Contaminated LVPs and the Origins of Validation


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This article begins by describing two incidents of large volume parenteral (LVP) contamination occurring in the United States in the early 1970's. Between 2,000 and 8,000 patients became septicemic during the first incident, and it was estimated that 10% of these infected patients eventually died. US FDA and CDC investigated both incidents and in 1976, FDA issued draft regulations to control the production and testing of LVPs.

The concept and origins of process validation can be attributed to this draft document, a document that was later withdrawn by FDA.

The article continues by describing the methods for qualifying and validating HVAC systems and cleanrooms. Next to human operators, HVAC is the second largest source of product contamination, so qualification and validation of these systems are essential.

This article appeared in the 30th anniversary edition of Pharmaceutical Technology magazine.

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Contaminated LVPs and the Origins of Validation

  1. 1. Contaminated LVPs and the Origins of Validation William Garvey quirement to validate production processes. Product quality was From a professional development standpoint, presumably ensured by collecting and analyzing drug samples. fundamental validation skills related to heating, Despite the law, there remained little inspectional focus on ventilation, and air conditioning (HVAC) must be process validation. This changed, however, when a nationwide thoroughly understood. Knowing the early history epidemic of septicemia occurred that was caused by contami- and development of validation is essential if one is nated intravenous fluids (large-volume parenterals, LVPs). Be- to understand the current set of regulations and tween July 1970 and April 1971 in many hospitals in the United States, there were outbreaks of nosocomial (hospital acquired) standards governing the industry today. This article septicemia caused by Enterobacter cloacae or E. agglomerans. All reviews the history and outcome of contamination of these hospitals used infusion products made by one manu- in large-volume parenteral drug products and, as facturer, and all affected patients had onset of septicemia while an example of efficient qualification receiving the company’s infusion products. methodologies, discusses the qualification Septicemia was epidemiologically and microbiologically requirements of modern HVAC systems. traced to intrinsic contamination of the company’s screw-cap closure for infusion bottles, which were sealed with a newly introduced elastomer liner. Investigations in the laboratory William Garvey is a validation consultant at and in the manufacturing plant into the mechanism of con- Millipore Corp., 290 Concord Rd., Billerica, MA 01821, tamination of these products revealed the following: tel. 978.715.1429, fax 978.715.1461, william_garvey@ • Epidemic strains were present in numerous areas through- out the manufacturing plants Where were you 30 years ago? • Viable microorganisms gained access to the interior of “I started in pharmaceuticals on May 4, 1981 with the old screw-cap closures after the autoclave step of production New England Nuclear, a highly regarded manufacturer of • Cooling closures actively drew moisture through the thread radiopharmaceuticals—not quite 30 years in industry, but interstices into the inner-most depths of the closure 26 years, and only 5 months of unemployment during this • Transfer of contaminants from closures to fluid was eas- time. I still have many of my old Pharm Tech magazines. ily effected by simple manipulations duplicating normal Validation is not easy, partly because it is misunderstood. I am trying to remedy this. Basically, I have a lot to say in-hospital use (1). and Pharm Tech is the medium I choose to use.” Nine deaths were initially attributed to this outbreak. Fur- ther analysis estimated that between 2000 and 8000 cases had T he year 2006 marked the 30th anniversary of the actually occurred. Not all cases ended with the death of a pa- formal introduction of process validation concepts tient. Nonetheless, nearly 10% of the case patients in the stud- and requirements by the US Food and Drug Ad- ied hospitals died while bacteremic or shortly thereafter (2). ministration. Despite more than 30 years of com- On closer examination, FDA, the Centers for Disease Con- mon usage, only recently have the theory and practice of trol and Prevention (CDC), and company officials discovered validation become fully developed and widely understood, several manufacturing problems. Although component biobur- although many misconceptions remain. den (bottles, caps, etc.) was acceptable pre- and poststeriliza- tion, product cooling and additional downstream processing Origins of validation were identified as the sources of contamination. Sterilizer cool- The concept and practice of pharmaceutical validation first be- ing water was considered a possible source of contaminants. came law in June 1963 with the publication of good manufac- Water for bottle cooling was obtained from a municipal source, turing practice (GMP) regulations. Before that, there was no re- and chlorine content was frequently below that required for
