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受检机构/公司：Denver Solutions,LLC DBA Leiters Health
城市：Englewood，Co 80112-7145
类型：Outsourcing Facility
FEI号：3013438582
OBSERVATION 1
There is a failure to thoroughly review any
unexplained discrepancy and the failure of a batch or any of its components to
meet any of its specifications whether or not the batch has been already
distributed.
未能彻底审查任何无法解释的差异，以及一个批次或其任何成分未能满足其任何质量标准，无论该批次是否已经分销。
西门的吐槽：这个观察项，比较有意思，除了效价的OOS和不良反应不充分以外，我个人觉得其他子项加在一起，是防污染控制异常，包括但不限于粒子的控制（生产时的粒子超标），内毒素检验oos，灯检资质的缺陷品库缺失常见缺陷，时间有限，不做单独吐槽
This was a repeat observation from the 2021
FDA inspection.
这是2021年FDA检查的重复观察项。
Specifically,
具体来说，
A. Investigation of potency
testing out-of-specification (OOS) for finished products was inadequate.
对成品的效价超标准(OOS)的调查不充分。
Deviation D23637-DEN was initiated for the OOS report of
Vancomycin HCL 1.5 g PF added to 0.9% Sodium Chloride 250 m IV Bag, batch # xxx
failed release potency testing at 205% due to an IV bag being dosed twice, date
of event: 10/19/2023. Also, D23382-DEN was initiated for OOS report of Oxytocin
for injection, Lot# xxx due to an IV bag with potency of 0% (non-dosed) during
the stability study on Day xxx date of event 12/4/2023. Your firm conducted an
investigation by weighing whole batches to identify any potential OOS IV bags
to be an outlier (approximately xxx more
than average weight). Three batches of vancomycin (batch# xxx) produced from
xxx were released for distribution based on the weighing data: however, your
OOS investigation was inadequate for the following:
偏差D23637-DEN是由于OOS报告将盐酸万古霉素1.5 g PF添加到0.9%氯化钠250
m静脉注射袋中，由于静脉注射袋分两次给药，批号xxx未能通过205%的效价放行测试，事件日期:2023年10月19日。此外，由于在2023年12月4日事件的第xxx天进行的稳定性研究期间使用了效价为0%的静脉注射袋(未给药), OOS报告的第xxx批次注射用催产素引发了D23382-DEN。贵公司进行了一项调查，对整批产品进行称重，以确定任何潜在的OOS静脉注射袋是否属于异常值(大约比平均重量多xxx)。根据称重数据，从xxx生产的三个批次的万古霉素(批号xxx)被放行销售:但是，您的OOS调查在以下方面是不充分的:
Your
investigation of deviation D23637-DEN was insufficient as it concluded that
there were no notable dosage irregularities regarding double-dosed and other
non-dosed instances within three of your vancomycin batches (batch# xxx) citing
their representation of merely xxx of the total batch size of xxx. However,
sampling approximately few samples from a batch of approximately xxx units
lacks the statistical significance required to justify such a conclusion. For example,
your firm took one to two random samples for release testing or stability
testing and detected one sample double-dosed and the other non-dosed for xxx different product batches.
您对D23637-DEN偏差的调查是不充分的，因为它得出的结论是，在您的三个万古霉素批次(批次# xxx)中，不存在关于双倍剂量和其他非剂量情况的显著剂量异常，引用它们仅代表xxx的总批次大小中的xxx。然而，从一批大约xxx个单位中抽取大约几个样本缺乏证明这一结论所需的统计显著性。例如，贵公司随机抽取一到两个样品进行放行测试或稳定性测试，发现xxx个不同批次的产品中，一个样品添加了双剂量，另一个样品未添加。
No
deviation was initiated to address the inconsistencies discovered during the
reconciliation of total units in batch records for three batches of vancomycin
injection (batch# xxx, # xxx, # xxx, ) in order to investigate the causes
behind the discrepancies in the actual yield of units with batch # xxx having more units, and batch # xxx ,# xxx having less units than the expected described
as follows:
在对三个批次的万古霉素注射液(批次# xxx、# xxx、# xxx)的批次记录中的总单位进行核对的过程中，没有发现任何偏差来解决发现的不一致，以调查单位实际产量差异背后的原因，批次# xxx的单位比预期的多，批次# xxx、# xxx的单位比预期的少，如下所述:
Reconciliation
of total units in batch records for the three batches of vancomycin for
injection with total units weighed for the same batch found apparent
discrepancies
将三个批次的注射用万古霉素批次记录中的总单位与同批次称重的总单位进行核对，发现明显的差异
Your firm
does not have adequate weight information of IV bags used in production (e.g.
weight variations) to conclude your OOS investigation despite limited data
available for samples weighed upon release of materials. Assessment of whether
an unit is OOS is based on the weight of final products within assumed
acceptance range.
