混合均一性要求相关资料

罗伊鲱

2003年资料：
http://pqri.org/blend-uniformity-working-group/
http://pqri.org/blend-uniformity/
最新进展：
http://www.ispe.org/blend-content-uniformity-initiative/publications, 2014
http://www.ispe.org/blend-content-uniformity-initiative/tools
Alternatives for Content Uniformity Acceptance Criteria and Stratified Sampling，2015-10-06

补充内容 (2016-5-10 15:29):
http://www.fda.gov/OHRMS/DOCKETS/98fr/992635gd.pdf
http://www.fda.gov/OHRMS/DOCKETS/98fr/03d-0493-gdl0001.pdf

罗伊鲱

07.11.2018

CurrentQuestions on Validation of Blend Uniformity - Stratified Sampling

混合均匀性验证的当前问题－分层取样

Validating blend uniformity is adecisive factor for the validation of solid dosage forms. In Europe, there areno regulatory provisions for this. This is different in the USA: according to21 Code of Federal Regulation (CFR) 211.110, the adequacy of mixing has to beregularly assessed. Until 2013, there was a FDA Draft Guidance which describedhow to realise this assessment. The FDA withdrew it in 2013 though.
验证混合均匀性是固体制剂验证的决定性因素。在欧洲，没有该方面的监管规定。这在美国是不同的：根据21CFR 211.110，混合的充分性必须定期评估。直到2013年，FDA才起草了一份指南草案，描述了如何实现该评估。但FDA在2013年将其撤回。

Now, what is today's state of the art with regard to the validation of blend uniformity? Toprovide guidance on that topic, the ISPE started a Blend Uniformity and ContentUniformity (BUCU) initiative. This initiative was the topic of a webinarorganised last year. In the following, please find a few questions and theanswers provided by the speaker Dr Gerrit Hauck, today at Basilea PharmaceuticalInternational AG.
现在，关于混合均匀性验证的技术水平是什么？为了在这一主题上提供指导，ISPE发起了混合均匀性和含量均匀性（BUCU）倡议。该倡议是去年组织的网络研讨会的主题。在下文中，请查看发言人Gerrit Hauck博士（现在在Basilea 制药国际公司）提供的一些问题和答案。

