The highlights of this document are as follows: This document provides a decision tree for the uniformity study in the mixing stage and the tabletting/filling stage.
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Sampling in mixing stage: the uniformity of the final mixture before tabletting or filling operation is the basis to ensure the uniformity of the finished product content, and it is also the best stage for sampling to study the mixing uniformity. In principle, the study of mixing uniformity at this stage should not be skipped, and the content uniformity of the final product should be directly detected.
The sampling points should be evenly distributed and representative. According to the structural characteristics of the mixing equipment, the dead angle of the mixing equipment is determined, the sampling points in different positions are selected, and the mixing effect of the samples is investigated by using appropriate tools for analysis. The sampling diagrams of square cone mixer, V-shaped mixer and double cone mixer are also provided. The recommended sampling point for mixed sampling is at least 10, and at least 3 mixed samples are taken from each sampling point.
Sampling in tabletting/filling stage * * * *: According to the whole process of tabletting/filling, the appropriate sampling position and sampling interval are preset, and the dosage unit is sampled and tested. The sampling point must cover the whole tabletting/filling operation. Sampling points should be roughly evenly distributed, and the influence of important events (for example, the feeding process of storage tanks and intermediate containers, the shutdown and restart of production equipment, etc.). ) should be focused on. It is suggested that the number of sampling points should be no less than 20, and each sampling point should sample at least 7 dosage units.
Acceptance criteria for mixing uniformity:
0 1
One sample was detected at each sampling point, and the relative standard deviation (RSD) of all samples was calculated. All individual values are within the range of 10.0% (absolute value) of the average.
(1) If the RSD is less than or equal to 5.0%, the measuring center controls the uniformity of the dosage unit. (2) if RSD >；; 5.0%, determine the mixing uniformity of the remaining samples (2 other samples at each sampling point).
02
Testing the mixing uniformity of the remaining samples: measure other mixed samples at each sampling point and calculate the RSD of all samples. All individual values are within the range of 10.0% (absolute value) of the average.
(1) If the RSD is less than or equal to 5.0%, determine the uniformity of the central control dosage unit (at least 20 sampling points, each sampling point shall detect at least 7 dosage units); (2) if RSD >；; 5.0%, investigate to determine whether the variability is caused by product/process problems or sampling/analysis errors. Acceptance criteria of uniformity in tabletting/filling process:
0 1
At least 3 dosage units were determined at each sampling point, the average value of each sampling point was between 90.0%- 1 10.0% of the target dose, and all single values were between 75.0%- 125.0% of the target dose.
(1) If RSD≤6.0%, the uniformity of controlled dose units in this batch of samples is qualified; (2) If the RSD is greater than 6.0%, determine the unit uniformity of the central control dose of the remaining samples (all single doses are not tested at each sampling point).
02
Uniformity detection of the central control dose unit of the remaining samples: determine the remaining samples that have not been detected and calculate the RSD of all samples. The average value of each sampling point is between 90.0%- 1 10.0% of the target dose. All individual values are between 75.0% and 125.0% of the target dose.
(1) If RSD≤6.0%, the uniformity of controlled dose units in this batch of samples is qualified; (2) If the RSD is greater than 6.0%, the content of this batch of samples is uneven. It is necessary to analyze all the data of the two stages to determine the potential sources of variability, so as to improve the production process. [image upload failed ... (picture -73956f- 1632725878663)]
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* * Technical guiding principles for the study of controlled dose mixing uniformity and unit uniformity of oral solid preparations * * * (draft for comment) * * * * I. Overview Oral solid preparations refer to tablets, capsules, granules and other solid preparations for oral administration. Mixing and tabletting/filling steps are key technological steps in the production of oral solid preparations. How to make the mixing uniformity of mixed materials and the unit uniformity of controlled dosage meet the production requirements, and ensure that each unit dosage of materials contains equal active substances is the premise to realize the uniform content of finished products. This guiding principle is formulated in order to further strengthen the application of QbD concept in the actual production of ICH, improve the risk control level in the production of oral solid preparations, and clarify the technical requirements for the study of uniformity of mixing and uniformity of centrally controlled dosage units. This guiding principle is mainly drafted with reference to relevant international technical documents/guiding principles, aiming at solving the problems of powder mixing uniformity and dosage unit uniformity in process control that the industry is concerned about, and providing research strategies for powder mixing uniformity and dosage unit uniformity in central control, so as to provide reference for the research of mixing uniformity and dosage unit uniformity in drug research and development and production. These guidelines apply to oral solid preparations. Based on the principle of risk assessment, the preparation applicant/pharmaceutical manufacturer should study the varieties that are assessed as medium and high risk by mixing or tabletting/filling process steps according to the characteristics of products and production processes. For example, China Pharmacopoeia requires that the content uniformity of oral solid preparations should be determined, and the risk of