近日，FDA 發布了以嶺萬洲國際制藥有限公司的警告信，缺陷涉及交叉污染和質量體系運行不善，如下：

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

FDA現場對該管道進行擦拭取樣，檢測到包括多種API殘留物。隨后該公司回復稱已啟動對留樣的檢測，以排查是否存在交叉污染。對此FDA并不接受，FDA表示：污染通常并非均勻分布。通過對批次中一小部分樣品進行回顧性檢測（例如，檢測留樣中是否存在其他活性成分殘留），在回顧性評估交叉污染程度方面存在局限性。

設備管道的連接處密封件已老化，現場使用膠帶進行覆蓋已批準的清潔SOP程序未包含如清潔設備風管的說明，包括拆卸和潔凈度目視檢查的指導。進而，FDA提出該公司質量部門未能充分履行質量職能并確保質量監督。該公司在回復中指出，設備的設計不利于清潔，并表示，正在更新清潔程序，要求進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，我們的調查人員發現了特定的違規行為，包括但不限于以下內容。
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、加工、包裝或存儲過程中，未使用設計適當、尺寸合適且位置合理的設備，以使其便于按預期用途操作及清潔維護（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設備在設計和維護上存在缺陷，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）的設計和維護未能確保（b)(4）持續緊密閉合，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（b)(4）進行擦拭取樣，檢測到包括（b)(4）在內的多種API殘留物。貴公司的（b)(4）設備用于生產多種藥品，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。貴方進一步表示，正在識別這些（b)(4) 生產的所有在有效期內的產品批次，并已啟動對留樣的檢測，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.貴公司的回復不充分。貴方的評估僅限于檢測每種成品藥的留樣是否含有在同一非專用設備上處理過的前一種原料藥，而非針對該設備處理過的所有原料藥對每個留樣進行檢測。此外，貴方未充分說明打算如何維護該設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.藥品生產操作中使用的設備設計應能保護藥品免受污染。污染表面的氣流可能導致（b)(4）中正在加工的藥品受到污染。對此類設備及其他設備進行可靠的設計、清潔和維護，對防止交叉污染至關重要。
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。通過對批次中一小部分樣品進行回顧性檢測（例如，檢測留樣中是否存在其他活性成分殘留）所獲得的數據，在回顧性評估批次其他部分的污染程度方面存在局限性。從少量樣本檢測中獲得的最低或最高結果，不太可能揭示出在貴公司所發現的污染風險下，批次中實際存在的最低和最高污染水平的真實范圍。因此，貴公司生產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.由于回顧性檢測在全面了解整個批次的代表性方面存在局限性，僅檢測留樣不足以確定污染問題的范圍并降低相關風險。貴公司的風險評估需要進一步的評估和科學依據，以反映交叉污染事件的性質，并確定已上市批次可能面臨的交叉污染風險程度。
In response to this letter, provide the following:收到本函后，請提供以下內容：

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計劃以實施設施和設備的日常、嚴密的運行管理監督。該計劃應確保（除其他事項外）及時發現設備 / 設施性能問題、有效執行維修工作、遵守適當的預防性維護計劃、及時對設備 / 設施基礎設施進行技術升級，以及完善持續管理評審體系。

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

開展全面回顧性風險評估，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。

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險評估。任何可能歸因于（b)(4) 交叉污染的副作用均應進行報告。

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

制定詳細的 CAPA 計劃，確保將（b)(4) 等高活性物質與其他藥品共用的設備進行隔離。

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).貴公司質量控制部門未能履行其職責，以確保所生產的藥品符合現行藥品生產質量管理規范（CGMP），并滿足既定的鑒別、規格、質量和純度標準（ 21 CFR 211.22 ）。
Your quality unit (QU) failed to adequately implement the facility’s quality function and ensure quality oversight. For example:貴公司質量部門（QU）未能充分履行工廠的質量職能并確保質量監督。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。因此，貴公司未能識別可見殘留物，導致可能存在交叉污染的藥品被投放市場。
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.在貴公司的回復中指出，（b)(4) 的設計不利于進行適當的清潔。貴公司承認，這導致（b)(4) 設備的（b)(4) 管道內殘留藥物物質。貴公司表示，正在更新清潔程序，要求進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.貴公司的回復不充分。一是貴公司未提供書面批準的程序以確保（b)(4）管道的充分拆卸和清潔。二是貴公司未能提供證據證明已實施糾正與預防措施（CAPA），以確保質量部門（QU）對（b)(4) 等高活性物質在共用設備上的交叉污染風險進行監督。
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備上生產（b)(4)—— 一種高活性藥物。（b)(4) 屬于危險藥物，若在治療范圍外使用可能導致（b)(4)
In response to this letter, provide:針對本函，請提供：
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:一項全面、獨立的評估及整改計劃，以確保貴公司質量部門（QU）被賦予有效履行職能的權限和資源。該評估應至少包括但不限于以下內容：

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的判定。

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

質量部門（QU）在整個運營過程中的監督條款，以評估對相關規范操作的遵守情況。

A complete and final review of each batch and its related information before the QU disposition decision.在質量部門做出放行決定前，對每一批次產品及其相關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.

對調查的監督和批準，以及履行質量部門的所有其他職責，以確保所有產品的鑒別、規格、質量和純度符合要求。

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.

對清潔有效性進行全面、獨立的回顧性評估，以評估交叉污染風險的范圍。評估內容應包括殘留物的特性、可能未被正確清潔的其他生產設備，以及對可能已放行銷售的交叉污染產品的評估。該評估需識別清潔程序和操作中的任何不足，并涵蓋用于生產多種產品的每一臺生產設備。

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.

根據清潔程序回顧性評估制定糾正與預防措施（CAPA）計劃，內容包括對清潔流程和操作的適當整改措施及完成時間表。提供設備清潔生命周期管理流程中漏洞的詳細總結。描述清潔程序的改進方案，包括提高清潔有效性的措施；加強對所有產品和設備清潔執行情況的持續驗證；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.

對貴公司用于調查偏差、差異、投訴、超標結果和故障的整體系統進行全面評估。提供詳細的整改行動計劃以完善該系統。您的行動計劃應包括但不限于以下方面的重大改進：調查能力、范圍確定、根本原因評估、糾正與預防措施（CAPA）有效性、質量部門（QU）監督以及書面程序。闡述貴公司將如何確保調查的所有階段均得到適當執行。

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.

對上市產品中檢測到未知雜質或未知峰的所有調查進行全面評估，并判定這些情況是否與潛在的交叉污染事件相關。