Instrument Validation and Inspection Methods

1.What is Validation?
At sites where products are developed and manufactured, a variety of equipment is used to create products through a complex series of work processes. To state that such products meet the expected quality standards, it is important to verify that the plant, equipment, and operational procedures are free of problems. Verification procedures must be established to ensure that the details of the verification are consistent, regardless of who performs it. The series of processes from performing the verification according to a defined procedure to documenting the verification results is generally known as "validation". Validation can be performed on a diverse range of objects, from tangible items such as plant and equipment to intangible work procedures and processes. This UV TALK LETTER describes details about the instrument validation of UV-VIS spectrophotometers.

2. Instrument Validation of a UV-VIS Spectrophotometer

Performance Items A spectrophotometer shines light at various wavelengths onto the sample and investigates the degree of absorption, reflection, and transmission of the light to perform qualitative or quantitative analysis of the sample. So, what sort of performance does a spectrophotometer offer? JIS K0115 "General rules for molecular absorptiometric analysis" prescribes the performance items that should be displayed by the instrument, as shown in Table 1. It can be seen from Table 1 that Table 1 Performance Items Listed in JIS K0115 Resolution Wavelength accuracy Wavelength repeatability Photometric accuracy Photometric repeatability Stray light Baseline stability Baseline flatness Noise level

the generic term "performance" encompasses various conditions depending on the point of focus. Instrument validation of a spectrophotometer involves selecting the items required to manage and determine the status of the instrument from among these performance items, andverifying them.

3. Performing Instrument Validation

The actual philosophy and method of performing instrument validation are described below using several performance items as examples.

Wavelength Accuracy

Fig. 1 Emission Lines of a Deuterium Lamp The emission lines of a deuterium or low-pressure mercury lamp or the absorption peaks of an optical filterfor wavelength calibration are generally used to verify the wavelength accuracy. Fig. 1 shows the energy spectrum of a deuterium lamp. A deuterium lamp is known to exhibit sharp energy peaks (emission lines) at 656.1 nm and 486.0 nm wavelengths. Consequently, the instruments wavelength accuracy can be verified by measuring the energy spectrum of a deuterium lamp, investigating the wavelength of the peak near 656.1 nm, and then comparing its wavelength value to 656.1 nm. For example, if the detected peak wavelength is 656.2 nm, the error from the true 656.1 nm value is 0.1 nm, and this becomes the wavelength accuracy of the instrument.

How many multiple emission lines (or absorption peaks) should be used to confirm the wavelength accuracy and what error is permitted depends on the level of instrument performance required for the development and manufacture of the product. In cases where a sample spectrum is measured and the peaks must be specified within an error of 1 nm, a wavelength accuracy of 0.1 nm is probably adequate.

Stray Light
Stray light is light outside the specified wavelength that shines onto the sample. For example, when measuring the absorbance using light at 220 nm, accurate measurements are not possible if a lot of light at wavelengths other than 220 nm hit the sample. Let us consider the case of 0.01 % stray light outside the specified wavelength. Due to the effects of the stray light, a sample with 1 % transmittance (2 Abs) appears to have a transmittance of 1.01 % (1.9957 Abs). Alternatively, a sample with 0.01 % transmittance (4 Abs) appears to have a transmittance of 0.02 % (3.6990 Abs). That is, errors of 0.0043 Abs and 0.3010 Abs, respectively, occur. This case reveals that the effects of stray light increase as the sample absorbance increases.

Fig. 2 Stray Light Measurements Using Nal Aqueous Solution The presence of stray light causes distortion in thecalibration curve. Consequently, an instrument with low stray light is required for the quantitation of high-concentration unknown samples (with high absorbance) using a calibration curve created with standard samples.

An aqueous solution that is known to not transmit light at a specific wavelength, such as sodium iodide (Nal), is used to evaluate the amount of stray light. For example, an aqueous solution of Nal does not transmit light at 220 nm. Initially, the transmittance is measured with a shutter block that

completely shuts out all light mounted in the sample compartment (transmittance X). Next, the transmittance is measured with the aqueous solution of Nal in the sample compartment (transmittance Y). The instruments stray light is defined as (Y X). This value is used to evaluate the level of stray light. Fig. 2 shows a schematic diagram of this situation.

