Biosimilar

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Template:Short description Script error: No such module "For". Template:Use mdy dates Template:Cs1 config A biosimilar (also known as follow-on biologic or subsequent entry biologic) is a biologic medical product that is almost an identical copy of an original product that is manufactured by a different company.[1] Biosimilars are officially approved versions of original "innovator" products and can be manufactured when the original product's patent expires.[2] Reference to the innovator product is an integral component of the approval.[3]

Unlike with generic drugs of the more common small-molecule type, biosimilar drugs generally exhibit high molecular complexity and may be quite sensitive to changes in manufacturing processes. Despite this heterogeneity, all biopharmaceuticals, including biosimilars, must maintain consistent quality and clinical performance throughout their lifecycle.[4]

Drug-related authorities such as the European Medicines Agency (EMA) of the European Union, the United States Food and Drug Administration (FDA), and the Health Products and Food Branch of Health Canada hold their own guidance on requirements for demonstration of the similar nature of two biological products in terms of safety and efficacy. According to them, analytical studies demonstrate that the biological product is highly similar to the reference product, despite minor differences in clinically inactive components, animal studies (including the assessment of toxicity), and a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics). They are sufficient to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is licensed and is intended to be used and for which licensure is sought for the biological product.Script error: No such module "Unsubst".

The World Health Organization (WHO) published its "Guidelines for the evaluation of similar biotherapeutic products (SBPs)" in 2009. The purpose of this guideline is to provide an international norm for evaluating biosimilars.[5][6][7][8]

The EMA has granted marketing authorizations for more than 50 biosimilars since 2006. The first biosimilar of a monoclonal antibody to be approved worldwide was a biosimilar of infliximab in the EU in 2013.[9] On March 6, 2015, the FDA approved the United States' first biosimilar product, the biosimilar of filgrastim called filgrastim-sndz (trade name Zarxio) by Sandoz.

Approval processes

United States

In the United States, the Food and Drug Administration (FDA) held that new legislation was required to enable them to approve biosimilars to those biologics originally approved through the PHS Act pathway.[10] Additional Congressional hearings have been held.[11] On March 17, 2009, the Pathway for Biosimilars Act was introduced in the House.[2] Since 2004 the FDA has held a series of public meetings on biosimilars.[12][13]

The FDA gained the authority to approve biosimilars (including interchangeables that are substitutable with their reference product) as part of the Patient Protection and Affordable Care Act signed into law by President Obama on March 23, 2010.Script error: No such module "Unsubst".

The FDA has previously approved biologic products using comparability, for example, Omnitrope in May 2006, but this like Enoxaparin was also to a reference product, Genotropin, originally approved as a biologic under the FD&C Act.[14]

On March 6, 2015, Zarxio obtained the first approval of FDA.[15] Sandoz's Zarxio is biosimilar to Amgen's Neupogen (filgrastim), which was originally licensed in 1991. This is the first product to be passed under the Biologics Price Competition and Innovation Act of 2009 (BPCI Act), which was passed as part of the Affordable Healthcare Act. But Zarxio was approved as a biosimilar, not as an interchangeable product, the FDA notes. And under the BPCI Act, only a biologic that has been approved as an "interchangeable" may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product. The FDA said its approval of Zarxio is based on review of evidence that included structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data and other clinical safety and effectiveness data that demonstrates Zarxio is biosimilar to Neupogen.Script error: No such module "Unsubst".

In March 2020, most protein products that were approved as drug products (including every insulin currently on the market since December 2019Template:Dated maintenance category (articles)Script error: No such module "Check for unknown parameters".) are scheduled to open up to biosimilar and interchangeable competition in the United States.[16] However, "chemically synthesized polypeptides" are excluded from this transition, which means that a product that falls within this category won't be able to come to market as a biosimilar or interchangeable product, but will have to come to the market under a different pathway.[16]

Background

Cloning of human genetic material and development of in vitro biological production systems has allowed the production of virtually any recombinant DNA based biological substance for eventual development of a drug. Monoclonal antibody technology combined with recombinant DNA technology has paved the way for tailor-made and targeted medicines. Gene- and cell-based therapies are emerging as new approaches.

