Some suggestions on modifying prescription and quality standard of Dispersible Pseudoephedrine Hydrochloride Compound Tablets (2002)
1. Some considerations on prescription selection and design
☆ In principle, except for the type and dosage of taste correction agent (sucrose, saccharin sodium), the type and quantity of other auxiliary materials shall not be changed, and the sum of the changed quantity shall not exceed 5%.
Because the original "the guiding principle of the new drug the supplement" (see attachment), if the material change sum not greater than 5% (including add, delete, taste masking agent or use other pigments, pigment taste masking agent replacement), basic can think obvious influence on product quality and performance may not change, declare data requires simple;If the total change of all excipients is more than 10% (including the change of excipients), it can be considered that the quality and performance of the product may have a significant impact on the change, the application data are more requirements, and even need to do the bioavailability equivalent experiment.
The choice of flavoring agent
At present, glycoprotein, citric acid and fresh creamer are used as flavoring agents. There should be a screening process of flavoring agent type and dosage.The application of fresh creamer similar to Guozhen seems to be restricted by the state and is not recommended.
Citric acid dosage selection
Due to the addition of citric acid can influence of the PH value of the products, which would influence the stability of the products, deal with its dosage (0, 1%, 2%, 3%, according to the prescribed amount) for inspection, the main indicators for traits (taste), content and related substances (attached map 4), both taste, stability, finally determine the final dosage of the drug.
The choice of the amount of essence
Crystal modified prescriptions used milk, do not belong to the essence, consider milk may have constraints, suggested that selects the essence of taste masking, the product prescription of the medicine is mainly for the bitter taste, smell, can choose chocolate aroma, masking and correct mint added sweeteners, also can consider to water-soluble lemon essence, but the choice of type, dosage should be according to the experiment.
Colorant selection
Provide the source of raw materials and quality standard number
Finalize the final prescription of the drug
Some suggestions for quality research work
☆ Negative interference in content determination
Positive control (3 main drugs were prepared in proportion), negative control (all excipients except 3 main drugs were prepared in proportion) and sample content determination were investigated to determine whether excipients interfered with the method. 3 maps should be attached.For specific methods, please refer to Page 2 of no.7.
If there is no interference, the recovery rate should be tested again to determine the feasibility of the method.
Other inspection items should be tested in 3 batches according to the original standard, and atlas or data should be attached.
Investigation of dissolution degree
Although the original quality standard has not been established after investigation, the change of auxiliary materials should be determined after investigation whether it has an impact on dissolution and how much impact it has. For specific methods, refer to the test data and literature data of dissolution degree attached to no. 10 data.
Stability study data
Three batches of samples need to be inspected, packaged in the market, and tested for accelerated stability (40℃, RH75%) respectively.
June (Assessment time 0, 1, 2, March, June;Assessment indicators: character, disintegration, content determination, related substances) and room temperature samples for 1 year (assessment time 0, 3, 6, 9, 12 months;Assessment indicators: characters, disintegration, content determination, related substances), a total of 3×5×2=30 maps are required.
Note: Determination of relevant substances has been included in the chromatogram.
Attached: Excerpt of guidelines for supplementary Application of new Drugs (chemicals)
2. Revise the prescription of preparation
The change of preparation prescription includes the change of excipient proportion, specification and type.The newly used excipients should not interact with the main drug, not affect the inspection and determination of the quality standards of the preparation, not affect the pharmacokinetic behavior in vivo, not reduce the efficacy of the product, and not cause new safety problems.
In view of the large number of dosage forms, the technical requirements for prescription changes in all dosage forms are not listed here.This article mainly discusses oral solid preparation.When the prescription of other preparations is changed, the relevant requirements of this article can be referred to, and according to the characteristics of the preparations, the problems and causes of the original prescription can be explained in detail, and the screening data, quality research data and stability test data of the new prescription can be provided. Pharmacological toxicology test and clinical study should be considered when necessary.
2.1 Changes that may not significantly affect product quality and performance
According to the prescription weight percentage, the change range of filler is ±5%, the change range of starch in disintegrant is ±3%, the change range of other is ±1%, the change range of film coating is ±1%, and the total change of all excipients should not be more than 5%.
Add, delete pigment, taste correction agent or use other pigment, taste correction agent substitute, also belong to this category.The function and characteristics of newly used pigment and taste correction agent should be consistent with the original substance, and should meet the requirements of medicinal use, and should not interfere with the inspection of quality standards.
The self-test report of three batches of samples and experimental data of influencing factors should be provided.
2.2 Changes that may affect product quality and performance.
According to the prescription weight percentage, the change range of filler is ±10%, the change range of starch in disintegrant is ±6%, the change range of other is ±2%, the change range of film coating is ±2%, and the total change of excipients should not be more than 10%.Such changes include changes in the grade of accessories and/or specifications (the type of accessories is not changed).It also includes the change of non-release control excipients, but this change does not cause significant change of drug release rate and mode.
Detailed prescription screening information should be provided.The sample dissolution curve should be consistent before and after the change of ordinary preparation.The dissolution curves of the samples before and after the change should be compared in three different media. The dissolution media can be water, 0.1N HCl, pH4.5 and pH 6.8 buffer according to pharmacopoeia.The delayed release preparation should be compared with the dissolution curves of the samples in 0.1N HCl (2 h) before and after the change, followed by a PH4.5-7.5 buffer.3 months accelerated test data for three batches of products should be provided.Provide three batches of sample self-inspection report and provincial inspection report.
Such changes do not require human bioequivalence tests for drugs that treat index width.For drugs with narrow therapeutic indices (see Appendix 3 for details), experimental data on single-dose bioequivalence in humans should be provided;An exemption from the bioequivalence test may be applied if an established in vitro or in vivo association exists.If the experimental results show that the product is not bioequivalent before and after the prescription change, clinical trials should be considered.
2.3 Changes that have significant impact on product quality and performance
According to the weight percentage of the prescription, the change of auxiliary materials such as filler agent and disintegrating agent exceeds the scope specified in 2.2, and the total change of auxiliary materials is more than 10%.This change includes the change of excipients for drug release control.
Detailed prescription screening information should be provided.The quality study should be re-conducted and the dissolution or release curves of the drug preparation should be consistent before and after the change.If a new impurity appears after a prescription change, the toxicity of the impurity should be studied to determine whether the safety of the product is acceptable.Three batches of products should be provided with 6-month accelerated test and room temperature retention sample data. For products with good stability, the expiry date can be determined by referring to the original product.Provide three batches of sample self-inspection report and provincial inspection report.
Experimental data on the bioequivalence of a single dose in humans should be provided.An exemption from the bioequivalence test may be applied if an established in vitro or in vivo association exists.If the experimental results show that the product is not bioequivalent before and after the prescription change, clinical trials should be conducted.
