In 1999, the Centers for Disease Control and Prevention (CDC) entered into the Public Health Preparedness and Response for Bioterrorism Cooperative Agreement (BCA) with 62 jurisdictions in the United States: the 50 states; the cities of New York and Chicago; Washington, DC; Los Angeles County; Puerto Rico; the U.S. Virgin Islands; Guam; Palau; the Federated States of Micronesia; American Samoa; the Northern Mariana Islands; and the Midway Islands. This cooperative agreement was created to improve both the local and the national public health infrastructures’ ability to respond to acts of bioterrorism, which is broadly defined to include toxic chemical exposure resulting from a terrorist act. Because funding was limited in the late 20th century, approximately $40 million was available for distribution to the jurisdictions’ public health laboratories (PHLs) for terrorism preparedness. Of these funds, about $4 million was reserved to fund four laboratories that would provide surge capacity should a chemical terrorism incident require more than the analytical resources of CDC’s National Center for Environmental Health’s Division of Laboratory Sciences (CDC/NCEH/DLS). Eventually, five laboratories were funded: the Wadsworth Laboratories at the New York State Department of Health; the Virginia Division of Consolidated Laboratories; the Michigan Department of Community Health Laboratory; the California Department of Health Services Division of Laboratory Science; and the New Mexico Department of Health State Laboratory Division.
The strategy behind this funding was to equip and staff these labs to serve their states’ needs and to provide CDC with additional analytical capability for priority terrorism-related chemicals, such as nerve agents, cyanide, or sulfur mustard, should the need arise. In a chemical terrorism incident or large-scale chemical accident, clinical samples would be delivered to CDC for analysis by the rapid toxic screen, a series of analytical methodologies and instrumentation that would quantitatively analyze the samples for 150 potential agents using highly sensitive target compound analysis methods. Medical toxicologists would interpret the analytical results, which would be presented in 36 hours or less.
Typically, in chemical exposure incidents, for every affected person, many others will think they might have been exposed and will present themselves at hospitals for assessment and treatment. Samples from people who are worried, but well, and the need for rapid sample analysis require a sample analysis surge strategy. The first strategy model proposed for the CDC/PHL partnership envisioned an Incident Response Laboratory at CDC. At this laboratory, multiple instrument systems and analysts would be prepared to respond to a terrorist attack that used chemical warfare agents (CWAs), such as the 1995 Aum Shinrikyo cult attack on the Tokyo subway. If the extent of the incident should exceed the capacity of the CDC Incident Response Laboratory, additional CDC resources would be converted from their normal environmental health analytical activities to respond to the need for additional CWA analytical capacity. The five funded state PHLs would be included in this expanded laboratory capability. As these state labs developed and demonstrated their expertise in CWA metabolite analysis, they would become primary resources during a chemical terrorism incident for post-rapid toxic screen assessment of people’s exposure to a chemical agent. This surge capacity role was formalized in 2003 when specific funding was dedicated from cooperative agreement funds to support these laboratories in this new role.
Chemical terrorism laboratory network
The CDC/PHL partnership proposed that funding from the cooperative agreement would be used between 1999 and 2002 to hire staff and to equip the laboratories for assessing human exposure to CWAs and toxic industrial chemicals. The Chemical Terrorism Laboratory Network (CTLN) was officially formed during Fiscal Year 2002 as a partnership between CDC and the five state public health labs.
In the CTLN strategy, human exposure to CWAs and chemicals would be assessed by measuring either the chemical itself or its metabolites in clinical samples such as blood or urine. Analysis methods developed at CDC would be transferred to the state public health labs through hands-on training at the CDC/NCEH/DLS facilities. With the funding provided, the PHLs would be required to purchase specific instruments; to hire staff, including one Ph.D. chemist as team leader; and to equip facilities to house the required instrumentation.
CDC would contribute by supplying validated analysis methods, by providing hands-on training for the implementation of these methods, and by establishing a program to demonstrate the network labs’ proficiency in producing timely, accurate, and precise results for assessing people’s exposure to toxicants. The program’s initial analytical focus was on the transferring methods that were developed to measure metabolites of CWAs. The discussions defining the proficiency testing program determined that both the CWA metabolites and the stable isotope-labeled internal standards were often not commercially available and, when available, were often extremely expensive. This limited availability prompted the creation of a materials program in which CDC would coordinate the preparation of calibration solutions and quality control samples in the appropriate biological matrix and in the properly diluted solutions of internal standards.
