Process Validation

In a general sense, validation is any mechanism that will establish a high degree of assurance that specific processes are achieving their objective. Its ultimate goal is to produce products that consistently meet predetermined specifications and quality attributes. Consistent quality (and improvement if possible) is a "must" for the health and well-being of the patient and should be an on-going process.

Several types of "quality control" can be developed for sterile compounding.

Media Fills

The Validation subsection of Section <1206> of the USP 24/NF19 describes an evaluation procedure commonly referred to as "media fills." The evaluation involves an operator manipulating microbial growth media (usually soybean casein digest medium) according to a prescribed validation procedure. The procedure requires multiple aseptic transfers to multiple containers. It is recommended that the validation procedure by done at peak periods of fatigue, stress, and pacing demands (e.g., immediately after normal production activity).

The premise behind media fills is that the growth medium will support the growth of the contaminating microbe, and this growth can be detected. The other requirement of the validation is that the media must be manipulated using the same aseptic techniques actually being evaluated.

It is important to note that this validation is not intended to be a one time evaluation. The USP 24/NF19 recommends that competent operators be challenged quarterly. Other references suggest that 40 validation sample should be prepared for each 800 admixtures prepared, or that 10 validation samples be prepared each month. Regardless of the frequency, a competent sterile compounder will need to be evaluated on a regular and on-going basis.

Sterilization

There are several types of sterilization but the most appropriate method will depend on the physical and chemical properties of the preparation and its packaging. Typically, dry heat, filtration, and steam sterilization are used with compounded preparation.

Sterility Testing

Of the two general types of tests, one involves the use of culture medium and the other uses biological indicators. When using culture medium, the test sample can be introduced directly into the medium or the sample can be filtered and the filter transferred to the culture medium. There are several media that can be used in these tests, such as Soybean-Casein Digest Medium (SCDM), Fluid Thioglycollate medium (FTM), and dithionite-thioglycollate broth HS-T.

Biological indicator is usually the preferred method of verifying sterility. It is a preparation of a specific microorganism that is resistant to a particular sterilization process. The microorganisms are embedded either on paper or on plastic strips and are included with the materials being sterilized. USP-NF General Chapter <1035> Biological Indicators for Sterilization states that there are three types of biological indicators: 1) Type 1: a biological indicator that included spores that are added to a carrier and package to maintain the integrity and viability of the incubated carrier 2) Type 2: a spore suspension that is inoculated on or into representative units of the preparation to be sterilized. This represents an inoculated preparation; however, a simulated inoculated preparation may be used if it is not practical to inoculate the actual product 3) Type 3: a self-contained indicator. It is designed so that the primary package, intended for inoculation following sterilization processing, contains the growth medium for recovery of the process-exposed microorganism. This form of biological indicator, together with the self-contained growth media, can be considered a system.

Sterility Testing Failures

USP-NF Chapter <797> addresses the actions that should occur when a pharmacy encounters a sterility failure of a compounded sterile preparation. The chapter is not prescriptive on how to perform an investigation. However, there are certain basic points that should be covered and documented since the compounder may be asked to reproduce the information for future audits or inspections.

If the CSP has been dispensed before starting a failure investigation, a recall should be initiated by appropriate personnel, and patients and physicians should be immediately contacted. A recall should be followed and fully documented. If the CSP has not been dispensed, it should be quarantined until the investigation is complete.

The investigation should have a systemic procedure to review all of the items associated with the compounding of the CSP. Records of the compounding activity should be reviewed and other sterility failures or out of specification results examined for trends or consistent failure points. Further investigation may be needed and it has been suggested to conduct the investigation of the pharmacy operations using the acronym PEEMM, which represents people, environment, equipment, materials, and methods.

Depyrogenation and Endotoxin Testing

Pyrogens are organic compounds that are soluble in water and are not removed by filtration. They usually are endotoxins produced by gram-negative bacteria and are found in the cell wall. Endotoxins are at least 1000 times more potent than any other microbial agent and are stable over long periods of time. The endotoxins increase capillary permeability, and in small concentrations cause a variety of adverse effects such as fever, diarrhea, altered resistance to bacterial infections, complement activation, and leukopenia followed by leukocytosis. In greater concentrations, they cause septic shock that can lead to multiple organ failure and death.

The endotoxin test is the simplest test to perform in-house at the time of compounding. The test uses disposable Limulus Amebocyte Lysate (LAL) catridges in a handheld spectrophotometer. During the testing procedure, kinetic chromogenic reagents and endotoxin controls are dried in the channels of the polystyrene catridge. Diluted medication is pumped though the channels and mixed with reagents. The software monitors optical density changes in the solution, determined to reaction times, and interpolates the results against an archived endotoxin standard curve. The analysis is automatic, and the results can be read and interpreted in 15 minutes.

The types of preparations that should be screened for pyrogens include injectable preparations, intrathecal preparations, and all high-risk level sterile preparations made in batches of 25 or more. The decision to do endotoxin testing is often determined by the cost. When time is a factor and results are needed before a preparation is administered, an in-house endotoxin test kit is preferable to submitting a sample to an independent laboratory for testing. If contract laboratory testing is deemed preferable, then determining the reliability and accuracy of the endotoxin testing offered is essential.

Other Methods

• A process validation might involve sending formulations to contract analytical laboratories for testing. Analysis of drug content, sterility, and pyrogenicity can be routinely done using randomly selected samples.
• Process validation could be observing and testing formulation variables such as color, clarity, uniformity of dispersion, odor, consistency, pH, specific gravity, etc.
• The validation could also be documenting adherence to formulation records, policies and procedures, SOPs using compounding records, or techniques or procedures. Some example forms for Home Infusion Pharmacies have been published.