CRDMO services for pharmaceutical preparations

Jiangxi Chiyan has a professional preparation technology platform and a professional team with rich experience, dedicated to providing customers with systematic preparation research and development services, to meet the needs of customers in different stages of research and development, and is committed to providing contract research and development CRDMO services in solid preparations, semi-solid preparations, liquid preparations and sterilization preparations. We have extensive research and development experience in controlled release formulations, particulate formulations, protein and peptide pharmaceutical formulations, and have handed over a number of mature products to customers. In addition, we can also apply for FDA/PMDA/EMEA and DCGI registration simultaneously.

Pre-prescription study 

For very small amounts of active pharmaceutical ingredients or candidate compounds with medicinal properties, we can provide professional pre-prescription services and mine valuable information to lead compounds into later stage development. Jiangxi Chiyan's pre-prescription research team has rich experience in the research and development of various compounds, helping customers successfully promote the early screening of compounds.

Preclinical evaluation of candidate compounds solubility 

• Solubility (acid-base solubility curve, simulated fasting intestinal fluid, simulated eating intestinal fluid, simulated artificial gastric fluid solubility, organic solvent solubility, solubility of compounds in different salt forms) 

• Stability (solution stability, solid stability, photostability of drugs by the International Coordination Committee of Technical Specifications for the Registration of Human Drugs) 

• Intrinsic properties (dissociation constant (Pka), oil-water partition coefficient (LogP), apparent partition coefficient (LogD), characteristic dissolution, etc.)

Prescription screening 

• Carrier screening (compatibility of raw materials and excipients, dissolution rate, etc.) 

• pH regulation and co-solvent selection 

• Surfactant solubilization and promote permeation 

• Nano-suspension (nanocrystals, nanoparticles, liposomes) 

• Microemulsion, microspheres 

• Solid dispersion 

• Particle size distribution (wet process, dry process)

• Hygroscopicity 

• Liquidity 

• Microemulsion, microsphere, solid dispersion 

• Solvent residue 

• Research on the compatibility of drug prescription ingredients and drug packaging materials 

• Microscopic observation, melting point, Pka, moisture, optical isomers, related substances, etc.

Crystal type study 

The crystal pattern was determined by X- single crystal diffraction or DSC 

• Study the stability of crystal forms such as melting point, solubility and particle size, investigate the stability of crystal forms under the conditions of influencing factors, and formulate crystal transformation research. 

• Develop API crystals for animal trials, clinical trials or to be marketed.

• Process research of the proposed crystal type (mixing method, standing, stirring crystallization method (natural, cooling, seed) Drying process (moisture standard, crystal water judgment——TG, DSC, single crystal culture, drying method, drying temperature) .

• Preparation process simulation (grinding, wet granulation, tablet pressing, etc.).

• Establish the quality standard of the proposed crystal form (melting point, solubility, particle size; IR, x-ray, DSC, TG).

Pharmaceutical analysis 

Jiangxi Chiyan provides a full range of pharmaceutical analysis services, including method development and method validation, analytical testing and release, stability studies, large-scale separation and CMC filing services. Advanced instruments and equipment, cutting-edge technology and experienced research team are the guarantee of our high quality, high efficiency and low cost service. Not only applicable to China CFDA declaration, but also FDA, EMEA and other global registration declaration.

Method development and method validation: 

• Multiple chromatographic techniques (HPLC, UPLC, GC, and IC) and detection techniques (UV, MS, MS/MS, ELSD, FID, fluorescence, etc.) to cater for different types of compounds 

• Provide analytical testing methods for the content and/or related substances of APIs and pharmaceutical preparations (tablets, capsules/liquid capsules, liquid preparations/emulsions, powders, pills/coated pills, injections, topical drugs, solid dispersants, etc.) for stability studies.

