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嘉峪檢測網(wǎng) 2021-09-23 22:26
近日，F(xiàn)DA發(fā)布了《行業(yè)指南：質(zhì)量相關(guān)受控通信問答》（草案），該文件包含了 FDA 當(dāng)前對在與藥企溝通過程中頻繁出現(xiàn)的質(zhì)量有關(guān)主題的觀點，從而讓企業(yè)在藥物開發(fā)活動中可以不需要提交受控通信給 FDA 就能向前推進(jìn)其工作。
問答包含以下領(lǐng)域
分組法/矩陣法
容器密閉器變化
溶出度
微生物（內(nèi)毒素）
批數(shù)
穩(wěn)定性試驗批數(shù)、擺放方向等
包裝
刻痕與片劑分割測試
仿制固體口服制劑的尺寸與形狀
問答部分翻譯如下：
1. Bracketing/Matrixing
分組/矩陣
Question:
問
Is it acceptable to use a bracketingapproach for the manufacture of the exhibit batches of a generic drug productwith multiple strengths produced from common bulk granulations (or blends)? Doall of these exhibit batches need to be put into the stability program?
采用同一制粒工藝（或混合）得到的物料生產(chǎn)多個劑量規(guī)格仿制藥展示批次時，是否可以使用分組法？是不是需要把所有這些展示批都放入穩(wěn)定性試驗計劃？
Answer:
答
A bracketing approach is acceptable for adrug product with multiple strengths, as long as the active and inactiveingredients are in the same proportion between the different strengths (i.e.,the strengths are dose proportional). According to the FDA guidance forindustry ANDAs: Stability Testing of Drug Substances and Products Questions andAnswers (May 2014), for abbreviated new drug applications (ANDAs), threeseparate intermediate bulk granulations (or blends) should be manufactured. Onebatch of bulk granulation (or blend) should be used to manufacture all thestrengths proposed. The other two bulk granulations (or blends) can be used tomanufacture only the lowest and the highest strengths. Three bulk granulations(or blends) should be used to manufacture the strength(s) tested in thebioequivalence (BE) studies.
同一藥品多個劑量規(guī)格時可以使用分組法，前提是不同規(guī)格的活性成分和非活性成分比例相同（即，各規(guī)格處方比例相同）。根據(jù) FDA 行業(yè)指南：ANDA：原料藥和制劑穩(wěn)定性試驗問答（201405），對于 ANDA，應(yīng)生產(chǎn) 3 個單獨的中間體制粒批次（或混合批次）。一個制粒批次（混合批次）用于生產(chǎn)所擬申報的所有規(guī)格，另 2 個制粒批次（混合批次）可只用于生產(chǎn)最低和最高規(guī)格。3 個制粒（或混合）批次應(yīng)該用于生產(chǎn) BE 研究中所用的受檢規(guī)格。
Stability data should be provided for threebatches of the highest strength and three batches of the lowest strength, andthree batches of the strength(s) tested in the BE studies if the strength usedin the BE study was not the highest or lowest strength. Release data should beprovided for all the batches that were manufactured.
應(yīng)提交 3 批最高劑量規(guī)格和 3 批最低劑量規(guī)格的穩(wěn)定性數(shù)據(jù)，如果 BE 研究所用劑量規(guī)格不是最低或最低規(guī)格，則還要有 BE 研究中所測試的規(guī)格的 3 個批次的穩(wěn)定性數(shù)據(jù)。應(yīng)提交所生產(chǎn)的所有批次的放行數(shù)據(jù)。
2. Container-Closure Changes
容器密閉器變化
Question 1:
問 1
If the reference listed drug (RLD) is asterile injectable drug product packaged in an ampule, can the generic productbe packaged in a vial?
如果 RLD(參比制劑) 為安瓿瓶裝無菌注射劑，仿制藥可以裝在西林瓶中嗎？
Answer 1:
答 1
A proposed generic drug product is notrequired to have the same container closure system (CCS) as the RLD. However,the ANDA generally must contain information to show that the proposed genericdrug product has the same conditions of use and the same labeling, with certainpermissible differences, as the RLD2. Refer to FDA guidance for industry DeterminingWhether to Submit an ANDA or a 505(b)(2) Application (May 2019).
