cleaning validation test results can be expressed as a limit test or cover a range of analyte concentration. The testing of the samples can consist of a specific method such as high performance liquid chromatography (HPLC), gas chromatography (GC), and mass spectrometry (MS) or a nonspecific method such as total organic carbon (TOC), pH and conductivity. The type of sample, expected results, and assay methodology used for testing also affect the determination and demonstration of the validation parameters.

Validation Parameters

The analytical performance characteristics, or validation parameters, as defined by the USP [3]include: accuracy, precision, specificity, detection limit, quantitation limit, linearity, range and
robustness. Definitions of the parameters are shown in Table 1. Validation elements differ for a method that covers a range or a limit (Table 2). Validation of a limit test requires fewer resources but the data results from testing provide less information. Addressing these performance characteristics provides assurance that a method meets proper standards of accuracy and reliability.

Validation Study

In order to validate a cleansing testing method, prepare a solution of the residue of interest at a concentration from which spots of appropriate size can be prepared. For example, pipet 200 μl of a solution with a concentration of five times the ARL. Inoculate in triplicate residue spots of known concentrations at 3-5 levels around the ARL on coupons of the material of construction of the manufacturing equipment. Wetted swabs recover the residue from the surface and solvent extracts the residue from the swab.

The recovery data demonstrates accuracy, precision, linearity and range. LOD and LOQ can be determined experimentally or estimated from the lowest sample recovered. Standard and sample solution stability should be determined experimentally. Specificity and robustness are dependent on the method employed.