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FDA关于生物等效性和生物利用度样品的储存规定
1. FDA对生物等效性样品的法规监管背景
1) 21CFR Sec. 320.38 Retention of bioavailability samples
21CFR 320.38生物利用度样品的留样
2) 21CFR Sec.320.63 Retention of bioequivalence samples
21CFR 320.63生物等效性样品的留样
3) Sec. 211.170 Reserve samples
制剂的cGMP章节下对留样的描述
4) Guidance titled as “ANDAs: Stability Testing of Drug Substances and Products” Q&A
《行业指南-ANDA：制剂和原料药稳定性检测的问答》
5) Guidance titled as “Handling and Retention of BA and BE Testing Samples”
《行业指南-生物利用度和生物等效性试验生物样品的处理和保存要求》
2.上述法规指南对样品储存的具体要求
1) 21CFR 320.38生物利用度样品的留样
Sec. 320.38 Retention of bioavailability samples. 生物利用度样品的留样
(a) The applicant of an application or supplemental application submitted under section 505 of the Federal Food, Drug, and Cosmetic Act, or, if bioavailability testing was performed under contract, the contract research organization shall retain an appropriately identified reserve sample of the drug product for which the applicant is seeking approval (test article) and of the reference standard used to perform an in vivo bioavailability study in accordance with and for the studies described in paragraph (b) of this section that is representative of each sample of the test article and reference standard provided by the applicant for the testing.
ANDA或补充申请的申请人依据FDC&A法令505章节递交资料时，若生物等效性试验由CRO开展，则CRO应保存适当识别的留样样品。留样样品为申请人寻求获批的产品（试验制剂）和参比制剂，二者用于依据章节b或章节b描述的体内生物利用度研究，由申请人提供的、且具有代表性的试验制剂和参比制剂。
(b) Reserve samples shall be retained for the following test articles and reference standards and for the studies described:
对于下述试验制剂和参比制剂及下述的研究，应保存留样：
(1) If the formulation of the test article is the same as the formulation(s) used in the clinical studies demonstrating substantial evidence of safety and effectiveness for the test article’s claimed indications, a reserve sample of the test article used to conduct an in vivo bioavailability study comparing the test article to a reference oral solution, suspension, or injection.
若试验制剂与临床研究中所使用的处方相同，且实质性证据论证了试验制剂所宣称适应症的有效性和安全性，则用于体内生物利用度研究中的试验制剂与与之对比的参比制剂的口服液、混悬液和注射剂需要留样。
(2) If the formulation of the test article differs from the formulation(s) used in the clinical studies demonstrating substantial evidence of safety and effectiveness for the test article’s claimed indications, a reserve sample of the test article and of the reference standard used to conduct an in vivo bioequivalence study comparing the test article to the formulation(s) (reference standard) used in the clinical studies.
若试验制剂与临床研究中所使用的处方不同，且实质性证据论证了试验制剂所宣称适应症的有效性和安全性，则用于体内生物等效性研究中的试验制剂和参比制剂需要留样
(3) For a new formulation, new dosage form, or a new salt or ester of an active drug ingredient or therapeutic moiety that has been approved for marketing, a reserve sample of the test article and of the reference standard used to conduct an in vivo bioequivalence study comparing the test article to a marketed product (reference standard) that contains the same active drug ingredient or therapeutic moiety.
针对已获批准的新处方、新剂型或API的新盐或酯类或治疗分子，则用于体内生物利用度研究中的试验制剂与与之对比的含相同API或治疗分子的上市获批产品（参比制剂）需要留样。
(c) Each reserve sample shall consist of a sufficient quantity to permit FDA to perform five times all of the release tests required in the application or supplemental application.
保留样品的数量应足够允许审评机构能将申请或补充申请中要求的5倍全检放行量。
(d) Each reserve sample shall be adequately identified so that the reserve sample can be positively identified as having come from the same sample as used in the specific bioavailability study.
每个留样均应充分识别，以便能清楚地识别样品来源于哪个特定生物利用度研究试验。
(e) Each reserve sample shall be stored under conditions consistent with product labeling and in an area segregated from the area where testing is conducted and with access limited to authorized personnel. Each reserve sample shall be retained for a period of at least 5 years following the date on which the application or supplemental application is approved, or, if such application or supplemental application is not approved, at least 5 years following the date of completion of the bioavailability study in which the sample from which the reserve sample was obtained was used.
留样样品应在产品标签规定的条件下储存，储存地点与样品分析地方进行隔离。留样样品储存期限应为ANDA申请或补充申请获批后至少5年，或ANDA申请或补充申请未批准，则储存期限为完成生物利用度研究后至少5年。
(f) Authorized FDA personnel will ordinarily collect reserve samples directly from the applicant or contract research organization at the storage site during a preapproval inspection. If authorized FDA personnel are unable to collect samples, FDA may require the applicant or contract research organization to submit the reserve samples to the place identified in the agency’s request. If FDA has not collected or requested delivery of a reserve sample, or if FDA has not collected or requested delivery of any portion of a reserve sample, the applicant or contract research organization shall retain the sample or remaining sample for the 5-year period specified in paragraph (e) of this section.
