What are the guidelines revealed in the technical guidelines for the study of the stability of biological products

Source: Dandelion / midsummer autumn night cloud 2015-01-23 Christmas 2014, CDE quietly released the technical guidelines for the stability of biological products on the official website for comments On the whole, this is a year-end surprise gift It can be said that the industry has been looking forward to this guiding principle for at least ten years As a member of the field of biological products, the author has been looking forward to the introduction of the guiding principles of the stability of biological products Compared with chemical medicine and traditional Chinese medicine, biological products have special properties, so it is difficult to apply the guiding principles of chemical medicine and traditional Chinese medicine in practical operation On the whole, compared with the past, this guiding principle has a lot less figures, and more guiding words such as "should try", "should consider" and "should meet" are used That is to say, this guiding principle tells us more about the purpose of making stability plan, carrying out stability research, acceptable limits and risks to be considered It has more guiding guidance than practical guidance The stability condition is flexible, which is the most flexible stability guiding principle I have seen There is no data throughout the "conditions" section It is not clear whether it is based on the Chinese pharmacopoeia or the foreign laws and regulations to establish the conditions for stability inspection, and there is no clear data on the range of temperature and humidity The key word of the whole chapter is "should", which should be considered and verified That is to say, the relevant conditions should be set according to the characteristics of the product, and no specific data is imposed Moreover, it is clearly stated in this chapter that the stability study under different humidity conditions can be omitted to prove that the packaging container and sealing system have good sealing performance That is to say, if humidity is not considered and general biological products are stored at low temperature, as long as the sealing property is proved, then the whole stability inspection condition does not need to monitor humidity strictly in accordance with the practice of traditional chemicals Of course, how to prove the tightness, it is necessary to refer to other guidelines "Some products may have multiple specifications, such as different loading capacity, different units or different weights In stability research, research scheme can be reasonably designed according to the representativeness of test samples to reduce the test frequency of some samples, or some representative test items can be selected according to product characteristics (such as specifications) In principle, the stability study shall be carried out according to the requirements for products of different specifications with different concentrations " This passage reminds us of the "bracket method" in ICH Reasonable design of the stability scheme makes it clear that not all specifications and loading of the same product need to be inspected for stability In the past, in the actual operation, it was generally believed that the cost and price of biological products were relatively high, and most of them were sterile preparations, with great risks Therefore, without clear guidance, the enterprises did as much stability inspection as possible, for fear of a flash, and also for fear of questioning by the supervision department However, many insiders put forward that the difference between stability and sample retention is mainly the placement conditions stipulated by laws and regulations Biological products are mostly stored at low or ultra-low temperature If the long-term stability conditions are just as low or ultra-low temperature as the retention samples, and there is no humidity requirement, then the stability and retention conditions are the same In fact, it is a waste of resources For patients, what is the practical significance of stability assessment? I have admired the stability solutions of Novartis and Pfizer, because they can do "simulation experiments", that is, to simulate the actual use of users For example, put the spray in use in the car, expose to the sun, or open a whole bottle of tablet Take one tablet every day to measure the quality of the last piece At present, enterprises usually inspect in the stability incubator, and the reserved samples are also stored in the marked conditions (generally in the sealed original packaging) This kind of investigation is quite different from the actual use Although many enterprises have taken this into consideration and are conducting experiments in this field, this is not a mandatory experiment The stability principle of biological products made clear the necessity of this kind of research: the research of simulating the actual use needs to consider the placing conditions, sampling time, sampling interval, sampling amount, the state of the packaging container, the influence of multiple insertion and extraction of syringes, etc Some biological products used for multiple use, longer single administration time (such as intravenous drip), need to be prepared before use, used in special environment (such as plateau low pressure, Ocean high salt fog and other environments), and small volume dosage forms with preparation or dilution process and other special use conditions should be carried out corresponding stability studies to evaluate the stability of the products in actual use In addition, in the "mark" column, it is clear: for products with multiple doses, the longest service life and placing conditions after opening shall be indicated For lyophilized products, the stability of lyophilized products after dissolution shall be specified, including the storage conditions and the longest storage period after dissolution This article greatly facilitates the actual user, the patient has made clear the storage time after the drug is unsealed, and also put forward the alert to the hospital nurses For the original clinical use of the control of the "gray zone", a warning reminder For non professional ordinary patients, this is a very meaningful measure, which indicates the shelf life of the drug in actual use, reduces the risk, and improves the scientific use of the drug The high requirements of transportation condition validation start from the cold chain transportation requirements of vaccines in recent years, and the originally relatively blank "time on the road" has been paid more and more attention This guiding principle takes transportation research as a separate chapter, which makes it clear that pharmaceutical enterprises need to bear the responsibility of transportation research In the past, the research of pharmaceutical companies is often limited to the laboratory Even if there are some compression tests, they are all done in the laboratory to simulate the natural conditions But now, we need to do practical research This study includes transportation routes, vehicles, distances, times In addition, the worst condition should be simulated, such as bumping, vibration, uncooled chain, etc This is the responsibility for product quality But in terms of operation, it's a bit of a puzzle how to simulate vehicles and different natural environments? Is it OK as long as there are other data proving that the seismic resistance and airtightness are good? It takes a long time from research to declaration, declaration to production The industry pays attention to more details such as stability inspection and verification, and expects more detailed guidelines or explanations The extension of validity has not been clear for a long time The declaration and registration are long-term and accelerated stability data reported for six months, and then the provisional validity period is 2 years by analogy This approach is based on the drug management registration method, as well as the chemical stability guidelines Based on the calculation formula, there is also a hypothesis, that is, the hypothetical chemicals are degraded according to the first-order degradation mode, and the trend chart of stability data is a beautiful downward arc But in fact, not to mention biological products, many chemicals are not in the first-class degradation mode The guiding principle of this time, in the result analysis section, did not mention the validity period and stability extrapolation, just said that the stability is the basis for the establishment of the validity period So, can we use the six-month data to infer the tentative two-year validity period at the time of declaration? The draft guidelines were not clearly stated However, the technical guidelines for stability research of chemical drugs (APIs and preparations) (online for comments on February 5, 2013) describe that: if it is proved reasonable, the validity beyond the actual observation time can be obtained by limited extrapolation based on the measured data obtained under long-term test conditions in the registration and application stage.