Name: failure of cleaning verification in pharmaceutical industry due to uncleanliness of stainless steel surface
Uploaded: 2017-08-11T15:00:00
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1.样品溶液
<ol>
	<li>计算基础的最大允许结转 (MACO) 治疗剂量标准药物清洗极限 (CL)。 注意： 在这里，药物 A 的清洗限制 (CL) 已被计算为 2.4 微克每 50 厘米2的基础的最大允许结转 (MACO) 治疗剂量标准。清洁验证是在 50%、 100%和 150%清洗限制执行的。清洁验证被评定为两种制剂 （2.5%及 60 %w / w 药物负载）。</li>
</ol>
2.清洗程序优惠券
<ol>
	<li>最初的方法<ol>
		<li>通过冲洗...

<ol>
	<li>. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Validation of cleaning processes (7/93). Guide to inspections validation of cleaning processes. , (2004).</li><li>. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Warning Letter: 320-12-08, Gulf Pharmaceuticals. , (2012).</li><li>. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Warning Letter: 320-12-058, Novartis Internationsl AG. , (2012).</li><li>. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Warning Letter: 05-10, Teva Parenterals Medicines, Inc. , (2009).</li><li>. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Warning Letter: 320-14-09, Tianjin Zhongan Pharmaceutical Co., Ltd. , (2014).</li><li>Mantel, M., Wightman, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Influence+of+the+surface+chemistry+on+the+wettability+of+stainless+steel.">Influence of the surface chemistry on the wettability of stainless steel.</a> Surf Interface Anal. 21, 595-605 (1994).</li><li>Odaka, K., Ueda, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Dependence+of+outgassing+rate+on+surface+oxide+layer+thickness+in+type+304+stainless+steel+before+and+after+surface+oxidation+in+air.">Dependence of outgassing rate on surface oxide layer thickness in type 304 stainless steel before and after surface oxidation in air.</a> Vacuum. 47, 689-692 (1996).</li><li>Kerber, S. J., Tverberg, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Stainless+Steel+Surface+Analysis.">Stainless Steel Surface Analysis.</a> Adv. Mater. Processes. , 33-36 (2000).</li><li>Kusumaningrum, H. D., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Survival+of+foodborne+pathogens+on+stainless+steel+surfaces+and+cross-contamination+to+foods.">Survival of foodborne pathogens on stainless steel surfaces and cross-contamination to foods.</a> Int J Food Microbiol. 85, 227-236 (2003).</li><li>Liu, L., Pack, B. W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Cleaning+verification+assays+for+highly+potent+compounds+by+high+performance+liquid+chromatography+mass+spectrometry:+Strategy,+validation,+and+long-term+performance.">Cleaning verification assays for highly potent compounds by high performance liquid chromatography mass spectrometry: Strategy, validation, and long-term performance.</a> J Pharmaceut. Biomed. 43, 1206-1212 (2007).</li><li>Lambropoulos, J., Spanos, G. A., Lazaridis, N. V. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Development+and+validation+of+an+HPLC+assay+for+fentanyl,+alfentanil,+and+sufentanil+in+swab+samples.">Development and validation of an HPLC assay for fentanyl, alfentanil, and sufentanil in swab samples.</a> J Pharmaceut. Biomed. 23, 421-428 (2000).</li><li>Chisti, Y., Moo-Young, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Clean-in-place+systems+for+industrial+bioreactors:+Design,+validation+and+operation.">Clean-in-place systems for industrial bioreactors: Design, validation and operation.</a> J. Ind. Microbiol. 13, 201-207 (1994).</li><li>Haidar Ahmad, I. A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Cleaning+verification:+Exploring+the+effect+of+the+cleanliness+of+stainless+steel+surface+on+sample+recovery.">Cleaning verification: Exploring the effect of the cleanliness of stainless steel surface on sample recovery.</a> J Pharmaceut. Biomed. 134, 108-115 (2017).</li></ol>

从不锈钢优惠券 API 残留量低和可变的经济复苏所作的主要贡献被追溯到缺乏明确规程的优惠券表面清理。清洁表面的优惠券导致一致、 准确的加标的回收和重复性好的结果。从不锈钢优惠券回收率高的示威，从制造设备使用经过验证的方法获得的实际清洗验证结果应该是准确和精确，反光的设备上的残留水平以最低风险的假阴性率为可能危及病人安全的产品的结转。
其次?...