经授权的FDA人员通常会在批准前检查阶段时直接从申请人或CRO的样品储存地点收集留样。若授权的FDA人员无法收集样品，则FDA可能会要求申请人或CRO提供样品至FDA指定的地方。若FDA未收集样品或未要求递送留样，或FDA未收集样品的一部分或未要求递送留样的的一部分，则申请人或CRO应将留样或剩余样品依据paragraph (e)的要求保存5年期限。
(g) Upon release of the reserve samples to FDA, the applicant or contract research organization shall provide a written assurance that, to the best knowledge and belief of the individual executing the assurance, the reserve samples came from the same samples as used in the specific bioavailability or bioequivalence study identified by the agency. The assurance shall be executed by an individual authorized to act for the applicant or contract research organization in releasing the reserve samples to FDA.
应要求将留样发放给FDA，申请人和CRO应提供一份书面保证书，包装留样与特定生物利用度和生物等效性试验研究中所使用的样品一致。授权的个人代表发放留样的申办方或CRO来出具此类保证书。
(h) A contract research organization may contract with an appropriate, independent third party to provide storage of reserve samples provided that the sponsor of the study has been notified in writing of the name and address of the facility at which the reserve samples will be stored.
如果CRO将第三方机构样品储存地点的名称和地址书面通知申办方，CRO可以与一个适宜且独立的第三方机构签订合同，要求第三方提供留样的储存。
(i) If a contract research organization conducting a bioavailability or bioequivalence study that requires reserve sample retention under this section or 320.63 goes out of business, it shall transfer its reserve samples to an appropriate, independent third party, and shall notify in writing the sponsor of the study of the transfer and provide the study sponsor with the name and address of the facility to which the reserve samples have been transferred.
开展生物利用度或生物等效性研究的CRO，依据本章节或320.63章节需要履行储存样品要求的，若破产停业，应将留样转移至一个适宜且独立的第三方机构，并书面通知试验申办方样品的转移，并将样品转移地点的名称和地址告知申报方。
2) 21CFR 320.63生物等效性样品的留样
The applicant of an abbreviated application or a supplemental application submitted under section 505 of the Federal Food, Drug, and Cosmetic Act, or, if bioequivalence testing was performed under contract, the contract research organization shall retain reserve samples of any test article and reference standard used in conducting an in vivo or in vitro bioequivalence study required for approval of the abbreviated application or supplemental application. The applicant or contract research organization shall retain the reserve samples in accordance with, and for the period specified in 320.38 and shall release the reserve samples to FDA upon request in accordance with 320.38.
ANDA或补充申请的申请人依据FDC&A法令505章节递交资料时，若生物等效性试验由CRO开展，则CRO应保存进行体内和体外生物等效性研究中所使用的试验制剂和参比制剂，以符合ANDA申请或补充申请的要求。CRO应依据320.38所规定的保存期限对样品进行储存，并依据320.38的规定，应FDA要求将样品提供给FDA。
3) 制剂的cGMP章节下对留样的描述
Sec. 211.170 Reserve samples. 211.170留样
(a) An appropriately identified reserve sample that is representative of each lot in each shipment of each active ingredient shall be retained. The reserve sample consists of at least twice the quantity necessary for all tests required to determine whether the active ingredient meets its established specifications, except for sterility and pyrogen testing. The retention time is as follows:
对能代表每批API、每次装运的经适宜识别的样品进行留样。留样量除无菌和热原检测外，应含至少2倍API全检量以确定API是否符合确立的质量标准。留样时间如下：
(1) For an active ingredient in a drug product other than those described in paragraphs (a) (2) and (3) of this section, the reserve sample shall be retained for 1 year after the expiration date of the last lot of the drug product containing the active ingredient.
除paragraphs (a) (2)和(3)章节制剂以外的API, API的留样时间为所含API生产的最后一批制剂的有效期后至少保存1年。
(2) For an active ingredient in a radioactive drug product, except for nonradioactive reagent kits, the reserve sample shall be retained for:
放射性药品中的API，除放射性试剂盒外，留样应储存：
(i) Three months after the expiration date of the last lot of the drug product containing the active ingredient if the expiration dating period of the drug product is 30 days or less; or
若药品的有效期为30天或更短，则API的留样时间为所含API生产的最后一批制剂的有效期后保存3个月。
(ii) Six months after the expiration date of the last lot of the drug product containing the active ingredient if the expiration dating period of the drug product is more than 30 days.
若药品的有效期为30天或更长，则则API的留样时间为所含API生产的最后一批制剂有效期后保存6个月。
(3) For an active ingredient in an OTC drug product that is exempt from bearing an expiration date under 211.137, the reserve sample shall be retained for 3 years after distribution of the last lot of the drug product containing the active ingredient.