The aim of instrument validation is to confirm that the instrument offers adequate performance for the inspectionand manufacture of products. When performing an actual validation, it is important to select the appropriate inspection items and to set the evaluation criteria based on a sound understanding of the required instrument performance.

4. Validation Is Diagnosis of the State of the Instrument

Fig. 3 Noise Level Measurement Results A spectrophotometer is made up of many components, some of which are consumables that deteriorate according to the time and frequency of operation. Instrument validation is also useful for determining the state of the constituent components of the instrument. Let's consider the noise level as an example. The noise level is one indicator of the condition of the light source (lamp) in the spectrophotometer. The noise level is defined as the maximum deviation (maximum distance between peak and trough) of the absorbance measured over one minute at a specific wavelength near 0 Abs. Fig.3 shows the graph of a measured noise level. As the relative noise increases when the emitted light intensity of the lamp drops off over time, the noise level becomes higher. A higher noise level means that the data reproducibility is lower. This has a negative effect when accurate photometric values are required. When it is necessary to detect extremely small absorption peaks, it may not be possible to detect the peaks correctly if the noise level is so high that they become buried in the noise.

The optical system of a spectrophotometer contains various mirrors for focusing and forming a spectrum. The surfaces of these mirrors can deteriorate over time. It is also possible for dust and dirt from the atmosphere to adhere to the mirror surfaces due to the environment where the instrument is installed. For example, the deterioration of a mirror that forms the spectrum can be one cause of the increase in stray light described above. Therefore, instrument validation can provide valuable information to diagnose the condition of an instrument. It is recommended to perform periodic instrument validation to continuously understand and manage the state of the instrument. It is also important to validate an instrument after consumables are replaced or the instrument is moved to a different place.

5. Automated Instrument Validation Using Software

A diverse range of performance items must be checked during instrument validation. Doing so manually takes a lot of time. It is easy for errors to occur during such a complex inspection procedure. A program designed to automate the measurements and calculations necessary for validation operations can significantly reduce the effort needed for instrument management. Shimadzu supplies dedicated UV Performance Validation Software for the instrument validation of UVVIS spectrophotometers. Fig. 4 shows a screen shot from the UV Performance Validation Software. This software simplifies setup of the inspection items, inspection conditions, and the evaluation criteria and automates the process through measurement, calculation, and evaluation. It offers a variety of functions to support instrument validation work, including management of inspection tools such as optical calibration filters, and printout of validation results reports. Fig. 5 shows an example of the instrument validation workflow using the software. It can be seen that the software permits accurate and efficient instrument validation.

6. Conclusions
This UV TALK LETTER introduced the following points:

Instrument validation is important to determine the status of instruments used for the development and manufacture of products. To perform an actual instrument evaluation, select the required performance items and set the appropriate evaluation criteria for the inspection. The effective application of a validation program permits accurate and efficient instrument validation.

Validation of hardware

IRPrestige-21
This time, I will talk about how the validation of FTIR. There is a meaning "(legally) to enable" and to validate in English. After you shop at department stores, is called the (are pushed to be Valid in the U.S.) with whom to press the stamp of "free" to the parking ticket at the cash register also validate in English. To prove the "validity, validate to authenticate - since it is to ensure that you have the inspection required in equipment, the equipment is operating correctly," I can use "and that" Enable " It is used in the sense that "the noun validation is now also used to mean "verification, validation, validation, and validation." So, I will talk about software validation and hardware validation of FTIR. You said that validation of hardware of FTIR, and as the method to examine and verify that the FTIR is operating correctly. In distributed IR, by measuring the spectrum of polystyrene film, I was checking by reading the peak wave number and also serves as a calibration of the wave number. That the state of the device appears in the power spectrum because there are many in FTIR, how to determine the size and shape of the power spectrum is used as a simple way. As daily inspections in our FTIR instrument, and has adopted the confirmation of the size and shape of the power spectrum. As how to check the FTIR finer, public institutions as well as a number of issues a standard. Japanese Industrial Standards (JIS), as a standard industrial-based American Society etc. (JIS ASTM, the American version) for Testing and Materials, there is a provision Japanese Pharmacopoeia, the European Pharmacopoeia (EP) in the pharmacopoeia. Let's take a look at each one defines what kind of standard.

