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In the process of drug production, the amount of raw materials used in feeding exceeds 100% of the feeding amount required by the formula, which is called excessive feeding. Generally speaking, in the process of drug application and registration, the prescription dosage in the application materials is not allowed If adjustments are made, the value of each component in the declared prescription must be strictly unchanged throughout the whole declaration process to ensure that the quality of the drug is controllable, safe and effective.
However, in the research and development and production of actual pharmaceutical preparations, some drugs have the phenomenon of “Excess Feed Of Material”. This “Excess Feed Of Material” includes not only the loss of individual raw materials, but also the loss of the overall quality of the preparation. In fact, this phenomenon occurs in It is a widespread phenomenon in the preparation process of pharmaceutical preparations, and it is also an important part of the quality control of pharmaceutical production.
Research and development, production, review, verification and other aspects have different meanings and understandings of “Excess Feed Of Material”, as well as the subject’s understanding and handling of its approval and supervision methods.
Based on the summary, analysis and interpretation of “Excess Feed Of Material” in drug declarations over the past few years, this study summarizes the scientific understanding of the phenomenon of “Excess Feed Of Material”, further explores its scientific evaluation, and puts forward a proposal for “Excess Feed Of Material”. The idea of rationalized evaluation of the phenomenon of “feeding” is for the industry to share and discuss.
1 Reasons For The Phenomenon Of “Excess Feed Of Material“
In the normal pharmaceutical preparation process, raw materials usually need to go through multiple steps to prepare qualified pharmaceutical preparations that meet clinical needs. In the long pharmaceutical preparation process chain, the main drug inevitably has to go through multiple steps. The process passes through a variety of special containers, and undergoes many process steps such as filtration and high-temperature sterilization that may cause adsorption and degradation of the main component drug. At the same time, there are transfers between different industrial containers such as stirring, configuration, and mixing. Residues, pipeline dead volume and other physical and chemical steps that may cause the loss of the main drug. Therefore, some developers of the drug preparation process choose to add an appropriate proportion of the main drug to the preparation process at the beginning of feeding, so as to Offset the main drug degradation and physical loss caused by the whole process of the preparation process to ensure the quality of the terminal preparation.
This “correction” method seems reasonable, but in fact it runs counter to the requirements of the strict supervision of pharmaceuticals today. If the company has any addition or subtraction of the raw material dosage in the registration data, even if it is only ±3%, It will also bring unpredictable changes and risks in the later stage of production intermediate control, finished product quality inspection, pharmacological stimulation, and clinical efficacy. Therefore, from the perspective of risk control of drug supervision, unless necessary, “Excess Feed Of Material ” is not recognized.
2 Mechanism Analysis Of “Excess Feed Of Material” And Consideration Of Review
In the actual application process, some drugs have to adopt the “over-dosing” process due to high loss, and some applicants have obtained approval and approval for the “over-dosing” process submitted. So what is the situation? To be recognized, or in other words, to what extent is the preparation of materials sufficient to make the behavior of “Excess Feed Of Material” possible to be recognized by the regulator? The following is an analysis of the objective rationality and verification of the phenomenon of “Excess Feed Of Material” from a technical perspective. Data requirements.
From the perspective of drug quality control, we divide the factors that may cause drug loss in the preparation process into two categories: physical loss and chemical loss. The evaluation methods are described below.
2.1 Chemical loss
During the preparation process, if encountering high temperature, high pressure, light and other environments, it may cause the degradation of the drug or excipients, resulting in a decrease in the effective content of the main drug and loss of the main drug components.
ICH Q8(R2) pointed out that: in general, it is not recommended to use excessive amounts of APIs in the production of pharmaceuticals to compensate for the degradation of the drug during production or during its validity period, or to attempt to extend the shelf life of the product. Any excessive use in the production of pharmaceutical preparations , regardless of whether it appears in the final preparation or not, it is necessary to prove whether the safety and effectiveness of the product have been considered. The certificate includes the following information: ① Exceeded amount. ② Reason for excess (that is, compensation for expected and proven production loss in the process). ③ The reason for the excessive amount.
Although ICH Q8(R2) clarifies that the purpose of overdose is not allowed if it is to compensate for the degradation during production or shelf life or to prolong the life of shelf life, some drugs that must be used for treatment are extremely poor in stability. The current level of production technology cannot completely inhibit its degradation or such drugs will not cause safety risks even if they degrade, so an excess is still allowed, for example, an excess of 20% is allowed for vitamin A preparations.