  2. 2. bacteriostasis. As bottles continued to cool after removal from agency, although many of the concepts, particularly validation, the sterilizer, ambient air and moisture infiltrated through the were voluntarily applied by industry nonetheless. bottle threads and into the cap liner. Disassembly and testing So began the start and evolution of validation practices and of cap inner components later demonstrated that environ- technologies to the seemingly complex set of rules and guide- mental contaminants, including the epidemic organisms, were lines used by industry today. Publications of the late 1970s and distributed within the caps. Bottle breakage was common- early 1980s, particularly those of the Parenteral Drug Associa- place after sterilization, and dextrose solutions were spilled tion (PDA), introduced the concept of qualification and vali- onto floors below conveyors and related equipment. Spillage dation to the industry at large. Companies began to qualify and actively promoted the growth of the epidemic organisms, cre- validate their sterilization processes initially, and then applied ating a high bioburden in critical processing areas (1). these same validation principles to other systems. With FDA’s 1987 Guideline on General Principles of Process Validation, the MILESTONE. 30 YEARS OF PHARMACEUTICAL TECHNOLOGY validation of equipment, systems and processes became wide- 1971.FDA investigates production processes for large- spread and mandatory as manufacturers of all drug types were alerted to FDA’s expectations for process validation (5). volume parenterals. The study follows a deadly outbreak of One example of this validation process is the qualification and nosocomial septicemia from infusion bottles contaminated validation of heating, ventilating, and air conditioning (HVAC), during product cooling and downstream processing. which is universal in the industry. The importance of HVAC to In late 1971, FDA began an intensive review and evaluation product quality and safety cannot be minimized. This important of LVP production because of justified concerns that not all concept was not lost on FDA, which should be evident for any- manufacturers could ensure the level of microbiological qual- one who reads these dated but insightful regulations. ity required for LVP drug products. This review was first lim- HVAC system qualification and validation ited to specific, individual manufacturing or container-closure problems. In 1973, the review expanded to include extensive The procedures for HVAC validation are now commonly un- sampling of LVP products, comprehensive facility inspections, derstood. HVAC system validation is always based on design. and detailed discussions between the industry and FDA (3). Engineers and owners design systems, and validation special- In March 1973, another outbreak of LVP-attributed sep- ists interpret these designs and reduce this information in the ticemia occurred, this time associated with a different manu- form of protocols. Quality assurance professionals and reg- facturer and a different product (5% dextrose in lactated ringers ulatory authorities review the designs at various stages of de- or D5LR). A hospital in Milwaukee reported three cases of sep- velopment to ensure compliance with GMP regulations and ticemia that developed within three hours from the start of in- appropriate industry standards (7). fusion. Hospital officials suspected that each 1-L bottle of D5LR The standard sequence for HVAC system validation is in- used was intrinsically contaminated. One patient died as a con- stallation (IQ), operational (OQ), and performance qualifi- sequence of their intravenous therapy, and another fell criti- cation (PQ). To ensure regulatory compliance, design review cally ill. Later, CDC learned of two additional cases of septicemia begins when drawings and specifications are approximately caused by contaminated D5LR, one at another Wisconsin hos- 35% complete, but always before long lead-time equipment pital and one in Ohio. The manufacturer recalled more than is ordered from vendors (7). Rarely are serious errors or omis- six lots of contaminated product. The recalled infusion was pre- sions noted during review of HVAC designs, because design pared by a newly modified process which included exposure of criteria are understood by reputable engineers and engineer- the bottles to increased pressure during the autoclave cycle (4). ing companies designing these systems. Concerned with the ongoing problems in the LVP industry, In nearly all pharmaceutical facilities, multiple air handlers FDA issued a draft proposal in February 1974 that defined re- exist, each designed to support a specific zone within the build- quirements and specifications for LVP manufacturing and pro- ing. Each zone is exhausted by one or more exhaust fans inter- cessing. This was followed with the publication of a draft sec- locked with the air-handling unit (AHU), and depending on de- tion to the Code of Federal Regulations, Part 212, “Current Good sign, return fans also. IQ and OQ protocol boundaries should Manufacturing Practice in the Manufacture, Processing, Pack- be set that encompass one AHU and the interlocked return and ing, or Holding of Large Volume Parenterals for Human Use,” exhaust fans only. HVAC zones do not operate in isolation but on June 1, 1976. This was the first time FDA had issued well- are influenced and controlled by conditions in adjacent zones. defined process standards for drug products, and although This is an important consideration when confirming room pres- these standards had been discussed with industry in advance, surizations and air-flow directions during OQ. many manufacturers objected to the limitations now being Information for validation purposes must be carefully se- placed on LVP manufacturing and the obstacles to innovation lected from approved HVAC design documents. Drawing sets (3). Consequently, the draft LVP regulations and proposed reg- and specifications literally contain thousands of field-verifi- ulations for small-volume parenterals were withdrawn by the able design elements. The validation process must provide a