并不要求所擬仿制藥采用與 RLD(參比制劑) 完全相同的容器密閉器系統(tǒng)（CCS）。但是 ANDA 一般必須包括有資料證明所擬仿制藥具備相同的使用條件和相同的標(biāo)簽，允許與 RLD(參比制劑) 存在一定差異。參見 FDA 行業(yè)指南：確定是否按 ANDA提交還是按 505(b)(2)申報（201905）。
The proposed CCS will be evaluated duringthe review process3. In the assessment of an ANDA’s proposed CCS, the Agencywill, among other things, evaluate any differences in the proposed CCS relativeto the RLD CCS and determine whether these differences would result in theproposed generic drug product not having the same conditions of use and thesame labeling (with certain permissible differences) as the RLD.
所擬 CCS 應(yīng)在審評過程中進(jìn)行評估。在對 ANDA 提出的 CCS 進(jìn)行評估時，F(xiàn)DA 會評估所擬 CCS 與 RLD(參比制劑) 的 CCS之間的所有差異，確定這些差異是否會導(dǎo)致所擬仿制藥不具備 RLD(參比制劑) 相同的使用條件和相同標(biāo)簽（允許一定程度差異）。
You should follow the recommendations inthe FDA guidance for industry Container Closure Systems for Packaging HumanDrugs and Biologics: Chemistry, Manufacturing, and Controls Documentation (July1999) for the chemistry, manufacturing, and controls (CMC) information thatshould be submitted in the ANDA.
應(yīng)遵守 FDA 行業(yè)指南：人用藥物和生物制品包裝所用容器密閉系統(tǒng)：CMC 文件（199907）中關(guān)于應(yīng)在 ANDA 中提交的 CMC 信息的建議。
Question 2:
問 2
Should a proposed generic ophthalmic drugproduct have the same cap color as the RLD when that color is not in line withthe American Academy of Ophthalmology (AAO) recommendation?
如果 RLD(參比制劑) 眼用藥品的蓋子顏色與美國眼科學(xué)會（AAO）建議不同，仿制藥是否要采用與 RLD(參比制劑) 相同的蓋子顏色？
Answer 2:
答 2
As described in the guidance for industry ContainerClosure Systems for Packaging Human Drugs and Biologics (July 1999), the capcolor of ophthalmic drug products should follow AAO color codes, or theapplicant should provide adequate justification for deviations from the AAOcolor coding system. For the proposed generic drug product, the Agencyrecommends that the color be in accordance with AAO recommendations.
正如行業(yè)指南：包裝人藥和生物制品所用容器密閉系統(tǒng)：CMC 文件（199907）中所述，眼科藥的蓋子顏色應(yīng)遵守 AAO 的顏色代碼，或者申報人應(yīng)該提供足夠的理由支持與 AAO 顏色代碼系統(tǒng)的差異。對于所擬仿制藥，F(xiàn)DA 建議根據(jù) AAO 建議確定其顏色。
In this Q&A, the term review also meansassessment, which is the term that CDER’s Office of Pharmaceutical Quality andOffice of Generic Drugs will generally use in place of review. Assessment meansthe process of both evaluating and analyzing submitted data and information todetermine whether the application meets the requirements for approval anddocumenting that determination.
在本問答中，術(shù)語“審評 review”亦表示“評估 assessment”，CDER 的 OPQ 和 OGD 經(jīng)常會用評估代替審評。評估表示評價和分析所提交的數(shù)據(jù)和資料，確定該申報資料是否滿足批準(zhǔn)要求并記錄該決定的過程。
Dissolution
溶出度
Question:
問
If the dissolution method for a proposedgeneric drug product is not available in the FDA Dissolution Methods Databaseor in the United States Pharmacopeia (USP), can the Agency provide thedissolution method for the product?
