Pharmaceutical Technology; APRIL 2011（2011年4月）

Common Deficiencies in Abbreviated New Drug Applications

Part 4: Manufacture (2.3.P.3) and Container Closure System (2.3.P.7)

Aloka Srinivasan and Robert Iser

仿制藥申報(bào)常見缺陷信解讀

第四部分：生產(chǎn)（2.3.P.3）和容器包裝系統(tǒng)（2.3.P.7）

Chemistry reviewers in the US Food and Drug Administration’s Office of Generic Drugs provide Part 4 of an overview of common deficiencies cited throughout the Chemistry, Manufacturing, and Controls section of abbreviated new dru appplications (ANDAs).

The reviewers aim to assist ANDA sponsors in building quality into their submissions by clarifying components of the applications. Part 4 addresses manufacture and container-closure.

食品和藥品管理局（FDA）仿制藥辦公室（Office of Generic Drugs）的化學(xué)審評(píng)員提供了第四部分的概述，列舉了簡化新藥/仿制藥申請(qǐng)（ANDAs）中化學(xué)、制造和控制部分的常見缺陷。

評(píng)審員的目標(biāo)是通過澄清申請(qǐng)的組成部分來幫助ANDA發(fā)起者，提高其申報(bào)的質(zhì)量。第四部分闡述生產(chǎn)和容器包裝系統(tǒng)。

Aloka Srinivasan, PhD,* is a team leader, and Robert Iser, M.S., is an acting director, both at the Office of Generic Drugs within the Office of Pharmaceutical Science, under the US Food and Drug Administration’s Center for Drug Evaluation and Research, Aloka.Srinivasan@fda.hhs.gov.

*To whom all correspondence should be addressed.

Aloka Srinivasan 博士是食品和藥品管理局（FDA）藥物審評(píng)與研究中心下屬的仿制藥辦公室（Office of Generic Drugs）的團(tuán)隊(duì)負(fù)責(zé)人，醫(yī)學(xué)碩士 Robert Iser 是代理主任。

所有的信件都可以寄給：Aloka.Srinivasan@fda.hhs.gov。

As part of FDA’s Office of Generic Drugs’ (OGD) ongoing effort to streamline the review process and reduce the number of deficiencies cited for abbreviated new drug applications (ANDAs), a series of articles is being published to provide transparency and clarity to applicants submitting applications in the question-based review (QbR) format. The articles highlight the need and significance of science-based justification in establishing drug substance (DS) and drug product (DP) specifications, in-process controls, choice of formulation, selection of a product design, and selection of the manufacturing processes. Part 1 of this series, which dealt with the deficiencies cited in the drug substance section, was published in January 2010 (1). Part 2 of the series regarding drug product composition and excipients and Part 3, regarding the control of the drug product and stability, were published in August 2010 (2) and February 2011 (3), respectively.

作為美國食品和藥物管理局（FDA）的一部分，仿制藥辦公室（OGD）正在努力簡化審評(píng)流程和降低審評(píng)中缺陷的數(shù)量，目前正在發(fā)表一系列文章，為“以基于問題審查（QbR）格式”提交申請(qǐng)的申請(qǐng)人提供透明度和清晰度。在建立原料藥（DS）和制劑（DP）質(zhì)量標(biāo)準(zhǔn)、過程控制、處方選擇、產(chǎn)品設(shè)計(jì)選擇，和生產(chǎn)工藝選擇中，這些文章強(qiáng)調(diào)了科學(xué)論證的必要性和重要性。ANDA申報(bào)常見缺陷系列第1部分發(fā)表于2010年1月，是關(guān)于原料藥部分提到的缺陷；第2部分發(fā)表于2010年8月，是關(guān)于藥品組成和輔料方面的缺陷；第3部分發(fā)表于2011年2月，是關(guān)于制劑的控制和穩(wěn)定性方法的缺陷。

The current article is the last of this series, with the focus on providing clarification regarding some common deficiencies cited in the drug product manufacturing (3.2.P.3) and the container closure system (3.2.P.7) portions of ANDA submissions using the Common Technical Document (CTD) and Question-based Review–Quality Overall Summary (QbR-QOS) format as a guide. See the sidebar for a list of some of the deficiencies and comments related to these sections. This is not an all-inclusive list of comments and deficiencies pertaining to the drug product manufacturing and container closure controls and information; but includes some questions that are cited frequently.

本文是該缺陷信系列的最后一篇文章，意圖是闡明，以通用技術(shù)文件（CTD）和基于問題審查的質(zhì)量總體概述（QbR-QOS）格式為指南，在遞交簡化新藥/仿制藥申請(qǐng)（ANDAs）中，引用的生產(chǎn)（3.2.P.3）和容器包裝系統(tǒng)（3.2.P.7）部分的，一些常見缺陷的意圖和重要性。該部分相關(guān)的缺陷和評(píng)論列表，請(qǐng)參閱側(cè)欄。這個(gè)列表不是包羅萬象的，但確實(shí)包括經(jīng)常被引用的注釋和有關(guān)生產(chǎn)和容器包裝控制和信息的缺陷。

Examples of Commonly Cited Manufacturing (3.2.P.3) and Container Closure System (3.2.P.7) Deficiencies and Comments

引用的常見生產(chǎn)（3.2.P.3）和容器包裝系統(tǒng)（3.2.P.7）缺陷舉例及評(píng)論**

1.Based on your commercial batch formula, it appears that an x% excess of API is being proposed. Please justify this proposed excess.

根據(jù)你們的商業(yè)處方，很明顯原料藥超出X%，請(qǐng)?zhí)峁┰撨^量的合理性。

2.We note that the reconciliation of your exhibit lots is very poor. Please include any investigations done to account for these losses and steps proposed to avoid similar losses during the production of the commercial lots.

我們注意到你們的展示批的物料平衡很差，請(qǐng)包含對(duì)這些損耗原因的調(diào)查以及采用步驟以避免商業(yè)生產(chǎn)中類似的損耗。

3.We were unable to locate a clear list of in-process controls with the proposed acceptance criteria in the QbR–QOS or the body of data. Please provide the same.

