（原创） FDA 《质量量度要求》指南草案 [反馈意见] 个人解读

lhqboy

wangfuliyxm 发表于 2016-6-10 13:07
学习了

你真学习了假学习了啊？

beiwei5du

很多在2016年末的revision 1（仍为draft)中有说明了，而且三个quality metrics是FDA进行计算的，并非企业计算提供。质量量度的基础数据是企业提供的（具体也有相关的列表，而且数据种类更多，并且给数据提供者相应的数据说明comments的机会（如果看起来异常的话）），同时三个质量量度指标结果仅仅是参考，FDA还会结合提交的其他数据整体上考虑，并且也非单个时间段考虑，会结合整个所有提及数据的整个时间整体考虑。quality metrics的结果也非公开的，仅仅FDA内部决策使用，而仅提供一个质量量度参与者名单公示。

beiwei5du

这个是北大后面跟进的一个的2015版的质量量度的一个评论，希望大家可以跟进讨论一下：@julia朱玉姣 @呼吸 @Jason

Line 222–223, “PQCR = the number of product quality complaints received for the product
divided by the total number of dosage units distributed in the current reporting timeframe.”

Comment:
1.  If the product Z is not produced in the current reporting timeframe but complaints are
received  for the batches  produced  in the previous reporting timeframe, shall the
complaints be counted in the current timeframe or  be updated  in  the previous?  If
counted in the current timeframe, the PQCR will have zero as denominator.
2.  For API products, the complaints are potentially more often on a whole batch than a
portion of a batch. Thus, for manufacturers producing the same API product with a
same number of batches  per year,  the manufacturer with a larger batch size may
naturally have a lower PQCR, since the numerator is identical while a larger batch size
means a larger denominator. For example, for the same API product, manufacturer X
produces 10 batches a year with a batch size of 10kg, and manufacturer Y produces
10 batches a year with a batch size of 100kg. Both of the manufacturers receive one
compliant on one batch. The PQCR of manufacturer X will be 10 times of that of Y.


Line 226–229,  “IOOSR = the number of OOS test results for lot release and long-term
stability testing invalidated by the covered establishment due to an aberration of the
measurement process divided by the total number of lot release and long-term stability
OOS test results in the current reporting timeframe.”

Comment:
1.  If the investigation shows  the OOS is caused by QA sampling aberration  instead of
QC testing, should the OOS be counted as an invalidated OOS test result?
2.  If the OOS investigation fails in finding the root cause, and the batch is finally released
based on statistically sound retesting and totality of evidence, should the OOS result
be counted and should it be counted as an invalidated OOS test results?



Line 320, “Specific criteria for the IOOSR data”

Comment:
If five samples from five batches for five  lot release tests are prepared in a row, and the
sample  preparation was incorrect for all the samples, thus resulting in five OOS test
results, should it be counted as five OOS test results and five invalidated OOS test results,
or one OOS test results and one invalidated OOS test results, considering  the five
mistakes made are actually sharing the same root cause.   

Line644–646, “Product Quality Complaint – a complaint involving any possible, including
actual, failure of a drug to meet any of its specifications designed to ensure that any drug
conforms to appropriate standards of identity strength, quality, and purity.”

Comment:
1.  If the API or intermediate manufacturer receives a quality complaint from the finished
product  manufacturer, and the investigation  eventually  shows the issue  actually
caused by the  latter. Should the complaint  still  be counted as a product quality
compliant on the API or intermediate manufacturer?
2.  If the API or intermediate manufacturer produces products with the same process and
standards, and delivers the products to five finished product manufacturer clients. The
API manufacturer receives one quality complaint from one of its five clients, indicating
the product does not meet  its  in-house purchasing standards, which is much tighter
than the USP as well as that of the other four clients. Should this complaint be counted
as a quality compliant that involves possible or actual  failure of  the drug to meet its
specifications designed to ensure that the drug conforms to appropriate standards of
identity strength, quality, and purity?

Line 673, “Appendix A.1: Applicable Inputs for a Product Report Submission, Application
Product, Finished Drug Product”

Comment:
1.  For product reporting establishments owning and manufacturing the product, none of
the four rows  in the  table  seems applicable.  Consider to add a new  row for this
circumstance.   
2.  Please provide examples and demonstrations for the Appendix A tables.

Line 718, “APPENDIX B: EXAMPLES”

Comment:
1.  Please  provide  examples  in the context of  API  and intermediate  manufacturing,
especially for Lot Acceptance Rate and Product Quality Complaint Rate.
2.  Specifically, for the Lot Acceptance Rate, how to define packaging product lots for API
and intermediate?

beiwei5du

这个是北大后面跟进的一个的2015版的质量量度的一个评论，希望大家可以跟进讨论一下

Line 222–223, “PQCR = the number of product quality complaints received for the product
divided by the total number of dosage units distributed in the current reporting timeframe.”

