In the third year of the reign of Xi Jinping and Li Keqiang there occurred many events in Chinese pharmaceutical circles. During the year FDA issued many alerts and CFDA released several announcements, causing people concerned on medicine quality and touching nerves of the pharmaceutical companies. Also during this year R & D of generic drugs and new medicines is fervent, resembling the scenario of the Spring and Autumn and Warring States Period in the long history of China. In order to "R & D of high-quality chemical pharmaceuticals", ISPE and Tongxieyi joined hands for the first time calling more than 400 professionals in pharmaceutical circles to gathered in Nanyuan of Suzhou discussing CMC events. Song Bingjia attended the conference by happenstance and wrote remarks to record his feelings. Address to the General Assembly CMC, Chemistry, Manufacture, and Control, Culture, Music, Chemical Drugs, Culture, Metrics, Compliance.
Song Bingjia's summary: China far lags behind India in pharmaceuticals industry viewed from FDA's ANDA and IND amount, an order of magnitude. For CMC, stability of the medicines, bioavailability (efficacy), side effects (safety) are very important.
The implications of CMC vary with people insights, and this time we discuss CMC based on three official interpretations emphasizing chemical (scientific)/production (engineering)/Control (management), culture (soft power)/music (artistic)/chemical drugs (small molecules - scientific), quality culture (system)/metrics (science)/compliance (rules). Preformulation study on pharmaceutical development Song Bingjia's summary: this involves many aspects requiring versatile people, seemingly simple, not simple to do.
Reverse engineering technical formulation of generic drugs: stable, producible, absorbable, elegant.
Formulation development: delicate culture (the ultimate).
Pprocedure: product selection -> ** preformulation-> prototype -> ** BE -> ** ANDA filing: reverse engineering
Recommendation: in-depth research on the original drugs (specifications, patents, spectroscopy, pharmaceutical companies characteristic); Apply reverse engineering techniques (including spectroscopy, metrology mathematical model -determine MCC grade using IR, and so on.
Song Bingjia's summary: To develop an excellent formulation needs perfect integration of science, engineering and art as cooking a delicious dish. To imitate a good dish, you had better peruse the recipe, the chef, his experience, and strive to develop own appreciation (sight, smell, taste, hearing, perception, intuition), and then practice, think and practice...... Can drug metabolism predict human body BE and guide formulation process selection? Methods to evaluate differences between generic drugs and original drugs: in vitro dissolution BE, BE human trials, human PD equivalent test, human clinical trials, more Beagles PK test
Song Bingjia's Summary: ? Or ? In fact, the unknown is unpredictable and the already known has nothing to do with prediction. The linear systems may be predictable, however the real world is essentially an nonlinear system and multi-variable, the experts' forecasters are mostly "afterthought" or "correlation". Prediction in reality shall take into account of black swan events, and the pharmaceutical professional who are interested can have a look of "Black Swan" and "Antifragile". Focus on pharmaceutical crystal form Song Bingjia's summary: Research on drug crystal form is throughout the whole process of drug development, closely related to drug Substance and drug Products as well as drug quality and patents. A seemingly simple thing is not easy to do. (emphasis on the crystal form research is as important as emphasis on other researches in drug development since drug development is in nature a systematic process, and every aspect of the system is important, in the end which is more important, as which organ is more important in human body, unable to be answered ......).
QbD: establish lifecycle approach for confidence in medicine quality, a comprehensive control strategy, QbD is a method of life-cycle approach helping to increase confidence in the quality.
Song Bingjia's summary: Quality depends on design and quality is a system. Real quality control idea shall be seeped into blood and brain, (incept, brainwashing, see movie - Inception) and the culture, becoming genetic heritage. To keep good quality depends on quality control is impossible as the black swan, only a good quality culture can prevail. The core of the development and design of oral controlled release formulations: the release curve (efficacy); impurity profiles (safety); formulation development process: literature information (specifications, EMA, FDA, Japan, BCS); controlled release, investigate whether "burst" occurs.
Song Bingjia's summary: To make it release as we want is not an easy thing, however let's consider AI later. Membrane controlled pellets and their pelletization techniques for precise treatment: dosage control; Pellets and pelletization techniques: a critical review, D. Ratul et al .., Int Res J. Pharm 4 (2013) 90-95
Song Bingjia's summary: later let's read a few review papers. Dry powder inhaler formulations - from development to production- topical delivery (pulmonary delivery) to lung, systematic delivery; Advair -GSK, Symbicort - AstraZeneca
Micronized (particle size measurement), mixing, filling (capsules, blister, reservoir)
Song Bingjia's summary: very expensive and not popular, let's ignore them instead,look for some articles to read. Formulation design and quality control of lipid medicine structure, Micelle, liposome, nano-emulsion, lipid nano-particles
Formulation parameters: particle size, drug loading, drug mass ratio, encapsulation efficiency
Pharmacokinetic parameters: half-life, targeted distribution, release profile.
Process: Organic solvent-soluble lipid molecules - "emulsification -" particle size control - "diafiltration -" drug loading- "sterile filtration -" Filling - "Quality Inspection
Song Bingjia's summary: very expensive and not popular, let's ignore them instead, look for some articles to read. Controllable preparation of emulsion - small pilot - medium pilot - small scale pilot for mass production: Scientificalness of formulation design; medium pilot: determination of critical process parameters, establishing quality control system (medium pilot - industrialization bridge); mass production: controllable preparation.
Formulation: medication, oil for injection: 10-30%, lecithin (*) (Quality is very important, concerning manufacturers), glycerol, water for injection and large milk particles have safety problems (> 5 um), integration of science and technology, small pilot, medium pilot and mass production are interlocking; join hands for innovation and win-win cooperation.
Song Bingjia's summary: engineering amplification needs to consider the equipment and experience, a matter of science and engineering. Technology transfer, process amplification and process validation shall explore and analyze three key elements: (1) Technology: R & D, amplification and verification (confirmation and assessment, resolve differences in R&D, verification); (2) Laws and regulations: registration application, the products are approved market available; (3) Project management: Technology transfer team, plans and summary report.
Two levels: (1) the transfer of knowledge and technology; (2) build staff capacity.
One core: (1) R & D, amplification and verification
One procedure: R & D of product and process - [Report on R & D of process (DHR)] - process amplification and technology transfer - [technology transfer report (TTR)] - [process flow document (PFD / MBR)] - process validation - [process validation report (PVR)] - registration application (CTD) - commercial production (APR)
Two products: (1) Medicine (2) Knowledge (technical file)
Product consistency: from clinical production to commercial production? ? ? Identical, same, equivalent?
Product R & D: (1) What is the product quality attributes or functional properties? (User needs); (2) How to measure? (3) How to establish quality standards? (meaningful and relevant)
Medicines: dose-response curve, process capability of clinical batch - consult with regulatory authorities to determine clinically relevant quality standards.
Song Bingjia's summary: Technology transfer is a system. Soft power earns point. What is the most important in the 21st century? Talent. Pharmaceutical formulation design, pharmaceutical degradation chemistry and QbD. Song Bingjia's summary: Scientists like detectives, observing, thinking, practicing, looking for clues and solving the case.