仿制药研发的一般流程
The general process of
generic drug development
如今的新法规对仿制药提出了新的要求，主要是以下几点Today's new regulations put forward new
requirements for generic drugs, mainly in the following aspects：
1、规范对被仿制药品的选择原则，即参比制剂的选择问题。Standardize
the selection principle of imitated drugs, that is, the selection of reference
preparations.
2、增加批准前生产现场的检查。Increase the
inspection of production site before approval.
3、按照要求提供申报资料，使申报规范，统一。Provide
application materials as required to make the application standardized and
unified.
4、强调了对比研究，是判断两者质量是否一致的重要方法之一。It is
emphasized that comparative study is one of the important methods to judge
whether the quality of the two is consistent.
5、强化了工艺验证，目的是确保大生产时能始终如一地按照申报工艺生产出质量恒定的产品。The
process validation is strengthened to ensure that products with constant quality
can be consistently produced according to the declared process during mass
production.
6、提出了晶型的要求，晶型的不同，溶解度和稳定性不同。The
requirements of crystal form are put forward. Different crystal forms have
different solubility and stability.
分析上述新要求和参考指导原则，从而得出结论By analyzing the above new requirements and
reference guidelines, it is concluded that:
1.安全性“同”Security
"same"：
对于安全性，口服固体制剂控制的主要为有关物质，而液体制剂除控制有关物质外，还需对防腐剂、氧化剂等对人体有影响的物质进行控制。因此，必须要将防腐剂含量测定定入质量标准。For safety, oral solid preparations are mainly
controlled by related substances, while liquid preparations need to control not
only related substances, but also preservatives, oxidants and other substances
that have an impact on human body. Therefore, the determination of preservative
content must be set into the quality standard.
研究的内容：静态上应包括杂质谱的对比，单个杂质的对比，杂质总量的对比。动态上的对比为影响因素试验、加速试验的对比，即稳定性对比研究。Research content: statically, it should include
the comparison of impurity mass spectrum, single impurity and total impurity.
The dynamic comparison is the comparison of influencing factor test and
accelerated test, that is, the comparative study of stability.
2.有效性“同”Validity
"same"：
对于口服固体制剂，口服混悬剂(包括干混悬剂)，溶出曲线是主要的控制指标[1];对于口服溶液剂，防腐剂、矫味剂、氧化剂、增溶剂及稳定剂的选用非常重要，控制点为口感、渗透压、PH及有无絮凝现象;对于局部用制剂(如鼻喷雾剂)，粒度分布、渗透压及黏度是主要控制指标。For oral solid preparations, the
dissolution curve of oral suspension (including dry suspension) is the main
control index [1]; For oral solution, the selection of preservatives, flavoring
agents, oxidants, solubilizers and stabilizers is very important. The control
points are taste, osmotic pressure, pH and flocculation; For local preparations
(such as nasal spray), particle size distribution, osmotic pressure and
viscosity are the main control indicators.
研究的内容：分别进行溶出曲线对比;粒度分布对比;渗透压及黏度对比。The content of dissolution curve was compared;
Comparison of particle size distribution; Osmotic pressure and viscosity
comparison.
3.晶型Crystal：
晶型的不同，药物的溶解度及稳定性有可能不相同，从而导致生物利用度不尽相同。而某个药物的晶型，文献资料很少;制剂中原料的晶型测定有一定的难度;在做成制剂的过程中，又不能保证晶型不产生变化。With different crystal forms, the
solubility and stability of drugs may be different, resulting in different
bioavailability. There is little literature on the crystal form of a drug; It
is difficult to determine the crystal form of raw materials in the preparation;
In the process of making the preparation, there is no guarantee that the
crystal form will not change.
但是，鉴于仿制药研究的特点，溶解度方面可通过溶出曲线对比来说明;稳定性方面可通过影响因素试验和加速试验的对比来说明。However,
in view of the characteristics of generic drug research, the solubility can be
explained by the comparison of dissolution curves; The stability can be
explained by the comparison of influencing factor test and accelerated test.
(从立项到申报，时间为10—12个月) (the time from project initiation to application is 10-12 months)
(约一周完成) (about one
week)
是否有合法原料提供;临床资料、不良反应资料及产品说明书等相关资料;国内及进口制剂剂型及规格;产品质量标准(原研标准、国内首仿标准、药典标准);原研处方组成及工艺研究资料;药品的稳定性资料;专利情况;生产注册情况(产品原研厂家、国内生产申报厂家数情况);参比制剂来源等。Whether legal raw materials are provided; Clinical
data, adverse reaction data, product instructions and other relevant data;
Dosage forms and specifications of domestic and imported preparations; Product
quality standards (original research standards, domestic first imitation
standards, Pharmacopoeia standards); Original prescription composition and
process research data; Stability data of drugs; Patents; Production
registration (original manufacturer of products and number of declared domestic
manufacturers); Source of reference preparation, etc.
1、 参比制剂的采购Procurement of reference
preparations
1)首选已进口或本地化生产的原研产品The original
research products that have been imported or produced locally are preferred;
2)如果无法获得原研产品，可以采用质量优良的在发达国家上市的药品，如在ICH（ International Conference on Harmonization of Techn ）成员国上市的同品种，即美国、欧盟或日本等国的同品种仿制产品。如果上述国家产品已经进口中国，可采用进口品。If the original research products cannot be
obtained, the drugs listed in developed countries with good quality can be
used, such as the same varieties listed in ICH member countries, that is, the
imitation products of the same varieties in the United States, the European
Union or Japan. If the products of the above countries have been imported into
China, they can be imported.
3)如果无法获得符合上述要求的对照品，则应在充分考虑立题合理性的前提下，采用多家国内上市的主流产品，进行深入的对比研究，所申报产品的质量应能达到其中最优产品的质量。If
it is impossible to obtain the reference substance that meets the above
requirements, on the premise of fully considering the rationality of the topic,
multiple mainstream products listed in China shall be used for in-depth
comparative research, and the quality of the declared products shall reach the
quality of the best one.
4)如果确实无法获得符合要求的已上市对照品，在充分考虑立题合理性的前提下，应按照新药研究的技术要求进行相应的研究。If
it is really impossible to obtain the listed reference substance that meets the
requirements, the corresponding research shall be carried out according to the
technical requirements of new drug research on the premise of fully considering
the rationality of the topic.
