Technical Risk Consideration Of Production Site Change Of Oral Solid Preparations Of Chemical Drugs

Changes in drug production sites may be related to changes in drug prescriptions, suppliers of raw and excipient materials, production processes, process parameters and batches, and other registration management matters, which is the most complicated of all change situations. This article discusses the technical risk considerations for the production site change of oral solid preparations of chemical drugs. Combining with some cases in the technical review, it expounds the relationship between key quality attributes and key process parameters or key control indicators and other influencing factors, with a view to providing guidance for drug manufacturers to change production sites. It provides reference and enlightenment on how to carry out research on production sites.

Part 1 Risk Assessment For Oral Solid Dosage Production Site Change

There are basically two reasons for the change of the drug production site of the drug marketing licensee and the manufacturer: one is that the overall relocation is required due to factors such as municipal planning or the adjustment of its own enterprise strategy; Enterprises need to expand batches and build new production lines. The change of drug production site, especially the site change of solid preparation of chemical drugs, is often accompanied by equipment update, batch enlargement and adjustment of process parameters, or simultaneous changes in the source and dosage of raw materials and auxiliary materials. Its technical risk considerations are somewhat similar to the process development of newly registered chemical solid preparations, including the properties of raw and auxiliary materials, key process steps, key process parameters, and key control indicators. Based on the concept of quality by design, starting from critical quality attributes (CQAs), analyze the influence and magnitude of factors such as material characteristics, process steps, equipment parameters and other factors in the preparation process production, and confirm the key materials in the product production process Attributes (critical material attributes, CMAs) and critical process parameters (critical process parameters, CPPs), etc., establish the relationship between product CMAs, CPPs and CQAs, and realize the risk assessment of the production process of the production site of the solid preparation.

This article takes the tablet in the common oral solid preparation as an example. The CQAs of tablets mainly include content, content uniformity, related substances, dissolution rate and dissolution profile, etc. When the production site of the tablet is changed, it is necessary to conduct a risk assessment on the properties of raw materials and auxiliary materials and each preparation process, and evaluate the impact of these factors on the above CQAs. According to the relevant guiding principles and combined with the review experience of more than 30 tablet varieties completed in the daily technical review work, the author will evaluate the risk assessment of the properties of raw materials and excipients and the impact of each preparation process on CQAs, see.

Part 2 Relationship Between CQAs And CPPs Or Key Control Indicators And Other Influencing Factors

2.1 Content And Content Uniformity

Assay and content uniformity are CQAs for oral solid dosage forms. Content determination focuses on the evaluation of the relative labeled amount of the main component, and content uniformity inspection focuses on evaluating the degree of dispersion of the main component’s relative labeled content in a unit of preparation. The content and content uniformity of preparations will be affected by many factors, which can usually be summarized as factors such as prescription and process.

2.1.1 Prescribing Factors

Prescription factors mostly involve the source and quality of raw materials and excipients. There are differences in the quality of raw and auxiliary materials from different sources, including impurity profiles, hygroscopicity, particle size distribution, and crystal forms. Among them, the particle size distribution of the raw material powder determines the size of the material surface area and affects the particle condition after granulation. Control the particle size of raw and auxiliary materials to an appropriate range through the crushing and sieving process, and it is easy to obtain particles with uniform particle size during granulation, and obtain intermediate products that meet the standards.

2.1.2 Process Factors

In the preparation process, the granulation, drying and mixing processes have a great influence on the content/content uniformity of the preparation product. The speed and time of stirring and chopping in the granulation process are important parameters for soft material molding. Under normal circumstances, too low agitation or chopping speed will cause particle uniformity and density to decrease, and problems such as unqualified content uniformity will occur during tablet compression. Stirring or chopping for a short time will cause the density, hardness and uniformity of the particles to decrease, cracks will appear during tableting, and the content uniformity will not be up to standard. For example, if a certain tablet declared by an enterprise changes the production site, it is also related to the change of production equipment and process parameters: the product is a small-scale preparation, the raw material drug belongs to the biopharmaceutics classification system (biopharmaceutics classification system, BCS) class IV, and the granulation process The changes involving chopping speed, chopping time, stirring speed and stirring time are all CPPs; the applicant theoretically converted the changed cutter speed and stirring speed, and carried out the process according to the theoretical cutting knife speed and stirring speed. verify. Results In the verification of the uniformity of the mixed granules in the mixing process, the RSD of the content of the mixed granules in the three batches was too large, and the dissolution behavior of the changed samples in the three media showed similar factor f2 values to the samples before the change and the reference preparation <50 and the content uniformity is unqualified. The final review conclusion was not to be filed.

