Visible residue limits
Fourman and Mullen described a visible residue limit (VRL) at approximately 100 μg per 2 × 2 in. swab area (6) or about 4
μg/cm2. Jenkins and Vanderwielen observed various residues down to 1.0 μg/cm2 with the aid of a light source (1). Neither offered details or data to substantiate the numbers and neither speculated about
the use of visual limits in relation to the 10 ppm limit. LeBlanc questioned whether a VRL as the sole acceptance criterion
could be justified (15).
Work at Merck's West Point, Pennsylvania, facility quantitated the use of VRLs for both pharmaceutical pilot plants and commercial
manufacturing facilities (18, 19). The experiments included a series of active pharmaceutical ingredients (APIs), excipients,
formulations, and detergents spotted onto stainless- steel coupons at decreasing concentrations until a group of observers
were unable to detect the residues. The experimentally determined VRLs compared favorably to the health-based and carryover
cleaning limits. For those compounds where the VRL was lower than the health-based and carryover limits, the VRL became the
primary measure of equipment cleanliness.
Parameters explored included distance, viewing angle, ambient-light level, and residue composition. Established, acceptable
viewing parameters for the vast majority of product residue on pharmaceutical manufacturing equipment were: < 10 ft, > 30°,
and > 200 lux respectively. The viewing angle proved to be the most critical factor when viewing cleaned equipment, particularly
when viewing corners and other non-flat surfaces. VRL training continues to emphasize the importance of the viewing parameters.
Additional studies demonstrated the effectiveness of VRL use. Swab data compared favorably with VRL data as part of a validation
study in a clinical packaging facility (20). A VRL study involving five APIs at three different sites demonstrated the ability
to transfer VRL data between sites (21). A statistical analysis of all available VRL data (21) demonstrated that as technique
improved, VRL data variability decreased. The analysis also concluded that the VRL of an API was representative of a given
formulation.
VRLs have replaced swab analysis for several applications, including: the introduction of new APIs or equipment into a facility,
routine use inspection after cleaning, periodic assessment of program effectiveness, technology transfer of cleaning methodology,
campaign-length extension, cleaning-procedure optimization, and reduced cleaning documentation during routine cleaning.
Comparison of VRL to 10 ppm
Table I : Comparison of visible residue limit (VRL) data.
|
The 10-ppm limit in the author's facility equated to 100 μg/25 cm2 swab or 4 μg/cm2 based on the swab area and the solvent volume used to extract the residue form the swab. As VRL limits were established,
they were compared to the 10-ppm swab limit for compounds for which the 10-ppm limit was lower than the health-based cleaning
limit. The majority of the VRL data generated were well below 4 μg/cm2 (see Table I). Once the sample- preparation parameters and spotting technique were refined, 89% of experimentally determined
VRLs were less than 2 μg/cm2 and 98% of the VRLs were below 4 μg/cm2 (see Table I).
Table II: Visible residue limit (VRL) data.
|
The VRL data for several commercial formulations are shown in Table II. All of the VRLs are well below the constant 4μg/cm2 limit. The data range from < 1.88 μg/cm2 and 1.45 μg/cm2 for Demser (metyrosine) and Emend (aprepitant) respectively, to <0.07 μg/cm2 for Sinemet (carbidopa-levodopa) and < 0.06 μg/cm2 for Aldomet (methyldopa). Differences between the 10-ppm adulteration cleaning limit and the VRL cleaning limit range from
a factor of about 2 for Demser to a factor of almost 70 for Aldomet (see Figure 1).
|
