Critical pharmaceutical process identification considering chemical composition, biological activity, and batch-to-batch consistency: A case study of notoginseng total saponins.

Objective: Critical pharmaceutical process identification (CPPI) is an important step in the implementation of quality by design concept to traditional Chinese medicines (TCMs). Risk assessment methods are usually used in CPPI. However, risk evaluation is usually subjective. The purpose of this work is to present a more objective CPPI method. Methods: A CPPI method considering chemical composition, biological activity, and batch-to-batch consistency was presented in this work. The manufacturing process of notoginseng total saponins (NTS) was investigated as an example. The changes of chemical composition, biological activity, and chemical composition consistency after main processes were measured and compared. A significant change of them indicated a critical process. Results: After extraction process and chromatography process, saponin purity and chemical composition similarity remarkably increased, and saponin content variations decreased. Thrombin inhibitory activity was remarkably decreased after chromatography process. Because of the large influences on NTS quality, extraction process and chromatography process were identified to be critical processes of NTS. Conclusion: Based on a comprehensive and objective examination of the role of each process, critical pharmaceutical processes can be identified. A similar method can also be applied to other TCM processes.

Critical process parameter identification of manufacturing processes of Astragali Radix extract with a weighted determination coefficient method.

Objective: Critical process parameters (CPPs) identification is an important step of the implementation of quality by design (QbD) concept. There are many CPP identification methods, such as risk analysis method, sensitivity analysis method, multiple linear regression method, standard partial regression coefficient (SPRC) method, and so on. The SPRC method can consider multiple process critical quality attributes (CQAs) simultaneously, but the determination of CPP number is subjective. Therefore, new CPP identification method is still required. Methods: The manufacturing process of Astragali Radix extract, which contained water reflux extraction, concentration, and ethanol precipitation, was used as an example. First, the multiple process CQAs were determined to be the yield of pigment, dry matter, sugars, and active ingredients. Second, the potential CPPs were determined by a knowledge organization method. Plackett-Burman designed experiments were then performed. A weighted determination coefficient ( R w 2 ) method was presented to identify CPPs. In this method, the importance of different CQAs was considered. Process parameters were removed one-by-one according to their importance index. The decrease in R w 2 was used to characterize the importance of the removed parameter. If the decrease of R w 2 was less than a preset threshold, the removed parameter was not a CPP. Results: During the manufacturing process of Astragali Radix extract, the potential CPPs determined by the knowledge organization method were water consumption, reflux extraction time, extraction frequency, ethanol content, ethanol consumption, and concentration endpoint. Reflux extraction time, the first ethanol consumption, the second ethanol consumption, and the second ethanol precipitation refrigeration temperature were found to be CPPs using the weighted determination coefficient method with the threshold of 10%. Conclusion: Using the weighted determination coefficient method, CPPs can be determined with all the CQAs considered based on their importance. The determination of CPP number is more objective compared with the SPRC method.

[Quantitative chromatographic fingerprint analysis of Sanye Tangzhiqing Decoction based on quality by design concept].

In this work,a high performance liquid chromatography-ultraviolet( HPLC-UV) detection technology was used to establish fingerprint analysis method for Sanye Tangzhiqing Decoction following an analytical quality by design( AQb D) approach. Firstly,column temperature,flow rate,and gradient elution conditions were determined as the method parameters needing to be optimized. Then according to the results of definitive screening design,three critical method attributes( CMAs) were identified,including peak number,the percentage of common peak area to total peak area,and retention time of the last peak. A stepwise regression method was used then to build quantitative models between CMAs and method parameters. Probability-based design space was calculated and successfully verified using the experimental error simulation method. After the analysis conditions were optimized,the contents of six components,namely chlorogenic acid,paeoniflorin,rutin,hyperoside,quercetin-3-O-ß-D-glucuronide,and salvianolic acid B were simultaneously determined. There were 19 common peaks in the fingerprint and their common peak area accounted for 96% of the total peak area. Both fingerprint and quantitative analysis methods were validated applicable in methodology study,and they can be applied to determine new samples.

[Comparison of two algorithms for development of design space-overlapping method and probability-based method].

In this work, two algorithms (overlapping method and the probability-based method) for design space calculation were compared by using the data collected from extraction process of Codonopsis Radix as an example. In the probability-based method, experimental error was simulated to calculate the probability of reaching the standard. The effects of several parameters on the calculated design space were studied, including simulation number, step length, and the acceptable probability threshold. For the extraction process of Codonopsis Radix, 10 000 times of simulation and 0.02 for the calculation step length can lead to a satisfactory design space. In general, the overlapping method is easy to understand, and can be realized by several kinds of commercial software without coding programs, but the reliability of the process evaluation indexes when operating in the design space is not indicated. Probability-based method is complex in calculation, but can provide the reliability to ensure that the process indexes can reach the standard within the acceptable probability threshold. In addition, there is no probability mutation in the edge of design space by probability-based method. Therefore, probability-based method is recommended for design space calculation.

[Detection of antioxidant activity of Danhong injection and its intermediate with a paper-based analytical device].

The paper-based analytical device (PAD) was applied in this study to analyze the antioxidant activity of Danhong injection and its intermediates. First polycaprolactone was printed on the surface of a filter paper with a 3D printing device. The modified filter paper was then prepared using polycaprolactone and solid paraffin as the modifiers. The PAD was prepared after adding DPPH ethanol solution to the modified filter paper. Ascorbic acid solutions with different concentrations were used as the positive drug on PAD. After the occurrence of color reactions, the PAD was dried, and the data of color were collected by a cell phone. The color component G and grayscale were selected as the potential indices for measurement according to the values of determination coefficients, detection limits, and effective number of digits. Qualitative and quantitative analysis of Danhong injection and the concentrate of aqueous extract were realized with the PAD. Because no significant differences were observed between the results obtained using the two potential indices, the average values of these two were used for analysis, and the antioxidant activity of Danhong injection and the concentrate of aqueous extract was equivalent to ascorbic acid solutions of 3.7, 46 g·L⁻¹, respectively. The PAD method presented in this work can be a simple method to determine biological activities of Chinese medicines and their intermediates.