如果所擬仿制藥的溶出度檢查方法在 FDA 的溶出方法數(shù)據(jù)庫或 USP 中沒有，F(xiàn)DA 是否可為該藥品提供溶出度檢查方法？
Answer:
答
When neither the USP dissolution method northe FDA’s Dissolution Methods Database provide a dissolution method for aproduct, the Agency recommends that applicants develop an appropriate anddiscriminating dissolution method for the proposed drug product, taking intoconsideration the method development and validation principles described in theUSP General Chapter <711> Dissolution or General Chapter <724> DrugRelease, and USP General Chapter <1092> The Dissolution Procedure: Developmentand Validation.
如果 USP 溶出度方法和 FDA 的溶出度方法數(shù)據(jù)庫均沒有為該產(chǎn)品提供溶出度檢測方法，F(xiàn)DA 建議申報人為所擬藥品開發(fā)具有識別力的適當(dāng)溶出度檢查方法，同時考慮 USP 通則<711>溶出度或通則<724>藥物放行，以及 USP 通則<1092>溶出度方法：開發(fā)和驗證中所述的方法開發(fā)和驗證原則。
Please note that the Agency considers thatdissolution should be product-specific and therefore the selection of thedissolution method and setting of the acceptance criterion/criteria should bebased on the dissolution data generated for the proposed drug product.Therefore, for the in vitro dissolution method to be used for quality control(QC) of your proposed drug product, the Agency recommends that irrespective ofthe source of the proposed dissolution method (USP, FDA, or in-house),additional dissolution studies be conducted to demonstrate the suitability ofthe selected method for the proposed drug product. For this purpose, the Agencyrecommends that the report for the development and validation of an in-housemethod or verification of a USP method being proposed for dissolution QCtesting be provided in the drug product’s ANDA submission, specifically inModule 3.2.P.54. The report should include complete information/data on: i)solubility of the drug substance(s); ii) adequacy of the selected dissolutiontesting conditions (i.e., apparatus, rotation speed, medium, volume, samplingtimes, etc.); iii) validation/verification of the robustness of the selecteddissolution method; iv) validation/verification of the analytical method usedto assay the dissolution samples; and v) demonstration of the discriminatingability of the dissolution method [for modified release products and immediaterelease drug products containing low soluble drug substance(s)].
請注意，F(xiàn)DA 認(rèn)為溶出度方法應(yīng)該是產(chǎn)品專用的，因此溶出度方法的選擇和可接受標(biāo)準(zhǔn)的設(shè)定應(yīng)該根據(jù)所擬藥品中得到的溶出度數(shù)據(jù)。因此，對于你所擬藥品 QC 所用體外溶出度方法，F(xiàn)DA 建議無論所擬溶出度方法來自何處（USP、FDA 或自建），均應(yīng)進(jìn)行更多溶出度研究，證明為所擬藥品選擇的方法的適用性。為此，F(xiàn)DA 建議在產(chǎn)品 ANDA 申報資料中放入準(zhǔn)備用于 QC 溶出度檢測的自建議方法的開發(fā)和驗證報告或 USP 方法的確認(rèn)，具體是放在模塊 3.2.P.5 中。報告應(yīng)包括有完整的資料/數(shù)據(jù)：（1）藥物成分的溶解度，（2）所選擇溶出度檢測條件的充分性（即儀器、旋轉(zhuǎn)速度、介質(zhì)、體積、取樣時間等），（3）所選擇溶出度方法耐用性的驗證/確認(rèn)，（4）用于溶出度檢測樣品分析的分析方法驗證/確認(rèn)，以及（5）證明溶出方法具有識別能力的證據(jù)【含有低溶解度藥物成分的改釋藥品和速釋藥品】。
Additionally, for generic immediate releasesolid oral drug products including a highly soluble drug substance (per theBiopharmaceutics Classification System (BCS) definition5), the Agencyrecommends that dissolution QC testing be conducted as described in FDA’sguidance for industry Dissolution Testing and Acceptance Criteria forImmediate-Release Solid Oral Dosage Form Drug Products Containing HighSolubility Drug Substances (August 2018). The information/data supporting thehigh solubility of the drug substance(s), as described in the BCS guidance (ICHguidance for industry M9 Biopharmaceutics Classification System-BasedBiowaivers (May 2021)) should be included in the ANDA submission (Module3.2.P.5 or Module 3.2.S.1.3), in addition to the proposed drug product’sdissolution data.