• Other special detection methods, such as dissolution (IR, ER, MR), solvent residues, genotoxic impurities, enantiomer separation, ion chromatography, microbial testing, etc 

• Provide experimental design for method development, process reports, method validation schemes and validation reports, and analytical methods 

• Provide solutions for all phases of IND/CTA or NDA/MAA applications

Analytical testing and release: 

• Provide analytical support for drug formulation development and cleaning validation 

• Provide a CoA or complete standardization report for the calibration of reference substances 

• Provides testing for structural identification and configuration confirmation of compounds 

• Structural identification of impurities or degradation products by LC/MS/MS and various NMR spectroscopy 

• Identify degradation pathways and provide declaration information 

• Provides Leachable/extractable detection

Stability study: 

• Stability of global drug registries; Test/tentative stability (pre-test); Stability of a drug after approval 

• Provide comprehensive services for stability study program design, project management, stability sample storage and testing, data trend analysis, drug shelf life assessment, and NDA/MAA submission dossier preparation 

• Storage conditions: 40°C/75%RH, 30°C/75%RH, 30°C/65%RH, 25°C/60%RH and light, or storage conditions specified by the customer include 2-8 ° C, - 20 ° C to 70 ° C, 25/40, 30/35, 40/20, 50/40 (new) 

• Qualified stability study constant temperature and humidity box (IQ/OQ/PQ certification); Multiple ways of electricity supply; Real-time temperature and humidity monitoring (dual system); Automatic alarm system

CMC Declaration Documents: 

• Dedicated filing writing team with extensive experience and a track record of successful filing both globally and in China 

• The documents provided can be based on the CTD template or in the form of customer requirements to meet the needs of different regions 

• Can further and preclinical toxicology research, clinical research and drug administration services integration to provide a full range of services

Formulation development

According to the characteristics of the dosage form, combined with the physicochemical properties and stability of the drug, considering the production conditions and equipment, we conducted process research, preliminarily determined the preparation process of laboratory samples, and established the corresponding process control indicators. We have equipment and instruments commonly used in process research and quality research of tablets, injections, capsules, granules, plasters, creams, sprays, gels, syrups, tinctures, oral liquid preparations and other preparations, as well as GMP pilot workshops for oral solid preparations. We also have the ability to develop new technologies such as slow-release preparations, nano preparations and fat emulsions.

Innovative drug formulation strategies: 

• Suspensions (micron suspensions & nano-suspensions) 

• Active pharmaceutical ingredient bottling 

• Perform trace filling of active pharmaceutical ingredients 

• Dry mixing and potting 

• Liquid capsule filling technology 

• Spray drying technology 

• Dry/wet granule and capsule filling/tablet pressing 

• Direct tablet pressing 

• Small pouch filling

Generic Drug Development and Strategy: 

• RLD selection, RLD comprehensive analysis 

• Screening of key prescription influencing factors 

• Production process parameter optimization based on QbD 

• Packaging materials and container screening 

• Process scaling and technology transfer 

• Stability inspection 

• Quality standard setting 

• Development of analytical methods

Preparation technical support:

• Air pulverization and grinding technology for micro-pulverization 

• Granulation after nano-suspension or micron suspension 

• Spray drying to prepare solid dispersion 

• Hot melt extrusion technology 

• Liquid capsule filling technology

New preparation technology services: 

• Single- or double-layer slow-release tablet formulation development (using skeleton and coating technology).

• Slow release or delayed release pellets filled capsules (slow-release pellets, particles, and tablets are loaded into hollow capsules to achieve slow release in vivo).

• Microsphere preparation technology (the drug is dissolved or dispersed in the polymer material, and then the solvent evaporation method is used to form a skeleton microsphere with a diameter of 1-25μm, with a slow-release effect). 

• Microcapsule preparation technology (natural or synthetic polymer materials are used to wrap the drug into a drug bank type structure, and the slow release of the drug is achieved by using a carrier with slow-release performance to make the capsule material). 

• Liposome technology (using thin film dispersion method, reverse phase evaporation method, etc., the drug is encapsulated in a vesicle composed of lipid bilayer to form a preparation).

