The evaluation threshold is raised! CDE releases important guiding principles for crystal form research, APIs, preparations...

Recently, CDE's official website has successively released a number of technical guidelines, among which the "Technical Guidelines for the Study of Crystal Forms of Chemical Generic Drugs (Draft for Comment)" received the most attention
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The research of crystal formation may seem simple, but it often brings unexpected troubles to technicians
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It can be said with certainty that an experienced API R&D personnel will definitely encounter troubles in crystal form; and how deep the crystal form should be researched is a question without a standard answer
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Therefore, at this time, the CDE issued this guiding principle, which has very good guiding significance
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PS: In the recent CDE supplementary documents, there have been in-depth studies on the required crystal form
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Why should crystal form be studied? Crystal formation research is not only the technological excellence of the industry, but also an important guarantee for the quality and safety of medicines
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Technically, the development of modern chemical drugs has experienced natural products and crude preparations, single-compound drug preparations, high-purity drugs, chiral drugs, and crystalline drugs today
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In terms of quality and safety, foreign representative cases are the withdrawal of ritonavir due to crystal form problems, re-research of prescriptions, and remarketing; domestic representative cases such as odorless chloramphenicol and rifampicol
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Therefore, the lack of research on crystal forms will seriously affect the safety, effectiveness, and controllable quality of drugs
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CDE has been paying attention to crystal form research.
The guidance given by CDE to the industry has actually been mentioned in multiple guidance documents in the past 20 years
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Of course, the research methods recommended at each stage fully reflect the technical background and industry development characteristics at the time; specific documents include "Guiding Principles for New Drugs (Chemical Drugs) Supplementary Application", "Technical Guidelines for Chemical Drug Quality Control Research", "Drugs Introduction to Analytical Methods of Crystal Forms", "Technical Guiding Principles for Chemical Drug Stability Studies", "Q6A (Quality Standards)-Testing Methods and Acceptance Standards for New APIs and New Drug Preparations", "Guiding Principles for Generic Drug Crystal Forms Research" ", "Technical Guiding Principles for the Preparation and Structural Confirmation of Chemical Pharmaceutical Raw Materials", etc.

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Recently, there are more introductions on crystal form research from a technical point of view.
It is the Four General Principles of the Chinese Pharmacopoeia 2020 edition; but from a scientific point of view, the draft of this guideline for comments can be said to be an excellent research on crystal form.
Summary of research ideas
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Analysis of the key content of "Technical Guidelines for the Study of Crystal Forms of Chemical Generic Drugs (Draft for Comment)" 1.
Original text: Applicants should select the appropriate crystal form based on the concept of risk assessment and a comprehensive understanding of the target quality profile of the reference preparation.
Carry out prescription process development
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Interpretation: Risk assessment, which evaluates the target quality of the reference preparation, is not limited to the developed crystal form of the original API; the appropriate crystal form refers to the service of preparation research on the basis of satisfying quality control
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2.
Original text: The research on the crystal form of chemical generic drugs mainly includes two aspects: one is the type of the raw material drug polymorph, the preparation, characterization and physical and chemical properties of the key crystal form; the second is the preparation process and efficacy of the polymorph of the raw material drug For possible effects, select the appropriate crystal form according to the research results
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Interpretation: The study of polymorphism should not stop at the end of the study of the crystal form consistent with the original research.
In-depth study of polymorphism and preparation is needed; the influence of crystal form on the preparation process and curative effect should have a certain research foundation and basis The results illustrate the reason for the choice of crystal form
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3.
Original text: The crystal form screening should focus on the crystal forms that may be generated or transformed during the preparation and storage of APIs and preparations
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For generic drugs, usually the crystal form consistent with the reference preparation should be selected.
If there is sufficient test data to prove that the generic drugs prepared by other crystal forms are bioequivalent to the reference preparation and have suitable stability, you can also choose to Different crystal forms of the reference preparation
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Regardless of the selected crystal form, sufficient physical and chemical properties and stability studies should be carried out on the selected crystal form
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Interpretation: Pay attention to crystal conversion and assess the risk; generic drugs are usually preferred to the crystal form consistent with the original research.
If there is a better crystal form and applied to the development of formulations, sufficient research is required
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The development of APIs and preparations is usually carried out in a division of labor, and even the API originates from outsourcing, and the crystal form is often determined.
However, in recent years, domestic generic drug companies have circumvented the original crystal form and successfully marketed
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This also further proves that domestic pharmaceutical companies are constantly improving their understanding of the quality of generic drugs-drugs and are daring to make breakthroughs
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4.
Original text: For imitation solid preparations, semi-solid preparations and suspensions, the main consideration should be the influence of the crystal form on the API and preparation process and stability, as well as the influence on the dissolution and bioavailability/bioequivalence of the preparation.
On the basis of fully studying the influence of the crystal form on it, it is determined whether it is necessary to control the crystal form of the drug
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For liquid preparations (such as oral liquids, injections, etc.
), it is recommended to pay attention to the possible influence of the different crystal forms of the API on the preparation process
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Interpretation: Whether solid drugs need to be controlled and in-depth crystal form research, the core is based on the data results of bioavailability and bioequivalence, "causes" and "effects" must be distinguished; at the same time, liquid preparations are also If the crystal form is to be studied, it cannot be considered that it is finally dissolved and used, so certain research is not carried out
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5.