mixing is great, so it is necessary to study the uniformity of mixing and the uniformity of centrally controlled dosage units. It is necessary to inspect the key batches in the whole product life cycle, such as process verification, clinical research, post-marketing changes, etc. Inspection lots should be evaluated according to product characteristics to ensure consistent product quality. According to the research results and quality risk management, the necessity of establishing effective control measures for batch mixing uniformity and dose unit uniformity in commercial production is evaluated. These guiding principles only represent the current views and understanding of the drug regulatory authorities. With the progress of scientific research, the relevant contents in this guiding principle will be continuously improved and updated. When applying these guiding principles to design and implement research, we can refer to good manufacturing practices (GMP) and other relevant technical documents at home and abroad. 2. Generally speaking, the uniformity of mixing and the uniformity of controlled dosage units are the key inspection indexes in the production process of oral solid preparations. The reasons that affect uneven mixing are usually related to the physical and chemical properties of materials (such as particle size and its distribution, hygroscopicity, etc.). ) and process characteristics (such as wet granulation, powder direct compression, etc. ). The preparation applicant/pharmaceutical manufacturer, as the main body of responsibility, should, according to the concept of QbD, combine the characteristics of products and production processes, conduct risk assessment on the factors that may affect the uniformity of mixing or control the uniformity of dosage units, design a reasonable sampling scheme, fully reflect the mixing effect of materials, establish a reasonable acceptance standard, and ensure that the content uniformity of finished products meets the requirements of the proposed objectives. This guiding principle aims to provide a research strategy for the uniformity of mixing and the uniformity of central control dosage units, so the decision tree (see annex 1 for details) does not specify the specific sampling scheme and acceptance criteria. When there are sufficient and reasonable reasons, the preparation applicant/pharmaceutical manufacturer can flexibly choose the preferred sampling scheme and acceptance criteria. No matter which method is chosen, the preparation applicant/pharmaceutical manufacturer should fully prove the rationality of the method to ensure the uniformity of the finished product content. Three. Sampling scheme This guiding principle recommends the adoption of stratified sampling method, which can collect single-dose samples at predetermined time/location intervals, or collect samples from high-risk places that may lead to unqualified content uniformity of finished products during tabletting/filling. These test results can be used to monitor the process that is most likely to cause the difference of finished products in production, guide the formulation of separate control schemes, ensure the uniformity of mixing and central control dosage unit to meet the requirements, and finally ensure the content uniformity of finished products. (I) Sampling in the mixing stage Any mixing operation in the production process can be evaluated for mixing uniformity, in which the final mixture uniformity before the tabletting or filling operation step is the basis for ensuring the content uniformity of finished products, and it is also the best stage for sampling to study the mixing uniformity. In principle, we should not skip the study of mixing uniformity at this stage and directly detect the content uniformity of the final product. When making the sampling plan for the mixed stage, the sampling points should be evenly distributed and representative. According to the structural characteristics of the mixing equipment, the dead angle of the mixing equipment is determined, the sampling points in different positions are selected, and the mixing effect of the samples is investigated by using appropriate tools for analysis. These sampling points should not only cover all materials, but also represent the most easily uneven mixing position in the whole mixing container. For example, for drum-type mixing equipment (such as square-cone mixer, V-shaped mixer and double-cone mixer), the sampling points should be at least distributed in the upper, middle and lower layers of the mixed materials and the discharge area (see Annex 2 for the general mixed sampling diagram). It is suggested that at least 10 sampling points should be selected in the mixing equipment and/or the intermediate material container, and at least 3 mixed samples should be taken from each sampling point. The sampling amount of a single sample should usually be in the range of 1- 10 times of the unit dose, and the whole sample should be used for mixing uniformity test. It is suggested to evaluate the influence of powder sampling quantity. When the sampling amount is more than 3 times of the consumption, it is necessary to demonstrate or scientifically explain and provide relevant basis. Secondary sampling should be avoided to ensure that the sampling amount can be used to determine the true mixing uniformity of the mixture. A large number of samples are taken in the mixer and/or intermediate container, and many batches of mixed materials are analyzed. Appropriate statistical analysis methods are applied to evaluate the mixing uniformity of the mixed materials, and any deviation in the samples is quantitatively evaluated. Judge whether the sample deviation is caused by insufficient mixing or sampling error. There is a significant deviation in a single sampling point, which may be caused by a certain factor, such as insufficient mixing, sampling error or material aggregation, or it may be the result of a combination of many factors. Significant deviation between different sampling points indicates insufficient mixing. (II) Sampling plan for tabletting/filling stage When formulating the sampling plan for tabletting/filling stage, the appropriate sampling position and sampling interval