Japan Industrial Standard (JIS)

There is a provision infrared spectroscopy General rules for the (JIS K0117) in IS. Inspection methods are listed in the "inspection method and correction of 6.3 spectrophotometer". It is written for the return of Ri provision for 100%, linearity, resolution, 0% and transmission (accuracy) and transmission frequency. I gives a very brief introduction to the method described in JIS. However, it is not mention of the standard values, and specific steps to JIS. (Accuracy) wavenumber I seek from the error of the indicated value of the equipment and the peak wavenumber position of substance ... peak wavenumber position is well-known (for example, carbon dioxide in the atmosphere, water vapor, polystyrene, ammonia, and indene) of. 0% transmittance 0% transmittance, ie, checks the error by the secondary emission spectra of samples or stray light by measuring a sample that does not pass through the .. optical. 100% transparent to measure the transmittance do not put the ... sample, to examine the 100% transmittance. Linearity and a calibration curve of the concentration ... and absorbance, and examines its linearity. Resolution is used, such as carbon dioxide ... ammonia, in the atmosphere, to examine separation degree of absorption peak (resolution). Repeat measurement accuracy I make sure that the measured more than once within a short period of time, a ... stable sample, in the accuracy within

specified variations in the measured value of the transmittance and the wave number.

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ASTM (American Society for Testing and Materials)

ASTM In, E1421-99 Standard Practice for Describing and Measuring Performance can be found in of Fourier Transform Mid-Infrared to (FT-MIR) Spectrometers Level Zero and Level One Tests. Unlike the pharmacopoeia which will be described later, and the JIS in ASTM, to measure the spectrum of polystyrene film and power spectrum, check whether there is any major change or malfunction of FTIR in the long term and short term. I gives a very brief introduction to the method described in E1421-99 Level Zero ASTM. Energy Spectrum Test - change of the power spectrum to compare the power spectrum at the time of the inspection ... and reference, check the changes in the long term. One Hundred Percent Line Test - 100% line change in a short period of time to calculate the 100% T line spectrum power spectrum was measured continuously ... inspection, check the change in a short time. Comparison with the reference measurement data of polystyrene - Polystyrene Test to evaluate by obtaining the difference between the spectrum of polystyrene film at the time of the inspection ... and reference. In FTIR-8400S/IRPrestige21, I am equipped with the standard validation program that conforms to Level Zero test of E1421-99 ASTM.

European Pharmacopoeia and Japanese Pharmacopoeia

It is described in the section adjustment method and apparatus in the general test method infrared absorption spectroscopy of the fourteenth amendment Japanese Pharmacopoeia first amendment.To test four items decomposition, wavenumber accuracy, reproducibility wave number, called transmittance reproducibility, standard value and procedure is established. In addition, common standards of the European Pharmacopoeia and (EP2000) (standardization) was held from fourteenth amendment Japanese Pharmacopoeia first amendment. The Company, as a method of validation of hardware FTIR, and not the method by JIS ASTM procedures are not defined clearly industrial purposes, and based on the Japanese Pharmacopoeia standards and procedures are clearly defined in the pharmaceutical industry I have adopted the method validation.

Contents of the Japanese Pharmacopoeia compliance validation program

So, I will introduce the validation program has been adopted in FTIR-8400S/IRPrestige-21. The items to be inspected, with five items power spectrum, decomposition, wavenumber accuracy, wave reproducibility, the transmittance reproducibility, check the performance of the device by comparing the specifications and measurements. Power spectrum can be carried out in the magnitude of the power spectrum performance evaluation the most basic of FTIR. It is normal that determines the magnitude of the power spectrum in the wave number specified is greater than the standard value, if greater than the standard value at the wave number of all specified. Decomposition for the decomposition, it has been described as right in the EP2000 and fourteenth amendment Japanese