Original text: When there are differences in the apparent solubility of different crystal forms of APIs, applicants are advised to pay attention to whether this difference will affect the bioavailability/bioequivalence of the preparation
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In addition, the Biopharmaceutical Classification (BCS) can scientifically evaluate the impact of polymorphism on the bioavailability/bioequivalence of preparations.
When using the BCS classification for evaluation, self-certification of the BCS classification of the product to be developed should be self-certified.
Interpretation: crystal form Different, will affect the dissolution and dissolution to a certain extent, and then affect the bioavailability/bioequivalence, which is the essence of the quality of the crystal form
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BCS classification, self-certification, and reuse of the decision tree given in this guide can satisfy the current logical basis for research and development
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6.
Original text: After proving that the generic drug is bioequivalent to the reference drug in vivo, the dissolution test can be used to evaluate the batch-to-batch consistency of the generic drug
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When the crystal form transformation may affect the bioavailability or bioequivalence of the preparation, the dissolution test can be used as a monitoring method, but research data should be provided to demonstrate that the dissolution method used can reflect the above changes
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Interpretation: Dissolution is an important content of formulation research and an important basis for proof of crystal form quality, but the most direct proof is the consistency between batches, not the consistency of crystal form! If there is a possibility of crystal conversion, or even crystal conversion has a significant impact on quality, the work related to dissolution needs to be done more deeply
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7.
Original text: After the preparation process steps of drying, pulverizing, granulating and tableting of the raw material drug, under the action of environmental factors such as temperature and humidity, the phenomenon of crystal transformation may occur, and the degree of crystal transformation often depends on different crystals.
The relative stability of the type, the energy barrier of phase transition, and the applied stress
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Sufficient research should be conducted on the crystalline transformation during the process
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Interpretation: In general, the crystal form research of APIs, the application materials list the preparation methods of different crystal forms, and seldom conduct in-depth research on crystal conversion.
However, the probability of crystal conversion is greatly improved when the API is processed to preparations.
There are APIs for crystal conversion, and sufficient research should be conducted to ensure that the quality of the API is controllable
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8.
Original text: The theoretical framework adopted by the decision tree is mainly based on the potential factors of polymorphs affecting the bioequivalence/bioavailability of preparations.
However, applicants are advised to still consider the impact of polymorphs on the robustness of the preparation process , And the impact on the stability of the formulation
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Interpretation: In the past, most of the formulation research was developed on the basis of a single crystal form; formulation developers usually do not accept APIs of different crystal forms, so they cannot give the results of the formulations developed for different crystal forms of API; this time The guidelines recommend that applicants conduct polymorphic preparation process research.
Objectively speaking, if implemented according to this, it will undoubtedly invest more or even double the research and development cost
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9.
Original text: If the metastable crystal form is selected, because the metastable crystal form may undergo crystal form transformation during the preparation process and storage process, relevant research needs to be carried out and it is necessary to determine whether to formulate the crystal form in the preparation quality standard according to the research situation.
Type check item
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Interpretation: In recent years, more and more drugs are poorly soluble drugs, and BCSII drugs account for a relatively large proportion.
Usually, dissolution control is used in preparations to replace crystal form control; if further control of crystal form is needed, solid state characterization is required Detection item
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The main pain point of solid-state characterization is the interference of excipients, and then the method needs to be developed.
In this process, the results of the polycrystalline research of the preliminary API are very needed.
Otherwise, the development of the method is easy and not comprehensive! In particular, it is not easy to detect, the result is very close to the crystal conversion, mixed crystal
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10.
Original text: The internationally recognized method for phase analysis can also perform qualitative or quantitative analysis of crystal forms to ensure the content of effective crystal forms in APIs or preparations
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Commonly used quantitative method comprising: a powder X-ray diffraction (PXRD), infrared spectroscopy (IR), differential scanning calorimetry (DSC), Raman spectroscopy (Raman), solid-state nuclear magnetic resonance spectroscopy (ssNMR) and the like
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Interpretation: The quantitative problem of crystal form is mentioned here
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Almost all of the crystal form research part in the registration application materials is currently qualitative research data; there is not much information on polycrystalline research, let alone quantitative research; but it seems that this is an important direction for future quality research of drugs (but Not sure if it will be required)
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There have been a lot of studies on the crystalline form of API, but it has not yet risen to a certain level.
The industry has not paid attention to the quantification of the crystalline form.
More academic circles have done more papers; this point is worth forming A certain amount of knowledge reserves can be used to carry out a certain amount of work, which will definitely benefit the quality research of the final drug
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Conclusion In general, the CDE issued this guide, which can better guide generic drug researchers to understand the true use of drug crystal forms, and recommends that the research of generic drug crystal forms should not be too SOP; in addition, it clarifies many crystal forms research Logic, especially the presentation of decision trees, will significantly improve the research level of the "pass line"
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In addition, this guide is all aimed at the crystal form research of generic drugs, and the current doubling of the crystal form research of innovative drugs, the industry needs more guidance, if you can take this opportunity to increase it to a level, come up with a decision tree, undoubtedly It will further promote the research of the whole life crystal form of drugs
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