ICH_Q11问答-中英对照

红色代表问题涉及到的ICH Q11章节号及相关指南# Questions Answers

5.1 ICH Q11 states that “A

starting material is

incorporated as a

significant structural

fragment into the structure

of the drug substance.”

Why then are

intermediates used late in

the synthesis, which

clearly contain significant

structural fragments, often

not acceptable as starting

materials?

The selection principle about “significant structural fragment” has frequently been misinterpreted as

meaning that the proposed starting material should be structurally similar to the drug substance.

However, as stated in ICH Q11, the principle is intended to help distinguish between reagents,

catalysts, solvents, or other raw materials (which do not contribute a “significant structural fragment” to the

molecular structure of the drug substance) from materials that do. It is not intended to dictate the selection

of either a very early or a very late intermediate as the starting material. A proposed starting material may

be several steps from commercially available materials, provided it is not a small number of chemical

transformation steps from the drug substance, and provided the justification acceptably addresses the

ICH Q11 general principles. The presence of a “significant structural fragment” should not be the sole

basis for of starting material selection. Starting materials justified solely on the basis that they are a

“significant structural fragment” probably will not be accepted as starting materials by regulatory

authorities, as the other principles for the appropriate selection of a proposed starting material also require

consideration.

5.1.1 ICH Q11指出“起始物料

是原料药结构的重要结

构片断。”那么为什么最

后合成步骤中用到的中

间体，明确含有重要结

构片断，却不能作为起

始物料呢？

“重要结构片断”这个选择依据经常被曲解为起始物料应该和原料药结构相似。但是，正如ICH Q11

所说，该原则旨在将试剂、溶剂及其他原料这些没有原料药“重要结构片断”的物料与起始物料区分

开来。并非让选择较前或较后的中间体作为起始物料。所选择的起始物料可以是市售物料通过几

个步骤合成，只要不是很少几步化学转换得到原料药即可。“重要结构片断”不应单独作为起始物料

选择的依据，只将这个作为论证起始物料的选择依据可能不会被药政官方所接受，因为其他的合

理的起始物料选择依据也要考虑在内。

5.2 ICH Q11 recommends

that “manufacturing steps

that impact the impurity

profile of the drug

substance should

normally be included in

the manufacturing

process described in

Section 3.2.S.2.2 of the

application.” At what

level would a related

For non-mutagenic related substances, an impurity that is likely to be present in the drug substance at a level

above the ICH Q3A Identification Threshold is considered to have an impact on the impurity profile of the

drug substance.

A mutagenic impurity that is likely to be present in the drug substance above 30% of the ICH M7

acceptable intake is usually considered to impact the impurity profile of the drug substance. Any of the

approaches described in ICH M7 can be used to determine which impurities are likely to be present above

the 30% threshold. The 30% threshold serves an analogous function in ICH M7 to the Identification

Threshold in ICH Q3A.

In line with ICH M7 and ICH S9, there are situations (e.g., when the drug substance is itself genotoxic, and

# Questions Answers

substance or mutagenic impurity be considered to impact the impurity profile of the drug substance? other circumstances as described in these guidelines) when the selection of the starting material for a drug substance does not need to specifically consider the mutagenic impurity profile at the levels described above. In such cases, mutagenic impurities are not considered to impact the impurity profile of the drug substance unless they are above the ICH Q3A Identification Threshold.

Impurities that persist through multiple steps of manufacture should be considered in conjunction with Q&A 5.3.

5.1.1 M7 Q3A S9ICH Q11建议“影响原料

药杂质概况的生产步骤

通常在申请文件

3.2.S.2.2章节生产工艺

部分描述”，什么水平的

杂质或致畸杂质会被认

为影响到原料药的杂质

概况？

对于非致畸杂质，该杂质水平高于ICH Q3A鉴定阈值时则被认为对原料药的杂质概况有影响。

原料药中可能出现的致畸杂质高于ICH M7可接受限度的30%则被认为对原料药的杂质概况有影

响。ICH M7中提到的方法均可用来测定哪些杂质可能高于30%阈值。ICH M7中30%阈值作用类似

于ICH Q3A的鉴定阈值。

与ICH M7和ICH S9一致，一些特殊情况如当原料药本身就是基因毒性时，及指南中提及的其他情

况时，原料药起始物料的选择依据不需要特别考虑上述情况。这种情况下，致畸杂质不作为影响原

料药杂质概况考虑在内，除非其水平高于ICH Q3A的鉴定阈值。

经过多步生产仍然存在的杂质应结合问答5.3进行考虑。

5.3 What is meant by

impurities that “persist” in

ICH Q11 Example 4?

ICH Q11 recommends that “manufacturing steps that impact the impurity profile of the drug substance should

normally be included in the manufacturing process described in Section 3.2.S.2.2 of the application.”