In addition, under normal circumstances, chemical loss is generally only for raw materials and excipients that are sensitive to certain environmental factors in the preparation process, and is selective, and the various components in the prescription will not decrease at the same time. Therefore, chemical loss will It brings imbalance or change of the prescription, so that the finished product at the end of the preparation process is inconsistent with the prescription designed for the prescription. At the same time, due to chemical loss in the prescription, the chemically changed raw materials will also bring degradation products into the prescription, such as hydrolyzed products etc. Therefore, the prescription changes brought about by chemical loss are dangerous. While bringing unpredictable safety risks to the prescription, it will also reduce the effectiveness of the finished preparation, which should be paid attention to during the review.
In order to cope with the possible chemical loss in the preparation process, some applicants have adopted the method of appropriately increasing the dosage of the raw material drug during feeding. The risks posed include but are not limited to: ①Simple increase in dosage, although it can also achieve the goal of making the finished product inspection qualified, but because there is no active analysis and removal of high-risk steps in the process that may cause degradation of the main drug, with With the increase of the dosage of the main drug, the amount of the degraded drug in the original preparation process also increases, resulting in an increase in the absolute number of impurities in the finished product, which brings the risk of unpredictable adverse drug reactions. ② Simply increasing the main drug However, other excipients in the prescription (including easily degradable excipients and relatively stable excipients under the preparation conditions) did not increase proportionally, resulting in changes in the ratio of the main drug to the excipients in the prescription, making the declared registered prescription different from the actual one. Inconsistent production prescriptions, which is a taboo in GMP production and management, will also cause changes in the powder engineering properties of pharmaceutical intermediate pellets, such as fluidity, bulk density, etc., resulting in changes in tablet compression force, tablet hardness, etc. , the entire production process is outside the scope of formulation design, which violates the principle of QbD and is not allowed by drug supervision.
2.2 Physical loss
In the process of pharmaceutical preparations, solid preparations have multiple links such as granulation, mixing, granulation, tablet compression, and subpackaging. In each step of the process, there is a possibility of loss of raw and auxiliary materials, such as the transfer process of the wet granulation process. , it is difficult to achieve 100% complete transfer, and it is inevitable that there will be some residues at the bottom of the container. If the fluidized bed process is used for granulation, during the high-temperature and high-speed preparation process, in addition to the high temperature of the air inlet, the heat of the main drug may be caused. In addition to increased instability, electrostatic adsorption on the container wall, deposition at the corners, dust bag filter, etc. will all lead to the loss of a part of the drug particles. During the operation of the high-speed tablet press, the hopper, turntable and dust removal Some of them also have the possibility of adsorbing drug powder. There is also a certain percentage of loss in sub-packaging, bottling and other links. The above factors add up. If the process verification and control are not strict enough, the drug loss will still be large. Therefore, it is necessary to examine the drug loss caused by process equipment and preparation process through strict verification.
In the process of liquid preparations, there are also various forms of losses such as the possible catalytic degradation of the drug by the metal of the pipeline and the coating, the loss of high temperature and high pressure sterilization, and the broken container during the transfer process. In innovative dosage forms, such as slow-controlled In the preparation process of release preparations, multi-layer tablets, liposomes in injections, emulsions, lipospheres and other dosage forms, the process points that may cause drug loss need to be evaluated and verified in detail to ensure the whole process of the preparation process. The loss situation in the system can be checked with data, which can be checked and traced. At the same time, the loss situation can be effectively controlled through verification.
To sum up, in the process scale-up of preparations, it is especially necessary to strengthen the effective verification of the data accumulation of process loss. Generally speaking, in the small test process, the loss may be relatively small due to the small number of equipment involved. With the pilot test and Large-scale commercial production involves more and more professional equipment. For example, in the mixing process, manual mixing or small-scale equipment may be used on the laboratory scale, but the properties of the blades and the three-dimensional space distribution of the mixing equipment used in large-scale production The situation may affect the adsorption and residue of the drug mixture. Even if the same container is used, the possible dead volume space in the container is different when using different stirring blades and space distribution. Therefore, it is necessary to According to cGMP requirements, a clear quantitative analysis and record of material loss is made to facilitate verification and traceability.
From the perspective of drug review, the physical loss is more of the material loss in the same proportion of raw materials and excipients, so it will not bring about changes in the ratio of raw materials and excipients in the prescription. The output, that is, the yield has been reduced. Therefore, from the perspective of safety risk and effectiveness control that drug review focuses on, the risks are limited and controllable.
What needs to be paid attention to is that due to the residues in the preparation process, it will bring a lot of hidden dangers to the continuous production of drugs. If the drug intermediates and powders left in the preparation pipelines and containers are not carefully cleaned between batches, they will be brought into the The next batch of products is being produced. At the same time, due to the length of the interval between batches of the manufacturer, if the residue degrades during the placement process, it may be brought into the next batch of product materials, resulting in Safety risks are difficult to predict. Therefore, it is necessary to strictly remove residues in the entire production and preparation process to increase the controllability of the entire production process, comprehensively control and reduce risk factors in the production process.