我們不能在基于問題審核-質(zhì)量綜述（QbR–QOS）或數(shù)據(jù)正文中清楚地查找工藝控制及其采用的可接受限度的列表，請(qǐng)?zhí)峁?/p>

4.Based on the fact that the limit for assay of the tablets during release is 95.0–105.0%, we recommend that an in-process composite blend assay is included with a range that is commensurate with the assay of the drug product during release testing.

根據(jù)片劑放行的含量限度為95.0–105.0%的事實(shí)，我們建議在放行檢測中增加與制劑含量范圍一致的混合工藝的含量測定。

5.In view of the low concentration of the active pharmaceutical ingredient in the final blend and also the dry blending and compression process used for manufacturing, please provide available information regarding the segregation potential of the blend under your manufacturing conditions, and the possible impact on the content uniformity.

考慮到用于生產(chǎn)的最終混合、干燥混合和壓片工藝中原料藥含量低，請(qǐng)?zhí)峁┰谀銈兩a(chǎn)條件下混合時(shí)潛在的分層的有關(guān)信息以及對(duì)含量均勻度的影響。

6.Please justify the proposed hardness range for the drug product by demonstrating that it meets the dissolution and friability criteria at the highest and lowest points of the proposed range.

請(qǐng)通過證實(shí)所提議的硬度范圍的最高點(diǎn)和最低點(diǎn)時(shí)制劑的溶出度和脆碎標(biāo)準(zhǔn)符合規(guī)定，來確認(rèn)制劑采用的硬度范圍的合量性。

7.Your description of the granulation end point is very subjective. We request you to provide us with information regarding an end point of the granulation stage based on the process development studies. Please provide information regarding the steps to be taken if a suitable granulate is not formed by allocated time of mixing and its effect on the quality of your final product.

你們有關(guān)制粒終點(diǎn)的描述非常主觀，我們要求你提供基于工藝開發(fā)研究有關(guān)制劑階段終點(diǎn)的信息。請(qǐng)?zhí)峁┎捎玫幕旌戏峙鋾r(shí)間等步驟是否能形成適宜的顆粒以及對(duì)終產(chǎn)品質(zhì)量的影響。

8.Please provide a justification for the moisture level proposed at the end of the wet granulation process and studies done to assess its impact on the quality of the granulate and the final product.

請(qǐng)?zhí)峁穹ㄖ屏９に嚱Y(jié)束時(shí)所采用的水分標(biāo)準(zhǔn)的合理性以及所進(jìn)行的研究評(píng)價(jià)其對(duì)顆粒和終產(chǎn)品質(zhì)量的影響。

9.Please clarify if you have a continuous monitoring program for the weight checks during tablet compression. In absence of this, the control strategy during compression appears to be inadequate. Please increase the frequency of tests for all critical quality attributes such as hardness, friability, and weight check (both average and individual) during the validation and commercial manufacturing to better ensure the product quality.

請(qǐng)闡明你們在壓片過程中是否有重量檢查的連續(xù)監(jiān)控程序，如果沒有的話，壓片過程的控制策略是不充足的，請(qǐng)?jiān)隍?yàn)證和商業(yè)生產(chǎn)中增加所有關(guān)鍵質(zhì)量屬性（如：硬度、脆碎度和重量檢查（平均和單個(gè)））檢測的頻率以保證產(chǎn)品質(zhì)量。

10.We note that your proposed design for the drug product consists of the odified release beads in capsules that may be sprinkled. Based on currently published literature regarding sprinkle capsules and the OGD draft guidance, Guidance for the Industry, Size of Beads in Drug Products Labeled for Sprinkle, we recommend that you include suitable control for the particle size of the coated beads in your drug product.

我們注意到你們采用的產(chǎn)品設(shè)計(jì)中膠囊含有緩釋圓珠可以分散用，基于當(dāng)前發(fā)布的關(guān)于分散型膠囊的文獻(xiàn)和仿制藥辦公室（OGD）指南草案“分散用制劑的圓珠大小”，我們建議你在你們制劑中包含對(duì)包衣圓珠粒徑的適宜控制。

11.A list of materials, approved for use in the manufacturing process of your drug product (a parenteral dosage form), are listed in the provided batch records. However, no justification is provided regarding the compatibility of the listed materials and the proposed drug product solution. Please provide your justification for listed process materials; and include any compatibility studies that may have been performed with the proposed drug product.

你們所提供的批記錄中制劑（一個(gè)注射用制劑）的生產(chǎn)工藝中所用的批準(zhǔn)物料的列表，未提供所列物料和所提議的制劑溶液的相容性的合理性，請(qǐng)?zhí)峁┧泄に囄锪系暮侠硇?，以及包括其與所提議制劑的相容性研究。

12.Please justify the proposed fill volume for your drug product (parenteral) based on the excess recommended in USP<1151>. Alternatively provide us with pharmaceutical development studies performed to assure that the proposed fill volume is sufficient to permit withdrawal of the labelled amount.

根據(jù)USP<1151>推薦的過量確認(rèn)你們所提議的制劑裝量的合理性，或者提供藥物開發(fā)研究以保證所提議的裝量能足夠按標(biāo)簽量倒出藥物。

13.Please provide information regarding performance testing of the containers based on USP<671>.

請(qǐng)?zhí)峁┗赨SP<671>進(jìn)行的容器性能檢測的相關(guān)信息。

14.Please provide moisture permeation data for the proposed blister pack.

請(qǐng)?zhí)峁┧嶙h泡罩包裝的水分滲透數(shù)據(jù)。

15.Please provide the results of leak test performed on the blister pack.

請(qǐng)?zhí)峁┡菡职b的泄漏檢測結(jié)果。

16.In terms of extractables, it is stated that during accelerated stability analysis, no recordable levels of new impurities were observed. Please comment on the adequacy of the proposed method with respect to the method capability of detecting and quantifying possible extractables from the stoppers.

