JP3911255B2

JP3911255B2 - Radiopharmaceutical manufacturing facility

Info

Publication number: JP3911255B2
Application number: JP2003148558A
Authority: JP
Inventors: 博彦山内; 均片山; 雅人大屋; 敬三小林; 静人代田; 雅記福田; 俊夫造賀; 真安藤; 圭小林
Original assignee: Nihon Medi Physics Co Ltd; Kajima Corp; Toyo Engineering Corp
Current assignee: Nihon Medi Physics Co Ltd; Kajima Corp; Toyo Engineering Corp
Priority date: 2003-05-27
Filing date: 2003-05-27
Publication date: 2007-05-09
Anticipated expiration: 2023-05-27
Also published as: JP2004353875A

Description

【０００１】
【産業上の利用分野】
本発明は放射性医薬品の製造施設に関し、とくに半減期の短い放射性医薬品を製造するための施設に関する。
【０００２】
【従来の技術】
ポジトロン断層撮影法（positron emission tomography；以下、PETということがある。）は、ポジトロン放出核種（例えば、フッ素-18（¹⁸F）。以下、放射性核種ということがある。）で標識された放射性医薬品（例えば、¹⁸F-フルオロデオキシグルコース（¹⁸F-FDG））を患者の体内に静脈注射や吸入により投与し、放射性医薬品が体内を移動して心臓・脳等の臓器やがん組織に集まる様子を断層像として画像化する検査方法である（非特許文献１参照）。生体の形態を画像化するX線CT（ComputedTomography）や核磁気共鳴画像法（Magnetic Resonance Imaging；MRI）に対し、PETでは形態の異常の有無に拘わらず代謝や血流等の生体内の生理学的・生化学的な機能を捉えて画像化することができるので、例えば活発に活動するがん組織等を明瞭に把握することができる。とくにブドウ糖代謝を反映する¹⁸F-FDG（以下、単にFDGという。）を用いたPETは、がんの早期発見等に有効であることから臨床への応用が進められており、FDGを医薬品として提供するための臨床試験も進められている。
【０００３】
FDG等の放射性医薬品は、画像化に必要な量の放射性核種を含むが、半減期に応じて有効性が徐々に低下する。とくにFDGは半減期が110分と短いため、従来のPETでは、医療機関内でFDGを製造して品質試験ののち直ちに診療に供する方法が一般的である。放射性医薬品を医療機関外の製造施設で製造して医療機関に提供する場合は、製造施設内での品質試験や梱包・出荷作業の時間、製造施設から医療機関までの搬送時間等を考慮して医薬品中の放射性核種の量を調整する必要がある。しかし、放射性核種の生産量には限界があり、調整を行うに足りる量が確保できない場合があるため（非特許文献２参照）、放射性医薬品の製造施設では品質試験や梱包・出荷作業を迅速に行い製造から出荷までの時間をできるだけ短縮することが重要である。
【０００４】
特許文献１は、図５に示すような放射性医薬品の製造施設（放射性物質取扱施設）141の一例を開示する。図示例の製造施設141は、放射性核種を製造するサイクロトロン室143に隣接させて放射性薬剤を製造するホットラボ（製剤室）142を設け、ホットラボ142内に合成装置用ホットセル150aと品質管理装置用ホットセル150bとからなるホットセル群140を設けている。ホットセル群140はインターフェースエリア151を囲むように配置され、インターフェースエリア151とホットセル群140の各ホットセル150a、150bとの間には出入扉（図示せず）が設けられ、インターフェースエリア151とホットラボ142との間にも出入扉152が設けられている。各ホットセル150a、150bはシャッター扉により仕切られ、床側に配置したバイアル搬送路により相互に接続されている。合成装置用ホットセル150a内においてサイクロトロン室143からの放射性核種を用いて放射性薬剤を合成し、バイアル瓶に注入する。バイアル瓶に注入した放射性薬剤はバイアル搬送路経由で品質管理装置用ホットセル150bへ送られ、品質試験に供される。ホットセル群140で製造され、試験された薬剤注入済のバイアル瓶は、最終的に各ホットセル150a、150bの出入扉とインターフェースエリア151の出入扉152とを介してホットラボ室142内に取り出され、前室153、154を介して各種試験研究工程へ送られる。放射性物質を取り扱うホットラボ室142は陰圧に保持されるので前室153から汚染エアを吸い込んで清浄度が低下する場合があり得るが、各ホットセル150a、150bは２重の出入扉によってホットラボ室142から仕切られているので清浄度の低下を最小限に抑えることができる。
【０００５】
また特許文献２は、図６に示すように、上述したホットラボ142内で放射性薬剤の品質試験を自動的に行う品質管理システムを開示する。図示例の品質管理システムは、自動合成装置160でバイアル瓶に注入された放射性薬剤を搬送するバイアル搬送装置170と、放射性薬剤に必要な品質試験を自動的に行う品質管理装置161と、搬送装置170及び品質管理装置161を制御する集中制御装置171とを有する。品質管理装置161には、バイアル搬送装置170を介して自動合成装置160から搬送されたバイアル瓶中の放射性薬剤を分注する分注ユニット165と、分注された放射性薬剤のサンプルの重量・放射能量・pHを測定する測定器163・164・167と、サンプルの純度（放射化学的純度、化学純度等）を分析する高速液体クロマトグラフ（HPLC）測定ユニット166とが設けられている。図示例の品質管理システムによれば、放射性薬剤の品質試験を人手によらず自動的に行うことができるので、作業員等の被曝を避けることができる。
【０００６】
【非特許文献１】
日本核医学会・ＰＥＴ核医学ワーキンググループ編集「ＰＥＴ検査Ｑ＆Ａ」日本核医学会・社団法人日本アイソトープ協会発行、2000年5月
【非特許文献２】
MARCEL GUILLAUME, ET AL. "Recommendation for Fluorine-18 Production", Appl. Radiat. Isot., Vol.42, No.8, pp.749-762, 1991
【非特許文献３】
川村邦夫著「医薬品の設計・開発・製造におけるバリデーションの実際」じほう、2002年7月31日、pp.98-103
【特許文献１】
特開２００３−０２１６９６号公報
【特許文献２】
特開２０００−３５６６４２号公報
【０００７】
【発明が解決しようとする課題】
特許文献１及び２で用いる品質管理装置161は、ホットラボ内で放射性薬剤を製造した直後に品質試験を行うことができるので、品質試験の迅速化にある程度寄与できる。但し、放射性薬剤の品質は上述した重量試験・放射能量試験・pH試験・純度試験により確認するだけでは充分でなく、更に無菌試験やエンドトキシン（endotoxin）試験によって確認する必要がある。無菌試験は薬剤中の微生物（細菌または真菌）の有無を確認する試験であり、エンドトキシン試験は医薬品中のグラム陰性菌由来のエンドトキシンを検出又は定量する試験である。無菌試験は14日以上を要するので放射性医薬品の出荷前に結果を確認することは困難であるが、エンドトキシン試験は比較的短時間で結果を得ることができるので、エンドトキシン試験の合格を確認した上で放射性薬剤を臨床使用することが望ましい。
【０００８】
しかし、特許文献１及び２で用いる品質管理装置161は、エンドトキシン試験を行うことができず、品質管理装置161による重量試験・放射能量試験・pH試験・純度試験を終了したのちにエンドトキシン試験を別途行わざるを得ない。このため特許文献１及び２の製造方法や品質管理方法では、エンドトキシン試験の結果を得るまでに管理装置161による試験時間とエンドトキシン試験時間との合計時間が必要となり、製造からエンドトキシン試験の結果を確認して使用するまでの時間が長くなる問題点がある。半減期が短い放射性医薬品を医療機関外の製造施設で製造するためには、エンドトキシン試験を含めた品質試験の時間をできるだけ短縮することが必要である。
【０００９】
そこで本発明の目的は、放射性医薬品のエンドトキシン試験を含めた品質試験を迅速に行うことができる製造施設を提供することにある。
【００１０】
【課題を解決するための手段】
図１の実施例及び図２の動線図を参照するに、本発明による放射性医薬品の製造施設１は、放射性医薬品の製造施設の気密壁３で囲まれた陰圧の高清浄度区域２内に作業員出入扉 11a で仕切られた放射性医薬品の前室 11 付き製剤室10を設け、高清浄度区域２内に同時開放しない２以上の扉16a、16bで仕切られた医薬品搬送口16を介して前室 11に連通する無菌試験室15を併設し、前室 11 及び無菌試験室 15 にそれぞれ個別に高清浄度区域２外の脱衣室 14 に連通するエアロック付き作業員出入口 12 及び 17 を設け、製剤室10の気密壁３に高清浄度区域２外の出荷準備室（図示例では梱包室）30に連通するエアロック付き搬出口25を設け、無菌試験室15の気密壁３に高清浄度区域２外の品質試験室27に連通するエアロック付き搬出口20を設け、製剤室10で調製した放射性医薬品を出荷準備室 30 へ搬送すると同時にその医薬品中の試験体を前室 11 及び搬送口16経由で無菌試験室15及び品質試験室27へ導入することにより放射性医薬品の無菌試験及び品質試験を出荷準備と並行に進行可能としてなるものである。
【００１１】
好ましくは、高清浄度区域２内に同時開放しない２以上の扉21a、21bで仕切られた資材搬送口21を介して製剤室10に連通すると共に作業員出入扉 11b を介して前室 11 に連通する資材準備室22を併設し、資材準備室22の気密壁３に高清浄度区域２外に連通するエアロック付き搬入口23を設け、放射性医薬品の資材を高清浄度区域２外から資材準備室22及び資材搬送口21経由で製剤室10へ搬入可能とする。更に好ましくは前室 11 の内圧を高清浄度区域２の内圧より相対的に高く保持するか、又は医薬品搬送口16及び／又は資材搬送口21をエアシャワー付きとし、エアシャワーの噴射により医薬品搬送口16及び／又は資材搬送口21の内圧を高清浄度区域２の内圧より高く保持する。高清浄度区域２を製造施設内の中央部に設け、製剤室10の搬出口25及び資材準備室22の搬入口23を製造施設１内の周縁部の異なる部位に向けて設けることが望ましい。
【００１２】
【発明の実施の形態】
図１は、放射性医薬品として無菌注射剤を製造する本発明の製造施設１の一実施例を示す。一般に放射性医薬品の製造施設は、医薬品製造に必要な清浄度管理を行えると共に、取り扱う原料が放射性同位体（radioisotope；以下、RIという。）であるため放射線障害を防止できる構造設備とする必要があり、清浄度管理及びRI管理の両者を満足する空調差圧管理を施す必要がある。医薬品の製造施設として、部屋毎に用途や作業内容に応じた複数の清浄度区分を設定し、無菌作業域を最も厳密な清浄度区分とし、各清浄度区分の高い領域を清浄度が１つ低い他の清浄度区分の領域で囲むレイアウトとし、２段階の清浄度区分領域を超えて通常は人や物が移動しないように設計する必要がある（非特許文献３参照）。他方、放射線取扱施設としては、施設内を外気に対して陰圧とする差圧管理が必要となる。以下、図示例を参照して本発明を説明するが、本発明の適用対象の放射性医薬品は無菌注射剤に限定されるものではない。
【００１３】
図示例の製造施設１は、清浄度区分としてクラス10,000（１ft³（立法フィート）空気中に含まれる所定粒径の微粒子数が10⁴個以下の清浄度区分）、クラス100,000（１ft³の空気中に含まれる所定粒径の微粒子数が10⁵個以下の清浄度区分）、無管理の３つのクラスを設定し、最も高いクラス10,000の清浄度区域２（以下、高清浄度区域２ということがある。）をクラス100,000の清浄度区域７（以下、中清浄度区域７ということがある。）で囲み、中清浄度区域７を無管理区域で囲むレイアウトとしている。高清浄度区域２及び中清浄度区域７はRI管理区域でもあるため、中清浄度区域７と無管理区域との間の開口部にはエアロックを設け、中清浄度区域７を外気及び無管理区域に対して陰圧とすると共に中清浄度区域７への微生物汚染を防止する。また、高清浄度区域２と中清浄度区域７との間には気密壁３を設け、気密壁３の開口部にはエアロック及び必要な清浄化設備（エアシャワー等）を設け、中清浄度区域７から高清浄度区域２への空気・人・物を介した微生物汚染の防止を図る。
【００１４】
高清浄度区域２内に放射性医薬品の無菌製剤室（ホットラボ）10と無菌試験室15とを併設し、両室を同時に開放しない２以上の扉11a、16a、16bで仕切られた搬送口11、16により連通する。製剤室10には、例えば図５に示すような合成装置用ホットセル150aをサイクロトロン室４と連通させて配置する。無菌試験室15は、放射性医薬品の無菌試験及びエンドトキシン試験を行う部屋である。搬送口11、16により製剤室10から無菌試験室15への放射性医薬品の試験体の搬送を可能とすると共に、搬送口11、16の扉11a、16a、16bにより無菌試験室15から製剤室10への微生物汚染を防止する。製剤室10と無菌試験室15との間には差圧が存在せず、しかも３つの扉11a、16a、16bは同時に開放しないので、無菌試験室15から製剤室10への直接的なエア吸い込みは発生しない。
【００１５】
図示例では、製剤室10に扉11aを介して連通する前室11を設け、前室11と無菌試験室15との間に同時開放しない２枚の扉16a、16b付きのパスボックス16を設け、前室11及びパスボックス16を搬送口（搬送路）としている。好ましくは、パスボックス16をエアシャワー付きとするか、又は前室11の内圧を製剤室10及び無菌試験室15の内圧、即ち高清浄度区域２の内圧より相対的に高く保持する。搬送口11、16をエアシャワー付きとするか又は内圧を相対的に高く保持することにより、無菌試験室15から製剤室10への微生物汚染を一層確実に防止できる。
【００１６】
製剤室10はエアロック付き搬出口25により中清浄度区域７の出荷準備室（図示例では梱包室）30と連通させ、無菌試験室15はエアロック付き搬出口20により中清浄度区域７の品質試験室27に連通させる。図示例では梱包室30を出荷準備室としているが、梱包室30に限らず他の適当な出荷準備室に製剤室10を連通させることができる。品質試験室27は無菌試験及びエンドトキシン試験以外の品質試験を行う部屋であり、搬出口20を介して製剤室10からの試験体を無菌試験室15から品質試験室27へ持ち込む。例えば図６に示す品質管理装置161を品質試験室27に設置し、試験体の重量試験・放射能量試験・pH試験・純度試験等を行う。中清浄度区域７に連通する搬出口20、25をエアシャワー付きとし、高清浄度区域２の清浄度低下を防止することが望ましい。
【００１７】
次に、製造施設１における物の流れ（動線）を示す図２を参照して、本発明の製造施設１における放射性医薬品の製造方法を説明する。同図では医薬品資材の流れを黒矢印で示し、調製した医薬品の流れを斜線付き矢印で示し、医薬品中の試験体の流れを白抜き矢印で示し、廃棄物の流れを点線矢印で示す。サイクロトロン室４で製造されたRI原料（ポジトロン放出核種）は、地下ピット（チューブ）を介して製剤室10の原料用安全キャビネットに搬送し、必要に応じて前処理（例えば合成）を施す。必要な前処理を施した後、RI医薬品原料として、更に製剤室10内の分注用キャビネットに持ち込まれる。分注用キャビネット内でRI医薬品原料を製剤バルクに加工し、製剤バルクを無菌ろ過しながら無菌資材（例えば、バイアル）に充填し、外観試験を行って放射性医薬品とする。無菌資材は、後述するように資材準備室22を介して製剤室10へ持ち込まれる。
【００１８】
製剤室10で調製した放射性医薬品は、一部を試験体として搬送口11、16経由で無菌試験室15へ搬送し、残りを搬出口25経由で梱包室30へ搬送して梱包する。梱包室30へ必要量だけ搬送し、残余の医薬品を製剤室10内の貯蔵箱に保管してもよい。梱包用資材は梱包準備室31から梱包室30へ持ち込む。無菌試験室15では、試験体の一部を用いて無菌試験及びエンドトキシン試験を直ちに開始する共に、残部を搬出口20経由で品質試験室27へ引き渡す。品質試験室27では、試験体を用いて重量試験・放射能量試験・pH試験・純度試験等を直ちに開始すると共に、長期間保存用の試験体を貯蔵室に搬送して保管する。梱包室30で梱包した放射性医薬品は出荷室32に搬入し、無菌試験室15及び品質試験室27の試験結果が出るまで保管してもよい。エンドトキシン試験を含む試験結果の合格が確認されたのち、梱包後の医薬品を風除室を通してトラックに積み込む。