2、 原料采购Purchase raw materials
可选用几个厂家的小样进行对比后，采购质量较好的(需提供原料厂家资质、发票、检验报告、标准、购销合同及长期供货协议等证明性文件)。Small samples from several manufacturers can be selected for
comparison, and those with good purchase quality (such supporting documents as
raw material manufacturer qualification, invoice, inspection report, standard,
purchase and sales contract and long-term supply agreement shall be provided).
3、 色谱柱及对照品采购Purchase of
chromatographic column and reference substance
在对原料质量标准、查询到的制剂质量标准分析的基础上，拟定标准草案。向原料供应厂家充分了解产品的色谱条件后，再对色谱柱及对照品进行采购。包括：色谱柱的型号，规格，生产厂家;对照品的种类(含异构体);对照品的规格;对照品的用途(UV或含测用);对照品采购量(注明价格)。Based on the analysis of the quality standard of raw
materials and the quality standard of the queried preparations, the draft
standard is drawn up. After fully understanding the chromatographic conditions
of the product from the raw material supplier, purchase the chromatographic
column and reference substance. Including: model, specification and
manufacturer of chromatographic column; Type of reference substance (including
isomers); Specification of reference substance; Use of the reference substance
(UV or including test); Purchase quantity of reference substance (indicate the
price).
4、 辅料采购Purchase of excipients：
根据国内辅料应用情况，对原研药的处方组成进行合理分析后确定辅料的采购(厂里已有辅料不采购、需提供辅料厂家资质、发票、检验报告、标准、购销合同等证明性文件)。According to the application of domestic excipients, the
prescription composition of the original drug is reasonably analyzed to
determine the procurement of excipients (the existing excipients in the factory
are not purchased, and the qualification of excipients manufacturers, invoices,
inspection reports, standards, purchase and sales contracts and other supporting
documents need to be provided).
辅料选用标准：首选药用级;无药用级，口服制剂及局部用制剂可选用食用级。若也无食用级，考虑更换辅料。Selection
standard of auxiliary materials: medicinal grade is preferred; There is no
medicinal grade, and edible grade can be selected for oral preparations and
local preparations. If there is no edible grade, consider replacing the
auxiliary materials.
5、 包材的采购Procurement of packaging
materials：
在参比制剂购买以后，参考参比制剂的包装材料，结合公司情况，拟定包材种类(厂里已有包材不采购、需提供包材厂家资质、发票、检验报告、标准、购销合同等证明性文件)：包材的种类(口服或注射级);包材的规格(包装规格);包材药用标准(药典标准或是注册标准);采购量。此项工作可放缓。After the reference preparation is purchased,
refer to the packaging materials of the reference preparation and combine with
the company's situation to formulate the type of packaging materials (the
existing packaging materials in the factory are not purchased, and the
manufacturer's qualification, invoice, inspection report, standard, purchase
and sales contract and other supporting documents need to be provided): the
type of packaging materials (oral or injection grade); Specifications of
packaging materials (packaging specifications); Pharmaceutical standard of
packaging materials (pharmacopoeia standard or registration standard); Purchase
volume. This work can be slowed down.
1、 原辅料及参比制剂的检验Inspection of raw and
auxiliary materials and reference preparations
(约一周完成about one week)：
确定原辅料的合法来源;参照药典标准或其他相关标准对原、辅料进行检验;出具检验报告书。Determine the legal source of raw and auxiliary
materials; Inspect the raw and auxiliary materials with reference to
Pharmacopoeia standards or other relevant standards; Issue inspection report.
对参比制剂进行全面的检测，检测项目应不仅限于拟定的制剂质量标准。如固体口服制剂应对参比制剂进行溶出曲线的测定，对PH值敏感的药物制剂测定5%混悬液PH值;液体制剂应加测黏度、渗透压及PH值等。检验结果汇总。The reference preparation shall be comprehensively
tested, and the test items shall not be limited to the proposed preparation
quality standard. For example, for solid oral preparations, the dissolution
curve of the reference preparation shall be measured, and the pH value of 5%
suspension shall be measured for pharmaceutical preparations sensitive to pH value;
Viscosity, osmotic pressure and pH value of liquid preparations shall be
measured. Summary of inspection results.
通过这一项目，可以基本了解制剂要达到的基本性能。Through this project, we can basically
understand the basic performance of the preparation.
2、 处方工艺摸索Exploration of prescription
technology
2.1 辅料相容性试验Compatibility test of
auxiliary materials
(1)口服固体制剂Oral solid preparation：
通过前期的信息调研中，得知原料性质比较稳定，对辅料及保存条件没有太多要求时Through the previous information research, it
is known that the properties of raw materials are relatively stable and there
are not many requirements for auxiliary materials and storage conditions：
若能查到原研药的处方组成，而拟定的辅料种类与原研药一致的情况下，可不做此试验;若在原研药处方的基础上，增加辅料种类，只需做增加的辅料相容性试验;若查不到处方组成，需做辅料相容性试验。If the prescription composition of the
original drug can be found, and the proposed type of excipients is consistent
with the original drug, this test may not be carried out; If the types of
excipients are added on the basis of the original prescription, only the
compatibility test of the added excipients is needed; If the prescription
composition cannot be found, the compatibility test of excipients shall be
conducted.
具体做法specific working means:
选若干种辅料，将辅料与主药按一定比例混合，取一定量，参照药物稳定性指导原则中影响因素的实验方法，在高温60度、强光、高湿(RH75%、RH92.5%)试验。分别于0天、5天、10天取样。重点考察性状、含量、有关物质等，必要时，可用原料药和辅料分别做平行对照实验，以判别是原料药本身的变化还是辅料的影响。Select
several kinds of auxiliary materials, mix the auxiliary materials with the main
drug in a certain proportion, take a certain amount, and conduct the test at
high temperature of 60 ℃, strong light and high humidity (rh75%,
rh92.5%) with reference to the experimental method of influencing factors in
the guiding principles of drug stability. Samples were taken on day 0, 5 and 10
respectively. Focus on the properties, content, related substances, etc. if
necessary, parallel control experiments can be conducted with API and
excipients respectively to judge whether it is the change of API itself or the
influence of excipients.
对原料性质完全不了解，或通过信息调研，得知原料性质不稳定，对辅料及保存条件有特殊要求时Do not know the nature of raw materials at all,
or know that the nature of raw materials is unstable through information
research, and there are special requirements for auxiliary materials and
storage conditions：
即使查到原研药的处方组成，仍建议做一辅料相容性试验，因为原辅料生产厂家不同，稳定性也不同，杂质种类也可能有差别。在这种情况下做法可以相对简单一些。Even if the prescription composition of the
original drug is found, it is still recommended to conduct a compatibility test
of excipients, because the stability is different due to different
manufacturers of raw and excipients, and the types of impurities may be
different. In this case, the practice can be relatively simple.
