Used for production of live attenuated viral vaccines long track record for production of polio and rabies vaccine the cell line was derived in 1962 from kidney epithelial cells of the african green monkey available from atcc at passage level 121 most vaccine manufacture is performed with cells at passage levels in the. Development of improved vaccine cell lines against. It is the responsibility of the vaccine manufacturer to establish the suitability of a cvv for vaccine production and to establish a vaccine. The mdck vaccine was well tolerated and provided protection equal to that with the vaccine made with egggrown viruses. The first important step in the vaccine field was the production of polio vaccine using monkey kidney cells by jonas salk in 1954 9, 10. Deputy director, division of viral products fdacberovrr. Annex 4 requirements for the use of animal cells as in. The development of a live, attenuated rubella virus vaccine by parkman et al, 3 and demonstration of its clinical effectiveness by meyer et al, 4 motivated us to adapt strain hpv77 to canine renal cell cultures. Many studies have demonstrated superior immunogenicity and safety of hdcvs relative to those using any other tissue culture, such as hamster kidney cells or vero cell vaccines. The use of this cell substrate for the production of rubeola vaccines has been previously reported. Cell substrates their use in the production of vaccines and. The cell culture vaccine process is suitable for largescale manufacture, and the process parameters can be ramped up and run routinely and cost effectively. Acceptability of cell substrates for production of.
Regulatory discussions on tumorigenic cell lines for vaccine production are evolving. Most influenza vaccines are made in embryonated hens eggs and require facilities that can only be used for this purpose. The hucmscs cell line ccrc1 represents a novel, safe and. Emerging and reemerging infectious diseases like the recent porcine influenza a virus h1n1 pandemic necessitated the availability of unprecedented amounts of vaccines. Another cell line being considered for influenza vaccine production is e1immortalised human retinal per. Primary and diploid cell culture systems are now being replaced by the use of continuous cell lines ccls.
Sep 27, 2017 cell line characterization is viewed as a key component of the assurance of product quality and safety, and this topic is discussed in detail in q5d. Cellculturederived influenza vaccine production the lancet. Characterization and qualification of cell substrates and. Current good manufacturing practices cgmp and cell substrate development. Cell based flu vaccine production does not require chicken eggs because the vaccine viruses used to make vaccine are grown in animal cells.
Traditionally animal cells have been used for the production of viral. Cell substrates for the production of viral vaccines. The who had been asked to take the lead in a global consultation process for setting standards for the safety assessment of new cell substrates and subsequently, in 2007 the who published results from the who study group on cell substrates for production of biologicals, geneva, switzerland, 1112 june 2007 and held its third meeting on. These will be discussed in view of novel molecular biology tools, available for the design of new viral vaccines for human use, and animal cell substrates. Most cell stocks, including mdck cells, can be stored frozen, and the supply needed for vaccine production can be generated quickly. Currently available designer cells for viral vaccine production per. Sep 12, 2011 studies showing that murine fibroblast cell lines are susceptible to infection with mouseadapted scrapie agent 11,12 increased concern that nonneuronal cell substrates used to propagate viruses for vaccine production might become infected with a tse agent contaminating some component of culture medium, especially bovine serum. Guidance for industry characterization and qualification of cell. Characteristics and viral propagation properties of a new. Candidate vaccine virus, cell culture, isolation, quality recommendations.
Cell culture methods in vivo tests using adult mice, suckling mice ic and guineapigs. Characterization and qualification of cell substrates and other biological starting materials used in the production of viral vaccines for the prevention and treatment of infectious diseases. The facilities could be used for other purposes, and production is scaleable. Research candidate cell substrates, vaccine production, and. Gardasil, innhuman papillomavirus vaccine types 6, 11, 16. The first who requirements for cell cultures used in the production of biologicals were formulated in 1959 as part of the production of inactivated poliomyelitis vaccine. A thorough characterization of cell substrates is essential to establish quality control systems. Characterization and qualification of cell substrates and other biological starting materials used in the production of viral vaccines for the prevention and treatment of. Seasonal influenza vaccines are produced either in embryonated hens eggs or on a cell substrate.