Product Lifecycle Management - Preparation Development Support: 

• Extend the market life cycle by giving new product properties to late-stage new compounds or compounds coming to market 

• Improved security 

• Increase effectiveness or provide new indications 

• Improve patient compliance and ease of use 

• Rapid onset, masking of taste, new drug delivery routes, etc. 

• Controlled or sustained release with reduced the frequency of administration

Extend the market exclusivity period： 

• Preparation innovation to achieve product differentiation and enhance product performance 

• Realize new product extensions 

• Create a potential market for new patent protection

Preparation quality study

The Preparation Quality Research (CMC) experts of Jiangxi Chiyan have nearly 20 years of work experience, are familiar with various ICH and NMPA regulations and guidelines, and have helped many customers successfully complete their pre-preparation and pharmaceutical preparation research, providing reliable data for submission. Among them, we have successfully assisted many clients in completing NMPA applications for Class 1.1, Class 3.1 and Class 6 new drugs.

Method development 

1. Related substances are impurities other than the main component of the drug, which may be raw materials, intermediates, reagents, decomposition, by-products, polymers, isomers, and degradation products produced in different storage, transportation and use processes. Because the content of the relevant substances is small, it is important to choose a specific, sensitive and reproducible detection method.

2. For drugs without standards, based on the nature of the drug, product characteristics, FDA, national pharmacopoeia, literature, etc., to develop and optimize the methods of the relevant substances, so as to meet the requirements of ICH and national pharmacopoeia for the relevant substances. 

3. In the research of existing national standard drugs, the existing national standards cannot be mechanically applied, and the principle of "imitation varieties rather than imitation standards" should be followed, that is, in the research and development of existing national standard drugs, the safety and effectiveness of developed products and listed products should be consistent as the goal, and personalized standards should be formulated for specific varieties.

Preparation analysis method development and validation: 

According to the characteristics of dosage forms and compounds, analytical methods were developed and validated. 

1. Enantiomer method verification 

2. Verification of analytical methods for relevant substances 

3. Verification of content uniformity method 

4. Verification of content determination method 

5. Verification of microbial methods 

6. Study on dissolution determination method 

7. Bacterial endotoxin detection of drugs 

8. Content determination of impurities

9. The content of verification includes: linear range, specificity, accuracy, precision, detection limit, quantitative limit, durability and system adaptability, etc. The specific verification content is subject to the requirements of pharmacopoeia.

Stability study: 

The characteristics of raw materials and preparations changed with time under the influence of temperature, humidity, light and other conditions to provide scientific basis for the production, packaging, storage, transportation conditions and validity period of drugs, so as to ensure the safety and effectiveness of clinical drug use. Stability research is one of the main contents of drug quality control research, which is closely related to drug quality research and the establishment of quality standards. Stability research has a specific stage and runs through the whole process of drug research and development.

1. According to the design stability of different dosage forms of products, different placement conditions are studied 

2. Different investigation items are covered according to different dosage forms 

3. Choose different packaging materials according to different dosage forms 

4. Investigate the time point based on the physicochemical properties and stability trends of drugs 5. Provide stability research program design, project management, stability sample storage and testing, data trend analysis, and drug shelf life evaluation

Stability research contents: 

1. Experimental/tentative stability studies (pre-experiments); Stability study of drug registration; Studies on the stability of approved drugs;

2. Provide comprehensive services of stability research program design, project management, stability sample storage and testing, data trend analysis, drug shelf life evaluation and NDA/MAA application dossier preparation; 

3. Storage conditions: 40°C/75%RH, 30°C/75%RH, 30°C/65%RH, 25°C/60%RH and light, or storage conditions specified by the customer including 2-8°C, -20°C, -70°C, 25/40, 30/35, 40/20, 50/40 (new);

4. Qualified stability research constant temperature and humidity box (IQ/OQ/PQ certification); Multiple ways of electricity supply; Real-time temperature and humidity monitoring (dual system); Automatic alarm system; 

5. Three batches of pilot test (declaration batch) stability test: a batch of a large number of samples to packaging influence factors; Study on the factors affecting the packaging of a batch of enlarged production belts; Accelerated test of three batches of samples; Intermediate condition test of three batches of large quantities of samples; Three batches of large samples for long-term testing.

