who to ensure international standards of quality, safety, immunogenicity, and efficacy for adoption by numerous countries. the process requires manufacturing consistency at who-contracted laboratories following good manufacturing practice (gmp). when un agencies are involved in vaccine licensure, individual nations collaborate by 1) issuing marketing authorization and a national license for the vaccine, its manufacturers, and distribution partners; and 2) conducting postmarketing surveillance, including records for adverse events after the vaccination program. the who works with national agencies to monitor inspections of manufacturing facilities and distributors for compliance with gmp and regulatory oversight. some countries choose to buy vaccines licensed by reputable national organizations, such as ema, fda, or national agencies in other affluent countries, but such purchases typically are more expensive and may not have distribution resources suitable to local conditions in developing countries. european union in the european union (eu), vaccines for pandemic pathogens, such as seasonal influenza, are licensed eu-wide where all the member states comply ("centralized"), are licensed for only some member states ("decentralized"), or are licensed on an individual national level. generally, all eu states follow regulatory guidance and clinical programs defined by the european committee for medicinal products for human use (chmp), a scientific panel of the european medicines agency (ema) responsible for vaccine licensure. the chmp is supported by several expert groups who assess and monitor the progress of a vaccine before and after licensure and distribution. united states under the fda, the process of establishing evidence for vaccine clinical safety and efficacy is the same as for the approval process for prescription drugs. if successful through the stages of clinical development, the vaccine licensing process is followed by a biologics license application which must provide a scientific review team (from diverse disciplines, such as physicians, statisticians, microbiologists, chemists) and comprehensive documentation for the vaccine candidate having efficacy and safety throughout its development. also during this stage, the proposed manufacturing facility is examined by expert reviewers for gmp compliance, and the label must have a compliant description to enable health care providers' definition of vaccine-specific use, including its possible risks, to communicate and deliver the vaccine to the public. after licensure, monitoring of the vaccine and its production, including periodic inspections for gmp compliance, continue as long as the manufacturer retains its license, which may include additional submissions to the fda of tests for potency, safety, and purity for each vaccine manufacturing step. india drugs controller general of india is the head of department of the central drugs standard control organization of the government of india responsible for approval of licences of specified categories of drugs such as vaccines and others like blood and blood products, iv fluids, and sera in india. postmarketing surveillance until a vaccine is in use for the general population, all potential adverse events from the vaccine may not be known, requiring manufacturers to conduct phase iv studies for postmarketing surveillance of the vaccine while it is used widely in the public. the who works with un member states to implement post-licensing surveillance. the fda relies on a vaccine adverse event reporting system to monitor safety concerns about a vaccine throughout its use in the american public. scheduling main article: vaccination schedule for country-specific information on vaccination policies and practices, see vaccination policy. in order to provide the best protection, children are recommended to receive vaccinations as soon as their immune systems are sufficiently developed to respond to particular vaccines, with additional "booster" shots often required to achieve "full immunity". this has led to the development of complex vaccination schedules. global recommendations of vaccination schedule are issued by strategic advisory group of experts and will be further translated by advisory committee at the country level with considering of local factors such as disease epidemiology, acceptability of vaccination, equity in local populations, and programmatic and financial constraint. in the united states, the advisory committee on immunization practices, which recommends schedule additions for the centers for disease control and prevention, recommends routine vaccination of children against hepatitis a, hepatitis b, polio, mumps, measles, rubella, diphtheria, pertussis, tetanus, hib, chickenpox, rotavirus, influenza, meningococcal disease and pneumonia. the large number of vaccines and boosters recommended (up to 24 injections by age two) has led to problems with achieving full compliance. to combat declining compliance rates, various notification systems have been instituted and many combination injections are now marketed (e.g., pentavalent vaccine and mmrv vaccine), which protect against multiple diseases. besides recommendations for infant vaccinations and boosters, many specific vaccines are recommended for other ages or for repeated injections throughout life – most commonly for measles, tetanus, influenza, and pneumonia. pregnant women are often screened for continued resistance to rubella. the human papillomavirus vaccine is recommended in the u.s. (as of 2011) and uk (as of 2009). vaccine recommendations for the elderly concentrate on pneumonia and influenza, which are more deadly to that group. in 2006, a vaccine was introduced against shingles, a disease caused by the chickenpox virus, which usually affects the elderly. scheduling and dosing of a vaccination may be tailored to the level of immunocompetence of an individual and to optimize population-wide deployment of a vaccine when it supply is limited, e.g. in the setting of a pandemic. economics of development main article: economics of vaccines one challenge in vaccine development is economic: many of the diseases most demanding a vaccine, including hiv, malaria and tuberculosis, exist principally in poor countries. pharmaceutical firms and biotechnology companies have little incentive to develop vaccines for these diseases because there is little revenue potential. even in more affluent countries, financial returns are usually minimal and the financial and other risks are great. most vaccine development to date has relied on "push" funding by government, universities and non-profit organizations. many vaccines have been highly cost effective and beneficial for public health. the number of vaccines actually administered has risen dramatically in recent decades. this increase, particularly in the number of different vaccines administered to children before entry into schools may be due to government mandates and support, rather than economic incentive. patents according