Thus, the time between the choice of seasonal influenza virus strains and availability of vaccine might be shortened to allow a change in production and incorporate late emerging strains. The fear that components from the production cell substrate could induce cancer in vaccine recipients was the main reason that tumorigenic cells were proscribed for vaccine manufacture for over 40. Acceptability of cell substrates for production of biologicals. We, fda, are providing you, manufacturers of viral vaccines, guidance for the characterization and qualification of cell substrates, viral seeds. These cells were developed in 1987 and designated as a master cell bank in 1998. Q5d derivation and characterization of cell substrates used. Properties of these substrates with focus on historical aspects pertaining to human vaccines. Production and control of the proposed cell culture derived vaccine may be compared to other licensed inactivated vaccines produced in cell culture such as inactivated poliomyelitis, hepatitis a and rabies. Transmissible spongiform encephalopathy tse agents have contaminated human tissuederived medical products, human blood components, and animal vaccines. Characterization of cell banks occurs at several points, namely, the parental cells, pre.
For example, in 1954, the american forces epidemiological board afeb had to decide on new substrates for production of a vaccine against acute respiratory disease caused by adenoviruses. The current approach to manufacturing a safe product includes the thorough characterization of the cell substrate, validation of the manufacturing process for removal andor inactivation of potential adventious agents. Characterization and qualification of cell substrates and other biological materials used in the production of viral vaccines for. Whereas reversion to virulence poses a safety risk with live attenuated vaccines, the potential for the presence of adventitious agents is also an issue of vaccine quality. With the discovery of sv40 as a rhesus agent capable of contaminating the vaccine, primary african green monkey kidney cell culture became the substrate of choice. Pdf history of cell substrates used for human biologicals. Quantitation in the evaluation of cell substrates for viral. The objective of this study was to determine the potential susceptibility to infection of 5 cell lines used or proposed for manufacture of biological products, as well as other lines. In addition, viruses isolated and propagated exclusively in cell. The results indicated that each type of mammalian cell currently used in the production of virus vaccines would be acceptable for these parameters of safety if similar control procedures were applied at the time the vaccines were manufactured. Derivation and characterisation of cell substrates used for. Herein we describe the development of the sementis copenhagen vector scv vaccine platform technology that comprises 1 a scv vaccine vector system that is unable to produce infectious viral progeny in vaccine recipients and 2 a scv cell substrate scs cell line, based on chinese hamster ovary cho cells, that can be used for scv vaccine production. This volume stems from a symposium sponsored by the w. Cell culture inactivated influenza vaccines annex to note.
Human viral vaccine manufacturing formed the basis. Characteristics and viral propagation properties of a new human diploid cell line, walvax2, and its suitability as a candidate cell substrate for vaccine production article fulltext available. History of cell substrates used for human biologicals article pdf available in developments in biological standardization 70. Development of a novel recombinant influenza vaccine in insect cells clifton mcpherson, protein sciences corporation. Studies showing that murine fibroblast cell lines are susceptible to infection with mouseadapted scrapie agent 11,12 increased concern that nonneuronal cell substrates used to propagate viruses for vaccine production might become infected with a tse agent contaminating some component of culture medium, especially bovine serum. Vaccines are manufactured using a wide range of cell substrates e. Research candidate cell substrates, vaccine production. Vector scv vaccine platform technology that comprises 1 a scv vaccine vector system that is unable to produce infectious viral progeny in vaccine recipients and 2 a scv cell substrate scs cell line, based on chinese hamster ovary cho cells, that can be used for scv vaccine production. The list includes a diversity of vaccine products, including live attenuated vaccines, inactivated or detoxified vaccines, subunit vaccines, polysaccharides, viruslike particles, and protein complexes. Requirements for measles vaccine general considerations part a.
Characteristics and viral propagation properties of a new human diploid cell line, walvax2, and its suitability as a candidate cell substrate for vaccine production. So vaccine products are more likely to retain their commercial value 4. Evolving scientific and regulatory perspectives for cell. Annex 3 requirements for measles, mumps and rubella vaccines. Cell substrates are cells used to manufacture biological products. Some advantages of using novel cell substrates for vaccine production enabling technology for among others. The top antirv hits from the primary screening assays were rescreened in a whoderived vero vaccine cell line, which was the cell substrate to be used for enhanced vaccine cell line develop, to. No vaccine production system is without shortcomings and cell based influenza vaccine platforms are not an exception. No evidence was found for rna tumor viruses by the biochemical or biophysical methods used. Three cell substrates, human diploid cells, continuous cell lines and primary cell lines, are always used for developing vaccines. The demand in new vaccines against emerging viral diseases, the increasing vaccine production volumes, and the stringent safety rules for manufacturing have made cell substrates mandatory viral vaccine producer factories. Evaluating novel cell substrates for use in vaccine. Request pdf on jul 14, 2015, francoise aubrit and others published cell substrates for the production of viral vaccines find, read and cite.
