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The advent of , the recently published United States Pharmacopeia (USP) chapter, entitled "Pharmaceutical Compounding-Sterile Preparations," has left the compounding pharmacist with the job of implementation.1 Numerous articles and guidelines exist to perform gap analyses between existing procedures and new requirements, but practical examples of what to implement are still in process.2-4 What follow are basic implementation plans for the microbiology, sterility, pyrogen and potency testing requirements of USP Chanter .

Contract Laboratory Testing

Many contract laboratories exist in the pharmaceutical, food and medical device industry that are well equipped to manage the needs of finished-product testing for compounding pharmacies. The issue of timing to get samples to the contract laboratory can usually be managed via overnight delivery service. Using a reputable and usually US Food and Drug Administration (FDA)-registered facility to accomplish these testing requirements can give the compounding pharmacist a certain comfort index. Customarily, contract testing laboratories would have all the validated procedures, methods and equipment required to perform all the USP Chapter specified testing. These operations are typically managed by trained professionals and are conducted in a quality-system environment designed for efficient processing of samples for environmental monitoring, sterility testing and pyrogen and potency testing. Not all compounding pharmacies have functional microbiology and chemistry laboratories, and using contract laboratory testing may he an interim Hx or a long-term solution. Assessment and documentation of the quality of the selected contract laboratory through an audit or quality questionnaire should he considered.

Pyrogen (Bacterial Endotoxin) Testing

A stated intent of USP Chapter is to prevent adverse patient reaction to "excessive bacterial endotoxins." Bacterial undotoxins (BET) are pyrogens (fever-producing agents) that are derived from the cell wall of grain-negative bacteria. Any substance that contacts the parenteral fluid must be nonpyrogenic. USP Chapter references LA.9P Chapter ' for BKl test methodologies and requires that all high-risk compounded sterile preparations (CSPs), produced in batches of greater than 25, be tested. However, it is prudent practice that the nonpyrogenic nature of all CSPs be assured. Nonpyrogenicity is typically confirmed in the pharmaceutical industry through the use of end-product batch (lot) testing. This is not always practical or possible in a compounding pharmacy operation. The FDA does, however, recognize alternatives to this practice, if it can be demonstrated that production process and materials of compounding arc controlled from a RRT contamination standpoint. Therefore, the compounding pharmacy has several possible approaches to meet the BET contamination requirement. Each lot of product could be tested, or a program that demonstrates that the compounding materials and processes are under control can be defined. Materials can be purchased with a nonpyrogenic certificate of analysis from the vendors. The compounding process can be assessed periodically to ensure that BET is not being inadvertently introduced into the process. This system assessment can be performed daily or on an alternatively scheduled basis. (see the discussion of testing frequency in the "Media-Fill Testing" section.)

Environmental Monitoring

Compounding of CSPs is normally conducted in a laminar flow workbench that provides a precisely controlled work environment suitable for CSP compounding. These units are designed to produce an International Organization for Standardization (ISO) Class 5 (US FS 209 E Class 100) working environment. Alternatively, barrier isolator systems can also be used for this purpose. Simply stated, all ISO Class $ (Class 100) areas should routinely be monitored for microbial air quality at a minimum of once a month, or weekly if high-risk compounding methods are employed. This frequency can be established only after initial studies of at least 3 consecutive compounding days yield acceptable results. This initial 3-day study provides a baseline of the indigenous microbial flora present in the compounding environment and demonstrates the proper functioning of the hood or isolator system. This testing is performed in addition to the biannually scheduled mechanical certification of the operation of the high-efficiency particulate air filters filtration system of the ISO Class $ equipment. Duplicate samples should be taken at opposite ends of the Class 5 area. The expected and desired result for air quality in Class S is zero microbial counts. In 3 consecutive days of sampling, a microbial count of no more than one colony forming unit on any 3 days is acceptable. Settle plates and/or active air sampling using such products as centrifugal air samplers or slit-toagar samplers can be used for this study. Settle plates would be exposed for the entire compounding procedure or no more than 4 hours whenever compounding takes place. It is also recommended that daily finger touch plates should be performed. This simple procedure requires the technician to periodically, during the compounding time period, sample his or her own fingertips by touching the surface of a Soybean casein Digest Agar (trypticase soy agar) plate. These plates are collected by a designated person and sent to the microbiology laboratory for processing. Fingertip plates should be sterile with a limit of no more than three colony-forming units per glove.

