Tuesday, October 13, 2009

推動疫苗產業,國光打頭陣

2009.10.08 【文.朱立群(Sam Ju/tr. by Chris Nelson)】

Adimmune: Spearheading the Vaccine Industry H1N1新流感疫情持續發威,捧紅了「國光生技」這家國內唯一獲准自製新流感疫苗的本土公司。其實,近20年來,它也是國內日本腦炎疫苗的唯一供應商,難怪國光總經理魏逸之充滿自信地說:「15歲以下的國人,一定都打過國光。」 The raging pandemic of novel H1N1 is rocketing Adimmune, the only local company authorized to manufacture a vaccine for this virus, to stardom. In the last 20 years, Adimmune has been the sole domestic supplier of Japanese encephalitis vaccine, so small wonder that the company’s general manager Ignatius Wei is flushed with pride as he says, “All children in Taiwan under age 15 must be inoculated with Adimmune” for Japanese encephalitis. 還不僅止於此!國光員工透露,就連北韓政府的高官,去年也曾私下透過關係,指名要打「國光牌」疫苗。 And it doesn’t stop there! An Adimmune employee reveals in confidence that even a high-ranking government official from North Korea mentioned Adimmune brand vaccine by name last year through a private channel. 此時此刻,在各國展開新流感疫苗搶奪大戰之際,作為國內唯一的人用疫苗廠,國光責無旁貸地扛起產製疫苗的責任。有人對它寄予期待,也有人用懷疑的眼神看著它。 At this very moment, as countries vie to develop vaccines, Adimmune, Taiwan’s sole producer of human vaccines, is shouldering the responsibility of manufacturing a vaccine for influenza A subtype H1N1. Some are placing great hopes on the company, while others are regarding it with a skeptical eye. 在全球疫苗需求快速成長、流感疫苗市場更可望在2012年達到200億美元的情況下,這場新流感危機,會是國光生技、甚至是國內疫苗產業發展的契機嗎? As global demand for vaccines grows, with the flu vaccine market set to reach US$20 billion in 2012, will the current novel H1N1 crisis become a turning point for Adimmune, or even the growth of the entire domestic vaccine industry?  7月30日傍晚,衛生署疾管局發布國內新流感疫情出現死亡首例。隔天一早翻開報紙,許多憂心的民眾都在問:到底何時才有疫苗可打? Taiwan’s Centers for Disease Control (CDC) announced in the evening of July 30 that the first death in Taiwan by novel H1N1 had occurred. As they unfolded the next morning’s paper, many anxious citizens were wondering when a vaccine would be available. 5個星期後,9月8日,國光召開記者會宣告新流感疫苗「安定伏」已經誕生,一瓶20c.c.,可分裝成40劑,衛生署審查通過後即可展開人體臨床試驗,250位受試者已經招滿。若一切順利,最快11月中即可開始全面施打。 Five weeks later, on September 8, Adimmune held a press conference to announce the birth of a vaccine for novel H1N1, for which one 20-cc bottle contains 40 doses. As soon as the Department of Health (DOH) gives the green light, human clinical trials on 250 subjects will commence. If all goes well, full-scale inoculations can commence in mid-November at the earliest. 自從7月10日以每劑新流感疫苗199元獲得疾管局的標案後大約只有當前國際市價每劑10歐元的一半,出於「便宜沒好貨」的心理,外界對於「國產」疫苗安全性的疑慮從未停止;再加上各路專家求好心切,人體試驗結果還沒出爐,就做出「寧可選擇感染後再服藥」、「雞蛋不應全放在一個籃子裡」、「國光並不具備疫苗自製能力」等批評。 