End-preparation Assessments and Tests for Compounded Sterile Preparations
Linda F. McElhiney, PharmD, RPh, FIACP, FASHP, FACA
The fungal meningitis tragedy that occurred in the fall of 2012 and the closure of NECC and AmeriDose has raised serious quality and safety concerns for health systems about outsourcing sterile preparations. Outsourcing has become a necessity to obtain sterile products that are currently on backorder. Although there are evaluation tools through the International Academy of Compounding Pharmacists (IACP) and the American Society of Health-System Pharmacists (ASHP) to assist hospital pharmacy leadership in selecting a compounding pharmacy or FDA-registered manufacturer that provides customized compounded preparations, there is still not a 100% guarantee that the contractor is following all of the United States Pharmacopeia (USP) standards for sterile compounding.1 Outsourcing sterile compounding can be very expensive and put a financial strain on a hospital pharmacy budget that is already tight. Pharmacy leadership in health systems are now considering the option of insourcing sterile compounding to reduce pharmacy expenses and control how these sterile preparations are compounded.
Many of the parenterals that are on manufacturer backorder, such as electrolytes used to prepare large volume parenterals, are relatively simple to compound. These commercial products are usually just the active ingredient dissolved in sterile water that is adjusted to a certain pH range and then sterilized by filtration and/or steam-autoclaved. It is also relatively easy to find information on the exact quantities of each ingredient through websites such as drugs.com, manufacturer package inserts, professional peer-reviewed journals, and credible compounding resources such as CompoundingToday.com. However, the key to preparing high-quality, safe, sterile preparations is end-preparation assessments and tests.
What are End-preparation Assessments and Tests?
The stated objective in the USP <797> chapter on sterile compounding is to provide and describe the conditions and practices required to safely compound sterile preparations in order to prevent harm and even death to patients receiving these medications. End-preparation assessments and tests ensure that the finished compounded sterile preparations (CSPs) are not contaminated with bacteria, fungus, endotoxins, particulate matter, or unintended chemicals. It also ensures that the patients will receive accurate doses and that the CSPs are compatible with the patients' body fluids, organs, and tissues. End-preparation assessments and tests are the final checks before a CSP should be dispensed and administered to a patient.
In health systems, many CSPs are batch-prepared and several patients may be treated daily with the same medications. If the batch-prepared CSP is not compounded properly or has been unintentionally contaminated, several patients could potentially suffer adverse events. It is imperative that if a health-system pharmacy department decides to insource and batch prepare CSPs on-site, each batch needs to be quarantined while certain assessments and tests are done to make sure that the CSP has been properly prepared and the patients' safety is not at risk. If any test fails, the compounding process should be analyzed to identify and correct any problems and the batch that failed testing should be destroyed. The pharmacy needs to be prepared and plan ahead because the testing can take up to 2 weeks to complete. The medical and nursing staff can be impatient with the testing process and may put some pressure on the pharmacist to release the CSP early. However, the patient's safety should not be compromised. Be prepared to offer an alternative treatment until the CSP has passed all of the testing and can be released.
Required and Recommended End-preparation Assessments and Tests
USP Chapter <797> states the assessments and tests that must be done on batch-prepared CSPs (25 units or greater) and high-risk level CSPs. These assessments and tests are the minimum that are required; however, there are recommend assessments and tests that may be done to further ensure the quality of the CSPs. Included with this document is a table that provides a list of all of these assessments and tests, and a brief discussion of these assessments and tests follows. All of the assessments and tests must be documented so that they can be reviewed if there are problems with the CSPs.
Required and Recommended Assessments and Tests for Batch-prepared Compounded Sterile Preparations.
|Physical inspection||Potency/purity testing|
|Compounding accuracy checks ||Particulate testing|
|Bacterial endotoxin testing|
All CSPs must be visually inspected to ensure that there is no unexpected precipitation, color change, cloudiness, or container leakage. A simple lighted box with a half-black and half-white background is a good tool to use for the visual inspection. Particulate or physical matter can easily be seen against the white background. Precipitation and cloudiness can easily be seen against the black background.
Compounding Accuracy Checks
All measurements should be double checked throughout the entire compounding process to ensure that the amount of each component is correct and to verify that the component is the correct chemical and salt form. Errors can be caught early in the compounding process using a double-check system before more expensive testing is done.
According to USP Chapter <797> standards, all high-risk level CSPs in batches of 25 or more single units or in multiple-dose vials (MDVs) must be tested for microbial (both bacterial and fungal) contamination. This is a minimum requirement, and the sterility testing process is described in USP Chapter <71> Sterility Tests. However, if a high-risk level CSP is batch prepared and can affect more than 1 patient, sterility testing is always recommended. If only 2 to 3 patients are receiving the CSP and all of them develop an infection due to microbial contamination of the CSP, the expense of treating all of those patients far exceeds the expense of sterility testing the batch.
