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Consistency Evaluation of Oral Solid Dosage
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As of May 2019, starting from the formal acceptance of the first conformity evaluation product in 2017, there have been nearly 900 oral solid dosage forms for conformity evaluation. The dosage forms include tablets, capsules, powders, sustained-release capsules, etc. At present, more than 200 product specifications have passed the consistency evaluation.
The consistency evaluation of oral solids usually includes two parts, one part is the efficacy consistency study based on bioequivalence studies or other clinical studies, and the other part is the quality consistency study based on in vitro pharmaceutical research.
For some varieties that can be exempted from bioequivalence studies, in vitro pharmaceutical studies are the most important means to evaluate their consistency.
Therefore, in vitro pharmaceutical research, as an important part of consistency research, is also the focus of review institutions and R&D and production units.
However, judging from the current application situation, the pharmaceutical research on the consistency evaluation of oral solid dosages is not perfect. Especially in recent years, the concept of drug review has gradually shifted from focusing on quality and light technology to paying equal attention to both technology and quality. The design, production control and other requirements related to the feasibility and controllability of large-scale production have been more detailed, and the defects found in this part and related supplementary content have also increased significantly.

1 Product Re-evaluation Research

The ultimate goal of the consistency evaluation of generic drugs is to be consistent with the quality and efficacy of the reference. Therefore, the re-study of the prescription and process of the consistency evaluation is also based on the analysis of the basic properties and requirements of the reference product.
In the early stage of research, the quality characteristics of the drug should be prospectively summarized, and follow-up research should be carried out on this basis, and the prescription process should be changed when necessary.

1.1 Target quality attribute analysis of the reference product

As the concept of quality comes from design is more widely accepted by the industry, the current consistency evaluation declaration generally attaches great importance to the analysis of the target quality attributes of the original product.
However, in addition to conventional information such as prescription composition and quality standards, insufficient attention has been paid to instructions and other literature information, which may result in insufficient analysis of key quality attributes, and will lead to deficiencies and deficiencies in subsequent research.
When analyzing the appearance of the reference product, the problem of nicks is often overlooked.
The FDA guideline “TabletScoring: Nomenclature, Labeling and Datafor Evaluation” [6] pointed out that if the RLD is a scored film, generic drugs recommend consistent scoring with the reference preparation. On the one hand, it is considered that patients do not need to consider too much when changing manufacturers. Dosage-related issues, while maintaining a consistent appearance with the reference formulation, are more conducive to generic drug companies competing in the market.
The FDA filing review guideline “ANDASubmissions-Refuse-to-ReceiveStandards” [7] also mentioned that unless the reason for the inconsistency of the score is sufficient, the FDA will reject applications for generic drugs that are inconsistent with the RLD score.
Although my country has not yet issued relevant requirements for scored tablets, when the appearance of the reference product is a scored tablet, and the usage and dosage of the instructions indicate that half of the tablet can be taken, the study of the corresponding content should be paid attention to for the consistency evaluation product. In addition, the individual drug guidelines issued by the FDA are generally an important reference for consistency evaluation studies.
Generally, individual drug guidelines are mainly based on bioequivalence research method guidelines, but there may also be requirements for in vitro evaluation indicators, such as the study of lansoprazole [8] and apixaban [9] oral dosages issued by the FDA In the guideline, in vitro nasal feeding is required to evaluate the compatibility of co-administration with food (if sauce) and other aspects. At present, the domestic evaluation guidelines for individual drugs are not perfect enough. If other regulatory agencies have found individualized requirements for the variety through literature search, the research also needs to consider the domestic application of the product to improve the relevant research as appropriate.

