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FDA于6月17日發(fā)布了對浙江華海藥業(yè)有限公司的警告信，這次檢查官是Justin A, Boyd，這個檢查官對華海很熟，2018年和Peter E.Baker一起襲擊華海的就是他。檢查風(fēng)格很細(xì)致，2025年1月16-24日在春節(jié)假期前夕，Justin A. Boyd和Jeffrey P.Raimondi再次來到華海進(jìn)行為期一周半的檢查，并簽發(fā)了483缺陷表。盡管華海進(jìn)行了整改答復(fù)，仍然收到FDA警告信。

該檢查官檢查后發(fā)483的比率高達(dá)75.19%，近期頻繁檢查國家：中國、印度。值得大家關(guān)注，文末有關(guān)于Justin A, Boyd的資料介紹。

華海警告信細(xì)節(jié)：

FDA檢查人員在多臺非專用設(shè)備表面（包括管道及相關(guān)閥門）發(fā)現(xiàn)殘留物。FDA稱臟污表面的氣流可能導(dǎo)致藥品受到污染。

檢查期間對這些殘留物進(jìn)行檢測，證實這些殘留物含有多種活性成分。

該公司在回復(fù)中稱交叉污染風(fēng)險極低，理由包括留樣藥品的檢測結(jié)果和交叉污染模擬實驗。

FDA認(rèn)為該公司的回復(fù)不充分。FDA認(rèn)為污染通常不是均勻分布，留樣檢測和交叉污染模擬實驗未能科學(xué)證明貴公司產(chǎn)品未受肉眼可見臟污設(shè)備的污染。此外，F(xiàn)DA認(rèn)為調(diào)查未將微生物污染作為潛在風(fēng)險因素進(jìn)行評估。

檢查人員在 ISO 5 級（A 級）區(qū)域的 HEPA 過濾器下方縫隙發(fā)現(xiàn)一塊 2 厘米 ×126 厘米的非無菌膠帶。該公司稱自 2024 年 4 月起使用該膠帶以方便清潔。

該公司的質(zhì)量部門（QU）未被告知在無菌區(qū)域使用非無菌膠帶，該膠帶一直在無菌區(qū)域內(nèi)未被注意到，直至 FDA 檢查人員在檢查中發(fā)現(xiàn)。

該公司稱通過評估氣流流型、清潔操作、環(huán)境監(jiān)測結(jié)果（非活性和活性粒子）以及批次和培養(yǎng)基灌裝回顧性審查，認(rèn)為對產(chǎn)品無影響。

FDA認(rèn)為該公司的回復(fù)是不充分的。該公司未回復(fù)對在灌裝操作期間進(jìn)行設(shè)施和設(shè)備改造時，質(zhì)量部門（QU）在確保其適當(dāng)性方面所起作用進(jìn)行全面評估。FDA表示：該公司的回復(fù)中未明確潔凈區(qū)改造是否無需質(zhì)量部門批準(zhǔn)，或質(zhì)量部門是否按既定程序和時間定期對潔凈區(qū)進(jìn)行目視檢查/巡檢。

該公司的片劑壓片拒收標(biāo)準(zhǔn)通過設(shè)定主壓壓力的上下限確定。該公司基于 “先前生產(chǎn)經(jīng)驗” 設(shè)定了拒收限和拒收率，但缺乏驗證數(shù)據(jù)以確保該比率適用于生產(chǎn)持續(xù)符合標(biāo)準(zhǔn)的藥品。FDA批評稱：生產(chǎn)工藝的每個重要階段必須經(jīng)過適當(dāng)設(shè)計。

該公司曾收到某批次產(chǎn)品溶出度測試不符合標(biāo)準(zhǔn)的投訴，該公司將其歸因于主壓壓力值過高。

缺陷翻譯如下：

The United States Food and Drug Administration (FDA) inspected your drug manufacturing facility, Zhejiang Huahai Pharmaceutical Co., Ltd., FEI 3003999190, at Xunqiao, Linhai, Zhejiang Province, from January 16 to 24, 2025.

