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近日，FDA 發(fā)布了以嶺萬洲國(guó)際制藥有限公司的警告信，缺陷涉及交叉污染和質(zhì)量體系運(yùn)行不善，如下：

多產(chǎn)品共線的某帶管道的生產(chǎn)設(shè)備上的某個(gè)部件，未能確保防止藥粉末回流污染正在生產(chǎn)的其他產(chǎn)品（這個(gè)缺陷很常見，很多設(shè)備如包衣機(jī)、沸騰干燥機(jī)、流化床等都可能存在這個(gè)問題）。

FDA現(xiàn)場(chǎng)對(duì)該管道進(jìn)行擦拭取樣，檢測(cè)到包括多種API殘留物。隨后該公司回復(fù)稱已啟動(dòng)對(duì)留樣的檢測(cè)，以排查是否存在交叉污染。對(duì)此FDA并不接受，F(xiàn)DA表示：污染通常并非均勻分布。通過對(duì)批次中一小部分樣品進(jìn)行回顧性檢測(cè)（例如，檢測(cè)留樣中是否存在其他活性成分殘留），在回顧性評(píng)估交叉污染程度方面存在局限性。

設(shè)備管道的連接處密封件已老化，現(xiàn)場(chǎng)使用膠帶進(jìn)行覆蓋已批準(zhǔn)的清潔SOP程序未包含如清潔設(shè)備風(fēng)管的說明，包括拆卸和潔凈度目視檢查的指導(dǎo)。進(jìn)而，F(xiàn)DA提出該公司質(zhì)量部門未能充分履行質(zhì)量職能并確保質(zhì)量監(jiān)督。該公司在回復(fù)中指出，設(shè)備的設(shè)計(jì)不利于清潔，并表示，正在更新清潔程序，要求進(jìn)行拆卸和清潔后檢查。