另外，對于含有高溶解度藥物成分（依據(jù) BCS 定義）的仿制速釋固體口服制劑，F(xiàn)DA 建議按 FDA行業(yè)指南：含高溶解度藥物成分的速釋固體口服固體制劑的溶出度檢測和可接受標(biāo)準(zhǔn)（201808）執(zhí)行溶出度 QC 檢測。除了所擬制劑的溶出度數(shù)據(jù)外，還應(yīng)在 ANDA 申報資料（模塊 e3.2.P.5 或模塊 3.2.S.1.3）包括如 BCS 指南所述（ICH 行業(yè)指南 M9 基于 BCS 的生物豁免（202105））的支持原料藥高溶解度的資料/數(shù)據(jù)。
Please note that the acceptability of theproposed dissolution method and acceptance criterion(a) will be determinedduring the ANDA review process based on the totality of the provideddissolution data/information and additional data/information may be requestedduring the submission review process.
請注意，在 ANDA 審核流程中，將根據(jù)所提交的全部溶出度數(shù)據(jù)/資料確定所擬溶出度方法和可接受標(biāo)準(zhǔn)的可接受度，在申報資料審評過程中，可能會要求提交其它數(shù)據(jù)/資料。
Microbiology (Endotoxin testing):
微生物（內(nèi)毒素檢測）
Question 1
問 1
How should a bacterial endotoxins testacceptance criterion be determined for the finished drug product?
如何確定制劑成品的細(xì)菌內(nèi)毒素檢測可接受標(biāo)準(zhǔn)？
Answer 1:
答 1
The finished drug product bacterialendotoxins test acceptance criterion should be determined based on the maximumdose that can be delivered within one hour as interpreted from the packageinsert. Special considerations can include:
制劑成品的細(xì)菌內(nèi)毒素檢測可接受標(biāo)準(zhǔn)應(yīng)該根據(jù)包裝說明書中所述的一個小時內(nèi)可給藥的最大劑量計算而得。特別注意事項包括：
Additional doses that may be administeredafter the initial dose,
在初始劑量之后給藥的增加劑量
Maintenance doses administered after an initialbolus dose,
在初始小量單次給藥之后攝入的維持劑量
Incremental dose increases, and
遞增劑量增加，以及
For anesthetics or other drugs for whichrepeat doses are administered until a desired clinical outcome is achieved, themaximum number of potential doses at the minimum specified time intervalbetween doses that could be administered in a one-hour period.
對于麻醉藥和其它重復(fù)給藥直至達(dá)到所需臨床結(jié)果的藥品，以最短指定時間給藥間歇時間計算一個小時內(nèi)可能最大潛在給藥數(shù)量
The USP General Chapter <85> BacterialEndotoxins Test recommended maximum endotoxin exposure is NMT 5 EU/kg(interpreted as within 1 hour) for most drugs based on an average patientweight of 70 kg. For drugs administered to pediatric patients, consult theWHO-CDC growth charts6 for average weight at the youngest patient age for theproposed generic drug.
USP 通則<85>細(xì)菌內(nèi)毒性檢測基于平均患者體重 70kg 建議大多數(shù)藥品最大內(nèi)毒素暴露值為 NMT 5EU/kg（解釋為 1 小時內(nèi)）。對于兒科患者給藥，參見 WHO-CDC 生長曲線得到所擬仿制藥最年輕患者的平均體重。
For drug products administered topically ona body surface area basis, the recommended maximum endotoxins exposure is 100EU per square meter.
對于以人體表面積為基礎(chǔ)的局部給藥藥品，建議最大內(nèi)毒素暴露值為 100EU/m2。
For drug products administeredintrathecally (or epidurally due to risk of inadvertent intrathecaladministration), the maximum recommended exposure is 0.2 EU/kg (in 1 hour).
