产品年度回顾是必须每批都回顾吗？？？

beiwei5du

请看下文：

Selection of product batches for review.

FDA revised its GMP in January 1995 toeliminate the requirement for the review of all batches produced in theprevious 12 months and to allow the review of a representative number ofbatches. The preamble to the revised GMP regulations states, however, that thereview of all batches would be appropriate when the review of a representativenumber of batches identifies an adverse trend. The EU and Q7A PQRs do not statethat all batches must be reviewed, other than rejected batches, but these twodocuments also do not specifically allow for the review of representativebatches. FDA defined representative batchesin the preamble ofthe GMP revision as batches that exhibited varying manufacturing experiencessuch as batches that were released, rejected or recalled, batches that were thesubject of FDA field alert reporting filings, batches with manufacturingdiscrepancies, and any batches with outcomes that might indicate the need forchange (8). FDA later refined the definition for representative to include eachbatch that was rejected for a different reason, or a different category ofrejection (10).

按照上文的意思，在美国和欧盟，年度回顾也不是必须涉及到all batches in the preceeding 12 months的，而是representative number of batches（但是必须包括所有的rejected batches,同时能体现varying manufacturing experiences，即各种类型的生产经验批次），但是实操层面又如何进行代表数量的批次选取呢？？每种生产经验类型的批次选多少呢？？统计方式是？？？

beiwei5du

选自CFR 211
§211.180   General requirements.

(e) Written records required by this part shall be maintained so that data therein can be used for evaluating, at least annually, the quality standards of each drug product to determine the need for changes in drug product specifications or manufacturing or control procedures. Written procedures shall be established and followed for such evaluations and shall include provisions for:

(1) A review of a representative number of batches, whether approved or rejected, and, where applicable, records associated with the batch.

(2) A review of complaints, recalls, returned or salvaged drug products, and investigations conducted under §211.192 for each drug product.

(f) Procedures shall be established to assure that the responsible officials of the firm, if they are not personally involved in or immediately aware of such actions, are notified in writing of any investigations conducted under §§211.198, 211.204, or 211.208 of these regulations, any recalls, reports of inspectional observations issued by the Food and Drug Administration, or any regulatory actions relating to good manufacturing practices brought by the Food and Drug Administration.

[43 FR 45077, Sept. 29, 1978, as amended at 60 FR 4091, Jan. 20, 1995]

下文选自 USA federal register(rule and regulation)
E. General RequirementsSection 211.180(e) requires thatwritten records be maintained so thatthe data contained therein are availableat least annually for evaluation of thequality standards for drug products.Proposed § 211.180(e)(1) was intendedto correct the misinterpretation that theregulation required the review of everybatch record for every drug productproduced during the year. The proposedrule revised the language to require atleast annually a review of arepresentative number of batch records.
10. One comment noted that currenttechnology makes it possible to usecomputer data to evaluate productquality data to detect adverse trends.The comment asserted that such anapproach permitted more effective andfrequent evaluation of such data.
The agency agrees that technologicaladvances can produce gains in both theaccuracy of data evaluation and thespeed at which the process can beconducted, and FDA encourages the useof technology that helps safeguard theintegrity of the manufacturing process.However, such computerizedinformation must be used as acomplement to, and not as a substitutefor, human judgment and intervention.Computerized assessments must bemonitored by qualified individuals todetect trends that may provide an earlyindication of changes in drug productspecifications or manufacturing orcontrol procedures that merit attentionand intervention. Moreover, otherfactors such as product complaints andrecall information may not be includedin the computer data.
11. Several comments requestedclarification about the types of recordssubject to the batch review requirement.The proposed rule was not intendedto change the types of records subject toannual review, but instead to allowreview of a representative number ofbatches in lieu of examining all recordsfrom every batch. FDA has, therefore,clarified the final rule to require areview of a representative number ofbatches, whether approved or rejected,and where applicable, recordsassociated with those batches.The overall intent of § 211.180(e) is toprovide manufacturers with reliableprocedures for reviewing the qualitystandards for each drug product. Thus,FDA advises that, although this finalrule does not in all cases require anannual review of every batch record,adopting a procedure to check everybatch record would clearly beappropriate if, for example, arepresentative review of batch recordsshowed an adverse trend in quality.
12. One comment advised that somefirms may confuse the requirementswith regard to the annual review ofrepresentative batches with therequirements for batch review prior tothe release of a product under § 211.192.FDA disagrees with the comment. Thefinal rule amends § 211.180(e), whichrequires that written records bemaintained so that data can be used forevaluating, at least annually, the qualitystandards of each drug product. Section211.192, by contrast, specificallyrequires a quality control unit to reviewdrug product production and controlrecords to determine compliance withwritten procedures prior to the releaseof a drug product batch. In brief,§ 211.180(e) involves a retrospectiveoverall evaluation of the adequacy of thequality standards for drug products,while § 211.192 involves acontemporaneous evaluation of a drugbatch to determine its conformity, at thetime of marketing, with current qualitystandards.
13. One comment suggested allowinga biennial review to permit trendanalysis when three or fewer productbatches are produced each year.FDA disagrees with this comment.The agency believes that a 2-yearinterval between formal review ofbatches is inadequate. Potentialproblems with product qualitystandards could go undetected andthereby delay recognition of a need torevise specifications or manufacturingor control procedures. If a serious erroris not detected for a long period, theresulting product could pose a threat topublic health and safety. Moreover, atrend analysis may be performed insituations where only a few batches areproduced annually by using batchesproduced in preceding years.
14. One comment strongly opposedthe proposed changes, stating that everybatch record must be reviewed to detect‘‘drift’’ or changes in specifications forcomponents, manufacturing processes,or other procedures. The commentasserted that, without reviewing everybatch, deleterious changes might beinstituted by a firm employee oremployees without the full knowledgeof their superiors, particularly the firm’sresearch and development group
The agency does not believe suchadditional measures are necessary. ThisCGMP provision does not stand alonebut must be read in context with otherCGMP regulations. Those regulationsprovide a variety of safeguards fordifferent stages and aspects of the drugmanufacturing process. It is the CGMPregulations, taken as a whole, that helpensure drug quality. Moreover, theconsequences of widespread disclosureof problems with drug product qualityresulting from a recall or otherameliorative action are sufficientlysevere to provide most firms with acontinuing incentive to maintainproduct quality. The agency hascarefully reviewed this issue andbelieves that the final rule will notreduce drug product quality（GMP法规的整体控制观念，切忌局部过度冗余评估）

