JP6716557B2 - 浸出物および/または抽出物の除去のための活性炭 - Google Patents
浸出物および/または抽出物の除去のための活性炭 Download PDFInfo
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- JP6716557B2 JP6716557B2 JP2017524356A JP2017524356A JP6716557B2 JP 6716557 B2 JP6716557 B2 JP 6716557B2 JP 2017524356 A JP2017524356 A JP 2017524356A JP 2017524356 A JP2017524356 A JP 2017524356A JP 6716557 B2 JP6716557 B2 JP 6716557B2
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- activated carbon
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- leachate
- extract
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Description
一実施態様において、標的分子は糖タンパク質である。
一実施態様において、標的分子は抗体である。
別の好ましい実施態様においては、活性炭は、有機ポリマー材料、好ましくはポリスチレンの熱分解によって得られる活性炭である。
好ましい実施態様において、活性炭は、5〜40μmの中間の粒径を有する。
1つの実施態様において、標的分子は、活性炭を含む1つ以上のフィルタを通す濾過によって浸出物および/または抽出物から分離される。
− 生物反応器における細胞培養
− 清澄化
− 精製
− 濾過。
好ましい実施態様において、液体を濾過装置内の活性炭と接触させ、それによって液体が活性炭を含む濾過装置を通過し、浸出液および/または抽出物が活性炭に結合し、一方で、液体および液体中に含まれる標的分子は、活性炭に結合しない。
本発明を詳細に説明する前に、本発明は特定の組成物またはプロセスステップに限定されず、かかるように変更することができることを理解されたい。単数形‘a’、‘an’および‘the’は、文脈上他に明確に指示されない限り、複数の指示対象を包含することに留意されたい。したがって、例えば、‘リガンド(a ligand)’への言及は複数のリガンドを包含し、‘抗体(an antibody)’への言及は複数の抗体などを包含する。
抽出物は、特定の時間、温度、および機械的な力の条件下で適切な溶媒に暴露された場合、標的分子と直接接触する任意の物質から標的分子または標的分子を含む液体に移動する化合物である。抽出物を放出する材料は、エラストマー、プラスチックまたはコーティング成分を含む。
典型的には、抽出物試験はモデル溶媒を用いて実施されるが、浸出物試験は実際の標的分子またはプロセス流体を使用する。
典型的には、抽出物は、誇張されたまたは攻撃的な条件下で得られるが、浸出物の試験は、通常のプロセス条件を使用する。
したがって、通常、浸出物は、抽出物のサブセットとして示される。いくつかの場合、プロセス流体または標的分子とプロセス器材との相互作用のために、いくつかの浸出物化合物は抽出物の一部ではない。抽出物および浸出物の詳細は、BPSA Extractables and Leachables Subcommittee, BioProcess Int. 2007, 5 (11), 36に見出される。
本発明の要旨は、活性炭、特に有機ポリマー材料の熱分解によって得られる活性炭を、使い捨て器材の使用からもたらされる浸出物および/または抽出物を除去するために使用し得るという知見である。国際公開第201404281号および米国特許出願第2014/046038号から、活性炭は一般に不純物を除去するための生物医薬の生産プロセスに使用し得ることが知られている。しかし、活性炭は、使い捨て器材の使用によって生じる浸出物および/または抽出物の除去に特に適していることが、まだ分かっていなかった。
− 上昇した温度−これは、製品溶液と使い捨て器材との接触中のこのプロセスステップにおいて、温度が少なくとも部分的に25℃を超えることを意味する。これは、例えば、細胞が典型的には37℃で培養される使い捨て生物反応器の場合である。
本発明の方法は、最初に、浸出物および/または抽出物を標的分子から除去するための、簡単で効果的な方法を提供する。活性炭は、標的分子に新たな汚染物質を添加するリスクを冒すことなく、精製プロセスに容易に含めることができる当該分野で公知の材料である。
上記および下記に引用された全ての出願、特許および刊行物、特に2014年11月6日に出願された対応する欧州特許出願EP 14003737.5の全開示は、参照により本明細書に組み込まれる。