缺陷翻譯如下：
During our inspection, our investigator observed specific violations including, but not limited to, the following.在我們的檢查過程中，我們的調(diào)查人員發(fā)現(xiàn)了特定的違規(guī)行為，包括但不限于以下內(nèi)容。
1. Your firm failed to use equipment in the manufacture, processing, packing, or holding of drug products that is of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance (21 CFR 211.63).貴公司在藥品生產(chǎn)、加工、包裝或存儲(chǔ)過程中，未使用設(shè)計(jì)適當(dāng)、尺寸合適且位置合理的設(shè)備，以使其便于按預(yù)期用途操作及清潔維護(hù)（21 CFR 211.63 ）。
Your non-dedicated manufacturing equipment was not designed and maintained appropriately to prevent potential cross-contamination of drug products.貴公司的非專用生產(chǎn)設(shè)備在設(shè)計(jì)和維護(hù)上存在缺陷，未能有效防止藥品的潛在交叉污染。
For example, (b)(4) were not designed and maintained to ensure that the (b)(4) consistently closes tightly, to prevent backflow of bulk drug powder into the (b)(4) duct. Residues were observed in the (b)(4) duct of (b)(4).例如，（b)(4）的設(shè)計(jì)和維護(hù)未能確保（b)(4）持續(xù)緊密閉合，以防止原料藥粉末回流到（b)(4）管道中。在（b)(4）的（b)(4）管道中觀察到了殘留物。
Numerous drug substance residues, including (b)(4), were recovered upon swabbing of (b)(4). Your (b)(4), are used to manufacture multiple drug products, including (b)(4) therapeutics such as (b)(4).通過對(duì)（b)(4）進(jìn)行擦拭取樣，檢測(cè)到包括（b)(4）在內(nèi)的多種API殘留物。貴公司的（b)(4）設(shè)備用于生產(chǎn)多種藥品，包括（b)(4）治療藥物（如（b)(4)）
In addition, junctions on the (b)(4) duct had degraded seals and were covered with tape.此外，（b)(4）管道的連接處密封件已老化，使用膠帶進(jìn)行了覆蓋。
In your response, you state you will replace the (b)(4) on (b)(4) to prohibit backflow into the (b)(4) ducting and replace the (b)(4) ducting on (b)(4) for ease of cleaning and sanitization. You further state you are identifying all batches of U.S. product within expiry from these (b)(4) and have initiated testing reserve samples for possible cross-contamination.在貴公司的回復(fù)中，貴方稱將更換（b)(4) 上的（b)(4)，以防止回流至（b)(4) 管道，并更換（b)(4) 上的（b)(4) 管道以便于清潔和消毒。貴方進(jìn)一步表示，正在識(shí)別這些（b)(4) 生產(chǎn)的所有在有效期內(nèi)的產(chǎn)品批次，并已啟動(dòng)對(duì)留樣的檢測(cè)，以排查是否存在交叉污染。
Your response is inadequate. Your assessment is limited to testing reserve samples of each finished drug product only for the presence of the preceding drug substance processed on the same non-dedicated equipment, instead of testing each reserve sample for all drug substances processed on the equipment. You do not adequately address how you intend to maintain this equipment to ensure the integrity of the seals.貴公司的回復(fù)不充分。貴方的評(píng)估僅限于檢測(cè)每種成品藥的留樣是否含有在同一非專用設(shè)備上處理過的前一種原料藥，而非針對(duì)該設(shè)備處理過的所有原料藥對(duì)每個(gè)留樣進(jìn)行檢測(cè)。此外，貴方未充分說明打算如何維護(hù)該設(shè)備以確保密封件的完整性。
Equipment used in pharmaceutical manufacturing operations should be designed to protect drug products from contamination. Air flow over dirty surfaces can cause contamination of the drug being processed in a (b)(4). Robust design, cleaning, and maintenance of this and other equipment are critical to prevent cross-contamination.藥品生產(chǎn)操作中使用的設(shè)備設(shè)計(jì)應(yīng)能保護(hù)藥品免受污染。污染表面的氣流可能導(dǎo)致（b)(4）中正在加工的藥品受到污染。對(duì)此類設(shè)備及其他設(shè)備進(jìn)行可靠的設(shè)計(jì)、清潔和維護(hù)，對(duì)防止交叉污染至關(guān)重要。
Contamination is generally not uniformly distributed. Data obtained from retrospectively testing a small proportion of a batch (e.g., reserve samples for the presence of previous active ingredient) 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 level that exists 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.污染通常并非均勻分布。通過對(duì)批次中一小部分樣品進(jìn)行回顧性檢測(cè)（例如，檢測(cè)留樣中是否存在其他活性成分殘留）所獲得的數(shù)據(jù)，在回顧性評(píng)估批次其他部分的污染程度方面存在局限性。從少量樣本檢測(cè)中獲得的最低或最高結(jié)果，不太可能揭示出在貴公司所發(fā)現(xiàn)的污染風(fēng)險(xiǎn)下，批次中實(shí)際存在的最低和最高污染水平的真實(shí)范圍。因此，貴公司生產(chǎn)批次中污染水平的變異范圍仍存在大量的殘留不確定性。
Because of the limitations of retrospective testing in gaining a representative understanding of the entire lot, testing reserve samples alone is insufficient to determine the scope of the contamination issues and mitigate the associated risks. Further evaluation and scientific rationale are needed in your firm’s risk assessment to reflect the nature of cross-contamination events and determine the degree of cross-contamination risk that may be posed to portion of marketed batches.由于回顧性檢測(cè)在全面了解整個(gè)批次的代表性方面存在局限性，僅檢測(cè)留樣不足以確定污染問題的范圍并降低相關(guān)風(fēng)險(xiǎn)。貴公司的風(fēng)險(xiǎn)評(píng)估需要進(jìn)一步的評(píng)估和科學(xué)依據(jù)，以反映交叉污染事件的性質(zhì)，并確定已上市批次可能面臨的交叉污染風(fēng)險(xiǎn)程度。
In response to this letter, provide the following:收到本函后，請(qǐng)?zhí)峁┮韵聝?nèi)容：

Your corrective action and preventive action (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(jì)劃以實(shí)施設(shè)施和設(shè)備的日常、嚴(yán)密的運(yùn)行管理監(jiān)督。該計(jì)劃應(yīng)確保（除其他事項(xiàng)外）及時(shí)發(fā)現(xiàn)設(shè)備 / 設(shè)施性能問題、有效執(zhí)行維修工作、遵守適當(dāng)?shù)念A(yù)防性維護(hù)計(jì)劃、及時(shí)對(duì)設(shè)備 / 設(shè)施基礎(chǔ)設(shè)施進(jìn)行技術(shù)升級(jí)，以及完善持續(xù)管理評(píng)審體系。

A comprehensive retrospective risk assessment that addresses all possible cross-contamination, including but not limited to, highly potent substances such as (b)(4).