  3. 3. high degree of assurance, not absolute assurance, that the HVAC system was installed and performs according to de- sign. Validation testing is not and cannot be exhaustive. PHOTO COURTESY OF ABB, LOW VOLTAGE DRIVES 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 sin- Figure 1: Newer HVAC designs feature variable frequency drives gle AHU and associated ductwork, instrumentation, dampers (VFDs). VFDs are replacing variable inlet vanes on fan scrolls as the and exhaust fans. AFDs are not drawn to scale, and systems method for air-volume and pressurization control. They alter the cannot be built entirely using AFDs. This is the purpose of frequency of the electrical supply to fan motors. As duct static duct drawings. AFDs are basic in that they identify system- pressure or air volume varies from setpoint, the VFD slows or critical components that must be inspected during IQ. Crit- increases motor speed proportionately. Modulation of fan motor speed ical items are those where a tag number is usually assigned: reduces energy consumption. Fans that use variable inlet vanes for these include AHU, exhaust fan, humidifier, air monitoring control purposes always operate at 100% rated motor speed. Pressure device, reheat coil, and so forth. and air volume control are also better when VFDs are used (6). An IQ protocol must be prepared for documenting the results of system inspection. Protocols should be designed to tions are inevitable. Deviations often occur because draw- record data into tables in protocols, with one table reserved ings are misinterpreted during protocol preparation, but for each major component (AHU, exhaust fan, etc.). A tab- construction errors do occasionally happen. It is far eas- ular protocol format ensures the appropriate comparison be- ier and much less costly to identify and correct a devia- tween design (specified condition) and system installation tion while construction is in progress. Significant addi- (actual condition) is performed. The validation engineer or tional project cost and schedule delays are inevitable when specialist should inspect system components while construc- rework is performed after the system is complete (8). Operational qualification. HVAC system OQ begins after sys- tion and installation are in progress for the following reasons: • Access to system components is easier and missed verifi- tem IQ is completed. Outstanding items from IQ may remain cations are minimized. Staging and ladders are usually in open, but provided these are limited in number and do not place, and ceilings and interstitial spaces remain open for affect system operation, OQ may proceed. It is important to entry. Insulation and other coverings that obscure instru- resolve IQ punchlist items and deviations promptly and to ments and dampers have not been applied. explain the circumstances of each in the IQ Summary Report. It is advisable to perform HVAC OQ concurrent with sys- tem commissioning. Recent changes in the pharmaceutical MILESTONE. 30 YEARS OF PHARMACEUTICAL TECHNOLOGY industry have placed added emphasis on commissioning to 1987. FDA releases its Guideline on General Principles of reduce validation costs and to accelerate project schedules. Process Validation, which applies to the validation of equipment, More owners and facility managers are using independent systems, and processes for all drug types. commissioning agents to commission HVAC and similar me- • Mechanical superintendents, installing contractors, and chanical systems. It is the responsibility of the validation team the engineering staff are available to assist with inspec- to interface early with the commissioning agent to benefit tions and answer questions. After trade and craft people from the synergy between commissioning and qualification. leave the site to go to another job, it is often very difficult Because commissioning is a noncompliant activity, the stan- to get them to return. dards for documentation and control are less formalized. • If properly implemented and timed, IQ often will be com- Commissioning affords the opportunity to debug and trou- plete within days of system mechanical completion. This bleshoot the system while avoiding some of the deviation re- helps ensure that the validation project schedule is opti- porting commonplace in validation. When properly com- mized and the facility is delivered on time. missioned, HVAC systems are turned over to the owner free • For larger engineered systems such as HVAC, IQ devia- of common operational defects that complicate OQ and PQ.