1.2 Re-study of prescription technology

In theory, it is very beneficial to ensure that the quality attributes of the imitation product and the reference product are consistent with the prescription process as close as possible.
In practice, because the detailed prescription and process information of oral solid dosages are not easy to obtain, oral solid dosages usually do not require complete consistency between the prescription and production process. Therefore, products that have been on the market in China, especially those that have been on the market for many years, have prescriptions and processes that are comparable to those of reference products. There may be a big difference.
The prescription and process are the basis for the subsequent in vivo effects of oral solid dosages. The difference between the prescription process and the reference product may cause the risk of subsequent in vivo and in vitro consistency.
This issue is usually the focus of the review, and it should also be the focus of the analysis of the R&D and production organization.
1.2.1 When there is no prescription change
In the absence of a change in the prescription process, many applicants tend not to discuss the issue of differences in the prescription process.
However, for the consistency evaluation products based on the reference preparation, even if the current prescription process has been in production for a period of time, it is still recommended to analyze the prescription of the reference preparation and conduct a reasonable risk analysis based on the corresponding differences. , Conduct targeted research.
Especially when there are excipients with special effects in the prescription of the reference product, such as the mainstream product HMGCoA reductase inhibitor on the market for lowering blood lipids, such as atorvastatin, rosuvastatin calcium, pitavastatin, etc., its structure Most of them contain the structure of 3,5-dihydroxy-6heptenoic acid, which may be sensitive to light, heat and humidity. According to the corresponding patent specifications such as US6316460 [10], CN1137684C [11], etc., it can be known that Prevent the formation of lactones and oxidation products by using pH adjuvants and polyvalent metal salts.
The original research composition patent of rosuvastatin calcium tablets mentioned that it uses calcium orthophosphate as a stabilizer [12].
In order to circumvent patents, the key excipients in the prescription of imitation products may be different from the original research, and other methods may even be adopted to prevent product degradation. Join in the discussion, and take the study of degradation products as the key evaluation index. The final selected prescription should be supported by sufficient data.
There are also some excipients that may affect the in vivo absorption of tablets, such as mannitol. The difference in such excipients has a high risk of in vivo consistency, and more attention should be given to further research.
1.2.2 There is a change in the prescription process
When the research finds that there are problems in the original prescription process, and the quality consistency with the reference product cannot be guaranteed, the prescription process change is generally required.
For the research of the formulation process change, the design based on the reference preparation should also be followed.
One of the current problems with changed products is that they do not provide information about the prescription process before the change.
Although the final research and evaluation are carried out around the changed prescription and process, in order to be able to effectively evaluate the risk of the change, the necessary basic information comparison before and after the change should still be provided in the data to ensure that the research data is complete Logical.
In addition, being able to provide relevant data may also provide more references for subsequent quality standards, storage conditions and the determination of expiry dates.

1.3 Restudy of the production process

As with the formulation research, if the variety of consistency evaluation involves changes in the formulation process, the process needs to be re-examined.
However, there are some earlier varieties on the market, and the initial process research has not been carried out in accordance with the new concepts and requirements. In such cases, attention should also be paid to the re-study and optimization of the production process control.
A common problem in the process research part is that process research is too modular. Usually, conventional process parameters are simply stipulated based on experience, and targeted attention to research details based on product characteristics and process characteristics is ignored.
For example, a drug that is sensitive to humidity and heat uses a process of wet granulation and oven drying. This process generally poses a greater risk to the drug. The rationality and controllability of the process should be paid attention to.
In the process of process re-evaluation, the first consideration should be whether it is necessary to optimize the process. If a similar process must be selected, in addition to the general drying temperature and time control, there should be further sensitive temperature thresholds and temperature thresholds for the degradation of the drug. The distribution of cold and hot spots inside the oven and the stability of the products at the hot spots are studied, and necessary challenge tests are carried out to fully support the determination of key process parameters.
For varieties with small specifications and low content, attention should be paid to the influence of the mixing process on the content uniformity.
In addition to considering the equal-volume incremental mixing method, it is recommended to replace the original manual mixing with a mixing equipment with controllable parameters to reduce the difference in mixing uniformity caused by different operators and reduce the fluctuation of content between batches.
Oral solid dosages generally have intermediates in granular or powder form before they are compressed or filled into capsules. Usually, the intermediates in this part are used as key intermediates for necessary control, such as content and moisture.
However, in the part of process research, the simple control mentioned above is usually not sufficient. The mechanical properties of powders and granules, such as fluidity, particle distribution, etc., often further affect the uniformity of subsequent tableting and capsule filling products. Therefore, reasonable evaluation should also be carried out in research and verification. The retained data is an important indicator of the consistency of the intermediate process of the product. This part of the data is often easily overlooked.
There is also a situation where risk analysis and necessary process research are not performed, and which parameters are not evaluated as key process parameters, and all the parameters involved in the process are included in the key process parameters. This approach is contrary to Quality stems from the basic concept of design.
For example, the heat sealing temperature in the aluminum-plastic blister packaging process is usually very easy to control within the target range. When the equipment and packaging materials are in a normal state, the risk of affecting the key quality attributes of the product is relatively low. The occurrence of this kind of situation in the data reflects that the researcher does not have a deep understanding of the product technology and process control, which may easily lead to defects in the process control.
The content is selected by the editor of Fanmogu after consulting the literature, and the layout and editing are original. If reprinted, please respect the results of labor and indicate that it comes from the Fanmogu official account.

