近日，FDA對Glenmark的警告信中提及穩定性試驗樣品測試逾期的缺陷：未能在取樣品取出后的規定時間內及時完成穩定性測試。很大一部分樣品的穩定性測試逾期 3 個月甚至更久。
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Your firm failed to follow an adequate written testing program designed to assess the stability characteristics of drug products (21 CFR 211.166(a)).貴公司未能遵循旨在評估藥品穩定性特征的充分書面測試程序（21 CFR 211.166 (a)）。
You failed to follow your written stability procedure for your finished drug products. For example, you did not complete timely stability testing for approximately (b)(4) stability samples for U.S. commercial drug products within the stipulated timeline ((b)(4) after sample pull). Stability testing was overdue by 3 months or longer for a large proportion of your samples.貴公司未能遵循成品藥的書面穩定性程序。例如，對于美國市售藥品的約（b）（4）個穩定性樣品，貴公司未在規定時間內（取樣后（b）（4））完成及時性穩定性測試。貴公司很大一部分樣品的穩定性測試逾期 3 個月甚至更久。
In your response, you provide details for the backlog of pending stability sample testing, root causes for the delays in stability testing, and state all delayed stability sample testing for U.S. commercial products was completed by December 2024, prior to the inspection. You also implemented quality and executive management oversight for reviewing progress of stability testing, metrics, and upcoming stability testing for resource availability. You developed plans to increase quality control (QC) resources to reduce delayed stability sample testing by increasing QC laboratory capacity, purchasing and qualifying additional equipment, and hiring additional personnel. You plan to perform a stability load assessment for stability samples pulled from March 2025 to December 2025 to evaluate the adequacy of resources in your QC laboratory.在貴公司的回復中，提供了待處理穩定性樣品測試的積壓詳情、穩定性測試延遲的根本原因，并說明在檢查前，即 2024 年 12 月前，所有美國市售產品延遲的穩定性樣品測試已完成。貴公司還實施了質量和高管管理層監督，以審查穩定性測試的進展、指標以及即將進行的穩定性測試的資源可用性。貴公司制定了增加質量控制（QC）資源的計劃，通過提高 QC 實驗室容量、購買和確認額外設備以及招聘額外人員來減少穩定性樣品測試的延遲。貴公司計劃對 2025 年 3 月至 2025 年 12 月抽取的穩定性樣品進行穩定性負荷評估，以評估 QC 實驗室資源的充足性。
Your response is inadequate. You do not include the test results from the delayed stability analyses or a copy of the investigation report with your written response to demonstrate whether backlogged stability testing was completed and adequately investigated for root cause. Also, you do not provide adequate information on your stability load assessment, with pre-defined criteria, to evaluate adequacy of resources for your stability testing program.貴公司的回復不充分。貴公司的書面回復中未包含被延遲的穩定性分析測試結果或調查報告副本，以證明積壓的穩定性測試是否已完成以及是否對根本原因進行了充分調查。此外，貴公司未提供有關穩定性負荷評估的充分信息（包括預定義標準），以評估穩定性測試計劃的資源充足性。
Additionally, your impact assessment for the delayed stability analyses does not adequately address the risk to patient safety. Your firm’s failure to perform stability dissolution testing for potassium chloride ER capsules and (b)(4) capsules within the specified testing period led to delays in detecting product quality failures, issuing field alert reports1 and conducting recalls in a timely manner. For example, in multiple instances, potassium chloride ER capsules dissolution failures were not observed for approximately 100 days after stability samples were pulled.此外，貴公司對延遲穩定性分析的影響評估未充分說明對患者安全的風險。貴公司未能在規定測試期內對氯化鉀緩釋膠囊和（b）（4）膠囊進行穩定性溶出測試，導致檢測產品質量不合格、發布現場警報以及及時開展召回工作均出現延遲。例如，在多個案例中，穩定性樣品取出約 100 天后才發現氯化鉀緩釋膠囊的溶出不合格問題。
Without an appropriate ongoing stability program, you lack adequate scientific evidence to support whether your drug products meet established specifications and retain their quality attributes through their labeled expiry.如果沒有適當的持續穩定性計劃，貴公司就缺乏充分的科學證據來證明貴公司的藥品是否符合既定標準，以及在標注的有效期內是否能保持其質量屬性。
In response to this letter, provide:針對本函，請提供：
o A copy of the completed stability data from the backlogged stability testing. Include a plan of action for any OOS results found from the stability analyses. o 積壓穩定性測試的完整穩定性數據副本。包括針對穩定性分析中發現的任何 OOS 結果的行動計劃。
o Your stability load assessment protocol relating to stability samples pulled from March 2025 to December 2025, and the report and CAPA assuring future resource adequacy. o 與 2025 年 3 月至 2025 年 12 月抽取的穩定性樣品相關的穩定性負荷評估方案，以及確保未來資源充足的報告和糾正與預防措施（CAPA）。
o A comprehensive, independent assessment and CAPA plan to ensure the adequacy of your stability program. Your remediated program should include, but not be limited to: o 一項全面、獨立的評估以及 CAPA 計劃，以確保貴公司穩定性計劃的充分性。經整改的計劃應包括但不限于：
Stability indicating methods.
