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2017年版EMA《化學原料藥生產起始物料的選擇和論證要求思考》
http://www.672701.live  2017-8-28 11:19:33  點擊率:2060


All the general principles above should be considered in selecting Starting Material(s), rather than strictly applying each general principle in isolation (see Example 4, Section 10.4).


在選擇起始物料時,要考慮上述所有的通則,而不僅僅單獨考慮嚴格適用某一個原則(參見例4,第10.4部分)。

Explanatory note 6: 注釋6

Scientific reasoning with appropriate justification, considering the whole synthetic approach and control strategy, and incorporating all the various principles outlined above, should be used in order to justify the selection of the starting materials. Often, applicants/manufacturers will select just a few criteria and use them to justify starting material selection, e.g.: “Compound X is a well-characterised isolated material of defined chemical properties and structure, and constitutes a significant structural fragment of the active substance. Therefore it is selected as a starting material as per ICH Q11.” This line of argumentation is not comprehensive and therefore not acceptable. Control strategy alone is not a sufficient justification of a starting material. Equally, a long synthetic process will not necessarily compensate for a poor control strategy.


在論述起始物料的選擇時,要采用適當的科學原理進行論述,考慮整個合成方法和控制策略,結合上列所有各類原則。通常,申報人/生產商會選擇少數幾個標準,使用它們對起始物料的選擇進行論述,例如,“化合物X特性清楚,被分離,具有清楚的化學特性和結構,成為原料藥的重要結構片斷,因此根據ICH Q11它被選擇作為起始物料”。這樣的論述不夠全面,因此不會被接受。僅僅只有控制策略的話,是不足以作為起始物料的論證依據的。同樣,合成路線很長并不能彌補很差的控制策略

5.1.2 Selection of starting materials for semi-synthetic drug substances 半合成原料藥的起始物料的選擇



在本指南中,半合成原料藥是指原料藥結構是由一部分化學合成結構和生物來源結構(例如,發酵、植物原料提取)合并而成。在有些情況下,申報人可以從來源物料(微生物或植物原料)開始描述生產工藝。當然,如果可以證明在合成步驟中分離出的一個中間體符合上述合成原料藥起始物料選擇的原則,則所分離出的中間體也可以提議作為起始物料。申報人尤其應評估是否可能對所擬的起始物料進行特性分析,包括其雜質譜、發酵或植物原料和提取工藝對原料藥的雜質譜是否有影響。要說明微生物和其它污染所帶來的風險。

Explanatory note 7: 注釋7

It is re-emphasised that a semi-synthetic starting material should comply with the general principles for starting materials already discussed above and summarised in explanatory note 6. If the fermentation step or extraction step is considered to be critical following the definition in explanatory note 2, and considering the potential for variability in fermentation process or extraction step, then it should be carried out under GMP.

5.2 Submission of information for starting material or source material 起始物料或來源物料的資料提交



申報人應識別所有擬定的起始物料或源物料,提交適當的質量標準。應論證所擬的合成和半合成原料藥的起始物料。

Explanatory note 8: 注釋8

Information on the manufacturers and suppliers of starting materials should be provided, including name and address, and a scheme of the synthetic route used to manufacture them, showing all reagents, catalysts and solvents used. Without this information, the suitability of specifications cannot be adequately assessed.


要提交起始物料生產商和供應商的資料,包括名稱、地址、生產所用合成路線圖、標示所用的所有試劑、催化劑和溶劑。沒有這些資料,就無法對質量標準的適用性進行適當評審。


The specification for a starting material should address impurities and is expected to consider suitable limits for known, unknown impurities and total impurities and where appropriate, limits for solvents, reagents and catalysts used during synthesis of a starting material. The acceptance criteria should be established based on origin, fate and purge of impurities present in the starting material, and where appropriate, should be designed to detect isomeric or other impurities which are potentially reactive and which may be carried through to the active substance.


起始物料的質量標準應包括雜質,應考慮對已知、未知雜質和總雜質制訂適當的限度,適當時還要制訂起始物料合成中所用的溶劑、試劑和催化劑的限度。應根據起始物料中出現雜質的來源、去向和清除情況建立可接受標準,適當時,應設計檢測異構體和其它可能反應,并帶入原料藥的雜質。


Analytical methods used should be validated. A tabulated summary of the results of the validation carried out should be provided if critical for the quality of the active substance However, it is not necessary to provide a validation report.