Recombinant therapeutic proteins are of a complex nature (composed of a long chain of amino acids, modified amino acids, derivatized by sugar moieties, folded by complex mechanisms). These proteins are made in living cells (bacteria, yeast, animal or human cell lines). The ultimate characteristics of a drug containing a recombinant therapeutic protein are to a large part determined by the process through which they are produced: choice of the cell type, development of the genetically modified cell for production, production process, purification process, formulation of the therapeutic protein into a drug.

After the expiry of the patent of approved recombinant drugs (e.g., insulin, human growth hormone, interferons, erythropoietin, monoclonal antibodies and more) any other biotech company can develop and market these biologics (thus called biosimilars).

The typical reference product has undergone numerous changes in its manufacturing processes, and such changes in the manufacturing process (ranging from a change in the supplier of cell culture media to new purification methods or new manufacturing sites) was substantiated with appropriate data and was approved by the EMA.

The current concept of development of biosimilar monoclonal antibodies follows the principle that an extensive state of the art physicochemical, analytical and functional comparison of the molecules is complemented by comparative non-clinical and clinical data that establish equivalent efficacy and safety in a clinical "model" indication that is most sensitive to detect any minor differences (if these exist) between the biosimilar and its reference monoclonal antibody also at the clinical level.

The EMA has recognized this fact, which has resulted in the establishment of the term "biosimilar" in recognition that, whilst biosimilar products are similar to the original product, they are not exactly the same.[17]

Originally the complexity of biological molecules led to requests for substantial efficacy and safety data for a biosimilar approval. This has been progressively replaced with a greater dependence on assays, from quality through to clinical, that show assay sensitivity sufficient to detect any significant difference in dose.[18] However, the safe application of biologics depends on an informed and appropriate use by healthcare professionals and patients. Introduction of biosimilars also requires a specifically designed pharmacovigilance plan. It is difficult and costly to recreate biologics because the complex proteins are derived from living organisms that are genetically modified. In contrast, small molecule drugs made up of a chemically based compound can be easily replicated and are considerably less expensive to reproduce. In order to be released to the public, biosimilars must be shown to be as close to identical to the parent innovator biologic product based on data compiled through clinical, animal, analytical studies and conformational status.[19][20]

Generally, once a drug is released in the market by the FDA, it has to be re-evaluated for its safety and efficacy once every six months for the first and second years. Afterward, re-evaluations are conducted yearly, and the result of the assessment should be reported to authorities such as FDA. Biosimilars are required to undergo pharmacovigilance (PVG) regulations as its reference product. Thus biosimilars approved by the EMA are required to submit a risk management plan (RMP) along with the marketing application and have to provide regular safety update reports after the product is in the market. The RMP includes the safety profile of the drug and proposes the prospective pharmacovigilance studies.

Several PK studies, such as studies conducted by Committee for Medicinal Products for Human Use (CHMP), have been conducted under various ranges of conditions; Antibodies from an originator's product versus antibodies from a biosimilar; combination therapy and monotherapy; various diseases, etc. on the purpose to verify comparability in pharmacokinetics of the biosimilar with the reference medicinal product in a sufficiently sensitive and homogeneous population.

Nomenclature

In the European Union, no unique identifier of a biosimilar medicine product is required, as the same rules are followed as for all biologics.Script error: No such module "Unsubst".

The US decided on a different approach, requiring the assignment of a four-letter suffix to the nonproprietary name of the original product to distinguish between innovator drugs and their biosimilars.[21] Japan has similar requirements.[22] The suffix approach has been criticized on the grounds of compromising the INN system and delaying the marketing of biosimilars.[22] Australia decided not to use a 4-letter suffix.[23][24][25]

A version of the four-letter suffix has been proposed to the WHO as the biological qualifier (BQ). It is not part of the international nonproprietary name (INN), but is proposed to be managed under the same registry.[26] The report 1 of the May 2017 WHO Expert Consultation on Improving Access to and Use of Similar Biotherapeutic Products, published in October 2017, revealed on page 4, that following the outcome arising from the meeting: "No consensus was reached on whether WHO should continue with the BQ... WHO will not be proceeding with this at present."[27]

