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


Information for validation purposes must be carefully selected from approved HVAC design documents. Drawing sets and specifications literally contain thousands of field-verifiable design elements. The validation process must provide a high degree of assurance, not absolute assurance, that the HVAC system was installed and performs according to design. Validation testing is not and cannot be exhaustive. Equipment inspections, test durations, sampling frequency, etc., must be carefully chosen to provide the high degree of assurance stated previously, while avoiding over testing. If proposed testing and inspections are not meaningful, or if the cost/benefit or cost/risk ratios are high, the testing or inspection should be reconsidered. If there is no regulatory requirement and if testing appears meaningless or costly, the test or verification should be omitted.

Installation qualification. Airflow drawings (AFDs) are the most useful of all HVAC design documents, and certainly fundamental to IQ. AFDs provide the system layout in schematic detail, and each drawing is often limited to a single AHU and associated ductwork, instrumentation, dampers and exhaust fans. AFDs are not drawn to scale, and systems cannot be built entirely using AFDs. This is the purpose of duct drawings. AFDs are basic in that they identify system-critical components that must be inspected during IQ. Critical items are those where a tag number is usually assigned: these include AHU , exhaust fan, humidifier, air monitoring device, reheat coil, and so forth.

An IQ protocol must be prepared for documenting the results of system inspection. Protocols should be designed to record data into tables in protocols, with one table reserved for each major component (AHU, exhaust fan, etc.). A tabular protocol format ensures the appropriate comparison between design (specified condition) and system installation (actual condition) is performed. The validation engineer or specialist should inspect system components while construction and installation are in progress for the following reasons:

  • Access to system components is easier and missed verifications are minimized. Staging and ladders are usually in place, and ceilings and interstitial spaces remain open for entry. Insulation and other coverings that obscure instruments and dampers have not been applied.
  • Mechanical superintendents, installing contractors, and the engineering staff are available to assist with inspections and answer questions. After trade and craft people leave the site to go to another job, it is often very difficult to get them to return.
  • If properly implemented and timed, IQ often will be complete within days of system mechanical completion. This helps ensure that the validation project schedule is optimized and the facility is delivered on time.
  • For larger engineered systems such as HVAC, IQ deviations are inevitable. Deviations often occur because drawings are misinterpreted during protocol preparation, but construction errors do occasionally happen. It is far easier and much less costly to identify and correct a deviation while construction is in progress. Significant additional project cost and schedule delays are inevitable when rework is performed after the system is complete (8).

Operational qualification. HVAC system OQ begins after system IQ is completed. Outstanding items from IQ may remain open, but provided these are limited in number and do not affect system operation, OQ may proceed. It is important to resolve IQ punchlist items and deviations promptly and to explain the circumstances of each in the IQ Summary Report.

It is advisable to perform HVAC OQ concurrent with system commissioning. Recent changes in the pharmaceutical industry have placed added emphasis on commissioning to reduce validation costs and to accelerate project schedules. More owners and facility managers are using independent commissioning agents to commission HVAC and similar mechanical systems. It is the responsibility of the validation team to interface early with the commissioning agent to benefit from the synergy between commissioning and qualification. Because commissioning is a noncompliant activity, the standards for documentation and control are less formalized. Commissioning affords the opportunity to debug and troubleshoot the system while avoiding some of the deviation reporting commonplace in validation. When properly commissioned, HVAC systems are turned over to the owner free of common operational defects that complicate OQ and PQ.

Airflow diagrams play an important part in HVAC system OQ because airflow directions, air volumes, and room pressurizations are commonly indicated on these drawings. AFDs often contain operational sequences in their margins. These sequences become the basis for system functional testing as well as an important part of the functional requirement specifications for the corresponding building management system.

As a noncompliant activity, commissioning does not include all typical HVAC system OQ tests and verifications. Nonetheless, HVAC OQ protocols must contain the following testing and documentation requirements at a minimum:

  • Standard operating procedures for system operation and maintenance are available (at least in draft form)
  • System instrumentation is calibrated (may be performed in combination with building management system IQ and OQ)
  • Operating sequences are verified. Startup and shutdown sequences are only occasionally verified during OQ, because once the system is operational, it is usually only deactivated for scheduled maintenance and repair.
  • Alarms and interlocks are tested and verified. This is typically a commissioning activity because alarms can cause fan shutdown, depending on the alarm. Interlocks are often critical to prevent room overpressurization and possible cross-contamination. Alarms often can be tested by changing operating setpoints at the BMS.
  • The system air-balance report is reviewed. Actual room-supply and exhaust-air volumes are compared with design-air volumes and must agree within 10% in both normal, emergency, and setback modes.
  • HEPA filter testing should be documented as successfully completed
  • Airflow laminarity must be demonstrated where unidirectional airflow has been designed. Contractors are commonly employed for this testing
  • Room-air change rates must be calculated and compared with design specifications. Often, air-change rates can be found in HVAC air-balance reports. Because room-air change rates are largely responsible for room cleanliness when HEPA filters are installed, air-change rates must meet specification
  • Room-to-room directional airflow must be verified. AFDs commonly include arrows that show airflow direction between rooms. HVAC zone diagrams may include pressurization symbols (+,-, or 0) that designate pressurization. Air moves in the direction of lower pressure. There may or may not be an absolute pressure specification (i.e., 0.05-in. water column), depending on the facility. Airflow direction can be verified, for example, by examining installed differential-pressure gauges, by opening doors slightly and passing a smoke stick or equivalent at the door opening, or by measuring differential pressure under (across) the door. Where an absolute pressure differential is specified, this must be verified using calibrated instrumentation.
  • Optional testing includes a 3–30 day burn-in period, where the system is observed for any signs of improper or incorrect operation. Temperature, humidity, and pressurization are passively monitored using the building management system. Because OQ is only a snapshot in time in the lifecycle of an HVAC system, this testing may prove beneficial for facilities and products where unexpected system failures cannot be tolerated.


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