Pharmacopoeia first amendment. It is evaluated to be acceptable and to determine the difference in transmittance of each if both exceed the standard value

2870cm absorption spectra were measured absorption spectra of polystyrene film of about 0.04mm thick, the -1 -1 resulting 2850 cm and minima near difference transmittance (%) at the maximum in the vicinity of 18% or -1 -1 more, and, 1589 cm and 1583Cm minimum of around and the difference of transmittance (%) at the maximum in the vicinity is 12% or more
Wavenumber accuracy and is described as the right to EP2000 and fourteenth amendment Japanese Pharmacopoeia first supplement on performance tests and on the performance of the wave number accuracy. The calculated at the wave number used to determine the peak wavenumber spectrum of polystyrene film was measured to determine whether it contains the allowable range in this program. It is judged acceptable peak wavenumber of all specified if within the allowable range.

(Cm wave number scale, characteristic absorption wave number of the following convention, a polystyrene film 1 of), corrected using some. In addition, Figures in brackets represent the acceptable range of values of these. -1 3,060.0 ( 1.5) cm -1 1,583.0 ( 1.0) cm -1 2,849.5 ( 1.5) cm -1 1154.5 ( 1.0) cm -1 1,942.9 ( 1.5) cm -1 1,028.3 ( 1.0) cm -1 1601.2 ( 1.0) cm

Wavenumber reproducibility reproducibility of the wave number, and is described as the right to the fourteenth amendment Japanese Pharmacopoeia first amendment. Specify three points the peak wave number in this program, is obtained in two measurements of polystyrene film the peak wave number of the actual at each point, and then determined by whether or not within the allowable range error between them. It is judged acceptable peak wave number of the wave number if the given within the allowable range all.

Transmission and 3000 ~ 1000cm polystyrene film reproducibility of the wave number, when measuring was -1 repeated twice and the absorption at several points in, 3000cm , the difference in wave number 5 cm near 1 -1 -1 or less, 1000 cm 1 cm in the vicinity to and within.

-1

It should be noted that the wavenumber reproducibility is not listed in the EP2000.

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Reproducibility of the transmittance for the reproducibility of the transmittance, in the EP2000 and fourteenth amendment Japanese Pharmacopoeia first amendment, and are described as below.

Transmission and 3000 ~ 1000cm polystyrene film reproducibility of the wave number, when measuring was repeated twice and the absorption at several points in the difference in the transmittance was 0.5% or less, ... and so.

-1

Specify three points a peak wavenumber This program is found in the two measurements the transmittance at each point is determined by whether or not within the allowable range error between them. It is judged acceptable difference in transmittance If it contains all of the allowable range. Behavior of the program validation program of Japanese Pharmacopoeia compatible, comes standard in IRsolution software that controls the FTIR-8400S/IRPrestige-21. Just follow the message you can do so simply by selecting from a menu of IRsolution, and displayed on the screen, you can do. You can check in all automatically when using the kit takes out external beam polystyrene film is mounted. When the measurement is completed, the report summarizing the test results are printed automatically. Validation execution result enlarged view power / polystyrene spectrum enlarged view

Validation program of Japanese Pharmacopoeia corresponding

Polystyrene film to be used for testing polystyrene film to be used for inspection, you can use the ones that are included with the FTIR of the Company. However, if traceability is required, the standard polystyrene film of SRM 1921a NIST (National Institute of Standards and Technology) - Please use Infrared Transmission Wavelength Standard the (Polystyrene Film).The SRM 1921a, polystyrene film about 38m thickness, 25mm diameter is attached to the holder of the paper of 5 11cm.National Institute Please use Infrared Transmission Wavelength Standard the (Polystyrene Film) - standard polystyrene film of SRM 1921a of Standards and Technology). Certificate attached to (certificate), storage method and how to handle, such as the expiration date is listed. As of December 2004, valid seems to be available until December 31, 2008. Please keep in a desiccator with the cover attached when not in use polystyrene film. In addition, it should not touch the polystyrene film surface, please do blow off with clean dry air dust. Of course, those contaminated or worse damage the polystyrene film is not valid.Certificate in (warranty), storage method and how to handle, such as the expiration date is listed. As of December 2004, valid seems to be available until December 31, 2008. Please keep in a desiccator with the cover attached when not in use polystyrene film. In addition, it should not touch the polystyrene film surface, please do blow off with clean dry air dust. Of course, those contaminated or worse damage the polystyrene film is not valid.