Drying temperature and time are the main factors affecting the drying process. If the drying time is too short or the drying temperature is too low, the moisture content of the granules will be too high, and sticking will occur during tablet compression, which will affect the robustness of the process and lead to a decrease in the content uniformity of the tablet. If the drying time is too long or the drying temperature is too high, the surface of the particles will be too dry, and it will be difficult to form, crack and material degradation (especially for heat-sensitive materials), resulting in unqualified product content.

In the mixing process, the mixing speed is low or the mixing time is short, it is difficult to ensure the degree of dispersion of the lubricant in the dry particles, and it is easy to form electrostatic adsorption groups, which affects the uniformity of mixing, thereby affecting the content and content uniformity of the product.

The size of the filling depth in the tableting process determines the difference in tablet weight, which affects the content and content uniformity; the difference in tableting speed needs to be matched with different speeds of the turntable and the speed of the forced feeder, which will affect the amount of filler, and then affect Content uniformity; in addition, some materials have large differences in thickness, and they are stratified due to the vibration of the equipment during high-speed tableting. If the materials have already stratified in the middle die hole, it will lead to differences in content and content uniformity. It is often necessary to reduce the tableting speed.

2.2 Related Substances

Related substances are one of the most important CQAs of oral solid dosage forms. In addition to the influence of the properties of raw materials and excipients, many process steps in the preparation process will lead to changes in them.

2.2.1 Prescribing Factors

Prescription factors are mostly related to the characteristics of raw materials and excipients, mainly involving types of raw materials, impurity levels and interactions. The particle size of the raw material drug, its own related substances, impurities (such as heavy metals, catalysts, etc.) and pH changes of the excipients will directly affect the impurity profile of the finished preparation. Raw and auxiliary materials of different types and with different impurity levels determine the related substances of the final product.

A company declares that the tablet that has passed the consistency evaluation changes the production site, and at the same time correlates with changes in production batches and process parameters. This variety is a BCS I product, which adopts the powder direct compression process. According to the stability data provided by the company, it is found that the smaller the particle size of the original powder, the more obvious the increase of the impurity A of the related substance under accelerated conditions. See Table 4. The review suggested that the enterprise should formulate the particle size limit of the original powder, and focus on the change of impurity A in the follow-up continuous stability inspection to ensure that the product quality meets the standard. For tablet products using powder direct compression technology, the impact of the particle size of the original powder on related substances often appears gradually during the product placement process.

Another tablet that has passed the consistency evaluation changes the production site, and is associated with changes in production equipment and process parameters. During the review, it was found that the impurity I of the related substance in the sample after the change was slightly higher than that before the change, and the growth trend of the impurity I of the related substance in the accelerated stability test was faster than that before the change. Through the analysis of historical production batch data, the applicant found that the change of the content of impurity Ⅰ, the product-related substance, was related to the pH of the excipient anhydrous calcium hydrogen phosphate. , the level of impurity I in the product increased significantly. Subsequently, anhydrous calcium hydrogen phosphate with pH>7 was used to re-produce the sample at the new site and carry out stability investigation. The accelerated 3-month stability results of the new sample showed that the level of impurity Ⅰ in the sample was basically unchanged during the placement process, and the site was changed. The data of the before and after samples are also basically consistent. The review suggested that the applicant should strictly control the excipient anhydrous calcium hydrogen phosphate in subsequent production, and include the pH value as CMAs in the internal control standard of the excipient anhydrous calcium hydrogen phosphate; Carry out quality review analysis to ensure product quality.

2.2.2 Process Factors

The moisture and temperature of materials in the preparation process have an important impact on the related substances of the preparation. If the temperature of the material is too high or the time is too long in the crushing and granulation process, it is likely to increase the related substances of the material. Excessive addition of wetting agent in the granulation process or improper use of drying temperature and drying time in wet granulation will lead to a substantial increase in the moisture content of the finished product. Chen Xi et al. [8] found that the water in penicillin V potassium tablets is positively correlated with related substances, and the increase of water in the finished preparation is likely to lead to the increase of related substances. During the fluidized bed granulation process, if the inlet air temperature is too high or the humidity is too low, the water on the particle surface evaporates too quickly, and a large number of large particles with dry outside and wet inside and dark color are obtained, which are prone to material degradation; the inlet air temperature during drying When the humidity is too low or the humidity is too high, the wet granules cannot be dried in time, and the moisture content is too high, which may increase the related substances of the finished product; when the temperature of the punch is too high in the tableting process, the particles may melt and easily form a eutectic mixture , the impurity level of the finished product will increase. The temperature of the tablet bed in the coating process will affect the related substances of the finished product, and heat-sensitive APIs need special attention. If there is a problem with the sealing of the packaging material during the packaging process, it will affect the inspection items such as related substances of the finished preparation.