【００１９】
なお図示例では、製剤室10に品質試験室27に連通するエアロック付き搬出口（エアシャワー付きパスボックス）19を設け、製剤室10から品質試験室27への試験体搬送を可能としている。何らかの理由により搬送口11、16が使用できない場合は、試験体を搬出口19経由で品質試験室27へ搬送し、試験体の一部を品質試験室27から搬出口20経由で無菌試験室15へ持ち込む。この場合は、搬出口19及び20が試験体の搬送口となり、中清浄度区域７から高清浄度区域２へ試験体を持ち込むことになるので、品質試験室27から無菌試験室15へ試験体を持ち込む際に試験体の外装に適当な消毒剤を噴霧する。
【００２０】
図２から分かるように、本発明の製造施設１は、製剤室10で調製した放射性医薬品を梱包室30へ向かう動線と無菌試験室15及び品質試験室27へ向かう動線とに分けるので、放射性医薬品の無菌試験及び品質試験と出荷準備とを並行に進めることができる。従って、エンドトキシン試験を含む医薬品の品質試験を迅速に行うことができ、半減期が短い放射性医薬品を製造後短時間で出荷することが可能となる。また、製剤室10と無菌試験室15との間、及び製剤室10・無菌試験室15を含む高清浄度区域２と梱包室30・品質試験室27を含む中清浄度区域７との間に適切なエアロックを設けているので、製剤室10の清浄度低下を確実に防止し、医薬品の安全性を確保できる。
【００２１】
こうして本発明の目的である「放射性医薬品のエンドトキシン試験を含めた品質試験を迅速に行うことができる製造施設」の提供を達成することができる。
【００２２】
また図示例の製造施設１は、高清浄度区域２に製剤室10及び無菌試験室27と共に資材準備室22を設け、医薬品の資材の保管や機器のメンテナンス等に使用している。資材準備室22は、同時に開放しない２以上の扉21a、21bで仕切られた資材搬送口21を介して製剤室10に連通する。図示例では、製剤室10と資材準備室22との間に設けたエアロック付きパスルームを資材搬送口21としている。好ましくは、資材搬送口21をエアシャワー付きするか、又は内圧を製剤室10及び資材準備室22の内圧、即ち高清浄度区域２の内圧より相対的に高く保持することにより、資材準備室22から製剤室10への微生物汚染を確実に防止する。資材準備室22は、エアロック付き搬入口23、24により中清浄度区域７の洗浄室28及び廊下40に連通している。中清浄度区域７に連通する搬入口23、24にはエアシャワー等の清浄化設備を設け、空気・人・物を介して中清浄度区域７から高清浄度区域２への微生物の拡散を防止する。
【００２３】
図２に黒矢印で示すように、放射性医薬品の製造に用いる資材を風除室から未検収品置場に受け入れ、必要な場合は原材料検収室において検収したのち無管理区域の倉庫33に保管する。倉庫33に隣接する開梱室34で外装箱等を取り除き、エアシャワー付きパスルーム35を通じて中清浄度区域７へ持ち込み、適当な消毒剤を噴霧したのちエアシャワー付き搬入口23を介して高清浄度区域２の資材準備室22へ搬入し、準備室22内の所定の場所に一時保管する。製剤室10・無菌試験室15・資材準備室22で使用する器具類等の洗浄・滅菌を必要とする資材（トング等）は、倉庫33から中清浄度区域７の洗浄室28へ持ち込み、洗浄室28で洗浄して滅菌缶に入れ、乾熱滅菌又は蒸気滅菌を行ったのち外装に適当な消毒剤を噴霧し、搬入口24を介して高清浄度区域２の資材準備室22へ搬入する。使用に際して、適当な消毒剤を噴霧したのち資材準備室22から資材搬送口21を介して製剤室10へ搬入する。製剤室10で使用後の器具は、放射能汚染がないことを確認したのち搬出口26から中清浄度区域７へ一旦搬出し、洗浄室28へ戻して洗浄すると共に滅菌缶に入れ、乾熱滅菌又は蒸気滅菌することにより再使用する。医薬品の梱包に用いる資材は、倉庫33からエアシャワー付きパスルーム35を介して中清浄度区域７の梱包準備室31へ直接持ち込む。
【００２４】
図２から分かるように、資材準備室22を設けることにより、製剤室10から搬出する放射性医薬品の流れ（搬出動線）と製剤室10へ搬入する資材の流れ（搬入動線）とを明確に分離することができるので、動線の交差による医薬品の汚染及び品質劣化を最小限に抑えることができる。また図示例の製造施設１では、高清浄度区域２を中央部に設け、製剤室10の搬出口25と資材準備室22の搬入口23とをそれぞれ製造施設１内の周縁部の異なる部位（例えば、方位が異なる部位）の梱包室30及び倉庫33に向けて設けているので、搬出動線と搬入動線との交差を確実に防止すると共に両動線を単純化できる。なお図示例では、製剤室10に中清浄度区域７の保管廃棄室43及び処理室42に連通するエアロック付き廃棄物搬出口26を設け、製剤室10で発生した廃棄物を搬出口26経由で保管廃棄室43及び処理室42へ搬出することにより、搬出動線及び搬入動線との交差を防止している。空になった廃棄物容器（ごみ箱）は、保管廃棄室43及び処理室42から洗浄室28又は資材準備室22へ戻し、適当な消毒剤を噴霧して再使用する。
【００２５】
【実施例】
図３は、図１の製造施設１における人の流れ（動線）の一例を示す。同図に示すように、中清浄度区域７では白衣（白衣と靴とディスポ帽子を含む）を着用し、高清浄度区域２では無塵服を着用することにより、各清浄度区域７、２の清浄度を管理する。無管理区域と中清浄度区域７との間には制服から白衣への更衣室36を設ける。また、中清浄度区域７と高清浄度区域２との間に白衣の脱衣室14（中清浄度区域側）と無塵服の着衣室13、18（高清浄度区域側）を設ける。高清浄度区域２への入退に関わる脱衣室14と着衣室13、18とを扉により分離し、着衣室13、18を脱衣室14に対して陽圧に保持する差圧を設定することにより、無塵服の微生物汚染を防止して一層確実な清浄度管理が可能となる。
【００２６】
更に図示例では、製剤室10及び資材準備室22に扉11a、11bを介して連通する前室11を設け、前室11をエアロック付き作業員出入口（エアシャワー室）12及び無塵服着衣室13を介して中清浄度区域７の脱衣室14に連通させ、無菌試験室15をエアロック付き作業員出入口（エアシャワー室）17及び無塵服着衣室18を介して同じ脱衣室14に連通させている。このように、製剤室10及び資材準備室22の入退用着衣室13と無菌試験室15の入退用着衣室18とを分けることにより、無塵服のコンタミ（菌の付着）を効果的に防止できる。無塵服着衣室13、18で無塵服を着用したのち手洗い・消毒を行い、エアシャワー12、17で汚れを落として前室11又は無菌試験室15に入室する。
【００２７】
製造施設１の見学者も、中清浄度区域７へ入るときに更衣室36で白衣を着用する。図示例の製造施設１は、中央部の高清浄度区域２を囲む中清浄度区域７内に廊下40を設け、廊下40を介して製造施設１の中央部と周縁部とを連通させている。例えば製剤室10、無菌試験室15、品質試験室27等の廊下側に透明部分（開閉不能な密閉ガラス窓等）を設けることにより、見学者は放射性医薬品の製造過程全体を廊下40から見て回ることができる。また、更衣室36に隣接させて汚染検査室37を設け、汚染検査室37に放射線汚染検査用のハンドフットクロスモニター（Personal Contamination Monitor）を設けている。ハンドフットクロスモニターを検査室37の退出用扉と連動させ、放射線汚染の未検査時又は汚染発見時は退出用扉の開放を禁止している。
【００２８】
図４は、図１の製造施設１における全ての入口から中清浄度区域７へ進入可能な動線（防虫ライン）を表したものである。製造施設１内への昆虫等の入り込みを防止するため、製造施設１の外部出入口と高清浄度区域２を囲む廊下40との間の全ての通路には、３重以上の扉・シャッターを設ける構造としている。１つの扉で昆虫等の進入率を20％に低減できると考えられており、３以上の扉を設けることにより昆虫等の進入確率を0.8％程度（＝0.2×0.2×0.2）とすることが期待できる。また、屋外に面する扉・シャッターは隙間のないものを選択し、開口周辺には窓を設置しないようにし、設置する場合は昆虫忌避灯及び忌避シートを併設する。更に、製造施設１の床を地面から80cm程度持ち上げ、製造施設１の周縁にコンクリート製の犬走り８を設ける等の対策により、歩行虫の進入を確実に防ぐ構造としている。
【００２９】
図示例では、サイクロトロン室４を放射線遮蔽型の地下ピットにより製剤室10と連通しているので、製剤室10の作業員等の放射線被曝を効果的に防止できる。また、サイクロトロン室４を低放射化コンクリート６製とすることにより、施設取り壊し時のコンクリート廃棄の容易化を図っている。更に図示例では、サイクロトロン室４に隣接する予備サイクロトロン室５を設け、将来的な放射線医薬品の需要増大にもサイクロトロン室の拡張により容易に対応可能な構造としている。なお、製剤室10や無菌試験室15、資材準備室22の蛍光灯は、清浄度を低下させずにメンテンスできるように、天井からアクセス可能な構造としている。
【００３０】
【発明の効果】
以上説明したように、本発明の放射性医薬品の製造施設は、製造施設内の高清浄度区域内に医薬品製剤室と共に同時開放しない２以上の扉で仕切られた搬送口を介して製剤室に連通する無菌試験室を併設し、製剤室と前記区域外の出荷準備室とをエアロック付き搬出口で連通し、無菌試験室と前記区域外の品質試験室とをエアロック付き搬出口で連通し、製剤室で調製した医薬品中の試験体を前記搬送口経由で無菌試験室及び品質試験室へ導入するので、次の顕著な効果を奏する。
【００３１】
（イ）製剤室で調製した放射性医薬品を出荷準備室と無菌試験室及び品質試験室とに同時に分配できるので、放射性医薬品の無菌試験及び品質試験と出荷準備とを同時に並行して進めることができる。
（ロ）従って、エンドトキシン試験を含む品質試験を迅速且つ確実に行うことができ、半減期が短い放射性医薬品の製造から出荷までの時間を短縮できる。
（ハ）高清浄度区域内に同時開放しない２以上の扉で仕切られた資材搬送口を介して製剤室に連通する資材準備室を併設することにより、医薬品の動線と資材（原材料）の動線とを明確に分離することが可能となり、動線の交差による医薬品の汚染及び品質劣化を最小限に抑えることができる。
（ニ）施設がコンパクトであり、都市部等の市街地にも小さな床面積で建設することができる。
（ホ）画像診断が実施できる診療センター等を併設し、FDGを製造して近隣の医療機関等にFDGを提供しつつ地域住民の健康管理・増進に貢献する複合施設とすることが可能である。
【図面の簡単な説明】
【図１】は、本発明の放射性医薬品製造施設の一実施例を示す図である。
【図２】は、図１の実施例における物の動線を示す説明図である。
【図３】は、図１の実施例における人の動線を示す説明図である。
【図４】は、図１の実施例における防虫ラインを示す説明図である。
【図５】は、従来の放射性医薬品製造施設の一例を示す図である。
【図６】は、従来の放射性医薬品の品質管理システムの一例を示す図である。
【符号の説明】
１…放射性医薬品製造施設
２…高清浄度区域３…気密壁
４…サイクロトロン室５…予備サイクロトロン室
６…低放射化コンクリート
７…中清浄度区域（RI管理区域）
８…犬走り 10…製剤室
11…前室（搬送口） 12…エアシャワー室
13…着衣室 14…脱衣室
15…無菌試験室 16…パスボックス（搬送口）
17…エアシャワー室 18…着衣室
19…エアロック付き搬出口（エアシャワー付き）
20…エアロック付き搬出口（エアシャワー付き）
21…資材搬送口（エアロック付きパスルーム）
22…資材準備室
23…エアロック付き搬入口（エアシャワー付き）
24…エアロック付き搬入口（エアシャワー付き）
25…エアロック付き搬出口（エアシャワー付き）
26…エアロック付き廃棄物搬出口（エアシャワー付き）
27…品質試験室 28…洗浄室
30…出荷準備室（梱包室）
31…梱包準備室 32…出荷室
33…倉庫 34…開梱室
35…エアシャワー付きパスルーム
36…更衣室 37…汚染検査室
38…除染室
40…廊下（管理区域廊下）
41…測定室
42…処理室 43…保管廃棄室
140…ホットセル群
141…製造施設（放射性物質取扱施設）
142…ホットラボ 143…サイクロトロン室
144…LAN 145…サイクロトロン電気室
146…試薬保管庫 147…品質検査室
148…質量分析室 149…汎用ホットラボ
150a…合成装置用ホットセル
150b…品質管理装置用ホットセル
151…インターフェースエリア
152…出入扉 153…前室
154…前室
160…自動合成装置 161…品質管理装置
162…ロボット 163…重量測定器
164…放射能測定器 165…分注ユニット
166…HPLC測定ユニット 167…pH測定ユニット
168…バイアル受け渡しユニット
169…バイアル受け渡しユニット
170…バイアル搬送装置 171…集中制御装置
172…気送管 173…分注装置[0001]
[Industrial application fields]
The present invention relates to a radiopharmaceutical manufacturing facility, and more particularly to a facility for manufacturing a radiopharmaceutical having a short half-life.
[0002]
[Prior art]
Positron emission tomography (hereinafter sometimes referred to as PET) is a positron emission nuclide (for example, fluorine-18 (¹⁸F). Hereinafter, it may be called a radionuclide. ) Labeled radiopharmaceuticals (e.g.,¹⁸F-fluorodeoxyglucose (¹⁸F-FDG)) is injected into a patient's body by intravenous injection or inhalation, and the radiopharmaceutical moves through the body and collects as a tomogram in the organs such as the heart and brain and cancer tissue. (Refer nonpatent literature 1). In contrast to X-ray CT (Computed Tomography) and Magnetic Resonance Imaging (MRI), which are used to image the morphology of living organisms, PET uses physiological and in vivo physiology such as metabolism and blood flow regardless of morphological abnormalities.・ Because biochemical functions can be captured and imaged, it is possible to clearly grasp, for example, actively active cancer tissues. Especially reflecting glucose metabolism¹⁸PET using F-FDG (hereinafter simply referred to as FDG) is effective in the early detection of cancer, and its clinical application has been promoted. Clinical trials to provide FDG as a pharmaceutical are also available. It is being advanced.
[0003]
