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In spite of the fact that it is a basic GMP requirement to release a batch only after final testing has been carried out, and although this is described clearly and explicitly in the pharmaceutical guidelines, FDA inspectors repeatedly encounter in some cases serious GMP violations in the area of quality control of finished products when they carry out inspections on site.

盡管GMP的基本要求是只有在最終檢測完成后才放行批次，并且在藥品指南中有明確的描述，但FDA檢查員在現(xiàn)場檢查時，在某些情況下，在成品質(zhì)量控制方面一再遇到嚴重的GMP違規(guī)行為。

 

The following chart shows the percentage of Warning Letters addressed to manufacturers of drug products because of deficiencies concerning the requirements of 211.165 over a period of five years.

下表顯示了在五年內(nèi)，由于放行檢測（21 CFR 211.165，法規(guī)內(nèi)容見文末）的缺陷而致藥品生產(chǎn)商的警告信的百分比。

 

Figure 1: Percentage of Warning Letters with notifications of deficiencies associated with the testing of the finished product according to 21 CFR 211.165 for the fiscal years 2019 - 2023

圖1：根據(jù)2019-2023財政年度21 CFR 211.165，含有與成品測試相關(guān)缺陷通知的警告信百分比

 

The percentage of Warning Letters citing 211.165 has settled at a little over 40% in the last two fiscal years. In absolute numbers this means 30 Warning Letters in the FY 2023 and 18 in the FY 2022.

 

在過去兩個財政年度，引用211.165條款的警告信比例穩(wěn)定在略高于40%的水平。在絕對數(shù)字上，在2023財年有30封警告信，2022財年有18封警告信。

Categorisation of GMP Deficiencies Associated with the Release Testing of the Finished Product

 

與成品放行檢測相關(guān)的GMP缺陷分類

The deficiencies described in the Warning Letters can be divided into the following categories:

 

警告信中所述的缺陷可分為以下幾類：

 

No Microbiological Testing

沒有微生物測試

 

One of the GMP deficiencies cited most often in the Waning Letters is the lack of testing of the finished product for objectionable microorganisms according to 211.165(b). FDA inspectors have observed this especially at producers of hand sanitizers.

在警告信中最常引用的GMP缺陷之一是未根據(jù)211.165(b)對成品進行不良微生物檢測。FDA檢查員發(fā)現(xiàn)，這種情況在洗手液生產(chǎn)商身上尤為明顯。

 

Incomplete Release Testing

不完整的放行檢測

 

This deficiency is described nearly as often. Contrary to the requirements of 211.165(a) according to which release testing shall include testing for compliance with the specifications of the finished product including identity and strength of the active ingredient, manufacturers have released their drug products on the basis of incomplete testing (such as odour, appearance or other physical parameters). In single cases the product was even released prior to the receipt of the test results.

這種缺陷幾乎經(jīng)常被描述。與211.165(a)的要求相反，放行檢測應(yīng)包括符合成品規(guī)格的測試，包括活性成分的特性和強度，生產(chǎn)商在不完整的測試結(jié)果（如氣味、外觀或其他物理參數(shù)）的基礎(chǔ)上放行了他們的藥品。在個別情況下，產(chǎn)品甚至在收到測試結(jié)果之前就被放行了。

 

The lack of testing of the batches of the finished product for impurities is also described several times in the Warning Letters.

在警告信中也多次描述了成品批次缺乏雜質(zhì)檢測的情況。

 

No Acceptance of Responsibility for the Release Testing

不承擔(dān)放行檢測的責(zé)任

 

Several contract companies finishing the product for instance by only filling it up have transferred the responsibility for release testing to the customer. But according to the FDA the production site carrying out the last manufacturing step immediately prior to the release of the drug product is obliged to carry out the batch release. FDA considers the transferral of responsibility to be a GMP violation.

一些CDMO生產(chǎn)了產(chǎn)品，例如只進行灌裝，然后把放行檢測的責(zé)任轉(zhuǎn)移給了客戶。但根據(jù)FDA的規(guī)定，在藥品放行前進行最后一個生產(chǎn)步驟的生產(chǎn)現(xiàn)場有義務(wù)進行批放行。FDA認為責(zé)任轉(zhuǎn)移是違反GMP的。

 

No Rejection of the Batch in Case of a Failed Release Testing

在放行檢測失敗的情況下，未拒絕該批產(chǎn)品

 

In several cases the quality control unit did not reject a batch or place a hold on it after the final testing failed.

