1 prescription technology
Excipients selection: Although the pharmaceutical administration allows the injection generic drugs to be different from the reference preparations in antibacterial agents, buffers, pH regulators, antioxidants, metal ion complexing agents, etc., the selected excipients should be as consistent as possible with the reference preparations for polypeptide preparations The stability of peptide chain is poor, acid, alkali and metal ions may cause peptide chain degradation;
there are many exposed amino and carboxyl groups in the structure of peptide drugs, which may interact with excipients to form related impurities; peptide drugs may have high-level structure, and slight differences in pH value and ionic strength may cause structural changes.
Solution preparation process: some peptide drugs are sensitive to pH value, oxygen content, ionic strength, etc. in the preparation process, short-term separation from the stable environment will cause adverse effects on peptide drugs. It is more important to grasp the details of the process. It is necessary to investigate the order of raw and auxiliary materials, mixing time, stirring speed and whether it needs to avoid light and deoxidization to determine whether it has an impact on the product quality.
For example, a polypeptide preparation was found to be stable in a relatively narrow pH range in the early process development process, and the pH control range of the proposed key process parameters was also relatively narrow. In the first process validation, it was found that the pH value after solution preparation was within the proposed control range, but the pH value of some final products was beyond the proposed control range.
The main reason is that after batch scale-up, the stirring performance of commercial production equipment is low, the dissolution time of peptide drugs is prolonged, and the pH value after drug configuration needs to reach steady state after a long time. After the detailed investigation of the mixing speed, time and other process parameters, the stable production of three consecutive batches of products was realized.
Lyophilization process: the stability of peptide drugs is limited, and freeze-drying injection is often selected when injection route is adopted. From the application data, most of the applicants only carry out the research for the purpose of freeze-drying, ignoring the impact of freeze-drying process on stability. In the process of freeze-drying, there may be many problems, such as buffer crystallization, pH shift, stabilizer morphology change, peptide space conformation change and so on, which can directly affect the stability of peptide drugs.
For example, for an imported polypeptide preparation, the proposed freeze-drying process needs to be kept at 40 ℃ for a long time. Since the proposed storage condition of the drug is 2-8 ℃, questions about the process are raised during the evaluation process, and the applicant is required to further provide the rationality of the freeze-drying process. The applicant provided the comparative data of product stability under different freeze-drying process conditions, and the results showed that the degradation impurities of the product in the long-term storage process were significantly less than that of the products freeze-dried under low-temperature conditions in the whole process when the product was put at a higher temperature in the second heating stage.
This process can be considered as “annealing” in freeze-drying process, which can release drug energy and improve microstructure, so as to further stabilize peptide drugs. Professor Michael Pikal of the United States has carried out in-depth research on this aspect [6], which can guide the development of freeze-drying process for polypeptide drugs.
Special packaging form: some hypoglycemic drugs use pre filling technology in cartridge. Due to the particularity of preparation process and use method, special research methods should be established. For example, in the production process of cartridge bottles, silicification process directly affects the smoothness of the inner wall, and then affects the accuracy of dosage. The spraying amount and uniformity of silicone oil should be controlled accordingly.
Due to the particularity of the drug delivery mode, such as air bubbles in the preparation, the pressure response will be inconsistent and the dosage will be inaccurate. Therefore, multiple injections can be adopted in the filling process to reduce the introduction of gas; This kind of medicine involves many punctures and other problems, so it is necessary to conduct a complete investigation on the sealing property of the packaging materials.
Compatibility problem: some peptide drugs are sensitive to metal impurities that may be introduced into the production equipment, and the introduction of trace impurities may cause peptide chain degradation, resulting in the degradation rate of the imitation product faster than that of the reference preparation. In order to study the compatibility of drugs with production equipment, filters and drug packaging materials, researchers should pay more attention to the inorganic impurities such as metal ions on the basis of the research contents of small molecular chemical drugs.
In addition, the dosage of peptide drugs is usually small. In order to ensure the accuracy of drug dosage, attention should be paid to the adsorption of drugs by production equipment, filter and packaging materials. If necessary, excessive feeding can be used to solve the problem, but sufficient basis should be provided.