However, as described in ICH Q11 Example 4, this principle does not necessarily apply when impurities

originate early in the manufacturing process and “persist” across multiple steps, provided that the steps

prior to the proposed starting material over which the impurities persist do not themselves impact the drug

substance impurity profile. In Example 4 there are multiple steps (from Compound B to Compound D)

that do not impact the drug substance impurity profile. Without this exception, these steps would have to

be included in Section 3.2.S.2.2 of the application. Impurities that persist may or may not react in subsequent

steps, but are not removed to the extent that they would no longer be considered to impact the drug substance

impurity profile [For “impact” see Q&A 5.2]. For example, an impurity that persists might have physico-

chemical properties (e.g., solubility) similar to other intermediates or the drug substance, like the enantiomer

in Example 4, which could make its removal intrinsically difficult.

ICH Q11 Example 4 illustrates that when the synthetic route contains an impurity that persists, it can be

# Questions Answers

acceptable to control the impurity in the starting material specification even though it impacts the impurity

profile of the drug substance. Therefore, it is not always necessary to include steps that form such an impurity

in Section 3.2.S.2.2, provided that the other ICH Q11 general principles are addressed [ICH Q11 Section

5.1.1]. Example 4 is not exclusive to stereoisomers and can be applied to other types of impurities that persist.

In Example 4 there are 3 chemical transformation steps between the starting material D and the drug

substance. The 3 steps in Example 4 are not intended to imply that 3 chemical transformation steps are

considered enough (see Q&A 5.6) in all cases, nor that 3 chemical transformation steps are mandatory.

In the case of Example 4, application of the ICH Q11 principles includes control of the enantiomer in the

specification of the proposed starting material D, in combination with the understanding that the steps

immediately prior to D do not impact the impurity profile of the drug substance.

5.1.1 10.4 Q3A ICH Q11例4杂质“持续

存在”的含义是什么？

ICH Q11建议“影响原料药杂质概况的生产步骤通常在申请文件3.2.S.2.2章节生产工艺部分描述”，

但是，如ICH Q11例4所述，当杂质在生产工艺前期生成并“持续存在”于多步时，只要起始物料前

面的步骤所生成的杂质对原料药的杂质概况没有影响，该建议未必适用。例4化合物B到化合物D

这两步合成都不影响原料药杂质概况。非例外情况，这些步骤都会包含在申请文件3.2.S.2.2章节。

持续存在的杂质可能或不可能参与后续反应，但是不会被去除到不再影响原料药杂质概况的程度（见

问答5.2）。例如，某一持续存在的杂质可能有某些理化性质，如溶解度等，类似于其他中间体或原

料药，就像例4中的对映异构体，去除的可能性就非常小。

ICH Q11例4阐明当合成路线包含持续存在的杂质时，即使它影响了原料药的杂质概况，在起始物

料的质量标准中对其进行控制是可以接受的。因此，只要ICH Q11 5.1.1章节里的其他原则都有考

虑，3.2.S.2.2章节未必需要描述生成这类杂质的步骤。例4并非只针对立体异构体，同样适用其他

类型持续存在的杂质。

例4起始物料D到原料药有3步化学反应，3步反应并不意味任何情况下3步反应就是足够的（见

问答5.6），也不意味3步反应是强制的。

例4中运用到的ICH Q11原则包括在起始物料D质量标准中控制异构体、确定起始物料D之前的

步骤对原料药的杂质概况没有影响。

# Questions Answers

5.4 How should an

applicant determine

which manufacturing

steps impact the profile of

mutagenic impurities in

the drug substance as part

of the selection and

justification of starting

materials?

As part of determining which manufacturing steps impact the impurity profile of the drug substance, the applicant

should first identify mutagenic materials that are likely to be formed or are introduced in the manufacturing

process. The applicant can then determine which steps contribute mutagenic impurities to the drug substance at a

level considered to impact the impurity profile (see Q&A 5.2).

The Hazard Assessment Elements from ICH M7 can be used to determine which of the actual and potential

impurities are considered to be mutagenic. For the selection and justification of starting materials, the following

approaches are recommended:

?Impurities that have been identified in the drug substance (“actual impurities”) should be assessed for mutagenicity.

?Reagents, solvents, and chemicals used in the synthesis from commercially available chemicals to the drug substance should be assessed for mutagenicity. Note that this will likely include assessment of the

mutagenicity of some reagents, solvents, and chemicals that are used in steps before the starting material that

is eventually proposed.

?Mutagenic substances that are impurities in commercially available precursors or synthetic intermediates, or that are formed as the result of side reactions during the synthesis, could also be present in the drug substance

at levels relevant to safety. However, such mutagenic impurities and by-products are usually present at much

lower concentrations than reagents, solvents, and intermediates. Therefore, the risk that such impurities will

carry over significantly into the drug substance from early reaction steps is lower than for reagents, solvents,

or intermediates from the same steps. The applicant should use risk-based reasoning to determine which

steps to include in the hazard assessment for this category of potential impurities, and include a discussion

of the risk assessment when identifying the point in the synthesis where these impurities and by-products are

included in the assessment of mutagenic impurities.

