Interpretations of the FDA's CGMP rules can often be read from Warning Letters as well as guidelines. A current Warning Letter describes the FDA's expectations of the Quality Control Unit for validations, among other things.
我們經(jīng)?？梢詮木嫘藕椭改现凶x到對FDA的CGMP法規(guī)的解釋?，F(xiàn)有一份警告信中描述了FDA對質(zhì)量部門關(guān)于驗證的期望。
With reference to 21 CFR 211.22, the FDA criticises in the Warning Letter that the quality control unit is not fulfilling its responsibility to ensure that drugs are manufactured in compliance with CGMP. The FDA understands that there must be written procedures on the tasks and responsibilities of the Quality Control Unit. These should show that the Quality Control Unit also has the "authority" to review and approve quality-related functions that have an impact on product quality.
關(guān)于21 CFR 211.22，F(xiàn)DA在警告信中批評質(zhì)量部門沒有履行其職責(zé)，確保藥品的生產(chǎn)符合CGMP。FDA解釋到，質(zhì)量部門的任務(wù)和責(zé)任必須有書面程序。這些應(yīng)該表明質(zhì)量部門也有“權(quán)力”來審查和批準(zhǔn)對產(chǎn)品質(zhì)量有影響的質(zhì)量相關(guān)職能。
And this includes process monitoring, which shows that the processes are stable and consistently deliver quality products. On this point, the FDA refers to 21 CFR 211.100 (a). In particular, the missing stage 3 in the FDA's process life cycle, "Continued Process Verification", is admonished here.
這包括過程監(jiān)控，以表明過程穩(wěn)定并始終如一地提供高質(zhì)量的產(chǎn)品。在這一點上，F(xiàn)DA引用了21 CFR 211.100（a）。特別是，這里提出了（該公司）缺乏FDA工藝生命周期中的第3階段“持續(xù)工藝確認”。
As a further (missing) responsibility of the Quality Control Unit, the FDA criticises in the Warning Letter, written, validated, reviewed and approved cleaning processes. These must be capable of removing residues from the surfaces that come into contact with the product in equipments that are used with several different products ("non-dedicated"). The FDA refers in this regard to 21 CFR 211.67 (b).
作為質(zhì)量部門的進一步（缺失）責(zé)任，F(xiàn)DA在警告信中批評了經(jīng)驗證，審查和批準(zhǔn)的書面清潔工藝。應(yīng)能夠去除多產(chǎn)品（“非專用”）共用設(shè)備中與產(chǎn)品接觸的表面上的殘留物。在這方面，F(xiàn)DA引用了21 CFR 211.67（b）。
With reference to the same paragraph, the FDA also criticises the lack of equipment maintenance procedures. These must also be established, reviewed and approved in writing in order to enable robust device operating conditions.
同時，F(xiàn)DA還批評了缺乏設(shè)備維護程序。應(yīng)以書面形式建立、審查和批準(zhǔn)，以實現(xiàn)穩(wěn)健的設(shè)備操作條件。
In detail, the FDA wants to see an overview of the validation programme and timelines for the process performance qualification (PPQ) runs of each individual product. Furthermore, the FDA expects a data-based and scientifically verifiable programme regarding process variability.
詳細地說，F(xiàn)DA希望看到每個產(chǎn)品的工藝性能確認（PPQ）運行的驗證計劃和時間表的概述。此外，F(xiàn)DA期望有一個關(guān)于工藝可變性的基于數(shù)據(jù)和科學(xué)可驗證的計劃。
Also urged is a cleaning validation programme with special emphasis on worst case conditions with regard to:
還敦促制定清潔驗證計劃，特別強調(diào)以下方面的最壞情況：
Drugs with higher toxicities
毒性最大的藥物
Drugs with higher active ingredient contents
含有較高活性成分的藥物
Drugs with low solubility in the cleaning reagent
在清洗劑中溶解度低的藥物
Drugs with characteristics that make them difficult to clean
具有難以清潔的特性的藥物
Swab sampling sites at locations that are most difficult to clean
在最難清潔的位置進行擦拭采樣
maximum holding times before cleaning
清潔前的最長保持時間
The FDA also requires an update of the change management system with regard to the introduction of new manufacturing equipment and new products.