在一些情況下，質(zhì)量部門在最終檢測失敗后沒有拒絕批次或?qū)⑵鋬鼋Y(jié)。

 

Use of Non-validated Methods for the Release Testing

使用未經(jīng)驗證的方法進行放行檢測

 

According to 211.165(e) only validated methods may be used for release testing. In some cases, FDA inspectors discovered that the quality control units released batches of the finished product after testing with non-validated methods.

根據(jù)211.165(e)，只有經(jīng)過驗證的方法才能用于放行檢測。在某些情況下，F(xiàn)DA檢查員發(fā)現(xiàn)質(zhì)量部門在使用未經(jīng)驗證的方法進行測試后放行了成品批次。

 

Follow-up Requests from the FDA

FDA的后續(xù)要求

 

Usually Warning Letters contain a follow-up request for documents/evidence in respect to each GMP deficiency associated with one of the paragraphs of CFR 211. In the case of 211.165 the FDA demands the following:

通常警告信包含對與CFR 211段相關(guān)的每個GMP缺陷的文件/證據(jù)的后續(xù)要求。在211.165案例中，F(xiàn)DA要求如下：

 

A list of chemical and microbial specificationsof the finished product, including the relevant test methods.

成品的化學(xué)和微生物標(biāo)準(zhǔn)清單，包括相關(guān)的測試方法。

 

Anaction plan and timelines for conducting full chemical and microbiological testing of retain samples of all batches distributed to the United States that are within expiry as of the date of the Warning Letter.

一份行動計劃和時間表，用于對所有在警告信有效期內(nèi)分銷到美國的批次的留樣進行全面的化學(xué)和微生物測試。

 

Asummary of the results obtained from testing retain samples.

留樣檢測結(jié)果摘要。

 

Acomprehensive independent assessment of the methods, procedures, equipment, documentation of the quality control unit, and analyst competencies. Based on this review, provision of a detailed plan to remediate the deficiencies and evaluation of the effectiveness of the laboratory system.

對質(zhì)量控制部門的方法、程序、設(shè)備、文件和分析人員能力進行全面的獨立評估。在此審查的基礎(chǔ)上，提供詳細的計劃，以糾正缺陷和評估實驗室系統(tǒng)的有效性。

 

If these proofs can be provided in the course of an FDA inspection the topic „release testing“ shouldn‘t pose a problem.

如果這些證據(jù)可以在FDA檢查過程中提供，那么“放行檢測”應(yīng)該不會構(gòu)成問題。

 

與放行檢測相關(guān)的法規(guī)要求

FDA對成品批次放行測試的要求如聯(lián)邦法規(guī)21 CFR 211.165所述，測試和放行分銷是強制性的。該條款的六節(jié)載有下列規(guī)定：

(a）每批成品放行前應(yīng)進行符合規(guī)格要求的測試。這包括測試活性成分的特性和強度。如果對壽命較短的放射性藥物進行無菌和/或熱原測試，只要盡快進行測試，這些放射性藥物可以在測試結(jié)果出來之前放行。

(b) 每批藥品應(yīng)進行適當(dāng)?shù)膶嶒炇覚z測，以確保無不良微生物。

(c) 任何取樣和測試計劃應(yīng)以書面程序描述，其中應(yīng)包括取樣方法和每批待測試的樣品數(shù)量。應(yīng)遵循上述書面程序。

(d) 質(zhì)量部門進行的取樣和檢測的接受標(biāo)準(zhǔn)應(yīng)足以確保藥品批次符合每一適當(dāng)?shù)囊?guī)格和適當(dāng)?shù)慕y(tǒng)計質(zhì)量控制標(biāo)準(zhǔn)，這是放行他們的條件。統(tǒng)計質(zhì)量控制標(biāo)準(zhǔn)應(yīng)包括適當(dāng)?shù)慕邮芩胶?或適當(dāng)?shù)木芙^水平。

(e) 所采用的檢測方法的準(zhǔn)確性、靈敏度、特異性和可重復(fù)性應(yīng)建立并形成文件。此類驗證和文件可以按照§211.194(a)(2)完成。

(f) 不符合制定的標(biāo)準(zhǔn)、規(guī)范和其他有關(guān)質(zhì)量控制標(biāo)準(zhǔn)的藥品應(yīng)當(dāng)予以拒收。可以進行再加工。在接受和使用之前，再加工的產(chǎn)品必須符合適當(dāng)?shù)馁|(zhì)量標(biāo)準(zhǔn)、規(guī)格和任何其他相關(guān)標(biāo)準(zhǔn)。

 

以下檢查指南包含了FDA檢查員在現(xiàn)場工作的指導(dǎo)方針：

 

FDA藥品質(zhì)量控制實驗室檢查指南（1993年7月）

FDA微生物藥品質(zhì)量控制實驗室檢查指南（1993年7月