Laboratory response network–chemical (LRN-C)
After the terrorist events of September 11, 2001, however, CTLN was short-lived. Funding for terrorism response expanded dramatically from $49.9 million in FY 2001 to $949.7 million in FY 2002, but this increased funding could not be used for chemical laboratory capability until the following year. In 2003, chemical terrorism response capability was required in all 62 jurisdictions covered by the Bioterrorism Cooperative Agreement. Fortunately, in 1999, CDC’s National Center for Infectious Diseases had created the Laboratory Response Network (LRN) to coordinate the activities of the many laboratories being funded to support bioterrorism surveillance and response. LRN provided the ideal mechanism to help expand the chemical terrorism response capability at public health laboratories, and tiny CTLN was assimilated into the newly created Laboratory Response Network – Chemical (LRN-C).
Although LRN had drawn upon an established infectious disease assessment capability in hospital and public health labs, LRN-C found that clinical chemical analysis capability was not common in many public health laboratories. A number of jurisdictions either had insufficient infrastructure to support a chemical analysis program or had no interest in creating such a program, although it was required by the cooperative agreement. LRN-C developed a four-level structure: All 62 jurisdictions would have a Level 3 component; some would have a Level 2 (laboratory) component; and the former CTLN labs, which would continue to be CDC’s surge capacity laboratories, would now be designated as Level 1 labs. CDC/NCEH/DLS, with the greatest lab capability, did not have a level designation.
Level 3 activities include reaching out to a jurisdiction’s medical facilities to establish the need to collect samples for suspected chemical terrorism incidents, indicate what samples to collect, and give instructions on how to properly package and ship those samples to the nearest lab with adequate analysis capability; in most cases this lab would be CDC. Level 2 activities were targeted to increase the public health labs ability to respond to the most likely source of toxicant exposure, refined, and restructured like the TR-32 to reflect current regulatory expectations and good practice.
Professionals from the Americas and Europe contributed to the production of GAMP 4 which is intended for suppliers and users in pharmaceutical manufacturing and related healthcare industries. This guide draws together key principles and practices and describes how they can be applied to determine the scope and extent of validation for different types of automated systems.
Benefits of this standard to industry users and suppliers echo those of the TR-32 and others include:
- Cost benefits, aiding the production of systems that are fit for purpose, meet user and business requirements, and have acceptable operation and maintenance costs
- Increased understanding of the subject and introduction of a common language and terminology
- Reductions in cost and time taken to achieve compliance systems
- Clarification of the division of responsibility between user and supplier
While GAMP addresses a broad range of issues related to validation of systems, another document that can assist cleanroom operators in maintaining 21 CFR Part 11 compliance is the joint PDA/ISPE publication “Complying with 21 CFR Part 11, Electronic Records and Electronic Signatures,” a companion document to GAMP 4.3
International standards and the groups that develop, maintain, archive, and promote them are the background for auditing within the regulated environment. Consideration must be given to adjunct drivers in the industry that help us conduct not only audits but daily performance, inspection, and maintenance of various processes.
ICH, or the International Conference on Harmonization, along with ISO 9001 standards, govern certain critical elements of the manufacturing process and how they are conducted. The American Society for Quality has been instrumental in supporting the industry and professionals who perform the operation, maintenance, inspection, and management of any systems within the industry.
ISO, the International Standards Organization, is a network of the national standards institutes of 155 countries, on the basis of one member per country, with a Central Secretariat in Geneva, Switzerland, that coordinates the system.
Between 1947 and the present day, ISO published more than 16,000 International Standards. ISO’s work program ranges from standards for traditional activities, such as agriculture and construction, through mechanical completion of their sixth analysis method, Level 2 labs were engaged in 24 PT exercises per year, or two PT exercises each month. The Level 1 labs had an even more crowded schedule with as many as 40 PT challenges per year.
A similar expansion of LRN-C’s material program was also required. Instead of preparing materials to stock six labs (CDC plus the five Level 1 labs) for validation, PT, and incident response, the network had to accommodate the now 47 participating labs; as a result, the number of vials required for each analysis increased from thousands to tens of thousands. In addition to the issues associated with the increase in volume, there were also logistics and timing issues. Training the large number of labs in the performance of the analysis method now required months under ideal circumstances and more than a year in reality. Also, with limited shelf life, a single large batch of materials produced for a method would provide early trainees with materials that might last for almost 2 years, while later trainees would have to purchase materials that might have a shelf life of 6 months or less. In addition, the vendors who created and ampoulized these solutions would have to stock these materials for 18 months before they were able to sell everything they had produced. The solution to both of these problems was to create multiple small batches of materials. This solution increased the work for the CDC quality assurance team but solved the problems for both the vendors and the PHL customers.
With the PT program stabilized and the PHLs generating acceptable analytical results, the network realized that being able to hit the analytical target was only part of the mission of a response network; there were other response aspects that a regularly scheduled PT program did not test. For example, the PHLs were required to collect clinical samples, to properly package the samples, and to ship them so that the shipment met shipping regulations and the samples arrived intact and compatible with the required analysis. The labs also had to be able to respond to an emergency. The network considered the following questions: Could the network’s emergency contact chain notify the right people of an emergency? Could samples reach the right laboratory? Could a lab respond to the need for a rapid analysis and report the results in a timely manner?