Microbial detection: 

1. Bacteriostatic test of drugs 

2. Sterility test method for sterilizing preparations 

3. Microbiological limit check of non-sterilizing preparations

Scale-up of preparations in small and pilot trials 

Preparation trial: 

Jiangxi Chiyan can realize oral, injection, external use and various preparations of the pilot test, equipped with the corresponding small test equipment for each dosage form, such as Dongfulong freeze-drying machine, Thermo Fei hot melt extruder, Yamato spray dryer.

Service content: 

According to the concept of quality by design (QbD), after the preliminary determination of QTPP (target product quality attribute) and CQA (key quality attribute), the preliminary Risk Assessment centering on CQA, the targeted prescription process experimental design (DOE) and research for high and medium risks are carried out. Obtain an understanding of critical material attributes (CMA), critical process parameters (CPP) and Control Strategy, tentatively prescribe processes and update risks.

Pilot test equipment, such as rotary sheet press, hopper mixer, etc. are used as far as possible to reduce the amplification failure caused by different principles of equipment (such as the difference in dwell time between a single stamping machine and a rotary sheet press).

To verify the understanding of the prescription process and confirm whether the CQA of the tentative prescription process product is guaranteed by the preparation of a small batch of samples; In the pilot stage, we not only pay attention to the quality of the finished product, but also establish the draft quality standard of the intermediate, and investigate the mixing uniformity, particle mobility, and the possibility of delamination in the process of tablet pressing or filling. At the same time, the influential factors and accelerated tests were carried out for 1 to 3 months with the small sample, in order to expose the stability problems as soon as possible, and provide references for the improvement of the prescription process, the formulation of the draft quality standards, and the stability of the subsequent pilot sample.

Scale-up of preparations: 

For oral solid preparation, after completing the pilot production and preliminary stability study of the preparation, confirming that the prescription process is feasible, the preliminary stability of the sample is good, and the proposed inner packaging material can ensure the preliminary stability of the sample, the relevant documents and materials can be prepared for pilot scale amplification.

Pilot scale file preparation

1. Pilot scheme 

2. Batch production & packaging records 

3. Draft of finished product quality standard 

4. Draft intermediate quality standard

Preparation of pilot materials: 

1. Receipt of raw materials

2. Procurement of accessories and packaging materials

3. Tablet pressing, capsule filling, aluminum mold confirmation or customization

The preparation of documents and materials is scheduled during the small pre-stabilization period to meet the high schedule time requirements of the new drug program. The pilot production process includes: 

1. Raw material pretreatment (mechanical crushing or air crushing, etc.) 

2. Mixing - box mixing or high shear mixing 

3. Granulation - wet granulation, dry granulation and fluidized bed granulation 

4. Drying - fluidized bed drying, oven drying 

5. Whole grain - fast grain equipment 

6. Tablet press - high-speed tablet press 

7. Capsule filling - capsule filling machine can fill particles, powders or pellets at the same time 

8. Coating - Efficient coating machine with digital display of key parameters 

9. Packaging -- aluminum plastic packaging, bottle packaging

The pilot documents are drafted and issued after coming into effect, and implemented under a sound management system; As a transition between pilot batch and clinical batch, the pilot batch is scaled up in accordance with the scale-up risk control strategy of process research and multi-variety experience, and the equipment is basically corresponding to the GMP workshop, which can realize seamless connection with the later GMP batch and ensure the smooth completion of the production of clinical samples. The pilot production samples are mainly used for analysis method verification and stability study.