Comment:
1.  If the product Z is not produced in the current reporting timeframe but complaints are
received  for the batches  produced  in the previous reporting timeframe, shall the
complaints be counted in the current timeframe or  be updated  in  the previous?  If
counted in the current timeframe, the PQCR will have zero as denominator.
相当于Z产品今年没有生产，上年Z产品的投诉在今年才收到，那么在今年计算的话按照公式计算的话，分母为0了！还是更新去年的PQCR??
2.  For API products, the complaints are potentially more often on a whole batch than a
portion of a batch. Thus, for manufacturers producing the same API product with a
same number of batches  per year,  the manufacturer with a larger batch size may
naturally have a lower PQCR, since the numerator is identical while a larger batch size
means a larger denominator. For example, for the same API product, manufacturer X
produces 10 batches a year with a batch size of 10kg, and manufacturer Y produces
10 batches a year with a batch size of 100kg. Both of the manufacturers receive one
compliant on one batch. The PQCR of manufacturer X will be 10 times of that of Y.
备注：Dosage Units – the total number of individual dosage units (e.g., 100,000 tablets, 50,000 vials, 50 kg), distributed or shipped under the approved application or product family (for non-application products) to customers, including distributors.
确实如果是分母是“the total number of dosage units distributed in the current reporting timeframe. ”的话，会出现批量越小，PQCR越大的问题


Line 226–229,  “IOOSR = the number of OOS test results for lot release and long-term
stability testing invalidated by the covered establishment due to an aberration of the
measurement process divided by the total number of lot release and long-term stability
OOS test results in the current reporting timeframe.”

Comment:
1.  If the investigation shows  the OOS is caused by QA sampling aberration  instead of
QC testing, should the OOS be counted as an invalidated OOS test result?
由于QA取样问题，造成的OOS值，也应该是无效OOS检测结果，为什么会这样问呢？？但是确实通过质量量度中定义的无效OOS，无法判断（aberration of the measurement process)
2.  If the OOS investigation fails in finding the root cause, and the batch is finally released
based on statistically sound retesting and totality of evidence, should the OOS result
be counted and should it be counted as an invalidated OOS test results?
确实针对于没有找到原因，但是基于 statistically sound retesting and totality of evidence最终放行的，这个OOS是不是能定义为invalidated OOS呢？？？确实这个定义不清楚。
注“Invalidated OOS – any out-of-specification result where the investigation identifies the source of the OOS result as an aberration of the measurement process.  Invalidation of a
discrete test result may be done only upon the observation and documentation of a test
event that can reasonably be determined to have caused the OOS result.For the
purpose of the quality metrics program, the following test events should be included:  (1)
lot release and stability test results only and, (2) all lot release and stability test results
that initially appear as OOS, even if invalidated by a subsequent laboratory investigation.


Line 320, “Specific criteria for the IOOSR data”

Comment:
If five samples from five batches for five  lot release tests are prepared in a row, and the
sample  preparation was incorrect for all the samples, thus resulting in five OOS test
results, should it be counted as five OOS test results and five invalidated OOS test results,
or one OOS test results and one invalidated OOS test results, considering  the five
mistakes made are actually sharing the same root cause.  
来自五批产品的五个样品连续进行放行检测，并且样品制备都错误，导致了五个OOS，是应该算作5个OOS和5个无效OOS，还是1个OOS结果和1个无效OOS，因为考虑到5个错误都实际上源自于同一个错误。

Line644–646, “Product Quality Complaint – a complaint involving any possible, including
actual, failure of a drug to meet any of its specifications designed to ensure that any drug
conforms to appropriate standards of identity strength, quality, and purity.”

Comment:
1.  If the API or intermediate manufacturer receives a quality complaint from the finished
product  manufacturer, and the investigation  eventually  shows the issue  actually
caused by the  latter. Should the complaint  still  be counted as a product quality
compliant on the API or intermediate manufacturer?
如果API厂商接受了制剂厂商的投诉，但是最终发现是制剂厂商的问题，那么这个投诉是否纳入API厂商的PQCR计算中??个人认为:按照道理来说如果是制剂厂商的问题，已经确认投诉非API，那么就不应该计算到API厂商的PQCR中计算，大家怎么看？？
2.  If the API or intermediate manufacturer produces products with the same process and
standards, and delivers the products to five finished product manufacturer clients. The
API manufacturer receives one quality complaint from one of its five clients, indicating
the product does not meet  its  in-house purchasing standards, which is much tighter
than the USP as well as that of the other four clients. Should this complaint be counted
as a quality compliant that involves possible or actual  failure of  the drug to meet its
specifications designed to ensure that the drug conforms to appropriate standards of
identity strength, quality, and purity?
如果API或者中间体厂家生产了药品，供应5个制剂客户，但是其中一个制剂客户投诉API未满足其内控标准（其内控标准比USP以及其他四个客户都要严格的多），那么这个投诉是否纳入API厂商的PQCR计算中？？按理来说没有满足客户的标准（intended use)，就应该考虑纳入。

Line 673, “Appendix A.1: Applicable Inputs for a Product Report Submission, Application
Product, Finished Drug Product”

Comment:
1.  For product reporting establishments owning and manufacturing the product, none of
the four rows  in the  table  seems applicable.  Consider to add a new  row for this
circumstance.   
2.  Please provide examples and demonstrations for the Appendix A tables.

Line 718, “APPENDIX B: EXAMPLES”

Comment:
1.  Please  provide  examples  in the context of  API  and intermediate  manufacturing,
especially for Lot Acceptance Rate and Product Quality Complaint Rate.
2.  Specifically, for the Lot Acceptance Rate, how to define packaging product lots for API
and intermediate?

小金库

非常感谢分享