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Phone (508) 251-3100, Fax (508) 251-3171, www.blockeng.com

APPLICATION NOTE AP0010612

Noncontact, Real-Time Cleaning Verification for Pharmaceutical Manufacturing
Abstract
Pharmaceutical firms have been seeking a faster and more efficient way to confirm that a 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 several hours during which time the vessel is idle. This Note describes a new non-contact technique that in real time can verify that a vessel is clean. The cost savings from less labor and materials as well as increased manufacturing throughput can provide paybacks in weeks.

Introduction
Infrared spectroscopy is a well established technique for detection and identification of contaminants on surfaces, in particular metallic surfaces. Detection levels can be as low as fractions of micrograms, depending on factors such as viewing/measurement angles and use of a polarized infrared beam. Detection of contaminants or residual materials on cleaned surfaces is important for a wide range of applications. Examples include contamination 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 and catheters).This application note focuses on the use of Block Engineerings LaserScan Analyzer (Fig. 1) as a handheld spectrometer, based on quantum cascade laser (QCL) technology, for monitoring the cleanliness of metal vessels used in pharmaceutical production. Figure 1: LaserScan Analyzer

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377 Simarano Drive, Marlborough, MA, 01752

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Problem Definition
In the production of pharmaceutical products there is strong potential for batch contamination related to the presence of residual materials such as active ingredients, cleaning agents, microorganisms, dust and particulates. Cleaning validation provides documented evidence that the cleaning processes used has cleaned to predefined limits. The goal is to prevent contamination that can influence the safety, efficacy, purity and quality of manufactured products. Pharmaceutical firms and other organizations have been seeking a reliable, real time, non-contact method for detecting surface contamination to replace the time consuming method currently used. The pharmaceutical industry defines (measures) cleanliness in terms of organic residues from previous production runs. Therefore, the standard methods of analyses include TOC (total organic carbon) analysis and liquid chromatography after controlled swabbing of the reaction vessel surfaces. These time and cost intensive techniques provide 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 is potentially confounded by the cleaning procedure itself, where cleaning agents, such as surfactants, by nature of their cleaning action may remain on the surface. After the production process, the reaction or mixing vessel is cleaned by a prescribed method which may involve a series of solvents and/or cleaning agents or acidic, alkaline and/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 are present, and if so, how are they are represented on the surface. One of the most common surfaces is stainless steel and the characteristics of that surface (polished or brushed or roughened) can dictate how the materials adhere. Laboratory experiments with cleaned brushed stainless steel surfaces have indicated that residues from solid compounds deposited from solvents tend to exist as islands of material and not a continuous 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 not necessarily uniformly distributed.

Proposed Solution LaserScan Analyzer Technology

Block proposes to utilize an optical, noncontact method, based on laser-based infrared spectroscopy. The LaserScan Analyzer is the result of many years of development at Block Engineering and utilizes infrared spectroscopy. Infrared technology has been used for decades under laboratory conditions and some of the most common instruments using it are called Fourier Transform Infrared (FTIR) Spectrometers. FTIR methods have

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377 Simarano Drive, Marlborough, MA, 01752

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been used, but these instruments use a diffuse infrared source so for these to work effectively 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 surface which creates a potential for further contamination, due to accidental contact. Because the LaserScan QCL technology uses a sufficiently strong, but eye safe laser, it can measure 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 and characteristic of the substance. Therefore, when the reflected light is collected by the LaserScans built-in detectors, a fingerprint-like pattern emerges, which contains all the necessary information for detection or analysis of the substance. Built-in libraries are typically 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 the contamination of a stainless steel surface by a pharmaceutical active ingredient. For the ease of the simulation, an over the counter analgesic and pain killer, acetaminophen (also known as Paracetamol) was used as a model compound (Figure 2). The goal for the cleaning validation is to attempt to monitor contaminant compounds down to or less than one microgram per square Figure 2: Acetaminophen (also known as Paracetamol) used as the model compound centimeter (1 g/cm2). The best way to uniformly apply a material to a surface in a controlled manner is to deposit the material from a dilute solution in an organic solvent. To demonstrate the process, a solution of acetaminophen in isopropyl alcohol was sprayed on the surface of a cleaned stainless steel coupon with an airbrush using a 2-dimensional pattern as shown in Figure 3 to provide a nominal concentration of ~0.3 Figure 3: Experimental sample application g/cm2. A witness surface procedure for simulation of cleaning validation measurement

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(aluminum foil) was used to verify the solution concentration via an independent TOC measurement. After spraying and evaporation of the solvent, it can be seen that the material is not evenly spread as a continuous thin film. The material from a macro point of view may appear to be evenly spread, but at a micro level the material effectively forms islands of material, where relative concentrations may range from detection limits of ~1 to 10s of micrograms. Blocks QCL based spectrometer provides a tightly collimated beam with a nominal dimension of 2mm x 4mm. With this tool it is possible to not only scan the surface for contamination but also differentiate locations that are higher in contaminant content. Figure 4 shows resultant spectra from the measurement of deposited acetaminophen on the surface of the stainless steel coupon. The measurements were made in an area that visually indicated the presence of deposited material. As the laser rasters across the steel surface, it encounters varying levels of concentration, as shown in Figure 4.

Figure 4: Spectra from two different locations with different levels of material (A and B) By taking the results of the sample shown in Figure 4-A and extrapolating, Block predicts we can detect residues down to <1 g/cm, potentially close to 0.2-0.5 g/cm.

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One of the significant benefits of the QCL based spectrometer is the aiming control as well as the ability to scan at a high data rate. This provides the ability to rapidly scan specific areas required by the cleaning validation protocol. An example of raster mapping of a surface is shown in Figure 5. The visual representation of the spectral map clearly supports the island clustering concept of a surface where a solution has been evaporated. This infrared mapping provides a conformational material distribution image which supports the visual image indicated in Figure 5.

Figure 5: Raster mapping of deposited acetaminophen, 250micron step resolution

Conclusions
This application note demonstrates that Blocks LaserScan is the optimal tool for measuring and analyzing material contamination on surfaces, a fundamental requirement of the cleaning validation process. The results show that surface contamination does not necessarily exist as a uniform, continuous layer. While the ideal specifications for cleaning validation might call for <1 g/cm2 detection sensitivity average, the more realistic measurement model is for the ability to remotely scan a surface and provide a positive identification of the presence of a contaminant. The spectral response may change as a function of the amount of material present, but either way the presence of material can be detected and low and high concentrations of material can be discriminated. The LaserScan provides a high sensitivity tool for the non-destructive and non-contact analyses of surfaces, for distances up to half a meter. Future devices will be much lighter (flashlight size) and have fiber optic attachments for hard-to-reach locations inside the vessels.

Block Engineering shall not be liable for errors contained herein or for incidental or consequential damages in connection with the furnishing, performance or use of this material. Information, descriptions, and specifications in this publication are subject to change without notice.

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