  4. 4. Airflow diagrams play an important part in HVAC system rection can be verified, for example, by examining installed OQ because airflow directions, air volumes, and room pres- differential-pressure gauges, by opening doors slightly and surizations are commonly indicated on these drawings. AFDs passing a smoke stick or equivalent at the door opening, often contain operational sequences in their margins. These or by measuring differential pressure under (across) the sequences become the basis for system functional testing as door. Where an absolute pressure differential is specified, well as an important part of the functional requirement spec- this must be verified using calibrated instrumentation. ifications for the corresponding building management system. • Optional testing includes a 3–30 day burn-in period, As a noncompliant activity, commissioning does not include where the system is observed for any signs of improper all typical HVAC system OQ tests and verifications. Nonethe- or incorrect operation. Temperature, humidity, and pres- less, HVAC OQ protocols must contain the following testing surization are passively monitored using the building and documentation requirements at a minimum: management system. Because OQ is only a snapshot in • Standard operating procedures for system operation and time in the lifecycle of an HVAC system, this testing may maintenance are available (at least in draft form) prove beneficial for facilities and products where unex- • System instrumentation is calibrated (may be performed in pected system failures cannot be tolerated. Performance qualification. HVAC system PQ begins only combination with building management system IQ and OQ) after OQ has been completed successfully. Because airborne MILESTONE. 30 YEARS OF PHARMACEUTICAL TECHNOLOGY viable and nonviable particulate levels, room bioburden, and 2003.The temperature/relative humidity control rely on a system op- European Commission releases its Guide erating as designed, the transition to PQ must occur only to GMP, Revision to Annex 1, Manufacture of Sterile Medicinal after OQ is complete and all deviations are resolved. Products for Humans and Veterinary Use. Like IQ and OQ, the test procedures for HVAC system PQ • Operating sequences are verified. Startup and shutdown are now well defined. Standard PQ acceptance criteria are pub- sequences are only occasionally verified during OQ, be- lished by organizations such as the European Commission (EC), cause once the system is operational, it is usually only de- International Organization for Standardization (ISO), and FDA. activated for scheduled maintenance and repair. Currently, the definitive standard for multinational compa- • Alarms and interlocks are tested and verified. This is typ- nies is the EC Guide to Good Manufacturing Practice, Revision ically a commissioning activity because alarms can cause to Annex 1, Manufacture of Sterile Medicinal Products (9). This fan shutdown, depending on the alarm. Interlocks are document provides supplementary guidance on the principles often critical to prevent room overpressurization and pos- and guidelines of GMP as applicable to sterile products such as sible cross-contamination. Alarms often can be tested by LVPs. One section in Annex 1 is specific to clean environments changing operating setpoints at the BMS. used for aseptic manufacturing. Annex 1 divides manufactur- • The system air-balance report is reviewed. Actual room- ing areas into letter grades (A, B, C, D) that closely correspond supply and exhaust-air volumes are compared with design- to the older Class 100, 10,000, and 100,000 conditions contained air volumes and must agree within 10% in both normal, in Federal Standard 109 (now cancelled). One notable differ- emergency, and setback modes. ence from previous standards is that air-sampling volumes have now increased to 1 m3, a change from the historical 1-ft3 sam- • HEPA filter testing should be documented as success- fully completed ple size specified in the LVPs. As expected, upward adjustments • Airflow laminarity must be demonstrated where unidi- have been made to particle limits because air-sample volumes rectional airflow has been designed. Contractors are com- have now increased by approximately 35 times. monly employed for this testing ISO 14644-1, “Cleanrooms and Associated Controlled En- • Room-air change rates must be calculated and compared vironments—Part 1: Classification of Air Cleanliness,” should with design specifications. Often, air-change rates can be be consulted when qualifying HVAC systems other than those found in HVAC air-balance reports. Because room-air supporting aseptic production. ISO 14664-1 assigns nine par- change rates are largely responsible for room cleanliness ticulate classifications to manufacturing areas, with Class 1 when HEPA filters are installed, air-change rates must the most demanding and Class 9 the least restrictive (10). ISO meet specification classes 5–9 are appropriate for all pharmaceutical facilities. • Room-to-room directional airflow must be verified. AFDs In solid-dosage facilities where airborne dusts are expected, commonly include arrows that show airflow direction be- it often makes little sense to monitor particulate levels while tween rooms. HVAC zone diagrams may include pressur- operations are in progress. However, baseline (static) infor- ization symbols ( , , or 0) that designate pressurization. mation is often useful, as this may provide a sign of HEPA Air moves in the direction of lower pressure. There may filter failure or other indication of unwanted particulation. or may not be an absolute pressure specification (i.e., 0.05- The proposed LVP regulations required that air microbial in. water column), depending on the facility. Airflow di- quality be monitored in both critical and noncritical areas, al-
