On April 2, Zhou Xiaotang, senior director of Medicilon’s preparation department, shared with us the formulation research strategy of innovative drugs. The content of the course is condensed below for everyone and displayed in the form of question and answer.
1. What regulations need to be paid attention to in the pharmaceutical research of innovative drugs?
2016 Circular 80
Requirements of the State Administration for Issuing New Registration Classification Application Materials for Chemical Drugs (for Trial Implementation)
2018 New Drug Phase I Clinical Trial Application Technical Guidelines
2018 Pharmaceutical Research Information Guide for Innovative Drugs (Chemical Drugs) Phase III Clinical Trials
1995 Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-derived Products
2003 INDs for Phase 2 and Phase 3 Studies
• ICH guidelines:
Quality Safety Efficacy Multidisciplinary
2. Pharmacy research Phase I clinical should pay attention to the safety of drugs from these three aspects:
• Sterility guarantee:
Production conditions of sterile preparations, sterilization/sterilization methods;
Methodological verification of related substances (regulations require that the research on specificity and sensitivity should be appropriately in-depth);
New drugs remain stable during phase I clinical trials
3. What major changes in Phase III clinical trials will affect the safety and effectiveness of the drug?
• Changes in the production methods of APIs;
• Changes in API process;
• Changes in the sterilization method of the API or preparation;
• Preparation process changes;
• Prescription changes;
• Change in dosage form;
• Packaging system changes;
• The limits of quality standards have been relaxed, testing items have been deleted, and key analysis methods have been significantly changed.
4. How to use the QbD concept to control product quality in the research process?
• The first step: the quality profile of the target product QTPP;
• Step 2: CQAs for key quality attributes;
• The third step: risk assessment; key material attributes CPPs, DoE, design space DS;
• The fourth step: control strategy.
5. How to choose the dosage form of innovative drugs?
• Physical and chemical properties: BCS classification, stability, solution stability;
• Bioavailability: absorption site, first pass effect, half-life t1/2, stability in the gastrointestinal tract
• Clinical requirements: route of administration, range of dosage, expected frequency of administration, clinical feasibility;
• Company strategy: target product characteristics, cost and time, and API status.
6. How to increase the solubility of poorly soluble drugs and improve their bioavailability?
• The first step: micronization of raw materials;
• The second step: increase surfactant;
• The third step: solid dispersion.
7. What are the precautions for prescription research of innovative drugs?
• There is still a lot of uncertainty in the prescription process of Phase I, do not follow the idea of generic drugs when researching, and research moderately;
• The excipients in the preparation should meet the requirements for medicinal use;
• Avoid using new auxiliary materials and new packaging materials, otherwise related declarations should be made;
• Track the key quality characteristics that affect the behavior of the drug in the whole clinical process, and summarize the information;
• Pay more attention to the impact of changes on dissolution behavior, and combine it with pharmacokinetics and toxicology;
• For special preparations, phase III clinical prescriptions and drug delivery devices should remain similar to commercial products;
• Do not neglect the compatibility of packaging materials in phase III clinical trials.
8. What should be paid attention to in quality research and stability research in phase I and phase III clinical trials?
|Phase I clinical||Phase III clinical|
|Quality||No need for comprehensive and complete analytical method verification (specificity, sensitivity, etc.); |
Refer to ICH Q3B for the study of preparation degradation pathways and degradation products;
The control strategy and analysis information of potential genotoxic impurities in raw materials refer to ICH M7.
|A comprehensive and complete analytical method verification is required; |
Focus on changes in quality standards;
The dissolution/release method needs to be established.
|Stability||The stability data should be able to support that the formulation meets the requirements during the clinical study.||Immediately use the currently formulated product to conduct compatibility stability research; |
Multi-dose packaging (except oral solid preparations), providing necessary stability after opening the package;
To ensure sufficient stability data for NDA, it is recommended to provide a formal stability study protocol.
9. Why did you choose Medicilon’s preparation department?
• Professional technology platform for insoluble innovative drugs
Technical platforms such as hot melt extrusion, micronization, solubilization technology, comprehensive evaluation in vivo and in vitro;
• Professional high-end preparation technology platform
Technical platforms such as inhalation drug delivery, ophthalmic drug delivery, transdermal drug delivery, sustained and controlled release drug delivery, and new particle system drug delivery;
• Perfect GMP production and quality system
• Experienced R&D team
Oral solid GMP workshop, GMP analysis laboratory, perfect QA system;
Rich experience in successful research and development of innovative drugs, consistency evaluation, and improved new drugs, experience in both China and the United States, and project management experience;
• One-stop preparation R&D service
A full set of formulation research (R&D + clinical sample production), safety evaluation, packaging material compatibil