對于鞘內(nèi)注射藥品（或因疏忽鞘內(nèi)給藥風(fēng)險而采用硬膜給藥），最大建議暴露值為0.2EU/kg（1 小時內(nèi)）。
Please note that USP monographs may containhistorical bacterial endotoxins test acceptance criteria that may not reflectthe maximum dose that can be interpreted from the current drug package insertof the RLD. The proposed endotoxin limit for a proposed generic product shouldbe based on dosing in the current RLD package insert. If the calculated limitis higher than the USP monograph limit, we recommend that applicants submit acontrolled correspondence to confirm acceptability with the Agency prior tosubmission of the ANDA.
請注意 USP 各論可能有些歷史的細(xì)菌內(nèi)毒素檢測可接受標(biāo)準(zhǔn)，未反映出 RLD(參比制劑) 當(dāng)前藥品包裝說明書中可詮釋的最大劑量。為一個所擬仿制藥提議的內(nèi)毒素限度應(yīng)該是基于當(dāng)前的 RLD(參比制劑) 包裝說明書。如果所計算的限度高于 USP 各論限度，我們建議申報人在提交ANDA 之前提交一份受控通信，確認(rèn) FDA 是否可接受。
Question 2:
問 2
Is it acceptable to omit bacterialendotoxin limits in the proposed specification for a topical ophthalmic drugproduct?
是否可接受刪除局部膏劑所擬質(zhì)量標(biāo)準(zhǔn)中的細(xì)菌內(nèi)毒素限度？
Answer 2:
答 2
Topical ophthalmic drug products aregenerally not required to be tested for bacterial endotoxins. Therefore, thefinished product release and stability specifications for topical ophthalmicproducts are not required to include testing for bacterial endotoxins unlessthe labeling indicates that the product is nonpyrogenic. However, if thelabeling for a topical ophthalmic product includes directions for use on anabraded eye and/or use during surgery, a bacterial endotoxin specification forthe drug product may be appropriate.7
外用眼膏制劑一般不需要檢測細(xì)菌內(nèi)毒素。因此，局部眼用制劑放行和穩(wěn)定性質(zhì)量標(biāo)準(zhǔn)不要求有細(xì)菌內(nèi)毒素項目，標(biāo)簽顯示產(chǎn)品為無熱源產(chǎn)品者除外。但是如果局部眼用制劑的標(biāo)簽中使用指導(dǎo)有包括在外科手術(shù)期間使用或用于受損眼部，則可能需要訂有細(xì)菌內(nèi)毒素標(biāo)準(zhǔn)。
Please note that this answer is specific tothis question and does not address other ophthalmic drug products, dosageforms, or combination products that include an ophthalmic drug productcomponent.
請注意本回答針對的是本問題，并不是解決其它眼用制劑、其它劑型，或包括有眼用制劑組份的組合產(chǎn)品。
Number of Batches
批數(shù)
Question 1:
問 1
If an applicant intends to have more thanone drug product manufacturing site in an abbreviated new drug application(ANDA), how many exhibit batches should be provided for each site?
如果申報人想要在 ANDA 中放進(jìn)多個制劑生產(chǎn)場所，每個場所要提供多少展示批？
Answer 1:
答 1
Stability data from three exhibit batchesmanufactured at each drug product manufacturing site for each strength shouldbe submitted in the ANDA, or a bracketing approach as described in Section 2above should be used. The applicant should submit data from at least threebatches of drug product that can include any one of the following batch sizes:
在 ANDA 中應(yīng)提交每個規(guī)格在每個制劑生產(chǎn)場所生產(chǎn)的 3 個展示批次的穩(wěn)定性數(shù)據(jù)，或者如上面第 2 部分所述采用分組方法。申報人應(yīng)按以下批量之一提交至少 3 批數(shù)據(jù)：
Three pilot scale batches, three batchesthat meet the minimum dosage form batch recommendations, whichever is larger, orthree commercial scale batches
3 批中試規(guī)模，或 3 個滿足最小劑型批次建議的批次，取其大者，或 3 批商業(yè)規(guī)模
Twopilot scale batches or two batches that meet the minimum dosage form batch
recommendations, whichever is larger, andone small scale batch
2 批中試規(guī)模，或 2 個滿足最小劑型批次建議的批次，取其大者，加 1 批小規(guī)模
Twocommercial scale batches and one small scale batch
2 批商業(yè)規(guī)模和 1 批小規(guī)模
This data should be submitted from eachdrug product manufacturing site.
