PPQ(プロセス製造適格性評価)の複雑さを乗り越える

April 18, 2021 by Elena Gontarz, PhD 5 分で読めます

カテゴリー | バイオ医薬品


プロセス性能適格性評価(PPQ)を実施する前に分析法の適格性を評価することは極めて重要です。分析法の性能特性に関する初期評価は、適切な分析法バリデーション、そして精度、真度、線形性などのバリデーションパラメータを確保するために欠かせません。最も重要な点は、このように分析法を検討することにより、製剤の品質と安全性だけでなく、規制当局が期待する品質への適合性を示すことができることです。これは上市実現の鍵となる要素です。

例えば、次の状況について考えてみましょう。ある企業が第III相段階で上市準備を進めていたときに、プロセスに問題が見つかりました。詳しい調査を実施し、分析法バリデーションを開始したところ、開発過程で分析法をしっかりと理解できていなかったことが判明しました。さらに、バリデーションの実施戦略とロジスティクスが非常に複雑であったため、バリデーションでの分析作業はもはや通常の分析作業ではなくなっていました。1回の測定に12時間を要する分析作業において、室内再現精度評価での測定値を用いた線形性の評価では、品質管理(QC)ラボでは認められなかった変動が複数認められました。根本原因分析の結果、当初の試験が非常に詳細で、時間がかかりすぎており、実施方法も一貫性を欠いていたため、バリデーション基準不適合が発生した可能性が考えられました。線形性/精度評価のための分析作業がQCラボでの分析作業を反映していなかったのです。 

このような問題が起こることは少なくなく、バイオ医薬品開発の最終段階で修正作業が必要となることもあります。しかし、これらは頑健な分析法バリデーションにより容易に低減可能なリスクです。


Elena Gontarz, PhD, Manager, Scientific and Technical Affairs

Elenaは分析法開発の領域エキスパートとして、製薬企業各社の分析法の開発、移管、適格性評価、バリデーションを支援しています。ミズーリ大学セントルイス校で生化学の博士号を取得した後、サーモフィッシャーサイエンティフィックの一員であるパセオンのAnalytical Development and Formulation Sciences Groupに加わり、第I相用治験薬製造から商用生産をカバーする分析法の開発に関する知識・技術力を磨きました。

また、製品の同等性/同質性試験や第III相強制分解試験の専門知識も備えており、Senior Analytical Development Scientistとして、技術チームとお客様を結ぶ窓口を務めていました。現在は、Manager of Scientific and Technical Affairsとしてお客様、そしてサーモフィッシャーサイエンティフィックのBusiness Development Groupを支援するとともに、サーモフィッシャーサイエンティフィック内のさまざまな技術開発プロジェクトを指揮しています。

 

Elenaがサーモフィッシャーにおいて商用生産プロセスのための分析サポート・分析法移管をどのように支援しているのか、また、医薬品受託製造開発機関(CDMO)はお客様とどのようなコミュニケーションを確保しているのかについてご紹介します。

Validation is important because the US Food and Drug Administration (FDA) and International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) requires it. During PPQ runs, you are varying certain parameters in the process, as well as trying to verify and validate a process can handle those variations. You’re already varying process parameters and therefore, you don’t want to vary other aspects of your experiment—i.e., your methods.

If your methods are validated, you’ll have confidence that the results are produced with a high level of accuracy and precision—you’ll know your optimal method operation range. It confirms what the center point is—where a method performs with the most precision and accuracy—because you will want to operate around that center point all the time. This ensures every single result you’re getting out of your process validation is sound—PPQ runs will be comparable to each other and they are analyzed by the same exact method.

Think about your critical product quality methods—i.e., purity, impurity, and potency methods. For example, when it comes to the FDA, most feedback we [Thermo Fisher] receive pertains to purity and potency methods which includes the aggregates, fragments, and the state of your molecule like oxidation, deamidation, and glycosylation. Cell-based assays must also be developed, preferably by the Phase III clinical study GMP batch releases, to ensure the potency of the biological molecule is monitored in an invivo setting.

Additionally, impurity always comes up for the regulatory agency because of the safety of the residual host cell proteins (HCPs) and the methods by which they are measured is important. For example, there is a set of high-risk HCPs that can have an adverse reaction with the human body. You’ll want to make sure you’re eliminating these throughout the purification process and the right method can identify them in the drug substance if they are still present. Finally, it’s important to remember that before Phase III, it is strongly recommended to have a residual HCP method that is process specific. While expanding methods to be process specific can be an incremental investment, it is critical to ensuring the success of your biology.

Think about your critical product quality methods—i.e., purity, impurity, and potency methods. For example, when it comes to the FDA, most feedback we [Thermo Fisher] receive pertains to purity and potency methods which includes the aggregates, fragments, and the state of your molecule like oxidation, deamidation, and glycosylation. Cell-based assays must also be developed, preferably by the Phase III clinical study GMP batch releases, to ensure the potency of the biological molecule is monitored in an invivo setting.

Additionally, impurity always comes up for the regulatory agency because of the safety of the residual host cell proteins (HCPs) and the methods by which they are measured is important. For example, there is a set of high-risk HCPs that can have an adverse reaction with the human body. You’ll want to make sure you’re eliminating these throughout the purification process and the right method can identify them in the drug substance if they are still present. Finally, it’s important to remember that before Phase III, it is strongly recommended to have a residual HCP method that is process specific. While expanding methods to be process specific can be an incremental investment, it is critical to ensuring the success of your biology.

The cell line and type of molecule in production are higher impact factors than size of project when considering an analytical method and its requirements. In general, biologics are extremely complicated, however, some are more complicated than others. For example, bispecific antibodies are relatively complex compared to conventional, monoclonal antibodies. This creates different methods and steps you must consider, especially when it comes to product quality. In short, if a more sophisticated and customized method is needed to assure the product quality, the closer it will need to be monitored.

First, ask a CDMO about their experience. How many method transfers have they done? What is the size, scale, and complexity of those transfers? You’ll want to validate their experience of transferring methods to ensure proper knowledge transfer is recorded in the method’s standard operating procedure. That’s what leads to successful method transfers—for the most part.

Also, be sure to inquire if they have their own platforms for method development. If a CDMO has developed their own methods and platforms, their analysts will more effectively be able to assess why a method is not performing. One of the major reasons a CDMO can be a strong partner is their ability to is to seamlessly and successfully conduct a method transfer and communicate why certain methods work better than others.

より良い分析法バリデーション戦略による製剤の品質と安全性の確保について解説したホワイトペーパーをご用意しました。是非ダウンロードしてご覧ください