Radiopharmaceuticals such as FDG contain the amount of radionuclide necessary for imaging, but their effectiveness gradually decreases with half-life. In particular, since the half-life of FDG is as short as 110 minutes, conventional PET generally uses FDG manufactured in a medical institution and immediately followed by a quality test. When manufacturing radiopharmaceuticals at a manufacturing facility outside the medical institution and providing it to the medical institution, take into account the quality test, packing / shipping time within the manufacturing facility, and the transportation time from the manufacturing facility to the medical institution. It is necessary to adjust the amount of radionuclide in the drug. However, there is a limit to the amount of radionuclide production, and it may not be possible to secure an amount sufficient for adjustment (see Non-Patent Document 2). It is important to reduce the time from manufacturing to shipping as much as possible.
[0004]
Patent Document 1 discloses an example of a radiopharmaceutical manufacturing facility (radioactive material handling facility) 141 as shown in FIG. The manufacturing facility 141 in the illustrated example is provided with a hot laboratory (formulation chamber) 142 for manufacturing a radiopharmaceutical adjacent to a cyclotron chamber 143 for manufacturing a radionuclide, and a hot cell 150a for a synthesizer and a hot cell 150b for a quality control device are installed in the hot laboratory 142. A hot cell group 140 is provided. The hot cell group 140 is disposed so as to surround the interface area 151, and an entrance / exit door (not shown) is provided between the interface area 151 and each hot cell 150a, 150b of the hot cell group 140. A doorway 152 is also provided in between. Each of the hot cells 150a and 150b is partitioned by a shutter door and connected to each other by a vial conveyance path arranged on the floor side. In the synthesizer hot cell 150a, a radiopharmaceutical is synthesized using the radionuclide from the cyclotron chamber 143 and injected into a vial. The radiopharmaceutical injected into the vial is sent to the quality control device hot cell 150b via the vial transport path and is subjected to a quality test. The drug-injected vials manufactured and tested in the hot cell group 140 are finally taken out into the hot lab chamber 142 via the doors of the hot cells 150a and 150b and the doors 152 of the interface area 151. It is sent to various test and research processes via chambers 153 and 154. Since the hot lab chamber 142 for handling radioactive substances is maintained at a negative pressure, the cleanliness may be reduced by sucking contaminated air from the front chamber 153. However, each hot cell 150a, 150b has a hot lab chamber 142 by a double entrance door. Since it is partitioned from, the reduction in cleanliness can be minimized.
[0005]
Patent Document 2 discloses a quality control system that automatically performs a quality test of a radiopharmaceutical in the hot laboratory 142 described above, as shown in FIG. The quality control system in the illustrated example includes a vial transport device 170 that transports a radiopharmaceutical injected into a vial by the automatic synthesizer 160, a quality control device 161 that automatically performs a quality test necessary for the radiopharmaceutical, and a transport device. 170 and a centralized control device 171 for controlling the quality management device 161. The quality control device 161 includes a dispensing unit 165 for dispensing the radiopharmaceutical in the vial transported from the automatic synthesizer 160 via the vial transporting device 170, and the weight / radiation of the sample of the dispensed radiopharmaceutical. Measuring instruments 163, 164, and 167 for measuring the capacity and pH, and a high-performance liquid chromatograph (HPLC) measuring unit 166 for analyzing the purity (radiochemical purity, chemical purity, etc.) of the sample are provided. According to the quality management system of the illustrated example, the quality test of the radiopharmaceutical can be automatically performed without human intervention, so that exposure of workers and the like can be avoided.
[0006]
[Non-Patent Document 1]
Edited by the Nuclear Medicine Society of Japan / PET Nuclear Medicine Working Group “PET Exam Q & A” published by the Japanese Nuclear Medicine Society / Japan Isotope Association, May 2000
[Non-Patent Document 2]
MARCEL GUILLAUME, ET AL. "Recommendation for Fluorine-18 Production", Appl. Radiat. Isot., Vol.42, No.8, pp.749-762, 1991
[Non-Patent Document 3]
Kunio Kawamura, “Practice of validation in the design, development and manufacture of pharmaceutical products” Jiho, July 31, 2002, pp. 98-103
[Patent Document 1]
JP 2003-021696 A
[Patent Document 2]
JP 2000-356642 A
[0007]
[Problems to be solved by the invention]
Since the quality control device 161 used in Patent Documents 1 and 2 can perform a quality test immediately after manufacturing a radiopharmaceutical in a hot lab, it can contribute to some extent to speeding up the quality test. However, it is not sufficient to confirm the quality of the radiopharmaceutical by the weight test, radioactivity test, pH test, and purity test described above, and it is also necessary to confirm the quality by a sterility test or an endotoxin test. The sterility test is a test for confirming the presence or absence of microorganisms (bacteria or fungi) in the drug, and the endotoxin test is a test for detecting or quantifying endotoxin derived from gram-negative bacteria in a pharmaceutical product. Since the sterility test takes more than 14 days, it is difficult to confirm the results before shipping the radiopharmaceutical, but the endotoxin test can be obtained in a relatively short time. In clinical use of radiopharmaceuticals is desirable.
[0008]
However, the quality control device 161 used in Patent Documents 1 and 2 cannot perform the endotoxin test, and after the weight test, radioactivity test, pH test, and purity test by the quality control device 161 are completed, the endotoxin test is separately performed. I have to do it. Therefore, in the manufacturing method and quality control method of Patent Documents 1 and 2, the total time of the test time by the control device 161 and the endotoxin test time is required to obtain the endotoxin test result, and the result of the endotoxin test is confirmed from the manufacturing. There is a problem that the time until use becomes long. In order to produce a radiopharmaceutical with a short half-life at a manufacturing facility outside a medical institution, it is necessary to shorten the time required for quality testing including endotoxin testing as much as possible.
[0009]
Accordingly, an object of the present invention is to provide a manufacturing facility capable of quickly conducting a quality test including a radiopharmaceutical endotoxin test.
[0010]
[Means for Solving the Problems]