The areas immediately surrounding the Class S area should be monitored at a minimum of every 6 months and monthly for medium- and high-risk compounding operations. These areas should be designed to function as TSO Class 7 (US FD 209 R Class 10,000) or ISO Class 8 (US FS 209 E Class 100,000) cleanliness zones. Only air samples are recommended to be taken outside the ISO Class 5 compounding space. At all times, one should have a rationale documented for where samples are taken, as well as where they are omitted. This rationale should be risk-based on the potential for product contamination. Because atmosphere and personnel arc the primary sources of microbial contamination, sampling sites should be selected in high-traffic areas where the potential exists for direct product contact or contact with product-contacting surfaces. A minimum of five samples should be taken throughout the compounding-room environment, immediately adjacent to the ISO Class S area.6

Sterility Testing

A test for sterility, as described by USP Chapter 7 which is referenced by , is not easy to perform. Requirements for sample size, bacteriostasis/fungistasis byproduct type, growth promotion, method validation, etc., must be considered. Although it is apparent that membrane nitration with 14-day incubation methodology is the method of choice, it is not always possible. Certain compounded products are turbid and require a subculturing step, which extends the incubation period by at least 4 additional days, for a total of not less than an 18-day incubation.

Sample size for small lots versus large lots may be discussed in specific state pharmacy regulations. The requirements outlined in (JSF Chapter for sample size and methodology may be different from those specified by state regulations. Therefore, [JSP sterility testing is not always a clear option for all products, and a written scientific-based rationale to support whatever methodology is selected for sterility testing must be prepared. Based on the above-indicated lack of consistency between recommended or required sterility testing methods, the testing approach could include daily media-fill testing, aliquot sampling or rapid analytical microbiology methods (sec the "Rapid Analytical Microbial Methods" section) or a combination of these procedures. In all cases, any recovered microbial growth should be characterized by means of a sterility-indicating test.

Media-Fill Testing

For assessing the competency of compounding personnel and aseptic processing procedures, the proper use of media-fill testing is one of the most powerful tools in the quality program. Semiannual media fills have keen the norm in aseptic pharmaceutical manufacturing for years/ To comply with UiSP Chapter , annual media 611s are required to assess the competency of the compounding professional for low- and medium-risk applications, and semiannual media R)Is are required for high-risk operations. It is strongly recommended that, in major compounding centers with multiple compounding professionals, media fills be performed at least quarterly to assess the continued control oi the compounding process. This can be accomplished by rotating people, compounding processes and time periods so that all combinations of personnel and compounding processes are evaluated. Environmental microbial sampling (see "Environmental Monitoring" section) should be conducted whenever a media fill is performed. Any media fill that is positive (ie, for microbial growth) should be characterized.

The actual methods used to perform media-fill challenges are specifically described, by risk type, in USF Chapter . However, a written rationale as to the applicability to each individual practice in the compounding center should be documented. Additionally, protocols defining the exact procedures should be prepared; and final reports documenting the results should be written and archived to document the competency of the compounding technicians, as well as the process itself. A media fill should reflect the actual class of manipulations routinely performed and include all potential interventions. It should be noted that the media-fill procedure is designed to provide a worst-case challenge to the compounding process. In some cases, more than one media-fill type will need to be performed, or at a minimum, the written rationale should justify the compounding challenge. With multiple operators rotating through multiple procedures, an efficient, cost-effective schedule can be implemented. Some centers find media fills performed every compounding day to be the best indication of sterility assurance.