After Adimmune won the CDC’s open bid at a vaccine price of NT$199 per dose on July 10 (as compared to the international market price of 10 euros per dose), outsiders’ misgivings about the safety of the “homegrown” vaccine ran unabated. With results of human trials not yet available, experts from many fields anxiously raised various criticisms: “It’s better to wait and treat people once they’re infected,” “Let’s not put all our eggs in one basket,” “Adimmune doesn’t have the capability to produce this vaccine on its own,” and so forth. 面對這些質疑,曾任衛生署長的現任國光生技董事長詹啟賢忿忿不平地向媒體抗議:「在衛生署把關下,若有安全瑕疵,(我們)一定整桶倒掉!」總經理魏逸之也表達不滿:「批評我們的人,根本沒來國光現場看過。」 Faced with such media questioning, Adimmune chairman Steve Chan, a former DOH minister, retorts, “If any defects are found during DOH checks, we will discard the entire batch.” General manager Ignatius Wei also expresses his dissatisfaction: “Those who disparage us have not personally observed Adimmune in operation. ”國光1960年代開始在台北縣樹林鎮生產血清及動物疫苗,當時就已和日本東京的「北里研究所」進行合作。北里的創辦人,就是發現「抗體」的日本細菌學家北里柴三郎。 In the 1960s, Adimmune was a manufacturer of blood serum and animal vaccines located in Shulin Township, Taipei County. At that time, the company was already working jointly with Tokyo’s Kitasato Institute, founded by Japanese bacteriologist Shibasaburo Kitasato, the discoverer of antibodies. 1982年,我國開始推行藥品及藥廠的優良作業規範(GMP)認證制度,與此同時,國光也思考轉型,決定朝專業的人用疫苗廠發展。5年後,國光關掉舊廠,搬到現址台中縣潭子鄉,並開始利用從北里學來的技術,生產日本腦炎、破傷風等疫苗。 In 1982, Taiwan launched the Good Manufacturing Practice (GMP) certification system for pharmaceutical companies. At the same time, Adimmune was considering a major change, deciding to specialize in human vaccine development. Five years later, Adimmune closed down its old plant and moved to its current address in Tanzi Township, Taichung County, and started to produce vaccines for tetanus and Japanese encephalitis using techniques developed at the Kitasato Institute. 1997年,當時身價百億的誠洲電子老闆廖繼誠,以台幣2億元買下國光經營權,並於2001年獲得行政院國家發展基金官股入股;此後國光升級轉型之路更積極,幾乎每年都派員到北里,實地學習雞胚胎蛋疫苗的生產製程。 In 1997, James Liao, multimillionaire general manager of ADI Corporation, purchased the operating rights for Adimmune in 2001 for NT$200 million with the help of public shares from the National Development Fund. After that, Adimmune became more aggressive in its upgrading efforts, sending employees on an annual basis to the Kitasato Institute to study the vaccine manufacturing process based on fertilized chicken eggs. 2002年,國光開始引進北里的季節性流感疫苗原液,自行在台中廠區填充、分裝之後,在國內販售。魏逸之表示,廖繼誠當時已在思考如何在台自製疫苗。 In 2002, Adimmune started importing seasonal flu vaccine in bulk from Kitasato Institute, bottling and packaging it at their Taichung plant and selling it domestically. Says Wei, at that time Liao was already thinking about how to produce vaccines in Taiwan.
