About the development of API.

long puzzled API companies: the development of D? Study R?
In the declaration of preparations, sometimes Europe and the United States need raw materials research and development information
because DMF and COS applications are not mandatory to provide, so the internationalization of the research and development part is very weak


Research on the API production process
For the study of the API production process
1) details the reasons for adopting the route, explains the difference and improvement with the reported route in the literature
2) and describes the reaction route and chemical reaction type being compared, including reaction conditions and yield
3), the reaction route, the chemical reaction type (indicating the reaction conditions and yield) and the process flow diagram

. , yield, possible impurities or other intermediate rest, main physical and chemical constants
. End-point control methods for step-by-step reactions
. Refining and quality control methods for major intermediates and finished products and providing corresponding data maps
4) chemical raw materials Sources, specifications and standards
5) pilot processes and data for the selection and breeding of strains
e antibiotics culture
conditions, extraction process and yield
6) at least 3 batches of samples (including equipment, production control parameters, feed volume, intermediates and finished product quantity and yield)
7) three waste treatment draft or detailed three waste treatment scheme
8) reference ICH CTD requirements
3. 2.S.2.2 Description of production process and process control
A brief description of production process and process control
a detailed description of the production process flowchart
a detailed description of the production process
production volume and yield
. 3.2.s.2.6 Process developmentprevious example - confirmation of primary
tate-phase esterification
the reaction belongs to two opposites, mixed and uniformly affect the reaction. Therefore, check the speed of stirring and the completion of the reaction.
of the key steps of the esterification reaction is . Q11 includes 9 parts and examples
1, introduction
2, scope
3, process development
4, description of production process and process control
5, starting material, raw material
6, quality control strategy
7, process verification/evaluation
8, submission of production process development and related information CTD format
9, product life cycle
10, example 1.Introduction
: How does Part 2 of CTD work?
several parts of CTD 3.2.s
and Q8, Q9 and Q10 are closely related
two different ways of research and development: traditional and progressive.
Traditional approach: Using repetition and test compliance
Progress: Risk management and scientific research
a design space and quality control strategy for unit operations
Improved management freedom

traditional and progressive ways are not mutually exclusive2.SCOPE scope for API (new) and others. Is the ICH Q6A and Q6B in the scope section defined api materials
some products may be officially required to follow the guidelines
does not include the requirements of officially approved changes
does not apply to the clinical research phase of drug research and development information declaration, but the research principles should be applied 3. production process development
3.1 General Principles
in order to obtain a stable production of the expected quality of the product process.3.1.1 The quality of the API is related to the quality of the preparation the quality requirements of the API are based on the requirements of the preparation
the nature of the API affects the QTPP 3.1.2 Process Development ToolQuality Risk Management (Q9).
Knowledge Management (Q10).
3.1.3 developed methods . Traditional, progressive, both; the development of
production processes should include at least the following elements: identifying key quality parameters; establishing a suitable process; and determining a quality control strategy.
's approach should also include elements such as systematic evaluation, understanding, and selection of processes,
combining quality risk management to establish appropriate quality control strategies, including design space and/or real-time release, continuous improvement and progress throughout the product's life chain.Simple experiment, obtained the following chart relationship, showing the effect of intermediate E moisture and time on hydrolysalstraditional methods
when using traditional methods, the above information is used to confirm an acceptable water content and return time range, in order to achieve the hydrolyte meets the limit of 0.30%. Typically, set a target value and a maximum allowed value, such as:
drying the intermediate E

to a maximum moisture value of 1.0%.
return time for the target is 1.5 hours, and the maximum return time is 4 hours.above the hydrolysal reaction: secondary reaction, formula:(F) refers to the concentration of intermediate F or advanced method
for the secondary reaction equation, through integration to explain in detail:
3.1.4 KEY quality parameters of API key mass parameters:
products physical, chemical, biological, or
microbial
nature or characteristics
will affect product quality changes