?For a starting material that is a commercially available chemical that is introduced late in the synthesis of the drug substance (and where its synthetic route is known) the final steps of that chemical’s synthesis should

be assessed for potential mutagenic impurities. In this case, because the starting material has already been

selected based on its commercial availability, the mutagenicity assessment should be used to ensure that the

controls on the starting material are adequate.

Information collected during the evaluation of potential mutagenic impurities can be submitted in an application

and could be valuable for multiple purposes. For example, the justification for a proposed starting material should

include information demonstrating that none of the steps immediately upstream (i.e., earlier in the synthesis) of

# Questions Answers

the proposed starting material impact the impurity profile of the drug substance. Also, the suitability of the

proposed control strategy can be supported with information about any mutagenic impurities formed or purged

in the manufacturing steps between the proposed starting material and the drug substance, or that are controlled

in the specification of the proposed starting material. The ICH Q11 exception for impurities that “persist” is also

applicable to mutagenic impurities (see Q&A 5.3). In addition, steps involving mutagenic reagents or impurities

may be before the starting material if they do not impact the impurity profile of the drug substance (see Q&A

5.5).

The approaches outlined in this Q&A are considered to be consistent with the principles in ICH M7, concerning

hazard assessment, risk characterisation of mutagenic impurities, and their control. Additionally, this Q&A is not

intended for the types of drug substances and indications for which ICH M7 does not apply (e.g., genotoxic drug

substances; advanced cancer indications per ICH S9). However, ICH M7 does not provide specific guidance on

how mutagenic impurity assessment can be used to justify selection of appropriate starting materials. This Q&A

addresses the application of the principles in ICH M7 to the selection and justification of starting materials, based

on the ICH Q11 concept of impact to the impurity profile of the drug substance.

5.1.1 10.4 M7作为筛选和论证起始物

料的一部分，申请人如

何确定哪些生产步骤影

响到原料药中的致畸杂

质？

确定哪些生产步骤影响原料药杂质概况，申请人首先应该确定的是可能在生产工艺中生成或引入的

致畸物料，然后确定哪些步骤生成了致畸杂质，可能对原料药杂质概况有影响（见问答5.2）。

ICH M7的危害评估要素可以用来确定哪些已知和潜在的杂质是致畸杂质。筛选和论证起始物料，建

议采用以下方法：

?原料药中已经确定的杂质（“实际存在的杂质”）应评估其致畸性。

?合成工艺中用到的市售试剂、溶剂、化学品及原料药都应评估其致畸性。注意可能还要评估起始物料之前步骤用到的试剂、溶剂和化学品的致畸性。

?致畸杂质可能存在于市售前体、合成中间体，或是生产工艺生成的副产物，也可能出现在原料药中，水平接近安全。然而，这类致畸杂质和副产物通常比试剂、溶剂和中间体的浓度要低很

多。因此，前期反应步骤这类杂质被引入原料药的风险要低于同样步骤用到的试剂、溶剂或中

间体。申请人应使用基于风险推论确定哪些步骤的潜在杂质需要风险评估，并对风险评估进行

讨论，生产工艺中需要按致畸杂质讨论的杂质和副产物。

?市售化学起始物料在原料药合成步骤后期引入，且其生产路线已知，化学合成的最后步骤应对潜在致畸杂质进行评估。这种情况下，由于起始物料已经确定，致畸评估可以确保对起始物料

# Questions Answers

的控制是足够的。

潜在致畸杂质评估过程中收集的信息可以在申报文件中呈现，且具有多种用途。例如，起始物料的

论证应包括证明合成起始物料的前期步骤对原料药的杂质概况没有影响；同时也要有合适的控制策

略支持任何生成、起始物料和原料药生产工艺去除或起始物料质量标准中控制的致畸杂质。除了“持

续存在”的杂质ICH Q11也适用于致畸杂质（见问答5.3）。此外，含有致畸试剂或杂质的生产步骤

可以在起始物料之前，只要它们对原料药的杂质概况没有影响（见问答5.5）。

这里提到的危害评估、致畸杂质风险识别及其控制与ICH M7里的原则一致。另外，本问答不适用

于ICH M7不适用的原料药和制剂（如基因毒性原料药；ICH S9中所定义的晚期癌症）。关于如何

评估致畸杂质进而论证起始物料的选择依据，ICH M7不给出专门的指南。该问答讲的是基于ICH

Q11关于影响原料药杂质概况的理念，运用ICH M7中的原则筛选和论证起始物料。

5.5 Do all steps that involve

mutagenic reagents,

impurities, or establish

regio- or stereochemical

configurations, need to be

included in the process

description in Section

3.2.S.2.2?