Question  问	Answer  答
Is an assessment of  blend uniformity via the acceptance value (AV) according to USP 905 generally  still tolerated? In particular with regard to the batch release?	USP 905 exclusively refers to the Uniformity of Dosage Units. The  Stratified Sampling scheme from the DRAFT Guidance dated 2003 was based on  the former, non-harmonised USP Content Uniformity (CU) monograph. Strictly  speaking, the use of the harmonised CU monograph in conjunction with the  scheme for routine production had never been formally accepted. Moreover, the FDA clearly positioned  itself in 2013: a batch release only  on the basis of <905> is rejected by the Agency, testing in accordance  with ASTME2810 is rather expected. The AV doesn't play any role in the  framework of the revised ISPE's BU/CU Guideline.
根据USP 905，通过接受值(AV)对混合均匀性的评估是否仍然可以接受?特别是关于批次放行?	USP 905专指剂量单位的均匀性。2003年指南草案的分层取样方案基于以前的非一致化USP含量均匀性(CU)专论。严格来说，使用一致化CU专论配合常规生产计划从未得到正式接受。此外，FDA在2013年明确立场：仅以<905>为基础的批次放行被监管部门拒绝，按照ASTME2810进行测试则更为期待。AV在修订后的ISPE BU/CU指南中没有任何作用。
In our process of  validation, the tolerated standard deviation is derived as acceptance  criterion depending on the sample size and mean in accordance with the label  claim from the ASTM. Is this procedure acceptable?	As long as you refer  to the tables laid down in ASTME2810, this procedure is - as far as I am  concerned - correct, however only insofar as you consider a pure random  sample. Stratified Samples require other statistics.
在我们的验证过程中，根据ASTM的标签声明，根据样本量和平均值，可接受的标准偏差被认为验收标准。这个方法可以接受吗？	只要你参考ASTME2810中列出的表格，该方法——就我而言——是正确的，但是只在你认为是纯粹的随机样本的情况下。分层样本需要其他统计数据。
Does the assessment  include reviews for normal distribution and trend test?	Testing the normal  distribution is not performed. The submission of a normal distribution is -  to my knowledge - accepted.
评估是否包括正态分布和趋势测试的评估？	未执行正态分布测试。服从正态分布，据我所知是可以接受的。
Does the approach of  validation of mixing remain the same for more than one API?	Usually yes, unless  one of the drug substances would be present in very high concentration so  that one could argue that a determination of the mixing homogeneity shouldn't  be required.
对于多个API，混合验证的方法是否保持不变？	通常是这样的，除非其中一种药物的浓度非常高，这样就可以认为不需要确定混合均匀性。
Is it acceptable for  revalidating established processes to validate according to USP <905>  or is there a risk of getting a finding in case of an inspection?	Basically, the FDA  has adopted a clear position and rejects the use of USP 905 for batch  release. According to me, this also excludes the use of USP 905 for  revalidation. Insofar, there is some risk that a US inspector would criticise  the procedure you described.
根据USP <905>对已建立的工艺进行再验证是否可以接受，或者在检查时是否存在发现的风险？	基本上，FDA已经采取了明确的立场，拒绝使用USP 905进行批次放行。根据我的说法，这也排除了使用USP 905进行再验证。到目前为止，美国检查员可能对你描述的规程吹毛求疵。
Do you apply  sampling already in the routine? How will you ensure in practice that samples  are taken at 30 sampling locations? Will the samples be combined and should I  take more in case that a pill falls off?	Yes, sampling at 20  or 40 sampling locations has to be exactly planned. We usually set the  sampling times on the basis of significant events and then distribute the remaining  samples according to the period between e.g. the beginning of the batch,  change of template and batch end. It is quite not unusual to take more than  e.g. 3 samples per locations so that for example a pill that fell off can be  replaced. We usually take reserve samples.
你是否已经在日常工作中应用取样？在实际生产中，你如何确保在30个取样位置进行取样？样本是否会合并，我是否应该多取一些以防止某药片失效？	是的，在20或40个取样点的取样必须精确计划。我们通常会根据重要的事件来设定采样时间，然后根据批次开始、更改模具和批量结束之间的时间来分配剩余的样品。在每个地点取多于3个样品是很正常的，例如，一个药品失败可以被替换。我们通常采取备用样品。
Will the ISPE  recommendation be soon implemented in a guideline?	To my knowledge, the  implementation in a guideline is not being planned. Through the publication  of the ISPE recommendation, a method aligned with the state of the art is now  available so that there is no actually need for a FDA Guideline.
ISPE的建议会很快在指南中实施吗？	据我所知，一个指南的实施没有计划。通过ISPE建议的发布，一种符合当前技术水平的方法现在可以使用了，因此实际上不需要FDA指南。
Is the ISPE table  provided validated? If yes, can the validation documents be made available?	The table as such is  - to my knowledge - not validated. This should be caught up for in operation.
提供的ISPE表格是否经过验证？如果是，是否能提供验证文件？	就我所知，这个表格本身并没有得到验证。这在实际操作中应该加以注意。
Should the  acceptance value be taken into consideration for BU and CU?	The acceptance value  only applies to the CU testing in accordance with USP 905. Within the scope  of ISPE's testing it is not applicable.
BU和CU的可接受值是否需要考虑？	可接受数值仅适用于符合USP 905的CU测试。在ISPE的测试范围内是不适用的。
Why is the USP  provision far less strict than the expectations of the FDA & Co?	In my opinion, many  tests traditionally used in the pharmaceutical industry are not particularly  demanding. Especially considerations about the risks for consumers are often  excluded from the test criteria. Especially in the USA, the scientific debate  is moving to more demanding tests.
为什么USP的规定远没有FDA的期望严格？	在我看来，许多传统上用于制药行业的测试并不是特别苛刻。对于消费者风险的考虑通常被排除在测试标准之外。特别是在美国，科学辩论正转向要求更高的测试。

Find out what is state of theart regarding the validation of blend uniformity for solids - in the Webinar Stratified Sampling -Update 2018 on 23November from 9 am to 10.30 h.

找出什么是关于固体混合均匀性验证的技术水平－在11月23日上午9点至10点30分的网络研讨会分层取样－2018年更新。

罗伊鲱

Establishing Acceptance Limits for Uniformity of Dosage Units: Part 1

Establishing Acceptance Limits for Uniformity of Dosage Units: Part 2

Establishing Acceptance Limits for Uniformity of Dosage Units: Part 3

Establishing Blend Uniformity Acceptance Criteria for Oral Solid-Dosage Forms

罗伊鲱

Publications by the Blend Uniformity and Content Uniformity (BUCU) Team
Published Articles
Current events in blend and content uniformity ( 4 MB)
Bergum, J.S., PhD, Prescott, J.K,, Tejwani, R.W., Garcia, T.P.,PhD, Clark, J., & Brown, W. (2014)
Pharmaceutical Engineering, 34(2), 28-39.
Abstract: This article presents a summary of the stratified sampling session held at the 2013 ISPE Annual Meeting.