可萃取物研究方面，在加速穩(wěn)定性分析中，未觀察到新雜質(zhì)的可記錄水平，請(qǐng)對(duì)所用方法及其方法對(duì)瓶塞中的可萃取物的相應(yīng)的檢測和定量能力進(jìn)行注釋。

17.During the extraction testing for the proposed stoppers, both water and IPA were utilized as extraction agents. However, there is no information provided regarding the use of drug product placebo solution in the extraction studies. As the drug product formulation includes excipients, which can act as chelating agents, please provide rationale why the drug product placebo solution was not used in the extraction studies; and if extraction data is available please provide these data.

在所用瓶塞的萃取檢測中，使用了水和異丙醇作為萃取劑，然而，在萃取研究中未提供制劑空白溶液研究的有關(guān)信息。因?yàn)橹苿┨幏街邪蟿╊愝o料，請(qǐng)?zhí)峁槭裁粗苿┛瞻兹芤翰挥糜谳腿⊙芯康脑蛞约笆欠裼休腿?shù)據(jù)，如果有的話，請(qǐng)?zhí)峁┻@些數(shù)據(jù)。

18.We note that based on the size of the proposed bottles, there will be significant amount of headspace for the package of x tablets. Since the dosage form is orally disintegrating tablets with low friability, mechanical shocks and abrasion during the transportation and storage can lead to chipping, abrasion or even breakage. Please provide any studies that were performed to demonstrate integrity of tablets during transportation and storage.

我們注意到基于所用的瓶子的尺寸，在x片包裝時(shí)有明顯的頂空。因?yàn)閯┬蜑橐姿樾缘目诒榔?、在運(yùn)輸和貯藏中的機(jī)械性沖擊和磨損可能導(dǎo)致碎屑、磨損或甚至裂片，請(qǐng)?zhí)峁┳C實(shí)在運(yùn)輸和貯藏過程中片子完整性所進(jìn)行的研究。

**Comments are usually not deficiencies and are found in section B of deficiency letters.

評(píng)論通常不是缺陷，見缺陷信的B章節(jié)項(xiàng)下。

2.3.P.3 Manufacture 生產(chǎn)

There are a myriad of manufacturing processes related to dosage forms available in the market. It is beyond the realm of this article to cover all this information. Thus, the focus will be chiefly on the deficiencies and other comments raised while reviewing the in-process data and controls. In-process controls (IPCs) and manufacturing data for the exhibit batches represent sections of ANDA submissions where a majority of manufacturing deficiencies are cited.

市場上有無數(shù)與劑型相關(guān)的生產(chǎn)工藝。本文并未涵蓋所有這些信息，而是將重點(diǎn)放在審查工藝數(shù)據(jù)和控制時(shí)提出的缺陷和其他評(píng)論。在遞交的ANDA申報(bào)中，引用的大部分生產(chǎn)缺陷是，與展示批相關(guān)的工藝控制（IPCs）和生產(chǎn)數(shù)據(jù)。

Before delving into IPCs, we would be remiss without noting a common deficiency with regard to proposed batch formula. A deficiency is often cited when the information regarding the actual manufacturing formula for the exhibit lot and the proposed commercial lots is not provided. It is preferable that the quantities of all the raw materials used in the formulation including those, which do not appear in the final formulation, be provided in a clear tabular format for ease of comparison. Any overages should be indicated clearly and justified. Overages and their acceptability have been discussed in detail in Part 2 of this series (2).

在深入研究工藝控制（IPCs）之前，對(duì)于擬議的批處方，我們可能因疏忽導(dǎo)致一個(gè)常見的缺陷產(chǎn)生。如果未提供展示批和擬定商業(yè)批的實(shí)際生產(chǎn)配方信息，通常會(huì)導(dǎo)致缺陷的產(chǎn)生。最好以清楚的表格格式提供配方所用的所有物料的量，包括未出現(xiàn)在最終配方中的物料（工藝過程有用到），以便比較。任何過量投料都應(yīng)該清楚地說明并證明是合理的。在本系列的第2部分，已對(duì)過量投料和接受標(biāo)準(zhǔn)進(jìn)行了討論。

In-process controls and results 工藝控制和結(jié)果

Generally speaking, there are several areas in the manufacturing section related to in-process controls and exhibit batch results that raise questions during the review of an ANDA. These areas can be broken down further into the following general categories: reconciliation, in-process tests, and the manufacturing process.

一般而言，ANDA審評(píng)期間，在生產(chǎn)部分與工藝控制和展示批結(jié)果相關(guān)的方面會(huì)導(dǎo)致問題的產(chǎn)生?？梢约?xì)分為以下幾個(gè)方面：平衡、過程檢驗(yàn)和生產(chǎn)工藝。

Reconciliation. 物料平衡

An issue that is often unaddressed in the ANDAs is unjustified, low reconciliation of the exhibit lots. In the QbR–QOS, as well as, the body of data, a table for reconciliation should be provided. Yield should be cumulative and all losses accounted for with adequate rationale for the losses. Applicants are routinely asked to demonstrate how the low reconciliation observed in the exhibit batches will be corrected or mitigated for the commercial process. ANDA applicants are encouraged to include a reference to any applicable investigation of losses to avoid deficiencies cited on this topic.

在ANDAs中，一個(gè)經(jīng)常被忽略的問題是，沒有說明展示批物料平衡差的原因。在基于問題審核-質(zhì)量綜述（QbR–QOS）和數(shù)據(jù)正文部分，應(yīng)提供物料平衡的表格。收率應(yīng)是累計(jì)的，應(yīng)為物料損失提供充分的理由。通常會(huì)要求申請(qǐng)人，在商業(yè)化工藝中，糾正或減少在展示批中觀察到的低的物料平衡。我們鼓勵(lì)A(yù)NDA申請(qǐng)者提供任何有關(guān)物料損失的適用調(diào)查的參考資料，以避免出現(xiàn)在本主題中提到的缺陷。

In-process tests. 過程檢驗(yàn)

Often, a clear description of the stages of manufacturing at which the sampling is performed for in-process controls is requested. On many occasions, ANDA applicants do not provide this information either in the QbR–QOS, or the Section 3.2.P.3.4, but reference the executed and the proposed commercial batch records, instead. To facilitate the review of the ANDA, this information should be provided and the QbR-FAQ document provides additional guidance on this point (4).