除211.137指定有效期外的产品，API留样应保存完成销售最后一批所含API生产的制剂的3年后。
(b) An appropriately identified reserve sample that is representative of each lot or batch of drug product shall be retained and stored under conditions consistent with product labeling. The reserve sample shall be stored in the same immediate container-closure system in which the drug product is marketed or in one that has essentially the same characteristics. The reserve sample consists of at least twice the quantity necessary to perform all the required tests, except those for sterility and pyrogens. Except for those for drug products described in paragraph (b)(2) of this section, reserve samples from representative sample lots or batches selected by acceptable statistical procedures shall be examined visually at least once a year for evidence of deterioration unless visual examination would affect the integrity of the reserve sample. Any evidence of reserve sample deterioration shall be investigated in accordance with 211.192. The results of the examination shall be recorded and maintained with other stability data on the drug product. Reserve samples of compressed medical gases need not be retained. The retention time is as follows:
对能代表每批制剂且经适宜识别的样品进行留样，留样应根据产品标签所规定的条件进行储存。留样应置与于商业化包装一致的包装材料内或具有基本相同特性的包装材料内进行储存。留样量除无菌和热原外，至少为2倍全检量以开展所需的试验。留样量除无菌和热原检测外，应含至少2倍全检量。除了paragraph (b)(2)章节所论述的药品外，来源于代表性批次的留样，经过可接受的统计程序抽样，应至少每年目检一次获取产品破坏的证据，除非目视可能会影响留样的完整性。任何留样破坏的证据应依据211.192进行调查。调查结果应与药品的其他稳定性数据一起记录并保存。压缩医疗气体的留样不需要保存，保存时间如下：
(1) For a drug product other than those described in paragraphs (b) (2) and (3) of this section, the reserve sample shall be retained for 1 year after the expiration date of the drug product.
除paragraphs (a) (2)和(3)章节制剂以外的制剂, 制剂的留样时间为制剂有效期后保存1年。
(2) For a radioactive drug product, except for nonradioactive reagent kits, the reserve sample shall be retained for:
放射性药品，除放射性试剂盒外，留样应储存：
(i) Three months after the expiration date of the drug product if the expiration dating period of the drug product is 30 days or less; or
若药品的有效期为30天或更短，则制剂的留样时间为制剂的有效期后保存3个月。
(ii) Six months after the expiration date of the drug product if the expiration dating period of the drug product is more than 30 days.
若药品的有效期为30天或更长，则制剂的留样时间为制剂的有效期后保存6个月。
(3) For an OTC drug product that is exempt for bearing an expiration date under 211.137, the reserve sample must be retained for 3 years after the lot or batch of drug product is distributed.
除211.137指定有效期外的产品，OTC产品应保存完成销售制剂的3年后。
4)《行业指南-ANDA：制剂和原料药稳定性检测的问答》问题Q10节选
Q10: How long do the three pilot scale batches, submitted as a part of an ANDA, need to be stored before destruction?
作为ANDA申报的中试批（俗称展示批）需要保存多久？
A10: Sample storage times are discussed in 21 CFR 320.38 and 21 CFR 320.63 in connection with bioequivalence study samples. In general, ANDA submission batch samples should be stored for 1 year after approval of the ANDA, and samples of the drug product used for bioequivalence studies must be stored following the requirements listed in 21 CFR 320.38 and 21 CFR 320.63. In addition, the guidance for industry on Handling and Retention of BA and BE Testing Samples may be helpful regarding the procedure for handling reserve samples from relevant bioavailability and bioequivalence studies. Additional information on sample quantities (for retention purposes) is discussed in 21 CFR 211.170 (a) and (b), Reserve Samples.
21 CFR 320.38 和21 CFR 320.63章节对生物等效性样品的储存时间有详细论述。通常，ANDA申报批应在ANDA获批后保存一年，而生物等效性样品应依据21 CFR 320.38和 21 CFR 320.63的规定进行保存。另外，《行业指南-生物利用度和生物等效性试验生物样品的处理和保存要求》在处理生物利用度和生物等效性样品的程序方面有所帮助。21 CFR 211.170 (a)和(b), Reserve Samples留样章节对样品数量（留样用途）有具体论述。
5)《行业指南-生物利用度和生物等效性试验生物样品的处理和保存要求》节选章节
V-保留样品数量章节规定：保留样品的数量应足够允许审评机构能将申请或补充申请中要求的5倍全检放行量。临床研究者可以从申报者或药品生产商处获得5倍全检量。对于口服固体制剂（如片剂、胶囊），认为试验制剂和参比制剂分别为300个单位的上限值足以符合5倍全检放行量的要求。
D-研究申报者和或药品生产商进行的企业内容研究章节规定：如果研究申报者和或药品生产商进行了上述研究，那么就应该将生产保留样品（21CFR 211.170）和BE研究保留样品（21CFR 320.38和320.63）分开进行保存。应将企业内临床研究单位作为独立的单位进行样品保存。应清楚记录关于试验物质和参比标准品的所有事项（如生产、购买、包装、运送记录），在检查期间应出示给FDA研究者。
参考文献：
1.21CFR数据库https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm
【转自：Alma药政法规解读】
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