例：经过查找原研药的处方，所用辅料为：XXX XXX XXX，在此基础上，将原料和所有辅料按一定常规用量混合，用原料及空白辅料做平行对照，在高温60度、强光、高湿(RH75%、RH92.5%)试验。分别于0天、5天、10天取样。重点考察性状、含量、有关物质等。Example: after searching the prescription
of the original drug, the auxiliary materials used are XXX. On this basis, the
raw materials and all auxiliary materials are mixed according to a certain
conventional dosage, and the raw materials and blank auxiliary materials are
used as parallel control. The test is carried out at high temperature of 60 ℃, strong light and high humidity (rh75%,
rh92.5%). Samples were taken on day 0, 5 and 10 respectively. Focus on the
character, content and related substances.
(2)液体制剂Liquid preparations：液体制剂可不进行此项试验liquid preparations may not be subject to this
test。
2.2 处方筛选Prescription screening
(一般采用单因素试验的方法，必要时候可采用正交法single factor
test method is generally adopted, and orthogonal method can be adopted when necessary)
通过上述的辅料相容性试验，对主药的稳定性有了基本的认识。Through the above compatibility test of
excipients, we have a basic understanding of the stability of the main drug.
(1)固体口服制剂Solid oral preparation：
①先按照辅料的常规用量和常规工艺，以制剂基本性能(如口服固体制剂颗粒的可压性、流动性及药片的硬度、脆碎度、水分等)为指标进行初步筛选。Firstly,
according to the conventional dosage and process of excipients, the basic
properties of the preparation (such as the compressibility and fluidity of oral
solid preparation particles and the hardness, brittleness and moisture of tablets)
are preliminarily screened.
②选出两到三个基本性能合格的处方样品，进行溶出度曲线测定，与原研制剂进行比较，找出差距，调节辅料的用量，使溶出曲线达到一致。Select
two or three prescription samples with qualified basic performance, determine
the dissolution curve, compare with the original preparation, find out the gap,
and adjust the dosage of excipients to make the dissolution curve consistent.
③确认两个或三个最佳处方工艺，分别作出小样，和原研产品对比进行影响因素研究，研究项目根据辅料相容性试验的结果来确定，基本上选用主药敏感的因素即可!不要求全部因素都做。Confirm two or three best prescription processes,
make small samples respectively, and compare with the original products to
study the influencing factors. The research items are determined according to
the results of the compatibility test of excipients. Basically, the sensitive
factors of the main drug can be selected! Not all factors are required.
④初步确定处方工艺。Preliminarily determine the
prescription process.
(2)液体制剂Liquid preparation：
①根据参比制剂的基本性能如黏度、口感、渗透压、PH值等来进行辅料的用量选择。The dosage of excipients is selected according
to the basic properties of the reference preparation, such as viscosity, taste,
osmotic pressure, pH value, etc.
②对于防腐剂的用量，若可以在原研的说明书或质量标准中查询到用量，可直接参照原研药的用量。若没有文献资料，需做一抑菌性试验，选用最低有效量。For
the dosage of preservative, if the dosage can be found in the original research
manual or quality standard, you can directly refer to the dosage of the
original research drug. If there is no literature, it is necessary to conduct a
bacteriostatic test and select the minimum effective amount.
具体做法：首先参考该防腐剂的常规用量，然后设定三至四个浓度，可以用等比的浓度。例如X的常规用量为0.2%—1.0%，可选用0.1%、0.2%、0.4%、0.8%四个浓度来进行试验。试验操作和判定标准参照中国药典附录。Specific
method: first, refer to the conventional dosage of the preservative, and then
set three to four concentrations, which can be equal to the concentration. For
example, the conventional dosage of X is 0.2% - 1.0%. Four concentrations of
0.1%, 0.2%, 0.4% and 0.8% can be selected for the test. Refer to the appendix
of CHP for test operation and judgment standards.
③选出一至两个基本性能合格的处方样品，与原研进行影响因素试验，实验项目可适当简化，如只进行高温60度这一条件即可，初步判定稳定性。Select one or two prescription samples with
qualified basic performance and conduct the influencing factor test with the
original research. The experimental items can be appropriately simplified. For
example, the stability can be preliminarily determined only under the condition
of high temperature of 60℃.
④初步确定处方工艺。Preliminarily determine the
prescription process.
3、 初步验证工艺Preliminary validation process
3.1 三批小试Three batches of small tests
用拟定的处方工艺放大生产三批，样品规模片剂可为1000片/批，液体制剂可为500g/批。并填写生产批记录。The proposed prescription process is used to scale
up the production of three batches. The sample scale can be 1000 tablets /
batch and 500g / batch for liquid preparations. And fill in the production
batch record.
3.2 样品检验Sample inspection
检验标准为参照原研、国内首仿或国内主流产品、药典等拟订的本品质量标准草案，草案应不低于被仿标准。产品合格，确定处方工艺;产品不合格，则重新进行处方工艺筛选。检测结果符合质量标准，并与参比制剂一致，出具检验报告单。The
inspection standard is the draft of the quality standard of the product
prepared with reference to the original research, the first domestic imitation
or domestic mainstream products, Pharmacopoeia, etc., and the draft shall not
be lower than the imitated standard. If the product is qualified, determine the
prescription process; If the product is unqualified, the prescription process
shall be screened again. The test results meet the quality standard and are
consistent with the reference preparation, and an inspection report is issued.
3.3 确定处方工艺Determine the prescription
process
在证实拟定处方工艺的可行性后，确定处方工艺。After confirming the feasibility of the
proposed prescription process, determine the prescription process.
4、 中试生产及工艺验证Pilot production and
process verification
根据公司条件及相关指导原则，拟定中试生产和工艺验证同时进行。因此，要求上一阶段的工作必须扎实，检测结果必须准确无误。According to the company's conditions and
relevant guiding principles, it is proposed to carry out pilot production and
process verification at the same time. Therefore, it is required that the work
in the previous stage must be solid and the test results must be accurate.
4.1 中试批量Pilot batch：
根据法规要求和公司现状，拟定每批批量为：口服固体制剂投料量为10公斤左右，根据此重量来折算万片数;液体制剂也为10公斤左右。According to the
requirements of laws and regulations and the current situation of the company,
it is proposed that the batch size of each batch is: the feeding amount of oral
solid preparation is about 10kg, which is converted into 10000 tablets
according to this weight; The liquid preparation is also about 10 kg.