BOO案雪恥記 The BOO debacle
從季節性流感、禽流感,再到最近的新流感,衛生署每年都為疫苗採購傷透腦筋。為了解決此一問題,疾管局在2006年初提出「流感疫苗自製計畫BOO(自建、自有、自營)案」,公開徵選國內外疫苗廠在台設廠,條件是,一年必須生產1,600萬劑以上的流感疫苗。 The annual vaccine purchasing efforts by the DOH for seasonal flu as well as for outbreaks like bird flu and now H1N1 are a true headache. To address this problem, the CDC proposed a BOO (Build, Own, Operate) program for homegrown flu vaccine production in early 2006, calling upon vaccine companies, both foreign and domestic, to build plants in Taiwan with the proviso that they produce at least 16 million doses of flu vaccine per year. 榜單揭曉後,取得第一議約權的國際大藥廠葛蘭素史克(GSK),因立法院提出技術轉移等附帶條件、加上各國爭相邀約,最終決定放棄在台設廠;第二順位的荷商諾貝爾(Akzo Nobel)又突遭其他藥廠併購,而排名第三的國光竟因不服落選,向行政法院提出「疾管局獨厚外商」的行政訴訟,雙方形同撕破臉。截至目前,這宗事關國人生命健康的BOO案已經停擺。 After the name list was published, the first in line for contract negotiation rights was the international pharmaceutical giant GlaxoSmithKline. But since the Legislative Yuan required certain additional conditions including technology transfer, and also because the company was being sought after by other countries, GSK eventually decided not to carry through. Next in line was the Dutch firm Akzo Nobel, which suddenly merged with another pharmaceutical company. Third on the list was Adimmune; however, the company had filed a lawsuit with an administrative court claiming that the CDC had been singling out overseas companies, leading to bad blood between the two sides. As things now stand, this public health BOO project has come to a halt. 然而,這場挫敗,卻給國光另一個發展的機會。2007年3月,全球第6大疫苗廠荷商Crucell,看上國光的代工能量以及北里的雞胚胎蛋技術,遂與國光簽訂技轉、代工、入股,及協助興建流感疫苗廠等合約。這些合作項目,為國光目前的新流感疫苗產製打下了基礎。 Yet this defeat gave Adimmune another opportunity to grow. In March 2007, Crucell, the world’s sixth largest vaccine company, noticed Adimmune’s OEM potential and its use of the Kitasato Institute’s fertilized chicken egg technology, and signed a contract with Adimmune that included technology transfer, OEM, a stake of shares, and support in building a flu vaccine plant. This cooperative framework formed the basis for Adimmune’s current H1N1 vaccine production. 其中,Crucell技轉的「仿病毒顆粒」(Virosome)佐劑技術最為關鍵。Virosome為一種不含病毒基因的空殼病毒,只有病毒的複製功能,卻沒有病毒的致病性;採用這種疫苗製造法,不需用到病毒株,也不以雞胚胎當作載體,可以避免卵蛋白引發的過敏,減低施打後的副作用。 The virosome technology provided by Crucell was key. A virosome is a virus shell that contains no viral genes: it has the replication of a virus, but not the virulence. This method of manufacturing vaccines requires no viruses and does not use chicken embryos as carriers, thus preventing allergies caused by ovalbumin and reducing side effects of inoculations. 這項合作提升了國光的研發技術,當時疾管局甚至發布新聞稿「恭賀」國光:「(BOO)落榜後,能體認其技術能力之不足,願與擁有細胞培養製造疫苗的Crucell公司合作,值得鼓勵,也是台灣防疫體系之幸。」 This collaborative effort enabled Adimmune to upgrade its R&D technology. The CDC issued a press release congratulating Adimmune: “After the failure of the BOO initiative, the ability [of Adimmune] to acknowledge its technical inadequacies and willingness to cooperate with Crucell, which possessed cell culture vaccine manufacturing capacity, is worthy of encouragement. [Adimmune] is indeed a credit to Taiwan’s disease control system.” 今年6月,國光斥資台幣30億元、完全按照歐盟PIC/S GMP標準設計、建造的5層樓新穎廠房落成啟用。有了Crucell仿病毒顆粒技術的加持,加上原有的北里製程,魏逸之驕傲地說,「這是全世界可以同時運作這兩種生產線──用雞胚胎培養的裂解病毒去活性,以及仿病毒顆粒型疫苗──的疫苗廠!」 In June, Adimmune invested NT$3 billion to build a new five-story plant that fully conforms to EU PIC/S standards. With the benefit of Crucell’s virosome technology added to the fertilized egg and split-virus vaccine technologies gained from the Kitasato Institute, Ignatius Wei proudly states, “This is the only vaccine plant in the world that can simultaneously run these two types of production line!” 確實,在全球每年秋冬之際流感疫苗大缺貨的情況下,與Crucell及北里的合作,開啟了國光疫苗的機會。一方面,國光雖是幫Crucell代工生產原液,但也取得自行充填並獨家銷售至日本、澳門及台灣的授權。另一方面,北里的雞胚胎蛋疫苗製程更是國光的主力,幾乎是獨占每年大約1.5億台幣的內需市場。 Indeed, faced with annual shortages of flu vaccine during the fall and winter flu season, Adimmune’s cooperation with Crucell and the Kitasato Institute has broadened the company's opportunities in vaccine production. For one thing, though Adimmune produces virus bulk for Crucell on an OEM basis, the company has also secured rights to package and exclusively sell product in Japan, Macao and Taiwan. Also, the Kitasato Institute fertilized egg process has become Adimmune’s mainstay, allowing it to corner a domestic market of around NT$150 million annually. 目前國光疫苗仍以內銷為主,2007與2008年的銷售額各為台幣1.9億及2.4億元,其中又以季節性流感為大宗,占6至7成。 Currently Adimmune still chiefly sells its vaccines domestically, with 2007 and 2008 sales revenues coming to NT$190 million and NT$240 million respectively. The major chunk of such vaccines—60% to 70%—are for seasonal flu.
