FDA 483表格：洁净区杀孢子剂的使用存在缺陷

FDA在2021年8月17至9月8日期间，对美国药企Boothwyn Pharmacy LLC进行了为期10天的检查， 并于2024年2月29日在其网站上公布了9页的483表格，共计9条观察项，主要内容如下：

1、首过空气受阻。

2、生产危险药品时没有提供足够的密封、隔离、工作表面清洁、器皿清洁和人员清洁以防止交叉污染。

3、设备、物料或用品在进入无菌加工区域前未消毒。

4、在洁净室和ISO 5无菌加工区域使用杀孢剂不充分。

5、ISO 5无菌加工区域有难以清洁、产生颗粒和明显污浊的设备或表面。

6、手套清洗/消毒后进行人员取样，手套指尖取样结果不能代表无菌加工环境，不能提供有意义的结果。

7、培养基模拟灌装未在最具挑战性或压力的条件下进行。

8、ISO 5区域未在动态条件下进行确认。

9、未能确认水的质量适合其在生产非无菌药品中的预期用途。

可以看出，本份483表格的绝大多数内容都与污染相关。

第4条观察项涉及到了ISO5（A/B级）杀孢子剂使用的相关缺陷，具体如下：

Observation 4 观察项4

The use of sporicidal agents in the cleanrooms and ISO 5 classified aseptic processing area was inadequate. Specifically,

在洁净室和ISO 5无菌加工区域使用杀孢子剂是不充分的。例如：

A.Your pharmacy technician (b)(4) did not allow the required (b)(4) contact time (also known as "dwell time"), per your procedures and the cleaning agent manufacturer's use directions, for your disinfectant/sporicidal cleaning agent (b)(4) when used on the floor of the sterile suite containing the laminar airflow workstation (LAFW), during (b)(4) cleaning on August 20, 2021. Most areas of the floor had a drying time of less than (b)(4). Additionally, (b)(4) did not use the disinfectant/sporicidal cleaning agent on the ceiling and walls of the ISO 7 classified buffer room. You failed to establish an adequate contact time for your sporicidal agent used to disinfect your aseptic processing areas. (b)(4) stated that the disinfectant/sporicidal cleaning agent may be allowed to dry prior to (b)(4), though the surface may not be touched afterwards for that length of time.

你们的生产人员XX在2021年8月20日清洁期间，按照你们的规程和清洁剂生产商的使用说明，你们的消毒剂/杀孢子剂在有层流气流工作站(LAFW)的无菌室地板上使用时，未达到规定的接触时间(也称为“停留时间”)。地板的大部分区域的干燥时间小于XXX。此外，XX未在ISO 7级别缓冲室的天花板和墙壁上使用消毒/杀孢子剂。你们没有为你们用于消毒无菌加工区域的杀孢剂建立足够的接触时间。XX述明，在XXXX之前可以让消毒剂/杀孢剂干燥，虽然此之后的一段时间内，不得触碰表面。 

B.Your pharmacy technician (b)(4) did not clean the (b)(4) located between the ISO 8 classified preparation room and the ISO 7 classified buffer room with a sporicidal agent or any cleaning agent during direct observation of the (b)(4) cleaning of the sterile suite containing the LAFW on August 20, 2021.

在2021年8月20日直接观察到，你们的生产人员XX在清洁有LAFW的无菌室时，没有使用杀孢子剂或任何清洁剂清洁位于ISO 8准备室和ISO 7缓冲室之间的XXX。

C.During the (b)(4) cleaning of the sterile suite containing the LAFW on August 20, 2021, your pharmacy technician (b)(4) inconsistently cleaned the walls of the ISO 7 classified ante room, switching back and forth between (b)(4) and (b)(4) such that only one solution or the other was used on sections of the walls, rather than using the (b)(4) first with a (b)(4) dwell time followed by a (b)(4) cleaning, per your cleaning procedures. For example, only (b)(4) was used to clean the back wall and far section of the right wall of the ante room. Also, both (b)(4) and (b)(4) were sprayed onto the (b)(4)simultaneously to clean the glass door leading from the ante room into the buffer room. No other sporicidal agent is used on a (b)(4) basis.