These untested response activities led to new exercise programs: the Sample Collection, Packaging, and Shipping (SCPaS) exercises and the Emergency Response Exercises. For SCPaS exercises, the PHLs were requested, and later required, to ship samples from 10 “patients” to CDC to be evaluated against rules for shipping, evidentiary, and analytical requirements. Participation in Emergency Response Exercises was required for all Level 1 and Level 2 labs. At 10:00 am at the PHL local time on Day 1, a CDC representative would telephone the PHL 24/7 emergency contact and advise him or her that samples would be arriving by a next-day priority shipment for analysis by a method that the laboratory was qualified to perform. The samples were to be analyzed, and the results reported to CDC as soon as the analysis was completed. These two exercises were thought to be the best assessments of a lab’s ability to respond to the emergency situations that the network was created to address.
While expanding the scope of laboratory support, the network determined that the transfer of analysis methods from CDC to the PHLs had to change in many ways but still needed to be conducted as hands-on training by subject matter experts. To maximize the effectiveness of the transfer and optimize the use of the limited training facilities, each PHL was required to send two trainees at a designated time; CDC would train two PHL staffs per week. Each PHL team would have a dedicated instrument and associated equipment in the training facility. In addition, each PHL staff would be taught by a team of three instructors so that a 2:1 student-to-instructor ratio could be maintained during the lab sessions even if one instructor was not available.
Many PHLs encountered difficulties in hiring qualified staff, and the experience and expertise level of the different laboratories varied greatly. To provide a minimum level of expertise with the specific instrument platform and analysis technique, a PHL had to perform a series of three steps before it could send students to CDC for analysis method transfer training. Step 1 was including instrument installation and familiarization as part of every instrument purchase; this step would assure that the instrument was properly installed and that the PHL staff had received fundamental exposure to the operation of the system. Step 2 was taking the instrument vendor’s standard operation course, delivered by the vendor to all potential operators at the PHL site. Step 3 was delivering a technique course, in which the capability of the analysis technique, instead of the operation of the instrument, was explored. This course was developed by CDC staff and delivered at the PHL site by the vendor’s technical support staff. After completing 3 weeks of preliminary training, PHL staff were permitted to enroll in their first CDC analysis method transfer course.
The validation exercises that began with CTLN have been continued as LRN-C has expanded. These exercises have been critical to trainees’ technique development when learning to perform the analysis; the exercises have provided an opportunity to integrate the analysis requirements with the resources of the laboratory infrastructure. Reporting results for the validation exercise has provided the basis for reporting other analytical results, whether PT, Emergency Response Exercises, or realworld response samples.
The ultimate exercise in the program is the full-scale Rapid Toxic Screen/Surge Capacity exercise, in which all major parts of the chemical terrorism incident response plan are exercised. In conjunction with a Level 3 or Level 2 PHL, a CDC/NCEH/DLS team creates a scenario for either a covert or overt exposure incident. Part of the team — usually the PT program staff — creates the required number of patient samples that are spiked with the appropriate agent or metabolite and ships these samples to the Level 2 or 3 PHL to distribute to participating hospitals. At a time selected by the PHL, the PHL calls the CDC Director’s Emergency Operations Center and describes the exercise incident. The relevant persons are notified, and the CDC Lab Response Team is scrambled and flown to the incident site for sample collection. The team collects the samples, either from the hospitals or from the PHL; packages the 40 samples required for the Rapid Toxic Screen; and returns to CDC.
At this point the rapid toxic screen process begins by accessioning the samples, dividing the blood and urine samples into the hundreds of aliquots required for the various tests, and delivering those aliquots to the analysts. The results of the tests are assembled and interpreted, and a report is issued to the PHL that requested CDC assistance. At this time samples can be analyzed for the causative agent if the Level 2 lab is qualified for the analysis, and additional samples are shipped from the incident site to the Level 1 labs to exercise their surge capacity role. All participating labs report their analysis results to CDC through LRN website capabilities, and a final report is issued. These hands-on, real-time exercises have been critical in identifying gaps in the response process and in building experience and confidence in the PHL staffs.
Since the early days of the Bioterrorism Cooperative Agreement, CDC has been working with its partners in public health labs, initially numbering five and now numbering 62, to improve the public health response to a large-scale chemical exposure incident. Partly by plan and partly by trial and error, a network has been created in which different members contribute to the program based upon their interests and abilities, which benefits everyone in the network.
Over the past 5 years, CDC and its partners have not only created a functional chemical incident response network but have also learned a number of important lessons, which will be covered in the next issue.
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