拿A(H1N1)練兵 Experimenting with H1N1
今年全球新流感疫情吃緊,瑞士的諾華、法國的賽諾菲巴斯德,澳洲的CSL、日本的北里等至少12家國際知名疫苗廠,都在與時間競爭。其中除了美國MedImmune公司做的是鼻腔噴劑疫苗,其他都是注射式疫苗。 Faced with the urgency of the global pandemic of novel H1N1, at least 12 internationally renowned vaccine producers, including Novartis of Switzerland, Sanofi Pasteur of France, CSL of Australia and the Kitasato Institute, are battling the clock. All of them produce injectable vaccines, except for the American firm MedImmune, which manufactures a nasal spray vaccine. 中國大陸的「國家食品藥品監督管理局」(SFDA)早在9月3日就通過北京科興生技(Sinovac)生產的「盼爾來福•1」疫苗。世界衛生組織預測,中國可能會是全球第一個施打的國家。 On September 3, mainland China’s State Food and Drug Administration approved the Sinovac-produced Panflu 1 vaccine. The World Health Organization predicts that China may become the world’s first nation to use an H1N1 vaccine. 國光在6月1日取得澳洲CSL公司分離出的A(H1N1)疫苗株之後,隨即在8月6日正式啟動疫苗生產計畫。每隔兩、三天的清晨6點鐘,裝載「疫苗蛋」的攝氏28至34度冷藏蛋車陸續駛進國光的大門;大清早,綠色外觀的新廠外,十多位男性員工已就「卸蛋」位置待命。 On June 1, Adimmune acquired influenza A virus subtype H1N1 vaccine isolated by CSL, and then officially launched its vaccine production program on August 6. Once every two or three days, insulated egg trucks carrying “vaccine eggs,” maintained at 28–34°C, enter Adimmune’s front gates at six in the morning, and outside the new green factory building, a dozen or so male employees await the order to unload the eggs. 「這些都是合乎疫苗生產用的SPF-like eggs,接近『無特殊病原』的種雞蛋。」魏逸之稱呼這些是「clean eggs」──為了避免不同動物體內的病毒交互感染,種雞所吃的飼料不得含有動物成分;牠們體內不得檢出腸炎沙門氏桿菌、雞白痢沙門氏桿菌、傷寒沙門氏桿菌,以及A型禽流感、禽白血病等病毒,也不得有賀爾蒙與抗生素的殘留。 “These are all SPF-like eggs specially produced for making vaccines: breeding eggs that are virtually ‘specific pathogen free,’” says Wei, who calls them “clean eggs.” To prevent cross-contamination of the virus from different animals, the feed eaten by the breeding hens cannot contain animal products; they cannot test positive for Salmonella enteritidis, Salmonella pullorum or Salmonella typhi, nor for avian flu or avian leukosis viruses; and they must also be free of external hormones and antibiotics. 國光的製程品管人員透露,疫苗蛋的「蛋齡」必須介於10至11天之間,蛋高5.5至5.8公分,直徑3.6至4公分,蛋重54至67公克,下蛋的種雞必須是28至57周產齡的母雞。以國光目前趕製新流感疫苗的進度來看,每個批次進蛋數目介於13萬至16萬顆之間,每一台蛋車可以裝載7萬顆蛋。 An Adimmune quality assurance worker tells us that the vaccine eggs must be aged between 10 and 11 days, with a length of 5.5 to 5.8 centimeters, a diameter of 3.6 to 4 cm, and weight of 54 to 67 grams. The hens laying the eggs must be between 28 and 57 weeks old. To get an idea of Adimmune’s progress in producing novel H1N1 vaccine, each batch contains between 130,000 and 160,000 eggs, and each egg truck can carry 70,000 eggs. 至於做成一劑新流感疫苗,需要用到幾顆雞胚胎蛋?國光完全採用北里的製程,魏逸之不便透露機密。