For example, in the preliminary development of a polypeptide preparation, the applicant found that metal ions could be introduced into the proposed production equipment, resulting in a significantly accelerated degradation rate of the product.
Due to the difficulty of replacing the production equipment, the applicant proposes to use disposable solution preparation bag in the liquid preparation process, which avoids the introduction of metal ions, thus ensuring the product quality.
Exclusive solvents and syringes: some polypeptide reference preparations have exclusive solvents and injection devices. When conducting research, generic pharmaceutical enterprises need to pay attention to whether the drugs are compatible with clinical common solvents and syringes, and the necessity of exclusive solvents and syringes should be fully evaluated.
For example, terlipressin reference preparation has a special solvent sodium chloride aqueous solution. The appendix of product quality standard specifies the concentration and pH value of sodium chloride in sodium chloride aqueous solution in detail. At present, the commonly used compatible solvent in clinical practice does not meet the requirements of the control limit of reference preparation.
The domestic listed terlipressin for injection did not specify the clinical compatible solvent, so it is necessary to evaluate the necessity of exclusive solvent and the influence of compatibility on product quality and patient tolerance.
2 quality research
Researchers should combine the characteristics of polypeptide drugs and carry out targeted investigation in quality research. For the peptide drugs with poor stability, attention should be paid to whether the pH value, properties, re dissolution time and initial impurity level are consistent with the reference preparation.
There may be a phenomenon that the control limit of quality standard is wide, and the imitation product can meet the requirements of the proposed quality standard, but there is still a certain difference compared with the reference preparation.
The above differences may indicate that the microenvironment of polypeptide drugs is different from that of the reference preparation. In the long-term stability study, problems may occur in the inspection items such as pH value, related substances and insoluble particles.
Researchers should pay attention to the above differences, understand and find out the reasons, so as to avoid problems in the long-term stability investigation and affect the application progress.
Related substances are one of the key projects in the quality research of polypeptide drug preparations. The quality research of preparation should be combined with the investigation results of related substances of API, pay attention to the investigation of degradation impurities, and focus on polymer impurities.
Polypeptides contain disulfide bonds, exposed amino groups and carboxyl groups, which are easy to form polymers due to dehydration of disulfide bonds or amino carboxyl groups.
The researchers should make clear whether the polymer impurities are the polymer formed by covalent bond, the aggregate formed by intermolecular force or the advanced structure fixed by peptide chain. If it is a polymer formed by covalent bond, there may be a greater risk of immunogenicity.
It is necessary to determine the structural consistency with the impurity in the reference preparation and ensure that its content is within the safe limit.
3 stability issues
The main reason is that the stability of polypeptide drugs is poor in solution state, and the compatibility stability can reflect the quality difference with reference preparation. Some polypeptide drugs need to be diluted by a large multiple if they are used according to the clinical actual concentration.
The real quality changes of the products may not be detected according to the analysis method in the proposed quality standard. If necessary, the dosage of compatible solution can be reduced, and the stability comparison with the reference preparation at the same compatibility concentration proves that the quality of the imitation product is not lower than that of the reference preparation.
It should be noted that the storage conditions of some polypeptide generic drugs on the market in China are more stringent than those of the reference preparations. For example, carbetoxine, the storage conditions of the reference preparations should not exceed 30 ℃ and should not be frozen. The storage conditions of domestic generic drugs were airtight and stored at 2-8 ℃.
The difference of storage conditions indicates that the stability of the products may be different. Further discussion may be due to the comprehensive reasons such as raw material drug, prescription, production technology, production equipment, packaging container and so on. The above problems show that the quality of generic drug is not consistent with the reference preparation, and the quality needs to be improved and improved.
The stability of the generic drug should be consistent with the reference preparation, and the storage conditions should not be more stringent than the reference preparation in principle.
4 epilogue
Because polypeptide drugs are special preparations between small molecule chemical drugs and protein drugs, although there are some difficulties in research and development, on the basis of full identification of drug risks, the establishment of corresponding control measures can effectively guarantee the product quality.
reference
Chinese Journal of new drugs, Vol. 29, No. 8, 2020
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