2 Production Information

Production information is one of the important components of the application materials. As with the requirements of generic drugs, the information in the production information part should be able to fully prove that the proposed production process can stably produce products of consistent quality on the proposed production line. .
Therefore, the process data is also an important basis for the technical review agency to evaluate whether the product process control meets the requirements.

2.1 Process description

The process description part generally requires a detailed process description with the largest batch currently produced as an example. The level of detail in the process description should be such that the professional technicians can repeat the production process completely according to the declared production process, and the production meets the standard The product.
However, judging from the submitted information, the completeness of the process description still needs to be improved and perfected, especially some detailed but very critical operation steps, including the pretreatment of raw and auxiliary materials, the order of material addition, and so on.
For example, a product uses magnesium stearate as a lubricant, but in order to avoid the problem of excessive lubrication caused by the total mixing time, the actual process of the total mixing setting is to use the granules and other auxiliary materials to mix for a period of time, then add the magnesium stearate Perform a short-time mixing, but the submitted process description only describes the total mixing time, and does not specify the steps of adding magnesium stearate separately. This will bring great risks to the subsequent on-site inspection and process confirmation and should be given Pay attention to.
Another example is that the wet granulator currently used by some manufacturers has two-level control, and the specific mixing speed cannot be known. One is that it is impossible to know the impact of the change in the number of rotations caused by the aging of the equipment on the product, and the other is that it will cause the process when the equipment is replaced in the future. It is difficult to transfer parameters. At this time, it is recommended to add other end-point control indicators as a supplementary measure for production control.

2.2 The basis of key process parameters and the problem of insufficient control

During the review and on-site inspection, it was found that some of the parameters required in the process verification or batch production records lacked basis or were insufficiently monitored.
For example, a certain product lists the hardness of the tablet as a key control index, but there is no hardness sampling and test result page in the production record, which cannot reflect the control of the key index during the production process.
Other common situations are that the proposed process parameters are too wide or inconsistent with reality. For example, the main pressure of the tablet press is 5~25KN, and the process verification and BE batch show that the actual main pressure is (15±2)KN. The process research part There is also no research data on the challenge of the upper and lower limits. The proposed maximum pressure even exceeds the pressure range of the tablet press. At this time, there may be doubts about the rationality of the process parameter range.
Therefore, for the key process parameters, there should be sufficient research data to support them. For the parameters that are not critical but also need to be controlled, it is recommended to combine the actual conditions of the equipment and the accumulation of data from multiple batches to draw up a reasonable range.

2.3 Process control logic and consistency issue

In the process information, the process description (including the main equipment list), the control of key process steps and intermediates, process verification and evaluation, and the production of clinical trials/bioequivalence (BE) samples are an organic whole that echoes before and after.
Full attention should be paid to the consistency of this part of the information and its consistency with the actual production situation.
The common problem is that the actual equipment, parameters in the batch production record are inconsistent with the process description and key process steps, or there is a difference between the BE batch record and the blank batch production record.
This situation is usually due to negligence in collating the data or the production process of the product after the BE batch production is adjusted. Therefore, in addition to the need to be more careful and rigorous in collating the data, the changes involved should be explained and the changes should be reasonably evaluated.
At the same time, it is recommended that important documents such as the revision of the blank batch production record should be recorded truthfully, and the change record should be attached to the blank batch production record.
Another situation is that there are research loopholes in process verification.
For example, the storage time of preparation intermediates is often stipulated in product batch production records. However, the stability study of intermediate storage and the index design of stability study in the data are insufficient, and the rationality of the storage time cannot be confirmed.
Therefore, the main control indicators in the batch production record should be evaluated, and then listed in the process specification and batch production record after sufficient confirmation