穩定性指示方法。
Stability studies for each drug product in its marketed container-closure system before distribution is permitted.
在允許分銷前，對每種藥品在其市售包裝容器系統中的穩定性研究。
An ongoing program in which representative batches of each product are added each year to the program to determine if the shelf-life claim remains valid.
一項持續計劃，每年將每種產品的代表性批次納入該計劃，以確定保質期聲明是否仍然有效。
Detailed definition of the specific attributes to be tested at each station (timepoint).
詳細規定每個時間點需測試的特定屬性。
All procedures that describe these and other elements of your remediated stability program.
描述經整改的穩定性計劃中這些及其他要素的所有程序。
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穩定性試驗樣品，應取出后在多久內檢測？
國外某公司SOP：
< 3 個月樣品：10 個工作日
3-6 個月樣品：15 個工作日
>6-24 個月樣品：21 個工作日
>24 個月樣品：30 個工作日
USP 最新發布的通則<1049.1>《生物技術及生物制品穩定性試驗》草案中也提及穩定性試驗時間零和樣品檢測時限的要求：
One item of particular importance for biologics is the stability study start date, or time zero. Time zero is defined as the date the material is placed at the applicable storage condition and the stability assessment begins, which may be the date of manufacture as discussed below. The storage condition includes temperature, light, and humidity, as applicable, and is otherwise independent of physical location. Note that regardless of the stability time zero, the expiration date for a batch is based on its date of manufacture and not the stability study start date. A product may have different time zero calendar dates for each storage condition. A change of location for a material while retaining the same storage condition doesnot alter the timezero (i.e. a product moved from a −20° warehouse to a−20°stability chamber doesnot alter the date of time zero because the material is held at the same condition in both locations). Thus, if the product is to be immediately stored after production at the same storage condition planned for long-term stability storage, as is common with biologics stored refrigerated or frozen, itis recommended that time zero is aligned to the date of manufacture.The manufacturer should establish whether it is permissible to leverage batch released at aasthe stability time zero data.
對于?物制劑來說，特別重要的?項是穩定性研究開始?期或時間零。時間零定義為物料置于適?的儲存條件下并開始穩定性評估的?期，它可能是生產?期。儲存條件包括溫度、光照和濕度（如適?），且與物理位置?關。請注意，?論穩定性時間零為何，批次的有效期均基于其?產?期，?不是穩定性試驗的開始?期。對于每種存儲條件，產品可能具有不同的時間零?歷?期。在保持相同存儲條件的情況下改變物料的位置不會改變時間零（即，從-20°倉庫移動到-20°穩定室的產品不會改變時間零的?期，因為物料在兩個位置都處于相同的狀態）。因此，如果產品在?產后要?即以所計劃的?期穩定性相同的儲存條件儲存，建議將時間零與?產?期對?。制造商應確定是否允許使用批放?數據作為穩定性時間零數據。
The pull window is the allowable range around the target pull date to remove the sample from the storage condition and initiate thetesting process. Manufacturers must establish the pull window permissible for each time point. Although manufacturers are expected to describe and manage target pull dates suitable for their product, the industry norm is to require a smaller pull window for shorter test points than longer test points. For example, a 1-month timepoint maybe subject to a shorter pullwindow of 4 days, where as a 24-month timepoint may be subject to a longer pull window. The intent is to ensure the product testing is representative of the time point when the product is removed from the storage condition.
拉動窗?是?標拉取?期左右的允許范圍，?于將樣品從儲存條件下取出并啟動樣品測試過程。制造商必須為每個時間點建?允許的拉動窗?。盡管制造商應描述和管理適合其產品的?標拉動?期，但?業規范是要求較短的測試點?較?的測試點使?更?的拉動窗?。例如，1個?的時間點可能會受到4天的較短拉取窗?的影響，?24個?的時間點可能會受到較?的拉取窗?的影響。?的是確保產品測試能夠代表產品從儲存條件下取出的時間點。
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