In the process of drug development, the quality study of intermediates in the synthesis pathway is an essential link still the most common practice in the industry for the quality control of intermediates is to use the area normalization method for a purity check. The result of such a course is that there are often API finished products incandescent residues, residual solvents, palladium (if used), and so on that exceed the standard. This shows that our quality research on the whole synthesis pathway is lacking and fails to achieve the purpose of intermediate quality control.
Purpose of developing quality standards for intermediates
Developing quality standards for intermediates is to produce APIs that meet regulatory requirements according to established processes if each intermediary meets quality standards. This requires a comprehensive risk assessment of the quality of APIs, such as traits, related substances, isomers, residual solvents, genotoxic impurities, metal ions, incineration residues, heavy metals, moisture, crystal shapes, particle size, etc. To find the source of risk to these qualities in the process.
The critical control points of API quality risk in the process should be identified, and corresponding control policies should be developed. For example, for the item of the burning residue of API, inorganic salt is used in the process, and the rationality and effectiveness of the desalting step in the process should be evaluated to ensure that the limit of the burning residue of API complies with the regulations. The intermediate only uses the area normalization method to check the purity, which only controls the risk of the substance concerned, which is far from enough. Other changes, such as inorganic salts, residual solvents, genotoxic impurities, etc., are uncontrolled, and it is only a matter of luck whether the API is qualified in these indicators. The following article discusses how the intermediates should be studied for items that need to be controlled.
Research projects
According to the synthesis process, they are combined with the impurity control strategy and the understanding of quality risk, a comprehensive assessment of the need for intermediates in the quality standards set into the test items.
01
Synthesis process
The tests that must be developed should be evaluated according to the synthesis process. For example, palladium carbon is a common catalyst used in synthesis, and we need to assess the residues of palladium in API. If only palladium is detected in API, there is a considerable risk that it will pass or fail. When palladium carbon reduction is used, there should be a strategy for palladium removal during the process, and the system should be studied to see if it is effective. The residual amount of palladium in a particular intermediate can be checked during the process optimization phase or even up to the pilot phase to ensure that the palladium in the finished product does not exceed the specified limit. After sufficient data to support the effectiveness of the palladium removal strategy, the residual amount of palladium of the intermediate can no longer be tested, i.e. the quality standard of the negotiator in the declaration information does not need to include a palladium check.
02
Impurity control strategy
The “impurities” mentioned in this paragraph are impurities in a broad sense, i.e., all components present in the finished API except API are impurities, including related substances, isomers, inorganic salts, residual solvents, genotoxic impurities, metal catalysts, water, etc. The impurity control strategy in the synthesis process is not only for related substances but for all contaminants. Intermediates’ quality standards can help improve the entire research content of impurity control strategies.
For such organic solvents used in the process, an effective control strategy for residual solvents should be developed. Suppose there needs to be more confident that the system is effective in the process. In that case, the residual amount of certain solvents can be studied in the intermediates to ensure that the residual solvent limits of the finished product meet the regulations. The same as the study of palladium above, if the residual solvent control strategy is confirmed to be effective, the intermediate quality standard can delete the corresponding check items.
03
Perception of quality risk
Whether an impurity control strategy is effective does not necessarily have to be confirmed by testing but should be judged by the level of risk the impurity poses to the quality of the finished product. Taking control of genotoxic impurities as an example, if acetyl chloride is used, the compound is particularly active, and if there is a process such as water washing or salt formation, the risk of its presence in API is shallow. There is no need to study it. The effectiveness and rationality of the control can be illustrated based on the chemical properties and the specific process.
Similar to the quality study process of starting materials, the quality study process of intermediates is also a risk management and dynamic process. For example, in the study of palladium and residual solvents in mediators mentioned above, at the beginning of the process, we think the risk of exceeding the standard of the finished product is high. Still, as the process optimization is carried out and the data analysis of multiple batches, the corresponding impurity control strategy is proved effective. The risk of exceeding the standard of the finished product becomes very low, and then the quality standard of intermediates can delete the corresponding check items. Finding the high-risk factors that were only realized after is also possible. For example, the conformational change of the chiral center in one step of the reaction was only discovered after. Then the isomer check item was added to the quality standard of the corresponding intermediate.
Breakdown
01
Characteristic
Appearance can initially determine the nature of the product, which needs to be formulated. Other physicochemical parameters such as solubility, melting point, and specific spin do not need to be studied in general, and exceptional cases are judged based on a combination of the four aspects above.
02
Substances of interest
This test item generally needs to be developed, and it is worth discussing how to control the substance of interest here. If we follow the control method of API, the data processing and method validation work increases much. I believe that the area normalization method can detect the intermediate substance of interest as long as the corresponding research data support it. See the limit formulation below for details.
03
Isomers
If an isomer check is developed for the starting material and no conformational change of the chiral center occurs during the process, the statement can be dispensed. It is only necessary to control the isomer at the critical step of the synthesis process, such as the reaction step, where the conformational change will occur.
04
Residual solvents
Organic solvents used in the process route need to be evaluated for their impact on the API, as detailed in the “Impurity Control Strategy” above.
05
Inorganic salts
If necessary (see “Impact on API” above), the content of inorganic salts in intermediates should be studied, either by developing a scorch residue test or by developing limits for specific ions, such as sulfate limits if sulfate is used in the process. For example, the finished product can not be used to assess the residual amount of inorganic salt-burning residue in valsartan sodium. The intermediates can be tested for burning residue before the salt to prove that the finished product inorganic salts meet the specification requirements.
06
Genotoxic impurities
Residues of suspected genotoxic impurities used or generated in the synthesis process, if the risk can be judged to be extremely low according to the chemical properties and synthesis process, can not be included in the test; otherwise, the residues in API should be studied according to the corresponding guidelines (such as “ICHM7″), can be studied in an intermediate whether it meets the limits of the specification, if not, should be studied in conjunction with the process optimization and determined An API qualified intermediates allowed limit value.
07
Other
Tests, such as particle size, crystal shape, content, etc., should be determined based on the ideas above to decide whether they need to be set to quality standards. It must be clear that the synthesis colleagues should suggest which particular indicators should be looked at based on their knowledge of the synthesis process.
Post time: Dec-09-2022
