The quality control area is a particular focus of the inspectors during every FDA inspection. Here, violations of GMP regulations are found particularly frequently, as can be read in numerous warning letters.
質(zhì)量控制領(lǐng)域是FDA檢查員在每次檢查中特別關(guān)注的焦點(diǎn)。在這里，違反GMP法規(guī)的行為尤其頻繁，這可以從大量的警告信中看到。
This article describes the type and frequency of GMP deficiencies in the quality control laboratories of the inspected companies on the basis of a systematic review of the Warning Letters citations. The data scope of this analysis includes the published Warning Letters of the fiscal years 2017 to 2021 (Oct. 2016 to Sept. 2021), which were addressed to manufacturers of finished medicinal products and contract laboratories. The citations examined refer to the following sections of the Code of Federal Regulations (21 CFR):
本文在對(duì)FDA警告信進(jìn)行系統(tǒng)性統(tǒng)計(jì)的基礎(chǔ)上，介紹了被檢查企業(yè)QC實(shí)驗(yàn)室GMP缺陷的類型和頻率。本分析的數(shù)據(jù)范圍包括2016年10月至2021年9月已公布的警告信，這些警告信是發(fā)給制劑成品生產(chǎn)商和合同實(shí)驗(yàn)室的。警告信引用的法規(guī)參考21 CFR的以下章節(jié)：
Subpart I – Laboratory Controls
子部分I - 實(shí)驗(yàn)室控制
211.160 General requirements 通用要求
211.165 Testing and release for distribution 檢測(cè)和放行
211.166 Stability testing 穩(wěn)定性測(cè)試
Subpart J – Records and Reports
子部分J -記錄和報(bào)告
211.194 Laboratory records 實(shí)驗(yàn)室記錄
The analysis of the frequency of GMP deficiencies assigned to the respective CFR paragraphs, considered over the period of 5 fiscal years, is shown in the following chart.
在5年期間，對(duì)各個(gè)GMP缺陷頻率的分析展示在了下圖中。
According to this, the most frequent GMP deficiencies in the quality control area concern the tests prior to release of the product as well as stability tests; the latter were cited particularly frequently in the last fiscal year (2021).
QC領(lǐng)域最常見(jiàn)的GMP缺陷涉及產(chǎn)品放行前的檢測(cè)以及穩(wěn)定性測(cè)試，后者在2021財(cái)年被提及的頻率尤其高。
§211.160 General requirements 通用要求
Your firm failed to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity.
你們公司未能建立實(shí)驗(yàn)室控制，包括科學(xué)合理和適當(dāng)?shù)囊?guī)范、標(biāo)準(zhǔn)、取樣計(jì)劃和測(cè)試程序，以確保成分、藥品容器、瓶蓋、中間物料、標(biāo)簽和藥品符合適當(dāng)?shù)蔫b別、強(qiáng)度、質(zhì)量和純度標(biāo)準(zhǔn)。
Unsuitable or non-validated test methods without scientifically supported significance are used, especially for microbiological controls.
使用了不合適的或未經(jīng)驗(yàn)證的沒(méi)有科學(xué)意義支持的檢測(cè)方法，特別是微生物控制方法。
Test specifications for incoming and final inspections are not available. Sampling plans are missing or unsuitable.
沒(méi)有進(jìn)場(chǎng)物料檢驗(yàn)和最終檢查的檢測(cè)標(biāo)準(zhǔn)，取樣計(jì)劃缺失或不合適。
Testing is done against unsuitable specifications.
測(cè)試是針對(duì)不合適的標(biāo)準(zhǔn)進(jìn)行的。
Critical changes to electronic equipment in the QC laboratory are made in an uncontrolled manner. Uncontrolled manipulation of electronic data is possible.
QC實(shí)驗(yàn)室中電子設(shè)備的重大變更是在不受控制的情況下進(jìn)行的，有機(jī)會(huì)可以不受控制地操縱電子數(shù)據(jù)。
Appropriate routine monitoring is lacking for the water system.
對(duì)水系統(tǒng)缺乏適當(dāng)?shù)某Ｒ?guī)監(jiān)測(cè)。
§211.165 Testing and release for distribution 檢測(cè)和放行
Your firm does not have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release. o Finished products are released for sale without testing for compliance with specifications. This is the most common violation of GMP rules cited in the Warning Letters with reference to 211.165. In isolated cases, this deficiency also affects active substances that are released for further processing without appropriate compliance testing. Non-validated test methods are used.
你們公司在放行前沒(méi)有對(duì)每批藥品進(jìn)行適當(dāng)?shù)姆纤幤纷罱K標(biāo)準(zhǔn)的實(shí)驗(yàn)室檢測(cè)，包括每種活性成分的鑒別和強(qiáng)度。成品未經(jīng)過(guò)符合標(biāo)準(zhǔn)的檢測(cè)就放行銷售。這是警告信中引用的最常見(jiàn)的違反GMP規(guī)范的行為。在個(gè)別情況下，這種缺陷也會(huì)影響未經(jīng)適當(dāng)合規(guī)性檢測(cè)就被放行用于進(jìn)一步加工的活性物質(zhì)。使用未經(jīng)驗(yàn)證的測(cè)試方法。
§211.166 Stability Testing 穩(wěn)定性測(cè)試
Your firm failed to establish and follow an adequate written testing program designed to assess the stability characteristics of drug products, and to use results of such stability testing to determine appropriate storage conditions and expiration dates.