No. The ICH Q11 general principles for selection of starting materials do not include a

recommendation that all steps involving mutagenic reagents or impurities should be included in the process

description in Section 3.2.S.2.2. Similarly, the general principles do not include a recommendation that all

steps that establish regio- or stereochemical configurations (which can therefore result in regio- or

stereoisomerism) should be included in Section 3.2.S.2.2. However, it is expected that the other ICH Q11

principles on impurities (Q&As 5.2, 5.3 and 5.4) and inclusion of enough of the manufacturing process (Q&A

5.6) be applied when deciding whether steps that involve mutagenic reagents, impurities, or establish regio-

or stereochemical configurations, need to be included. As an example, a mutagenic compound could be

introduced prior to the starting material or be the starting material itself provided the ICH Q11 general

principles are addressed.

5.1.13.2.S.2.2章节工艺描述是

否需要包含所有涉及致

畸试剂、杂质、区域选

择或立体化学构型的步

骤？

不需要。ICH Q11筛选起始物料的总则并未建议所有涉及致畸试剂或杂质的步骤应包含在3.2.S.2.2

章节工艺描述中。同样，总则也未建议所有确定区域选择或立体化学构型（从而导致区域选择或立

体易购）的步骤应包含在3.2.S.2.2章节。但是，当决定生产步骤是否涉及致畸试剂、杂质、区域选

择或立体化学构型时，需要运用ICH Q11关于杂质控制的其他原则（问答5.2、5.3和5.4）并且包

含足够的生产工艺（问答5.6）。如某一致畸化合物可能先于起始物料引入，或作为起始物料本身需

要满足ICH Q11总则。

5.6 ICH Q11 states that

“enough of the drug

substance manufacturing

In deciding whether enough of the drug substance manufacturing process is described in Section 3.2.S.2.2

of the application, the following considerations should be applied:

# Questions Answers

process should be described in the application…” What considerations should an applicant apply in the selection of the proposed starting materials to assure that enough of the drug substance manufacturing process will be described in the process description in Section 3.2.S.2.2 of the application? The applicant should first evaluate which chemical transformation steps in the manufacturing process impact the impurity profile of the drug substance. These steps should normally be included in Section 3.2.S.2.2 (Q&As 5.2, 5.3, 5.4).

Next, the applicant should examine the steps immediately upstream of those steps that impact the impurity profile of the drug substance. These steps should also be included in Section 3.2.S.2.2 if:

?They include a unit operation that has been added to the manufacturing process to control specific impurities that would otherwise impact the impurity profile of the drug substance. Adding multiple purification steps prior to a proposed starting material would not be considered appropriate in order to support its justification.

?They need to be carefully controlled (e.g., within narrow parameter ranges) to prevent generation of impurities that would otherwise impact the impurity profile of the drug substance.

After these considerations, if the evaluation would result in only a small number of chemical transformation steps, then it is generally appropriate to include one or more additional chemical transformation steps in Section 3.2.S.2.2. This is to ensure that enough steps are conducted under GMP and to mitigate risks associated with contamination and future changes to the synthetic route or supplier of the starting material. The following paragraphs provide further clarification on this risk mitigation and should be considered together.

?Although ICH Q11 does not specify how many steps should be performed under GMP, ICH Q11 recommends the inclusion of “multiple chemical transformation steps” in Section

3.2.S.2.2 in order to reduce the risk of contamination and support the effective implementation of the

control strategy throughout the product lifecycle. When there would be a small number of steps there is an increased risk of contamination that needs to be addressed by the applicant in their starting material justification, and will often be best mitigated by including one or more additional steps in Section

3.2.S.2.2.

Potential risks from future changes to the starting material synthesis should also be considered (see Q&A 5.14). In particular, when the proposed starting material is many steps

downstream from commercially available chemicals, there is an increased likelihood of changes

to its route of synthesis. There is therefore an increased risk that impurities generated in future

# Questions Answers

syntheses may not be detected or purged appropriately if the starting material is only a small

number of steps from the drug substance. In order to determine how many additional steps to

include, the applicant may also consider other approaches to risk mitigation; for example,

inclusion of analytical methodologies in the specification of the proposed starting material that

are designed to detect a wide range of possible impurities based on different physical and

chemical separation and detection principles and with appropriate acceptance criteria for

unspecified impurities.

The applicant should include in their justification of the proposed starting material a comprehensive

description of what factors were considered in deciding whether enough of the drug substance

manufacturing process is provided in Section 3.2.S.2.2 of the application to ensure that risks are

appropriately mitigated.