各制劑生產(chǎn)場所分別提交上述數(shù)據(jù)。
Orientation
方向
Question 1:
問 1
If the generic drug product is a “forinjection” (sterile lyophilized powder), can stability data for exhibit batchesbe generated using only one orientation?
如果仿制藥是“注射用 ”（無菌凍干粉），展示批的穩(wěn)定性數(shù)據(jù)是否可以僅使用一個擺放方向？
Answer 1:
答 1
According to the FDA guidance for industry ANDAs:Stability Testing of Drug Substances and Products Questions and Answers (May2014), “For primary batches of liquids, solutions, semi-solids, andsuspensions, the product should be placed into an inverted (or horizontal)position and an upright (or vertical) position.” Since lyophilized powders donot fall under one of these categories, exhibit batches for drug products thatare sterile lyophilized powders may be placed on stability in one orientationalone, provided that the ANDA submission includes an adequate justification forthe orientation selected.
根據(jù) FDA 行業(yè)指南：ANDA：原料藥和制劑穩(wěn)定性測試問答（201405），“對于液體、溶液、半固體和混懸液內(nèi)包產(chǎn)品，要采用正向（或水平）方向和倒置（或垂直）方向放置。”由于凍干粉不屬于上述類別，因此無菌凍干粉制劑的展示批穩(wěn)定性測試可以只放置一個方向，前提是 ANDA 申報資料中有足夠的理由支持所選的方向。
Question 2:
問 2
If a product is packaged usingblow-fill-seal technology and the container is composed of a single material,can stability data for exhibit batches be generated using only horizontal orupright orientation?
如果產(chǎn)品使用吹灌封技術(shù)，且容器使用的是一次性材料，展示批的穩(wěn)定性數(shù)據(jù)是否可以僅為使用水平或正向放置產(chǎn)生的數(shù)據(jù)？
Answer 2:
答 2
For products packaged using blow-fill-sealtechnology, stability studies on exhibit batches may be performed in oneorientation alone, as long as the orientation provides maximal contact for thedrug product with container closure system components, including the seal andneck. See guidance for industry Nasal Spray and Inhalation Solution,Suspension, and Spray Drug Products — Chemistry, Manufacturing, and ControlsDocumentation (July 2002).
對于使用吹灌封技術(shù)的產(chǎn)品，展示批的穩(wěn)定性測試可僅采用一種方向，前提是該放置方向能讓藥品接觸最多的容器密閉器系統(tǒng)部件。參見行業(yè)指南：鼻噴霧劑和吸入溶液、混懸液和噴霧制劑—CMC 文件（200207）。
Therefore, stability testing conducted inthe horizontal position would be acceptable if adequate justification is providedin the submission to demonstrate that the position selected represents themaximum contact of the drug product and container closure system components.Stability testing conducted only in the upright or vertical position wouldgenerally be unacceptable due to the lack of exposure of the drug product tothe seal and the twist-off neck area.
因此，如果在申報資料中提交了足夠的論證證明所選擇的方向代表了藥品最大程度接觸容器密閉系統(tǒng)部件，則可以接受水平方向放置的穩(wěn)定性檢測。僅采用垂直方向執(zhí)行的穩(wěn)定性測試一般來說不能接受，因為缺少制劑暴露于密封區(qū)域和瓶頸擰斷區(qū)域的情況。
Packaging
包裝
Question 1:
問 1
Should the three exhibit batches for ageneric product be fully packaged in the proposed marketed packaging?