应在用于制造的中间体及其后续版本之前验证非专用设备的清洁和在产品的活性药物成分 (Api)，改变以防止交叉污染。清洁程序应包含足够的细节，以使操作者能以重现性好和有效的方式，每种类型的设备，这些程序应根据美国食品和药物管理局 (FDA) 要求1验证。无数的警告信，由于不足清洗2，，34、 未能验证清洗的验证方法，以及未能遵循 FDA 已发出5的清洗程序。21 CFR §211.67 概述了成功的清洗验证所需的要求。
它是清洁验证分析方法的验证上不锈钢优惠券与同一表面/完成作为制造设备的行业标准。不锈钢优惠券 （例如，50 厘米2） 用于表示设备表面的清洁验证实验在实验室里。期间的发展，这些分析方法验证的利益 （即，应恢复从设备表面的残留） 样本被涨到了目标残留测定的最大允许结转 (MACO) 限制的不锈钢优惠券上。基于接受曝光极限的定义为，病人可以得到接触过，没有健康的不良影响 （没有观察到不良-影响-级，NOAEL） 的限制，确定了这一级别。
分析师或进行抽汲的制造经营必须遵循结构化的程序，以确保经济复苏是可再生的无论由谁进行抽汲。程序应明确详细说明拭子类型、 使用数量的拭子，稀释剂，溶剂用量，精确的扫描模式，适用于采样表面，所花费的时间抽汲、 提取样品，检测（紫外、 荧光、 质谱、 总有机碳等）的方法，萃取技术从拭子头的物质数量的笔画数等。
此外影响样品回收的优惠券，表面、 因此，在设备表面的所有上述因素也发挥了作用。沉积的薄膜材料表面上的或由于一个或多个不锈钢 （如、 铁、 铬和镍） 中的元素的氧化态的变化，可能修改表面的优惠券6，，78。再生的表面的不锈钢优惠券回其原始状态的定量的交换过程的成功至关重要。研究，不锈钢优惠券不被恰当地清洁，表明恢复包括分析师到另一个，不同的药物或各种穗水平9，，1011，变异性。上一张优惠券十复制恢复中的标准偏差可达 14%和 26%五优惠券9日。它是重要的是注意到，相对标准偏差 (Srel) 值增加随着越来越多的复制或随着越来越多的使用优惠券 （即，而不是在相同的优惠券上扣五次五优惠券）11。在这种情况下，变化不能解释为随机波动。尽管如此，他们的研究结果可以解释我们的清洁表面的优惠券会影响经济复苏。在本文中描述的结果说明恢复结果显著增加和减少变异性正确清洁表面的不锈钢优惠券后。
清洁--就地 (CIP) 是设备的清洁表面，包括最小或没有拆卸设备自动化的方式。在 CIP 清洗过程，期间连续洗与其后酸基地定义的过程执行删除有机和无机残留物。表面活性剂、 螯合的化合物或络合剂通常添加到 CIP 解决方案提高效率的清洗设备表面的任何产品。清洗效率取决于几个参数，包括选择和浓度的 CIP 解决方案 （即，类型和组成基地、 酸及表面活性剂），清洗时间、 温度 (通常为 60-80 ° C)、 污染类型和难清洁部分12的存在。基于类型的药物产品，CIP 解决方案 100 和 200 已选择要用于清洗不锈钢优惠券用于清洁验证，因为它模拟的 CIP 过程用于清洗生产设备。
这项研究报告影响药物残留回收不锈钢优惠券的表面的不同因素的影响，并建议为小分子、 治疗蛋白和抗体分析清洗方法开发的最佳做法。一贯地打扫优惠券表面良好定义过程缺乏被确定为低和可变的经济复苏的主要原因。当表面的优惠券正确清洗13得到高、 重现性好的恢复。