Referring to the embodiment of FIG. 1 and the flow diagram of FIG. 2, a radiopharmaceutical manufacturing facility 1 according to the present invention is surrounded by an airtight wall 3 of the radiopharmaceutical manufacturing facility.Negative pressureIn high cleanliness area 2Worker doorway 11a Partitioned byRadiopharmaceuticalFront chamber 11 WithFormulation room 10 is provided and partitioned into two or more doors 16a and 16b that do not open simultaneously in the high cleanliness area 2.MedicineVia transport port 16Front chamber 11The sterility test room 15 communicating with theFront chamber 11 And sterility testing room 15 The dressing room outside the high cleanliness area 2 individually 14 Worker entrance with air lock that communicates with 12 as well as 17 Provided,The airtight wall 3 of the preparation room 10 is provided with a discharge port 25 with an air lock that communicates with a shipping preparation room 30 (packing room in the illustrated example) outside the high cleanliness area 2, and the airtight wall 3 of the sterility test room 15 is highly clean. Radiopharmaceuticals prepared in the preparation room 10 with an outlet 20 with an airlock communicating with the quality test room 27 outside the area 2The shipping preparation room 30 The drug at the same timeThe test specimen insideFront chamber 11 as well asBy introducing it into the sterility test room 15 and the quality test room 27 via the transport port 16, the sterility test and quality test of the radiopharmaceutical can proceed in parallel with the preparation for shipment.
[0011]
Preferably, it communicates with the preparation chamber 10 through a material transfer port 21 partitioned by two or more doors 21a and 21b that are not simultaneously opened in the high cleanliness area 2.With worker doorway 11b Through the anteroom 11 Communicate withA material preparation room 22 is also provided, and an air-locked entrance 23 that communicates with the outside of the high cleanliness area 2 is provided in the airtight wall 3 of the material preparation room 22 so that radiopharmaceutical materials can be supplied from outside the high cleanliness area 2 It is possible to carry into the preparation room 10 via 22 and the material transfer port 21. More preferablyFront chamber 11 The internal pressure of the product is kept relatively higher than the internal pressure of the high cleanliness area 2, or the medicineThe transport port 16 and / or material transport port 21 is equipped with an air shower, and by air shower injectionMedicineThe internal pressure of the transfer port 16 and / or the material transfer port 21 is kept higher than the internal pressure of the high cleanliness area 2. It is desirable that the high cleanliness area 2 is provided in the center of the manufacturing facility, and the outlet 25 of the preparation chamber 10 and the inlet 23 of the material preparation chamber 22 are provided toward different parts of the peripheral edge in the manufacturing facility 1.
[0012]
DETAILED DESCRIPTION OF THE INVENTION
FIG. 1 shows an embodiment of a production facility 1 of the present invention for producing a sterile injection as a radiopharmaceutical. In general, radiopharmaceutical manufacturing facilities need to be able to control the cleanliness necessary for pharmaceutical manufacturing and to have a structure that can prevent radiation damage because the raw materials handled are radioisotopes (hereinafter referred to as RI). It is necessary to perform air conditioning differential pressure management that satisfies both cleanliness management and RI management. As a pharmaceutical manufacturing facility, multiple cleanliness categories are set for each room according to the application and work content, the aseptic work area is set as the strictest cleanliness area, and each area with a high cleanliness area has one cleanliness. It is necessary to design the layout so as to surround a region of another low cleanliness section so that a person or an object does not normally move beyond the two stages of cleanliness section (see Non-Patent Document 3). On the other hand, as a radiation handling facility, differential pressure management is required in which the negative pressure in the facility against the outside air is required. Hereinafter, the present invention will be described with reference to the illustrated examples, but the radiopharmaceutical to which the present invention is applied is not limited to a sterile injection.
[0013]
The manufacturing facility 1 in the example shown is class 10,000 (1 ft) as a cleanliness category.^Three(Legal leg) The number of fine particles with a given particle size in the air is 10^FourCleanliness classification of less than one), class 100,000 (1ft^ThreeThe number of fine particles with a predetermined particle size contained in the air is 10^FiveCleanliness class of less than 1), unmanaged 3 classes are set, and the highest class cleanliness area 2 (hereinafter sometimes referred to as high cleanliness area 2) is classified as class 100,000 cleanliness area 7 ( Hereinafter, the layout is surrounded by a medium cleanliness area 7), and the medium cleanliness area 7 is surrounded by an unmanaged area. Since the high cleanliness area 2 and the medium cleanliness area 7 are also RI management areas, an air lock is provided at the opening between the medium cleanliness area 7 and the uncontrolled area, and the medium cleanliness area 7 is outside and free of air. Negative pressure is applied to the management area and microbial contamination of the medium cleanliness area 7 is prevented. In addition, an airtight wall 3 is provided between the high cleanliness area 2 and the medium cleanliness area 7, and an air lock and necessary cleaning equipment (such as an air shower) are provided at the opening of the airtight wall 3 so that the medium cleanliness is achieved. Prevention of microbial contamination through air, people, and things from the high temperature zone 7 to the high cleanliness zone 2.
[0014]
A radiopharmaceutical aseptic preparation room (hot lab) 10 and a sterility test room 15 are provided in the high cleanliness area 2, and the transport port 11 is partitioned by two or more doors 11a, 16a, 16b that do not open both rooms simultaneously. Communicate with 16 In the preparation chamber 10, for example, a synthesis apparatus hot cell 150 a as shown in FIG. 5 is arranged in communication with the cyclotron chamber 4. The sterility test room 15 is a room for performing radiopharmaceutical sterility tests and endotoxin tests. The transport ports 11 and 16 enable radiopharmaceutical specimens to be transported from the preparation chamber 10 to the sterilization test chamber 15, and the doors 11a, 16a, and 16b of the transport ports 11 and 16 allow the transport of the radiopharmaceutical specimen from the sterility test chamber 15 to the preparation chamber 10. To prevent microbial contamination. Since there is no differential pressure between the preparation chamber 10 and the sterility test chamber 15 and the three doors 11a, 16a, 16b do not open at the same time, direct air suction from the sterility test chamber 15 to the preparation chamber 10 Does not occur.
[0015]