Bioparallel

Different from biosimilars, many new antibodies are being developed with the goal to be structurally different (to not violate patents) but functionally very similar to their reference drugs. Similarly, in advanced therapy medicinal products, such as Chimeric Antigen Receptor T-cell (CAR-T) therapy, the exchange of one component by a similar component (e.g. one promoter by another to drive CAR expression), generates structurally different, but functionally similar copies of drugs. There is no established term for such biologics, but the terms "bioparallels" or "me-too biologics" (in reference to me-too drugs) have been proposed.[28][29] Within the current frameworks of the US and EU approval processes, these drugs require evaluation as new biological entities. Bioparallels compete with their reference medicines on price but have the advantage of being able to enter the market earlier.

Biobetter

The term "biobetter" refers to a biological drug that is an improved version of an existing biological drug. Unlike biosimilars, the term “biobetter” is used informally without any official and universally accepted definition. While biosimilars try to copy an existing biological drug (the "reference medicine") as closely as possible,[30][31] biobetters try to improve on it.[32] Since the term biobetter is informal, there is no rule which regulatory pathway they need to go through to be approved. When the improvement to the original drug is merely in the formulation (thus, e.g., adding additional modes of administration), the drug might be regulated as a biosimilar. However, if the active pharmaceutical ingredient (API) has been modified, the drug needs to be evaluated as a new biological entity. Even without changes to the API, the biobetter needs to be evaluated as a new biological entity (requiring a biologics license application), if it shows better clinical outcomes compared to the reference medicine. The latter happened e.g. to Zymfentra, an antibody biosimilar that can be given subcutaneously, whereas its reference medicine infliximab was only approved for intravenous administration.[33] Biobetters compete in the market based on their improved features, and are thus different from bioparallels, which compete on price, and which imitate the functionality of a reference medicine as closely as possible, but without violating the associated intellectual property.

Australia

Biosimilars available in Australia include adalimumab, bevacizumab, enoxaparin, epoetin lambda, etanercept, filgrastim, follitropin alfa, infliximab, insulin aspart, insulin glargine, pegfilgrastim, rituximab, teriparatide, and trastuzumab.[34]

Egypt

A research article about "Maximizing the benefits of using biosimilars in Egypt" proposed a regulatory framework for biosimilars in Egypt. The article summarized the recommendations of a number of stakeholders.[35]

Key Findings and Recommendations of the article
  1. Pricing: The experts suggested a mandatory discount of 30–40% on the price of the first biosimilar compared to its originator, with subsequent biosimilars receiving additional discounts. It was also recommended that biosimilar prices be revised periodically, either annually or biennially.
  2. Reimbursement: A significant emphasis was placed on using Health Technology Assessment (HTA), specifically cost-effectiveness analysis (CEA) and budget impact analysis (BIA), when manufacturers seek to extend reimbursement indications beyond those of the originator. Additionally, experts proposed that the first biosimilar, offering a minimum 50% discount compared to the originator, be granted immunity from removal from the formulary for a specified period.
  3. Uptake: The study highlighted the need for policies that enhance both prescriber and patient acceptance of biosimilars. Strategies include disseminating educational materials, implementing financial incentives for prescribing biosimilars as first-line therapy, and using co-payments to encourage the choice of less expensive biosimilars over more costly biologics.
  4. Post-Marketing and Pharmacovigilance: The importance of establishing registries and conducting real-world evidence studies to monitor biosimilar efficacy and safety was also emphasized. A pharmacovigilance framework specific to biosimilars and biologics was suggested to be more effective than the existing general framework.

European Union

Biosimilar medicines approved in the European Union (EU) are interchangeable with their reference medicine or with an equivalent biosimilar.[36]