開展全面回顧性風(fēng)險(xiǎn)評(píng)估，涵蓋所有可能的交叉污染情況，包括但不限于（b)(4) 等高活性物質(zhì)。

A comprehensive risk assessment from analysis of adverse drug events for all affected drug products. Any side effects possibly attributable to cross-contamination with (b)(4) should be reported.

通過分析所有受影響藥品的不良事件開展綜合風(fēng)險(xiǎn)評(píng)估。任何可能歸因于（b)(4) 交叉污染的副作用均應(yīng)進(jìn)行報(bào)告。

A detailed CAPA plan to implement segregation of highly potent substances such as (b)(4) from equipment shared with other drug products.

制定詳細(xì)的 CAPA 計(jì)劃，確保將（b)(4) 等高活性物質(zhì)與其他藥品共用的設(shè)備進(jìn)行隔離。

2. 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).貴公司質(zhì)量控制部門未能履行其職責(zé)，以確保所生產(chǎn)的藥品符合現(xiàn)行藥品生產(chǎn)質(zhì)量管理規(guī)范（CGMP），并滿足既定的鑒別、規(guī)格、質(zhì)量和純度標(biāo)準(zhǔn)（ 21 CFR 211.22 ）。
Your quality unit (QU) failed to adequately implement the facility’s quality function and ensure quality oversight. For example:貴公司質(zhì)量部門（QU）未能充分履行工廠的質(zhì)量職能并確保質(zhì)量監(jiān)督。例如：
You failed to have an adequate procedure to clean (b)(4). Your approved procedure did not include sufficient directions to clean the (b)(4) ducts, including directions on disassembly and visual inspection for cleanliness. Thus, you failed to identify visible residue with the possibility of cross-contaminated drug products being released to the market.貴公司未能制定充分的（b)(4）清潔程序。已批準(zhǔn)的程序未包含清潔（b)(4）管道的充分說明，包括拆卸和清潔度目視檢查的指導(dǎo)。因此，貴公司未能識(shí)別可見殘留物，導(dǎo)致可能存在交叉污染的藥品被投放市場(chǎng)。
In your response you identify (b)(4), was not designed to facilitate appropriate cleaning. You acknowledge this resulted in residual drug substances inside the (b)(4) duct of your (b)(4). You indicate that you are updating your cleaning procedures to require disassembly and post cleaning inspection.在貴公司的回復(fù)中指出，（b)(4) 的設(shè)計(jì)不利于進(jìn)行適當(dāng)?shù)那鍧崱ＹF公司承認(rèn)，這導(dǎo)致（b)(4) 設(shè)備的（b)(4) 管道內(nèi)殘留藥物物質(zhì)。貴公司表示，正在更新清潔程序，要求進(jìn)行拆卸和清潔后檢查。
Your response is inadequate. You do not provide a written approved procedure that would ensure adequate disassembly and cleaning of the (b)(4) duct. And you fail to provide evidence you have implemented CAPA measures ensuring QU oversight of cross-contamination risks from highly potent substances, such as (b)(4), on shared equipment.貴公司的回復(fù)不充分。一是貴公司未提供書面批準(zhǔn)的程序以確保（b)(4）管道的充分拆卸和清潔。二是貴公司未能提供證據(jù)證明已實(shí)施糾正與預(yù)防措施（CAPA），以確保質(zhì)量部門（QU）對(duì)（b)(4) 等高活性物質(zhì)在共用設(shè)備上的交叉污染風(fēng)險(xiǎn)進(jìn)行監(jiān)督。
You also manufacture (b)(4), a highly potent drug on the same shared equipment. (b)(4) is a hazardous drug that can cause (b)(4) if administered outside of its therapeutic range.貴公司還在同一共用設(shè)備上生產(chǎn)（b)(4)—— 一種高活性藥物。（b)(4) 屬于危險(xiǎn)藥物，若在治療范圍外使用可能導(dǎo)致（b)(4)
In response to this letter, provide:針對(duì)本函，請(qǐng)?zhí)峁?br /> A comprehensive, independent 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:一項(xiàng)全面、獨(dú)立的評(píng)估及整改計(jì)劃，以確保貴公司質(zhì)量部門（QU）被賦予有效履行職能的權(quán)限和資源。該評(píng)估應(yīng)至少包括但不限于以下內(nèi)容：

A determination of whether procedures used by your firm are robust and appropriate.

