A Risk-Based Approach to Cleaning Validation of APIs

Abstract

Arisk-based assessment of cleaning validation of an Active Pharmaceutical Ingredients (API) facility is reviewed. The potential application of visible residue limits (VRL) in cleaning validation
is explained for both pharmaceutical pilot plant and manufacturing facilities. VRLs are the level down to which API residues are visible to a group of trained observers operating under defined viewing conditions.
The author describes the development of a VRL program in an API manufacturing facility including sample and viewing parameters. The effects of observer distance, ambient light intensity, viewing angle and residue appearance were quantitated and the best opportunities for success were defined. Potential applications of VRL implementation were identified in both pilot plant and manufacturing settings.

Introduction

Information regarding cleaning validation in facilities that manufacture active pharmaceutical ingredients (APIs) is limited (1 - 4). The objectives of cleaning validation efforts in the API area are the same as those in the pharmaceutical production area but the areas are fundamentally different. The API facility includes reactors, transfer lines and pipes, pumps, filters, centrifuges and dryers making cleaning validation more challenging. Although up to 90% of the total equipment surfaces are visible, many of the visible equipment surfaces are not within reach of the operator.
The areas that are not visible often represent some of the worst-case locations in the equipment such as low-flow areas or parallel flow routes. These surfaces cannot be visually inspected without the aid of remote access capabilities, such as a remote video system. It must be decided whether to test these areas either with such a remote video system, dismantle the equipment for direct visual examination, or monitor with an indirect test such as rinse sampling. Rinse sampling is by far the most convenient form for monitoring these remote areas on an ongoing basis.
A validated cleaning program based on quantitative visual inspections in conjunction with swab or rinse testing is possible. Acceptable visible residue limits (VRLs) can be established in conjunction with and compared to swab results. Assuming the swab results demonstrated a validated cleaning procedure, if the results are in agreement, then the VRLs may be used going forward. This is the same argument that has been successfully used to defend the use ofrinse sampling established in conjunction with swab results.
The use of only visual examination to determine equipment cleanliness was proposed as far back as 1989 by Mendenhall (5). He found that visible cleanliness criteria were more rigid than quantitative calculations and clearly adequate. The FDA, in their "Guide to Inspection of Validation of Cleaning Processes," limited the potential acceptability of a visually clean criterion to use between lots of the same product (6). LeBlanc also explored the role of visual examination as the sole acceptance criterion for cleaning validation (7). The adequacy of visible residue limits continues to be a topic of discussion.
Visible cleanliness is the absence of any visible residue after cleaning. Although this is a seemingly straightforward definition, a number of factors influence any determination. The most obvious is the observer. Not only the observer's visual acuity, but also training on what to observe, influences the outcome of a visual inspection. The levels of illumination in the inspection areas and shadows caused by the equipment influence what is seen. The distance and the angle of the observer from the equipment surface also have an effect. Finally, the individual residues that comprise a given formulation affect the overall visible residue limit.
Fourman and Mullen determined a visible limit at approximately 100 μg per 2 x 2 in. swab area (8) or about 4μg/cm2. Jenkins and Vanderwielen observed various residues down to 1.0 μg/cm2 with the aid of a light source (9).
For this study, the visible residue limits of active pharmaceutical ingredients were determined.
Observers viewed residues under viewing conditions similar to those encountered in both a pilot plant facility and a commercial manufacturing facility.

Visible Residue Parameters

Pilot Plant Study
Since the determination of a visible residue limit is, to a large extent, subjective, the variables associated with studying visible residue were defined, and then experimental parameters for the study were established. The parameters considered were: residue, surface material, light intensity, distance, angle, and observer subjectivity (10).