Contaminated LVPs and the Origins of Validation - Pharmaceutical Technology

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Contaminated LVPs and the Origins of Validation
Fundamental validation skills related to heating, ventilation, and air conditioning must be thoroughly understood. Knowing the early history and development of validation is essential to understand the current set of regulations and standards governing the industry. This article reviews the history and outcome of contamination in large-volume parenteral drug products and discusses the qualification requirements of modern HVAC systems.


Pharmaceutical Technology


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.


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