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近日，F(xiàn)DA發(fā)布了《21 CFR 211.110 的合規(guī)性考慮 草案》（21CFR 211：即藥品CGMP條款，21 CFR 211.110款內(nèi)容為中間產(chǎn)品及藥品的取樣），其中描述了FDA當(dāng)前對(duì)符合 CGMP法規(guī)中中間產(chǎn)品及藥品取樣要求的考慮，以確保批次一致性和藥品完整性。此外，該指南還討論了使用先進(jìn)制造技術(shù)制造的藥品的相關(guān)質(zhì)量考慮。還討論了制造商如何將過(guò)程模型整合到商業(yè)制造控制策略中。

 

 

I.  INTRODUCTION

介紹

 

This guidance, when finalized, will describe considerations for complying with the requirements in 21 CFR 211.110 to ensure batch uniformity and drug product integrity. In addition, this guidance discusses related quality considerations for drug products that are manufactured using advanced manufacturing. It also discusses how manufacturers can incorporate process models into commercial manufacturing control strategies.2,3

 

本指南最終確定后，將描述遵守 21 CFR 211.110 中要求的注意事項(xiàng)，以確保批次一致性和藥品完整性。此外，本指南還討論了使用先進(jìn)制造技術(shù)制造的藥品的相關(guān)質(zhì)量考慮。還討論了制造商如何將過(guò)程模型整合到商業(yè)制造控制策略中2,3。

 

This guidance appliesto the manufacture of human drug products,including biological products, and animal drug products;these will be collectively referredto as drug products in this guidance. This guidance does not apply to the manufacture of active ingredients.

 

本指南適用于人用藥品（包括生物制品）和動(dòng)物藥品的制造;在本指南中，這些商品統(tǒng)稱為藥品。本指南不適用于活性成分的制造。

 

In general, FDA’s guidance documents do not establish legally enforceable responsibilities. Instead, guidances describethe Agency’s currentthinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.

 

一般來(lái)說(shuō)，F(xiàn)DA 的指導(dǎo)文件沒有規(guī)定法律上可執(zhí)行的責(zé)任。相反，指南描述了FDA當(dāng)前對(duì)某個(gè)主題的看法，除非引用了特定的監(jiān)管或法定要求，否則應(yīng)僅將其視為建議。在機(jī)構(gòu)指南中使用 should 一詞表示建議或推薦某事，但不是必需的。

 

II. BACKGROUND

背景

 

To ensure batch uniformity and drug product integrity, the current good manufacturing practice (CGMP) regulations4 require, among other things, that manufacturing processes are designed and controlled to ensure that in-process materials consistently and reliably meet predetermined quality requirements.5This guidance explains the requirements for drug product manufacturing in § 211.110. This guidance also describes considerations for the use of advanced manufacturing (e.g., 3D printing, continuous manufacturing)6and the use of process models as a part of commercial manufacturing control strategies. FDA supports the adoption of advanced manufacturing as a foundation for improving the overall qualityand availability of drug products for patients.

 

為確保批次一致性和藥品完整性，現(xiàn)行藥品生產(chǎn)質(zhì)量管理規(guī)范 （CGMP） 法規(guī)要求設(shè)計(jì)和控制制造過(guò)程，以確保中間產(chǎn)品始終如一地可靠地滿足預(yù)定的質(zhì)量要求。本指南解釋了 § 211.110 中的藥品生產(chǎn)要求。本指南還描述了使用先進(jìn)制造（例如 3D 打印、連續(xù)制造）6 的注意事項(xiàng)，以及將工藝模型用作商業(yè)制造控制策略的一部分。FDA 支持采用先進(jìn)制造作為提高患者藥品整體質(zhì)量和可用性的基礎(chǔ)。

 

Advanced manufacturing is a term for an innovative pharmaceutical manufacturing technology or approach that has the potential to improve the reliability and robustness of the manufacturing process and supply chain and increase timely access to quality medicines for the American public. Advanced manufacturing can integrate novel technological approaches, use established techniques in an innovative way, or apply production methodsin a new domain wherethere may be limited experience or no defined best practices. Advanced manufacturing can potentially be used for new or currently marketed large or small molecule drugs.7

 

先進(jìn)制造是指一種創(chuàng)新的制藥技術(shù)或方法，該技術(shù)或方法有可能提高制造過(guò)程和供應(yīng)鏈的可靠性和穩(wěn)健性，并增加公眾及時(shí)獲得優(yōu)質(zhì)藥物的機(jī)會(huì)。先進(jìn)制造可以整合新的技術(shù)方法，以創(chuàng)新的方式使用現(xiàn)有技術(shù)，或?qū)⑸a(chǎn)方法應(yīng)用于經(jīng)驗(yàn)可能有限或沒有明確最佳實(shí)踐的新領(lǐng)域。先進(jìn)制造技術(shù)可能用于新的或目前上市的大分子或小分子藥物。

 

All manufacturers, regardless of whetherthey are using advanced manufacturing, should apply a scientific- and risk-based approach to controlling processes and ensuring drug product quality.