通常，需要對(duì)過程控制中取樣所處的生產(chǎn)階段進(jìn)行清楚的描述。在很多情況下，ANDA申請(qǐng)者未在基于問題審核-質(zhì)量綜述（QbR–QOS）中，也未在3.2.P.3.4中提供此信息，而是引用已執(zhí)行的和擬議的商業(yè)批記錄。為了便于ANDA審評(píng)，應(yīng)該提供這些信息，QbR-FAQ文件提供了額外的指導(dǎo)。

Also, the frequency of testing during compression or other similar processes should be proposed and justified based on batch size and equipment used. Additionally, when changes are made to the release or regulatory/shelf-life specifications for the drug product, the applicant should assess the impact on the proposed in-process controls and revise them accordingly (e.g., disintegration, dissolution, residual solvents, etc.). In general the in-process controls should not be more relaxed than the drug product release criteria.

此外，在壓片或其他類似過程中測試的頻率應(yīng)該根據(jù)批量大小和使用的設(shè)備來建議和論證。此外，當(dāng)藥品的放行標(biāo)準(zhǔn)或監(jiān)管/貨架期標(biāo)準(zhǔn)發(fā)生變化時(shí)，申請(qǐng)人應(yīng)評(píng)估對(duì)擬議的過程控制的影響，并相應(yīng)地進(jìn)行修訂（如崩解、溶出、殘留溶劑等）。一般來說，過程控制不應(yīng)該比藥品放行標(biāo)準(zhǔn)更寬松。

A frequently asked question for solid oral dosage forms is regarding adequate in-process control of the blend, based on the acceptance criteria for the assay of the drug product. This is especially common when the release assay criterion for the drug product is tighter than the commonly proposed range of 90.0–110.0% of the labeled amount. In these cases, a composite blend assay with proposed range comparable to that of assay of the drug product during routine release analysis is desirable.

固體口服劑型常被問到的一個(gè)問題是，如何根據(jù)藥品檢測的接受標(biāo)準(zhǔn)，對(duì)物料混合均一性進(jìn)行適當(dāng)?shù)倪^程控制。當(dāng)藥物產(chǎn)品的放行檢測標(biāo)準(zhǔn)比標(biāo)示量通常建議的范圍90.0%～110.0%更嚴(yán)格時(shí)，這種情況尤其常見。在這些情況下，建議混合物的含量擬定范圍與常規(guī)放行分析中藥物產(chǎn)品的含量范圍一致。

For parenterals, deficiencies are often cited regarding adequate or excess fill volume. Usually, containers for parenterals are filled with volumes in slight excess of the labeled amount that is to be withdrawn. The excess volume is meant to be sufficient to permit withdrawal and administration of the labeled amount. It is recommended that the US Pharmacopeial Convention’s USP<1>and<1151>should be followed for excess volume (5). However, excess volume may be justified at lower than recommended in USP<1151>. This may be justified based on data, on multiple containers, demonstrating that the intended volume can be extracted consistently or by inclusion of a routine extractable volume test. Large overfills, exceeding USP<1151>, should also be appropriately justified as this excess may pose a potential safety concern.

對(duì)于注射用藥物，缺陷主要是關(guān)于足夠或過量的灌裝量。通常情況下，注射用藥物的容器里裝的藥量比標(biāo)簽上要取出的藥量稍微多一點(diǎn)。超出的數(shù)量應(yīng)足以允許取出標(biāo)示量。過量體積，推薦遵循US藥典公約USP <1> and <1151>。然而，在低于USP <1151>的推薦值時(shí)，過量的體積可能是合理的。這可以基于多個(gè)容器上的數(shù)據(jù)來證明，如可以始終取出擬定的體積，或包括進(jìn)行的提取體積測試。超過USP <1151>的過量灌裝也應(yīng)該被適當(dāng)?shù)刈C明，因?yàn)檫@種過量可能造成潛在的安全隱患。

Manufacturing process. 生產(chǎn)工藝

For manufacturing processes which involve dry blending, the ANDA applicant is frequently questioned regarding the possibility of powder segregation. It is well known that achieving and maintaining homogeneous blends of powders are critical for establishing the quality of the solid pharmaceutical dosage forms, especially in formulations involving small amounts of highly potent components. In most cases, the individual components of the blend are powders with differing physical characteristics such as particle size distribution, density, shape, and cohesiveness. These materials may demonstrate tendency to segregate and lead to lack of homogeneity of the final blend. Thus, it is desirable that the ANDA applicant demonstrate a thorough understanding of the blending process and possibility of powder segregation in the pharmaceutical development section, 3.2.P.2. Additional controls for a blend may include, but should not be limited to, particle size distribution of the various components of the blend, particle size distribution of the final blend, flow characteristics and density.

對(duì)于干法生產(chǎn)工藝，ANDA申請(qǐng)人經(jīng)常被問及粉末偏析/隔離的可能性。眾所周知，實(shí)現(xiàn)和保持粉末的均勻混合對(duì)于建立固體藥物劑型的質(zhì)量至關(guān)重要，特別是對(duì)含有少量高活性成分的配方。大多數(shù)情況下，混合物的單個(gè)成分是具有不同物理特性的粉末，如粒度分布、密度、形狀和粘結(jié)性。這些物質(zhì)可能會(huì)表現(xiàn)出偏析的傾向，導(dǎo)致最終的混合物均勻性差。因此，ANDA申請(qǐng)人最好在藥物開發(fā)部分（3.2.P.2）論證對(duì)混合過程和粉末偏析的可能性的全面了解?；旌衔锏钠渌刂?，包括但不限于各組分的共混物的粒度分布、最終共混物的粒度分布、流動(dòng)特性和密度。

The justification of the proposed tablet compression controls (usually the hardness range) is often requested from the ANDA applicant. The proposed range of hardness during compression and during release or stability testing, should to be justified by demonstrating that the drug product meets the dissolution and the friability criteria at the lowest and the highest points of the proposed ranges. However, the ANDA applicant may refer to studies performed during pharmaceutical development as justification for the proposed range.