2.3 Dissolution Rate And Dissolution Curve

Dissolution rate and dissolution curve, as important indicators for the quality evaluation of oral solid preparations, play an important role in controlling the effectiveness, safety and quality controllability of drugs. For drugs with a narrow therapeutic window, the dissolution behavior of the drug is particularly critical to ensure the safety of the drug. Jiang Xiongping[9] proposed that the dissolution rate of drugs with a narrow therapeutic window should be controlled to avoid burst release, so as to ensure the safety of such drugs. In this study, factors such as prescription and process are used to investigate the influence on the dissolution rate and dissolution curve of the preparation, see.

2.3.1 Prescribing Factors

When the production site of the preparation is changed, the source or quality of the raw material drug is different, especially the crystal form and particle size will directly affect the dissolution rate and dissolution curve of the solid preparation. The source and quality of excipients such as binders and disintegrants are different, which will also affect the in vitro dissolution behavior of oral solid dosage forms.

2.3.2 Process Factors

In the pulverization process, the pulverization process directly affects the particle size of the API, and may affect the crystal form of the API, thereby changing the dissolution behavior of the solid preparation. This problem is especially important for poorly soluble drugs.

The granulation process takes high-speed shear agitation granulation as an example. The high-speed shear agitation granulation is cut multiple times by a high-speed rotating chopper to form fine, uniform particles. The smaller the particles, the larger the surface area after dispersion, and the faster the drug will dissolve. Therefore, the particle size and powder properties of the intermediate dry particles of the preparation have a greater impact on the dissolution behavior. Reasonable analysis of powder mechanical properties of powders and granules in process research is an important basis for ensuring qualified properties of solid preparation intermediates and bioequivalence of products. It has been reported in the literature that the rotational speed of the agitator, the amount of water added, and the granulation time have a significant impact on the particle size, which will affect the dissolution behavior of the tablet. The author also has such cases in the daily technical review. For example, if a certain tablet declared by an enterprise changes the production site (the variety is BCS Ⅳ, and is associated with changes in production equipment and process parameters), the granulation process involves chopping speed, chopping time, stirring speed and chopping knife Changes in the number of blades. During the review, in addition to suggesting that the applicant compare the powder properties of the blended granules before and after the change, the mixing uniformity of the blended granules, and the tablet weight difference, hardness, dissolution profile, and quality and stability of the finished product during the tableting process, Considering the increase in the number of flying knives after the change and the longer chopping time will lead to finer particles, it is recommended that the applicant provide a reasonable basis for the conversion of the changed cutter speed and the relationship with the number of cutter blades and provide the change The basis for determining the latter parameters. Considering that this product is a BSC Ⅳ product, the single dissolution curve provided by the applicant cannot fully evaluate the impact of parameter adjustment on the dissolution behavior. The review suggested that the dissolution curves of ≥ 3 media should be investigated and compared with the samples before the change and the reference preparation. comparing.

In the tableting process, pressure is one of the important process parameters that affect dissolution. Increase the pressure, the particles in the tablet will be compressed more compactly, the hardness will increase accordingly, the internal porosity will decrease, water will hardly invade, and the tablet will be difficult to disintegrate. , the dissolution slowed down. In addition, different tableting speeds have different fluctuations in the punch pressure. Increasing the tableting speed will increase the degree of pressure deviation, and the hardness of the tablet will fluctuate accordingly, resulting in differences in the dissolution behavior of tablets within a batch. In the coating process, the weight gain of the coating is the key factor affecting the dissolution behavior of the preparation in the coating process. Accurate control should be carried out during the coating process. Overweight or underweight may affect the dissolution behavior of the preparation. In addition, coating parameters such as spray gun atomization pressure, spray speed, coating pan rotation speed and inlet air temperature will affect the uniformity and density of the coating film, thereby affecting the dissolution behavior of the coated tablet.

Part 3 Discussion

When the production site of oral solid preparations is changed, there are many related changes involved and the situation is complicated. Applicants should fully assess the risks and comprehensively consider the impact of multivariate factors such as CMAs, CPPs and control indicators on the CQAs of the preparation. Carry out sufficient research with reference to the “Technical Guidelines for Pharmaceutical Change Research of Listed Chemical Drugs (Trial)” to control the risk within an acceptable range, ensure the smooth implementation of the site change, and keep the drug quality and curative effect consistent before and after the change.