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Continuous Monitoring, Control and Validation of a Cleaning Process : A CIP Application

Introduction

A process diode array spectrophotometer is installed directly onto a batch reactor, continuously tracking the concentration of contaminants in the washing/rinsing cycle of a pharmaceutical plant.

During each rinse cycle, the contaminates concentration will reach a plateau; at this point, the rinse can not remove any more contaminants. Determining this point during the cleaning process is critical—in determining the efficiency of a given wash cycle, assuring the purity level of the reactor, and minimizing the wash time.

UV VIS absorbance techniques are ideal for continuous monitoring of active material in a wash cycle: water and methanol, usually the rinsing substances, do not absorb in the UV, and the high absorbance signals in the low UV of most contaminates allows for detection down to 1 PPM. The IR or NIR wavelength range cannot be used for the CIP process monitoring due to the interference from the rinsing substance, namely water or methanol. A high-resolution full spectrum analyzer is essential—the same analyzer is used for monitoring various active materials, each requiring a dedicated analysis method. An imbedded industrial computer is used to create and store the methods for each contaminant.

The following paper discusses an application in the pharmaceutical industry where a cleaning solution is used to wash reactor chambers between production batches. The solution is continuously monitored by an ultraviolet (UV) diode array process spectrophotometer.

UV Spectrophotometry: Theory and Application

Many active ingredients show distinct Ultra Violet (UV), VISible (VIS) or Short Wave Near Infrared (SWNIR) absorbance spectra and therefore can be monitored by spectroscopic techniques. UV-VIS-SWNIR spectrophotometry is the study of the absorbance or emission of light at different wavelengths (190-1100 nm), and can be related to the concentration of the absorbing components. Using this process, operators can determine when to stop recycling a fully loaded solution through the system and add fresh cleaner. Spectroscopy is the study of the absorbance and emission of electromagnetic radiation (light) by matter. A collection of frequencies absorbed by a sample is its absorbance spectrum. Ultraviolet and visible radiation make up just a small part of the electromagnetic spectrum, which includes many other forms of radiation, such as radio, infrared, cosmic and X rays.

When light passes through or is reflected from a sample, the amount of light absorbed is the difference between the incident radiation, I0, and the transmitted radiation, I. The amount of light that is absorbed is expressed as either transmittance or absorbance:
Transmittance: T= (I/I0)
Absorbance: A=log (I0/I)

Beer Lambert’s law relates the absorbance to the concentration of a certain component at a certain wavelength:
A(λ) = ε(λ) C d
Where: A = absorbance
λ = wavelength
C = concentration
d = path length

An absorbance spectrum is a plot of the absorbance at different wavelengths. Since the components of interest are usually high absorbents, a very low detection limit can be achieved while still maintaining high accuracy. This technique, when applied to high-absorbing components, can go down to one part per million (ppm), or lower.

A Clean in place (CIP) Process in the Pharmaceutical Industry

Validation of cleaning procedures is of utmost importance to the pharmaceutical, food, and specialty chemicals industries. The following application is one example of how an industrial spectrophotometer can be used to develop, validate, and control a cleaning process. The following describes a process whereby reactor chambers are washed between production batches. The cleaning process consists of several wash cycles; in each, a certain amount of cleaning solution (in this case, methanol) is recycled through the system (Figure 1).

Figure 1: Some of the recycled solvent is diverted to a small by-pass flowing through the spectrometer. After reaching a steady state a new batch of cleaning solvent is loaded and the process is repeated until the concentration of impurities reaches a pre-set threshold value

The Process

An industrial spectrophotometer was installed on-line and programmed to measure trace impurities in the washing cycle. A complete UV spectrum of the solvent flowing through the flow cell was measured and processed via a preprogrammed method to continuously give the concentration of the active ingredient.

The cleaning of the reactor chambers occurs as follows: During each wash cycle, a certain amount of methanol is circulated through the chamber, pumps, valves, and flow system. The concentration of the active ingredient in the methanol increases until a steady state is reached and the cleaning/rinsing cycle is considered to be complete. A new batch of clean methanol is then loaded and the same process is repeated.

For maximum efficiency, the cycling of methanol should be terminated when the concentration of the active ingredient reaches a plateau (Figure 2). Alternatively, the time derivative could be monitored to maximize sensitivity to the zero-change state. Continuing the wash past this point would be ineffective. Currently, time-based strategies are implemented in most reactor washing processes, with additional validation by laboratory testing.

Figure 2: Washing cycle - Timing diagram: The concentration of the active ingredient in the methanol increases until it reaches a plateau. The same occurs for each wash. The 1st derivative of the concentration with time (dc/dt) approaches zero when the process reaches steady state. The UCL (Upper Control Limit) is also shown.

The Analyzer

A UV-VIS diode array process spectrophotometer was utilized. The spectrophotometer consisted of four major subunits:

  1. a source that generates electromagnetic radiation;
  2. a dispersion device that selects a particular wavelength from the broad band radiation of the source;
  3. a sample area; and
  4. a detector to measure the intensity of radiation.

For the light source to cover the UV-VIS, a long-life pulsed-xenon lamp was used. The combination of dispersion and spectral imaging was accomplished by the use of a concave holographic grating. The grating dispersed the light onto the diode array at an angle proportional to the wavelength.

The diode array detectors are assemblies of individual photodiodes in a linear array. The array has 1024 elements. Light (of all wavelengths) falls on the diode array and is measured simultaneously. An instantaneous spectrum from 190-800 nm is obtained by electronically scanning the array.

The Analysis

Given the nature of the process, the active ingredients vary between reaction batches; consequently, several calibration and analysis methods are usually required. The spectrophotometer’s operational software includes various mathematical evaluation routines, providing the tools needed for frequent method modification. Once a method is developed and stored with calibration standards, the method switching for tracking various active ingredients is trivial.

The absorbance spectra of some active ingredients are shown in Figure 3. Note the low detection levels of the analytical method.

Applying the Technology to Precision Cleaning

As demonstrated in Figure 3, technology like this can work with both aqueous and solvent systems. The pharmaceutical application described in this paper is similar to many parts cleaning designs in that the parts remain in the same chamber while wash and rinse solutions are cycled through it. The detector could be linked to the control system of the washer, prompting it at the correct moment to move from wash to rinse or from rinse to final rinse.

Figure 3: Absorbance spectra of some active materials, the high absorbance of low concentration samples should be noted

This article gave a case demonstration of how a process diode array spectrophotometer was installed directly on a batch reactor to continuously track the concentration of active ingredients (now contaminants) in a washing/rinsing cycle. This technique might also be effectively applied in various other critical cleaning scenarios. For instance, this type of validation process could prove very useful to those concerned with developing cleaning strategies, monitoring active ingredients at the pilot plant stage of certain precision formulating operations, and determining the efficiency of a final cleaning process. Since many active ingredients show distinct UV absorbance features, UV spectrophotometry could be applied to a variety of cleaning applications.

In the pharmaceutical industry, built-in validation and diagnostic hardware routines are essential when utilizing any analytical technique that monitors active materials. But validation of a cleaning process—any cleaning process—is important not only in terms of how well a solution cleans, but how efficiently an operation is set up to clean.

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