How the Delayed Distribution: CRITICAL COMPONENTS OF THE INFLUENZA VACCINE PROCESS
The public and private sectors both play extensive and critical roles in the influenza vaccine process. Primary responsibilities of the public sector include monitoring changes among circulating influenza viruses, annually updating the vaccine strains, monitoring the vaccine’s effectiveness and coverage rates, and developing recommendations to guide vaccine use. Primary responsibilities of the private sector include the production, distribution, and administration of the vaccine. Both sectors share the responsibility for ensuring the safety and potency of the vaccine. The manufacturers conduct quality-control checks at all stages of the production process while the FDA conducts safety and potency checks on monovalent and trivalent vaccine lots before they are released. In addition, the FDA conducts inspections of plants to ensure that each manufacturer is adhering to current GMP standards. Although complicated, and to a certain extent “fragile,” the current system has worked remarkably well for several decades and has been able to provide increasing doses of vaccine for the U.S. since the 1980s. Some of the key steps of the process are briefly reviewed.
Global Surveilllance
The ability of vaccine to provide protection against influenza depends on a close antigenic match between the strains contained in the vaccine and the circulating viruses. In practice, changes in antigenicity among circulating viruses occur frequently because influenza A and B viruses both undergo antigenic “drift,” a process in which genetic mutations among influenza viruses result in the production of antigenic variants. Eventually, some of the variants begin to circulate widely and replace older strains. Because antibodies to older strains or to previous vaccinations might not provide protection to one of the newer antigenic strains, the emergence of new strains must be monitored closely so that the vaccine strains can be updated as needed. Typically, each of the vaccine strains is updated about every one to three years. online pharmacy no prescription needed
The monitoring of influenza viruses is accomplished through a global surveillance system maintained by the World Health Organization (WHO). In the U.S., approximately 120 laboratories associated with state health departments, universities, and large hospitals and other laboratories associated with the Department of Defense provide surveillance data and isolates of currently circulating viruses. Approximately 110 laboratories in 83 other countries also participate in the WHO system and provide information and isolates from their countries to reference centers located in Atlanta, London, Melbourne, and Tokyo. As one of the four global reference centers, the Influenza Branch of CDC coordinates national influenza surveillance and helps to facilitate international surveillance efforts. Isolates sent to CDC by U.S. laboratories and by some international laboratories are characterized for their antigenic and molecular features. All of the surveillance and strain characterization information is made available to the vaccine strain-selection process.
Annual Strain-Selection Process
The process of selecting strains for U.S. influenza vaccine is a broadly collaborative effort involving several public health agencies and representatives from a broad range of private sector groups. Each year, three strains are selected at two public meetings, usually held in January and March, of the Vaccine and Related Biological Products Advisory Committee (VRBPAC), an advisory group to the FDA. At the VRBPAC meetings, national and international surveillance data on viruses and related disease activity and other relevant information, such as the ability of antibodies induced by current vaccines to cover newer viruses, are reviewed. Typically, selection of the strains by VRB-PAC begins at the January meeting and is completed at the March meeting. The FDA has the final responsibility for selecting the influenza strains that will be used in influenza vaccines sold in the U.S. In the period between the two FDA meetings, the WHO convenes a separate meeting to recommend influenza vaccine strains for the Northern Hemisphere (another WHO meeting is held in September to recommend strains for Southern Hemisphere influenza vaccines). Although the WHO recommendations are not binding, most countries usually adhere to them. In the future, the timing of the FDA and WHO meetings might be changed so the WHO meeting precedes a consolidated FDA meeting. The selection of vaccine strains at the January meeting is complicated by the need to balance two critical considerations. On the one hand, selecting as many vaccine strains as possible in January is highly desirable from a manufacturing point of view. The early selection of strains provides the maximum amount of time possible to produce vaccine and provides the maximum cushion if unforeseen and unpredictable difficulties arise while growing or processing the strains. However, the “correct” selection of vaccine strains that are expected to predominate in the following winter is absolutely essential for an effective vaccine and their selection depends on the availability of an adequate amount of surveillance and strain characterization information from the current influenza season and the preceding summer. Sometimes, a less than desirable amount of information on circulating viruses is available in January if, for example, the influenza season has started late, or activity levels have been low and few viruses have been isolated, or because the flow of surveillance information or isolates has been impeded for other reasons. buy kamagra
In some years, the emergence of a new and significantly important virus strain (e.g., the emergence of the influenza A (H3N2) virus Sydney strain in 1997) can occur after the vaccine strain selection process has been completed. The practical solution has been to select at least one strain at the January VRBPAC meeting, so that manufacturers can begin producing some of the vaccine strains, with the remaining strains selected in March.
