Analysis of Supplementary Material Problems in Consistency Eva

Understanding and Analysis of the problem of Auxiliary Materials in consistency Evaluation

For the research and standard of the excipients for injection, the Chinese pharmacopoeia gradually increased the loading strength and the standard requirement. Because excipients are closely related to the safety of injection, 2015 Chinese Pharmacopoeia has collected 23 excipients for injection, which will be increased in the future. At present, many published pharmaceutical excipients in the naming specifications are not reflected, the level is reflected, need to pay attention to distinguish.

First, several requirements for the selection of excipients in injection

(I) it should be ensured that the excipients themselves are first and foremost safe and stable;

(II) relevant reviews of supporting materials;

(3) the requirements of purity and biological load should be high;

(4) it is necessary to have corresponding quality standard for quality control. The quality standard can be drawn up by enterprises themselves. If there is a standard in Chinese pharmacopoeia, the standard should be adopted to control it, and the standard in mainstream national pharmacopoeia can also be referred to.

(5) the safety of excipients may be determined by animal experiments. The safety, effectiveness, stability and quality controllability of the auxiliary materials should be related to the raw materials and package materials, and the compliance can not be regarded as the main research content.

2. Requirements for evaluating the consistency of injection

The type and amount of excipients in a generic injection should generally be the same as a reference preparation. The same amount of excipients is 95% of the corresponding excipients used in reference preparations. If special solvent is attached, it should be the same as the special solvent prescription of reference preparation. However, the specifications of the excipients in the reference preparation are difficult to determine, the purity of the excipients is high in theory, the level of bacterial endotoxin is low, and the risk will be reduced.

The problem of overdosing should be carried out with reference to the requirements of ICH Q 8. In principle, we do not want the injection to be overdosed, but we can refer to the requirements of the Chinese Pharmacopoeia for a certain amount of excess in order to eliminate the influence of the residual part of the solution on the accuracy of the dosing.

III. Quality requirements of excipients for injection

Quality standards, Chinese pharmacopoeia standards should be followed first. If the Chinese Pharmacopoeia is not published, it is necessary for the excipient material enterprise to draw up it by itself. When selecting, we should consider the reasonableness of the project setting, the applicability of the method, the rationality of the limit and whether the sample meets the standard or not.

The functional problems of excipients need to be concerned or investigated, such as the molecular weight and substitution of the suspension agent carboxymethyl cellulose sodium, the critical micelle concentration of surfactant, the maximum drug loading, and the safety. Biological limits, etc., should be studied and explained.

Excipient production process, quality, name, standard requirements must meet production requirements or pharmacopoeia requirements. Otherwise, it is necessary to study according to the new excipients.

The safety evaluation of new excipients must be carried out first to ensure the safety of the excipients. The CDE and the Pharmacopoeia Commission have issued the corresponding guiding principles.

III. Consideration of different functional excipients

[化] bacteriostatic agent

In principle, injections are not allowed. The injection itself should be aseptic. For the injection which can not be sterilized, filtration may also be a problem. In this case, bacteriostatic agents must be added in the aseptic condition, and the specifications of the bacteriostatic agents, the reasons for the addition and how to ensure the satisfaction of the requirements must be explained.

Antioxidant

Many pharmaceutical formulations are easy to oxidize, although there are many ways to control them, such as filling inert gases, adding Antioxidants and antioxidants, and choosing antioxidants is also a specific problem.

[化] buffering agent

Many drugs are easy to hydrolyze, by adding a certain buffer, can prevent the rapid hydrolysis of drugs.

[医]metal-chelator

In many cases, the hydrolysis and oxidation of drugs are affected by the catalysis of metal ions, which can be reduced or even eliminated by adding metal chelating agents. EDTA in the United States is used relatively more, and CALCIUM iodide sodium is recommended in China. Because EDTA chelates calcium and produces calcium loss. Therefore, when choosing, we need to consider whether to use it for a long time or for a short time. If it is used briefly, it is possible to use EDTA.

Filler

Fillers are mainly for freeze-dried preparations, play the role of filling protection. Two temperatures should be considered in the selection of excipients: one is low eutectic point and the other is critical temperature. These two key temperatures should be taken into account in the selection of freeze-dried protectants (lactose, mannitol, polyvinylethone and Dextran) and buffers.

Solubilizer

Similar to surfactants, but different in some properties, the biological load and CMC (critical micelle concentration) should be taken into account in their use.

Osmotic pressure regulator

There are some differences between the theoretical calculation and the actual measurement results.

No Foam

High molecular material is easy to produce bubbles in the production process, it is difficult to ensure the quantity of filling is up to standard during pouring, and it is difficult to operate when cladding, so it is necessary to add, and must be explained.

For injection, the auxiliary material factor is always a very important factor. Before explaining the prescription and process clearly, we must explain the basis of the choice of excipients, the source of the excipients, the quality standard, the specification, the dosage and so on. This is a necessary condition, is also a sufficient condition!