5.1.1

5.2.1

6.1ICH Q11指出“应在申请

文件中充分描述原料药

的制造工艺”，申请人在

筛选起始物料时需要考

虑些什么，从而确保原

料药生产工艺在

3.2.S.2.2章节工艺描述

部分充分描述？

为了确定申请文件3.2.S.2.2章节是否提供足够的原料药生产工艺描述，需要考虑以下几点：

申请人应首先评估生产工艺中哪些化学反应步骤影响了原料药的杂质概况。这些步骤通常应包含在

3.2.S.2.2章节（问答5.2、5.3、5.4）。

其次，申请人应审查这些步骤中对原料药杂质概况有影响的的上游步骤。这些步骤应包含在3.2.S.2.2

章节，如果：

?为了控制可能影响原料药杂质概况的特定杂质，这些步骤包含的单元操作已经增加到生产工艺中去。在起始物料之前增加多步纯化，这通常认为不是的合理支持依据。

?这些步骤需要小心控制（如在精密的参数范围内），从而避免生成可能影响原料药杂质概况的杂质。

最后，经过上述考虑，如果评估仅有少数的化学合成步骤，通常应在3.2.S.2.2章节额外增加一到多

个化学合成步骤。这样做是为了确保GMP条件下进行了足够的生产步骤，避免污染带来的风险及

后续起始物料合成路线或供应商发生的变更。下面内容对风险降低做了详细说明，也要一起考虑。

?尽管ICH Q11没有规定GMP条件下应进行多少步骤，但是其建议在3.2.S.2.2章节包含“多个化学合成步骤”，以便降低污染风险，且有效支持产品整个生命周期内的控制策略。当生产步骤较

# Questions Answers

少，污染的风险就会增加，这就需要申请人在起始物料的论证中进行说明，而最好的解决方法

就是在3.2.S.2.2章节额外增加一到多个生产步骤。

起始物料合成工艺日后的变更带来的潜在风险也应考虑在内（见问答5.14）。特别是当

起始物料是从经多步生产的下游的市售化学品采购所得，它的合成路线变更的可能性就

会增加。如果起始物料到原料药只有少数的几步，那么它日后在原料药生产工艺中生成

的杂质不被发现或合理去除的风险就会增加。为了确定额外增加几步，申请人可能还需

要考虑其他的降低风险的方法；例如，基于不同的物理和化学分离方法和检测原则，及

非特定杂质合理的可接受标准，在起始物料质量标准中增加分析方法，检测可能广泛存

在的杂质。

申请人应在起始物料论证中详细说明，为确保合理降低风险，在决定是否有足够的原料药生产工艺

呈现在3.2.S.2.2章节时都考虑了哪些因素。

5.7 Should all the ICH Q11

general principles be

considered and met in

selecting starting

materials?

Applicants should consider all of the ICH Q11 principles in the selection and justification of proposed

starting materials, rather than selecting just a few principles and using them to justify starting materials. If

a proposed starting material does not meet all of the general principles, a rationale should be provided

explaining why the starting material is considered appropriate.

5.1.1 5.2.1在筛选起始物料时，是

否需要考虑且符合ICH

Q11的所有总则？

在起始物料筛选和论证中，申请人应考虑所有的ICH Q11原则，而不是只选择几个原则来作为论

证依据。如果筛选的起始物料不符合所有的原则，应提供合理的说明，解释为什么选择此作为起

始物料。

5.8 Do the ICH Q11 general

principles for selection of

starting materials apply to

processes where multiple

chemical transformations

are run without isolation of

intermediates?

Yes. The ICH Q11 general principles apply to processes where multiple chemical transformations are run

without isolation of intermediates. In the absence of such isolations (e.g., crystallization, precipitations),

other unit operations (e.g., extraction, distillation, the use of scavenging agents) should be in place to

adequately control impurities and be described in the application. The drug substance synthetic process

should include appropriate unit operations that purge impurities.

The ICH Q11 general principles also apply for sequential chemical transformations run continuously. Non

isolated intermediates are generally not considered appropriate starting materials.

5.1.1 5.2.1ICH Q11筛选起始物料的

总则是否适用于多步化学

适用。ICH Q11总则适用于多步化学转变，没有中间体分离的工艺。没有分离（如析晶、沉淀），

其他单元操作，如萃取、蒸馏、使用清除剂等，应能充分控制杂质并在申请中予以描述。原料药合

# Questions Answers

合成，没有中间体分离的

工艺？

成工艺应包含能够去除杂质的合理单元操作。

ICH Q11总则也适用于连续进行的化学转变。未分离的中间体通常不作为起始物料。

5.9 Do the ICH Q11 general

principles for selection of

starting materials apply to

the selection of starting

materials for linear and

convergent syntheses?

Yes. The ICH Q11 general principles apply to the selection of starting materials for linear or convergent

syntheses. The ICH Q11 general principles should be applied independently to each branch of a convergent

synthesis, unless the point of convergence of the branches occurs upstream of an appropriate starting

material.