The VRBPAC (and WHO) recommendations also usually are worded to allow the regulatory authorities and the manufacturers an important degree of latitude in selecting the actual strains to be used in the vaccine by indicating that a virus “like” the recommended strain can be used in the vaccine. This means that a virus that is antigenically similar to the recommended vaccine strain can be used in the vaccine. This approach is important because it allows the manufacturers to identify and use virus strains with manufacturing properties suitable for that manufacturer. One drawback is that the use of different vaccine strains by different companies in some years can lead to considerable confusion among providers and the general public.
Manufacturing Considerations
Many of the influenza vaccine production steps used by the manufacturers are considered proprietary, but in general, the manufacturing steps include the growth of vaccine strains in embryonated eggs, the production of monovalent concentrates, the formulation of trivalent vaccine, the processes to ensure the inactivation, sterility, safety, and potency of the vaccine, the updating of the product inserts, and the filling, packaging and distribution of the vaccine. The FDA (and the manufacturers) must test and review several test results to ensure that the vaccine meets specifications before the FDA can release vaccine for distribution. cialis canadian pharmacy
A few key points related to the vaccine production process are worth emphasizing. First, the manufacture of influenza vaccine involves inherent uncertainties each year because one or more of the vaccine strains usually change every year, and the intrinsic growth and processing properties of viruses can vary. Moreover, even after preliminary testing for growth and processing characteristics, the way in which different viruses will respond to the specific production methods employed by a manufacturer is not fully known until full scale manufacturing has started. Second, the time pressures to complete key steps are relentless. The manufacturing process has evolved into a year-round activity in which preparations for the following year must begin almost immediately after cessation of vaccine production for the immediate year. Starting one step often depends upon the completion or near-completing of preceding steps, making the timing of each step critical. For example, the ordering of the embryonated eggs must occur a year or more in advance, limiting the ability of manufacturers to respond quickly to unforeseen shortfalls or delays in the production of vaccine by other manufacturers.
In practice, the intense time pressures have affected the manufacturing process in several ways. For example, the identification of strains that might potentially be used in the vaccine, as well as characterization of their growth and processing properties, now begins well in advance of the actual selection of the vaccine strains by VRBPAC. Candidate vaccine viruses are provided to the manufacturers as early as possible so the manufacturers can study their growth and processing properties of specific viruses. Other laboratories also help to develop suitable candidate “high growth” influenza A viruses, which are essential for producing influenza A viruses in the amounts needed to meet current levels of vaccine demand. Another example is the common practice whereby manufacturers begin growing and processing a virus strain at risk to themselves, before the first strain selection meeting, to attempt to maximize vaccine supplies.
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The Regulatory Process
The FDA and the manufacturers work together to ensure the potency and safety of the influenza vaccine sold in the U.S. For example, FDA staff prepare and provide the reagents used by the manufacturers (and the FDA) to test the potency of vaccine lots. Monovalent bulk lots of vaccine are tested both by the manufacturers and by the FDA. After the monovalent lots have been released by the FDA, the companies blend them to make trivalent vaccine, which then is submitted to the FDA again for further testing and final release. The FDA also inspects the vaccine manufacturers to ensure that their production processes and plants are in compliance with current GMPs. If these standards are not met, and if substantial amounts of time are needed to correct the problems, then disruptions and delays can occur in the production schedule of the vaccine. Steps taken by manufacturers to upgrade facilities or to enhance production capacity can also affect production.
The Distribution System
The system for distributing influenza vaccine from manufacturers to vaccine recipients is complex and not centralized. Individual manufacturers employ different vaccine distribution strategies, and deliver varying amounts of vaccine to the market on different schedules. Some manufacturers distribute vaccine solely through secondary distributors, who sell vaccine to other distributors or to providers. Other companies will sell vaccine directly to end-users. The system as a whole involves hundreds of primary, secondary, and tertiary distribution companies, pharmacies, and many tens of thousands of providers.
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Most vaccine distribution and administration is accomplished within the private sector with relatively small amounts of vaccine purchased and distributed by the federal government or local state health departments. For example, between 1999 and 2001, CDC purchased an average of 1.8 million doses of vaccine each year, on behalf of many state health departments. Other states purchase vaccine directly from manufacturers or large distributors. In addition, the Department of Defense purchases influenza vaccine to immunize its forces.