在2021年8月20日对有LAFW的无菌室进行清洁期间，你们的生产人员不一致地清洁了ISO 7前室的墙壁，在XX和XXX之间来回切换，使得只在部分墙壁上使用了一种溶液，而不是按照你们的清洁程序先使用XX并停留XXX时间，然后使用XXXX进行清洁。例如，仅使用XX清洁前室的后墙和右墙的远端。另外，将XX和XXX同时喷洒到XXX上，以清洁从前置室通往缓冲室的玻璃门。在XX的基础上不使用其他杀孢子剂。

D.On August 19, 2021, your pharmacy technician (b)(4) did not clean the interior ceiling "grate" of the BSC with a sporicidal agent before or after producing ''TRICHLORMETHAZIDE-DEXAMETHASONE ACETATE 10 MG/ 0.5 MG/ML INJ" (lot 08192021@11) and "GLYCOPYRROLATE 0.2 MG/ML INJ" (lot 08192021@12), purported to be sterile. She stated she does not clean the ceiling "grate" during routine (b)(4), or (b)(4) cleaning, nor between products.

2021年8月19日，你们的生产人员在生产号称无菌的XX和XXX(批号XXXX)之前或之后，未使用杀孢子剂清洁BSC的内部天花板“格栅”。她表示，在常规XX或XXX清洁期间，她不会清洁天花板“格栅”，也不会在生产不同产品的间隙进行清洁。

E.On August 20, 2021, your pharmacy technician (b)(4) did not clean the interior back wall "grate" of the laminar airflow workstation (LAFW) with a sporicidal agent before or after producing "AMMONIUM CHLORIDE 2% INJ" (lot 08202021@5), purported to be sterile. He stated he does not clean the back wall "grate" of the LAFW during routine (b) (4) cleaning, nor between products.

2021年8月20日，你们的生产人员在生产XX(批号XXX)之前或之后未使用杀孢子剂清洁层流工作站(LAFW)的内部后墙“格栅”，该产品号称是无菌的。他说他在常规XX清洁期间没有清洁LAFW的后墙“格栅”，也没有在生产不同产品的间隙进行清洁。

FDA清洁消毒相关的缺陷（2022-2023）

“Disinfecting agents and [cleaning pads] [cleaning wipes] used in the ISO 5 classified aseptic processing areas were not sterile. ”

ISO 5级无菌工艺区使用的消毒剂和[清洁擦][清洁布]不是无菌的。

“[Equipment was] [Materials or supplies were] not disinfected prior to entering the aseptic processing areas. ”

 [设备][物料或耗材]在进入无菌工艺区之前未进行消毒。

“Disinfectant contact time (also known as ”dwell time“) and coverage of the item being disinfected were insufficient to achieve adequate levels of disinfection.”

消毒剂的接触时间（也称为“停留时间”）以及在被消毒物品上的覆盖范围不够，无法达到充分消毒水平。

“The use of sporicidal agents in the [cleanrooms] [ISO 5 classified aseptic processing] area was [inadequate] [infrequent]. ”

在[洁净室][ISO 5级无菌工艺区][不充分][不经常]使用杀孢子剂。

“a. You failed to validate your written cleaning procedure for your laminar flow (b)(4) and your cleanrooms where your products are manufactured. Additionally, you failed to establish the effectiveness of disinfectants used in this procedure.

b. Your written procedure for cleaning the (b)(4) and cleanroom did not specify the contact time for disinfectants.”

a.您未能验证您的层流(b)(4)和制造产品的洁净室的书面清洁程序。此外，您未能确定此程序中使用的消毒 剂的有效性。

b.您清洁(b)(4)和洁净室的书面程序没有指定消毒剂的接触时间。