通常會(huì)要求ANDA申請(qǐng)人提供擬定壓片控制（通常是硬度范圍）的合理性。可以通過論證，在擬定范圍的最低點(diǎn)和最高點(diǎn)，藥物產(chǎn)品符合溶出度和脆碎度質(zhì)量規(guī)范，說明在壓片期間和放行或穩(wěn)定性檢驗(yàn)中硬度范圍的合理性。然而，ANDA申請(qǐng)人可以參考在藥物開發(fā)期間進(jìn)行的研究作為擬議范圍的依據(jù)。

When an applicant uses a wet granulation process, it is preferred that a quantitative end point determination is proposed. As factors such a solvent addition and granulation time may be critical to producing consistent, high quality product process, adequate controls should be in place. In many cases, a deficiency is cited if no control or justification is provided by the applicant and the sole control proposed is a subjective, visual observation. For high shear processes, suitable controls may be related to the change in power consumption with respect to the granulation equipment (e.g. amperage). For fluid bed processes, moisture content can be a suitable control for end point of the desired granules. The applicant may also choose to justify the proposed processing ranges of solvent addition, granulation time, etc., during pharmaceutical development studies.

當(dāng)申請(qǐng)人采用濕法工藝時(shí)，建議采用定量的終點(diǎn)測定方法。由于添加溶劑和制粒時(shí)間等因素，對(duì)生產(chǎn)出一致、高質(zhì)量的產(chǎn)品可能至關(guān)重要，因此應(yīng)采取適當(dāng)?shù)目刂拼胧Ｔ谠S多情況下，如果申請(qǐng)人沒有提供控制或理由，而提出的唯一控制是一種主觀的、目視的觀察，就會(huì)導(dǎo)致缺陷的產(chǎn)生。對(duì)于高剪切工藝，適當(dāng)?shù)目刂瓶赡芘c造粒設(shè)備的功耗變化有關(guān)（如安培）。對(duì)于流化床工藝，可以采用含水率對(duì)所需顆粒終點(diǎn)進(jìn)行適當(dāng)?shù)目刂啤Ｉ暾?qǐng)人也可以在藥物開發(fā)研究期間，論證所建議的添加溶劑、制粒時(shí)間范圍的合理性。

Other issues that arise during review of ANDA submissions,with respect to use of wet granulation processes, are controls for the granulation solvent used. If organic solvents are used in the granulation, appropriate controls should be proposed during the process and/or in the drug product release specification. The following of the recommendations found in USP<467>and OGD Q&A documents may ensure that the residual solvents are adequately identified controlled (5, 6). If water is used as the granulating solvent, it is recommended that a control for water content be proposed, with rationale for the proposed criterion as a function of impact on the stability and quality of the product. Studies to assess impact of water content on product stability and quality may be performed during pharmaceutical development.

在ANDA審評(píng)過程中，關(guān)于濕法制粒工藝的其他問題是對(duì)所用制粒溶劑的控制。如果在制粒過程中使用有機(jī)溶劑，在工藝規(guī)程和/或產(chǎn)品放行標(biāo)準(zhǔn)中應(yīng)進(jìn)行適當(dāng)?shù)目刂啤SP<467>和OGD Q&A（Questions and Answers）文件中的以下建議，可確保殘留溶劑得到充分識(shí)別和控制（5,6）。如果使用水作為制粒溶劑，建議對(duì)水的含量進(jìn)行控制，并根據(jù)其對(duì)產(chǎn)品穩(wěn)定性和質(zhì)量的影響，對(duì)所提出的標(biāo)準(zhǔn)進(jìn)行說明。評(píng)估水含量對(duì)產(chǎn)品穩(wěn)定性和質(zhì)量影響的研究可在藥物開發(fā)過程中進(jìn)行。

Dosage forms comprising multi-unit beads (pellets) or multi-particulates in capsules are a growing area for ANDA applicants. These dosage forms are convenient as they have the capability of providing optimal release profiles (e.g. some varied combination of immediate, delayed and extended release) for single drugs or drug combinations. An added advantage of these dosage forms are as the possibility of alternative administration techniques for certain populations, such as sprinkling beads (pellets) onto soft food. Since many of the beads (pellets) are manufactured as coated, modified release products in order to retain their integrity during mastication, it has been proposed in a draft guidance from the FDA (7), that the bead size be limited to not more than 2.0 mm. Thus, it is recommended that in-process controls be incorporated which establish the final bead size for these dosage forms. In addition, if the dosage form is comprised of multiple controlled release delivery systems (i.e., immediate, delayed and/or extended release pellets), in-process controls need to put in place at the appropriate manufacturing stages for the beads, which establish and monitor the release profile of the beads.

由多單位微球或膠囊中的多顆粒組成的劑型是ANDA申報(bào)中不斷增長的領(lǐng)域。這些劑型很使用，因?yàn)樗鼈兡転閱我凰幬锘蛩幬锝M合提供最佳的釋放特性（如，普通/立即、遲釋和緩釋的組合）。這些劑型的另一個(gè)優(yōu)點(diǎn)是為某些人群提供替代給藥技術(shù)的可能性，如可在軟性食品上撒顆粒。由于許多微球制劑是作為涂覆的、經(jīng)過修飾的釋放產(chǎn)品生產(chǎn)的，以便在咀嚼過程中保持其完整性，F(xiàn)DA在一份指南草案中建議，微粒尺寸應(yīng)不大于2.0mm。因此，建議在過程控制中確定劑型中微粒尺寸的大小。此外，如果劑型由多個(gè)控釋釋放系統(tǒng)組成（如，普通/立即、遲釋和緩釋微球），則需要在適當(dāng)生產(chǎn)階段實(shí)施過程控制，以建立和監(jiān)測微球的釋放情況。

Finally, deficiencies may be cited in the case of parenterals, and other liquid formulations, when justification is not provided regarding the compatibility of the listed manufacturing equipment process materials and the drug product solution. Again, compatibility of the dosage form with the process materials which come in direct contact with the dosage form during manufacturing is recommended to be a part of pharmaceutical development studies.

