The Risks and Problems Caused by Non-sterile Pharmacy Procedures
On the whole, the risk to patients appears to spring from three main elements: quality of the compounding materials, non-compliance with compounding best practices, and non-sterile facilities.
Fatalities
Concerns about the health and safety of confined patients were heightened in the 1960s and 1970s by the chagrined discovery that one of the culprits was contamination during the administration of medication and non-sterile compounding procedures. (1) The first to take up the cudgels in this respect was the US Pharmacopeial Convention, Inc. that put together the National Coordinating Committee on Large Volume Parenterals (NCCLVP). Even then, the goals were clear: to redress the instances of microbial contamination, massive adulteration with bacterial endotoxin, significant errors in compound strength or components, and ingredient errors in compounded sterile preparations (CSPs) that lead to patient harm and even fatalities. (8)
Compliance with Voluntary Standards
Despite having progressed to the point of crafting and putting forward standards for preparing, labeling, and doing quality checks on pharmacy department admixtures, the NCCLVP simply dissolved in the 1980s mainly because compliance was voluntary. Nonetheless, the FDA was insistent that pharmacies needed to do their part to mitigate the incidence of hospital-acquired infections and patient mortality. Under pressure, important segments of the industry – the American Society of Health-System Pharmacists (ASHP), the United States Pharmacopeia (USP) as a regulatory body, and the National Association of Boards of Pharmacy (NABP) – each created and released practice recommendations. These at least established the principle that pharmacists were professionally responsible for the proper preparation, labeling, storage, and delivery of CSPs.
As a kind of interim measure, USP followed up by releasing chapter <1074>, “Dispensing Practices for Sterile Drug Products Intended for Home Use” in 1992. This section of the National Formulary effectively served as a refresher guideline for community pharmacists on preparing and dispensing sterile drug preparations for in-home use. This covered, of course, the entire spectrum, including environmental conditions, aseptic technique, quality assurance, training all those concerned (including patients and in-home caregivers), testing compounds prior to release, storage, and expiration dating. But even though the USP was a regulatory agency, what became known as “<1206>, Sterile Drug Products for Home Use” was a purely voluntary reference as indicated by the chapter numbering (10, 11).
A 1993 Technical Assistance Bulletin (TAB), “Quality Assurance for Pharmacy-Prepared Sterile Products” released by ASHP was well-intentioned in that the document detailed quality assurance and operating parameters for every possible practice setting: hospital pharmacy departments, long-term care homes, community/retail pharmacies and managed-care organizations. This was the first extant document that proposed the three-level risk categories (see section C, “Risk Levels” below). The TAB failed to make headway with the profession because, on one hand, some pharmacists wanted more specific procedures and standards and, on the other hand, others objected to the cost of implementing “excessive” measures since no evidence of effectiveness was provided.
Around the same period, another response by the ASHP to FDA pressure was to issue the ASHP “Guidelines on Quality Assurance for Pharmacy-Prepared Sterile Products” concerning sterile procedures and compounding standards. Again, compliance was voluntary and only a minority of pharmacies implemented the suggested rigor in practice. (5)
Benchmark and follow-up surveys of hospital pharmacy directors done in both 1995 and 2003 had essentially the same findings. As few as one in twenty hospital pharmacies bothered to comply in any significant way. Not even the perils associated with compounded risk-level-1 preparations (see the following section, “Risk Levels”) would convince the lion’s share of pharmacies to adopt the proper garb, for example. (7)
Risk Levels
Under guidelines from USP <797>, a pharmacist may assess the tolerable risk for a given compounding need according to storage conditions when the ingredients are already at or close to “beyond-use dates” and according to these three levels of environmental and procedures risk: (8)
LOW – Air quality in the compounding room is up to ISO Class 5 (Class 100) standards. Mechanical manipulation is confined to the aseptic opening of ampoules and sterilized needles penetrating sterile vial stoppers to fill sterile syringes. All devices ancillary to administration are also sterile. The compounding task itself is limited to transferring, measuring, and mixing the component medications in sealed containers.