2.4 Batch problem

The varieties of consistency evaluation have been approved for market production. For products that are normally produced, it is recommended that products of normal production batch size be directly used for BE research and registration application, which can effectively avoid the difficulty of subsequent batch connection research.
During the review, the BE/registered batch and the actual mass production batch were indeed inconsistent. As the connection between the BE batch and the mass production batch had to be evaluated, on the one hand, it would inevitably increase the workload of the experimental research and also give the review. Increased the difficulty.
For products with process changes, since the process has not been approved after the change, the batch setting should be cautious at this time.
For batch requirements, please refer to the “General Requirements for the Scale of Registration of Chemical Generic Drugs (Trial)” [13]. At the same time, full consideration should be given to the production scale of the original recipe and the production capacity of the commercial production line. It is not recommended to control costs. If the batch size is too small, if the BE batch and the final industrialized batch are too different, it may cause the risk of re-BE.
The batch of oral solid dosages is generally calculated based on the final total blend.
In the process of the production organization of oral solid dosages, there may be multiple sub-batch granules for total mixing. At this time, the actual batch of sub-batch granules also needs to be paid attention to.
Especially in the subsequent production scale-up, since the granule preparation process is usually a key process step for oral solid dosage, the feasibility of scale-up should be evaluated based on the scale of sub-batch granules. When conducting process research, it is also necessary to fully investigate the quality consistency between sub-batch.

2.5 The issue of bioequivalence batches

Bioequivalence batch products are one of the most critical batches in the entire consistency evaluation process. Bioequivalence batch products should be evaluated as comprehensively as possible, and sufficient data and samples should be retained for subsequent follow-up Supplementary research and inspection, this is also a problem that is easily overlooked.
In addition to the inspection data and dissolution profile data that must be provided, the process control data involved in the production, such as the powder properties of the granule intermediates, the quality consistency between sub-batch granules, and the sampling of various physical and chemical parameters of the tablets It is recommended to keep the detection conditions.
If there are any subsequent changes, it can be based on the data retained in the BE batch, which will be of great help to the evaluation of the quality consistency after the change.
In addition, although some consistency evaluation products that do not involve changes in the prescription process can be marketed normally, it is still recommended to keep a sufficient number of BE batch products for future reference.
The content is selected by the editor of Fanmogu after consulting the literature, and the layout and editing are original. If reprinted, please respect the results of labor and indicate that it comes from the Fanmogu official account.