最后，如果對(duì)所列的生產(chǎn)設(shè)備工藝材料和藥品溶液的相容性/配伍沒有提供合理的理由，在注射用藥物和其它液體制劑的申報(bào)中，可能會(huì)導(dǎo)致缺陷。此外，建議將劑型與生產(chǎn)過程中直接接觸劑型的工藝材料的相容性作為藥物開發(fā)研究的一部分。

These comments only scratch the surface with regard to types of in-process controls and data that are provided in submitted applications. Deficiencies will be cited for these and other manufacturing processes if it is apparent the processes are not well understood; and it is imperative that adequate justification be provided so that the risk of problems occurring during commercialization be minimized.

這些評(píng)論只是遞交的申請(qǐng)中有關(guān)過程控制和數(shù)據(jù)的冰山一角。如果對(duì)這些和其它生產(chǎn)工藝，明顯未進(jìn)行合理的闡述，也會(huì)導(dǎo)致缺陷的產(chǎn)生；且必須提供充分的理由，以盡量減少商業(yè)化過程中出現(xiàn)問題的風(fēng)險(xiǎn)。

2.3.P.7 Container Closure System 容器包裝系統(tǒng)

With respect to the container and closure system (CCS), there are related questions in 2.3.P.2.4 and 2.3.P.7 of the QbR–QOS. Often information in one or both sections are missing or inadequate. There are assumptions made, based on previously approved ANDAs, which lead to ANDA applicants not providing necessary information in their submissions. While it is generally appropriate to reference approved CCS from other ANDA, it may not always be appropriate if specific drug substance or drug product characteristics need to be mitigated by the use of a specific CCS (e.g. moisture protection, light protection, droplet size, use of an inert system, etc.). If a statement is provided referencing products that have been approved using the same packaging system, then a copy of the test results for the components should be provided in the body of data, and in some cases, justification that this previously approved system is appropriate to the specific product based on the existence of similar drug substance or product characteristics.

關(guān)于容器包裝系統(tǒng)（CCS），在基于問題審核-質(zhì)量綜述（QbR–QOS）的2.3.P.2.4和2.3.P.7部分有相關(guān)問題。通常，在其中一個(gè)部分或兩個(gè)都未提供相應(yīng)信息或信息不充分。有一些是基于先前批準(zhǔn)ANDAs的假設(shè)，導(dǎo)致ANDA申請(qǐng)人在申報(bào)資料中未提供必要的信息。盡管可以參考其它已批準(zhǔn)ANDA的容器包裝系統(tǒng)（CCS）信息，但如果一個(gè)特定的容器包裝系統(tǒng)（CCS）對(duì)原料藥或制劑性質(zhì)起保護(hù)時(shí)（如，防潮、防光、粒徑、采用惰性系統(tǒng)等），則不合適。如果提供了聲明，引用產(chǎn)品已獲批準(zhǔn)使用相同的包裝系統(tǒng)，此時(shí)應(yīng)在數(shù)據(jù)正文部分提供該組件測試結(jié)果的副本；在一些情況下，應(yīng)提供說明，依據(jù)已知的相似的原料藥或產(chǎn)品性質(zhì)，之前批準(zhǔn)的系統(tǒng)適用于特定的產(chǎn)品。

In the development section (2.3.P.2.4) of the QbR–QOS, the following question is linked to the rationale for choice of the container closure system:

• What specific container closure attributes are necessary to ensure product performance?

Whereas in 2.3.P.7, specific details on the chosen system should be provided to answer this QbR question:

• What container closure system(s) is proposed for packaging and storage of the drug product? Has the container closure system been qualified as safe for use with this dosage form?

In the development section, the rationale for choosing a CCS should be provided. This is an opportunity for the sponsor to discuss any studies conducted to identify any critical attributes including suitability (protection, compatibility, and performance) and safety of the CCS. It is recommended to take into consideration the recommendations and information found in current FDA guidance (8) to decide critically of attributes based on the dosage form.

在基于問題審核-質(zhì)量綜述（QbR–QOS）的開發(fā)部分（2.3.P.2.4），下面的問題與選擇容器包裝系統(tǒng)的基本原理有關(guān)：

• 需要哪些特定的容器包裝屬性來確保產(chǎn)品性能？

在2.3.P.7，應(yīng)提供所選系統(tǒng)的具體信息來回答這個(gè)QbR問題：

• 建議采用什么容器包裝系統(tǒng)來包裝和儲(chǔ)存藥物產(chǎn)品？容器包裝系統(tǒng)用于該劑型已界定是安全的嗎？

在開發(fā)部分，應(yīng)提供容器包裝系統(tǒng)（CCS）選擇的理由。這是申請(qǐng)者討論進(jìn)行研究的機(jī)會(huì)，以確定容器包裝系統(tǒng)的關(guān)鍵屬性，包括適用性（保護(hù)、兼容性和性能）和安全性。建議考慮當(dāng)前FDA指南（8）中的建議和信息，根據(jù)劑型確定關(guān)鍵屬性。

Suitability for use. 使用的適宜性

Suitability for use includes multiple characteristics of the CCS with respect to performance, functionality, and safety. In too many cases, testing that will be used to ensure CCS performance and safety is not provided or is poorly documented. Relevant compendial test results and controls (e.g., USP<381>,<87>,<88>,<660>,<661>, and<671>) should be also provided, as appropriate (5). These tests are intended to demonstrate CCS identity, performance, suitability, compatibility and safety. If this information is lacking deficiencies will be cited.