FDA于2025年1月16日至24日檢查了你們位于浙江省臨海市潯橋的藥品生產(chǎn)工廠浙江華海藥業(yè)有限公司，編號FEI 3003999190。

This warning letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations (CFR), parts 210 and 211 (21 CFR parts 210 and 211).

本警告信總結(jié)了成品藥品嚴(yán)重違反CGMP規(guī)定的情況。見21 CFR第210和211部分。

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).

由于你們的生產(chǎn)、加工、包裝或保存的方法、設(shè)施或控制不符合CGMP，你們的藥品根據(jù)FD&C Act第501(a)(2)(B)條，21 U.S.C. 351(a)(2)(B)條被認(rèn)定為摻假。

We reviewed your February 14, 2025 response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

我們詳細(xì)審查了你們2025年2月14日對FDA 483的回復(fù)，并確認(rèn)收到了你們后續(xù)的回復(fù)。

During our inspection, our investigators observed specific violations including, but not limited to, the following.

在我們的檢查中，我們的檢查人員發(fā)現(xiàn)到的具體違規(guī)行為，包括但不限于以下情況。

During our inspection, our investigators observed specific violations including, but not limited to, the following.

在檢查過程中，我們的檢查人員發(fā)現(xiàn)了具體違規(guī)行為，包括但不限于以下內(nèi)容。

1. Your firm failed to clean, maintain, and, as appropriate for the nature of the drug, sanitize and/or sterilize equipment and utensils at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements (21 CFR 211.67(a)).

貴公司未能按藥品性質(zhì)適當(dāng)清潔、維護(hù)設(shè)備及器具，并在適當(dāng)時間進(jìn)行消毒和 / 或滅菌，以防止設(shè)備故障或污染導(dǎo)致藥品安全性、特性、效價、質(zhì)量或純度超出官方或其他既定要求 (21 CFR 211.67(a))。

You manufacture prescription drug products used to treat various conditions such as (b)(4). Your cleaning procedures for your non-dedicated manufacturing equipment are inadequate. Our investigators observed residue on surfaces of several non-dedicated (b)(4), including (b)(4) ducts and associated valves, which had been documented in the cleaning records as having undergone product changeover cleaning. Your firm was also cited for unknown residue in the (b)(4) duct of a (b)(4) during a previous FDA inspection. Air flow over dirty surfaces can facilitate contamination of the drug being processed in an (b)(4). Additionally, your analytical testing during the inspection confirmed these residues contained multiple active ingredients. Furthermore, residues were observed on both product contact and non-contact surfaces of the (b)(4) equipment, which were previously indicated as clean.

貴公司生產(chǎn)用于治療多種病癥（如 (b)(4)）的處方藥。貴公司非專用生產(chǎn)設(shè)備的清潔程序不充分。檢查人員在多臺非專用 (b)(4) 設(shè)備表面（包括 (b)(4) 管道及相關(guān)閥門）發(fā)現(xiàn)殘留物，而清潔記錄中卻記載這些設(shè)備已完成更換產(chǎn)品清潔。在 FDA 此前的檢查中，貴公司也曾因 (b)(4) 設(shè)備的 (b)(4) 管道內(nèi)存在未知殘留物被通報。臟污表面的氣流可能導(dǎo)致 (b)(4) 中處理的藥品受到污染。此外，檢查期間的分析測試證實這些殘留物含有多種活性成分。另外，在 (b)(4) 設(shè)備的產(chǎn)品接觸和非接觸表面均觀察到殘留物，而這些表面此前被標(biāo)注為已清潔。

In your response, you state that there is minimal risk for cross-contamination. Your rationale includes the test results of reserve drug product samples, as well as cross-contamination simulation experiments. You also indicate that you have revised your cleaning procedures, and you explain that (b)(4) and (b)(4) equipment are now appropriately inspected to verify cleanliness, which is recorded in your cleaning records.