3 Acceptable limit of “Excess Feed Of Material” in drug evaluation
In the actual production of drugs, due to the variety of workshop equipment involved, there will always be inevitable production tolerances, it is necessary to carry out targeted verification of the differences, and on this basis, targeted Control, in accordance with the concept of GMP, implement effective control over the whole process of drug production.
In drug R&D and formulation design, the degradation and loss that may occur in actual production should be predicted prospectively, and continuous attention should be paid to it during the actual production scale-up process, and effective measures should be taken to control it.
For the phenomenon of “excessive feeding” in the application materials, it is recommended to carry out targeted production process verification on the basis of sufficient research and development, and conduct traceability and quantitative analysis of “excessive feeding”. For example, activated carbon depyrogenation is common in the production of injections. Generally speaking, due to the indiscriminate adsorption of activated carbon, it will bring a certain loss of drugs and related excipients. Therefore, it is necessary to carry out actual production verification of adsorption loss to evaluate the loss caused by adsorption + filtration and assess the possible impact of changes in the formulation ratio brought about by such physical loss on the quality of the final product.
Another example is in the technological process of oral capsules and tablets, there are often steps of sieving and granulation, as well as the steps of transferring granules between different containers, and the loss of tablet presses and capsule filling machines. For the loss of each related step, It should be evaluated through the verification of sufficient large-scale production batches, and implement the concepts of GMP and QbD. In order to meet the requirements of domestic and foreign regulatory agencies under increasingly stringent regulatory requirements.
Another example is the preparation of semi-solid ointment for external use, which often requires proper heating to promote the dissolution of lipid raw materials, and there is also a certain dead volume in the transfer between different containers of semi-finished products, and in the packaging process. Therefore, the cleaning verification requirements Relatively high. At the same time, it is also necessary to carry out the verification of the corresponding process residues, so as to effectively trace back and control the whole process of the preparation process.
4 Overdose Design in Innovative Drugs
According to the literature, the laser perforated osmotic pump tablet with slow and controlled release function is characterized by a hard semi-permeable membrane on the outer layer and a double layer inside, one layer contains API layer, and the other layer is hyperosmotic after absorbing water. The driving layer. Drugs rely on the driving force generated by hypertonicity and are continuously released through the laser holes. However, due to the inherent defects of this type of preparation and the physical and chemical properties of the API itself, there are always very few drugs that are effective in the tablet. The final point of the running pathway cannot be completely pumped out or the drug has reverse osmosis phenomenon, so that a small part of the drug is stored in the tablet shell. In order to maintain the effectiveness of the drug, it needs to be overdosed. For example, Glipid produced by Pfizer 10% overdose of doxazosin sustained-release tablets (Ruiyining); ) over 10%. The content limits of the above three kinds of laser-drilled osmotic pump tablets all increase the lower limit control level compared with the lower limit level of ordinary tablets. For example, the content limit of doxazosin mesylate controlled release 99.8%~110.3% of the content”, the increase of this content limit requires process verification, stability inspection and method verification.
In addition, the formulation design of transdermal release preparations also uses the characteristics of the concentration difference of the drug to promote the drug release, and uses a higher concentration of the formulation to control the drug release rate through the skin through membrane control or the passive transport control of the skin itself. The release speed of the drug should be adjusted to meet the required curative effect and safety requirements. The real drug effect is only the part that penetrates the skin and enters the systemic circulation, which is not absolutely related to the drug amount in the reservoir.
In addition to pharmaceutical control, the design of the main drug loading of the above two innovative preparations should also be adjusted and designed in combination with clinical feedback, so that the dose design meets the needs of clinical treatment. “It has gone beyond the physical or chemical loss in the general sense, but should be considered in combination with the therapeutic characteristics of the drug. Since a single dose contains the dose of the original multiple administrations, such as accidental destruction of the structure of the preparation, or instantaneous burst release , will cause the dosage of patients to be doubled in a short period of time. It is suggested that the drug’s therapeutic window and other safety information should be combined to improve the formulation design and minimize the risk of patients in clinical use.
5 Summary And Outlook
“Excessive dosing” is a common process phenomenon in drug R&D and production scale-up. It involves the fields of drug production control and impurity management, and it is also the trend of deepening GMP management. The analysis is carried out, and a brief introduction is given to its evaluation technical requirements, hoping to guide readers to deepen their understanding of the concept of QbD and GMP management, and in the future research and development and production practice, continue to strengthen the understanding and control of the details of the drug preparation process , and make continuous efforts to provide high-quality medicines to clinics.