Brief summary of formulation technology and production technology

[technical article of chinapharma.com] on December 22, 2017, CDE again issued a new "New Deal" for drug research and development: technical requirements for conformity assessment of listed chemical generic drugs (injection) (Draft for comments) As a member of the pharmaceutical research and development field, the Christmas festival atmosphere can not resist our passion for research and development We learned the technical requirements well over the weekend, in order to keep up with the new situation and new normal of drug review and approval, and have a deeper understanding of drug research and development The study of formulation process and production is summarized as follows: 1 The first three items of the general outline clearly point out the requirements of safety and effectiveness, which is also the general outline of all drug approvals and guiding principles for all drug research and development However, it is also pointed out that only those with clinical value can have the qualification of conformity evaluation and re evaluation, that is to say, they can simply distinguish those that have been received by FDA from those that have not been received by FDA, and carry out conformity evaluation and re evaluation respectively, implying that the safety and effectiveness data that have not been received by FDA are still lacking, and the re evaluation method is still under discussion Gayne injection has always been the main dosage form of adverse drug reaction information notification 2 The order of selection of reference preparation is clear The original research and import, the American reference, the European Union reference, and the Japanese reference also put forward the varieties that the original research stopped production, and RS drugs marked by FDA orange peel book can be selected However, for the drugs that the original research no longer produced, but authorized production or transfer by the holder, the priority level is not clearly selected It will cause certain problems to pharmaceutical enterprises, such as the determination process of azithromycin tablet reference preparation, which makes many enterprises tangled 3 The prescription considers that the type and dosage of excipients in the injection generic drugs should generally be the same as the reference preparations However, a gap was also made to allow different formulations of bacteriostatic, buffer (including conventional pH regulator) or antioxidant in the reference preparation, and to prove the safety and effectiveness of the product To a certain extent, this reflects the open and scientific attitude of the State Food and Drug Administration towards the evaluation of injection prescription As long as the safety and effectiveness of the prescription can be proved, the different prescription is also acceptable Secondly, it also leaves a gap for the research and development or evaluation of the original product with preparation protection, such as moxifloxacin hydrochloride injection, which has been disturbed in the past few years, if it can be proved The stability of glucose and sodium chloride is consistent and can be approved; it also provides direction for the development of elusive injection prescription in the future 4 In the process research, it is considered that the overfilling is consistent with the original research; the use of activated carbon is not recommended; in the production process, the compatibility research should be carried out for the filter element and silica gel tube in contact with the liquid medicine In my opinion, the research scheme should be considered in combination with the prescription, and the influence of pH value of solution preparation, cosolvent, etc on the filter element and silicone tube in direct contact should also be considered in specific varieties 5 Process verification and control Combining and refining the sterilization / aseptic process validation guidelines and the basic technical requirements of chemical injection, it clearly requires the package tightness validation and retention time validation, and further strengthens the requirements of pharmaceutical production process and quality assurance; at the same time, it requires the microbial monitoring of the pharmaceutical solution before filtration produced by the sterilization process, and it is necessary to define the intermediate quality control Trend, once beyond the scope of microbial load validation, the release of its products may need further risk assessment 6 The batch requirements specify the volume, and the batch samples must be registered in the commercial production line, which can be 2 batches of large + 1 Batch size is small; for the limited production equipment conditions, if the registered batch size is consistent with the commercial batch size, even if it is smaller than the specified volume, it is also recognized, but its batch size is considered as a major change, and the enterprise needs to weigh the batch size based on the future market prospect and production cost 7 API In the original API quality standard, the requirements for related substances are improved, and the subtext is that if necessary, the analytical method shall be re verified in combination with the impurity control strategy of API production process evaluation; the clarity and color of solution, solvent residue, bacterial endotoxin, microbial limit and other tests shall be clearly increased, and relevant verification data shall be provided to meet the injection process and requirements Quality control requirements For pharmaceutical manufacturers, the audit and quality control of API suppliers are the key API suppliers without strict quality control system will lose the market, while those with high quality assurance may increase the price, leading to the increase of drug cost Therefore, when the holder applies for registration, it can provide more than two raw material suppliers, which is conducive to its future market competition It also hopes that CDE will provide guidance on the research needed to select multiple raw material suppliers in the application stage 8 Auxiliary materials meet the requirements for injection However, this sentence often makes enterprises feel difficult, because in addition to the auxiliary materials for injection included in the 15th edition of the Pharmacopoeia, many other buffers, antioxidants, osmotic pressure regulators, chelators, etc do not have clear Pharmacopoeia requirements, so enterprises need to formulate internal control standards based on their own product characteristics By comparing the difference between the pharmaceutical grade and the injection grade, it can be seen that the injection grade is more strict than the pharmaceutical grade in the limit of heavy metals, microorganisms and endotoxins, and the control limit of other unreceived adjuvants can be referred to Injection manufacturers may also need to help suppliers who are not willing to improve excipient standards to develop new standards, and even help excipient suppliers to provide refining processes and improve analytical methodology validation, which is also a major challenge 9 It is not recommended to use low borosilicate glass and sodium calcium glass as the packaging materials If such glass products are used, the re evaluation is to change to medium borosilicate, which will inevitably increase the cost, which is also a historical debt But it is also one of the key to improve the quality of injection In addition to vials and ampoules, the quality of rubber stoppers also needs to be taken into account The commissioned research market of package compatibility will ignite again In a word, in the process of re evaluation of injection consistency, it will inevitably lead to the disappearance of many approvals Injection R & D is on the right way to improve the quality of injection drugs! Original title: injection consistency evaluation preparation technology, do not understand here