在回復(fù)中，貴公司稱交叉污染風(fēng)險極低，理由包括留樣藥品的檢測結(jié)果和交叉污染模擬實驗。貴公司還表示已修訂清潔程序，并解釋稱目前已對 (b)(4) 和 (b)(4) 設(shè)備進(jìn)行適當(dāng)檢查以確認(rèn)潔凈度，相關(guān)結(jié)果記錄在清潔記錄中。

Your response is inadequate. Your risk assessment, which included testing of reserve product samples and cross-contamination simulation experiments failed to scientifically demonstrate your products are free of contaminants from your visibly dirty equipment. Additionally, your investigation did not include an assessment for microbial contamination as a potential risk factor.

貴公司的回復(fù)不充分。你們的風(fēng)險評估，包括留樣檢測和交叉污染模擬實驗，未能科學(xué)證明貴公司產(chǎn)品未受肉眼可見臟污設(shè)備的污染。此外，調(diào)查未將微生物污染作為潛在風(fēng)險因素進(jìn)行評估。

Contamination is generally nonuniformly distributed. Data obtained from retrospectively testing a small proportion of a batch (e.g., retain samples) is limited in its ability to retrospectively assess the extent of contamination in other portions of a batch. The lowest or highest results obtained from testing a small sample size is unlikely to reveal the true range of minimum and maximum contamination levels that exist in a batch exposed to the contamination hazards identified at your firm. Consequently, the range of variability of contamination levels in batches produced by your firm remain characterized by substantial residual uncertainty.

污染通常不是均勻分布。通過對批次小部分樣品（如留樣）進(jìn)行回顧性檢測獲得的數(shù)據(jù)，在評估批次其他部分污染程度時存在局限性。小樣本檢測的最低或最高結(jié)果，不太可能揭示貴公司存在污染風(fēng)險的批次中實際存在的污染水平的最低和最高范圍。因此，貴公司生產(chǎn)批次的污染水平變異性范圍仍存在大量殘留不確定性。

2. Your firm failed to perform operations within specifically defined areas of adequate size and to have separate or defined areas or such other control systems necessary to prevent contamination or mix-ups in aseptic processing areas (21 CFR 211.42(c)(10)).

貴公司未能在特定且面積足夠的區(qū)域內(nèi)開展操作，也未設(shè)置獨立或界定的區(qū)域或其他必要控制系統(tǒng)，以防止無菌處理區(qū)域的污染或混淆 (21 CFR 211.42(c)(10))。

You also manufacture (b)(4) drug products used to treat various conditions including (b)(4). Our investigator observed a 2 cm x 126 cm piece of a non-sterile tape between (b)(4) below the HEPA filters and above the (b)(4) in an ISO 5 (Grade A) area. The (b)(4) were not securely fastened. One (b)(4) was hanging lower than the other (b)(4) and appeared to be missing a screw. Your firm stated that the tape was used to facilitate cleaning between the (b)(4) since April 2024. Your quality unit (QU) was not informed of the use of non-sterile tape in an aseptic area, and the tape remained in the classified area unnoticed until FDA investigators observed it during this inspection.

貴公司還生產(chǎn)用于治療多種病癥（包括 (b)(4)）的 (b)(4) 藥品。檢查人員在 ISO 5 級（A 級）區(qū)域的 HEPA 過濾器下方 (b)(4) 與 (b)(4) 上方之間，發(fā)現(xiàn)一塊 2 厘米 ×126 厘米的非無菌膠帶。(b)(4) 未牢固固定，其中一個 (b)(4) 懸掛高度低于另一個，且似乎缺少一顆螺絲。貴公司稱自 2024 年 4 月起使用該膠帶以方便 (b)(4) 之間的清潔。你們的質(zhì)量部門（QU）未被告知在無菌區(qū)域使用非無菌膠帶，該膠帶一直在無菌區(qū)域內(nèi)未被注意到，直至 FDA 檢查人員在本次檢查中發(fā)現(xiàn)。

In your response, you state that there is no impact to the product following an assessment of your airflow patterns, cleaning practices, environmental monitoring results (non-viable and viable particulates), and retrospective review of batches and media fills.

