Creating Standard Operating Procedures for Particle Size Analyzers

With the increasing emphasis on method transfer within large pharmaceutical companies, the correct formulation of Standard Operating Procedures (SOPs) for particle sizing is becoming of paramount importance in ensuring that consistent results are obtained—not only within the same laboratory but also in different laboratories across the world. Studies show that there is a clear hierarchy to sources of variation between measurements (see Table 1). The latter two error sources are the largest, and are under the direct control of the user. The creation and management of SOPs are the key to reducing these two possibilities of error and variation, and obtaining the best results from your instrument.

Table 1. Sources of variation

Aims

There are two reasons for the creation of an SOP:

• To eliminate user and laboratory variability so that everyone within an organization can make useful measurements and detect real variations in product with confidence
• To satisfy a regulatory authority that a laboratory or method is compliant with Good Laboratory Practice.

Therefore the main requirements of an SOP are:

• Achieving a method that is the best available, and which can be transferred with confidence to any part of the world
• If the measurement operation is to be subject to regulatory scrutiny, a detailed traceable record is kept of every step in the process of creat-ing the SOP

Leave Nothing to Chance

When writing the SOP make sure that every parameter specified is standard and not subject to local variation. Following are some suggestions to assure this happens:

Define the compound to be measured. If the compound exists in several forms (anhydrous/crystalline etc.) make sure that it is clearly understood which form is the subject of the SOP.

Specify a sampling method. Sampling variations can account for variations of up to 30% if care is not taken. If the sample is to be withdrawn from a bag of powder, be aware of the stratification, which can occur with handling. Make sure that the sample is thoroughly mixed or riffled. If the sample is a suspension, make sure that it is thoroughly agitated before withdrawing a sample.

Find a suitable dispersant. The best dispersant is the most inert, least toxic, cheapest material which best disperses the material as a fine cloud of primary particles. If a true non-solvent can not be found, then a saturated solution may be the only (non-ideal) option. Concerns and cautions with saturated solutions include possible toxicity, cost, time consumed in creating and filtering saturates, temperature control, etc. If no data can be found from reference sources, then a series of solubility tests must be carried out using dispersants which are most likely to be suitable. It is useful to combine these experiments with a test of the dispersibility of the material in the various candidate dispersants. Place samples of the various dispersants in watch glasses or small beakers and disperse the material in the beakers.

Things to Look For

Does the material visibly dissolve? Does the material agglomerate, float or refuse to disperse readily (a surfactant or ultrasound may help)? Does the material seem to stick to the glass (this will usually be determined by the polarity of the solvent)? Put a drop of each suspension onto a microscope slide (without a cover glass) and take a photomicrograph of each to show how well each dispersant works. These photographs should be held on file to show any auditor who may want to query the thoroughness of the work.

Measure the material in the particle sizer using the various dispersants. Perform repeat measurements to check the stability of each dispersion. Does the material agglomerate over time? Do the fines disappear? Does the obscuration change significantly? Keep all the results on file to justify your choice of the correct dispersant. If the material still fails to disperse properly in the "best" dispersant that can be found, then it will be necessary to repeat the exercise using various surfactants or additives until a satisfactory combination is found. Keep all the results of all the tests on file. Once the best combination is found, define the method that was used to achieve the measurement. Remember the object of the exercise is to eliminate any variability.

Your specification will include the following variables:

• The instrument used and all the settings
• If a solvent is used as the dispersant, specify the grade which should be used
• If water is used as the dispersant, specify whether it is deionized or distilled. Never specify tap water for multisite SOPs—the surface chemistry differences created by the different concentrations of ions in different water supplies will guarantee that no two users obtain agreement of results.

Standardize Instrument Operation

Whenever possible you should standardize instrument operation and keep a centralized method common to most SOPs. In an organization producing many hundreds of materials, including a description of the actual operation of the instrument in every single SOP would be tedious. Consequently it is normal practice to produce a single set of centralized operational descriptions which describe how the instrument should be set up, operated, and shut down for each type of measurement (large volume wet/small volume wet/dry) which is commonly undertaken. These descriptions can then be referred to in subsequent SOPs for individual products which can then simply describe any exceptions or variables. In this way, the SOP can simply be produced as a form detailing the relevant values for all the possible instrument settings and measurement variables such as the concentration and quantity of any surfactant used in the measurement, etc...

For more information: Mark Bumiller, vice president, Malvern Instruments, Inc., 10 Southville Rd., Southborough, MA 01772. Tel: 508-480-0200, ext. 222. Fax: 508-460-9692.