European Union approved biosimilars[37]
Active substance Reference product Biosimilar medicines
Adalimumab Humira[38] Amgevita,[39] Amsparity,[40] Cyltezo,[41] Halimatoz,[42] Hefiya,[43] Hukyndra,[44] Hulio,[45] Hyrimoz,[46] Idacio,[47] Imraldi,[48] Kromeya,[49] Libmyris,[50] Solymbic,[51] Trudexa,[52] Yuflyma[53]
Bevacizumab Avastin[54] Abevmy,[55] Alymsys,[56] Aybintio,[57] Equidacent,[58] Mvasi,[59] Onbevzi,[60] Oyavas,[61] Vegzelma,[62] Zirabev[63]
Enoxaparin sodium Clexane[64] Inhixa,[64] Thorinane[65]
Epoetin alfa Eprex/Erypo Abseamed,[66] Binocrit,[67] Epoetin Alfa Hexal,[68] Retacrit,[69] Silapo[70]
Etanercept Enbrel[71] Benepali,[72] Erelzi,[73] Lifmior,[74] Nepexto[75]
Filgrastim Neupogen[76] Accofil,[77] Biograstim,[78] Filgrastim Hexal,[79] Filgrastim ratiopharm,[80] Grastofil,[81] Nivestim,[76] Ratiograstim,[82] Tevagrastim,[83] Zarzio[84]
Follitropin alfa Gonal-F[85] Bemfola,[86] Ovaleap[87]
Infliximab Remicade[88] Flixabi,[89] Inflectra,[90] Remsima,[91] Zessly[92]
Insulin aspart NovoRapid[93] Fiasp,[94] Insulin aspart Sanofi,[95] Kirsty,[96] NovoMix,[97] Ryzodeg[98]
Insulin glargine Lantus[99] Abasaglar,[100] Semglee[101]
Insulin lispro Humalog[102] Insulin lispro Sanofi[103]
Pegfilgrastim Neulasta[104] Cegfila,[105] Fulphila,[106] Grasustek,[107] Pelgraz,[108] Pelmeg,[109] Udenyca,[110] Stimufend,[111] Ziextenzo[112]
Ranibizumab Lucentis[113] Byooviz,[114] Ranivisio,[115] Ximluci[116]
Rituximab MabThera[117] Blitzima,[118] Ritemvia,[119] Rituzena,[120] Rixathon,[121] Riximyo,[122] Ruxience,[123] Truxima[124]
Somatropin Genotropin[125] Omnitrope[125]
Teriparatide Forsteo[126] Movymia,[127] Terrosa[128]
Tocilizumab RoActemra[129] Tyenne[130]
Trastuzumab Herceptin[131] Herzuma,[132] Kanjinti,[133] Ogivri,[134] Ontruzant,[135] Trazimera,[136] Zercepac[137]

United States

As of October 2024, the US FDA has approved 60 biosimilars.[138][139]

BPCI Act

The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) was originally sponsored and introduced on June 26, 2007, by Senator Edward Kennedy (D-MA). It was formally passed under the Patient Protection and Affordable Care Act (PPAC Act), signed into law by President Barack Obama on March 23, 2010. The BPCI Act was an amendment to the Public Health Service Act (PHS Act) to create an abbreviated approval pathway for biological products that are demonstrated to be highly similar (biosimilar) to a Food and Drug Administration (FDA) approved biological product.[140] The BPCI Act is similar, conceptually, to the Drug Price Competition and Patent Term Restoration Act of 1984 (also referred to as the "Hatch-Waxman Act") which created biological drug approval through the Federal Food, Drug, and Cosmetic Act (FFD&C Act). The BPCI Act aligns with the FDA's longstanding policy of permitting appropriate reliance on what is already known about a drug, thereby saving time and resources and avoiding unnecessary duplication of human or animal testing. The FDA has released a total of four draft guidelines related to biosimilar or follow-on biologics development. Upon the release of the first three guidance documents the FDA held a public hearing on May 11, 2012.[141]

In 2018, the FDA released a Biosimilars Action Plan to implement regulations from the BPCI, including limiting the abuse of the Risk Evaluation and Mitigation Strategy (REMS) system for evergreening and transitioning insulin and human growth hormone to regulation as biologics rather than drugs.[142]

