Briefing Document: FDA Compliance Program 7346.832M for Biological Product Manufacturers
[中譯] 簡報文件：針對生物製劑製造商的 FDA 查廠計畫 7346.832M

Executive Summary
[中譯] 執行摘要

FDA Compliance Program 7346.832M, set for implementation on May 14, 2026, establishes a modernized, risk-based framework for Prelicense Inspections (PLIs) and Preapproval Inspections (PAIs) of biological product manufacturers.
[中譯] FDA 查廠計畫 7346.832M 預定於 2026 年 5 月 14 日實施，針對生物製劑製造商的上市前查廠 (PLI) 與核准前查廠 (PAI)，建立了一個現代化且以風險為基礎的框架。

Managed by the Center for Drug Evaluation and Research (CDER), the program focuses on protein drug substances and drug products regulated under the Public Health Service (PHS) Act.
[中譯] 該計畫由藥物評估與研究中心 (CDER) 管理，重點關注受公共衛生服務 (PHS) 法案管制的蛋白質原料藥與製劑。

The program shifts toward a holistic risk assessment to determine the necessity of on-site inspections, increasingly utilizing "Alternative Tools" (ATs) such as remote interactive evaluations and Mutual Recognition Agreements (MRAs).
[中譯] 該計畫轉向全面的風險評估以決定實地查廠的必要性，並逐漸增加「替代工具 (ATs)」的使用，例如遠端互動評估與相互承認協議 (MRAs)。

When inspections occur, they are governed by two primary objectives: verifying adherence to application commitments and Current Good Manufacturing Practice (CGMP), and performing rigorous data integrity audits.
[中譯] 當執行查廠時，將由兩大主要目標主導：驗證是否遵守申請承諾與現行優良製造規範 (CGMP)，以及執行嚴格的數據完整性稽核。

Failure to meet these standards results in a "Withhold" recommendation, directly impacting the approval of Biologics License Applications (BLAs).
[中譯] 若未能符合這些標準將導致「不予核准 (Withhold)」的建議，直接影響生物製劑許可證申請 (BLAs) 的核准。

Program Scope and Regulatory Foundation
[中譯] 計畫範圍與法規基礎

The program covers manufacturing establishments—including those for drug substances (DS) and drug products (DP)—involved in original or supplemental BLAs.
[中譯] 該計畫涵蓋參與原始或補充 BLAs 的製造廠——包含原料藥 (DS) 與製劑 (DP) 製造廠。

Regulated Products
[中譯] 受管制的產品

The scope includes biological products meeting the definition of "protein" under 21 CFR 600.3(h)(6) (polymers greater than 40 amino acids).
[中譯] 範圍包含符合 21 CFR 600.3(h)(6) 中「蛋白質」定義的生物產品（大於 40 個胺基酸的聚合物）。

Key examples include:
[中譯] 主要範例包含：

• Monoclonal antibodies and Antibody-Drug Conjugates (ADCs).
  [中譯] 單株抗體與抗體藥物複合體 (ADCs)。
• Enzymes, growth factors, and cytokines.
  [中譯] 酵素、生長因子與細胞激素。
• Insulin and insulin analogues.
  [中譯] 胰島素與胰島素類似物。
• Botulinum toxins and fusion proteins.
  [中譯] 肉毒桿菌毒素與融合蛋白。

Statutory Authority
[中譯] 法定權限

Manufacturers must comply with:
[中譯] 製造商必須遵守：

• PHS Act Section 351: Ensures safety, purity, and potency.
  [中譯] PHS 法案第 351 條：確保安全性、純度與效價。
• 21 CFR Parts 600 & 601: Licensing and general biological standards.
  [中譯] 21 CFR 第 600 與 601 部分：許可證與一般生物製劑標準。
• FD&C Act Section 501(a)(2)(B): Statutory CGMP requirements.
  [中譯] FD&C 法案第 501(a)(2)(B) 條：法定 CGMP 要求。
• 21 CFR Parts 210 & 211: Finished pharmaceutical CGMPs.
  [中譯] 21 CFR 第 210 與 211 部分：最終藥品 CGMP。
• 21 CFR Part 820: Quality Management System Regulation (QMSR) for combination products.
  [中譯] 21 CFR 第 820 部分：針對複合性產品的品質管理系統法規 (QMSR)。

Risk-Based Inspection Strategy
[中譯] 以風險為基礎的查廠策略

The FDA employs an Integrated Quality Assessment (IQA) team to determine if an inspection is necessary.
[中譯] FDA 聘用整合品質評估 (IQA) 團隊來決定是否需要進行查廠。

This decision is based on a facility’s preparedness and the overall risk profile.
[中譯] 該決定基於廠區的整備度與整體風險概況。

Risk Assessment Factors
[中譯] 風險評估因素

• Facility History: Compliance status, inspection history, and profile code status.
  [中譯] 廠區歷史：合規狀態、查廠歷史與基本資料代碼狀態。
• Product Complexity: Novelty of the drug or complexity of the manufacturing process.
  [中譯] 產品複雜度：藥物的新穎性或製造流程的複雜性。
• Hazard Signals: Biological Product Deviation Reports (BPDRs), recalls, complaints, and Field Alert Reports (FARs).
  [中譯] 危害訊號：生物製劑偏差報告 (BPDRs)、回收、客訴與現場警報報告 (FARs)。

