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Stages Of Development Of Generic Drugs
Oral Solid Preparations, Tablets
1. Chemical Properties, Production And Control In The Development Of Oral Solid Preparations
Through the analysis of the components within the packaging material of the control drug, the basic information about the control drug is obtained
(1) Prescription ingredients
(2) Bioequivalence information
(3) Miscellaneous
2. Chemical Properties, Production And Control In The Development Of Oral Solid Preparations
The formulation process was studied backwards based on the aforementioned studies, including the evaluation of three batches of different batches of control drugs
(1) Potency / Purity
(2) Impurity distribution curve (related substances).
(3) Content uniformity
(4) Weight difference
(5) Dissolution curve
(6) Disintegration time
(7) Hardness and brittleness
CGMP Specifications That Meet Regulatory Requirements
Conduct a system-based CGMP audit of production facilities
(1) Quality system
(2) Material system
(3) Facilities and equipment systems
(4) Production system
(5) Packaging and labeling systems
(6) Laboratory control system
3. Chemical Properties, Production And Control In The Development Of Oral Solid Preparations
Pre-Prescription Research
(1) Develop appropriate analytical methods for APIs
(2) Impurity reference standards (United States Pharmacopeia or other sources).
(3) Characteristics and certification of APIs, including physicochemical characteristics studies, such as: dissolution, density, particle size distribution, polymorphism (any properties related to prescription).
(4) Technical specifications for excipients (acceptable standards and test methods in accordance with USP and NF standards) Excipient characteristic certification, including compatibility studies with APIs
CGMP Specifications That Meet Regulatory Requirements
(1) Qualification of SUPPLIERS of APIs and excipients, including audits and comprehensive testing of three different batches.
(2) Establishment of acceptable API and excipient standards and corresponding analytical methods.
(3) Verification and validation of these analytical methods.
(4) From the perspective of the current GMP, Prepare a pre-prescription research report or summary summary.
4. Chemical Characteristics, Production And Control In The Development Of Oral Solid Preparations
Prescription Development
(1) Prescription screening (composition) is based on control drug formulations and indoor studies).
(2) Describe the initial process (platform) for the preparation of prototype products (DP) of generic drugs.
(3) Elaborate on the initial specifications of the drug, including the identification, digital or graphic arrangement on the surface of the drug.
(4) Produce a small batch of drugs that have been researched and developed, and test them according to the manufactured product specifications, which includes the assessment of the impurity distribution of the drug, and the comparison with the control drug, and the dissolution curve study.
(5) Accelerate stability experiments (up to 3 months) on the drug to assess the stability of the developed formula.
(6) Verification and validation of analytical methods, including through forced degradation studies of pharmaceutical products, to show that the analytical methods used can indicate stability.
(7) Selection of container sealing system (CCS), including resin composition, specification, test method, dmf number of supplier, etc.
CGMP Specifications That Meet Regulatory Requirements
(1) Properly record the results of the study and write a report or summary of the development and preparation of pharmaceutical preparations in order to support further development of the formulation.
(2) Prepare the correct analytical method validation protocol and final report.
(3) Supplier qualification certification, including the test of the first three batches of the container sealing system.
Note: The application of CCS i.e. packaging containers and seal management systems during FDA approvals is highly recommended.
5. Chemical Properties, Production And Control In The Development Of Oral Solid Preparations
Process Understanding, Characterization And Optimization ( Amplification).
(1) Check the key parameters of each unit operation and implement the scope of process control, for example
(2) Questions about the uniformity of the mixed content (is the mixing time critical?). What is the sampling plan and sampling method that oversees the uniformity of the mixed content? What are the analytical methods and acceptable criteria for the uniformity of mixed content? and so on).
(3) The minimum detection limit (time, temperature, etc.) of the dry process
(4) Weight difference control of tablet pressing
(5) etc.
(6) It can produce some products of different output scales for research and development. To support any identified critical parameters and in-line control ranges, sufficient experimental data need to be collected. Technical specifications for pharmaceutical products need to be established.
