ANDA培训资料：ANDA研发流程.doc

Generic Drug Product Development Stages(Oral Solid Dosage Forms, Tablets)StageChemistry, Manufacturing & Controlsin Drug Product Development CGMP Complianceto Meet Regulatory Requirements1Drug Packaging Insert Study to obtain basic information on RLD, such as（） Components in the formulation BE information Etc.System based CGMP preparation1)Quality System2)Materials System3)Facilities and Equipment System4)Production System5)Packaging and Labeling System6)Laboratory Control System2Reverse Engineering Study, including evaluation of three different lots of RLD for: Potency/purity Impurity profile (related substances) Content uniformity Weight variation Dissolution profile（12） Disintegration time Hardness and Friability 3Pre-formulation Studiesa) Analytical method developmentb) Acquiring API and impurity reference standards (USP or other sources)c) API characterization（性质描述） and qualification, including chemical and physical properties studies, such as solubility, density, particle size distribution（粒度分布）, polymorphism（多晶现象） (any attributes relevant to the formulation)d) Excipients specifications (acceptance criteria and testing methods to meet USP/NF standards), and excipients characterization and qualification, including compatibility with API.a) Qualification of API and excipients suppliersb) Establish acceptance criteria for API and excipients and corresponding analytical methodsc) Validation or verification of these analytical methodsd) Preparation of pre-formulation study report or summary from CGMP perspective4Formulation Developmenta) Formulation selection (components and composition) based on RLD formulation.b) Define initial process (platform) for preparation of prototype generic drug product (DP), c) Define the specifications for DP, including logo and number artwork preparation on the surface of the drug product.d) Produce one small research and development DP batch and test the product according to finished product specifications, including the evaluation of DP impurity profile and conducting dissolution profile study with comparison with RLD products.e) Place the DP on accelerated stability study (up to 3 months) to evaluate the stability of the formulation developed.f) Analytical method validation or verification, including forced degredation studies on DP to demonstrate that the analytical method used is stability-indicatingg) Container closure selection, including component resin, specification, test methods, suppliers DMF.Properly document study results and preparation of DP formulation development report or summary to support the formulation for further development.5Process Understanding and Optimization (Scale-up)a) Identification of the criticl parameter(s) in each unit operation and impleament in-process control ranges, such as Blend content uniformity (BCU) issue (Is the blending time critical? What is the sampling plan and sampling method to monitor BCU? What is the analytical method and specification for BCU? Etc. LOD in dry process (time, temperature, etc.) Weight variation control in tablet compression b) Several development batches in varies batch size may be produced for research and development purpose. Adequate experimental data should be collected to support any critical parameters identified and in-process control ranges used in scale-up process.c) The final DP specifications should be established.Document justification on critical parameter identification and their in-process control ranges,Preparation of product and process development report or summary to support the critical parameters and their control ranges used for process validation.Validation Master Plan (VMP) for this specified product should be prepared at this stage. It should be served as a “road map” to start qualification and validation works.6Engineering or Demonstration Batch Manufacture*a) Preparation of batch record (BR) for Engineering or demonstration batch manufactureb) Reviewing drafted BR and ensuring the critical parameter(s) are adequately identified and the in-process control ranges are properly implemented.c) A comprehensive sampling plan should be considered to collect more data at this scale.d) The batch size should be at least 100,000 tablets or 10% of proposed commercial batch size. e) It is highly recommended that engineering or demonstration batch be produced by using commercial manufacturing equipment. f) The final DP release tests should meet established specifications. * This engineering or demonstration batch manufacture could be an optional depending upon the research and development study performed and related manufacturing experience a firm has.Following work should be completed before demonstration preparation: Qualification of related Facilities and systems (such as, HVAC, waster system, etc) Qualification ( DQ, IQ, OQ and PQ) of the equipment used in manufacturing of the DP Preparation of equipment cleaning validation protocol Analytical methods validation or verificationThe engineering or demonstration batch manufacture process should follow CGMP requirement, such as: Proper data record on BR The 2nd person as checker QA review and release BR7BE Pilot Study* Using the samples from engineering or demonstration batch 3 5 persons compared with RLD* This is also an optionContract out8Bio-batch or Submission Batch Preparationa) Manufacturing a bio-batch or submission batch under CGMP controls Executed batch record should include yield in each unit operation, final DP units manufactured and packaged, as well as batch reconciliation data and draft label.b) Bio-batch release testing and issue COA Dissolution profile (12 units and 5 time points) compared with RLD batch. Tested according established specificationc) Establish stability protocol Testing time points (0,1,2,3 M for accelerated and 0,2.18.24 for long-term conditions) Intermediate condition if necessary Stability test attributes (Appearance, purity, related substances, dissolution, etc.)d) Perform DP stability study as appropriate (at least 3 months under accelerated condition) for submission purposePreparation of final DP development report (combination of pre-formulation, formulation and process develo