Rapid Analytical Microbiology Methods

New technology is in the initial stages of development and implementation in the pharmaceutical and medical device industries. One or more of these technologies may be suited for application as a sterility-indicating test for the pharmacy compounding operation. One such test is the Scan RDI System from Chemuncx, Inc. (Paris, France), which uses solid-phase cytometry to measure, within hours, the presence of viable organisms. The test could be used to test a direct nliquot of the CSP and obtain results in hours, or an enrichment technique could be used to improve sensitivity and obtain results within 1 to 2 days. This would obviously be a significant improvement over the UiSP 14- to 18-day membrane sterility test. It must be cautioned that the Scan RDl test would not be a replacement for UiSF Chapter at this time. However, with the afore-mentioned enrichment method, an early warning of contamination could be possible within 1 to 2 days. This may be of significant value if USF Chapter testing cannot be accomplished or when potential product-sterility issues are being investigated.

Interpretation of Results

Many of these test results may be new to the compounding professional and, therefore, time should he devoted to understanding their significance. The safety of ClSPs is dependent upon all the quality systems working together. Microbiology data are only one aspect of this total integrated quality program. Any excursions must be evaluated in context. Is the excursion real? Does it impact patient safety? Is this a system error or data collection error? What do I do? The procedure and rationale used in these types of investigations, which are referred to as out-of-specification (OOS) investigations, must be documented. The OOS investigation is designed to ascertain the root cause(s) of the adverse observation and to identify the appropriate corrective and preventive actions to resolve the problem and prevent it from recurring in the future.

Quality-Assurance Program

A CSP provider must have a functional, formal quality-assurance program. The program should provide a mechanism for the monitoring, evaluation and continuous improvement of the compounding operation. Throughout this article we have discussed the need to provide documented protocols, standard operating procedures, rationales and evidence of compliance with the many requirements of USP Chapter . This requirement for documentation, as well as the information itself, provides the framework of an effective quality-assurance system. The program must be dynamic and, therefore, requires periodic reassessment to ensure sustained compliance.

References

1. United States Pharmacopeial Convention, Inc. United States Pharmacopeia 27-National Formulary22. Rockville, MD: US Pharmacopeial Convention, Inc.; 2004: 2350-2370.

2. Rahe H. Overview of USP Chapter "Pharmaceutical CompoundingSterile Preparations": The potential impact for compounding pharmacies. /JPC2004; 8(2): 89-94.

3. Kastango ES. ASHP Discussion Guide on USP Chapter Pharmaceutical Compounding-Sterile Preparations. Bethesda, MD: American Society for Health-System Pharmacists/Baxter Healthcare Corporation; 2004.

4. [No author listed.] American Society of Hospital Pharmacists. ASHP guidelines on quality assurance for pharmacy-prepared sterile products. Am J Health Syst Pharm 2000; 57:1150-1169.

5. United States Pharmacopeial Convention, Inc. United States Pharmacopeia 27-National Formulary 22. Rockville, MD: US Pharmacopeial Convention, Inc.; 2004: 2169-2173.

6. [No author listed.] Guidance for industry sterile drug products produced by aseptic processing-current good manufacturing practice. [U.S. Food and Drug Administration Website.] September 2004. Available at: www.fda.gov/cder/guidance/5882fnl.htm. Accessed October 22, 2004.

7. United States Pharmacopeial Convention, Inc. United States Pharmacopeia 27-National Formulary 22. Rockville, MD: US Pharmacopeial Convention, Inc.; 2004: 2157-2162.

8. [No author listed.] PDA. PDA Technical Report No. 13 Revised: Fundamentals of Environmental Monitoring Program. Bethesda MD: PDA, Inc.,'September/October 2001.

Ross A. Caputo, PhD * Anne Huffman, BS * Robert Reich, BS, MS * Pharmaceutical Systems, Inc. * Mundelein, Illinois

Address correspondence to: Ross A. Cnjmto, PbD, Pharunicentkal Systems, Inc., 909 Orchard Street, Mmidele'm, U. 60060

Copyright International Journal of Pharmaceutical Compounding Jan/Feb 2005
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