医药FDA培训资料.ppt

Active Pharmaceutical Ingredient A discussion from CGMP perspective April 2006 1 What is an Active Pharmaceutical Ingredient? oThe intended use clause: Any substance or mixture of substances intended to be used in the manufacture of a drug (medicinal) product and that, when used in the production of a drug, becomes an active ingredient of the drug product. 2 What is an Active Pharmaceutical Ingredient? oThe pharmacological activity clause: Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure and function of the body 3 What is an Intermediate? oA material produced during API processing that undergoes further molecular change or purification before it becomes the API oMay or may not be isolated 4 Regulatory Status of APIs in US oDefinition of “drug” in the Federal Food, Drug, and Cosmetic Act encompasses APIs oSection 501(a)(2)(B) of the Act requires that all drugs be manufactured, processed, packed, and held in accordance with current good manufacturing practice oCGMP regulations (21 CFR 210 and 211) apply only to preparation of drug products 5 APIAPI DrugDrug ProductProduct Chemical & Biological Chemical & Biological ProcessingProcessing (synthesis, fermentation, (synthesis, fermentation, extraction, purification)extraction, purification) Physical ProcessingPhysical Processing (granulating, dissolving, (granulating, dissolving, mixing, compressing)mixing, compressing) Different Facilities, Equipment and ProcessesDifferent Facilities, Equipment and Processes Process Characteristics API Vs. Drug Product 6 Characteristics of API Processes oAPIs can be produced by chemical or enzymatic reactions, recombinant DNA, fermentation, recovery from natural materials, or a combination of these processes oUsually involves synthesis, extraction, or crystallization resulting in significant changes to starting materials/intermediates oTypically include purification steps 7 Characteristics of DP Processes oDrug products formulated using bulk raw materials that are usually subjected to quality control by end users oGenerally involves physical processing and manipulations oTypically do not include purification steps 8 ICH Q7A oSince US FDA does not have a regulation specifically addressing GMP requirement regarding API manufacturing oTherefore, ICH Q7A is used as a GMP compliance reference 9 Process water quality Starting materials Blending of intermediates and APIs In process controls Process validation Reprocessing/Reworks Recovery of materials and solvents CGMP Issues in API Processes 10 11 Table 1 Applying Q7A Increasing GMP Expectations 12 Applying Q7A Chemical Manufacturing Production of API Starting Material Introduction of API Starting Material Production of Intermediates Isolation & Purification Physical Processing & Packaging Outside scope Covered by Q7A 13 Applying Q7A Classical Fermentation/ Establishment /Maintenance of Working Cell Banks Introduction of Cells into Fermentation Isolation & Purification Physical Processing & Packaging Outside scope Covered by Q7A 14 Designating Where API Production Begins “The company should designate and document the rationale for the point at which production of the API begins. For synthetic processes, this is known as the point at which “API starting materials” are entered into the process.” 15 Designating Where API Production Begins “From this point on, appropriate GMP, as defined in the guidance, should be applied to these intermediate and/or API manufacturing steps.” CDEFIAPI ABCDE FIAPI 16 Definition: API Starting Materials oMaterial used in production of an API that is incorporated as a significant structural fragment into the structure of the API oMay be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or may be produced in-house oAre normally of defined chemical properties and structure 17 Why Initiate GMP Controls With Use of API Starting Materials? “As a general rule, however, it is reasonable to expect GMP concepts to start to become applicable at that point where a starting material enters a biological or chemical synthesis or series of processing steps, where it is known that the end product will be a BPC.” Reference: Sept. 1991 Guide to Inspection of Bulk Pharmaceutical Chemicals, Page 3 18 Spectrum of CGMP Controls in API Manufacturing Apply GMP controls beginning with the use of API starting materials Controls increase as process proceeds to final isolation and purification steps Degree of control depends on process and manufacturing stage 19 USP Expectations Process Water Quality (1) Drug Products Potable water not acceptable for preparation of USP dosage forms Purified Water generally used for non-sterile dosage production APIs Potable water acceptable for preparation of USP drug substances Purified water often used in later isolation and purification steps 20 Process Water Quality (2) oWater used in the