CGMP Specifications That Meet Regulatory Requirements
1) Confirmation documents for determining the key parameters and their online control range.
2）Prepare product and process development reports or summaries to support the determination of key parameters and the scope of control in production at pilot and commercial production scales.
6. Chemical Properties, Production And Control In The Development Of Oral Solid Preparations
(1) Production of project batch or verification batch
(2) Batch record preparation for engineering or verification batch production
(3) Review the drafting of the batch records and ensure that the validated key parameters and their online control scope are correctly implemented.
(4) At this scale, a comprehensive sampling plan needs to be considered to collect more data.
(5) Tablets that must be mass-produced are at least 100,000 tablets or 10 percent of the commercially available batch.
(5) It is strongly recommended to use commercial-scale production equipment that will be used in the future to produce engineering or verification batch products.
(6) The final drug distribution test needs to comply with established technical specifications.
The production of engineering or validation batches is optional and can be based on the research and development carried out
Research and relevant production experience of the company to decide.
CGMP Specifications That Meet Regulatory Requirements
(1) The validation master plan for a specific product must be prepared at this stage. It will be used as a roadmap to begin product-related certification and validation work.
(2) The following work must be completed according to the verification master plan before the certification batch or the pilot batch production.
(3) Related equipment and systems (e.g. air conditioning system, water system verification).
(4) Verification of equipment required in production (design confirmation, installation confirmation , operation confirmation and performance confirmation).
(5) Preparation of equipment cleaning verification scheme (4) Verification of analytical methods.
7. Chemical Properties, Production And Control In The Development Of Oral Solid Preparations
1) Pilot-scale studies of bioequivalence to obtain bioequivalence information on products used internally.
(1) Samples using engineering or validation batches
(2) Comparison of bioequivalence data for 3 to 5 people with data on controls
This is also optional.
8. Chemical Properties, Production And Control In The Development Of Oral Solid Preparations
Preparation Of Biological Batches Or Declaration Batches
1) Produce biological batches or declaration batches in accordance with CGMP specifications
The batch record performed should include information such as the benefits of each unit operation , the production and packaging of the final drug unit, the batch process data and the draft label
2) Issuance and testing of biological batches and issuance of finished product factory certificates
(1) Dissolution curve compared with control drugs (12 units and 5 treatment points).
(2) Testing is carried out according to established specifications
Establish A Stability Scenario
(1) Test time point (0, 1, 2, March for accelerated test 0, 3.6.9.12.18.24 for stability test under long-term conditions).
(2) If necessary, intermediate condition tests are also required.
(3) Stability test properties (appearance, purity, related substances, dissolution, etc.).
In order to achieve the purpose of submission, a suitable drug stability test (at least 3 months under accelerated conditions) needs to be performed
CGMP Specifications That Meet Regulatory Requirements
Preparation of the final drug development report (or synthesis of pre-prescription studies, prescription studies, and process development summaries.
Note: The report is a fundamental component of the drug development and quality overview sections of the ANDA declaration.
9. Chemical properties, production and control in the development of oral solid preparations
Bioequivalence Studies
(1) The use of biological or declared samples is compared with the control drug
(2) 24 to 36 patients, cross-over studies
CGMP Specifications That Meet Regulatory Requirements
Bioequivalence studies must be conducted in clinical laboratories, which is consistent with the GLP requirements of FDA.
10. Chemical Properties, Production And Control In The Development Of Oral Solid Preparations
Preparation of ANDA Application Submission Documents: Preparation of ANDA applications in CTD format.
Preparations For Pre-Approval Inspections
CGMP Specifications That Meet Regulatory Requirements
1) Complete the preparation of the pre-approval inspection from the perspective of the CGMP specification through the evaluation of the GMP system on site.
2) Preparation of the process verification program, starting or completing the process verification by producing three consecutive batches of verification batches according to the commercial production scale, and preparing the verification report.
Note: Process validation is not required prior to ANDA approval. However, the validation plan must have been completed at the time of pre-approval inspection.