贵公司没有生产中使用的静脉注射袋的足够重量信息(例如重量变化)来完成你们的OOS调查，尽管物料放行时样品称重的可用数据有限。评估一个单位是否为OOS是基于假设验收范围内的最终产品的重量。
B. Investigation into endotoxin
testing OOS for finished products was inadequate described as follows:
对成品OOS内毒素检查的调查不充分，如下所述:
Your firm
invalidated 0OS # 22008-DEN for Bevacizumab 2.5 mg/0.1 ml (25mg/mL) Repackaged,
Ophthalmic Injection, 0.1 ml in a 1 mL Syringe, Lot # xxx, dated 2/23/2022, regarding
endotoxin levels by testing new sample vials and did not conduct testing on the
original sample vial to determine whether the root cause stemmed from the tubes
used in assay testing or the original sample itself. Despite your investigation
finding that the likely root cause was low-level contamination of endotoxin in
the test tubes used for the assay.
贵公司于2022年2月23日对新样品瓶进行了内毒素水平检测，从而使第22008-DEN号0.1毫升(25毫克/毫升)分装于1毫升注射器中的0.1毫升贝伐单抗眼用注射液(批号xxx)失效，并且未对原样品瓶进行检测以确定根本原因是来自含量测定检测中使用的试管还是原样品本身。尽管你的调查发现可能的根本原因是用于检测的试管中内毒素的低水平污染。
Your firm
invalidated the OOS results from your contract laboratory without adequate justification.
For example, O0S 22015-DEN for Ketamine HCl (10 mg/ml) 5ml in a 5ml Syringe. Date:
6/23/2022 and 00S 23024-DEN for Ketamine HCl (10 mg/mL) 5ml in a 5ml Syringe,
Lot # xxx, Date: 8/19/2023 showed initial OOS results in the contract
laboratory, but passing results for in-house testing and/or from a second
contract laboratory. Investigation from the first contract laboratory confirmed
the initial OOS results, and the endotoxin test method for ketamine has been
validated by that laboratory.
你的公司在没有充分理由的情况下宣布你的委托实验室的OOS结果无效。比如O0S 22015-DEN对于5ml注射器中的盐酸氯胺酮(10 mg/ml) 5ml。日期:2022年6月23日和00S 23024-DEN 5ml注射器中的5ml盐酸氯胺酮(10 mg/mL)，批号xxx，日期:2023年8月19日显示委托实验室的初始OOS结果，但通过了内部测试和/或第二个委托实验室的结果。来自第一个委托实验室的调查确认了初始OOS结果，并且氯胺酮的内毒素检测方法已经过该实验室的验证。
西门的吐槽：这里的三方实验室OOS已经被确认有效（内部+第二家三方），后面仍旧无理由的归为无效OOS……
All three
batches were released for distribution.
所有三个批次均已分销。
C. Your firm has received 6
unexpected adverse drug reaction (ADR) for endophthalmitis after use of Avastin
and 4 ADRs after use of Moxifloxacin for injection since 2021. Investigations
into each ADR could not identify definite root causes with no deficiencies
being observed in the product and process. however, your firm did not conduct
microbiology testing of retain samples during the investigation.
自2021年以来，贵公司已收到6例因使用阿瓦斯丁引起眼内炎的不良反应，4例因使用注射用莫西沙星引起的不良反应。对每个ADR的调查无法确定明确的根本原因，在产品和工艺中没有观察到缺陷。然而，贵公司在调查过程中没有进行微生物测试或保留样品。
D.Since 2022, your firm has
documented 19 OOS potency deviations linked to inaccurate tare weights. For
example, on 4/20/2023, 00S # for Succinylcholine Chloride 20 mg/mL PF (from
API). 10mL in 10m BD Syringe, Batch # xxx , was reported with low potency,
likely due to inaccurate tare weight. However, it was not until 4 months later,
on 8/22/2023, that CAPA #23009 was initiated to address this issue. The CAPA
remained open without valid justification during this inspection period. Consequently,
your firm continued to report potency deviations associated with inaccurate
tare weight (OOS# 24008.0OS# 24009 in 2024).