Welcome to cdc stacks candidate cell substrates, vaccine. Cell substrates and their use in the production of vaccines and other biologicals was held october 2326, 1978. Production of viral vaccines generally involves inoculation of a cell substrate with a vaccine seed and purification of bulk product from these cells after a sufficient time for replication of the virus or production of vaccine proteins. Refer to the help section for more detailed instructions. Asher, title research candidate cell substrates, vaccine production, and transmissible, year. Preclinical and clinical demonstration of immunogenicity by. Candidate cell substrates, vaccine production, and transmissible spongiform encephalopathies. Pdf use of pcrbased assays for the detection of the. Production of viral vaccines generally involves inocula tion of a cell substrate with a vaccine seed and purification of bulk product from these cells after a sufficient time for replication of the virus or production of vaccine proteins. Quantitation in the evaluation of cell substrates for. Tests for extraneous agents in viral vaccines for human use 2. Characterization and qualification of cell substrates and other.
Subhuman primate diploid cell lines suitable for virus vaccine production are disclosed as well as the production of the cultures. The exact role of various immune mechanisms in the protective efficacy of the hpv l1 vlp vaccine remains to be determined. Since then, the use of primary cell substrates, such as primary chicken embryo fibroblasts cefs, has greatly facilitated vaccine manufacturing. Cell isolated viruses potentially provide another source of supply of viruses for vaccine production in cell culture. Evaluating novel cell substrates for use in vaccine manufacture wcbp, january 14, 2009 philip r. The 1996 revision describes the characterization and testing of continuous cell line and diploid cell substrates, with the general manufacturing requirements applicable to. Producers of biologicals and national control authorities can obtain cultures of these vero cells free of charge, as well as additional.
Hits produced from this primary screen were validated in the african green monkey kidney cell line vero, which is used for the production of the licensed polio virus vaccine. These substrates are gaining increasing acceptance. Seasonal influenza vaccines shall be compliant with the ph. More recently, diploid cells of human origin have been used to produce poliovirus vaccine, thus introducing an alternate acceptable cell substrate for vaccine production. Advances and challenges in vaccine development and. The recent licensure of a vero cell derived live virus vaccine acam2000, smallpox vaccine has coincided with an explosion in the development of a range of new viral vaccines, ranging from liveattenuated pediatric vaccines against rotavirus infections to inactivated wholevirus vaccines against h5n1 pandemic influenza.
In particular, monkey diploid cell lines are disclosed. Health, general bovine spongiform encephalopathy health aspects creutzfeldtjakob disease disease susceptibility disease transmission medical research medicine, experimental primates prions prions proteins vaccines contamination. Development of improved vaccine cell lines against rotavirus. The cell substrates used in the production of licensed or investigational viral vaccines for human use include primary cells, continuous cell lines ccls, and human diploid cell lines hdcs 3,6. Changing the growth substrate from eggs to cell culture raises issues at all stages of the process, from surveillance to the assay of vaccines.
Vaccines also are more difficult to develop and manufacture than many other biologics and thus are more difficult to make in generic form. Seasonal influenza vaccines are produced either in embryonated hens eggs or on a cell culture substrate. Regulatory, biosafety and safety challenges for novel cells. Since rapid production of large amounts of influenza vaccine depends on the availability of fertile hens eggs to grow the viruses, there is an urgent need for the development of alternative cell culture systems, which would allow rapid scaleup of production in the event of a pandemic. Within the animal cell group, there are a number of cell types use for production. The challenge in standardizing cell substrates is to balance the desire for a very efficient production system with the goal of minimizing risks. Select up to three search categories and corresponding keywords using the fields to the right. Today, the spectrum of substrates used for production of licensed and investigational vaccines ranges from primary cells sometimes still within the animal to designed continuous cell lines. Alton jones cell science center, lake placid new york.