活性炭材料を用いた浸出物および/または抽出物の静的結合
以下の実験のために、商業的に入手可能の材料(例えば、活性炭100772, Bluecher GmbH, Erkrath, Germany (“BL772”);活性炭100562, Bluecher GmbH, Erkrath, Germany (“BL562”);Adsorba(R) 150C hemoperfusion cartridge, Gambro Dialysatoren GmbH, Hechingen, Germanyからの活性炭(“Gambro”); LiChrolut(R) EN(40-120μm) , Merck KGaA, Darmstadt, Germany (“Lichrolut”); Polyspher PST 10, Merck KGaA, Darmstadt, Germany (“DVB particles”))を真空オーブンで40℃、24時間乾燥し、その後、乾燥した材料1グラムをガラスフラスコに秤量した。その後、0.1g/Lに溶解した試験分子と水15mlをガラスフラスコへ入れた。ガラスフラスコは、その後15分間シェーカーにかけた。振とうした後、ガラスフラスコを4000回転/分で15分間遠心分離した。溶液を濾過し、ヘッドスペースGC−MSにかけた。数値は3回測定の平均値である(図1−2)。
達成された結果は、“BL 772”がモデル溶液から酢酸エチルを吸着するために首尾よく使用され得ることを確認する。
以下の例では、1回使用のアセンブリを純水でテストした:
10L溶液バッグのMobius(R)使い捨てアセンブリ(ガンマ線照射(最小25〜40kGy;MS0010L30EP、EMD Millipore Corporation, Billerica, MA, USA)は、Lynx STコネクタ(STC21THN01、EMD Millipore Corporation, Billerica, MA, USA)とチュービング(Pharma 50, 7486040801PU-6, EMD Millipore Corporation, Billerica, MA, USA)へ接続され、10L溶液バッグの雌ルアー(5621000821、EMD Millipore Corporation, Billerica, MA, USA)をMobius(R)ディスポーザブルアセンブリ(ガンマ線照射(最小 25−40kGy;,Billerica, MA, USA))へ接続した;
このアセンブリをMobius(R)ウイルスクリアランスユニット(EMD Millipore Corporation, Billerica, MA, USA)に設置し、10Lの純水をユニットの蠕動ポンプを用いて毎時1.5Lの流速で流した。処理した水を、室温でMobius(R)使い捨てアセンブリ10L溶液バッグに集めた。
活性炭を充填したガラスカラムを通した1回使用のアセンブリ処理水の濾過は、抽出物/浸出物レベル(FIA−MS−ESI+法による)を<ppmの範囲に減少させ、非常に鋭いブレークスルー・プロファイルを示した。
Millistak+(R)CR40フィルタによる1回使用のアセンブリ処理水の濾過は、MilliQの水質に対応して抽出物/浸出物レベル(FIA−MS−APCI−、APCI+法による)を減少させた。
したがって、1回使用アセンブリ使用後の抽出物/浸出物除去のためのMillistak+(R)CR40装置の使用は、ほぼ完全な抽出物/浸出物除去をもたらす。
以下の例では、1回使用のアセンブリを純水でテストした。20L溶液バッグのMobius(R)使い捨てアセンブリ(ガンマ線照射(最小25〜40kGy;TF20020LGE1、EMD Millipore Corporation, Billerica, MA, USA))は、チュービング (Pharma 50, 7486040801PU-6, EMD Millipore Corporation, Billerica, MA, USA)へのLynx STコネクタ(STC21THN01、EMD Millipore Corporation, Billerica, MA, USA)と接続され、20L溶液バッグのMobius(R)使い捨てアセンブリ(ガンマ線照射(最小25〜40kGy; TF20020LGE1、EMD Millipore Corporation, Billerica, MA, USA))へ雌ルアー(5621000821、EMD Millipore Corporation, Billerica, MA, USA)と接続したSHC膜を有する光学XL600フィルタ(EMD Millipore Corporation, Billerica, MA, USA)を備えたクロマトグラフィ用Smart Flexware(R) Assembly(EMD Millipore Corporation, Billerica, MA, USA)が続く;