FDA還要求在新生產(chǎn)設(shè)備和新產(chǎn)品的引入方面，更新變更管理系統(tǒng)。
警告信原文翻譯如下：
Your firm’s quality control unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22)
貴公司的質(zhì)量部門未能履行其職責(zé)以確保所生產(chǎn)的藥品符合CGMP，并符合特性，含量，質(zhì)量和純度的既定規(guī)范（21 CFR 211.22）
Your firm failed to establish an adequate Quality Unit (QU) to ensure that:
貴公司未能建立充分的質(zhì)量部門（QU）來確保：
Adequate procedures were established and written for roles and responsibilities of the QU to have the responsibility and authority to review and approve quality related functions that impact product quality (21 CFR 211.22(d)).
為QU的角色和職責(zé)建立并編寫了適當(dāng)?shù)某绦颍载撠?zé)和授權(quán)審查和批準(zhǔn)影響產(chǎn)品質(zhì)量的質(zhì)量相關(guān)功能（21 CFR 211.22（d））。
An ongoing written program for monitoring process control was established to ensure stable manufacturing operations and consistent drug quality (21 CFR 211.100(a)).
建立監(jiān)控工藝控制的持續(xù)書面程序，以確保穩(wěn)定的生產(chǎn)操作和一致的藥物質(zhì)量（21 CFR 211.100（a））。
Cleaning processes were written, validated, reviewed, and approved for cleaning nondedicated manufacturing equipment to ensure that residues are adequately removed from the product contact surfaces of manufacturing equipment during cleaning (21 CFR 211.67(b)).
已編寫、驗證、審查和批準(zhǔn)用于清潔非專用制造設(shè)備的清潔工藝，以確保在清潔過程中充分去除制造設(shè)備產(chǎn)品接觸表面上的殘留物（21 CFR 211.67（b））。
Equipment maintenance procedures were established, written, reviewed, and approved for your drug manufacturing equipment to ensure robust equipment operations (21 CFR 211.67(b)).
已建立、編寫、審查和批準(zhǔn)藥品制造設(shè)備的維護程序，以確保設(shè)備穩(wěn)健運行（21 CFR 211.67（b））。
Your response is inadequate. You intend to establish and implement procedures to comply with CGMPs. However, you did not provide detailed corrective action and preventive actions (CAPA) plan to systematically address the deficiency.
你們的回復(fù)是不充分的。你們打算建立和實施這些程序以符合CGMP。但是，你們沒有提供詳細的糾正措施和預(yù)防措施 （CAPA） 計劃來系統(tǒng)地解決缺陷。
Your firm’s quality systems are inadequate. See FDA’s guidance documentQuality Systems Approach to Pharmaceutical CGMP Regulations for help implementing quality systems and risk management approaches to meet the requirements of CGMP regulations 21 CFR, parts 210 and 211 at https://www.fda.gov/media/71023/download.
貴公司的質(zhì)量體系是不充分的。請參閱FDA的指導(dǎo)文件藥品CGMP法規(guī)的質(zhì)量體系方法，以幫助實施質(zhì)量體系和風(fēng)險管理方法，以滿足CGMP法規(guī)21 CFR，第210和211部分的要求，https://www.fda.gov/media/71023/download。
In response to this letter, provide the following:
回復(fù)此函，請?zhí)峁?/span>
A comprehensive assessment and remediation plan to ensure your QU is given the authority and resources to effectively function. The assessment should also include, but not be limited to:
全面的評估和補救計劃，以確保你們的QU獲得有效運作的權(quán)力和資源。評估還應(yīng)包括但不限于：
A determination of whether procedures used by your firm are robust and appropriate
確定貴公司使用的程序是否穩(wěn)健和適當(dāng)
Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices
規(guī)定在整個操作過程中進行QU監(jiān)督，以評估對適當(dāng)做法的遵守情況
A complete and final review of each batch and its related information before the QU disposition decision
在作出QU處置決定之前，對每批產(chǎn)品及其相關(guān)信息進行全面和最終審查
Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products
監(jiān)督和批準(zhǔn)調(diào)查并履行所有其他QU職責(zé)，以確保所有產(chǎn)品的特性，含量，質(zhì)量和純度
A detailed summary of your validation program for ensuring a state of control throughout the product lifecycle, along with associated procedures. Describe your program for process performance qualification, and ongoing monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control.