Cell culture inactivated influenza vaccines european medicines. The discussion in 2006 was focused on ccls, new cell substrates for vaccine development, and the who vero reference cell bank 1087. Viral vaccines and their manufacturing cell substrates wiley online. In the development of novel substrates used for production of human vaccines there has been significant progress made in recent years. While the production of attenuated and inactivated vaccines requires the. Guideline on quality aspects on the isolation of candidate influenza. At this level, one particular concern is the use and choice of the cell substrate used for viral vaccines production.
Cell culture eliminates the issue of allergic reactions to residual egg proteins, and the scalable nature of the process allows for greater flexibility of production in response to increased. Cell substrates for the production of viral vaccines request pdf. Furthermore, a number of available guidelines and requirements are relevant to the cell substrates used for vaccine production, such as. Influenza virus changes constantly, making vaccine production challenging. Potential pandemic influenzas and the need for an effective, safe, and highspeed vaccine production platform have been widely discussed in the scientific community. Cell based antigen production may offer a faster and more stable production of vaccines compared to embryonic chicken eggs, which produce 12 vaccine doses per chicken egg. At 2 present, for example, in addition to primary animal 3 cell culture, diploid cell lines, both of human and 4 animal origin, are in routine use, as, for example, 5 the mumps, rubella, ipv vaccines. Safety and quality are important issues for vaccines. Vaccines against seasonal and pandemic influenza and the. It is believed that the vaccine provides protection by inducing typespecific. Meeting report who study group on cell substrates for. Characterization and qualification of cell substrates and other biological materials used in the production of viral vaccines for infectious disease indications, cber, biologics. Candidate cell substrates, vaccine production, and transmissible spongiform encephalopathies pedro piccardo, larisa cervenakova, irina vasilyeva, oksana yakovleva, igor bacik, juraj cervenak, carroll mckenzie, lubica kurillova, luisa gregori, kitty pomeroy, and david m. Apr 15, 2015 issues related to cell culturederived influenza vaccines.
Candidate cell substrates, vaccine production, and. Most inactivated influenza vaccines are produced by growing influenza viruses in eggs. The process has given a safe and effective product for decades. The main benefit of cell based vaccines is the ability to rapidly produce vaccine supplies during an impending pandemic. Cell lines cell substrates chimeric vaccines viral vaccines viruslike particles. Issues of benefits and risks have been discussed in the present symposium in the preceding paper 2. Viral vaccines and their manufacturing cell substrates. It is the responsibility of the vaccine manufacturer to establis h the suitability of a cvv for vaccine production and to establish a vaccine. Subhuman primate diploid cell lines as substrates for virus vaccine production. Cell substrates their use in the production of vaccines. Characterization and qualification of cell substrates and other biological materials used in the production of viral vaccines for infectious disease indications. Table 2 lists the number of different cell substrates used in vaccine development and manufacture. The typical cell culture production process can be run in batch sizes of practical scale, sufficient to provide vaccine quantities for interpandemic periods and pandemics.
How to choose the correct cell line for producing your viral vaccine. We, fda, are providing you, manufacturers of viral vaccines, guidance for the. Addressing challenges of vaccine production like virus production with adherent cells, many new vaccines in development are using new cell substrates. The induced t cell responses may play an important role in establishing longlived b cell immune memory. Pdf candidate cell substrates, vaccine production, and. Compared with allantoic fluid, the raw materials and substrates required for cellculturebased vaccine production are better defined or characterized. The vero cell culture has an advantage for licensure because other licensed vaccines, such as that for poliovirus, are produced in this substrate. To adapt to todays market needs, cell based vaccine production.
Besides being vulnerable to occasional contamination, the cells must be free from additional or specific extraneous agents relevant to the species of origin of the cell. Sep 01, 2006 the cell culture vaccine process is suitable for largescale manufacture, and the process parameters can be ramped up and run routinely and cost effectively. And in addition to 6 being manufactured in the human diploid cell, live ipv. However, the vero cell line is not the only one to consider for production of influenza vaccine. Regulatory, biosafety and safety challenges for novel. This activity includes revision of the who requirements 1 as well as proposals for the development of measurement standards for the purpose of cell substrate evaluation. C6 cells are highly permissive for influenza viruses and can be efficiently transfected.