US approved biosimilars

Date of Biosimilar FDA Approval Biosimilar Product[138] Original Product[138]
March 2015[143] filgrastim-sndz/Zarxio filgrastim/Neupogen
April 2016[144] infliximab-dyyb/Inflectra infliximab/Remicade
August 2016[145][146] etanercept-szzs/Erelzi etanercept/Enbrel
September 2016[147][148] adalimumab-atto/Amjevita adalimumab/Humira
April 2017[149] infliximab-abda/Renflexis infliximab/Remicade
August 2017[150] adalimumab-adbm/Cyltezo adalimumab/Humira
September 2017[151][152] bevacizumab-awwb/Mvasi bevacizumab/Avastin
December 2017[153][154] trastuzumab-dkst/Ogivri trastuzumab/Herceptin
December 2017[155] infliximab-qbtx/Ixifi infliximab/Remicade
May 2018[156][157] epoetin alfa-epbx/Retacrit epoetin alfa/Procrit
June 2018[158][159] pegfilgrastim-jmdb/Fulphila pegfilgrastim/Neulasta
July 2018[160] filgrastim-aafi/Nivestym filgrastim/Neupogen
October 2018[161] adalimumab-adaz/Hyrimoz adalimumab/Humira
November 2018[162] pegfilgrastim-cbqv/Udenyca pegfilgrastim/Neulasta
November 2018[163] rituximab-abbs/Truxima rituximab/Rituxan
December 2018[164] trastuzumab-pkrb/Herzuma trastuzumab/Herceptin
January 2019[165] trastuzumab-dttb/Ontruzant trastuzumab/Herceptin
March 2019[166] trastuzumab-qyyp/Trazimera trastuzumab/Herceptin
April 2019[167] etanercept-ykro/Eticovo etanercept/Enbrel
June 2019[168] trastuzumab-anns/Kanjinti trastuzumab/Herceptin
June 2019[169] bevacizumab-bvzr/Zirabev bevacizumab/Avastin
July 2019[170] rituximab-pvvr/Ruxience rituximab/Rituxan
July 2019[171] adalimumab-bwwd/Hadlima adalimumab/Humira
November 2019[172] pegfilgrastim-bmez/Ziextenzo pegfilgrastim/Neulasta
November 2019[173] adalimumab-afzb/Abrilada adalimumab/Humira
December 2019[174] infliximab-axxq/Avsola infliximab/Remicade
June 2020[175] pegfilgrastim-apgf/Nyvepria pegfilgrastim/Neulasta
July 2020[176] adalimumab-fkjp/Hulio adalimumab/Humira
December 2020[177] rituximab-arrx/Riabni rituximab/Rituxan
July 2021[178] insulin glargine-yfgn/Semglee insulin glargine/Lantus
September 2021[179] ranibizumab-nuna/Byooviz ranibizumab/Lucentis
December 2021[180] insulin glargine-aglr/Rezvoglar insulin glargine/Lantus
December 2021[181] adalimumab-aqvh/Yusimry adalimumab/Humira
February 2022[182] filgrastim-ayow/Releuko filgrastim/Neupogen
April 2022[183] bevacizumab-maly/Alymsys bevacizumab/Avastin
May 2022[184] pegfilgrastim-pbbk/Fylnetra pegfilgrastim/Neulasta
August 2022[185] ranibizumab-eqrn/Cimerli ranibizumab/Lucentis
September 2022[186] pegfilgrastim-fpgk/Stimufend pegfilgrastim/Neulasta
September 2022[187] bevacizumab-adcd/Vegzelma bevacizumab/Avastin
December 2022[188] adalimumab-aacf/Idacio adalimumab/Humira
May 2023[189] adalimumab-aaty/Yuflyma adalimumab/Humira
August 2023[190] natalizumab-sztn/Tyruko natalizumab/Tysabri
September 2023[191] tocilizumab-bavi/Tofidence tocilizumab/Actemra
October 2023[192] ustekinumab-auub/Wezlana ustekinumab/Stelara
December 2023[138] bevacizumab-tnjn/Avzivi bevacizumab/Avastin
February 2024[138] adalimumab-ryvk/Simlandi adalimumab/Humira
March 2024[138] denosumab-bbdz/Jubbonti denosumab/Prolia
March 2024[138] denosumab-bbdz/Wyost denosumab/Xgeva
March 2024[138] tocilizumab-aazg/Tyenne tocilizumab/Actemra
April 2024[138] ustekinumab-aekn/Selarsdi ustekinumab/Stelara
April 2024[138] trastuzumab-strf/Hercessi trastuzumab/Herceptin
May 2024[138] aflibercept-yszy/Opuviz aflibercept/Eylea
May 2024[138] aflibercept-jbvf/Yesafili aflibercept/Eylea
May 2024[138] eculizumab-aeeb/Bkemv eculizumab/Soliris
June 2024[138] ustekinumab-ttwe/Pyzchiva ustekinumab/Stelara
June 2024[138] filgrastim-txid/Nypozi filgrastim/Neupogen
June 2024[138] aflibercept-mrbb/Ahzantive aflibercept/Eylea
July 2024[138] eculizumab-aagh/Epysqli eculizumab/Soliris
August 2024[138] aflibercept-abzv/Enzeevu aflibercept/Eylea
August 2024[138] aflibercept-ayyh/Pavblu aflibercept/Eylea
September 2024[138] ustekinumab-aauz/Otulfi ustekinumab/Stelara