In the illustrated example, the preparation chamber 10 is provided with a front chamber 11 that communicates with the door 11a, and a pass box 16 with two doors 16a and 16b that are not simultaneously opened is provided between the front chamber 11 and the sterility test chamber 15. The front chamber 11 and the pass box 16 are used as a transfer port (transfer path). Preferably, the pass box 16 is provided with an air shower, or the internal pressure of the front chamber 11 is kept relatively higher than the internal pressure of the preparation chamber 10 and the sterility test chamber 15, that is, the internal pressure of the high cleanliness area 2. By providing the transport ports 11 and 16 with an air shower or keeping the internal pressure relatively high, microbial contamination from the sterility test chamber 15 to the preparation chamber 10 can be more reliably prevented.
[0016]
The preparation room 10 communicates with the shipping preparation room 30 (packing room in the illustrated example) 30 in the medium cleanliness area 7 through the outlet 25 with the airlock, and the sterility test room 15 communicates with the medium cleanliness area 7 through the outlet 20 with the airlock. Communicate with quality testing room 27. In the illustrated example, the packing room 30 is a shipping preparation room, but the preparation room 10 can be communicated not only with the packing room 30 but also with other suitable shipping preparation rooms. The quality test room 27 is a room for performing a quality test other than the sterility test and the endotoxin test. The test body from the preparation room 10 is brought into the quality test room 27 from the aseptic test room 15 through the carry-out port 20. For example, the quality control device 161 shown in FIG. 6 is installed in the quality test room 27, and a weight test, a radioactivity test, a pH test, a purity test, etc. are performed on the specimen. It is desirable that the outlets 20 and 25 communicating with the medium cleanliness area 7 are equipped with an air shower to prevent a decrease in cleanliness in the high cleanliness area 2.
[0017]
Next, with reference to FIG. 2 which shows the flow (flow line) of the thing in the manufacturing facility 1, the manufacturing method of the radiopharmaceutical in the manufacturing facility 1 of this invention is demonstrated. In the figure, the flow of pharmaceutical materials is indicated by black arrows, the flow of prepared pharmaceuticals is indicated by hatched arrows, the flow of test specimens in the pharmaceutical is indicated by white arrows, and the flow of waste is indicated by dotted arrows. The RI raw material (positron emission nuclide) produced in the cyclotron chamber 4 is transferred to a raw material safety cabinet in the preparation chamber 10 through an underground pit (tube) and subjected to pretreatment (for example, synthesis) as necessary. After performing the necessary pretreatment, it is brought into the dispensing cabinet in the preparation room 10 as an RI pharmaceutical raw material. The RI drug raw material is processed into a drug product bulk in a dispensing cabinet, and the drug product bulk is filled into aseptic material (for example, a vial) while performing aseptic filtration. Aseptic materials are brought into the preparation room 10 through the material preparation room 22 as described later.
[0018]
A part of the radiopharmaceutical prepared in the preparation chamber 10 is transported to the sterility test chamber 15 via the transport ports 11 and 16 as a test body, and the rest is transported to the packing chamber 30 via the transport outlet 25 and packed. A necessary amount may be conveyed to the packing room 30 and the remaining medicine may be stored in a storage box in the preparation room 10. The packing material is brought from the packing preparation room 31 into the packing room 30. In the sterility test room 15, a sterility test and an endotoxin test are immediately started using a part of the test body, and the remainder is delivered to the quality test room 27 via the carry-out port 20. In the quality test room 27, a weight test, a radioactivity test, a pH test, a purity test, etc. are started immediately using the test specimen, and a test specimen for long-term storage is transported to the storage room for storage. The radiopharmaceuticals packed in the packing room 30 may be carried into the shipping room 32 and stored until the test results of the sterility test room 15 and the quality test room 27 are obtained. After the test results including the endotoxin test are confirmed to pass, the packed medicine is loaded onto the truck through the windbreak room.
[0019]
In the illustrated example, the preparation chamber 10 is provided with an outlet with air lock (pass box with air shower) 19 that communicates with the quality test chamber 27 so that the specimen can be conveyed from the preparation chamber 10 to the quality test chamber 27. When the transport ports 11 and 16 cannot be used for some reason, the test specimen is transported to the quality test chamber 27 via the carry-out port 19 and a part of the test specimen is transferred from the quality test chamber 27 via the carry-out port 20 to the sterility test chamber 15. Bring it to. In this case, since the outlets 19 and 20 serve as transport ports for the test specimen, and the test specimen is brought from the medium cleanliness area 7 to the high cleanliness area 2, the specimen is transferred from the quality test room 27 to the aseptic test room 15. Spray a suitable disinfectant on the exterior of the test specimen.
[0020]
As can be seen from FIG. 2, the manufacturing facility 1 of the present invention divides the radiopharmaceutical prepared in the preparation room 10 into a flow line toward the packing room 30 and a flow line toward the sterility test room 15 and the quality test room 27. Radiopharmaceutical sterility testing and quality testing and shipping preparation can proceed in parallel. Therefore, it is possible to quickly carry out quality tests of pharmaceuticals including endotoxin tests, and to ship radiopharmaceuticals having a short half-life in a short time after production. Also, between the preparation room 10 and the sterility test room 15, and between the high cleanliness area 2 including the preparation room 10 and the sterility test room 15, and between the cleanliness area 7 including the packing room 30 and the quality test room 27. Since an appropriate air lock is provided, it is possible to reliably prevent a decrease in the cleanliness of the preparation chamber 10 and ensure the safety of the medicine.
[0021]
In this way, it is possible to provide the “production facility capable of quickly conducting a quality test including a radiopharmaceutical endotoxin test” which is an object of the present invention.
[0022]
The manufacturing facility 1 in the illustrated example has a material preparation room 22 together with a preparation room 10 and a sterility test room 27 in the high cleanliness area 2, and is used for storage of pharmaceutical materials, equipment maintenance, and the like. The material preparation room 22 communicates with the preparation room 10 through a material transfer port 21 partitioned by two or more doors 21a and 21b that are not opened simultaneously. In the illustrated example, a passroom with an airlock provided between the preparation chamber 10 and the material preparation chamber 22 is used as the material transfer port 21. Preferably, the material preparation chamber 22 is provided with an air shower at the material conveyance port 21 or by maintaining the internal pressure relatively higher than the internal pressure of the preparation chamber 10 and the material preparation chamber 22, that is, the internal pressure of the high cleanliness area 2. To prevent microbial contamination of the preparation chamber 10 from The material preparation room 22 communicates with the cleaning room 28 and the corridor 40 in the medium cleanliness area 7 through the inlets 23 and 24 with air locks. Cleaning facilities such as an air shower are installed at the entrances 23 and 24 communicating with the medium cleanliness area 7 to spread microorganisms from the medium cleanliness area 7 to the high cleanliness area 2 through air, people and objects. To prevent.
