On-line control of CIP process in Pharmaceuticals

Supplier: B-R Controls
05 November, 2007

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 contaminants 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

UV VIS absorbance techniques are ideal for continuous monitoring of active material in a wash cycle as water and methanol, usually the rinsing substances, do not absorb in UV, and the high absorbance in the low UV of most contaminants allows for detection down to 1ppm. A high-resolution full spectrum analyzer is essential 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.

Here we discuss 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 a UV diode array process spectrophotometer.

UV Spectrophotometry: Theory and Application
Many active ingredients show distinct Ultra Violet (UV), VISible (VIS) or Near Infrared (NIR) absorbance spectra and therefore can be monitored by spectroscopic techniques. UV-VIS-NIR spectrophotometry is the study of the absorbance 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.

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 absorbance to concentration of a certain component at a certain wavelength:
A(l) = e(l) Cd

Where: A = absorbance
l = wavelength
C = concentration
d = path length

An absorbance spectrum is a plot of the absorbance at different wavelengths. Since the components of interest usually absorb well, a very low detection limit can be achieved while still maintaining high accuracy.

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 demonstrates how a spectrophotometer can be used to develop, validate, and control a cleaning process where 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 (Fig 1).

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.

During each reactor wash cycle, a certain amount of methanol is circulated through the chamber 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 process repeated.

For maximum efficiency, the cycling of methanol should be terminated when the concentration of the active ingredient plateaus. 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.

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

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

For the light source 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 which disperses 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. 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.

Applying the Technology to Precision Cleaning
The pharmaceutical application described in this paper is similar to many 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.

This technique can also be applied in various other critical cleaning scenarios and could prove very useful to those developing cleaning strategies, monitoring active ingredients at the pilot plant stage of precision formulating operations, and determining the efficiency of a final cleaning process.

In the pharmaceutical industry, built-in validation and diagnostic hardware routines are essential when utilizing any analytical technique that monitors active materials.  Validation of a 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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