GMP clinical sample production and packaging 

In order to better meet customers' demand for one-stop service for preparation research and development, Jiangxi Chiyan has cooperated with the establishment of an oral solid preparation workshop in accordance with GMP, which can be used for raw materials crushing, weighing, mixing, granulating, drying, whole grain, tablet pressing, capsule filling, coating and packaging, etc., while improving the level of drug production and quality management system. In this way, we can not only carry out research and development, testing and stability studies of generic drugs for customers, but also carry out research and development, production, packaging, testing and stability studies of innovative drugs in clinical phase I and phase II, and provide CRDMO services.

Service content: 

The main functions include the following aspects, which can be served by unit modules or as a whole 

1. Raw material grinding (micro-pulverization)

2. Weighing - Weighing each precision balance under the hood system 

3. Mixing - box mixing or high shear mixing 

4. Granulation - wet granulation, dry granulation and fluidized bed granulation 

5. Drying - fluidized bed drying, oven drying 

6. Whole grain - fast grain equipment 

7. Tablet press - high-speed tablet press with digital display of key parameters

8. Capsule filling - capsule filling with digital display of key parameters, which can be filled with particles, powders or pellets 

9. Coating - Efficient coating machine with digital display of key parameters 

10. Packaging -- aluminum plastic packaging, bottle packaging

The advantage of this workshop is that it is fully managed in accordance with GMP specifications to ensure stable and reliable product quality, traceable quality profiles, complete functions, flexible production, especially suitable for the preparation of samples for phase I clinical research. 

Jiangxi Chiyan clinical production packaging can provide a choice of product labels required for single blind and double blind clinical trials, and provide different types of clinical production packaging services in accordance with current GMP standards according to customer requirements.

Consistency evaluation of preparation products 

In terms of generic drug quality consistency evaluation, Jiangxi Chiyan has successfully completed a number of quality consistency evaluation cases, has rich experience in generic drug research and development, and can provide you with more professional consistency evaluation services.

The "Generic drug quality consistency evaluation" is mainly for the quality reevaluation of oral solid preparations of generic chemical drugs approved before the promulgation and implementation of the new version of the "Drug Registration Administration Measures" in 2007, mainly including tablets, capsules and granules, etc., and the evaluation mainly examines the consistency of pharmaceutical quality and efficacy. The pharmaceutical quality evaluation mainly investigated whether the domestic generic preparation and the reference preparation were consistent in key quality indexes such as dissolution degree and related substances. If the quality is inconsistent, the company needs to redevelop the product prescription process.

Jiangxi Chiyan generic drug quality consistency evaluation comprehensive service platform can provide the following comprehensive services: 

The quality of the reference preparation was compared with that of generic drugs

 1. Determine the determination conditions of four dissolution curves, determine the dissolution curves of the reference preparation and the imitation preparation, and compare the dissolution curves;

 2.Determine the relevant substances, isomers and other methods, and determine the relevant substances, contents, isomers, etc., of reference preparations and imitation preparations;

 3. Study the crystal form of the raw material used in the reference preparation and the generic preparation;

 4. Stability studies (including influencing factors, acceleration and long-term).

Prescription process secondary development services

1. The quality of the original preparation agent needs to be studied more deeply; 

2. Conduct sufficient research on the properties of the APIs; 

3. Adjust and optimize the prescription and process, and ensure the durability of the prescription process through step-by-step amplification; 

4. Pilot scale up/production technology transfer; 5. Quality research.

Animals BE service

Jiangxi Chiyan has cooperated with GLP-qualified animal laboratories and testing centers, which can conduct animal BE experiments with large animals such as beagle dogs or crab-eating monkeys, providing data support for the optimization of preparations and reducing clinical BE risks

Report templates and SOPs 

1. Meet customer requirements to complete the corresponding analysis terms; 

2. Provide accurate and compliant documents; 

3. Provide high quality raw data such as traceability integrity, in line with NMPA requirements. 

Registration and declaration 

1. Data processing of registration information 

2. Sorting and translating registration materials 

3. Registration and declaration