5.1.1 5.2.1ICH Q11筛选起始物料的

总则是否适用于线性和收

敛性合成的起始物料的筛

选？

适用。ICH Q11总则适用于线性和收敛性合成的起始物料的筛选。收敛性合成的每个分支都应参考

ICH Q11总则，除非分支的汇聚点出现在起始物料的上游。

5.10 What considerations are

important for starting

material specifications?

Applicants should provide and justify a specification (which includes a list of tests, references to analytical

procedures, and appropriate acceptance criteria) for all proposed starting materials as part of the control

strategy.

The specification of a starting material should include tests for identity and purity (e.g., controls on

impurities), and could include acceptance criteria for assay, specified, unspecified and total impurities,

residual solvents, reagents, elemental impurities and mutagenic impurities. Tests and acceptance criteria

should be based on process knowledge and control strategy. The analytical procedures used should be

suitably validated. The justification of the specification should include evaluation of the risks and the ability

of the subsequent steps to purge impurities.

5.1.1

5.2.1

6.1起始物料筛选需要重点考

虑什么？

作为控制策略的一部分，申请人需要提供起始物料的质量标准及其制定依据，包括检验列表、选用

的分析方法和可接受标准。

起始物料的质量标准应包含鉴别和纯度测试（如杂质控制），设定含量、特定杂质、非特定杂质和

总杂、残留溶剂、试剂、元素杂质和致畸杂质的可接受标准。检测项目和可接受标准应基于对工艺

的了解和控制策略。使用的分析方法应经过合理验证。质量标准的制定依据应包括风险评估及后续

步骤去除杂质的能力。

5.11 For starting materials that Information on how the proposed starting material is made (e.g., a flow chart of the starting material

# Questions Answers

are not commercially available chemicals, what information should be provided on the synthetic route? manufacturing process, showing all reagents, catalysts and solvents used) should be provided to help justify the controls applied to the starting material. Information about the actual and potential impurities in the proposed starting material should be included.

5.2.1对于不市售的起始物料，

关于合成路线需要提供什

么信息？

需要提供起始物料是如何获得的信息，如起始物料生产工艺流程图，显示所有使用的溶剂、试剂、

催化剂，从而有助于对起始物料的控制进行讨论。还应包含起始物料的已知和潜在杂质信息。

5.12 What is the difference

between a commercially

available chemical and a

custom synthesised

chemical?

ICH Q11 states that “a commercially available chemical is usually one that is sold as a commodity in a pre-

existing, non-pharmaceutical market in addition to its proposed use as starting material”. A definition of

“custom synthesised chemical” was not provided in ICH Q11, but a custom synthesised chemical is

generally understood to be one that is made specifically to a drug substance manufacturer’s requirement,

either in-house or externally, or available for purchase but where the only use is for pharmaceutical

manufacture.

ICH Q11 makes an important distinction between commercially available chemicals and custom synthesised

chemicals. An applicant generally need not justify the use of a commercially available chemical as a starting

material, whereas a custom synthesised chemical proposed as a starting material should be justified in

accordance with the ICH Q11 general principles.

The availability of a chemical from multiple suppliers should not be the sole basis for the designation of a

chemical as a commercially available starting material. This includes situations where a custom synthesized

chemical has become available over time from multiple suppliers. Such chemicals should still be justified

according to the ICH Q11 general principles for selection of starting materials. The reference to “non-

pharmaceutical market” in the ICH Q11 description of commercially available chemicals was included to

preclude intermediates from being claimed as commercially available chemicals.

It can be acceptable for a starting material that is demonstrated to be a commercially available chemical to

enter late in the synthesis, e.g., in the last chemical transformation prior to the drug substance.

A chemical manufactured at small scale can be suitable as a commercially available starting material

provided that the scale is sufficient for the manufacture of the drug substance and that the chemical is also

# Questions Answers

used in a pre-existing, non-pharmaceutical market.

In some cases, a chemical that does not meet the definition of a commercially available chemical (e.g., it

does not have a non-pharmaceutical use) but is simple enough in structure may be accepted as a starting

material with little justification (e.g., protected natural amino acids as pharmaceutical building blocks).

5.2.1市售化学品和委托合成化

学品的区别是什么？

ICH Q11指出“除用作起始物料外，市售化学品通常作为已存在的、非药用的商品进行销售”。“委

托合成化学品”的定义在ICH Q11中并未给出，但是委托合成化学品通常是指针对原料药生产商要

求专门生产的，自制或外包生产，或外购但是只用作药物生产。

ICH Q11明确指出了市售化学品和委托合成化学品的区别。申请人通常不需要对市售的起始物料进

行讨论说明，而委托合成的化学品作为起始物料则需要按照ICH Q11总则进行讨论说明。

一个化学品来自多个供应商不能单独作为定义起始物料为市售的依据，这里面包含了随着时间的推

进委托合成化学品来自多个供应商的情况，这类化学品仍应按照ICH Q11起始物料的筛选总则进行

论证说明。ICH Q11描述的市售化学品限定“非药用市场”即排除了作为市售存在的中间体。

起始物料作为市售化学品出现在工艺的最后步骤是可以接受的，如在得到原料药之前的最后一步化

学转换。

小试生产的化学品可以作为市售起始物料，只要其批量足够原料药生产，且该化学品是作为已存在

的、非药用的商品进行销售。

某些情况下，化学品不符合市售的定义，如具有药用用途，但是如果其结构足够简单，作为起始物

料也有可能是接受的，且不需要论证说明，如作为药用构件保护天然氨基酸。

5.13 What information should be

included in the application

about a starting material

that is a commercially

available chemical?