manufacture of APIs should be demonstrated to be suitable for its intended use oUnless otherwise justified, water should at a minimum, meet WHO guidelines for drinking (potable) water (ICH Q7A) oIf tighter chemical and/or microbiological specifications are necessary, these should be established 21 Process Water Quality (3) oWater used in final isolation and purification steps of a non-sterile API intended for producing a sterile drug product should be monitored and controlled for: oTotal microbial counts oObjectionable organisms oEndotoxins 22 Blending of Intermediates/APIs (1) Blend UniformityQuality of material introduced into blend APIsDrug products 23 Blending of Intermediates/APIs (2) oDefined as the process of combining materials within the same specification to produce a homogeneous intermediate or API oDoes not include: nIn process mixing of fractions from single batches nCombining fractions from several batches for further processing 24 Blending of Intermediates/APIs (3) oOOS batches should not be blended with other batches oAcceptable blending operations include: nBlending batches to increase batch size nBlending tailings from batches of the same intermediate/API to form a single batch 25 Blending of Intermediates/APIs (4) oEach batch introduced into a blend should have been: nManufactured using an established process nIndividually tested and found to meet appropriate specifications prior to blending 26 Blending of Intermediates/APIs (5) oBlended batch should be tested for conformance to established specifications, where appropriate oWhere physical attributes of the API are critical, blending operations should be validated to show homogeneity of the combined batch 27 Blending of Intermediates/APIs (6) oShould include testing of critical attributes that may be affected by the blending process, such as: Particle size distribution Bulk density Tap density 28 Blending of Intermediates/APIs(7) oIf blending could adversely affect stability, stability testing of final blended batches should be performed oExpiry or retest date of blended batch should be based on the manufacturing date of the oldest tailings or batch in the blend 29 Critical Operations oCritical weighing, measuring, or subdividing operations should be witnessed or subjected to an equivalent control oOther critical activities should be witnessed or subjected to an equivalent control 30 Process Deviations Any deviation should be documented and explained Critical deviations should be investigated 31 Time Limits (1) oShould be met if specified in the master production instruction oDeviations from time limits should be documented and evaluated 32 Time Limits (2) oMay be inappropriate when processing to a target value where completion of process steps are determined by in- process sampling and testing oIntermediates held for further processing should be stored under appropriate conditions to ensure suitability for use 33 In-Process Sampling & Controls (1) oIn-process controls and acceptance criteria should be defined based on information gained during developmental stage or from historical data oType/extent of testing and acceptance criteria depends on: nNature of intermediate or API nReaction or process step nDegree of variability introduced by process 34 In-Process Sampling & Controls (2) oLess stringent in-process controls may be appropriate in early processing steps oTighter controls may be appropriate for later processing steps Early steps ABCDEFAPIDEFAPI Increasing GMPs 35 In-Process Sampling & Controls (3) oCritical in-process controls should be in writing and approved by the quality unit oQualified production personnel can perform in-process controls and adjust process without prior QC approval if adjustments are made within pre- established limits approved by QC unit 36 In-Process Sampling & Controls (4) OOS Out of specification (OOS) investigations are not normally needed for in-process tests performed for the purpose of monitoring and/or adjusting the process 37 Process Validation Dosage Forms Vs. APIs Validate all manufacturing steps, such as cleaning, weighing, measuring, mixing, blending, filling, packaging and labeling Validate critical processing steps determined to impact the quality and purity of the API Drug Products APIs 38 Definition of Critical “A process step, process condition, test requirement, or any other relevant parameter or item that must be controlled within predetermined criteria to ensure that the API meets its specification.” 