[0023]
As shown by the black arrow in FIG. 2, the material used for the production of the radiopharmaceutical is received from the windbreak room into the unexamined product storage area, and if necessary, it is inspected in the raw material inspection room and then stored in the warehouse 33 in the unmanaged area. In the unpacking chamber 34 adjacent to the warehouse 33, remove the outer box, etc., bring it into the medium cleanliness area 7 through the passroom 35 with air shower, spray the appropriate disinfectant, and then clean through the entrance 23 with air shower. It is carried into the material preparation room 22 in the second zone and temporarily stored in a predetermined place in the preparation room 22. Materials (tongues, etc.) that require cleaning and sterilization of equipment used in the preparation room 10, sterility test room 15 and material preparation room 22 are brought from the warehouse 33 to the cleaning room 28 in the medium cleanliness area 7 for cleaning. After washing in the chamber 28 and putting in a sterilization can, dry heat sterilization or steam sterilization, spray an appropriate disinfectant on the exterior, and carry it into the material preparation room 22 in the high cleanliness area 2 through the entrance 24 . In use, after spraying a suitable disinfectant, the material is transferred from the material preparation chamber 22 to the preparation chamber 10 through the material transfer port 21. After confirming that there is no radioactive contamination, the equipment after use in the preparation room 10 is once transported from the outlet 26 to the medium cleanliness area 7 and returned to the cleaning room 28 for cleaning and placed in a sterilized can. Reuse by sterilization or steam sterilization. Materials used for packing medicines are brought directly from the warehouse 33 to the packing preparation room 31 in the medium cleanliness area 7 via the pass room 35 with air shower.
[0024]
As can be seen from FIG. 2, by providing the material preparation room 22, the flow of the radiopharmaceuticals carried out from the preparation room 10 (unloading flow line) and the flow of the materials carried into the preparation room 10 (loading line) are clearly defined. Since they can be separated, contamination and quality deterioration of pharmaceuticals due to intersection of flow lines can be minimized. In addition, in the manufacturing facility 1 in the illustrated example, the high cleanliness area 2 is provided in the center, and the outlet 25 of the preparation chamber 10 and the inlet 23 of the material preparation chamber 22 are different parts of the peripheral portion in the manufacturing facility 1 ( For example, since it is provided toward the packing room 30 and the warehouse 33 in different directions), it is possible to reliably prevent the crossing of the carry-out flow line and the carry-in flow line and simplify both flow lines. In the illustrated example, the preparation chamber 10 is provided with a waste discharge outlet 26 with an airlock that communicates with the storage disposal chamber 43 and the processing chamber 42 in the medium cleanliness zone 7, and the waste generated in the preparation chamber 10 is passed through the outlet 26. In this case, the crossing with the carry-out flow line and the carry-in flow line is prevented. The empty waste container (trash can) is returned from the storage waste chamber 43 and the processing chamber 42 to the cleaning chamber 28 or the material preparation chamber 22, and sprayed with an appropriate disinfectant for reuse.
[0025]
【Example】
FIG. 3 shows an example of a human flow (flow line) in the manufacturing facility 1 of FIG. As shown in the figure, by wearing a white coat (including a white coat and shoes and a disposable hat) in the medium cleanliness area 7, and wearing dust-free clothes in the high cleanliness area 2, each cleanliness area 7, 2 Manage the cleanliness. A changing room 36 from a uniform to a lab coat is provided between the unmanaged area and the medium cleanliness area 7. Also, a white coat undressing room 14 (medium cleanliness area side) and dust-free clothes dressing rooms 13 and 18 (high cleanliness area side) are provided between the medium cleanliness area 7 and the high cleanliness area 2. Separate the dressing room 14 and the dressing rooms 13 and 18 related to entering and leaving the high cleanliness area 2 with a door, and set a differential pressure to keep the dressing rooms 13 and 18 positive with respect to the dressing room 14 Thus, microbial contamination of dust-free clothing can be prevented and more reliable cleanliness management can be achieved.
[0026]
Furthermore, in the illustrated example, the preparation room 10 and the material preparation room 22 are provided with a front room 11 that communicates with the doors 11a and 11b, and the front room 11 is provided with a worker entrance / exit with air lock (air shower room) 12 and dust-free clothing. The chamber 13 is connected to the undressing room 14 in the medium cleanliness area 7, and the sterility test room 15 is connected to the same undressing room 14 via the worker entrance with air lock (air shower room) 17 and the dustless clothes dressing room 18. Communicate. In this way, by separating the entrance / exit dressing room 13 in the preparation room 10 and the material preparation room 22 and the entrance / exit dressing room 18 in the sterility test room 15, contamination of dust-free clothes (adherence of bacteria) is effective. Can be prevented. After wearing dust-free clothes in the dust-free clothes dressing rooms 13 and 18, hand washing and disinfection are performed, and the air showers 12 and 17 are cleaned to enter the front room 11 or the sterility test room 15.
[0027]
A visitor of the manufacturing facility 1 also wears a white coat in the changing room 36 when entering the medium cleanliness area 7. The manufacturing facility 1 in the illustrated example has a corridor 40 in the middle cleanliness area 7 surrounding the high cleanliness area 2 in the center, and the central portion and the peripheral edge of the manufacturing facility 1 communicate with each other through the corridor 40. . For example, by providing a transparent part (such as a closed glass window that cannot be opened and closed) on the corridor side of the preparation room 10, sterility test room 15, quality test room 27, etc., the visitor sees the entire radiopharmaceutical manufacturing process from the corridor 40. I can turn around. Further, a contamination inspection room 37 is provided adjacent to the changing room 36, and a hand foot cross monitor (Personal Contamination Monitor) for radiation contamination inspection is provided in the contamination inspection room 37. The hand foot cross monitor is interlocked with the exit door of the examination room 37, and the opening of the exit door is prohibited when radiation contamination is not inspected or when contamination is detected.