See also

References

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  1. ↑ Blanchard, A., Helene D'Iorio and Robert Ford. "What you need to know to succeed: Key trends in Canada's biotech industry " Insights, Spring 2010
  2. ↑ a b Script error: No such module "Citation/CS1".
  3. ↑ Script error: No such module "citation/CS1".
  4. ↑ Script error: No such module "Citation/CS1".
  5. ↑ Template:Cite report
  6. ↑ Template:Cite report
  7. ↑ Template:Cite report
  8. ↑ Template:Cite report
  9. ↑ Script error: No such module "citation/CS1".
  10. ↑ Script error: No such module "citation/CS1".
  11. ↑ Hearing: Assessing the Impact of a Safe and Equitable Biosimilar Policy in the United States. Subcommittee on Health Wednesday, May 2, 2007 Template:Webarchive
  12. ↑ Script error: No such module "citation/CS1".
  13. ↑ Script error: No such module "citation/CS1".
  14. ↑ Script error: No such module "citation/CS1".
  15. ↑ Script error: No such module "citation/CS1".
  16. ↑ a b Script error: No such module "citation/CS1". Template:PD-notice
  17. ↑ EMEA guideline on similar biological medicinal products Template:Webarchive
  18. ↑ Script error: No such module "Citation/CS1".
  19. ↑ Script error: No such module "Citation/CS1".
  20. ↑ Script error: No such module "Citation/CS1".
  21. ↑ Script error: No such module "citation/CS1".
  22. ↑ a b Script error: No such module "Citation/CS1".
  23. ↑ Script error: No such module "citation/CS1".
  24. ↑ Script error: No such module "citation/CS1".
  25. ↑ Script error: No such module "citation/CS1".
  26. ↑ Script error: No such module "citation/CS1".
  27. ↑ Script error: No such module "citation/CS1".
  28. ↑ Script error: No such module "citation/CS1".
  29. ↑ Script error: No such module "Citation/CS1".
  30. ↑ Script error: No such module "citation/CS1".
  31. ↑ Script error: No such module "citation/CS1".
  32. ↑ Script error: No such module "Citation/CS1".
  33. ↑ Script error: No such module "citation/CS1".
  34. ↑ Script error: No such module "citation/CS1".
  35. ↑ Script error: No such module "Citation/CS1".
  36. ↑ Script error: No such module "citation/CS1".
  37. ↑ Script error: No such module "citation/CS1".
  38. ↑ Script error: No such module "citation/CS1".
  39. ↑ Script error: No such module "citation/CS1".
  40. ↑ Script error: No such module "citation/CS1".
  41. ↑ Script error: No such module "citation/CS1".
  42. ↑ Script error: No such module "citation/CS1".
  43. ↑ Script error: No such module "citation/CS1".
  44. ↑ Script error: No such module "citation/CS1".
  45. ↑ Script error: No such module "citation/CS1".
  46. ↑ Script error: No such module "citation/CS1".
  47. ↑ Script error: No such module "citation/CS1".
  48. ↑ Script error: No such module "citation/CS1".
  49. ↑ Script error: No such module "citation/CS1".
  50. ↑ Script error: No such module "citation/CS1".
  51. ↑ Script error: No such module "citation/CS1".
  52. ↑ Script error: No such module "citation/CS1".
  53. ↑ Script error: No such module "citation/CS1".
  54. ↑ Script error: No such module "citation/CS1".
  55. ↑ Script error: No such module "citation/CS1".
  56. ↑ Script error: No such module "citation/CS1".
  57. ↑ Script error: No such module "citation/CS1".
  58. ↑ Script error: No such module "citation/CS1".
  59. ↑ Script error: No such module "citation/CS1".
  60. ↑ Script error: No such module "citation/CS1".
  61. ↑ Script error: No such module "citation/CS1".
  62. ↑ Script error: No such module "citation/CS1".
  63. ↑ Script error: No such module "citation/CS1".
  64. ↑ a b Script error: No such module "citation/CS1".