仿制藥的 3 個展示批次是否要全部包裝在所擬上市包裝中？
Answer 1:
答 1
In accordance with FDA guidances forindustry on Q1A(R2): Stability Testing of New Drug Substances and Products (November2003) and ANDAs: Stability Testing of Drug Substances and Products Questionsand Answers (May 2014), one of the three exhibit batches should be completelypackaged using all the proposed marketed configurations. This batch could beeither a pilot scale or a small scale batch. The other two exhibit batchesshould be packaged in sufficient quantity to comply with 21 CFR 211.166(a)(1-5)and 211.166(b). All batches, including the small scale batch, should bepackaged using commercial packaging equipment or similar equipment. Differentbatches of packaging material should be used where the packaging material couldaffect drug product performance and/or delivery.
根據(jù) FDA 行業(yè)指南 Q1A(R2)：新原料藥和制劑的穩(wěn)定性測試（200311）和 ANDA：原料藥和制劑穩(wěn)定性測試問答（201405），3 個展示批次中有一批應(yīng)該使用所有所擬上市參數(shù)完整包裝。該批次應(yīng)是中試規(guī)?；蛐∫?guī)模批量，另 2 個展示批應(yīng)該按 21 CFR 211.166(a)(1-5) 和 211.166(b)包裝足夠數(shù)量。所有批次，包括小規(guī)模批次，均應(yīng)使用商業(yè)化包裝設(shè)備或類似設(shè)備包裝。如果包裝材料會影響藥品性能和/或給藥情況，則要使用不同批次包裝材料包裝。
Question 2:
問 2
For a combination product consisting of apen injector device with an injectable drug product filled in a cartridge, isit acceptable to package only the amount required for stability into thecartridges and pen injector device for the three exhibit batches submitted inthe ANDA?
對于含有筆式注射器，將注射藥品灌裝在筆筒中的組合產(chǎn)品，是否可以接受 ANDA 中提交的 3 個展示批次只包裝穩(wěn)定性檢測所需數(shù)量到筆筒中和筆式注射器中？
Answer 2:
答 2
For a pen injector device used with aninjectable drug product filled in a cartridge and other similar products, werecommend that all three of the exhibit batches be completely filled intocartridges. As described in FDA guidances for industry Q1A(R2): StabilityTesting of New Drug Substances and Products (November 2003) and ANDAs:Stability Testing of Drug Substances and Products Questions and Answers (May2014), one of the three batches should be entirely assembled into the peninjector devices. The other two primary stability batches should have asufficient number of samples packaged and assembled into the pen injectordevices for stability and reserve samples, in accordance with 21 CFR211.166(a)(1-5), 211.166(b), and 211.170.
對于將注射用藥品灌裝在筆筒同的筆式注射裝置和其它類似產(chǎn)品，我們建議所有 3 個展示批次均完整灌裝到筆筒中。如 FDA 行業(yè)指南 Q1A（R2）：新原料藥和制劑的穩(wěn)定性測試（200311）和 ANDA：原料藥和制劑穩(wěn)定性測試問答（201405）所述，3 批中應(yīng)該有 1 批完整裝配到筆式注射器中，另 2 批基本穩(wěn)定性批次應(yīng)該包裝有足夠數(shù)量的樣品并裝配至筆式注射器中用于穩(wěn)定性留樣和法定留樣，滿足 21 CFR 211.166(a)(1-5), 211.166(b)和 211.170 要求。
Question 1:
問 1
Is the reference listed drug (RLD)considered to have functional scoring when it is not mentioned in the labelingand half the tablet does not match the lowest labeled dose?
如果 RLD(參比制劑) 的標(biāo)簽里沒有說明其是刻痕藥片，片劑的一半并不符合最低標(biāo)示劑量，是否還認(rèn)為 RLD(參比制劑) 有功能性刻痕？
Answer 1:
答 1
Any scoring on the RLD should be consideredfunctional scoring, and therefore, the generic product should have similarscoring. According to FDA guidance for industry Tablet Scoring:
Nomenclature, Labeling, and Data forEvaluation (March 2013), “scoring configuration of generic drug products shouldbe the same as the RLD.” We recommend that split tablet testing be performedand the data submitted in the ANDA; otherwise, the Agency may refuse to receivethe ANDA due to inconsistent scoring configuration between the RLD and the testproduct. (FDA guidance for industry ANDA Submissions – Refuse-to-ReceiveStandards, Rev. 2 (December 2016)).