 

所有制造商，無(wú)論是否使用先進(jìn)制造，都應(yīng)采用基于科學(xué)和風(fēng)險(xiǎn)的方法來(lái)控制工藝并確保藥品質(zhì)量。

 

This approach should be based on robust product and process understanding. Manufacturers must maintainthe process in a state of controlover the life of the process to ensure drug product quality, even as materials, equipment, production environment, personnel, and manufacturing procedures change.8Planning and executing a system that monitors process performance and drug product quality helps ensure that a state of control is maintained. An effective monitoring system helps maintain a state of control in multiple ways, which include helping manufacturers:

 

這種方法應(yīng)基于對(duì)產(chǎn)品和工藝的深刻理解。制造商必須在工藝的整個(gè)生命周期內(nèi)保持工藝處于受控狀態(tài)，以確保藥品質(zhì)量，即使物料、設(shè)備、生產(chǎn)環(huán)境、人員和制造程序發(fā)生變更。規(guī)劃和執(zhí)行監(jiān)控工藝性能和藥品質(zhì)量的系統(tǒng)有助于確保保持控制狀態(tài)。有效的監(jiān)控系統(tǒng)以多種方式幫助保持控制狀態(tài)，其中包括幫助制造商：

 

(1) ensure that processes and controls are continuously capable of producing a drug product of desired quality; and (2) identify areas for continual improvement.9 In addition, § 211.110(a) requires that manufacturers establish and follow writtenprocedures “that describethe in-process controls, and tests, or examinations to be conducted on appropriate samples of in-process materials of each batch.” Section 211.110(c) also requires that in-process materials are “tested for identity, strength, quality, and purity as appropriate, and approved or rejected by the quality control unit,during the production process, e.g., at commencement or completion of significant phases or after storage for long periods.”

 

確保工藝和控制能夠持續(xù)生產(chǎn)出所需質(zhì)量的藥品;以及 （2） 確定需要持續(xù)改進(jìn)的領(lǐng)域。此外，§ 211.110（a） 要求制造商建立并遵循書面程序，“描述對(duì)每批中間產(chǎn)品的適當(dāng)樣品進(jìn)行的過(guò)程控制、測(cè)試或檢查”。第 211.110（c） 節(jié)還要求中間產(chǎn)品“在生產(chǎn)過(guò)程中（例如，在重要階段開始或完成或長(zhǎng)期儲(chǔ)存后）經(jīng)過(guò)適當(dāng)?shù)奶匦?、?qiáng)度、質(zhì)量和純度測(cè)試，并由質(zhì)量控制單位批準(zhǔn)或拒絕。

 

III.  GENERAL CONSIDERATIONS FOR IN-PROCESS SAMPLING AND TESTING

過(guò)程中（中控）取樣和檢測(cè)的一般考慮

 

Under section501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act, a drug is deemedto be adulterated if it is not produced in accordance with CGMP. The CGMP regulations for drug products are in 21 CFR parts 210 and 211, and FDA monitors drug product manufacturers' compliance with these regulations.10The CGMP regulations contain minimum requirements for the methods, facilities, and controls used in manufacturing, processing, packing, and holding of drug products. The CGMP regulations also provide flexibility for manufacturers to use better, more efficient methods to meet CGMP requirements because these innovative methods benefit patients.11The determination of whether in-process controls, and tests, or examinations meet the regulatory requirements in § 211.110 primarily depends on the nature of the drug product (e.g., dosage form) and the type of process used by the manufacturer. Knowledge and understanding that manufacturers gain from robust product and process development are an important basis for establishing and maintaining control strategies throughout the lifecycle of a drug product. This helps ensure that drug products have the required quality attributes.12

 