Alternative Tools (ATs) in Lieu of Inspection
[中譯] 替代查廠的工具 (ATs)

If the risk assessment supports facility preparedness, the FDA may utilize:
[中譯] 若風險評估支持廠區已具備整備度，FDA 可能會利用：

• Mutual Recognition Agreements (MRAs): Reviewing inspection records from trusted foreign regulatory partners (e.g., EU, UK, SwissMedic).
  [中譯] 相互承認協議 (MRAs)：審閱來自可信賴外國法規合作夥伴（例如歐盟、英國、瑞士藥監局）的查廠記錄。
• Remote Regulatory Assessments: Requesting records under section 704(a)(4) of the FD&C Act.
  [中譯] 遠端法規評估：依據 FD&C 法案第 704(a)(4) 條要求提供記錄。
• Remote Interactive Evaluations (RIE): Utilizing livestreaming and remote document review.
  [中譯] 遠端互動評估 (RIE)：利用直播與遠端文件審閱。

Objective 1: CGMP and Application Compliance
[中譯] 目標一：CGMP 與申請書合規性

This objective evaluates the effectiveness of the establishment's quality systems across six primary domains.
[中譯] 此目標評估該廠品質系統在六個主要領域的有效性。

Quality System Oversight
[中譯] 品質系統監督

• Quality Unit: Must have independent authority to release/reject materials and oversee investigations into Out-of-Specification (OOS) results, deviations, and CAPAs.
  [中譯] 品質單位：必須擁有獨立權限來放行/拒收物料，並監督超標 (OOS) 結果、偏差與預防及矯正措施 (CAPA) 的調查。
• Change Management: Robust systems must be in place to evaluate manufacturing changes, particularly those involving "Established Conditions" (ECs) as defined in ICH Q12.
  [中譯] 變更管理：必須具備穩健的系統以評估製造變更，特別是涉及 ICH Q12 所定義的「既定條件 (ECs)」之變更。
• Senior Management: Must demonstrate commitment to quality by providing adequate staffing and resources for facility upgrades.
  [中譯] 高階管理層：必須透過提供充足的人力與資源進行廠區升級，展現對品質的承諾。

Facilities and Equipment
[中譯] 廠房與設備

• HVAC and Segregation: Systems must prevent cross-contamination, especially in multiproduct facilities.
  [中譯] 空調監控系統與隔離：系統必須防止交叉污染，特別是在多產品設施中。
• Special attention is paid to air pressure differentials and HEPA filter integrity.
  [中譯] 需特別注意氣壓差與 HEPA 濾網的完整性。
• Water Systems: Water for Injection (WFI) is generally required for all DS manufacturing steps for mammalian cell-derived products.
  [中譯] 水系統：哺乳動物細胞衍生產品的所有原料藥製造步驟，通常都需要使用注射用水 (WFI)。
• Cleaning Validation: For shared equipment, cleaning must be validated to prevent carryover.
  [中譯] 清潔確效：對於共用設備，必須驗證清潔程序以防止殘留。
• High-risk products (toxins or spore-formers) require specialized containment.
  [中譯] 高風險產品（毒素或孢子形成菌）需要專門的防護隔離。

Material Management
[中譯] 物料管理

• Cell Banks: Master Cell Banks (MCB) and Working Cell Banks (WCB) must be stored under monitored conditions with restricted access to prevent mix-ups or contamination.
  [中譯] 細胞庫：主細胞庫 (MCB) 與工作細胞庫 (WCB) 必須儲存於受監控的環境中並限制人員進出，以防止混淆或污染。
• Supplier Qualification: Critical raw materials and single-use/disposable equipment must be supported by risk-based qualification programs and reliability verification of Certificates of Analysis (COAs).
  [中譯] 供應商確認：關鍵原物料與單次使用/拋棄式設備必須有基於風險的確認計畫，以及檢驗分析證明 (COA) 的可靠度驗證作為支持。

Production and Process Controls
[中譯] 生產與製程管制

• Upstream (Cell Culture): Monitoring of cell growth, titers, and passage numbers.
  [中譯] 上游（細胞培養）：監控細胞生長、力價與繼代次數。
• Unprocessed bulk must be tested for adventitious agents (viruses, mycoplasma).
  [中譯] 未加工的散裝批料必須進行外來因子（病毒、黴漿菌）的測試。
• Downstream (Purification): Verification that chromatography resins and Ultrafiltration/Diafiltration (UF/DF) membranes are used within validated lifetimes.
  [中譯] 下游（純化）：確認層析樹脂與超過濾/透析過濾 (UF/DF) 膜在確效的壽命內使用。
• Viral Clearance: Unit operations like low pH hold, detergent inactivation, and nanofiltration must strictly adhere to validated parameters.
  [中譯] 病毒清除：低 pH 值保持、清潔劑去活化與奈米過濾等單元操作，必須嚴格遵守確效的參數。