39 Validation oShould extend to those operations determined to be critical to the quality and purity of the API oCritical parameters/attributes are normally identified during the development stage or from historical data, along with ranges necessary for reproducible operations 40 Examples of Process Parameters oTemperature oPressure oVacuum oTime (Duration) oFlow Rate oCooling Rate oAgitation Speed 41 Prospective Validation oNormally performed for all API processes oValidation of API process should be completed before commercial distribution of the final drug product manufactured from that API 42 Concurrent Validation oConducted when data from replicate production runs are unavailable: nLimited number of API batches produced nAPI batches produced infrequently nAPI batches produced by a validated process that has been modified 43 Concurrent Validation oBatches can be released and used in production of drug products for commercial distribution based on thorough monitoring and testing of the API batches 44 Retrospective Validation (1) oException for well established processes used without significant changes to API quality due to changes in: nRaw materials nEquipment nSystems nFacilities nProduction process 45 Retrospective Validation (2) oMay be used where: nCritical quality attributes and critical process parameters have been identified nAppropriate in-process acceptance criteria and controls have been established 46 Retrospective Validation (3) oMay be used where (Contd): oProcess/product failures attributed mostly to operator error or sporadic equipment failures unrelated to equipment suitability oImpurity profiles have been established for existing API 47 Retrospective Validation (4) oBatches should be nRepresentative of all batches produced during the review period, including those that failed specifications nSufficient in number to demonstrate process consistency nRetained samples can be tested 48 Periodic Evaluate-Validated Systems oSystems/processes should be periodically evaluated to verify that they are still operating in a valid manner oNo need for revalidation if significant changes have not been made and a quality review confirms system or process consistently produces acceptable material 49 Validation of APIs Used In Clinical Trials (1) oProcess validation normally inappropriate because of nProcess changes during API development nProduction of a single or limited number of API batches 50 Validation of APIs Used In Clinical Trials (2) oProcess validation should be conducted in accordance with Section 12 (ICH Q7A) when batches are produced for commercial use, even when such batches are produced on a pilot or small scale 51 Impurity Profiles (1) oDescribes the identified and unindentified impurities present in an API typical batch produced by a specific controlled production process 52 Impurity Profiles (2) oShould include: nIdentity or some qualitative analytical designation nRange of each impurity observed nClassification of each identified impurity (e.g., inorganic, organic, solvent) 53 Impurity Profiles (3) oImpurity profile should normally be established for each API except those derived from: nHerbal origin nAnimal tissue origin nBiotechnology 54 Impurity Profiles (4) The impurity profile should be compared at appropriate intervals against the impurity profile in the regulatory submission or compared against historical data in order to detect changes to the API resulting from modifications in raw materials, equipment operating parameters, or the production process 55 Reprocessing and Reworking Dosage Forms Vague distinction between activities Reprocessing is atypical Reprocessing rarely improves drug quality APIs Clear distinction between activities Reprocessing is typical Reprocessing generally improves API quality 56 Definition of Reprocessing Introducing an intermediate or API, including one that does not conform to standards or specifications, back into the process and repeating a crystallization step or other appropriate chemical or physical manipulation steps that are part of the established manufacturing process 57 Definition of Reworking Subjecting an intermediate or API that does not conform to standards or specifications to one or more processing steps that are different from the established manufacturing process to obtain acceptable quality material 58 Reprocessing vs. Reworking Reprocessing Intermediates and APIs Conforming or non- conforming batches Subject batch to one or more steps that are part of established process Reworking Intermediates and APIs Only non- conforming batches Subject batch to one or more steps that are different from established process 59 Reprocessing oReprocessing of intermediates and APIs is generally acceptable oIf reprocessing is used for a majority of batches, it should be included as part of the standard manufacturing process oContinuation of a process step after an in-process control test shows it is incomplete is considered part of the normal process, not reprocessing 60 Reworking (1) oReason for non-conformance should be investigated before reworking batches oReworked batches should be subjected to appropriate evaluation, testing, stability testing, if warranted,