驗證程序的詳細摘要，以確保整個產(chǎn)品生命周期中的控制狀態(tài)以及相關(guān)程序。描述你們的工藝性能確認計劃，以及對批次內(nèi)和批次間變異的持續(xù)監(jiān)控，以確保持續(xù)的控制狀態(tài)。
A timeline for performing appropriate process performance qualification (PPQ) for each of your marketed drug products.
為你們的每種已上市藥品執(zhí)行適當(dāng)?shù)墓に囆阅艽_認 （PPQ） 的時間表。
An assessment of each drug product process to ensure that there is a data-driven and scientifically sound program that identifies and controls all sources of variability, such that your production processes will consistently meet appropriate specifications and manufacturing standards. This includes, but is not limited to, evaluating suitability of equipment for its intended use, sufficiency of detectability in your monitoring and testing systems, quality of input materials, and reliability of each manufacturing process step and control.
對每個藥品工藝進行評估，以確保有一個數(shù)據(jù)驅(qū)動且科學(xué)合理的程序來識別和控制所有可變性來源，以使你們的生產(chǎn)工藝始終符合適當(dāng)?shù)臉?biāo)準(zhǔn)和生產(chǎn)標(biāo)準(zhǔn)。這包括但不限于評估設(shè)備對其預(yù)期用途的適用性、監(jiān)控和測試系統(tǒng)中可檢測性的充分性、輸入物料的質(zhì)量以及每個生產(chǎn)工藝步驟和控制的可靠性。
See FDA’s guidance document Process Validation: General Principles and Practices for general principles and approaches that FDA considers appropriate elements of process validation athttps://www.fda.gov/regulatory-information/search-fda-guidancedocuments/process-validation-general-principles-and-practices.
請參閱FDA的指導(dǎo)文件《工藝驗證：一般原則和實踐》，了解FDA在 https://www.fda.gov/regulatory-information/search-fda-guidancedocuments/process-validation-general-principles-and-practices 中認為工藝驗證的適當(dāng)要素的一般原則和方法。
Appropriate improvements to your cleaning validation program, with special emphasis on incorporating conditions identified as worst case in your drug manufacturing operation. This should include but not be limited to identification and evaluation of all worst-case:
適當(dāng)改進你們的清潔驗證計劃，特別強調(diào)在你們的藥物生產(chǎn)操作中納入被確定為最壞情況的條件。這應(yīng)包括但不限于識別和評估所有最壞情況：
drugs with higher toxicities
毒性較高的藥物
drugs with higher drug potencies
含有較高活性成分的藥物
drugs of lower solubility in their cleaning solvents
在清潔劑中溶解度較低的藥物
drugs with characteristics that make them difficult to clean
具有難以清潔的特性的藥物
swabbing locations for areas that are most difficult to clean
擦拭最難清潔區(qū)域的位置
maximum hold times before cleaning
清潔前的最長保持時間
In addition, describe the steps that must be taken in your change management system before introduction of new manufacturing equipment or a new product.
此外，請描述在引入新制造設(shè)備或新產(chǎn)品之前必須在變更管理系統(tǒng)中采取的步驟。
A summary of updated SOPs that ensure an appropriate program is in place for verification and validation of cleaning procedures for products, processes, and equipment.
更新的SOP摘要，確保有適當(dāng)?shù)某绦騺眚炞C和確認產(chǎn)品，工藝和設(shè)備的清潔程序。
Your CAPA plan to implement routine, vigilant operations management oversight of facilities and equipment. This plan should ensure, among other things, prompt detection of equipment/facilities performance issues, effective execution of repairs, adherence to appropriate preventive maintenance schedules, timely technological upgrades to the equipment/facility infrastructure, and improved systems for ongoing management review.
你們的 CAPA 計劃對設(shè)施和設(shè)備實施常規(guī)、警惕的運營管理監(jiān)督。除其他事項外，該計劃應(yīng)確保迅速發(fā)現(xiàn)設(shè)備/設(shè)施性能問題，有效執(zhí)行維修，遵守適當(dāng)?shù)念A(yù)防性維護計劃，及時對設(shè)備/設(shè)施基礎(chǔ)設(shè)施進行技術(shù)升級，并改進不斷進行管理審查的制度。
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