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Noncontact, Real-Time Cleaning Verification For

Noncontact, Real-Time Cleaning Verification For

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Published by: jljimenez1969 on Sep 27, 2013
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377 Simarano Drive, Marlborough, MA, 01752 Phone (508) 251-3100, Fax (508) 251-3171, www.blockeng.com
Noncontact, Real-Time Cleaning Verification for Pharmaceutical Manufacturing
Pharmaceutical firms have been seeking a faster and more efficient way to confirm thata manufacturing vessel is sufficiently clean to start another batch. The current method of taking swab samples and processing them at a central lab using HPLC takes severalhours during which time the vessel is idle. This Note describes a new non-contacttechnique that in real time can verify that a vessel is clean. The cost savings from lesslabor and materials as well as increased manufacturing throughput can providepaybacks in weeks.
Infrared spectroscopy is a well established technique for detection and identification of contaminants on surfaces, in particular metallic surfaces. Detection levels can be as lowas fractions of micrograms, depending on factors such as viewing/measurement anglesand use of a polarized infrared beam. Detection of contaminants or residual materials oncleaned surfaces is important for a wide range of applications. Examples includecontamination in the production environment for pharmaceutical and foods products(such as the cleanliness of reaction vessels), adhesion of coatings (such as paints,polymers and adhesives) and sterility of medical device surfaces (such as implants andcatheters).Thisapplication note focuseson the use of Block
™ Analyzer 
 (Fig. 1) as a handheldspectrometer, based onquantum cascade laser (QCL) technology, for monitoring thecleanliness of metalvessels used inpharmaceuticalproduction.
Figure 1
377 Simarano Drive, Marlborough, MA, 01752 Phone (508) 251-3100, Fax (508) 251-3171, www.blockeng.com
Problem Definition
In the production of pharmaceutical products there is strong potential for batchcontamination related to the presence of residual materials such as active ingredients,cleaning agents, microorganisms, dust and particulates. Cleaning validation providesdocumented evidence that the cleaning processes used has cleaned to predefinedlimits. The goal is to prevent contamination that can influence the safety, efficacy, purityand quality of manufactured products. Pharmaceutical firms and other organizationshave been seeking a reliable, real time, non-contact method for detecting surfacecontamination to replace the time consuming method currently used.The pharmaceutical industry defines (measures) cleanliness in terms of organicresidues from previous production runs. Therefore, the standard methods of analysesinclude TOC (total organic carbon) analysis and liquid chromatography after controlledswabbing of the reaction vessel surfaces. These time and cost intensive techniquesprovide an averaged or integrated result and do not necessarily represent the surface or how materials are distributed over the surface. Also, the assessment of cleanliness ispotentially confounded by the cleaning procedure itself, where cleaning agents, such assurfactants, by nature of their cleaning action may remain on the surface. After the production process, the reaction or mixing vessel is cleaned by a prescribedmethod which may involve a series of solvents and/or cleaning agents or acidic, alkalineand/or surfactant solutions. Any one of these may leave residual material, and there
could be an accumulation of materials on the surface once the “cleaning” process is
complete. Pharmaceutical organizations must determine whether residual materials arepresent, and if so, how are they are represented on the surface. One of the mostcommon surfaces is stainless steel and the characteristics of that surface (polished or brushed or roughened) can dictate how the materials adhere. Laboratory experimentswith cleaned brushed stainless steel surfaces have indicated that residues from solid
compounds deposited from solvents tend to exist as “islands” of material and no
t acontinuous thin coating, due to the coalescing of materials during the evaporation
process and nucleation around surface features and “dust particles”. Therefore, an
accurate measurement technique has to take into account that material is notnecessarily uniformly distributed.
Proposed Solution
LaserScan™ Analyzer Technology
Block proposes to utilize an optical, noncontact method, based on laser-based infraredspectroscopy. The LaserScan
™ Analyzer is the result of many years of development at
Block Engineering and utilizes infrared spectroscopy. Infrared technology has been usedfor decades under laboratory conditions and some of the most common instrumentsusing it are called Fourier Transform Infrared (FTIR) Spectrometers. FTIR methods have
377 Simarano Drive, Marlborough, MA, 01752 Phone (508) 251-3100, Fax (508) 251-3171, www.blockeng.com
been used, but these instruments use a diffuse infrared source so for these to workeffectively they either have to make contact with the surface (use of ATR methods) or the measurement head has to get very close (within a centimeter or so) to the surfacewhich creates a potential for further contamination, due to accidental contact. Becausethe LaserScan QCL technology uses a sufficiently strong, but eye safe laser, it canmeasure residues on surfaces from distances of six inches or greater.The fundamental principle behind this technology is that, when infrared light reflects off of substances, it gets absorbed or reflected at rates that are absolutely unique to andcharacteristic of the substance. Therefore, when the reflected light is collected by the
built-in detectors
, a “fingerprint”
-like pattern emerges, which contains all thenecessary information for detection or analysis of the substance. Built-in libraries aretypically used to pattern and provide real-time detection or analysis. Furthermore,LaserScan is a lightweight handheld unit that provides readings in seconds.
Experimental Results
In this application note cleaning validation is demonstrated by a simulation of thecontamination of a stainless steel surface by a pharmaceutical active ingredient. For theease of the simulation, an over the counter analgesic and painkiller, acetaminophen (also knownas Paracetamol) was used as amodel compound (Figure 2). Thegoal for the cleaning validation isto attempt to monitor contaminantcompounds down to or less thanone microgram per squarecentimeter (
1 µg/cm
). The bestway to uniformly apply a materialto a surface in a controlledmanner is to deposit the materialfrom a dilute solution in anorganic solvent. To demonstratethe process, a solution of acetaminophen in isopropylalcohol was sprayed on thesurface of a cleaned stainlesssteel coupon with an airbrushusing a 2-dimensional pattern asshown in Figure 3 to provide anominal concentration of ~0.3µg/cm
. A witness surface
Figure 2: 
Acetaminophen (also known asParacetamol) used as the model compound 
Figure 3: 
Experimental sample application procedure for simulation of cleaning validationmeasurement 

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