It is even prudent to do sterility testing if the CSP is being administered to a single patient. Intrathecal pain medication is often prepared from nonsterile ingredients for individual patients with pain pumps, and the solution may be in the pump for at least a month. This CSP can be dispensed and administered to the patient before the testing is complete and, if there is any microbial contamination, the microbe can be identified and the patient can be notified and treated early before an infection fully develops.
Bacterial Endotoxin (Pyrogen) Testing
All high-risk level CSPs that are prepared in batches of 25 or more single units or in MDVs, except inhalation and ophthalmic dosage forms, must be tested for endotoxins to ensure that they do not exceed excessive limits, according to the USP Chapter <85> Bacterial Endotoxins Test and USP Chapter <151> Pyrogen Tests standards. If intraocular injections or topical ophthalmic preparations are compounded for use in ophthalmic surgical cases, endotoxin testing may be recommended because there have been some reported association between the presence of endotoxins and toxic anterior segment syndrome (TASS), which is an acute inflammation of the anterior chamber of the eye following cataract surgery.2
Potency and purity testing is not required; however, it is recommended for medication that has a narrow therapeutic dosage range. It should be done initially to ensure that the concentration of a CSP with a new compounded formula or change in the compounding process meets standards. The concentration should be within ±10% of the labeled concentration.
Sometimes errors, such as using the wrong salt form of a drug to prepare a CSP, can be discovered using this testing. For example, 180 mg of epinephrine bitartrate powder is needed to prepare a 1-mg/mL epinephrine solution because the bitartrate salt form is heavier than the base form. Using 100 mg of the epinephrine bitartrate powder to make 100 mL of a 1-mg/mL epinephrine solution will actually result in an epinephrine concentration of 0.56 mg/mL.
Particulate matter can usually be seen during a visual inspection of the final CSP; however, there are instances when the solution should be analyzed by a laboratory according to the testing method described in USP Chapter <788> Particulate Matter in Injections. For example, an ethanol lock solution must be sterilized by filtration, but ethanol can break down certain filters and create particulate matter that is difficult to see in a visual assessment. A microscopic particle count test may be necessary to detect the presence of this particulate matter.
The pH of a solution can affect the stability of a drug and may affect the comfort of administration of the solution. A pH reading may be done to determine if the solution is within a compatible range for the drug. Although doing a pH is not a required test, it is an inexpensive, simple test to do. The pH of a solution can change over time and degrade the drug.
In-house Testing Versus Contracted Laboratories
Physical assessments, accuracy checks, and pH are generally done in-house during the compounding process. The pharmacist doing these assessments and tests needs to be knowledgeable about the appearance and pH range of each CSP and is responsible for reviewing the compounding log to ensure that the CSP has been properly prepared and the quantities are correct. All pharmacies should have a pH meter and a lighted black/white box for assessing CSPs.
Although there are in-house testing kits for endotoxin and sterility testing, they may not comply with the USP testing standards. There is also a possibility that the pharmacist can be accused of bias because he or she may be doing everything (i.e., compounding, testing, interpreting the results, documenting the results). This could become a serious issue if there is a problem with a CSP or a reported adverse event.
Contracting an analytical laboratory to do the sterility, endotoxin, and potency testing can be a significant expense in the hospital pharmacy budget, but is necessary when insourcing and batch preparing CSPs. There are advantages to using a contracted laboratory:
- Testing is done according to the USP standards.
- The results are accurate, specific, and unbiased.
- The testing results can be accessed online, downloaded, printed as a Certificate of Analysis, and attached to the compounding log record.
For a fee, contracted laboratories can do the assessment and testing (e.g., pH, appearance, visual inspection) that is usually done in-house. They also offer additional testing that may be useful in verifying new compounded formulas, verifying pharmacy personnel's aseptic technique, investigating diversion cases, and identification of unknown substances. Testing offered may include:
- Drug or microbial identification
- Specific gravity
- Timed stability studies
Insourcing and batch preparing CSPs can be a viable option for a health system. It can significantly decrease drug-spending costs, and the pharmacy has a complete record of the compounding process. The key to preparing high-quality, safe, sterile preparations and meeting USP standards is end-preparation assessments and tests.
- United States Pharmacopeial Convention, Inc. USP on Compounding: A Guide for the Compounding Practitioner. [USP Website.] 2013. Available at: www.usp.org/store/products-services/usp-compounding. Accessed January 16, 2013.
- Hellinger WC, Bacalis LP, Edelhauser HF et al; Task Force on Cleaning and Sterilization of Intraocular Instruments. Recommended practices for cleaning and sterilizing intraocular surgical instruments. J Cataract Refract Surg 2007; 33(6): 1095-1100.
Linda F. McElhiney, PharmD, RPh, FIACP, FASHP, FACA
Compounding Pharmacy Operations Coordinator
Indiana University Health
550 N. University Boulevard, AOC 6201
Indianapolis, IN 46202