Recommendations for the assessment of blend and content uniformity. Part 1: Modifications to withdrawn FDA draft stratified sampling guidance
Garcia, T., Bergum, J., Prescott, J., Tejwani, R., Parks, T., Clark, J., Brown, W., Muzzio, F., Patel, S., Hoiberg, C. (2014)
Journal of Pharmaceutical Innovation, 10(1), 76-83
Abstract: This paper describes the ISPE sponsored Blend Uniformity and Content Uniformity Group’s proposed modifications to the withdrawn FDA draft guidance document for industry “Powder Blends and Finished Dosage Units – Stratified In-Process Dosage Unit Sampling and Assessment.” The Group’s recommendations targeted FDA’s primary concerns that led to the withdrawal of the draft guidance document, which were insufficient blend uniformity testing and a lack of confidence that the results from USP Uniformity of Dosage Units testing ensure the content uniformity of a batch. The approach clarifies when triplicate blend samples should be analyzed, and the importance of performing variance component analysis on the data to identify root causes of non-uniformity. This particular approach uses acceptance criteria based on ASTM E2810 and E2709 for demonstrating dosage unit uniformity, which provides increased confidence that future samples drawn from the batch will comply with USP Uniformity of Dosage Units. However, alternative statistical methods, sampling plans and acceptance criteria may be substituted for that listed in this paper based on risk and scientific justifications. The approach also links blend and content uniformity to the three stages of the lifecycle process validation approach.

Recommendations for the Assessment of Blend and Content Uniformity. Part 2: Technical Discussion of Sampling Plans and Application of ASTM E2709/E2810
Abstract: This paper provides a technical discussion of the sampling plans and acceptance criteria recommended in, “Recommendations for the Assessment of Blend and Content Uniformity. Part 1: Modifications to Withdrawn FDA Draft Stratified Sampling Guidance.” As discussed in that paper, these plans and criteria are but one choice of a set of plans and criteria that are acceptable to demonstrate blend and content uniformity. This paper provides details and justifications regarding the selection and implementation of the sampling plans and criteria recommended in Part 1.

Presentations
Recommended Changes to Withdrawn FDA Draft Stratified Sampling Guidance Document
( 790 KB)Provides an overview of the BUCU Initiative, its proposal, and progress

lenovol421

抢个沙发，谢谢分享。

syhorchid

下载慢慢学习

罗伊鲱

Statistical Approaches for PPQ Options and Outcomes
http://www.infoscience.com/JPAC/ManScDB/JPACDBEntries/1394123790.pdf

State of Control Over the Lifecycle and Process Validation (New and Legacy Products)
http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/Manufacturing/UCM329487.pdf

胜利者

顶起

liangliangliu12

下载下来慢慢学习，谢谢分享

selinahan

这么多好的资料，需要慢慢看

詹姆斯易

英文太差，表示放弃

亦心

下载慢慢学习，谢谢楼主

山人2011

mark，有时间再看。

罗伊鲱

缘起https://www.ouryao.com/forum.php?mod=viewthread&tid=304662

davidcone

FDA以前的那个2003年的指南草案已经取消了。不过可以作为参考之用。

木头1985

mark，有时间再看。

新华123

谢谢，很好的帖子。我遇到一个问题。一个胶囊产品，
放行规格要求含量是1.9-2.1mg/粒。
测含量均匀度，要求是按照EP药典2.9.6Uniformity of content of single-dose preparation 判定放行。
TEST B
Capsules, powders other than for parenteral use, granules,
suppositories, pessaries. The preparation complies with the
test if not more than one individual content is outside the
limits of 85 per cent to 115 per cent of the average content
and none is outside the limits of 75 per cent to 125 per cent
of the average content. The preparation fails to comply with
the test if more than 3 individual contents are outside the
limits of 85 per cent to 115 per cent of the average content
or if one or more individual contents are outside the limits of
75 per cent to 125 per cent of the average content.
我遇到一个问题，这个Average content必须要在含量的要求范围之内吗？（1.9-2.1）

werewolfman

学习学习。

houmeina

太赞了，如果有人能否系统的发一个混粉均一性的技术文件那就更更赞了。

Judy

totoo1212

占座看看

totoo1212

想请教个问题，在测混粉含量均匀性的时候，取1~3倍剂量，然后质量人员需要按需称取一部分样品，还是全部转移至容量瓶中，精密称定？