  5. 5. though this was not accepted practice at the time. Allowable instrumentation because a true indication of room tempera- microbial levels or the types of organisms permitted were not ture and relative humidity does not exist. specified because little historical data were available to FDA. The LVP regulations of 1976 clearly recognized the impor- In time, however, voluntary standards and guidance docu- tance of designing, operating, and validating HVAC systems ments appeared that manufacturers agreed to comply with. as one of several means for protecting product quality. FDA Both the United States Pharmacopeia and EC Guide to Good understood that the production of contaminated LVPs could Manufacturing Practice provide recommended microbial stan- have been avoided if HVAC and other critical systems were dards that many manufacturers observe, although these stan- properly designed and validated. These dated regulations es- dards are not legally enforceable. With proper HVAC design tablished design criteria, materials of construction, and per- and construction, room finish selections, disinfection proce- formance standards for many systems and equipment used dures, and personnel gowning, there are few difficulties at- by industry today. Although never formally implemented, a taining and then maintaining these standards. lasting effect remains, which currently influences the design For all particulate-controlled areas in most types of facili- and validation of modern facilities. The contribution of the ties, both nonviable and viable airborne particulate monitor- 1976 LVP regulations to drug safety and quality is largely un- ing must be performed. PQ testing also must include the enu- known but should be appreciated by all-critical design stan- meration of surface bioburden using RODAC plates or swabs, dards and the origins of validation were their outcome, de- preferably before and always after room sanitization and clean- tails that are seldom recognized or understood. ing. Nonviable airborne particulates are measured using cal- References ibrated laser-type particle counters while rooms are operat- ing under both static and dynamic conditions (i.e., with 1. D.C. Mackel et al., “Nationwide Epidemic of Septicemia Caused by personnel present performing all expected operations and ac- Contaminated Intravenous Products: Mechanisms of Intrinsic Con- tivities). Dynamic conditions present a genuine challenge to tamination,” J. Clin. Microbiol. 2 (6), 486–497 (1975). an HVAC system to maintain air quality, and the test results 2. “Nosocomial Bacteremias Associated with Intravenous Fluid Ther- obtained provide insight into the contaminants products will apy—USA” Morbidity and Mortality Weekly Report special supple- likely be exposed to. Three days of monitoring under each set ment (Center for Disease Control, Atlanta, GA, Mar. 6 1971). of conditions are usually adequate to detect excursions. Air 3. FDA, “Human Drugs—Current Good Manufacturing Practice in and surface sampling are always conducted where critical op- Manufacture, Processing, Packing or Holding of Large Volume Par- erations are performed (e.g., at vial filling or where aseptic enterals, and Request for Comments Regarding Small Volume Par- connections are made). Those areas where sterile materials enterals,” Fed. Regis. 40 (106), 22202–22208 (June 1, 1976). are open to the environment, even momentarily, must be mon- 4. “Epidemiological Notes and Reports: Septicemias Associated with itored during PQ. This includes stopper bowls on filling ma- Contaminated Intravenous Solutions—Wisconsin, Ohio,” Morbid- chines and where filled vials are loaded into lyophilizers. ity and Mortality Weekly Report (Center for Disease Control, At- HVAC PQ also includes testing to prove that rooms and areas lanta, GA, Mar. 17, 1973) pp. 99. are maintained within specified ranges of temperature and rel- 5. FDA, Guideline On General Principles Of Process Validation (Food ative humidity. This testing may be performed using room in- and Drug Administration, Rockville, MD, May 1987). strumentation, provided that instruments are calibrated and 6. X. Mao, “Energy Saving Tips for Desiging Air Handling Units the building management system is qualified. One useful test (AHUs) in Cleanrooms,” Pharm. Eng. 26 (2), 1–5 (2006). is to demonstrate equivalency between portable temperature/rel- 7. W. Garvey, “Essentials of Validation Project Management, Part 1,” ative humidity instrumentation and the building management Pharma. Technol. 29 (12), 68–76 (2005). system itself. Handheld instruments are placed in the geomet- 8. W. Garvey, “Essentials of Validation Project Management: Part 2,” ric center of the room to be measured. Instruments are acti- Pharma. Technol. 30 (1), 72–86 (2006). vated and allowed to collect data for 24 hours or more. Col- 9. EC, Guide to Good Manufacturing Practice Revision to Annex 1, Man- lected data are then compared with data recorded by the building ufacture of Sterile Medicinal Products (European Commission, Brus- management system during the same time period. There should sels, Belgium, May 2003). be a close correspondence between both the portable instru- 10. ISO 14644-1: Cleanrooms and Associated Controlled Environments- ment and building management system data. If not, one should Part:1 Classification of Air Cleanliness (International Organization challenge the placement of the building management system for Standardization, Geneva, Switzerland, 1999). P T © Reprinted from PHARMACEUTICAL TECHNOLOGY, July 2007 Printed in U.S.A. RP1457EN00