The list of key quality parameters will develop
typical key quality parameters:
affect identification, purity, biological activity, impact stability
bio-products and RAW drug-related high
impurities: is a class of important API key quality parameters
complex products: key quality parameters are difficult to confirm
3.1.5 establish the relationship between material properties, process parameters and raw materials key quality parameters. the production process research and development process should be confirmed which material properties and process parameters should be controlled
materials in the upstream and downstream of the process differentiation
removal capacity of the process
detectable capacity.
Traditional Methods: Batch Production History and Some Single Variable Experiments
Progressive Methods:
Thorough understanding of the various influences and identification of potential sources of variation of process parameters
Which material properties and process parameters have the greatest impact Design space examples - Chemicals Designs and Experiments
Mechanism Research
Analysis and evaluation data: establishing the right scope, design space.
developed a small-scale model -- to assist in process research.
3.1.6 Design space . Design space for ICH Q8 preparation research
The resulting process should verify the main focus of the design space of
chemical drugs





Process development information logic, easy to read, easy to understand
allow different ways to provide research and development information,
's recommendations to refer to
3.2.1 overall research and development summary summary begins:
describes the important nodes of process development (milestones)
explanation - to ensure the quality of the API
summary to include the following items:
API key quality parameters listed in the summary.
description of the development stage of production process and quality control strategy
Introduction to the nature of the material and process parameters
Introduction to the development of the design space;
The following content follows the process research and development umbrella after the preparation of
3.2.2 API key quality parameters should list the key quality parameters of THE
compliant explanation


(e.g. 3.2.P.2.2.1, ingredients of the preparation)
3.2.3 History of the production process Description of the process development process
Chronological order: until the commercial process
reflects the preparation process for the application
provides a description and discussion of key changes
the reasons for the changes explain
the impact of the changes on the quality of the API
for biotechnological products or biological products
For more information, refer to Q5E
, which can include preclinical and clinical research
3.2.4 production development studies process establishment - what research and risk analysis has been conducted (in the form of a table).
Each study and risk analysis listed - marking purpose/purpose
when submitting a study and risk assessment: the purpose of the study, the data collected, the analysis carried out, the conclusions formed, the impact on the process study or further process research.
to the recommended operating conditions for commercial production processes (3.2.S.2.2). . Description of production process and process control Description of production process: A commitment of the applicant
to provide a process flowchart and a detailed description of each step
indicates the central control and design space.
design space for complex products (e.g. biological products):
can submit future changes in the design space
biological products - more complex
batch division
batch and batch quantity 5. Selection of starting materials and raw materials
5.1 Total
5.1.1 Starting material selection of synthetic API Start phase (before starting material): changes in the nature and operating conditions of
materials have little impact on the quality of API
"Several steps" risk: physical properties of
API The composition, transfer, and removal of impurities
API are all occurring in the final steps
the pre-process impurities have more opportunities to remove, but a few are not official evaluation control is adequate
and production steps affecting impurities profiles should be included in (3.2.S.2.2.2).
API synthesis of each, the starting material will be applicable to Q7
stational material
the key structural fragments of the API


chemical structure, clear propert
ies;
should be considered in general, not adopted in isolation. 5.1.2 Selection of semi-synthetic API starting materials Semi-synthetic API: both chemical synthesis and bio-sourced ingredients (e.g. from fermentation or extraction from plant raw materials).
1: The process of the source material begins (microbial or plant raw materials).
Situation 2: Starting from the isolated intermediates
enough to comply with the above-mentioned starting material selection principle
properties and impurities can be detected
fermentation, plant raw materials and leaching processes affect controllable
microbial contamination and other pollution controllable 5.1.3 Biological products raw material selection cellry
is the starting point of biological products production. The description of the cell bank is in ICH Guide Q5A, Q5B, and Q5D.
information about the starting or source items for 5.2 . State the starting material or source material
to provide appropriate quality standards
clarify the rationale 5.2.1 reasonableness of the selection of synthetic API starting material .