法规要求：中试产品必须在GMP车间进行生产;所用设备应和将来大生产所用设备相同或原理及设备参数相同;批量为不少于以后大生产的1/10。Regulatory requirements: pilot products must be produced in
GMP workshop; The equipment used shall be the same as the equipment used in
mass production in the future, or the principle and equipment parameters shall
be the same; The batch shall not be less than 1 / 10 of the mass production in
the future.
4.2 中试生产Pilot production：
用确定的工艺在车间生产三批中试产品;填写生产批记录。Use the
determined process to produce three batches of pilot products in the workshop;
Fill in the production batch record.
4.3 工艺验证Process validation：
收集、评估整个工艺设计阶段及生产全过程的数据资料，确立工艺能持续一致地生产出符合质量要求的产品的有科学依据的证据。Collect and evaluate the data of the whole
process design stage and the whole production process, and establish the
scientific evidence that the process can continuously and consistently produce
products that meet the quality requirements.
资料内容包括：工艺验证的立项、方案、审批、报告、评价和建议、工艺验证证书。The data content includes: project initiation,
scheme, approval, report, evaluation and suggestion of process verification,
and process verification certificate.
在药品研发中，质量研究是重点。参考指导原则，现将质量研究分成四个部分：质量研究项目的选择及方法初步确定;质量标准的方法学验证;质量对比研究;质量标准的制定。In drug research and
development, quality research is the focus. Referring to the guiding
principles, the quality research is divided into four parts: the selection of
quality research projects and the preliminary determination of methods;
Methodological validation of quality standards; Quality comparative study;
Formulation of quality standards.
1、 质量研究项目的选择及方法初步确定Selection of quality
research projects and preliminary determination of methods
可称为“质量标准草案的初步建立”，此项工作应在辅料相容性试验之前完成。It
can be called "preliminary establishment of draft quality standard",
which should be completed before the compatibility test of auxiliary materials.
1.1 遵循“就高不就低”的原则。结合所查询的产品质量标准(原研标准、ChP、EP、BP英国药典、USP、JP等，如何查询?)和药典对具体剂型的要求，确定出质量标准草案。静脉注射剂处方中加有抗氧剂、抑菌剂、稳定剂和增(助)溶剂等，眼用制剂处方中加有防腐剂等，应对相应的辅料进行定量研究。Follow
the principle of "high, not low". Combined with the queried product
quality standards (original research standards, CHP, EP, BP, USP, JP, etc., how
to query?) And the requirements of the pharmacopoeia for specific dosage forms,
and determine the draft quality standard. Antioxidants, bacteriostatic agents,
stabilizers and enhancers (cosolvents) are added to the prescriptions of
intravenous injections, and preservatives are added to the prescriptions of
ophthalmic preparations. The corresponding excipients should be studied
quantitatively.
对于国家药品标准中收载的项目，首先应考虑选用标准中收载的检测方法。For the items contained in the national drug
standards, the detection methods contained in the standards should be
considered first.
1.2若有关物质检测方法多种并存时，建议初步对比研究来确定方法。如有杂质对照品，用杂质对照品来确认方法的可行性;如没有杂质对照品，可做一强制降解试验(需要特别注意的是降解程度为5%~10%左右，在此情况下判定物料平衡才有意义)，来初步判定检测方法的可行性。If
there are many detection methods for related substances, it is suggested to
conduct preliminary comparative study to determine the method. If there is
impurity reference substance, use impurity reference substance to confirm the
feasibility of the method; If there is no impurity reference substance, a
forced degradation test can be carried out (it should be noted that the
degradation degree is about 5% ~ 10%, and it is meaningful to judge the
material balance in this case) to preliminarily determine the feasibility of
the detection method.
判定标准：有杂质对照品时，系统适用性、分离度、有效检出、精密度及重现性。Judgment criteria: applicability, resolution,
effective detection, precision and reproducibility of the system when there is
impurity reference substance.
无杂质对照品时，系统适用性、降解杂质的有效检出、物料平衡。When there is no impurity reference substance,
the system applicability, effective detection of degraded impurities and
material balance.
1.3 质量标准草案的初步建立。Preliminary
establishment of quality standard draft.
2、 质量标准的方法学验证Methodological
validation of quality standards
具体分为两个方面：方法的初步验证和系统的方法学验证。It is divided into two aspects: the preliminary
verification of the method and the systematic methodological verification.
2.1 质量标准的初步验证(在中试之前完成) Preliminary verification of quality standards (completed
before pilot test)
①在配合处方工艺筛选检验时，就是质量标准初步验证的过程。例如辅料相容性试验、参比制剂与小试产品的对比检验、小试产品的影响因素试验等，就可以对方法的可行性进行一个初步的判断。When
cooperating with prescription process screening and inspection, it is the
process of preliminary verification of quality standards. For example, the
compatibility test of excipients, the comparative test between the reference
preparation and small-scale test products, and the test of influencing factors
of small-scale test products can make a preliminary judgment on the feasibility
of the method.
在这时，方法学研究偏重于验证国家标准中的检测方法和条件是否适用，重点考察方法的专属性和准确度。如方法学研究结果显示方法不适用，应首先分析原因，通过调整处方工艺等以使方法适用;在原因无法确认的一些极端条件下，才考虑建立新的检测方法，但新方法首先要按照化学药物质量控制研究相关指导原则进行研究，还需通过比较研究证实与原方法具有同等的控制程度。At
this time, methodological research focuses on verifying whether the detection
methods and conditions in the national standards are applicable, focusing on
the specificity and accuracy of the methods. If the research results of
methodology show that the method is not applicable, we should first analyze the
reasons and adjust the prescription process to make the method applicable;
Under some extreme conditions for which the reason cannot be confirmed, the
establishment of a new detection method is considered. However, the new method
must first be studied in accordance with the relevant guiding principles of chemical
drug quality control research, and the same degree of control as the original
method needs to be confirmed through comparative research.
因此，原则上不要更换已有的国家药品标准的色谱条件。当分离度达不到时，可适当调整流动相的比例。Therefore, in principle, do not replace the
chromatographic conditions of the existing national drug standards. When the
separation degree cannot be reached, the proportion of mobile phase can be
adjusted appropriately.