公司所用程序是否健全且適當(dāng)?shù)呐卸ā?/span>

Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices.

質(zhì)量部門（QU）在整個(gè)運(yùn)營(yíng)過程中的監(jiān)督條款，以評(píng)估對(duì)相關(guān)規(guī)范操作的遵守情況。

A complete and final review of each batch and its related information before the QU disposition decision.在質(zhì)量部門做出放行決定前，對(duì)每一批次產(chǎn)品及其相關(guān)信息的完整最終審核。

Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products.

對(duì)調(diào)查的監(jiān)督和批準(zhǔn)，以及履行質(zhì)量部門的所有其他職責(zé)，以確保所有產(chǎn)品的鑒別、規(guī)格、質(zhì)量和純度符合要求。

A comprehensive, independent retrospective assessment of your cleaning effectiveness to evaluate the scope of cross-contamination hazards. Include the identity of residues, other manufacturing equipment that may have been improperly cleaned, and an assessment whether cross-contaminated products may have been released for distribution. The assessment should identify any inadequacies of cleaning procedures and practices, and encompass each piece of manufacturing equipment used to manufacture more than one product.

對(duì)清潔有效性進(jìn)行全面、獨(dú)立的回顧性評(píng)估，以評(píng)估交叉污染風(fēng)險(xiǎn)的范圍。評(píng)估內(nèi)容應(yīng)包括殘留物的特性、可能未被正確清潔的其他生產(chǎn)設(shè)備，以及對(duì)可能已放行銷售的交叉污染產(chǎn)品的評(píng)估。該評(píng)估需識(shí)別清潔程序和操作中的任何不足，并涵蓋用于生產(chǎn)多種產(chǎn)品的每一臺(tái)生產(chǎn)設(shè)備。

A CAPA plan, based on the retrospective assessment of your cleaning program, that includes appropriate remediations to your cleaning processes and practices, and timelines for completion. Provide a detailed summary of vulnerabilities in your process for lifecycle management of equipment cleaning. Describe improvements to your cleaning program, including enhancements to cleaning effectiveness; improved ongoing verification of proper cleaning execution for all products and equipment; and all other needed remediations.

根據(jù)清潔程序回顧性評(píng)估制定糾正與預(yù)防措施（CAPA）計(jì)劃，內(nèi)容包括對(duì)清潔流程和操作的適當(dāng)整改措施及完成時(shí)間表。提供設(shè)備清潔生命周期管理流程中漏洞的詳細(xì)總結(jié)。描述清潔程序的改進(jìn)方案，包括提高清潔有效性的措施；加強(qiáng)對(duì)所有產(chǎn)品和設(shè)備清潔執(zhí)行情況的持續(xù)驗(yàn)證；以及所有其他必要的整改措施。

A comprehensive assessment of your overall system for investigating deviations, discrepancies, complaints, out-of-specification results, and failures. Provide a detailed action plan to remediate this system. Your action plan should include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, CAPA effectiveness, QU oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.

對(duì)貴公司用于調(diào)查偏差、差異、投訴、超標(biāo)結(jié)果和故障的整體系統(tǒng)進(jìn)行全面評(píng)估。提供詳細(xì)的整改行動(dòng)計(jì)劃以完善該系統(tǒng)。您的行動(dòng)計(jì)劃應(yīng)包括但不限于以下方面的重大改進(jìn)：調(diào)查能力、范圍確定、根本原因評(píng)估、糾正與預(yù)防措施（CAPA）有效性、質(zhì)量部門（QU）監(jiān)督以及書面程序。闡述貴公司將如何確保調(diào)查的所有階段均得到適當(dāng)執(zhí)行。

A complete assessment of all investigations where unknown impurities or unknown peaks were detected in marketed product and a determination if these are associated with potential cross-contamination events.

對(duì)上市產(chǎn)品中檢測(cè)到未知雜質(zhì)或未知峰的所有調(diào)查進(jìn)行全面評(píng)估，并判定這些情況是否與潛在的交叉污染事件相關(guān)。