  65. ↑ Script error: No such module "citation/CS1".
  66. ↑ Script error: No such module "citation/CS1".
  67. ↑ Script error: No such module "citation/CS1".
  68. ↑ Script error: No such module "citation/CS1".
  69. ↑ Script error: No such module "citation/CS1".
  70. ↑ Script error: No such module "citation/CS1".
  71. ↑ Script error: No such module "citation/CS1".
  72. ↑ Script error: No such module "citation/CS1".
  73. ↑ Script error: No such module "citation/CS1".
  74. ↑ Script error: No such module "citation/CS1".
  75. ↑ Script error: No such module "citation/CS1".
  76. ↑ a b Script error: No such module "citation/CS1".
  77. ↑ Script error: No such module "citation/CS1".
  78. ↑ Script error: No such module "citation/CS1".
  79. ↑ Script error: No such module "citation/CS1".
  80. ↑ Script error: No such module "citation/CS1".
  81. ↑ Script error: No such module "citation/CS1".
  82. ↑ Script error: No such module "citation/CS1".
  83. ↑ Script error: No such module "citation/CS1".
  84. ↑ Script error: No such module "citation/CS1".
  85. ↑ Script error: No such module "citation/CS1".
  86. ↑ Script error: No such module "citation/CS1".
  87. ↑ Script error: No such module "citation/CS1".
  88. ↑ Script error: No such module "citation/CS1".
  89. ↑ Script error: No such module "citation/CS1".
  90. ↑ Script error: No such module "citation/CS1".
  91. ↑ Script error: No such module "citation/CS1".
  92. ↑ Script error: No such module "citation/CS1".
  93. ↑ Script error: No such module "citation/CS1".
  94. ↑ Script error: No such module "citation/CS1".
  95. ↑ Script error: No such module "citation/CS1".
  96. ↑ Script error: No such module "citation/CS1".
  97. ↑ Script error: No such module "citation/CS1".
  98. ↑ Script error: No such module "citation/CS1".
  99. ↑ Script error: No such module "citation/CS1".
  100. ↑ Script error: No such module "citation/CS1".
  101. ↑ Script error: No such module "citation/CS1".
  102. ↑ Script error: No such module "citation/CS1".
  103. ↑ Script error: No such module "citation/CS1".
  104. ↑ Script error: No such module "citation/CS1".
  105. ↑ Script error: No such module "citation/CS1".
  106. ↑ Script error: No such module "citation/CS1".
  107. ↑ Script error: No such module "citation/CS1".
  108. ↑ Script error: No such module "citation/CS1".
  109. ↑ Script error: No such module "citation/CS1".
  110. ↑ Script error: No such module "citation/CS1".
  111. ↑ Script error: No such module "citation/CS1".
  112. ↑ Script error: No such module "citation/CS1".
  113. ↑ Script error: No such module "citation/CS1".
  114. ↑ Script error: No such module "citation/CS1".
  115. ↑ Script error: No such module "citation/CS1".
  116. ↑ Script error: No such module "citation/CS1".
  117. ↑ Script error: No such module "citation/CS1".
  118. ↑ Script error: No such module "citation/CS1".
  119. ↑ Script error: No such module "citation/CS1".
  120. ↑ Script error: No such module "citation/CS1".
  121. ↑ Script error: No such module "citation/CS1".
  122. ↑ Script error: No such module "citation/CS1".
  123. ↑ Script error: No such module "citation/CS1".
  124. ↑ Script error: No such module "citation/CS1".
  125. ↑ a b Script error: No such module "citation/CS1".
  126. ↑ Script error: No such module "citation/CS1".
  127. ↑ Script error: No such module "citation/CS1".
  128. ↑ Script error: No such module "citation/CS1".
  129. ↑ Script error: No such module "citation/CS1".
  130. ↑ Script error: No such module "citation/CS1".
  131. ↑ Script error: No such module "citation/CS1".