讨论Discussion：在前期的处方筛选中，质量标准并没有真正建立，最终确定的质量标准可能不一样。这种情况下，认为处方筛选的数据仍然可以放入申报资料中，这和处方筛选的目的并不背离，同时也反映出质量研究的开展过程。In
the early prescription screening, the quality standard has not been really
established, and the final quality standard may be different. In this case, it
is considered that the data of prescription screening can still be put into the
application data, which does not deviate from the purpose of prescription
screening, but also reflects the development process of quality research.
②出具三批小试样品的检验报告书。Issue the inspection
report of three batches of small test samples.
2.2 系统的方法学验证Methodological
verification of the system
在初步验证的基础上，需对质量标准进行系统的方法学验证。方法学验证所用样品应采用中试产品。On the basis of preliminary verification,
systematic methodological verification of quality standards is required. The
samples used for methodological validation should be pilot products.
验证项目(品种及剂型不同检测项目不同) Validation items (different test items for different
varieties and dosage forms)：
性状;鉴别(理化鉴别和光谱鉴别);一般检查项(按中国药典制剂通则);微生度检测(需进行完整的方法学验证试验);溶出度，有些可以和含量一起验证; character; Identification (physical and chemical
identification and spectral identification); General inspection items
(according to the general principles of preparations in Chinese Pharmacopoeia);
Microbiological detection (complete methodological validation test is
required); Dissolution, some can be verified together with content;
有关物质(需进行完整的方法学验证试验);含量测定(需进行完整的方法学验证试验)、卫生学方法学验证。Relevant
substances (complete methodological validation test is required); Content
determination (complete methodological validation test is required) and
hygienic methodological validation.
其中重点是有关物质和含量的方法学验证。The focus is on the methodological verification
of substances and contents.
有关物质验证的内容有The contents related to substance verification
include：
系统适用性System applicability：
取样品，按照有关物质供试品浓度配制溶液，进样，记录图谱。理论板数应
符合规定，分离度应大于2.0或符合规定、拖尾因子应0.8-1.2或符合规定。Take the sample, prepare the solution according to the
concentration of relevant substances, inject the sample and record the spectrum.
Theoretical plate number In accordance with the regulations, the
separation degree shall be greater than 2.0 or comply with the regulations, and
the tailing factor shall be 0.8-1.2 or comply with the regulations.
有已知杂质并且杂质对照品可获得的：杂质对照品溶液连续进样的峰面积的相对标准差应不大于 2.0%，保留时间的相对标准差应不大于1.0%。另外，理论板数应符合规定，分离度应大于 2.0或符合规定、拖尾因子应0.8-1.2或符合规定。If there are known impurities and the impurity
reference is available: the relative standard deviation of the peak area of the
continuous injection of the impurity reference solution shall not be greater
than 2.0%, and the relative standard deviation of the retention time shall not
be greater than 1.0%. In addition, the number of theoretical plates shall meet
the regulations, the separation degree shall be greater than 2.0 or meet the
regulations, and the tailing factor shall be 0.8-1.2 or meet the regulations.
专属性Specificity：
空白溶剂干扰试验、空白辅料试验、强制降解试验(高温、强光、强氧化、强酸、强碱等)、已知杂质定位试验、峰纯度检查(二极管阵列检测、质谱检测)。Blank solvent interference test, blank excipient test,
forced degradation test (high temperature, strong light, strong oxidation,
strong acid, strong alkali, etc.), known impurity positioning test, peak purity
inspection (diode array detection, mass spectrometry detection).
检测限与定量限Detection limit and quantitation limit：
一般采用信噪比法。有已知杂质并且杂质对照品可得的，须用已知杂质对照品同时做。信噪比10：1，为定量限;信噪比为3：1，为检测限。The
signal-to-noise ratio method is generally used. If there are known impurities
and the impurity control sample is available, the known impurity control sample
must be used at the same time. The signal-to-noise ratio is 10:1, which is the
quantitative limit; The signal-to-noise ratio is 3:1, which is the detection
limit.
线性范围Linear range：
一般做5~7个浓度，如40%、60%、80%、100%、120%、150%(相对于自身对照浓度)的系列溶液。取该系列溶液进样，记录色谱图，计算回归方程。Generally,
make a series of solutions with 5 ~ 7 concentrations, such as 40%, 60%, 80%,
100%, 120% and 150% (relative to their own control concentration). Inject this
series of solutions, record the chromatogram and calculate the regression
equation.
若有已知杂质并且杂质对照品可得的，则取已知杂质对照品另作线性关系试
验(以定量限为起始浓度点)，供试品中已知杂质峰面积，应在线性范围内。If
there are known impurities and the impurity control sample is available, take
the known impurity control sample for another linear relationship test ,the peak
area of known impurities in the test sample shall be within the linear range
after the test (taking the quantitative limit as the starting concentration
point).
精密度Precision：
包括重复性和中间精密度。重复性：6份供试品;中间精密度：不同时间、不同人员、不同仪器，6份供试品，与重复性试验的6个数据一起进行比较。Including
repeatability and intermediate precision. Repeatability: 6 test samples;
Intermediate precision: 6 test samples at different times, different personnel,
different instruments, and compared with the 6 data of repeatability test.
溶液稳定性Solution stability：
准确度Accuracy：
一般以回收率试验进行验证。无已知杂质的，可不做。有已知杂质的，须做加样回收试验验证准确度。Generally, it is verified by recovery test. If
there is no known impurity, it can not be done. The accuracy of known
impurities must be verified by adding samples.
讨论：有关物质的检测中，要检测的是杂质，而不是原料。因此，认为在有已知杂质对照品，并且在标准中对此杂质进行了单独控制的时候，方法学验证的内容应围绕着已知杂质展开，不可以用原料来代替。当无已知杂质对照品时，才用原料代替(自身对照，如1%对照，0.5%对照，0.1%对照)。Discussion: in the detection of relevant substances,
impurities should be detected, not raw materials. Therefore, it is considered
that when there is a reference substance with known impurities and this
impurity is separately controlled in the standard, the content of
methodological verification should focus on the known impurities and cannot be
replaced by raw materials. When there is no reference substance with known
impurities, raw materials can be used instead (self reference, such as 1%
reference, 0.5% reference, 0.1% reference).
在做强制降解试验时，同时用空白辅料平行做强制降解试验，特别是含有特殊辅料的，如防腐剂等在紫外有吸收的辅料。During the forced degradation test, the blank
excipients shall be used for the forced degradation test in parallel,
especially the excipients with special excipients, such as preservatives, which
have absorption in UV.