beiwei5du

但是在TGA上却有此Q&A
22. Do all batches for which manufacture has commenced have to be included in Product Quality Reviews (PQR)s?

Yes. For example, also all batches for which the manufacture was terminated, delayed or has failed are expected to be included in the PQRs. When grouping is applied, all batches of all products in each group are expected to be included in the PQR.

静水蓝心

看来法规也是各有各的主张，不尽然相同的。

zysx01234

对于要回顾的产品来说，当然是每批都要回顾的，作图的时候可以将不合格批剔除掉单独说明，否则计算标准偏差明显偏大。

scslk0045

谢谢楼主的分析

xqliu

学习一下啦，谢谢提供分享。

beiwei5du

What constitutes a "representative number of batches" that must be reviewed periodically for quality standards under the CGMP regulations?

Reference: 21 CFR 211.180(e), General requirements [Subpart J - Records and Reports], 21 CFR 314.81(b)(1), Other post marketing reports [Subpart B - Applications]

The annual review established by 211.180(e) is for the purpose of "evaluating the quality drug standards of each drug product to determine the need for changes in drug product specifications or manufacturing or control procedures". The selection of records to be reviewed needs to consider "records required by this part" which have "data therein" and include the records specified in 211.180 (e)(1) and 211.180(e)(2).

The number of batches whose associated records will be reviewed must achieve the purpose of the review. Any reasonable approach to achieve the purpose can be acceptable; the word "representative" was inserted into this regulation in January 1995 to simply confirm that every batch does not necessarily have to be included.

Reviewing batches which exhibit varying manufacturing experiences is a critical element in ensuring that a "representative" selection is made. Batches showing different categories of experiences would include those that:

(1) Have been approved, rejected, and recalled;

(2) have unexplained discrepancies;

(3) were the subject of FARs (field alert reports); and,

(4) have any other kind of outcome that may indicate changes are needed.

Where any of these categories include multiple problems, the number of batches selected for review should fully represent the different kinds of problems in each category.

Every drug product must have at least one batch included in the annual review. Different products may not be grouped by "similar processes" or any other similar approach, because the necessary differences in the process and/or specifications which make each product unique may result in different manufacturing outcomes.

Contact for further info: Nicholas Buhay, HFD-325, 301-594-0098; e-mail: buhay@cder.fda.gov

一沙一叶

有问题的至少要被涵盖进去

一沙一叶

beiwei5du 发表于 2016-10-30 15:26
What constitutes a "representative number of batches" that must be reviewed periodically for quality ...

看来你是找了很多资料了

22311862

对于要回顾的产品来说，当然是每批都要回顾的，作图的时候可以将不合格批剔除掉单独说明，否则计算标准偏差明显偏大。

小金库

谢谢分享。

jssben

好贴，谢谢分享！