Contaminated LVPs and the Origins of Validation 4

Performance qualification. HVAC system PQ begins only after OQ has been completed successfully. Because airborne viable and nonviable particulate levels, room bioburden, and temperature/relative humidity control rely on a system operating as designed, the transition to PQ must occur only after OQ is complete and all deviations are resolved.
Like IQ and OQ, the test procedures for HVAC system PQ are now well defined. Standard PQ acceptance criteria are published by organizations such as the European Commission (EC), International Organization for Standardization (ISO), and FDA.
Currently, the definitive standard for multinational companies is the EC Guide to Good Manufacturing Practice, Revision to Annex 1, Manufacture of Sterile Medicinal Products (9). This document provides supplementary guidance on the principles and guidelines of GMP as applicable to sterile products such as LVPs. One section in Annex 1 is specific to clean environments used for aseptic manufacturing. Annex 1 divides manufacturing areas into letter grades (A, B, C, D) that closely correspond to the older Class 100, 10,000, and 100,000 conditions contained in Federal Standard 109 (now cancelled). One notable difference from previous standards is that air-sampling volumes have now increased to 1 m3, a change from the historical 1-ft3 sample size specified in the LVPs. As expected, upward adjustments have been made to particle limits because air-sample volumes have now increased by approximately 35 times.
ISO 14644-1, "Cleanrooms and Associated Controlled Environments—Part 1: Classification of Air Cleanliness," should be consulted when qualifying HVAC systems other than those supporting aseptic production. ISO 14664-1 assigns nine particulate classifications to manufacturing areas, with Class 1 the most demanding and Class 9 the least restrictive (10). ISO classes 5–9 are appropriate for all pharmaceutical facilities. In solid-dosage facilities where airborne dusts are expected, it often makes little sense to monitor particulate levels while operations are in progress. However, baseline (static) information is often useful, as this may provide a sign of HEPA filter failure or other indication of unwanted particulation. 
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,

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). 
3. FDA, "Human Drugs—Current Good Manufacturing Practice in Manufacture, Processing, Packing or Holding of Large Volume Parenterals, and Request for Comments Regarding Small Volume Parenterals," Fed. Regis. 40 (106), 22202–22208 (June 1, 1976).
4. "Epidemiological Notes and Reports: Septicemias Associated with Contaminated Intravenous Solutions—Wisconsin, Ohio," Morbidity and Mortality Weekly Report (Center for Disease Control, Atlanta, GA, Mar. 17, 1973) pp. 99.
5. FDA, Guideline On General Principles Of Process Validation (Food and Drug Administration, Rockville, MD, May 1987).
6. X. Mao, "Energy Saving Tips for Desiging Air Handling Units (AHUs) in Cleanrooms," Pharm. Eng. 26 (2), 1–5 (2006). 7. W. Garvey, "Essentials of Validation Project Management, Part 1," Pharma. Technol. 29 (12), 68–76 (2005).
8. W. Garvey, "Essentials of Validation Project Management: Part 2," Pharma. Technol. 30 (1), 72–86 (2006).
9. EC, Guide to Good Manufacturing Practice Revision to Annex 1, Manufacture of Sterile Medicinal Products (European Commission, Brussels, Belgium, May 2003).
10. ISO 14644-1: Cleanrooms and Associated Controlled Environments-Part:1 Classification of Air Cleanliness (International Organization for Standardization, Geneva, Switzerland, 1999).

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