所用的分析方法應進行驗證。如果分析方法對于原料藥的質量非常關鍵,則需要采用表格總結的方式提交驗證結果。當然,并不需要提交驗證報告。


5.2.1 Justification of starting material selection for synthetic drug substances 合成原料藥起始物料選擇的論證


The applicant should provide a justification for how each proposed starting material is appropriate in light of the general principles for the selection of starting materials outlined above in Section 5.1.1. This can include information on:


申報人應提交資料,根據5.1.1部分所列的起始物料選擇通則,論述為什么各所擬起始物料是適當的。論述可以包括以下資料


· The ability of analytical procedures to detect impurities in the starting material

· 分析方法可以檢測到起始物料中的雜質


· The fate and purge of those impurities and their derivatives in subsequent processing steps

· 這些雜質及其在之后工藝步驟中的衍生物的去向和清除,


· How the proposed specification for each starting material will contribute to the control strategy

· 所擬的各起始物料的質量標準如何實現控制策略

Explanatory note 9: 注釋9

The suitability of a starting material needs to be justified against the principles in section 5.1 as a whole, rather than against selected individual bullet points. Critical to satisfactory justification of a starting material, and for the assessment of the justification, is the description of the formation, fate and purge of impurities. The dossier must contain an appropriate discussion on known and unknown impurities including residual solvents, catalysts, metals and reagents. The starting material specifications should include tests and acceptance criteria for specified, unspecified and total impurities (including (potential) genotoxins) and where appropriate, limits for solvents, reagents and catalysts used during their synthesis. An inadequate discussion on impurities renders evaluation of the proposed starting materials and their specifications impossible.


起始物料的適用性需要根據5.1部分中的原則作整體論述,而不只是針對選擇的單個項目進行論述。要讓起始物料的論述讓人滿意,對論證內容進行評審時最關鍵的是描述雜質的形成、去向和清除。申報文件中必須包括對已知和未知雜質的適當討論,包括殘留溶劑、催化劑、金屬和試劑。起始物料質量標準應包括已知、未知和總雜質(包括潛在的基因毒性)的檢驗方法和可接受標準,適當時,應包括原料藥合成中所用溶劑、試驗和催化劑的限度。如果對雜質的討論不夠充分,評審人員就無法對所擬的起始物料及其質量標準進行評估。


The applicant should provide, as part of the justification, a flow diagram outlining the current synthetic route(s) for the manufacture of the drug substance, with the proposed starting materials clearly indicated. Changes to the starting material specification and to the synthetic route from the starting material to final drug substance are subject to regional, post-approval change requirements. In addition, regional requirements concerning starting material suppliers may also be applicable.


申報人應提交原料藥現行生產的合成路線流程圖作為論述的一部分,在其中清楚標明所擬的起始物料。對起始物料質量標準和起始物料到原料藥之間合成路線的變更要符合地方對預批準變更的要求。另外,地方當局對起始物料供應商的要求也是適用的。

Explanatory note 10: 注釋10

The quality of the proposed starting material must be sufficient, in combination with the control strategy, to ensure the quality of the active substance. The manufacturing route of a starting material and information on manufacturers* should also be provided to allow an adequate assessment of the suitability of starting materials and their specification. If any synthetic steps used to manufacture the starting materials are considered critical and are either close to the active substance (in terms of number of synthetic steps) or impact its impurity profile, then the re-definition of starting materials to an earlier point should be considered, bearing in mind the whole synthetic route and the control strategy (see explanatory note 2).


所擬起始物料的質量必須達到足夠的標準,與控制策略一起,用于保證原料藥的質量。起始物料的生產路線和生產商資料也需要在申報資料中提交,以使得評審人員能對起始物料和其質量標準的適用性進行評審。如果起始物料生產中某合成步驟被認為是關鍵的,并接近原料藥(指合成步驟數)或對雜質譜有影響,則應考慮重新定義起始物料,將其移至較前的點,這時一定要考慮整個合成路線和控制策略(參見注釋2)。


It is emphasized that it is the legal responsibility of the marketing authorisation holder to maintain the quality of the active substance throughout its lifecycle. Implicit in this is that changes to the synthetic route to the starting materials should always be assessed for their impact on the quality of the active substance, and any resultant modifications such as changes to specifications or manufacturers of the starting material(s) should be applied for by way of appropriate variations. The active substance manufacturer, which may frequently be independent of the applicant, has a very important role to play in this and is also responsible for ensuring the quality of the active substance it manufactures.