根據(jù)FDC法第 501（a）（2）（B） 條，如果藥品未按照 CGMP 生產(chǎn)，則視為摻假。藥品的 CGMP 法規(guī)載于 21 CFR 第 210 和 211 部分，F(xiàn)DA 負(fù)責(zé)監(jiān)督藥品制造商對(duì)這些法規(guī)的遵守情況。CGMP 法規(guī)包含對(duì)藥品制造、加工、包裝和儲(chǔ)存中使用的方法、設(shè)施和控制措施的最低要求。CGMP 法規(guī)還為制造商提供了靈活性，讓他們可以使用更好、更有效的方法來(lái)滿足 CGMP 要求，因?yàn)檫@些創(chuàng)新方法使患者受益。確定過(guò)程控制、測(cè)試或檢查是否符合 § 211.110 中的法規(guī)要求，主要取決于藥品的性質(zhì)（例如，劑型）和制造商使用的工藝類型。制造商從穩(wěn)健的產(chǎn)品和工藝開發(fā)中獲得的知識(shí)和理解是建立和維護(hù)藥品整個(gè)生命周期控制策略的重要基礎(chǔ)。這有助于確保藥品具有所需的質(zhì)量屬性。

 

To ensure conformance to drug productquality requirements, the manufacturer should identify which critical quality attributes13and in-process material attributes to monitor and control.

 

為確保符合藥品質(zhì)量要求，制造商應(yīng)確定需要監(jiān)測(cè)和控制的關(guān)鍵質(zhì)量屬性和中間產(chǎn)品的屬性。

 

Section 211.110allows flexibility in the in-process controls, and testing,or examinations that are employed to ensure that processes deliver in-process materials and drug products with the appropriate quality attributes. To ensure that drug products have the properties that they are represented to possess, the in-process materials used throughout the manufacturing process should be of consistent quality.

 

211.110 允許在過(guò)程控制和測(cè)試或檢查方面具有靈活性，以確保工藝交付具有適當(dāng)質(zhì)量屬性的中間產(chǎn)品和藥品。為確保藥品具有其所具有的特性，在整個(gè)制造過(guò)程中使用的加工物料應(yīng)具有一致的質(zhì)量。

 

In addition to identifying which critical quality attributes and in-process material attributes to monitor, the manufacturer should define and justify where and when the proposed in-process controls, and testing, or examinations that are used to monitor those attributes should occur. The definition and justification should be based on the manufacturer’s understanding of the product and the process. Under§ 211.110(c), “[i]n-process materials shall be tested for identity, strength, quality, and purity as appropriate, and approved or rejected by the qualitycontrol unit, duringthe production process, e.g., at commencement or completion of significant phases or after storage for long periods.” As noted in the preamble of the final rule, “Current Good Manufacturing Practice in Manufacture, Processing, Packing, or Holding,” FDA declined to define the term significant phase.14Instead, FDA stated that “significant phases in the processing of drug products can vary greatly depending on the methods used and nature of the individual products.”15 Therefore, the regulations generally allow flexibility in the determination of significant phases depending on the manufacturing process and the drug product. Manufacturers should define the significant phases in their manufacturing processes; however, FDA evaluates the adequacy of these determinations and the supporting scientific rationale during application assessment and on inspection. The manufacturer shoulduse a scientific- and risk-based approach to determine what constitutes a significant phase and to justify when and where the appropriate tests or examinations should occur relative to a significant phase. It is important to choose the appropriate in-process controls, and tests, or examinations to ensure the quality of in-process materials as well as the performance of the manufacturing process. Process monitoring and control decisions that result in minor equipment and process adjustments do not typically need additional quality unit16 approval if all of the following conditions are met: (1) the adjustments are within the preestablished and scientifically justified limits; (2) these limits have been approved by the qualityunit in the master production and control recordand the controlstrategy; and (3) the production data is reviewed by the quality unit before approval or rejection of a batch.17,18

 