[0028]
FIG. 4 shows a flow line (insect control line) that can enter the medium cleanliness area 7 from all the entrances in the manufacturing facility 1 of FIG. In order to prevent insects and the like from entering the manufacturing facility 1, all the passages between the external entrance and exit of the manufacturing facility 1 and the corridor 40 surrounding the high cleanliness area 2 are provided with three or more doors / shutters. It has a structure. It is thought that the entry rate of insects etc. can be reduced to 20% with one door, and the entrance probability of insects etc. should be about 0.8% (= 0.2 × 0.2 × 0.2) by providing 3 or more doors. I can expect. Also, select doors and shutters that face the outdoors with no gaps, do not install windows around the openings, and install insect repellent lamps and repellent seats. In addition, the structure of the manufacturing facility 1 is lifted about 80 cm from the ground and a concrete dog run 8 is provided around the periphery of the manufacturing facility 1 to prevent the entry of walking insects.
[0029]
In the illustrated example, since the cyclotron chamber 4 communicates with the preparation chamber 10 by a radiation shielding underground pit, radiation exposure of workers in the preparation chamber 10 and the like can be effectively prevented. Moreover, the cyclotron chamber 4 is made of low activation concrete 6 to facilitate the disposal of concrete when the facility is demolished. Further, in the illustrated example, a preliminary cyclotron chamber 5 adjacent to the cyclotron chamber 4 is provided, and a structure that can easily cope with future demand for radiopharmaceuticals by expanding the cyclotron chamber. The fluorescent lamps in the preparation room 10, the sterility test room 15, and the material preparation room 22 are structured to be accessible from the ceiling so that maintenance can be performed without degrading the cleanliness.
[0030]
【The invention's effect】
As described above, the radiopharmaceutical manufacturing facility of the present invention communicates with the drug product room through the transport port partitioned by two or more doors that do not open simultaneously with the drug product drug room in the high cleanliness area of the manufacturing facility. The sterility test room is connected, the preparation room outside the area communicates with the shipping outlet with an air lock, and the sterility test room communicates with the quality test room outside the area with an air lock outlet. Since the test body in the medicine prepared in the preparation room is introduced into the sterility test room and the quality test room through the transport port, the following remarkable effects are obtained.
[0031]
(B) Since the radiopharmaceutical prepared in the preparation room can be distributed simultaneously to the shipment preparation room, the sterility test room, and the quality test room, the sterility test and quality test of radiopharmaceuticals and the preparation for shipment can be carried out simultaneously in parallel. .
(B) Therefore, quality tests including endotoxin tests can be performed quickly and reliably, and the time from production to shipment of a radiopharmaceutical having a short half-life can be shortened.
(C) By providing a material preparation room in the high cleanliness area that communicates with the drug product room through a material transfer port that is partitioned by two or more doors that do not open simultaneously, the flow of drugs and materials (raw materials) It becomes possible to clearly separate the flow line, and the contamination and quality deterioration of the pharmaceutical product due to the crossing of the flow line can be minimized.
(D) The facility is compact and can be constructed in urban areas such as urban areas with a small floor area.
(E) It is possible to create a complex facility that contributes to the health management and promotion of local residents while manufacturing FDG and providing FDG to neighboring medical institutions, etc., along with a medical center that can perform diagnostic imaging. .
[Brief description of the drawings]
FIG. 1 is a diagram showing an embodiment of a radiopharmaceutical production facility of the present invention.
FIG. 2 is an explanatory diagram showing flow lines of objects in the embodiment of FIG.
FIG. 3 is an explanatory diagram showing human flow lines in the embodiment of FIG. 1;
4 is an explanatory view showing an insect repellent line in the embodiment of FIG. 1. FIG.
FIG. 5 is a diagram showing an example of a conventional radiopharmaceutical manufacturing facility.
FIG. 6 is a diagram showing an example of a conventional radiopharmaceutical quality control system.
[Explanation of symbols]
1 ... Radiopharmaceutical manufacturing facility
2 ... High cleanliness area 3 ... Airtight wall
4 ... Cyclotron room 5 ... Preliminary cyclotron room
6 ... Low activation concrete
7 ... Medium cleanliness area (RI management area)
8 ... Dog running 10 ... Formulation room
11 ... Front room (conveying port) 12 ... Air shower room
13 ... Dressing room 14 ... Dressing room
15… Sterility test room 16… Pass box (conveying port)
17… Air shower room 18… Clothing room
19 ... Exit with air lock (with air shower)
20 ... Exit with air lock (with air shower)
21… Material transfer port (passroom with airlock)
22… Material preparation room
23… Airport with air lock (with air shower)
24… Airport with air lock (with air shower)
25 ... Exit with air lock (with air shower)
26 ... Waste outlet with air lock (with air shower)
27 ... Quality test room 28 ... Cleaning room
30 ... Shipping preparation room (packing room)
31 ... Packing preparation room 32 ... Shipping room
33 ... Warehouse 34 ... Unpacking room
35… Passroom with air shower
36… Change room 37… Contamination inspection room
38. Decontamination room
40 ... corridor (control area corridor)
41… Measurement room
42… Processing room 43… Storage waste room
140… Hot cell group
141… Manufacturing facility (radioactive material handling facility)
142 ... Hot lab 143 ... Cyclotron room
144 ... LAN 145 ... Cyclotron electrical room
146 ... Reagent storage 147 ... Quality inspection room
148 ... Mass spectrometry room 149 ... General-purpose hot lab
150a… Hot cell for synthesizer
150b ... Hot cell for quality control equipment
151… Interface area
152 ... Doorway 153 ... Front room
154… The front room
160 ... Automatic synthesis device 161 ... Quality control device
162 ... Robot 163 ... Weighing instrument
164 ... Radioactivity measuring instrument 165 ... Dispensing unit
166 ... HPLC measurement unit 167 ... pH measurement unit
168… Vial delivery unit
169… Vial delivery unit
170 ... Vial transport device 171 ... Central control device
172 ... Pneumatic tube 173 ... Dispensing device