Laboratory and Packaging
[中譯] 實驗室與包裝

• Analytical Methods: Must be validated and consistently executed within performance parameters.
  [中譯] 分析方法：必須經過確效，並在效能參數內保持一致的執行。
• Stability Program: Must confirm product stability through expiry, including the placement of the first three commercial batches on stability.
  [中譯] 安定性試驗計畫：必須確認產品直到保存期限前的安定性，包含將前三批商業批次納入安定性試驗。
• Labeling: Strict reconciliation of labels issued versus used to prevent mix-ups.
  [中譯] 標示：嚴格核對已發行與已使用的標籤，以防止混淆。

Objective 2: Data Integrity Audit
[中譯] 目標二：數據完整性稽核

The inspection team performs a forensic-level audit of data submitted in the application to ensure it is accurate and complete.
[中譯] 查廠團隊將針對申請書中提交的數據執行鑑識級別的稽核，以確保其準確性與完整性。

The following table:
[中譯] 下列表格：

Integrity Type [中譯] 完整性類型	Definition [中譯] 定義
Factual Integrity [中譯] 事實完整性	"Correspondence between data observed on-site and data submitted in the application (e.g., matching chromatograms)." [中譯] 「現場觀察到的數據與申請書中提交數據之間的一致性（例如：相符的層析圖譜）。」
Contextual Integrity [中譯] 脈絡完整性	"Whether submitted data is representative of all testing (e.g., including failed results or aborted runs)." [中譯] 「提交的數據是否具有所有測試的代表性（例如：是否包含了失敗的結果或中斷的運行）。」

Key Audit Areas
[中譯] 關鍵稽核領域

• Computerized System Validation (CSV): Systems must have audit trails that are configured, enabled, and locked.
  [中譯] 電腦化系統確效 (CSV)：系統必須具備已完成設定、已啟用且被鎖定保護的稽核追蹤功能。
• Access Controls: Prohibiting shared passwords and ensuring system administrators are independent of the personnel generating the records.
  [中譯] 權限控管：禁止共用密碼，並確保系統管理員與產生記錄的執行人員是各自獨立的。
• Raw Data Review: Comparing original laboratory notebooks and electronic metadata against summary reports to identify "testing into compliance" or unauthorized data deletion.
  [中譯] 原始數據審閱：將原始實驗室筆記與電子元數據，與最終的摘要報告進行比對，以揪出「測到過為止」或未經授權刪除數據的行為。

Special Technical Considerations
[中譯] 特殊技術考量

The program includes specialized attachments for complex technologies:
[中譯] 該計畫包含針對複雜技術的專門附件：

• Antibody-Drug Conjugates (ADCs): Focuses on conjugation reaction parameters (temperature, time) and the removal of unconjugated payloads.
  [中譯] 抗體藥物複合體 (ADCs)：著重於共軛反應參數（溫度、時間）與未結合有效載荷的移除。
• Spore-Forming Microorganisms: Requires distinct "crossover points" and dedicated equipment to prevent the spread of spores.
  [中譯] 孢子形成微生物：需要明確的「交叉點」與專用設備以防止孢子散播。
• Highly Potent or Toxic Products: Carryover limits for shared equipment must be based on a toxicologically-derived Acceptable Daily Exposure (ADE).
  [中譯] 高效價或高毒性產品：共用設備的殘留限制必須基於毒理學推導的每日可接受暴露量 (ADE)。
• Lyophilization: Operations must be supported by shelf temperature mapping and "worst-case" fill heights.
  [中譯] 凍乾技術：操作必須具備層板溫度分佈驗證與「最差情況」充填高度的支持。

Inspection Outcomes and Administrative Strategy
[中譯] 查廠結果與行政策略

The FDA issues a recommendation based on the combined findings of the inspection team and the application assessors.
[中譯] FDA 會根據查廠團隊與申請書評估員的綜合發現發出建議。

Recommendations
[中譯] 建議

• Approve: Granted when no significant CGMP issues or data integrity concerns exist.
  [中譯] 核准 (Approve)：當沒有重大的 CGMP 問題或數據完整性疑慮時授予。
• Withhold: Triggered by significant deficiencies, such as failure to follow application commitments, data manipulation, or unapproved major manufacturing changes.
  [中譯] 不予核准 (Withhold)：由重大缺失所觸發，例如未遵守申請承諾、數據操弄或實施未經核准的重大製造變更。

Reporting and Response
[中譯] 報告與回覆

• Form FDA 483: If issued, the firm must submit a written response to the items listed within 15 business days.
  [中譯] FDA 483 表格：若被開立，公司必須在 15 個工作天內對列出的項目提交書面回覆。
• Establishment Profile: Profiles are only updated if the inspection covers a new profile class code and results in an "Approve" recommendation.
  [中譯] 基本資料：只有當查廠涵蓋新的基本資料分類代碼並獲得「核准」建議時，才會更新基本資料。
• Communication: Significant deficiencies affecting other marketed products must be communicated to the CDER Office of Compliance (OC) immediately.
  [中譯] 溝通：影響其他上市產品的重大缺失必須立即通報 CDER 合規辦公室 (OC)。