An applicant generally need not justify the use of a commercially available chemical as a starting material

(see ICH Q11, Section 5.2.1). However, the applicant should provide basic information (chemical name,

chemical formula, and molecular weight), information on the impurity profile, and how the control strategy

for the manufacturing process justifies the starting material specification.

If the drug substance manufacturer needs to perform additional purification steps to ensure the consistent

quality of a commercially available starting material, ICH Q11 also recommends that the additional

# Questions Answers

purification steps should be included in Section 3.2.S.2.2 as part of the drug substance manufacturing

process.

It is also recognized that on occasion, detailed information on the manufacturing process of a commercially

available chemical may not be readily available to the applicant due to restrictions of intellectual property.

However, well documented synthetic routes that are publicly available can provide important information

that should be considered when evaluating potential impurities (e.g., known use of metal catalyst). The

applicant should set appropriate controls and should justify the proposed specification for the actual and

potential impurities that are reasonably expected in a proposed starting material, based on the scientific

knowledge and available information.

For all starting materials, applicants should set appropriate controls and be able to justify the proposed

specifications.

5.2.1市售的起始物料在申请文

件中应提供哪些信息？

市售的起始物料申请人通常不需要论证说明（见ICH Q11 5.2.1章节）。但是，申请人应提供基本信

息：化学名、化学式和分子量、杂质概况和生产工艺控制策略如何制定了起始物料的质量标准。

如果想要确保市售起始物料的质量均一性，原料药生产商需要进行额外的纯化操作，ICH Q11也建

议额外的纯化操作也应作为原料药生产工艺的一部分，包含在3.2.S.2.2章节。

有时由于知识产权保护，申请人可能无法获得市售化学品详细的生产工艺信息。但是，公开的合成

路线能提供重要的信息，在评估潜在杂质时需要考虑，如知道使用了金属催化剂。申请人应基于科

学知识和现有信息，对起始物料制定合理的控制并对其质量标准中的已知和潜在杂质进行合理说

明。

对于所有的起始物料，申请人应合理控制并对质量标准进行论证说明。

5.14 Does ICH Q11 include

specific guidance for post-

approval changes to steps

prior to the starting material

(e.g., changes in synthetic

route, reagents, solvents,

starting material supplier)?

No. Post-approval changes to steps prior to starting materials are not explicitly covered in ICH Q11.

However, ICH Q11 does describe fundamental science and risk-based concepts that should be used to

evaluate the impact of post-approval changes to the process after the starting material (ICH Q11 Section 9 –

Lifecycle Management), and these same concepts should be applied to evaluate the impact of changes prior

to the starting material.

For example, changes prior to the starting material should be evaluated for their impact on the starting

# Questions Answers

material (e.g., on current and potential new impurities, including potentially mutagenic and elemental

impurities) and when appropriate on the drug substance. The evaluation could be based on risk assessment

and scientific understanding of the proposed change and its proximity to the starting material. The

evaluation should include an assessment of the control strategy (e.g., adequacy of the specification for the

starting material, including analytical procedures’ abilities to detect any new impurities).

As stated in ICH Q7 Q&A document Section 13.1, each party in the supply chain is responsible for

transferring information related to quality or regulatory changes to the next customer in the supply chain so

that the information is transferred along the supply chain to the drug product manufacturer in a timely

manner.

Post-approval changes to information on the starting material should be reported to regulatory authorities in

accordance with regional regulations and guidelines.

5.1.1 5.2.1 9

Q7关于起始物料之前步骤的

批准后变更（如变更合成

路线、试剂、溶剂、起始

物料供应商），ICH Q11

是否有明确的指南？

没有。ICH Q11没有明确说明起始物料之前步骤的批准后变更。但是，ICH Q11的确提出了基础科

学和基于风险的理念，用于评估批准后变更对起始物料后续工艺的影响（ICH Q11第9章节 – 生命

周期管理），在评估起始物料之前的变更影响时也应运用相同理念。

例如，应评估起始物料之前的变更对起始物料和原料药的影响（如现有的和潜在的新杂质，包括潜

在的致畸杂质和元素杂质）。评估可以基于风险评估和对所提变更的科学认识，及与起始物料的接

近程度。评估还应包含对控制策略的评估（如起始物料质量标准的充分性，含有足够的分析能力检

测新杂质）。

ICH Q7问答文件第13.1章节指出，供应链中的各方均有责任将质量或法规相关的变更信息传递给

供应链中的下一客户，以便信息及时地顺着供应链向下传递给制剂生产商。

按照地区法规和指南规定，起始物料的批准后变更应报告给药政官方。

5.15 Can the lifecycle section of

ICH Q11 apply to Lifecycle

Management of Starting

Materials?