to the world health organization, the biggest barrier to vaccine production in less developed countries has not been patents, but the substantial financial, infrastructure, and workforce requirements needed for market entry. vaccines are complex mixtures of biological compounds, and unlike the case for prescription drugs, there are no true generic vaccines. the vaccine produced by a new facility must undergo complete clinical testing for safety and efficacy by the manufacturer. for most vaccines, specific processes in technology are patented. these can be circumvented by alternative manufacturing methods, but this required r&d infrastructure and a suitably skilled workforce. in the case of a few relatively new vaccines, such as the human papillomavirus vaccine, the patents may impose an additional barrier. when increased production of vaccines was urgently needed during the covid-19 pandemic in 2021, the world trade organization and governments around the world evaluated whether to waive intellectual property rights and patents on covid-19 vaccines, which would "eliminate all potential barriers to the timely access of affordable covid-19 medical products, including vaccines and medicines, and scale up the manufacturing and supply of essential medical products". production vaccine production is fundamentally different from other kinds of manufacturing – including regular pharmaceutical manufacturing – in that vaccines are intended to be administered to millions of people of whom the vast majority are perfectly healthy. this fact drives an extraordinarily rigorous production process with strict compliance requirements that go far beyond what is required of other products. depending upon the antigen, it can cost anywhere from us$50 to $500 million to build a vaccine production facility, which requires highly specialized equipment, clean rooms, and containment rooms. there is a global scarcity of personnel with the right combination of skills, expertise, knowledge, competence and personality to staff vaccine production lines. with the notable exceptions of brazil, china, and india, many developing countries' educational systems are unable to provide enough qualified candidates, and vaccine makers based in such countries must hire expatriate personnel to keep production going. vaccine production has several stages. first, the antigen itself is generated. viruses are grown either on primary cells such as chicken eggs (e.g., for influenza) or on continuous cell lines such as cultured human cells (e.g., for hepatitis a). bacteria are grown in bioreactors (e.g., haemophilus influenzae type b). likewise, a recombinant protein derived from the viruses or bacteria can be generated in yeast, bacteria, or cell cultures. after the antigen is generated, it is isolated from the cells used to generate it. a virus may need to be inactivated, possibly with no further purification required. recombinant proteins need many operations involving ultrafiltration and column chromatography. finally, the vaccine is formulated by adding adjuvant, stabilizers, and preservatives as needed. the adjuvant enhances the immune response to the antigen, stabilizers increase the storage life, and preservatives allow the use of multidose vials. combination vaccines are harder to develop and produce, because of potential incompatibilities and interactions among the antigens and other ingredients involved. the final stage in vaccine manufacture before distribution is fill and finish, which is the process of filling vials with vaccines and packaging them for distribution. although this is a conceptually simple part of the vaccine manufacture process, it is often a bottleneck in the process of distributing and administering vaccines. vaccine production techniques are evolving. cultured mammalian cells are expected to become increasingly important, compared to conventional options such as chicken eggs, due to greater productivity and low incidence of problems with contamination. recombination technology that produces genetically detoxified vaccines is expected to grow in popularity for the production of bacterial vaccines that use toxoids. combination vaccines are expected to reduce the quantities of antigens they contain, and thereby decrease undesirable interactions, by using pathogen-associated molecular patterns. vaccine manufacturers the companies with the highest market share in vaccine production are merck, sanofi, glaxosmithkline, pfizer and novartis, with 70% of vaccine sales concentrated in the eu or us (2013).: 42 vaccine manufacturing plants require large capital investments ($50 million up to $300 million) and may take between 4 and 6 years to construct, with the full process of vaccine development taking between 10 and 15 years.: 43 manufacturing in developing countries is playing an increasing role in supplying these countries, specifically with regards to older vaccines and in brazil, india and china.: 47 the manufacturers in india are the most advanced in the developing world and include the serum institute of india, one of the largest producers of vaccines by number of doses and an innovator in processes, recently improving efficiency of producing the measles vaccine by 10 to 20-fold, due to switching to a mrc-5 cell culture instead of chicken eggs.: 48 china's manufacturing capabilities are focused on supplying their own domestic need, with sinopharm (cnpgc) alone providing over 85% of the doses for 14 different vaccines in china.: 48 brazil is approaching the point of supplying its own domestic needs using technology transferred from the developed world.: 49 delivery systems a woman receiving a vaccine by injection one of the most common methods of delivering vaccines into the human body is injection. the development of new delivery systems raises the hope of vaccines that are safer and more efficient to deliver and administer. lines of research include liposomes and iscom (immune stimulating complex). notable developments in vaccine delivery technologies have included oral vaccines. early attempts to apply oral vaccines showed varying degrees of promise, beginning early in the 20th century, at a time when the very possibility of an effective oral antibacterial vaccine was controversial. by the 1930s there was increasing interest in the prophylactic value of an oral typhoid fever vaccine for example. an oral polio vaccine turned out to be effective when vaccinations were administered by volunteer staff without formal training; the results also demonstrated increased ease and efficiency of administering the vaccines. effective oral vaccines have many advantages; for example, there is no risk of blood contamination. vaccines intended for oral administration need not be liquid, and as solids, they commonly are more stable and less prone to damage or spoilage by freezing in transport and storage. such stability reduces the need for a "cold chain": the resources required to keep vaccines within a restricted temperature range from the manufacturing stage to the