MEDIUM – On top of what prevails under “low-risk”, this risk level is defined by the fact that lengthy single compounding or batch processing is involved, the compound will be administered over a period of days, aseptic manipulations are complicated by multiple volume transfers, and the CSPs do not include broad-spectrum bacteri.
HIGH – Nonsterile ingredients and devices are used, the nonsterile compound is left standing at least six hours before terminal sterilization, purity and potency of ingredients are merely assumed and not checked. As well, at least one of these is exposed to air quality that does not meet ISO Class 5 standards: ingredients, components, devices, and mixtures (8).
Adding to the risk spectrum is “beyond use dating”. Based on the manufacturer’s proostaticduct labeling and USP <797>, this represents the optimal storage time for CSPs according to storage temperature (see Table 1 below).
Table 1: Beyond-Use Dating Based on Risk Level and Temperature
Meeting the Sterility Challenge
Even as the ASHP Guidelines were being crafted, a Society survey of short-term, nonfederal hospitals concerning quality assurance for intravenous admixture preparation revealed practices that would have to be accommodated or optimized:
With respect to the manner of preparation, first of all, nearly all pharmacy departments prepared sterile drugs at need though almost two-thirds also admitted to batch preparation for compounds that are more often in demand. Batch preparation is obviously more conducive to deliberate compliance with the sterile procedure while the absence of ready reserve when the medical order bears the word “stat” can predispose to hurried “sterile” procedure.
There was a constant need for re-training pharmacists and pharmacy technicians in aseptic technique, the popular educational means being lectures or videotapes, “hands-on” training, manuals of policies and procedures, and direct observation by experienced senior pharmacists.
Virtually all pharmacies were equipped with laminar-airflow hoods though only three-fourths limited staff access to rooms so equipped, just half bothered to re-certify the hoods at the requisite twice-yearly intervals or changed prefilters monthly, as required by proper aseptic technique.
Half the pharmacies lacked policies and standard operating procedures for ensuring purity, concentration, sterility, or non-pyrogenicity.
Fewer than one in three conducted either environmental or sterile product tests for contamination by bacteria or pyrogens, the substances that cause fevers. In both cases, constructive remedies include filtration, distillation, chromatography, or inactivation.
Two-thirds of pharmacies responding to “stat” requests relied solely on microbial filtration to ensure that they could dispense sterile compounds. Even worse, 84% of batch processing also implemented only microbial filtration.
The First Line of Defense: Product Quality
Over four dozen cases of substandard quality or efficacy of compounded sterile preparations have been brought to the attention of the Food and Drug Administration (FDA) by pharmacy departments of hospitals. Given the time span of nearly two decades over which these occurred, from 1990 to the present, the prevalence of the problem may seem extremely tiny. In many cases, however, it was found that product quality and expiry periods had been so compromised that the FDA was prompted to issue product recalls.(6)
In the case of community pharmacies, a 2001 survey by the FDA of a tiny sample – 29 product samples from as many compounding pharmacies – selected at random from around the nation also uncovered quality problems but no sterility failures. It may be indicative that around one-third of the sample compounds had sub-par potency. Once again, sick patients were paying for, and receiving, medication that was at least ineffective and at worst would lull them into complacency when aggressive treatment might be called for. (6)
Enforceability of USP<797>
USP released Chapter <797>, “Pharmaceutical Compounding—Sterile Preparations” on January 2004 as the first legally enforceable set of requirements and standards for CSP’s. From then on, pharmacy departments and community pharmacies were regulated and could be inspected by such accreditation organizations as the Joint Commission on Accreditation of Healthcare Organizations (JCAHO), Accreditation Commission for Health Care, and the Community Health Accreditation Program for strict adherence to sterile procedures. Pharmacies also came under the purview of the FDA and state boards of pharmacies for compliance with sterile compounding procedures, although the latter is something of a “post hoc” exercise since looking into sterile practices is discretionary during routine inspection visits but mandatory and thorough when deaths occur (8).