你們公司未能建立和遵循充分的書(shū)面檢測(cè)程序，以評(píng)估藥品的穩(wěn)定性特性，并使用該穩(wěn)定性測(cè)試的結(jié)果來(lái)確定適當(dāng)?shù)膬?chǔ)存條件和有效期。
The test methods used in the studies do not demonstrate stability.
研究中使用的測(cè)試方法沒(méi)有證明其穩(wěn)定性。
The stability studies do not include current container and closure systems.
穩(wěn)定性研究不包括當(dāng)前的容器和封閉系統(tǒng)。
Microbial stability or sterility of the products is not tested.
未檢測(cè)產(chǎn)品的微生物穩(wěn)定性或無(wú)菌性。
Only short-term stability studies are carried out;long-term studies to validate the declared shelf life are missing.
只進(jìn)行短期穩(wěn)定性研究，目前還缺乏驗(yàn)證所宣布的有效期的長(zhǎng)期穩(wěn)定性研究。
There is no analytical recording or quantitative measurement of impurities in the stability studies.
在穩(wěn)定性研究中沒(méi)有雜質(zhì)的分析記錄或定量測(cè)量。
OOS results occur several times during the stability study, but are not further investigated; nevertheless, the study data serve to validate the shelf life.
OOS結(jié)果在穩(wěn)定性研究中多次出現(xiàn)，但沒(méi)有進(jìn)一步研究。然而，研究數(shù)據(jù)用于驗(yàn)證有效期。
The analytical methods for the stability tests are not validated.
穩(wěn)定性試驗(yàn)的分析方法沒(méi)有得到驗(yàn)證。
There is no on-going stability testing programme.
沒(méi)有持續(xù)的穩(wěn)定性測(cè)試計(jì)劃。
Data from older studies are used to justify the shelf life; stabilitystudies involving the current supplier and the current production site do not exist.
使用舊的穩(wěn)定性研究數(shù)據(jù)來(lái)證明有效期的合理性，不存在涉及當(dāng)前供應(yīng)商和當(dāng)前生產(chǎn)場(chǎng)地的穩(wěn)定性研究。
Stability studies are completely missing.
穩(wěn)定性研究完全缺失。
§211.194 Laboratory Records 實(shí)驗(yàn)室記錄
Your firm failed to ensure that laboratory records included complete data derived from all tests necessary to assure compliance with established specifications and standards.
你們公司未能確保實(shí)驗(yàn)室記錄包含所需的所有測(cè)試的完整數(shù)據(jù)，以確保符合既定規(guī)范和標(biāo)準(zhǔn)。
Documentation is incomplete, missing
文檔不完整，缺失
OOS results
OOS結(jié)果
Root cause analysis of OOS results
OOS結(jié)果的根本原因分析
Data from failed tests
失敗測(cè)試的數(shù)據(jù)
Re-test data, data on which the information on the certificateof analysis is based
重測(cè)數(shù)據(jù)，數(shù)據(jù)用于產(chǎn)生COA
Data on microbiological tests as well as relevant information (e.g. incubation times, materials, etc.), data that should actually be documented according to the audit trail
微生物測(cè)試數(shù)據(jù)以及相關(guān)信息(如培養(yǎng)時(shí)間、物料等)，應(yīng)根據(jù)審計(jì)追蹤記錄的數(shù)據(jù)
Batch numbers
批號(hào)
Data on shelf life of standards
標(biāo)準(zhǔn)品的有效期數(shù)據(jù)
Unofficial records are used (uncontrolled Excel files or notes accessible to everyone, which are later destroyed).
使用非正式的記錄(不受控制的Excel文件或每個(gè)人都可以訪問(wèn)的筆記，后來(lái)被銷毀)。
Records are falsified, data is "invented"; audit trails are not secured against manipulation.
記錄是偽造的，數(shù)據(jù)是“虛構(gòu)的”，審計(jì)追蹤不能防止被操縱。
The analysis of the warning letters shows that in many cases, the basic requirements for GMP-compliant work in the quality control laboratory as well as special requirements, e.g. for the performance of stability studies, are violated; the frequency of the latter has increased significantly in recent years.
對(duì)警告信的分析表明，在許多情況下，QC實(shí)驗(yàn)室GMP合規(guī)工作的基本要求以及穩(wěn)定性研究等特殊要求被違反，近年來(lái)，后者的頻率顯著增加。
All in all, this kind of insight into the deficiency reports that repeatedly appear in the warning letters and the scenarios described there, some of them in detail, can be useful for preparing for an upcoming FDA inspection.
總而言之，這種對(duì)警告信中反復(fù)出現(xiàn)的缺陷報(bào)告的觀察和學(xué)習(xí)，其中一些的細(xì)節(jié)，可以為即將到來(lái)的FDA檢查做準(zhǔn)備。
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