自2022年以来，贵公司已经记录了19起OOS是与不准确皮重相关的效价偏差。例如，在2023年4月20日，00S #用于氯化琥珀胆碱20毫克/毫升PF(来自API)。据报告，批号为xxx的10m BD注射器中的10mL效价较低，可能是由于皮重不准确。然而，直到4个月后，即2023年8月22日，CAPA #23009才开始解决这一问题。在检查期间，CAPA在没有正当理由的情况下仍然开放。因此，贵公司继续报告与不准确皮重相关的效力偏差(OOS# 24008.0OS# 24009，2024年)。
E. The alarms for non-viable
particles in the ISO 5 aseptic processing area were not thoroughly investigated
before batch release. For example, deviation (#D22272, dated 5/7/2022), during
the filling of Ropivacaine for injection, Lot# XXX, on 5/7/2022,stated “unknown
FMS alarms persisted for approximately 5 minutes". The root cause of this
occurrence remained undetermined: nevertheless. The batch was released based on
environmental monitoring data, including units filled during the alarm period.
在批放行前，ISO
5无菌生产区的非活性粒子报警没有得到彻底调查。例如，2022年5月7日批号为XXX的注射用罗哌卡因灌装过程中出现偏差(#D22272，日期为2022年5月7日)，简述为“不明FMS警报持续约5分钟”。这起事件的根本原因仍未确定:尽管如此。该批次产品（包括警报期间灌装的产品）已根据环境监测数据被放行。
西门的吐槽：这个我在之前单位，做粒子监控系统冗余的时候，有跟我们现场QA同事讨论过，很麻烦，如果是丢数据，可能可以通过一系列EM数据和检测数据佐证。这里是粒子报警且五分钟，在不全面的评估情况下，其实很难确保粒子污染被排除。这里对于产品检验的一个点，所谓的检验只是对于按照科学的抽检出来的部分样品的检验，而不是所谓的百分百检验，而100%灯检，也是人眼可及的检验……
F. Your current visual inspection
qualification does not cover some types of rejects identified and characterized
from visual inspection in both syringes and vials described in the defect
library found from the executed batches and identified later. A comparison of
particle types in your defect library to the visual inspection xxx in vials and
syringes is described as follows:
您当前的灯检资质确认不包括通过外观检查在注射器和西林瓶中识别和表征的某些类型的不合格品，这些不合格品在缺陷库中描述，这些缺陷库是从已执行的批次中发现的，并在以后进行识别。缺陷库中的颗粒类型与西林瓶和注射器中目视检查xxx的比较如下:
However,
your firm has not investigated these discrepancies and its impact on visual
inspection qualifications.
然而，贵公司没有调查这些差异及其对灯检资质的影响。
西门的吐槽：所有来自生产线的代表性缺陷都应包括在该样品集/缺陷品库中（各家翻译都有点不一样，大家能理解这个kit就好），下图来自2023GMP指南，可见异物来源
样品集会过期，样品集必须定期重新制备。一般而言需要定期确认样品集/缺陷品库(anywhere 大家知道意思知道就好)的有效性。所有来自生产线的代表性缺陷都应包括在该样品集中。需要制造一些缺陷，但如果可以，应从生产中获取。这些缺陷需要分类。
2. 培训用样品集可以使用多长时间？
ECA 的灯检指南有如下回答 Training kits should contain all kind of defects and must be updated constantly with new evolving defects out of production. Expiry of specific defects depends on nature (a crack will not expire; small particles may clot together…). The set must be regularly released and reinspected by a supervisor. 培训系列样品集应包含各种缺陷并且必须随着不断变化的生产缺陷不断更新。特定缺陷过期是由于其本身的特性（裂纹不会过期;小颗粒可能凝结在一起）。该样品集必须定期由主管放行和复检。
类似的观察项
FDA483:灯检人员培训不足，包括但不限于缺陷品库不含毛发缺陷品，初始缺陷品库一直长期使用，测试时间重叠等
然后，胖友们，电子数据谁来审核，调研，再帮填写下呗，扫描填写，已经填写的请忽略，虾虾侬
感谢了，我周二，会把统计结果分享下