Claims

In the high- pressure cleanliness area of the negative pressure surrounded by the hermetic wall of the radiopharmaceutical manufacturing facility, a preparation room with an anterior chamber of the medicine partitioned by a worker entrance door is provided, and two or more do not open simultaneously in the area A sterility test chamber communicating with the anterior chamber through a drug delivery port partitioned by a door, and a worker entrance with an airlock individually communicating with the undressing chamber outside the area in the anterior chamber and the sterility test chamber, respectively An air lock carrying port communicating with the shipping preparation chamber outside the area is provided in the hermetic wall of the preparation room, and the air lock carrying the air lock communicating with the quality test room outside the area is provided in the air tight wall of the sterility test room. By providing an outlet and transporting the medicine prepared in the preparation room to the shipping preparation room, the test body in the medicine is introduced into the sterility test room and the quality test room via the front chamber and the transport port, and the sterility of the medicine Testing and quality testing Shipment preparation and manufacturing facilities of radiopharmaceuticals to be as can proceed in parallel.

2. The manufacturing facility according to claim 1, wherein the product facility communicates with a preparation chamber through a material transfer port partitioned by two or more doors that are not simultaneously opened in the high cleanliness area, and communicates with an anterior chamber through a worker doorway. Provided with a material preparation room, provided with an air-locked inlet that communicates outside the area on the airtight wall of the material preparation room, and the drug material from outside the area to the preparation room via the material preparation room and material transfer port Radiopharmaceutical manufacturing facility that can be brought in.

The radiopharmaceutical manufacturing facility according to claim 1 or 2 , wherein the internal pressure of the anterior chamber is maintained relatively higher than the internal pressure of the high cleanliness area .

In the manufacturing facility according to any one of claims 1 to 3 , the medicine conveyance port and / or the material conveyance port is provided with an air shower, and the internal pressure of the drug conveyance port and / or the material conveyance port is set to the high purity by air shower injection. A facility for manufacturing radiopharmaceuticals that is kept above the internal pressure of the temperature zone

5. The manufacturing facility according to claim 1 , wherein the high cleanliness area is provided in a central portion of the manufacturing facility, and the outlet of the preparation chamber and the inlet of the material preparation chamber are different from each other in the peripheral portion of the manufacturing facility. Radiopharmaceutical manufacturing facility established for the site.

The manufacturing facility according to claim 5 , wherein a corridor surrounding the high cleanliness area of the central portion is provided, and the central portion and the peripheral portion in the manufacturing facility are communicated with each other through the corridor.

The radiopharmaceutical manufacturing facility according to claim 6 , wherein three or more doors are provided in all passages between the external entrance and the hallway of the manufacturing facility.

In any of the manufacturing facilities of claims 1 to 7, manufacturing facilities radiopharmaceutical comprising an air lock for communicating the high cleanliness area and the area outside the conditioned air shower.

A preparation room with an anterior chamber for the medicine separated by a worker doorway in a high cleanliness area of negative pressure surrounded by an airtight wall of a radiopharmaceutical manufacturing facility, and two or more that do not open simultaneously in the area A sterility test chamber communicating with the anterior chamber through a drug delivery port partitioned by a door, and a worker entrance with an airlock individually communicating with the undressing chamber outside the area in the anterior chamber and the sterility test chamber, respectively An air lock carrying port communicating with the shipping preparation chamber outside the area is provided in the hermetic wall of the preparation room, and the air lock carrying the air lock communicating with the quality test room outside the area is provided in the air tight wall of the sterility test room. By providing an outlet and transporting the medicine prepared in the preparation room to the shipping preparation room, the test body in the medicine is introduced into the sterility test room and the quality test room via the front chamber and the transport port, and the sterility of the medicine Testing and quality testing Shipping preparation and allowed to proceed in parallel, at least a manufacturing method of a radiopharmaceutical comprising shipping the medicament results after confirmation of the endotoxin test in the sterility testing chamber.

In the manufacturing method of Claim 9, it communicates with the preparation room through the material conveyance port partitioned off by the two or more doors which do not open simultaneously in the high cleanliness area, and communicates with the front room through the worker doorway. Provided with a material preparation room, an airlocked inlet that communicates outside the area is provided in the airtight wall of the material preparation room, and the medicine material is transferred from the outside of the area to the preparation room via the material preparation room and the material transfer port. A method for manufacturing radiopharmaceuticals.