should be preset according to the whole process of tabletting/filling process, and the dosage unit should be sampled and tested. The sampling point must cover the whole tabletting/filling operation. Sampling points should be roughly evenly distributed, and the influence of important events (for example, the feeding process of storage tanks and intermediate containers, the shutdown and restart of production equipment, etc.). ) should be focused on. The survey results of these sampling points can be used to monitor the steps that are most likely to affect the content uniformity of finished products in the production process. It is suggested that at least 20 sampling points should be sampled online during the whole batch of tabletting/filling, and at least 7 dosage units should be sampled at each sampling point. For some special cases, such as small batch, short process time, etc. , unable to reach the recommended sampling point. After providing sufficient scientific explanation, the sampling points can be appropriately reduced. The mixing uniformity results of the above-mentioned mixed materials are compared with the unit data of the central control dose. Investigate any differences in the comparison results and analyze the root causes of the differences. According to the analysis results, consider whether it is necessary to re-formulate the formula to optimize the physical properties of the powder or optimize the production process. Four. Acceptance criteria When evaluating the uniformity of mixing and the uniformity of controlled dosage unit, the applicant/pharmaceutical manufacturer shall formulate reasonable acceptance criteria according to the control range of product content and content uniformity. The concept of risk control should be combined to determine the appropriate detection amount in order to comprehensively evaluate the content uniformity of products. The following is an example of the acceptance criteria provided by the guidelines according to the sampling plan listed in Part III above. (1) Acceptance criteria for mixing uniformity * *
If the high RSD is due to sampling/content determination error, the uniformity of dosage units should be controlled (at least 20 sampling points should be determined, and at least 7 dosage units should be detected at each sampling point); If the high RSD is due to product/process related reasons, the mixing uniformity is unacceptable. (2) Acceptance criteria for unit uniformity of central control dose
5. Other sampling plans recommended in consideration of these guiding principles are not applicable to all production situations. When the preparation applicant/pharmaceutical manufacturer encounters special circumstances in the implementation process, such as the sampling points can not reach the recommended 20 sampling points, or the production process needs to increase sampling points after risk assessment, or the sampling amount is not within the recommended unit dose range, the preparation applicant/pharmaceutical manufacturer can also adopt other sampling schemes and adjust the acceptance criteria accordingly. However, the theoretical basis and scientific explanation of alternative sampling scheme should be provided, and the acceptance criteria should be reasonable to ensure the uniformity of mixing and the uniformity of central control dose unit meet the requirements of the proposed goal. For narrow therapeutic index drugs, the accuracy of unit dose has a great influence on the effectiveness and safety of drugs. Therefore, it is suggested that the preparation applicant/pharmaceutical manufacturer should formulate a stricter sampling scheme, investigate the uniformity of mixing and the uniformity of central control unit dose, and formulate stricter acceptance criteria according to scientific knowledge and risk assessment of products. Attachment of intransitive verb * * * Attachment 1: Decision tree of mixing stage and tablet/filling stage [image-E7E47-1632725878665]
Attachment 2: Schematic diagram of fully mixed sampling square cone mixer [image-ba6488-1632725878665].
v-mixer[Image-E09ED- 1632725878665]]
Double cone mixer [image upload failed ... (picture-1FBD 67-1632725878664)]
Seven. Explanation of terms * * * * Powder mixing uniformity: refers to the uniformity of mixed materials. Process dosage unit: refers to the uncoated or packaged individual capsules and tablets in production. Stratified sampling: refers to a method of collecting representative samples. Single-dose samples can be selected from each determined position of the research batch or from different stages or periods of the production process. While covering the whole production process, sampling points should also choose high-risk places that may lead to unqualified content uniformity of finished products. Weight correction: refers to a mathematical correction method to eliminate the influence of wood chip weight difference on mixing uniformity. For example, for a tablet with a specification of 20mg, the theoretical tablet weight is 100mg, the measured main drug content and tablet weight are 19.4mg and 98mg respectively, and the weight correction result is (19.4 ÷ 98) ÷ (20 ÷1. RSD: refers to the relative standard deviation. Relative standard deviation (RSD)= standard deviation (SD)/ arithmetic mean of calculation results (X)× 100%. Eight. Reference [1] drug GMP guide: oral solid preparations China Medical Science and Technology Press, 20 10. [2] China Pharmacopoeia (2020 Edition) China Medical Science and Technology Press, 2020. [3] FDA guidelines for industry and As: analysis of mixing uniformity [4] FDA guidelines for industrial powder mixtures and finished product dosage units-sampling and evaluation of dosage units during stratification [5] Suggestions for evaluation of mixing and content uniformity: revision of the withdrawn draft FDA stratified sampling guidelines. Ph Journal of Drug Innovation 20 15, 10 76-83 [6] Evaluation of mixing and content uniformity. ASTM E2709/ E28 10 sampling scheme and technical discussion on its application. Journal of medical innovation 20 15, 10 84-97
The original text is here; Interpretation and refinement of CDE "guiding principle of mixing uniformity", the RSD standard of content is 5%! ( aisoutu.com )