活性炭を充填したガラスカラムを通した1回使用のアセンブリ処理水の濾過は、抽出物/浸出物レベル(FIA−MS−ESI+法による)を<ppm範囲に減少させ、ブレークスルー・プロファイルを示さなかった。
したがって、1回使用アセンブリ使用後の抽出物/浸出物除去のためのMillistak+ (R)CR40装置の使用は、ほぼ完全な抽出物/浸出物の除去をもたらす。
Claims (13)
- 標的分子が、標的分子を含む液体を活性炭と接触させることによって、生産および/または精製プロセスで使用される器材からもたらされる浸出物および/または抽出物から分離される、前記標的分子の精製方法であって、標的分子が分子量10000以上のタンパク質であり、活性炭が有機ポリマー材料の熱分解によって得られる活性炭である、前記方法。
- 有機ポリマー材料が、ポリスチレン、ポリアミド、ポリカーボナート、ポリメチルペンテン、ポリエチレン、ポリエステル、ポリビニルまたはポリプロピレンであることを特徴とする、請求項1に記載の方法。
- 標的分子が糖タンパク質であることを特徴とする、請求項1または2に記載の方法。
- 標的分子が抗体であることを特徴とする、請求項1〜3のいずれか一項に記載の方法。
- 浸出物および/または抽出物が、以下の成分:
アセトアルデヒド、トルエン、2−ヘキサノン、アセトン、2−ブタノン、酢酸エチル、ビスフェノールA、ベンジルアルコール、トリメチルシラノール、ホルムアルデヒド、フタル酸ビス(2−エチルヘキシル)、酢酸1−メチルエチルエステル、2,4−ジ−t−ブチルフェノール、2−オクタノン、2−ペンタノン、3,3−ジメチル−2−ブタノン、3−エトキシ−プロパン、3−ヘキサノン、3−メトキシ−1−ブタノール、ブタナール、シクロヘキサノン、エタノール、ギ酸、ヘプタエチレングリコール、ヘキサナール、メチルイソブチルケトン、ペンタナール、t−ブタノール、テトラヒドロフラン、ギ酸メチル、
のいずれか1つ以上であることを特徴とする、請求項1〜4のいずれか一項に記載の方法。 - 標的分子の活性炭との接触が、pH3〜9で行われることを特徴とする、請求項1〜5のいずれか一項に記載の方法。
- 器材が使い捨て器材であることを特徴とする、請求項1〜6のいずれか一項に記載の方法。
- 活性炭が5〜40μmの平均粒子径を有することを特徴とする、請求項1〜7のいずれか一項に記載の方法。
- 標的分子が活性炭を含む1以上のフィルタを通す濾過によって浸出物および/または抽出物から分離されることを特徴とする、請求項1〜8のいずれか一項に記載の方法。
- 以下のステップ:
− バイオ反応器中の細胞培養
− 清澄化
− クロマトグラフィ精製
− 濾過
の1以上を含む製造および/または精製方法に使用されることを特徴とする、請求項1〜9のいずれか一項に記載の方法。 - 使い捨て機器が25℃を超える温度および/または使い捨て機器の機械的変形と組み合わせて使用されるプロセスステップ、ならびに/あるいは使い捨て機器内の標的分子の滞留時間が1時間を超えるプロセスステップの後で、標的分子が、活性炭と接触されることを特徴とする、請求項1〜10のいずれか一項に記載の方法。
- 分子量10000以上のタンパク質である標的分子を含む液体から、生産および/または精製プロセスで使用される器材からもたらされる浸出物および/または抽出物を除去するための、有機ポリマー材料の熱分解によって得られる活性炭の使用。
- 液体が濾過装置の活性炭と接触されることを特徴とする、請求項12に記載の使用。
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2015
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US10793592B2 (en) | 2020-10-06 |
US20170313741A1 (en) | 2017-11-02 |
CA2966764A1 (en) | 2016-05-12 |
CN107635657A (zh) | 2018-01-26 |
KR102398719B1 (ko) | 2022-05-16 |
CN107635657B (zh) | 2021-02-12 |
JP2018500288A (ja) | 2018-01-11 |
KR20170084155A (ko) | 2017-07-19 |
EP3215246A1 (en) | 2017-09-13 |
CA2966764C (en) | 2022-10-18 |
SG11201703672QA (en) | 2017-06-29 |
WO2016070957A1 (en) | 2016-05-12 |
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