  132. ↑ Script error: No such module "citation/CS1".
  133. ↑ Script error: No such module "citation/CS1".
  134. ↑ Script error: No such module "citation/CS1".
  135. ↑ Script error: No such module "citation/CS1".
  136. ↑ Script error: No such module "citation/CS1".
  137. ↑ Script error: No such module "citation/CS1".
  138. ↑ a b c d e f g h i j k l m n o p q r s t Script error: No such module "citation/CS1". Template:PD-notice
  139. ↑ Script error: No such module "citation/CS1".
  140. ↑ Script error: No such module "citation/CS1". Template:PD-notice
  141. ↑ Script error: No such module "Citation/CS1".
  142. ↑ Script error: No such module "citation/CS1".
  143. ↑ Script error: No such module "citation/CS1".
  144. ↑ Script error: No such module "citation/CS1".
  145. ↑ Script error: No such module "citation/CS1".
  146. ↑ Script error: No such module "citation/CS1".
  147. ↑ Script error: No such module "citation/CS1".
  148. ↑ Script error: No such module "citation/CS1".
  149. ↑ Script error: No such module "citation/CS1".
  150. ↑ Script error: No such module "citation/CS1".
  151. ↑ Script error: No such module "citation/CS1".
  152. ↑ Script error: No such module "citation/CS1".
  153. ↑ Script error: No such module "citation/CS1".
  154. ↑ Script error: No such module "citation/CS1".
  155. ↑ Script error: No such module "citation/CS1".
  156. ↑ Script error: No such module "citation/CS1".
  157. ↑ Script error: No such module "citation/CS1".
  158. ↑ Script error: No such module "citation/CS1".
  159. ↑ Script error: No such module "citation/CS1".
  160. ↑ Script error: No such module "citation/CS1".
  161. ↑ Script error: No such module "citation/CS1".
  162. ↑ Script error: No such module "citation/CS1".
  163. ↑ Script error: No such module "citation/CS1".
  164. ↑ Script error: No such module "citation/CS1".
  165. ↑ Script error: No such module "citation/CS1".
  166. ↑ Script error: No such module "citation/CS1".
  167. ↑ Script error: No such module "citation/CS1".
  168. ↑ Script error: No such module "citation/CS1".
  169. ↑ Script error: No such module "citation/CS1".
  170. ↑ Script error: No such module "citation/CS1".
  171. ↑ Script error: No such module "citation/CS1".
  172. ↑ Script error: No such module "citation/CS1".
  173. ↑ Script error: No such module "citation/CS1".
  174. ↑ Script error: No such module "citation/CS1".
  175. ↑ Script error: No such module "citation/CS1".
  176. ↑ Script error: No such module "citation/CS1".
  177. ↑ Script error: No such module "citation/CS1".
  178. ↑ Script error: No such module "citation/CS1".
  179. ↑ Script error: No such module "citation/CS1".
  180. ↑ Script error: No such module "citation/CS1".
  181. ↑ Script error: No such module "citation/CS1".
  182. ↑ Script error: No such module "citation/CS1".
  183. ↑ Script error: No such module "citation/CS1".
  184. ↑ Script error: No such module "citation/CS1".
  185. ↑ Script error: No such module "citation/CS1".
  186. ↑ Script error: No such module "citation/CS1".
  187. ↑ Script error: No such module "citation/CS1".
  188. ↑ Script error: No such module "citation/CS1".
  189. ↑ Script error: No such module "citation/CS1".
  190. ↑ Script error: No such module "citation/CS1".
  191. ↑ Script error: No such module "citation/CS1".
  192. ↑ Script error: No such module "citation/CS1".

Script error: No such module "Check for unknown parameters".

Further reading

  • Script error: No such module "Citation/CS1".
  • Script error: No such module "Citation/CS1".

External links

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