关于强制降解试验，不仅是方法学验证的内容，而且是对产品的降解途径、杂质谱及产品稳定性判定的过程。仿制药相关指导原则要求仿制品与原研药应比较杂质谱、杂质量及降解途径。因此，建议把研试品与原研药平行进行强制降解试验(均约5~10%)，这样可以直观比较两者的降解途径是否一致;降解物是否有差异;检查方法对两者的专属性差别(由于拟定的方法多是原研药的检测方法)。平行对比破坏性试验研究，是评价研制药和被仿药质量是否相同的重要手段。The forced degradation
test is not only the content of methodological verification, but also the
process of judging the degradation pathway, impurity mass spectrum and product
stability of the product. The relevant guiding principles of generic drugs
require that the impurity spectrum, impurity quality and degradation pathway of
the generic products and the original drug should be compared. Therefore, it is
suggested to carry out the forced degradation test (about 5 ~ 10%) in parallel
with the original drug, so as to directly compare whether the degradation
pathways of the two drugs are consistent; Whether there are differences in
degradation products; The specificity of the inspection methods for the two is
different (because the proposed methods are mostly the detection methods of the
original drug). Parallel comparative destructive test research is an important
means to evaluate whether the quality of developed drugs is the same as that of
imitated drugs.
关于强制降解试验中物料平衡的问题On material balance in forced degradation test：
①首先，降解强度为5%~10%左右。Firstly,
the degradation intensity is about 5% ~ 10%.
②有杂质对照品时，计算出校正因子，将校正因子代入计算。When there
is impurity reference substance, calculate the correction factor and substitute
the correction factor into the calculation.
③做峰纯度检查(二极管阵列检测)，二极管阵列检测的作用不仅是峰纯度检查，另外，还反映出杂质及主药的总体紫外吸收情况。可以计算在不同波长处的物料平衡情况(按具体品种而定)。Do peak purity test (diode
array test). The function of diode array test is not only to check the peak
purity, but also to reflect the overall UV absorption of impurities and main
drugs. The material balance at different wavelengths can be calculated
(depending on the specific variety).
④计算方法computing method：通过与正常样的总峰面积对比。具体做法：建议取一定量的样品溶解，作为母液，分别从母液中取一定量进行个因素的降解试验，再与此母液做的正常样进行对比，这样做出的结果才可靠。By
comparing the total peak area with the normal sample. Specific method: it is
suggested to take a certain amount of sample to dissolve as the mother liquor,
take a certain amount from the mother liquor respectively for the degradation
test of three factors, and then compare it with the normal sample made of this
mother liquor, so that the result can be reliable.
3)出具三批中试样品检验报告书。Issue the inspection
report of three batches of medium-sized samples.
3、 质量对比研究Quality comparative study
(采用中试产品pilot products are adopted)
质量对比研究是判断仿制药与被仿制药质量 “一致性”或“等同性”的重要方法，可以全面了解产品的质量特征，为仿制药注册标准的建立提供依据。Quality
comparison research is an important method to judge the "consistency"
or "equivalence" of the quality of generic drugs and generic drugs.
It can fully understand the quality characteristics of products and provide a
basis for the establishment of generic drug registration standards.
3.1 溶出曲线对比研究Comparative study on
dissolution curve：
一般采用在四种溶出介质(如pH1.2、pH4.5、pH6.8和水)中的溶出曲线对比的方法，用f2因子法(f2>50)来比较原研药和仿制品的曲线相似性。(溶出介质的选择可参考谢沐风的文献) Generally, the dissolution curves in four dissolution media
(such as pH 1.2, pH 4.5, pH 6.8 and water) are compared, and the F2 factor
method (F2 > 50) is used to compare the curve similarity between the
original drug and the imitation product. (for the selection of dissolution
medium, please refer to Xie Mufeng's Literature)
注意事项Notices：
①用于比较的两种制剂含量差值应在 5%以内。The
content difference between the two preparations used for comparison should be
within 5%.
②计算时所选取的时间点间隔无需相等，但两制剂所取时间点必须一致;且计算时间点应不少于 3个;由于该计算结果有依赖于比较时间点个数的特性，故在溶出率 85%(缓释80%以上)以上的时间点应不多于一个。溶出量应按累计溶出量来计算。The interval
of time points selected in the calculation need not be equal, but the time
points taken by the two preparations must be the same; And the calculation time
point shall not be less than 3; Since the calculation result depends on the
number of comparison time points, there should be no more than one time point
when the dissolution rate is more than 85% (sustained-release more than 80%).
The dissolution amount shall be calculated according to the cumulative
dissolution amount.
③除 0时外，第一选取时间点溶出结果的变异系数应不得过
20%，自第二时间点至最后时间点溶出结果的变异系数应不得过10%。如超出，应从仪器适用性或样品均一性的角度考虑予以解决。Except
for 0, the coefficient of variation of the dissolution results at the first
selected time point shall not exceed 20%, and the coefficient of variation of
the dissolution results from the second time point to the last time point shall
not exceed 10%. If exceeded, it shall be solved from the perspective of
instrument applicability or sample uniformity.
3.2 杂质的对比研究(此项内容可与方法学验证同做) Comparative study of impurities (this content can be done
together with methodological verification)：
对于有关物质检查，由于原料药制备工艺、制剂处方工艺的不同，仿制药的杂质种类和被仿制药可能不同，因此要求进行对比研究，分析仿制药和被仿制药中杂质的种类和含量情况。For the inspection of relevant substances, due
to the different preparation process and formulation process of API, the types
of impurities in generic drugs and generic drugs may be different. Therefore,
comparative research is required to analyze the types and contents of
impurities in generic drugs and generic drugs.
①可通过强制降解试验及影响因素试验的对比研究，来比较仿制药与原研药的杂质种类、降解途径及杂质大小。Through
the comparative study of forced degradation test and influencing factor test,
the impurity types, degradation pathways and impurity sizes of generic drugs
and original drugs can be compared.
②对于复方制剂来讲，首先应对杂质进行归属。采用方法：分别做单个原料、空白辅料及制剂的强制降解试验。For
compound preparations, impurities should be assigned first. Methods: the forced
degradation tests of single raw material, blank excipient and preparation were
carried out respectively.