適用的適宜性，包括容器包裝系統(tǒng)（CCS）在性能、功能和安全性方面的多種特性。在很多情況下，要么未提供、要么未詳細(xì)記錄為確保CCS的性能和安全性而進(jìn)行的測試。如合適，應(yīng)提供相應(yīng)藥典標(biāo)準(zhǔn)測定結(jié)果和控制（如 <381>, <87>, <88>, <660>, <661>, 和<671>）。這些測試旨在證明CCS的特性、性能、適用性、兼容性和安全性。如未提供，將導(dǎo)致缺陷的產(chǎn)生。

Any other testing or certification, such as Code of Federal Regulations (CFR) references to demonstrate suitability of use for pharmaceutical products, should be also provided. (e.g., 21 CFR sections 174–186 provide a list of materials that are safe for use in direct or indirect food contact) (9).

In many cases, for solid oral products, the most crucial container closure development studies are related to drug product chemical stability. Although tablet integrity (physical stability) may need to be studied for low hardness or highly friable tablets such as orally disintegrating tablets (ODTs) or chewable tablets. Further discussion on this topic can be found later in the article.

還應(yīng)提供其他測試或認(rèn)證，如證明藥品使用適宜性的《聯(lián)邦法規(guī)》（Code of Federal Regulations, CFR）參考資料。（如，聯(lián)邦法規(guī) 第21篇174–186節(jié)提供了直接或間接接觸食物時(shí)安全使用的物料清單）。

在很多情況下，對(duì)于口服固體制劑，最至關(guān)重要的容器包裝開發(fā)研究關(guān)系到產(chǎn)品的化學(xué)穩(wěn)定性。對(duì)于低硬度或高易碎的片劑，如口崩片（ODTs）或咀嚼片，需要對(duì)片劑的完整性（物理穩(wěn)定性）進(jìn)行研究。關(guān)于這個(gè)主題的進(jìn)一步討論，參加后文。

For any drug products that incorporate delivery devices (e.g. nasal sprays, inhalation products, oral solutions, ophthalmics, etc.), pharmaceutical development studies conducted with respect to demonstration of performance should be discussed. Performance testing of the CCS might include dropper consistency, calibration of delivery device, droplet size, etc. It may also be necessary to compare the ANDA product performance with the reference listed drug (RLD) to demonstrate similar dosing will occur.

對(duì)于包含遞送裝置的藥物產(chǎn)物（如鼻腔噴霧劑、吸入制劑、口服溶液、眼藥等），應(yīng)討論關(guān)于性能論證的藥物開發(fā)研究。容器包裝系統(tǒng)（CCS）的性能測試可能包括點(diǎn)滴器的一致性、輸送裝置校準(zhǔn)、液滴尺寸。也可能有必要將ANDA產(chǎn)品性能與參比制劑（RLD）進(jìn)行比較，以論證具有類似的劑量。

Specific cases. 具體案例

In the case of parenteral products, and other drug products that are solutions or suspensions, compatibility testing should be provided (e.g., extractables and leachables for the stoppers or the CCS materials, as applicable, dye or adhesive migration from labeling, etc.). If this information is not provided, deficiencies have and will continue to be cited. Also, the analytical method used for the analysis should be appropriate for the detection of the extractables and leachables from the CCS. While proposing quality or safety limits for the extractables and leachables, it should be remembered that these are not covered by the International Conference on Harmonization (ICH) Q3B (R2) guideline or the related ANDA impurity guidance (10, 11). Thus, the acceptance criteria proposed should be supported by sound rationale, based on available toxicological information in the public domain, or information provided in the applicable CFR sections (9).

對(duì)于注射用藥物，和溶液或懸浮液的其它藥物，應(yīng)提供相容性研究結(jié)果（如塞子或容器包裝材料的可提取物和浸出物，如適用，標(biāo)簽上染料或粘合劑的遷移）。如果未提供這些信息，會(huì)或?qū)?huì)導(dǎo)致缺陷的產(chǎn)生。另外，所用分析方法應(yīng)適用于來自于容器包裝材料的可提取物和浸出物的研究。由于國際協(xié)調(diào)會(huì)議ICH Q3B（R2）指南或相關(guān)的ANDA雜質(zhì)指南（10,11）并未涵蓋可提取物和浸出物的質(zhì)量或安全限度，因此，應(yīng)基于公共可用的毒理學(xué)信息或CFR（聯(lián)邦法規(guī)）章節(jié)中提供的信息，為可接受標(biāo)準(zhǔn)提供合理的依據(jù)（9）。

In USP<1>, closures for multiple-dose containers permit the withdrawal of the contents without removal or destruction of the closure (5). The closure permits penetration by a needle and, upon withdrawal of the needle, closes at once, protecting the container against contamination. Suitable controls (e.g., coring, seal-sealing, fragmentation, etc.) should be in place to demonstrate that the stopper is adequate if it is intended to be used in a multiple use product.

根據(jù)USP <1>，可以在不移除或破壞包裝的情況下，提取多劑量容器中的內(nèi)容物（5）。包裝可以允許針的滲透，和一旦將針拔出，容器立即封閉，以保護(hù)內(nèi)容物不被污染。應(yīng)進(jìn)行適當(dāng)?shù)目刂疲ㄈ缛⌒尽⒚芊?、破碎等）以證明，塞子可用于多劑量包裝制劑。

With respect to blister packages, an often cited deficiency is a lack of data to demonstrate that the blister components protect the product from moisture. We recommend that data be provided for moisture permeation of the proposed blister pack. Additionally, as an in-process, and in some cases for release and stability analysis, a leak test may be necessary.