在回復(fù)中，貴公司稱通過評估氣流流型、清潔操作、環(huán)境監(jiān)測結(jié)果（非活性和活性粒子）以及批次和培養(yǎng)基灌裝回顧性審查，認(rèn)為對產(chǎn)品無影響。

Your response is inadequate. Your response lacks a comprehensive evaluation of your QU’s role in assuring the suitability of the facility and equipment when modifications are made during filling operations. It is unclear in your response if modifications to classified areas are permitted without QU approval or if the QU regularly performs visual inspections of classified areas according to established procedure and timeframes. While your response states that the tape was used to facilitate cleaning by filling a gap between the (b)(4), your response did not address the FDA investigators’ observation that the (b)(4) were not properly and securely fastened.

貴公司的回復(fù)是不充分的。你們的回復(fù)對在灌裝操作期間進(jìn)行設(shè)施和設(shè)備改造時，質(zhì)量部門（QU）在確保其適當(dāng)性方面所起作用的全面評估有所欠缺。你們的回復(fù)中未明確潔凈區(qū)改造是否無需質(zhì)量部門批準(zhǔn)，或質(zhì)量部門是否按既定程序和時間定期對潔凈區(qū)進(jìn)行目視檢查/巡檢。盡管回復(fù)稱膠帶用于填補(bǔ) (b)(4) 之間的間隙以方便清潔，但未回應(yīng) FDA 檢查人員關(guān)于 (b)(4) 未正確牢固固定的觀察結(jié)果。

3. Your firm failed to establish adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100(a)).

貴公司未能制定充分的生產(chǎn)和工藝控制書面程序，以確保所生產(chǎn)藥品具有其宣稱的特性、效價、質(zhì)量和純度 (21 CFR 211.100(a))。

Tablet compression rejections are established by setting the upper and lower limits of the main compression force. While your firm established reject limits and rates based on “prior manufacturing experience,” your firm lacks validation data for your U.S. marketed drug products to ensure the rates are suitable for producing drug products which consistently meet specifications. Of note, on at least one occasion, your firm received a complaint for a batch of product that failed specification for dissolution testing which you attributed to high main force compression value.

你公司的片劑壓片拒收標(biāo)準(zhǔn)通過設(shè)定主壓壓力的上下限確定。盡管貴公司基于 “先前生產(chǎn)經(jīng)驗” 設(shè)定了拒收限和拒收率，但缺乏驗證數(shù)據(jù)以確保該比率適用于生產(chǎn)持續(xù)符合標(biāo)準(zhǔn)的藥品。值得注意的是，貴公司至少有一次收到某批次產(chǎn)品溶出度測試不符合標(biāo)準(zhǔn)的投訴，貴公司將其歸因于主壓壓力值過高。

Process validation evaluates the soundness of design and state of control of a process throughout its lifecycle. Each significant stage of a manufacturing process must be designed appropriately and assure the quality of raw material inputs, in-process materials, and finished drugs. Process qualification studies include intensive monitoring and testing throughout each significant process stage to characterize intra-batch variation and evaluate batches to determine whether an initial state of control has been established.

工藝驗證評估工藝設(shè)計的合理性及在整個生命周期中的受控狀態(tài)。生產(chǎn)工藝的每個重要階段必須經(jīng)過適當(dāng)設(shè)計，并確保原料輸入、中間產(chǎn)品和成品的質(zhì)量。工藝確認(rèn)研究包括在每個重要工藝階段進(jìn)行密集監(jiān)測和測試，以表征批內(nèi)變異并評估批次，以確定是否已建立初始控制狀態(tài)。

Successful process qualification studies are necessary before commercial distribution. Thereafter, ongoing vigilant oversight of process performance and product quality is necessary to ensure you maintain a stable manufacturing operation throughout the product lifecycle.

成功的工藝確認(rèn)研究是商業(yè)分銷前的必要條件。此后，必須對工藝性能和產(chǎn)品質(zhì)量進(jìn)行持續(xù)嚴(yán)格監(jiān)測，以確保在產(chǎn)品整個生命周期中維持穩(wěn)定的生產(chǎn)操作。