要求如下The requirements are as follows：
3.3 检测方法的对比研究(与方法学验证同时进行) Comparative study of detection methods (conducted simultaneously
with methodological verification)：
如果研究发现国家药品标准中一些检测方法不适用于研制产品，为进一步验证是检测方法存在问题，还是研制产品自身存在质量问题，可以采用被仿制药进行对比研究。If it is found that some detection methods in
the national drug standards are not suitable for the development of products,
in order to further verify whether there are problems in the detection methods
or the quality problems of the developed products, the generic drugs can be
used for comparative research。
4、 质量标准的制定Formulation of quality
standards
(结合对比研究结果、稳定性研究结果制定It is formulated
in combination with the results of comparative research and stability research)：
4.1 可在国家药品标准的基础上，参考国外药典及参考文献，增加必要的检测项目。On
the basis of national drug standards, refer to foreign Pharmacopoeia and
references to add necessary test items.
4.2 检测方法：如新建方法与国家药品标准中收载方法相比无明显优点时，因国家药品标准已经过较长时间和多家单位的验证，建议仍采用国家药品标准中收载方法。Test
method: if the new method has no obvious advantages compared with the loading
method in the national drug standard, it is recommended to still use the
loading method in the national drug standard because the national drug standard
has been verified by many units for a long time.
4.3 限度Limit：有多种方法可参考时，限度的制定遵循“就高不就低”的原则。When there are many methods
for reference, the formulation of limit follows the principle of "high,
not low".
4.4 分别制定货架期标准及放行标准，即注册标准和内控标准，写入申报资料。Formulate
shelf life standards and release standards, namely registration standards and
internal control standards, and write them into the application materials.
1、 影响因素试验Influencing factor test：
取中试一批和参比制剂，除去内包装，分散为单层置适宜的条件下进行。一般包括高温(60或40度)、高湿(92.5%、75%)、光照试验。分别于第5天和第10天取样检测，重点考察性状、含量、有关物质，高湿试验增加吸湿增重项。Take
a batch of pilot test and reference preparation, remove the inner packaging,
disperse into single layer, and carry out under appropriate conditions.
Generally, it includes high temperature (60 or 40 degrees), high humidity
(92.5%, 75%) and light test. Samples were taken on the 5th and 10th day respectively,
focusing on the properties, content and related substances. The moisture
absorption and weight gain items were added in the high humidity test.
以上为影响因素稳定性研究的一般要求。根据药品的性质必要时可以设计其他试验，如考察pH值、氧、低温、冻融等因素对药品稳定性的影响。对于需要溶解或者稀释后使用的药品，如注射用无菌粉末、溶液片剂、干混悬剂等，还应考察临床使用条件下的稳定性。The
above are the general requirements for the stability study of influencing
factors. According to the properties of drugs, other tests can be designed when
necessary, such as investigating the effects of pH value, oxygen, low
temperature, freezing and thawing and other factors on the stability of drugs.
For drugs that need to be dissolved or diluted, such as sterile powder for
injection, solution tablets, dry suspensions, etc., the stability under
clinical use conditions should also be investigated.
2、 加速试验Accelerated test：
取拟上市包装的三批样品进行，建议在比长期试验放置温度至少高15℃的条件下进行。一般可选择 40℃±2℃、RH75%±5%条件下进行 6 个月试验。在试验期间第
0、1、2、3、6个月末取样检测考察指标。如在 6 个月内供试品经检测不符合质量标准要求或发生显著变化，则应在中间条件
30℃±2℃、RH65%±5%同法进行 6个月试验。具体温度，可以参考原研药的说明书中贮藏一项。Take three batches of samples to
be packaged on the market. It is recommended to carry out the test at a
temperature at least 15 ℃ higher than the storage temperature of the
long-term test. Generally, the test can be conducted for 6 months under the
conditions of 40 ℃± 2 ℃ and rh75% ± 5%. Take samples at the end of the month 0, 1, 2, 3 and 6
during the test to detect the inspection indicators. If the test article fails
to meet the requirements of the quality standard or changes significantly
within 6 months, the test shall be carried out in the same method under the
intermediate conditions of 30 ℃± 2 ℃ and rh65% ± 5% for 6 months. For the specific temperature, refer to the
storage item in the instructions of the original drug.
讨论Discuss：关于稳定性试验对比研究，法规要求研制产品的稳定性不得低于已上市产品的稳定性。在通过强制降解试验和影响因素试验的对比以后，对两者的稳定性有了一定程度的了解。As
for the comparative study of stability test, the regulations require that the
stability of the developed products shall not be lower than that of the listed
products. Through the comparison of forced degradation test and influencing
factor test, we have a certain understanding of their stability.
①若产品本身比较稳定，参比制剂可只取0月和加速6月时样品来进行对比。If the product itself is relatively stable, the
reference preparation can only take the samples in 0 month and accelerated 6
months for comparison.
②若产品本身就不稳定，建议参比制剂和三批中试制剂同步进行对比。If the
product itself is unstable, it is recommended to compare the reference
preparation with three batches of pilot preparations simultaneously.
3、 长期试验Long-term test：
长期试验是在上市药品规定的贮存条件下进行，目的是考察药品在运输、保存、使用过程中的稳定性，能直接地反映药品稳定性特征，是确定有效期和贮存条件的最终依据。The long-term test is carried out under the
storage conditions specified for listed drugs. The purpose is to investigate
the stability of drugs in the process of transportation, storage and use, which
can directly reflect the stability characteristics of drugs and is the final
basis for determining the validity period and storage conditions.
取三批中试样品在 25℃±2℃、RH60%±10%条件进行试验，取样时间点为0月、3月、6月、9月、12月、18月、24月、36月。Take
three batches of pilot test samples for test under the conditions of 25 ℃± 2 ℃ and rh60% ± 10%. The sampling time points are 0 month, March, June,
September, December, 18 month, 24 month and 36 month.
长期试验时间的选择应依据产品稳定性情况、与被仿制药稳定性的比较情况、拟定有效期等综合考虑。申请注册时，一般应提供不少于6个月的长期稳定性研究资料。The
selection of long-term test time shall be based on the stability of the
product, the comparison with the stability of the generic drug, and the
proposed validity period. When applying for registration, the long-term
stability research data of no less than 6 months shall generally be provided.
4、 中间条件试验Intermediate condition test
30℃±2℃、RH65%±5%(若长期试验采用此条件，则可不再进行中间条件试验)。30 ℃± 2 ℃, RH65% ± 5% (if this condition is adopted in the long-term test, the
intermediate condition test may not be carried out).
5、 稳定性研究结果的评价Evaluation of stability
research results
根据稳定性研究的结果，结合原研药的情况，确定包装材料、贮藏及有效期。According to the results of stability study and
the situation of the original drug, determine the packaging materials, storage
and validity period.