要強調的是上市許可持有人承擔著法定責任,要在其生命周期中維護原料藥的質量。在此表示的意思是,起始物料合成路線的變更都要評估其對原料藥質量的影響,所有可能會產生影響的修訂例如,起始物料質量標準或生產商的變更應進行適當的變更申報。原料藥生產商,通常是獨立于申報人的,在此扮演了非常重要的角色,也有責任保證其所生產的原料藥的質量。


* When ICH Q11 mentions starting material suppliers, this is interpreted within the EU as manufacturers.


當ICH Q11提到起始物料供應商時,在EU內是作為生產商來解釋的。

An applicant generally need not justify the use of a commercially available chemical as a starting material. 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. Chemicals produced by custom syntheses are not considered to be commercially available. If a chemical from a custom synthesis is proposed as a starting material, it should be justified in accordance with the general principles for the selection of starting materials outlined above in Section 5.1.1.


一般來說,申報人不需要論證其采用商業或獲得的化學品作為起始物料。商業可獲得的化學品通常是指作為已存在、除其起始物料的用途外,非制藥行業市場的商品。訂制合成的化學品并不是商業可獲得的。如果提議一個訂制合成的化學品作為起始物料,則應根據5.1.1部分所列的起始物料選擇通則進行論述。


In some instances, additional purification steps by the drug substance manufacturer might be called for to ensure the consistent quality of a commercially available starting material. In these instances, the additional purification steps should be included as part of the description of the drug substance manufacturing process. Specifications should normally be provided for both incoming and purified starting material.


在有些情況下,原料藥生產商可能會對起始物料進行額外的精制,以保證商業獲得的起始物料質量穩定性。在這種情況下,應將精制步驟包括在原料藥生產工藝中,作為其一部分。要提交進廠起始物料和精制后的起始物料的質量標準。

Explanatory note 11: 注釋11

A statement that a material is commercially available may not be considered sufficient to justify it as a starting material without additional supporting information. It is the responsibility of the applicant to show that a commercially available starting material is not custom synthesised, but a commodity material used in a non-pharmaceutical market, and to provide supportive documentation in the dossier demonstrating so. It is also a requirement to demonstrate that the quality of a commercially available starting material is adequate for use in the manufacture of an active substance. To enable the assessment of any requirement for further purification of a commercially available material, the information on the impurity profile should be presented for assessment.


僅僅聲明一種物料是商業可獲得,而沒有其它支持性資料,可能會被認為是不夠充分的,不能證明其可以作為起始物料。申報人有責任說明該商業可獲得的起始物料不是訂制合成的,而是非制藥市場所用的商業化物料,在申報資料中提交支持性文件進行證明。還要證明商業可獲得的起始物料的質量足以滿足原料藥的生產使用要求。為使得評審人員可以評估對商業可獲得物料進一步精制的必要性,還需要提交雜質譜的資料。

5.2.2 Justification of starting material selection for semi-synthetic drug substances 半合成原料藥起始物料選擇的論證


If an isolated intermediate is proposed as the starting material for a semi-synthetic drug substance, the applicant should provide a justification that explains how the proposed starting material complies with the general principles for the selection of starting materials outlined above in Section 5.1.1. Otherwise, the applicant should describe the manufacturing process starting from the microorganism or botanical material, as appropriate, and these materials should be qualified.


如果提議將一個分離出的中間體作為半合成原料藥的起始物料,則申報人要提交一份論述,解釋所擬的起始物料是如何符合5.1.1部分中所列的起始物料選擇通則的。否則,申報人則應描述從微生物或植物原料開始的生產工藝,適當時還應對這些物料進行確認。

References: 參考文獻

1. ICH Guideline Q11 on Development and Manufacture of Drug Substances (chemical entities and biotechnological / biological entities) CHMP/ICH/425213/2011 (ICH Q11) ICH Q11原料藥研發和生產指南(化學實體和生物技術/生物實體)

2. Chemistry of New Active Substances (CPMP/QWP/130/96, Rev 1) 新活性物質的化學部分

3. Chemistry of active substances 3AQ5A 活性物質化學部分

4. Active substance-master-file procedure CHMP/QWP/227/02 活性物質主文件程序

5. ICH Guideline Q11 on Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients CPMP/ICH/4106/00 (ICH Q7) ICH Q11 活性藥用成份GMP指南

6. The Rules Governing Medicinal Products in the European Union, Volume 4, Good Manufacturing Practice, Part II: Basic Requirements for Active Substances used as Starting Materials EU GMP第二部分:作為起始物料的活性物質的基本要求

全文完。

 

 
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