對(duì)于泡罩包裝，經(jīng)常被引用的缺陷是，未提供數(shù)據(jù)證明泡罩組件具有防水作用。我們建議提供擬議泡罩包裝的水分滲透/防潮數(shù)據(jù)。此外，在過程控制，和在某些情況下的放行和穩(wěn)定性分析中，有必要進(jìn)行泄露測試。

Occasionally inquiries are made regarding integrity of tablets during transportation and storage. This is common when the dosage form is an ODT or some other low hardness tablet (e.g., chewable tablet), which are packaged in bottles having large headspace. It is well known that tablets are constantly subjected to mechanical shocks and abrasion during the transportation and storage. Such stresses can lead to chipping, abrasion or even breakage of orally disintegrating tablets, which are known to have low friability. It is therefore important for the ANDA applicant to demonstrate that the tablets are able to withstand such stress without damage and provide information to assure the integrity of the tablets during transportation and storage. In use and “shipping” studies should be taken into consideration when designing low hardness products, as well as, other dosage forms that may be affected by transportation.

有時(shí)，需要調(diào)查，在運(yùn)輸和儲(chǔ)存期間，藥片的完整性。當(dāng)藥品為口崩片（ODT）或其它低硬度片劑（如咀嚼片），這些藥片被包裝在具有較大空間的瓶子中，這種情況很常見。眾所周知，藥片在運(yùn)輸和儲(chǔ)存過程中不斷受到機(jī)械沖擊和磨損。由于口腔崩解片的脆性較低，這些作用力會(huì)導(dǎo)致其碎裂、磨損甚至斷裂。因此，重要的是ANDA申請(qǐng)人要證明這些藥片能夠承受這樣的壓力而不受損害，并提供信息以確保藥片在運(yùn)輸和儲(chǔ)存期間的完整性。在設(shè)計(jì)低硬度產(chǎn)品，以及其他可能受運(yùn)輸影響的劑型時(shí)，應(yīng)考慮進(jìn)行使用和“運(yùn)輸”研究。

Conclusion 結(jié)論

This concludes our discussion on the commonly cited deficiencies in ANDA submissions. To summarize the entire series, ANDA applicants should endeavor to demonstrate product and process understanding; and provide sound scientific and regulatory justification for all information provided and all controls that are proposed in their applications.

本節(jié)總結(jié)我們對(duì)ANDA申報(bào)中常見缺陷的討論?？偟膩碚f，ANDA申請(qǐng)人應(yīng)該努力展示對(duì)產(chǎn)品和工藝的理解；并為申請(qǐng)中提供的信息和擬定的控制，提供科學(xué)合理的依據(jù)。

As stated throughout, this series is not intended to be an all-inclusive list of deficiencies cited, but only a survey of what types of information are being requested from ANDA applicants, since the implementation of the QbR-QOS format. Throughout the series, the authors have attempted to provide some rationale for citation of common deficiencies. The phrase “pharmaceutical development” has appeared like a refrain in every section of every article. This underlines the importance of adequate pharmaceutical development studies, performed during the initial development of the drug product, which in turn leads to justification for the chosen materials, formulations and processes; and may reduce the instances of such deficiencies being cited.

正如本文所述，由于QbR-QOS的實(shí)施，本系列文章并不是要列出所有被引用的缺陷，而是調(diào)查需要ANDA申請(qǐng)人提供所需信息的類型。在整個(gè)系列中，作者試圖為常見缺陷的引用提供一些合理說明?！八幬镩_發(fā)”一詞出現(xiàn)在每一篇文章的每一部分。這突出了在藥物產(chǎn)品的初步開發(fā)期間進(jìn)行充分的藥物開發(fā)研究的重要性，這可以進(jìn)一步論證所選材料、配方和工藝的合理性；并可能減少此類缺陷被引用的實(shí)例。

Numbering in section heads correspond to those in the Common Technical Document (CTD).

分段編號(hào)與通用技術(shù)文件（CTD）中的編號(hào)相對(duì)應(yīng)。

Acknowledgments 致謝

The authors wish to acknowledge Keith Webber, PhD博士, Acting Office Director代理辦公室主任, OGD仿制藥辦公室; Lawrence Yu, PhD, Deputy Director副主任 for Science, OGD; and Vilayat A. Sayeed, PhD, Director of Chemistry Division III, OGD, for their input and encouragement as the authors put together this series of articles. We would also like to thank Devinder S. Gill, PhD, Deputy Director of Chemistry Division III, OGD, for his contributions as co-author of Parts 2 and 3 of this series.

Disclaimer 免責(zé)聲明

The views and opinions in this article are only those of the authors and do not necessarily reflect the views of policies of FDA.

本文所表達(dá)的觀點(diǎn)僅代表作者個(gè)人觀點(diǎn)，并不代表FDA的觀點(diǎn)或政策。

References 參考文獻(xiàn)

1. Srinivasan and R. Iser, Pharma. Technol. 34 (1), 50–59,(2010).

2. A. Srinivasan, R. Iser and D. Gill, Pharma. Technol. 34 (8), 45–51(2010).

3. A. Srinivasan, R. Iser and D. Gill, Pharma. Technol. 35 (2), 58–67(2011).

4. FDA, QbR Frequently Asked Questions (June 4, 2007).

5. USP 33–NF 28 (US Pharmacopeial Convention, Rockville, MD,2011).

6. FDA OGD, Residual Solvents in ANDAs: Questions and Answers (Rockville, MD, Oct. 28, 2008), www.fda.gov/downloads/AboutFDA/CentersOffices/CenterforDrugEvaluationandResearch/ucm119607.pdf.

7. FDA, Draft Guidance for Industry: Size of Beads in Drug Products Labeled for Sprinkle (Rockville, MD, January 2011).

8. FDA, Guidance to Industry: Container Closure Systems for Packaging Human Drugs and Biologics (Rockville, MD, May 1999).

9. FDA, “21 CFR 176 Indirect Food Additives: Paper Board and Paperboard Components through 21 CFR 186 Indirect Food Additives Affirmed as Generally recognized as safe (Rockville MD, Apr. 1, 2010).

10. ICH, Q3B, Impurities in New Drug Products (R2) (Geneva, July 2006)

11. FDA, OGD, Guidance for Industry: ANDAs: Impurities in Drug Products ((Rockville, MD, November 2010).

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