The proposed LVP regulations required that air microbial quality be monitored in both critical and noncritical areas, although
this was not accepted practice at the time. Allowable microbial levels or the types of organisms permitted were not specified
because little historical data were available to FDA. In time, however, voluntary standards and guidance documents appeared
that manufacturers agreed to comply with. Both the United States Pharmacopeia and EC Guide to Good Manufacturing Practice provide recommended microbial standards that many manufacturers observe, although these standards are not legally enforceable.
With proper HVAC design and construction, room finish selections, disinfection procedures, and personnel gowning, there are
few difficulties attaining and then maintaining these standards.
For all particulate-controlled areas in most types of facilities, both nonviable and viable airborne particulate monitoring
must be performed. PQ testing also must include the enumeration of surface bioburden using RODAC plates or swabs, preferably
before and always after room sanitization and cleaning. Nonviable airborne particulates are measured using calibrated laser-type
particle counters while rooms are operating under both static and dynamic conditions (i.e., with personnel present performing
all expected operations and activities). Dynamic conditions present a genuine challenge to an HVAC system to maintain air
quality, and the test results obtained provide insight into the contaminants products will likely be exposed to. Three days
of monitoring under each set of conditions are usually adequate to detect excursions. Air and surface sampling are always
conducted where critical operations are performed (e.g., at vial filling or where aseptic connections are made). Those areas
where sterile materials are open to the environment, even momentarily, must be monitored during PQ. This includes stopper
bowls on filling machines and where filled vials are loaded into lyophilizers.
HVAC PQ also includes testing to prove that rooms and areas are maintained within specified ranges of temperature and relative
humidity. This testing may be performed using room instrumentation, provided that instruments are calibrated and the building
management system is qualified. One useful test is to demonstrate equivalency between portable temperature/relative humidity
instrumentation and the building management system itself. Handheld instruments are placed in the geometric center of the
room to be measured. Instruments are activated and allowed to collect data for 24 hours or more. Collected data are then compared
with data recorded by the building management system during the same time period. There should be a close correspondence between
both the portable instrument and building management system data. If not, one should challenge the placement of the building
management system instrumentation because a true indication of room temperature and relative humidity does not exist.
The LVP regulations of 1976 clearly recognized the importance of designing, operating, and validating HVAC systems as one
of several means for protecting product quality. FDA understood that the production of contaminated LVPs could have been avoided
if HVAC and other critical systems were properly designed and validated. These dated regulations established design criteria,
materials of construction, and performance standards for many systems and equipment used by industry today. Although never
formally implemented, a lasting effect remains, which currently influences the design and validation of modern facilities.
The contribution of the 1976 LVP regulations to drug safety and quality is largely unknown, but should be appreciated by all—critical
design standards and the origins of validation were their outcome, details that are seldom recognized or understood.
William Garvey is a validation consultant at Millipore Corp., 290 Concord Rd., Billerica, MA 01821, tel. 978.715.1429, fax 978.715.1461,
william_garvey@millipore.com
Where were you 30 years ago?
"I started in pharmaceuticals on May 4, 1981 with the old New England Nuclear, a highly regarded manufacturer of radiopharmaceuticals—not
quite 30 years in industry, but 26 years, and only 5 months of unemployment during this time. I still have many of my old
Pharm Tech magazines. Validation is not easy, partly because it is misunderstood. I am trying to remedy this. Basically, I have a lot
to say and Pharm Tech is the medium I choose to use."
References
1. D.C. Mackel et al., "Nationwide Epidemic of Septicemia Caused by Contaminated Intravenous Products: Mechanisms of Intrinsic
Contamination," J. Clin. Microbiol.
2 (6), 486–497 (1975).
2. "Nosocomial Bacteremias Associated with Intravenous Fluid Therapy—USA" Morbidity and Mortality Weekly Report special supplement (Center for Disease Control, Atlanta, GA, Mar. 6 1971).
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