Compounding
Lastly, there occurs the question of whether permitting pharmacies to continue compounding is worth the cost of the numerous environmental, skill and quality assurance standards that aseptic technique demands. Part of his efforts to reform the health sector was President Clinton’s signing the US Food and Drug Administration Modernization Act (FDAMA) of 1997. Section 503A, entitled “Pharmacy Compounding,” took the view that letting pharmacies continue compounding difficult preparations on an ad hoc or “stat” basis raised patient risk to unacceptable levels and therefore granted the FDA oversight for such compounds. Not surprisingly, hospitals challenged in court the limitation on their freedom to compound. In 2001, the Supreme Court struck down Section 503A as “unconstitutional”.
At the risk of stating the obvious, the enforceable guidelines in USP <797> apply to all licensed pharmacies and all medical disciplines in any healthcare setting where sterile preparations are compounded. This means not just pharmacists but also technicians, nurses and physicians in hospitals, satellite pharmacies, office practices, and extended-care facilities. The enforceable guidelines cover:
Engineering controls in pharmacy compounding clean rooms that meet ISO Class 5 hoods in an ISO Class 8 environment. This is applicable to both simple admixtures compounds employing using closed system transfer and to “low” or “medium” risk procedures listed in item C) below.
Full sterile procedures and aseptic practice in nursing stations, patient rooms/bedside and outpatient care centers.
Risk level as to actual compounding, segmented into: 1) Low and Medium – when several vials of lyophilized powder are reconstituted with sterile diluent before being transferred singly to minibags or to make up a large amount of parenteral solution; and, 2) High – when the reconstituted solution is first passed through an empty bottle. (8)
Risk level as to liquids: 1) Low – Simple admixtures; 2) Medium – Admixtures with multiple additives, batch processing for use over several days, hydration solutions, reconstituting several single-dose vials of small volume parenterals or antibiotics; and 3) High – Ingredients are in powder form and are non-sterile (as in the case of injectable nutrition solutions, morphine, narcotics in general), compounds having no bacteriostatic component, transfers using open systems, or where the final container still has to be sterilized (8)
Passive environmental measures: even proper ventilation helps prevent dangerous accumulations of bacteria and pyrogens. The higher the risk, the greater the need for isolating anterooms, laminar airflow workbenches, and putting in other barriers to airborne particles. Proper engineering expertise is required to install or retrofit ceiling and exhaust fans with integrated high efficiency particulate air (HEPA) filters. Expert outside advice is also valuable for: a) confirming that refrigerators, computers, and printers should be removed from the compounding area for the bacterial or pyrogen accumulation risk they pose; and, b) the often-overlooked step of installing plastic-coated “clean room grade” tiles in place of the highly-porous acoustic ceiling tiles often used or substituting seamless vinyl floor covers for porous wood, concrete, marble or the grout used to line ceramic tiles. (10)
It is also critical to implement systematic process and preparation quality controls. Since it goes without saying that pharmacists and pharmacy technicians require proper refresher training and supervision, systematic quality assurance means working towards the goal of CSP sterility by “manualizing” compounding procedures so as to more easily predict where critical quality failures might take place and putting controls in place that assure consistent sterility. Accomplishing this requires researching guidance documents or bringing in experts to consult on suitable aseptic techniques, systematic process validation procedures, and methods for checking at least correctness of compound content, sterility and stability (see also following item G) of the finished CSP.
Beyond-Use Dating requires vigilance where a) stability of chemical entities in solution is concerned and b) absolute sterility. While storage conditions can extend expiration date, one must follow an “all or nothing” standard for sterility: the finished CSP must have no viable microorganisms at all. USP <797> gives guidance on the operating principles and risk levels (see also section I-C above) associated with protecting patients from this microbial contamination route. Specifically, Table 2 in USP <797> provides the practical limits for maximum beyond-use dating unless the finished CSP is once again tested for sterility. If done according to the stringent requirements of USP <71>, the pharmacist can re-label a maximum-use date that still meets the optimal chemical stability period authoritative references assign the compound or solution.
It is also preferable that compounds and solutions be pyrogen-free but there is some flexibility in this regard.
Conclusion
To sum up, the necessary parameters for ensuring sterility in pharmacy compounding count adherence to USB <797> specifications for aseptic procedures in all venues, sterile practice according to risk level of the CSP and facilities, ventilation, construction or retrofitting to “clean-room” materials and ISO Class 8 standards, and conforming with USP <71> sterilization procedures when extended beyond-use dating is desired.