除了確定需要監(jiān)控的關(guān)鍵質(zhì)量屬性和中間產(chǎn)品的屬性外，制造商還應(yīng)定義并論證所建議的工藝控制以及用于監(jiān)控這些屬性的測(cè)試或檢查的位置和時(shí)間。定義和論證應(yīng)基于制造商對(duì)產(chǎn)品和工藝的理解。根據(jù) § 211.110（c），“在生產(chǎn)過(guò)程中，例如，在重要階段開始或完成或長(zhǎng)期儲(chǔ)存后，應(yīng)酌情對(duì)中間產(chǎn)品進(jìn)行特性、強(qiáng)度、質(zhì)量和純度測(cè)試，并由質(zhì)量控制單位批準(zhǔn)或拒絕。正如最終規(guī)則“當(dāng)前制造、加工、包裝或保存的良好生產(chǎn)規(guī)范”的序言中所述，F(xiàn)DA 拒絕定義“重要階段”一詞。相反，F(xiàn)DA 表示，“藥品加工的重要階段可能會(huì)因所使用的方法和各個(gè)產(chǎn)品的性質(zhì)而有很大差異。因此，法規(guī)通常允許根據(jù)制造工藝和藥品靈活地確定重要階段。制造商應(yīng)定義其制造過(guò)程中的重要階段;但是，F(xiàn)DA 會(huì)在申請(qǐng)?jiān)u估和檢查期間評(píng)估這些決定的充分性以及支持科學(xué)依據(jù)。制造商應(yīng)使用基于科學(xué)和風(fēng)險(xiǎn)的方法來(lái)確定什么是重要階段，并證明相對(duì)于重要階段應(yīng)在何時(shí)何地進(jìn)行適當(dāng)?shù)臏y(cè)試或檢查的合理性。選擇適當(dāng)?shù)墓に嚳刂?、測(cè)試或檢查以確保中間產(chǎn)品的質(zhì)量和制造過(guò)程的性能非常重要。如果滿足以下所有條件，則因設(shè)備和工藝的微小調(diào)整而導(dǎo)致的工藝監(jiān)測(cè)和控制決策通常不需要額外的質(zhì)量部門批準(zhǔn)：（1） 調(diào)整在預(yù)先設(shè)定且經(jīng)論證的范圍內(nèi);（2） 這些限值已在主生產(chǎn)和控制記錄和控制策略中得到質(zhì)量單位的批準(zhǔn);（3） 質(zhì)量部門在批準(zhǔn)或拒絕批次之前審查生產(chǎn)數(shù)據(jù)。

 

In-process testing strategies should be dictated by the nature of the drug and the manufacturing processes. Manufacturers should ensure that innovative strategies that streamline in-process testing provide sufficient assurance of product quality. The manufacturer should employ a scientifically sound and appropriate sampling and testing strategy for quality attributes at appropriate points19 in the process that are adequate to ensure drug product quality. The manufacturershould employ time-based sampling plans for quality attributes, where appropriate (e.g., time-based measurement of the change in dryer outlet temperature during powder drying processes, which can be used as a surrogate measurement for moisture content).

 

過(guò)程中（中控）的檢測(cè)策略應(yīng)由藥物的性質(zhì)和制造過(guò)程決定。制造商應(yīng)確保簡(jiǎn)化過(guò)程測(cè)試的創(chuàng)新策略為產(chǎn)品質(zhì)量提供足夠的保證。制造商應(yīng)在流程中的適當(dāng)點(diǎn)采用科學(xué)合理且適當(dāng)?shù)馁|(zhì)量屬性抽樣和測(cè)試策略，以確保藥品質(zhì)量。制造商應(yīng)在適當(dāng)?shù)那闆r下對(duì)質(zhì)量屬性采用基于時(shí)間的抽樣計(jì)劃（例如，在粉末干燥過(guò)程中對(duì)干燥機(jī)出口溫度的變化進(jìn)行基于時(shí)間的測(cè)量，這可以用作水分含量的替代測(cè)量）。

 

In addition to appropriate flexibility in where and when in-process sampling and testing should occur, the regulations provide flexibility in how in-process material and drug product testing is conducted. The preamble to the final rule states that a sampling plan “can mean both a plan for collection of physical units for testing, or it can mean a schedule by which an examination of some sort is done.”20 Although in-process controls, and tests, or examinations of in-process materialsare required,21 sampling does not necessarily require steps for physically removingin- process materials to test their characteristics. Innovative technologies allow in-line, at-line, or on-line measurements in place of physical sample removal for laboratory testing,22and these measurements can be used in conjunction with process models.

 

除了在何時(shí)何地進(jìn)行過(guò)程中（中控）取樣和檢測(cè)方面具有適當(dāng)?shù)撵`活性外，這些法規(guī)還在如何進(jìn)行中間產(chǎn)品和藥品檢測(cè)方面提供了靈活性。最終規(guī)則的序言指出，取樣計(jì)劃“既可以指收集物理單元進(jìn)行測(cè)試的計(jì)劃，也可以指進(jìn)行某種檢查的時(shí)間表。盡管需要對(duì)中間產(chǎn)品進(jìn)行工藝控制、測(cè)試或檢查，但取樣并不一定需要物理取出中間產(chǎn)品以測(cè)試其特性。創(chuàng)新技術(shù)允許在線測(cè)量代替物理取出樣品以進(jìn)行實(shí)驗(yàn)室測(cè)試，并且這些測(cè)量可以與工藝模型結(jié)合使用。