3 Common Problems in the Control of Raw Materials

3.1 API

Since the varieties for consistency evaluation have been approved for marketing, most of them use APIs that have been approved.
However, in research, we should still pay attention to the quality control of APIs.
3.1.1 Some APIs were approved earlier, and there is a big gap between the quality control requirements and the current requirements. For example, the control of related substances does not meet the requirements of the latest standards. At this time, the current requirements should be combined First, the internal control standards of the raw material drug should be improved before it can be used in the production of preparations.
3.1.2 As product development usually requires a certain R&D cycle, it was found in the review that during the development of the formulation, process changes to the API may occur, such as expanding production, changing crystallization solvents, improving quality standards, etc. In addition, there may be changes in the supplier of APIs.
Preparation declaration may face the problem of different processes or sources of BE batch materials and subsequent batch materials.
During research and development, adequate communication should be maintained with the API supplier. If there is a change in the production process or the supplier, it should be assessed whether the change in the raw material will affect the key quality attributes of the formulation, and necessary change studies should be conducted on this basis .
3.1.3 The most prominent problem in the control of key attributes of APIs is the lack of control over the particle size of APIs.
Regardless of the BCS classification of APIs, particle size, as one of the factors affecting the quality of the product, should be evaluated and demonstrated as necessary.
In some data, the particle size control is relatively simple, such as through sieving control or only D90, but for the research showing that the particle size may affect the dissolution, especially the insoluble drugs, the fine particle size control should also be considered, and the particle size distribution index should be included. Within the scope of internal control.
If there is a micronization process, it is recommended to include the micronization step as a key process parameter.
Another situation is that the API supplier has crushed the raw materials as required and used directly by the formulation manufacturer. At this time, the particle size distribution index should still be clearly displayed in the data. If the raw materials are not processed before use, attention should also be paid to the raw materials Stability of particle size during drug placement.
3.1.4 Potentially toxic impurities in APIs should also be paid attention to.
Many APIs have not been officially released when ICHM7 was released, so no relevant research has been conducted.
Taking into account the high safety risks caused by toxic impurities, during the consistency evaluation period, the study should be completed in conjunction with the declaration of the preparation and relevant information should be provided, or the API supplier should be urged to complete the relevant research and supplement the record for evaluation.
The API process may involve some clearly genetically toxic structural substances, such as benzene sulfonate esters, and it is recommended that the control conditions be stated in the application materials.
3.1.5 Some APIs have polymorphism, and most API patents of consistency evaluation varieties have expired. In order to ensure the consistency of in vivo and in vitro studies, it is recommended to use APIs of the same crystal type as the reference formulation as much as possible. Develop, and pay attention to whether there are changes in the crystal form of the API during the process, especially the changes that may be caused to the crystal form in the process of wet granulation, etc., and make corresponding discussions in the application materials.
For varieties with low specifications or low content, if it is suggested that the crystal form may affect the quality of the preparation, a suitable method should be considered for the confirmation of the crystal form to ensure the stability of the crystal form in the process [15].
In addition, attention should also be paid to the crystal form changes during the stability study.

3.2 Accessories

In order to avoid the risk of delayed delivery, there is a problem that there are multiple suppliers of the same auxiliary material for the varieties that have been on the market and are routinely produced.
Part of the application materials only reflect one accessory supplier, but there are multiple suppliers in actual production, and there may be inconsistencies between the review and the on-site inspection.
At this time, in accordance with the requirements of the change guideline, combined with the characteristics and uses of the excipients, the risk should be assessed and the change research should be carried out. If the assessment considers that it is a minor change that will generally not affect product quality, supplier audits should be conducted to ensure that each supplier has the ability to provide qualified auxiliary materials, and the necessary change assessment data should be available for review.

3.3 Inner packaging materials

The inner packaging material is an important part of ensuring the stability of the product within the validity period, but all countries have their preference for the use of packaging materials. For example, the United States uses more high-density polyethylene bottles, and Europe and Japan use more blister packaging.
There are differences between the internal packaging materials of some domestic marketed varieties and the reference preparations. During the consistency evaluation process, the influence of different internal packaging materials on the stability of the variety should be fully studied to ensure that the products are qualified within the validity period.
For products that have good sales on the market and need to be taken for a long time, the packaging specifications and packaging forms have been recognized by patients. During the consistency evaluation process, although they are inconsistent with the original research, they can consider not changing the packaging under the premise of ensuring the quality of the product during the expiration date. Specifications and packaging form to meet patient compliance.

4 Concluding Remarks

In recent years, as my country’s pharmaceutical companies move towards internationalization, the State Food and Drug Administration has joined ICH, and internationally universal R&D and review concepts have been gradually implemented in China. Among them, ICHQ8 [16] and Q9 [17] are represented by ” The concept of “Quality comes from design” is also widely accepted by the industry and applied in the research and development and review of generic drugs.
The core concept of “Quality comes from design” is that the quality of medicines is not tested, but assigned during design and production.
Therefore, in the study of consistency evaluation, regardless of whether the change of the prescription process is involved, the concept of “quality comes from design” should be adhered to, and more attention should be paid to the development of prescription process and process control to fully ensure the success of product development. Rate, and follow-up conventional production can effectively ensure uniform and reproducible product quality.
After the product is approved, you should also continue to pay attention to the latest information of the reference variety, as well as the update of related guiding principles and research and development concepts, and further optimize the prescription process and improve the product quality when necessary.
The ultimate goal is to establish a complete and reasonable quality assurance system to ensure that the production and quality control of the varieties that pass the consistency evaluation can truly reach the international advanced level, and the entire product life cycle after approval can reach the quality and efficacy of the reference. Consistent, so as to better serve public health.

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