<table style="border-collapse:collapse;width:964pt" width="1285">
	<colgroup>
		<col style="width:265pt" width="353" />
		<col style="width:401pt" width="535" />
		<col style="width:250pt" width="333" />
		<col style="width:48pt" width="64" />
	</colgroup>
	<tbody>
		<tr height="21" style="height:15.75pt">
			<td height="21" style="width:265pt;height:15.75pt" width="353">stainless steel coupons</td>
			<td class="xl67" style="width:401pt" width="535">&#160;GlobePharma (New Brunswick, NJ ).&#160;</td>
			<td class="xl16" style="width:250pt" width="333">SS316-20RA-50cm2</td>
			<td style="width:48pt" width="64"></td>
		</tr>
		<tr height="21" style="height:15.75pt">
			<td class="xl16" height="21" style="height:15.75pt">Clean in place solutions (CIP100 and CIP200)&#160;</td>
			<td class="xl68" style="width:401pt" width="535">were obtained from Steris Corporation (Mentor, OH)</td>
			<td>1D10BG</td>
			<td>Alkaline detergent and acid detergent, respectively</td>
		</tr>
		<tr height="21" style="height:15.75pt">
			<td class="xl16" height="21" style="height:15.75pt">Positive displacement pipettes</td>
			<td class="xl68" style="width:401pt" width="535">Gilson (Middleton, WI).&#160;</td>
			<td></td>
			<td></td>
		</tr>
		<tr height="34" style="height:25.5pt">
			<td height="34" style="height:25.5pt">HPLC grade water</td>
			<td class="xl68" style="width:401pt" width="535">Millipore Milli-Q Advantage Water Purification System (Darmstadt, Germany)&#160; or from Honeywell Burdick &#38; Jackson (Muskegon, Michigan)</td>
			<td>7732-18-5</td>
			<td></td>
		</tr>
		<tr height="21" style="height:15.75pt">
			<td class="xl16" height="21" style="height:15.75pt">HPLC grade Methanol</td>
			<td class="xl68" style="width:401pt" width="535">EMD</td>
			<td>MX0475-1</td>
			<td></td>
		</tr>
		<tr height="17" style="height:12.75pt">
			<td height="17" style="height:12.75pt">glacial acetic acid&#160;</td>
			<td class="xl68" style="width:401pt" width="535">EMD</td>
			<td>MAX0073P5</td>
			<td></td>
		</tr>
		<tr height="21" style="height:15.75pt">
			<td class="xl16" height="21" style="height:15.75pt">HPLC grade Acetonitrile&#160;</td>
			<td class="xl68" style="width:401pt" width="535">J.T. Baker (Avantor Performance Materials, Center Valley, PA)</td>
			<td>75-05-8</td>
			<td></td>
		</tr>
		<tr height="17" style="height:12.75pt">
			<td height="17" style="height:12.75pt">Trifluoroacetic acid</td>
			<td class="xl68" style="width:401pt" width="535">J.T. Baker (Avantor Performance Materials, Center Valley, PA)</td>
			<td>75-05-8</td>
			<td></td>
		</tr>
		<tr height="21" style="height:15.75pt">
			<td class="xl17" height="21" style="height:15.75pt">Chromatography column Zorbax Eclipse</td>
			<td class="xl68" style="width:401pt" width="535">&#160;XDB-C18, 4.6 x 100 mm, 3.5 &#181;m HPLC column</td>
			<td>UNSPSC &#8211; 41115709</td>
			<td></td>
		</tr>
		<tr height="21" style="height:15.75pt">
			<td class="xl16" height="21" style="height:15.75pt">Vanquish UHPLC system&#160;</td>
			<td class="xl68" style="width:401pt" width="535">Thermo Fisher Scientific, Germering, Germany</td>
			<td></td>
			<td></td>
		</tr>
		<tr height="21" style="height:15.75pt">
			<td class="xl16" height="21" style="height:15.75pt">Branson B8510 Ultrasonic cleaner&#160;</td>
			<td class="xl68" style="width:401pt" width="535">Branson Ultrasonics (Danbury, CT, USA)</td>
			<td>model (8510-D7H)</td>
			<td></td>
		</tr>
	</tbody>
</table>

failure of cleaning verification in pharmaceutical industry due to uncleanliness of stainless steel surface

这项工作的目的是找出影响医药残留回收表面的不锈钢优惠券的参数。一系列因素进行评估，包括药物产品穗水平、 扣过程、 药物辅料比率，分析师向分析师变异性、 盘中变异性和清洁程序的优惠券。一贯地打扫优惠券表面良好定义过程缺乏被确定为低和可变的经济复苏的主要原因。评估的清洁表面的地方清洁解决方案 (CIP) 优惠券给高价回收 (&#62; 90%) 和可重复性 （Srel≤ 4%） 无论以前评估的条件。该方法已成功应用的清洁验证的小分子 (MW &#60; 1,000 Da) 以及大分子 (MW 到 50,000 Da)。

从最初的尝试清洗验证药物代表结果都列在表 2。优惠券洗干净根据实验部分中的详细步骤之前，不一致的结果得出不同穗层面，对于不同比例的 API/辅料，不同分析师，甚至在不同的日子同样的分析师。观察到的变异性的复苏中需要加以解决，为一些结果失败的验证要求 (60%&#60; 恢复 &#60; 150%)，如为 60%的药物恢复负载限制，在所有清洗。
<p class="jove_content"...

Watch this Scientific Journal Video about Failure of Cleaning Verification in Pharmaceutical Industry Due to Uncleanliness of Stainless Steel Surface at JoVE.com

Failure of Cleaning Verification in Pharmaceutical Industry Due to Uncleanliness of Stainless Steel Surface

一贯地打扫优惠券表面良好定义过程缺乏被确定为低和可变的经济复苏，在清理核查的主要贡献。这份手稿描述的清洗不锈钢优惠券正确的协议。

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