It is recommended to NIST SRM 1921a as of polystyrene film, but it is a situation where it is not available there is no stock in the NIST 27 June 2005. So I also recommend NIST traceable Polystyrene Test film for the secondary standard NIST-traceable International Crystal Laboratories of (ICL) made. This article is Shimadzu GL Sea and we deal with (list price 38,100 yen).International Crystal Laboratories of (ICL) made NIST traceable I also recommend Polystyrene Test film. This article is

Changes in the Japanese Pharmacopoeia 14th Edition first amendment

I think already, who have been made the validation based on the previous edition of the Japanese Pharmacopoeia also come. In the fourteenth amendment Japanese Pharmacopoeia first amendment which was promulgated on December 27, 2002, the "decomposition" "wavenumber accuracy" has been amended as shown in the table. The wavenumber accuracy, the definition of the number in () there was many of the misunderstanding was particularly clear. Table of amendments Japanese Pharmacopoeia

Item

Fourteenth amendment Japanese Pharmacopoeia

2870cm of absorption spectra obtained and -1 a minimum in the vicinity, 2851 cm that they are 18% or more, and the difference of transmittance (%) at the maximum of the -1 vicinity, 1589 cm and 1583Cm minimum of -1 around difference of transmittance (%) at the maximum of around 10%that is equal to or greater than. Among the absorption band below typically the polystyrene film, the wave number scale, corrected using some. The values in parentheses represent the accuracy at which these values have been established .
-1

Fourteenth amendment Japanese Pharmacopoeia first amendment

2870cm of absorption spectra obtained 1 -1 and minima near 2850 cm that they are 18% or more, and the difference of transmittance (%) at the maximum of the -1 vicinity, 1589 cm and 1583Cm minimum of -1 around near difference of transmittance (%) at the maximum of the 12% that is equal to or greater than.
-

Decomposition

Wavenumber accuracy

3,027.1 ( 0.3) 2924 ( 2) 2,850.7 ( 0.3) 1944 ( 0.3) 1,871.0 ( 0.3) 1801.6 ( 0.3) 1,601.4 ( 0.3)

1583.1 ( 0.3) 1,181.4 ( 0.3) 1154.3 ( 0.3) 1,069.1 ( 0.3) 1,028.0 ( 0.3) 906.7 ( 0.3) 698.9 ( 0.5)

(Cm wave number scale, characteristic absorption wave number of the following -1 convention, a polystyrene film of), corrected using some. The values in parentheses indicate the range of acceptable values for these values . 3,060.0 ( 1.5) cm -1 2,849.5 ( 1.5) cm -1 1,942.9 ( 1.5) cm -1 1601.2 ( 1.0) cm
-1

1,583.0 ( 1.0) cm -1 1154.5 ( 1.0) cm -1 1,028.3 ( 1.0) cm

-1

Qualification periodic inspection, operation and validation (Operational Qualification)

Is a thing of the same idea (OQ) validation, periodic inspection, Operational Qualification. Both, is a way to do inspection and calibration of the FTIR instrument in the procedure defined on a regular basis. The Company, I recommend the program to OQ validation and periodic inspection.

Validation of software

Execution of falsification check program

You need to verify that, as well as to check that the hardware is working correctly, software is working correctly. However, it you are becoming large ones the user to check black-box testing of the input / output of the test data the function is not possible for all of the software FTIR. However, unlike the hardware, the influence of the manufacturing process of the individual products on the product quality is small in the case of software, the product quality is determined by the development process most. Therefore, it is possible to check with a tamper check program that the files that make up the software becomes corrupted or does not or is removed, verify that the major features such as basic data analysis capabilities and security features to work correctly on the user side will. On the other hand, I will be verified by the software or have been developed properly, the computer validation during development has been carried out properly.