另注意Note：包材相容性试验Compatibility test of
packaging materials：
包材的选择参考原研制剂，最好与原研材质相同。对于口服固体制剂，用拟定的包装做加速试验及长期试验即可;对于液体制剂和半固体制剂，需考察包材材料中的成分(尤其是添加剂成分)是否会渗出至药品中，引起产品质量的变化(如力百汀塑化剂事件)。The selection of packaging
materials refers to the original research preparation, and it is better to be
the same as the original research material. For oral solid preparations, the
proposed packaging can be used for accelerated test and long-term test; For
liquid preparations and semi-solid preparations, it is necessary to investigate
whether the components in the packaging materials (especially the additive
components) will seep into the drugs and cause changes in product quality (such
as the event of Lipitor plasticizer).
这项是难点，只有通过与包材商的沟通，请包材商进行自我控制。This is a difficult point. Only through
communication with the packaging material supplier, the packaging material
supplier is requested to carry out self-control.
1)大多数仿制药的研究只需要提供药理毒理文献研究资料即可，这中情况下可以查阅国内外文献数据，找到该药物药理毒理资料进行整理归纳总结。Most
studies on generic drugs only need to provide pharmacological and toxicological
literature research data. In this case, we can consult the literature data at
home and abroad to find the pharmacological and toxicological data of the drug
for sorting and summarizing.
2)局部用制剂应在GLP实验室，根据品种需进行刺激性、过敏性、溶血性试验。如丙酸氟替卡松鼻喷剂需进行刺激性试验。Topical
preparations shall be tested in GLP Laboratory for irritation, allergy and
hemolysis according to the variety. For example, fluticasone propionate nasal spray
needs to be tested for irritation.
(稳定性试验完成后1个月内Within
1 month after the completion of stability test)
1、 综述资料General information
1)药品名称Drug name。
2)证明性文件。需注意科技查新报告的委托查询，一般在稳定性试验中期委托查询。Supporting
documents. Attention should be paid to the entrusted inquiry of scientific and
technological novelty search report, which is generally entrusted in the middle
of stability test.
3)立题目的与依据(有国家局颁布的撰写技术指导原则，可以在查询资料后即可撰写)。Purpose and basis of topic setting (there are technical
guidelines for writing issued by the National Bureau, which can be written
after querying the data).
4)对主要研究结果的总结及评价(有国家局颁布的撰写技术指导原则，可以在进入稳定性考察后撰写)。Summary and evaluation of main research results (there are
technical guidelines for writing issued by the National Bureau, which can be
written after entering the stability investigation).
5)药品说明书、起草说明及相关参考文献(根据原研药的说明书)。Drug instructions, drafting instructions and relevant
references (according to the instructions of the original drug).
6)包装、标签设计样稿。Sample of packaging and
label design.
2、 药学研究资料(附件2为7—15项) Pharmaceutical
research data (7-15 items in Annex 2)
仿制药(六类)，必须按照国家局颁布的CTD格式来撰写。其他类，推荐按CTD格式撰写。Generic drugs
(Category 6) must be written in accordance with the CTD format issued by the
National Bureau. For other classes, it is recommended to write in CTD format.
1) CTD格式申报主要研究信息汇总表Summary of main
research information declared in CTD format
2) CTD格式申报资料撰写要求Requirements for
writing application materials in CTD format
3、 药理毒理研究资料Pharmacological and
toxicological research data
16)药理毒理研究资料综述(根据相关技术指导原则) Summary of pharmacological and toxicological research data
(according to relevant technical guidelines)
21)局部用制剂提交：过敏性(局部、全身和光敏毒性)、溶血性和局部(血管、皮肤、黏膜、肌肉等)刺激性等特殊安全性试验资料和文献资料。For topical preparations, special safety
test data and literature materials such as allergy (local, systemic and
photosensitive toxicity), hemolysis and local (blood vessel, skin, mucosa, muscle,
etc.) irritation shall be submitted.
4、 临床试验资料Clinical trial data
28)国内外相关的临床试验资料综述。Review of relevant
clinical trials at home and abroad.
29)临床试验计划及研究方案。Clinical trial plan
and research scheme.
30)临床研究者手册。Clinical investigator
Handbook.
31)知情同意书样稿、伦理委员会批准件。Sample of
informed consent form and approval document of ethics committee.
32)临床试验报告。Clinical trial report.
后两项为报生产时所需资料。The latter two items are the data required for
production.
1)将资料连同电子申报表报省局，准备现场核查。Submit the
data together with the electronic declaration form to the Provincial Bureau for
on-site verification.
2)动态三批现场工艺核查，抽样送检省药检所复检。Dynamic three
batches of on-site process verification, sampling and submission to the
Provincial Drug Control Institute for re inspection.
固体口服制剂做生物等效性;溶液剂一般可免临床;局部用制剂一般需做临床试验。Bioequivalence of solid oral preparations;
Generally, the solution can be exempted from clinical use; Topical preparations
generally need clinical trials.
临床试验完成后，整理资料，申报省局。After
the clinical trial is completed, sort out the data and apply to the Provincial
Bureau.
目录Catalogue
一、综述Review
二、仿制药研发项目汇总Summary of generic drug R & D projects
三、仿制药的研发具体步骤Specific steps of generic drug research and
development：
(一)产品信息调研Product
information research
(二)前期准备(约一个月完成)
Preliminary preparation (completed
in about one month)：
1、参比制剂的采购Purchase reference
preparation
2、原料采购Purchase raw materials
3、色谱柱及对照品采购Purchase of
chromatographic column and reference substance
4、辅料采购Purchase of excipients：
5、包材的采购Procurement of packaging
materials：
(三)处方工艺研究Study
on prescription technology
1、原辅料及参比制剂的检验Inspection of raw and
auxiliary materials and reference preparations
2、处方工艺摸索Exploration of prescription
technology
3、初步验证工艺Preliminary validation
process
4、中试生产及工艺验证Pilot production and
process verification
(四)质量研究Quality
research
1、质量研究项目的选择及方法初步确定Selection of
quality research projects and preliminary determination of methods
2、质量标准的方法学验证Methodological validation
of quality standards
3、质量对比研究Quality comparative study
4、质量标准的制定Formulation of quality
standards
(五)稳定性研究(中试产品)
Stability study (pilot product)
(六)药理毒理研究Pharmacological
and toxicological studies
(七)申报资料的撰写、整理Writing
and sorting of application materials
(八)申报临床及申报现场核查Clinical
application and on-site verification
(九)临床研究Clinical
Research
(十)申报生产Declaration
for production