Yes. In addition to what is submitted in the application, the applicant’s Pharmaceutical Quality System

(PQS) should address residual risks to the drug substance quality associated with future changes upstream of

the defined starting material.

The Lifecycle Management section of ICH Q11 reinforces management’s responsibility described in ICH

# Questions Answers

Q10, which is applicable to starting material lifecycle management. ICH Q10 Section 2.7 (Management of

Outsourced Activities and Purchased Materials) recommends that ‘The pharmaceutical quality system,

including the management responsibilities described in this section, extends to the control and review of any

outsourced activities and quality of purchased materials. The pharmaceutical company is ultimately

responsible to ensure processes are in place to assure the control of outsourced activities and quality of

purchased materials’.

ICH Q7 Sections 7 (Materials Management) and 13 (Change Control), ICH Q7 Q&A document Sections 7

and 13, as well as ICH Q10 Section 2.7 (Management of Outsourced Activities and Purchased Materials)

provide guidance that can be applied to the management of starting materials and starting material suppliers.

ICH Q9 and its Annexes provide guidance on the use of principles for quality risk management which can

be applied to future changes related to the starting materials (e.g., new starting material suppliers,

manufacturing processes, or specifications).

5.2.1

9

Q7 Q7 Q&A Q9 Q10 ICH Q11生命周期章节是

否适用于起始物料的生命

周期管理？

适用。除了申请文件需要递交的信息外，申请人的药品质量体系（PQS）应说明既定起始物料日后

的上游变更对原料药质量的潜在风险。

ICH Q11生命周期管理章节强调的是ICH Q10中提出的管理的责任，适用于起始物料生命周期管

理。ICH Q10第2.7章节（外包活动和购买原料的管理）建议：“药品质量体系，包括本章节描述的

管理职责，延伸至对所有外包活动和购买物料质量的控制和审核。为确保外包活动受控且购买的物

料质量可靠，制药公司对确保相关程序的有效实施负绝对责任。”

ICH Q7第7章节（物料管理）、第13章节（变更控制），ICH Q7问答第7和13章节，及ICH

Q10第2.7章节（外包活动和购买原料的管理），为起始物料及其供应商的管理提供了指导。

ICH Q9及其附件对使用质量风险管理原则提供了指导，可应用于日后起始物料的相关变更（如新增

起始物料供应商、生产工艺或质量标准变更）。

5.16 Is a “starting material” as

described in ICH Q11 the

same as an “API starting

material” as described in

Yes. ICH Q11 states that the Good Manufacturing Practice (GMP) provisions described in ICH Q7 apply to

each branch of the drug substance manufacturing process beginning with the first use of a “starting

material”. ICH Q7 states that appropriate GMP (as defined in that guidance) should be applied to the

manufacturing steps immediately after “API starting materials” are entered into the process (see ICH Q7

# Questions Answers

ICH Q7? Q&A Question 1.1). Because ICH Q11 sets the applicability of ICH Q7 as beginning with the “starting

material”, and ICH Q7 sets the applicability of ICH Q7 as beginning with the “API starting material”, these

two terms are intended to refer to the same material.

ICH Q7 states that an “API Starting Material” is a raw material, intermediate, or an API that is used in the

production of an API. ICH Q7 provides guidance regarding good manufacturing practices for the drug

substance; however, it does not provide specific guidance on the selection and justification of starting

materials. When a chemical, including one that is also a drug substance, is proposed to be a starting

material, all ICH Q11 general principles still need to be considered.

5.1.1 5.2.1 Q7ICH Q11中提到的“起始

物料”等同于ICH Q7中的

“API起始物料”吗？

等同。ICH Q11指出ICH Q7中的GMP条例适用于原料药生产工艺从初次使用“起始物料”开始的每

个分支。ICH Q7指出GMP针对“原料药起始物料”进入工艺生产步骤后（见ICH Q7问答1.1）。

由于ICH Q11限定了ICH Q7的适用性从“起始物料”开始，ICH Q7限定了其适用性从“原料药起始

物料”开始，因此这两点所指是相同物料。

ICH Q7指出“原料药起始物料”是用于生产原料药的原料、中间体或API。ICH Q7为原料药良好生

产操作提供了指导；但是，关于起始物料的筛选和论证它并没有给出专门指导。当一个化学品，同

时是原料药作为起始物料时，ICH Q11的所有原则都需考虑。