RLD(參比制劑) 上所有刻痕均認(rèn)為是功能性刻痕，因此仿制藥應(yīng)該有類似的刻痕。根據(jù) FDA 行業(yè)指南：片劑刻痕：命名法、標(biāo)簽和評估用數(shù)據(jù)（201303），“仿制藥的刻痕參數(shù)應(yīng)該與 RLD(參比制劑) 相同”。我們建議進(jìn)行藥片分割測試并在 ANDA 中提交數(shù)據(jù)，否則，F(xiàn)DA 會因為其刻痕參數(shù)與 RLD(參比制劑) 不同而拒收該 ANDA。（FDA 行業(yè)指南：ANDA 申報—拒收標(biāo)準(zhǔn)，R2，201612）
Question 2:
問 2
If the RLD has partial score lines, can theproposed generic product have a full score line(s)?
如果 RLD(參比制劑) 有局部分刻線，所擬仿制藥是否要有全部分刻線？
Answer 2:
答 2
When the RLD has partial score lines, thegeneric can have a full score line(s) to produce partial doses equivalent tothat of the RLD as indicated in the approved labeling. Scoring between the RLDand generic products should be consistent to ensure that the patient is able toadjust the dose by breaking the tablet in the same manner, such that thepatient can switch from the RLD to the generic product without encounteringproblems related to the dose. Additionally, consistent scoring assures thatneither the generic product nor the RLD has an advantage in the marketplacebecause one is scored and one is not. For additional information, see FDAguidance for industry Tablet Scoring: Nomenclature, Labeling, and Data forEvaluation (March 2013).
如果 RLD(參比制劑) 有局部分刻線，則仿制藥可以有全部分刻線得到等同于RLD(參比制劑) 已批準(zhǔn)標(biāo)簽中所指的那部分劑量。RLD(參比制劑) 和仿制藥之間的分刻應(yīng)該一致，確?；颊呖梢酝ㄟ^相同方式掰開藥片調(diào)整劑量，這樣患者就可以從 RLD(參比制劑) 切換到仿制藥而不會面臨與劑量有關(guān)的問題。另外，刻痕一致也確保仿制藥或 RLD(參比制劑) 都不會因為一個有刻痕另一個沒有而在市場上占有優(yōu)勢。更多信息參見 FDA 行業(yè)指南：片劑刻痕：命名法、標(biāo)簽和評估用數(shù)據(jù)（201303）。
Size and Shape of Generic Solid Oral DosageForms
固體口服仿制制劑的尺寸和形狀
Question:
問
If the reference listed drug (RLD) has beendiscontinued and there is no information on its shape and size, is itacceptable to use the shape and size of the FDA designated reference standardto design the generic product?
如果 RLD(參比制劑) 已退市，并且沒有其形狀和尺寸信息，是否可接受使用 FDA 指定參比制劑的形狀和尺寸來設(shè)計仿制藥品？
Answer:
答
In cases where the RLD is not availablebecause it has been discontinued for reasons not associated with safety andefficacy, FDA may have designated a reference standard. The FDA designatedreference standard is recommended to be used in in-vivo bioequivalence studiesas well as comparative in-vitro studies. In this situation, if information onthe size and shape of the RLD are not available, it is acceptable to use thesize and shape of the FDA designated reference standard to develop the genericproduct provided it meets the recommendations in the size and shape guidance.
如果 RLD(參比制劑) 已因為與安全性和有效性無關(guān)的原因退市而無法獲得，F(xiàn)DA 可能指定了另一個參比制劑。FDA 建議在體內(nèi) BE 研究和體外比較研究時使用指定的參比制劑。在此情況下，如果無法獲得 RLD(參比制劑) 的尺寸和形狀信息，可以接受使用 FDA 指定參比制劑的尺寸和形狀開發(fā)仿制藥品，前提是其滿足尺寸和形狀指南中的建議。
來源：Internet
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