不過據瞭解,從「蛋」到「疫苗」需要經過6道步驟、共需7天:(1) 病毒接種與培養;(2) 病毒採收;(3) 過濾、純化病毒液;(4) 用乙醚裂解病毒顆粒;(5) 去除病毒活性;(6) 調劑、充填。 How many fertilized eggs are needed to manufacture one dose of novel H1N1 vaccine? Wei is unwilling to divulge the trade secret of the Kitasato Institute process used by Adimmune. But roughly speaking it’s divided into six steps, requiring seven days: Virus inoculation and culture; virus harvest; sedimentation, filtering and purification of the virus liquid; cracking the virus shells with ether; deactivating the viruses; blending and packaging.
疫苗產業終見曙光 Dawning vaccine industry
詹啟賢去年6月才從李明亮手中接下國光董事長的棒子,兩人都曾擔任衛生署長,也都對國人自製疫苗的發展著力深刻。 Chan took over the chairmanship of Adimmune from Lee Ming-liang in June 2008. Both men have served as DOH ministers, and both have devoted themselves to the development of homegrown vaccines. 詹啟賢在署長任內,積極推動醫護人員施打流感疫苗;李明亮2007年8月甫一接任國光董事長,不但急著找媒體記者談國人自製流感疫苗的急迫性,更大力延攬曾在美國疾管局任職的流行病學家、中研院生醫所研究員何美鄉,借調至國光出任研發長。 During Chan’s term as minister, he gave impetus to the inoculation of health workers with the flu vaccine. In August 2007 Lee became chairman of Adimmune, during which time he sought out media reporters to talk about the urgency of homegrown flu vaccines and invited Ho Mei-shang, former epidemiologist for the US Centers for Disease Control and researcher at Academia Sinica’s Institute of Biomedical Sciences, to serve as head of R&D at Adimmune. 何美鄉舉美國為例指出,美國白宮設有「國家疫苗委員會」,受總統的調度,相較之下,我國類似的機制是由衛生署指揮,層級似乎太低。 Ho cites the example of the US National Vaccine Advisory Committee, which is under the authority of the president. Taiwan’s corresponding system is managed by the DOH, which places it at too low a level. 政策高度不夠之外,魏逸之認為,社會各界普遍對疫苗產業認識不清。他特別要解釋媒體對國光的誤解:「國內的人用疫苗廠就只有國光一家,而國際大廠現在自己生產都來不及了,怎麼可能還來參與台灣的採購招標?」他抱怨,「獨厚國光」的說法,太沒有道理。 With such policy shortcomings, Wei believes that there’s a great lack of understanding of vaccines in society as a whole. He targets the media’s misunderstandings of Adimmune in particular: “Adimmune is the only domestic human vaccine manufacturer. And with major international firms unable to produce enough on time, how can they participate in open bidding in Taiwan?” he complains: the idea that “only Adimmune benefits” simply doesn’t make sense. 看來,即便已在製造疫苗的道路上獨行了四十多年,國光生技要成為帶動國內疫苗產業發展的火車頭,該努力的不該只有國光自己,還應包括政府、媒體,以及社會大眾。        Apparently, even though Adimmune has been producing vaccines on its own for over four decades, if the company is to spearhead the drive for domestic development of vaccines, then it can’t rely merely on its own efforts; the government, media and general public must also do their parts.

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