Immediate Release Solid Oral SUPAC

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Guidance for Industry on Scale-Up and Post approvalChanges for Immediate Release Solid OralDosage FormsbyP.NADANASABAPATHIJr Research AssociateApex Laboratories P Ltd : 

Guidance for Industry on Scale-Up and Post approvalChanges for Immediate Release Solid OralDosage FormsbyP.NADANASABAPATHIJr Research AssociateApex Laboratories P Ltd

PURPOSE OF GUIDANCE : 

PURPOSE OF GUIDANCE This guidance provides recommendations to sponsors of NDA's, ANDA's, and AADA's who intend, during the post approval period, to changes the components or composition; the site of manufacture scale-up/scale-down of manufacture; and/or manufacturing (process and equipment) of an immediate release oral formulation.

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The guidance defines: levels of change; recommended chemistry, manufacturing, and controls tests for each level of change 3) in vitro dissolution tests and/or in vivo bioequivalence tests for each level of change 4)documentation that should support the change.

DEFINITION OF TERMS : 

DEFINITION OF TERMS A. Batch A specific quantity of a drug or other material produced according to a single manufacturing order during the same cycle of manufacture and intended to have uniform character and quality, within specified limits B. Contiguous Campus Continuous or unbroken site or a set of buildings in adjacent city blocks. C. Dissolution Testing Case A: Dissolution of Q = 85% in 15 minutes in 900 milliliters (mL) of 0.1N hydrochloride (HCl), using the United States Pharmacopeia (USP) <711> Apparatus 1 at 100 revolutions per minute (rpm) or Apparatus 2 at 50 rpm. Case B: Multi-point dissolution profile in the application/compendial medium at 15, 30, 45, 60, and 120 minutes or until an asymptote is reached for the proposed and currently accepted formulation. Case C: Multi-point dissolution profiles performed in water, 0.1N HCl, and USP buffer media at pH 4.5, 6.5, and 7.5 (five separate profiles) for the proposed and currently accepted formulations. Adequate sampling should be performed at 15, 30, 45, 60, and 120 minutes until either 90% of drug from the drug product is dissolved or an asymptote is reached.

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D. Drug Product A drug product is a finished dosage form (e.g., tablet, capsule, or solution) that contains a drug substance, E. Drug Substance An active ingredient that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of a disease. F. Equipment Automated or non-automated, mechanical or non-mechanical equipment used to produce the drug product, including equipment used to package the drug product. G. Formulation A listing of the ingredients and composition of the dosage form. H. Justification Reports containing scientific data and expert professional judgment to substantiate decisions. I. New Drug Substance Any substance that, when used in the manufacture, processing, or packing of a drug, causes that drug to be a new drug, but does not include intermediates used in the synthesis of such substance

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J. Operating Principle Rules or concepts governing the operation of the system. K. Pilot Scale For solid oral dosage forms this is generally taken to be, at a minimum, one-tenth that of full production, or 100,000 tablets or capsules, whichever is larger. L. Process A series of operations and/or actions used to produce a desired result. M. Ranges The extent to which or the limits between which acceptable variation exists. N. Same Agreeing in kind, amount; unchanged in character or condition. O. Scale-up The process of increasing the batch size. P. Scale-down The process of decreasing the batch size. Q. Similar Having a general likeness.

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R. Significant body of information A significant body of information on the stability of the drug product is likely to exist after five years of commercial experience for new molecular entities, or three years of commercial experience for new dosage forms. S. Validation Establishing through documented evidence a high degree of assurance that a specific process will consistently produce a product that meets its predetermined specifications and quality attributes. A validated manufacturing process is one that has been proven to do what it purports or is represented to do. The proof of validation is obtained through collection and evaluation of data, preferably beginning from the process development phase and continuing through the production phase. Validation necessarily includes process qualification (the qualification of materials, equipment, systems, buildings, and personnel), but it also includes the control of the entire processes for repeated batches or runs.

COMPONENTS AND COMPOSITION CHANGES : 

COMPONENTS AND COMPOSITION CHANGES the guidance focuses on changes in excipients in the drug product. Changes in the amount of drug substance are not addressed by this guidance. Changes in components or composition that have the effect of adding a new excipient or deleting an excipient are defined at Level 3

Level 1 Changes - unlikely to have any detectableimpact on formulation quality and performance. : 

Level 1 Changes - unlikely to have any detectableimpact on formulation quality and performance. Deletion or partial deletion of an ingredient which affect the color or flavor of the drug product; or change in the ingredient of the printing ink to another approved ingredient. Changes in excipients, expressed as percentage (w/w) of total formulation, less than or equal to the following percent ranges:

Test Documentation : 

Test Documentation Chemistry Documentation Application/ compendial release equirements and stability testing. Stability testing: one batch on long-term stability data reported in annual report. Dissolution Documentation None beyond application/compendial requirements. In Vivo Bioequivalence Documentation Annual report (all information including long-term stability data).

Level 2 Changes - a significant impact onformulation quality and performance. : 

Level 2 Changes - a significant impact onformulation quality and performance. Level 2 change vary depending on three factors: therapeutic range, solubility, and permeability. Therapeutic range is defined as either narrow or non-narrow. Drug solubility and drug permeability are defined as either low or high. High solubility drugs are those with a dose/solubility volume of less than or equal to 250 mL. Permeability is defined as the effective human jejunal wall permeability of a drug and includes an apparent resistance to mass transport to the intestinal membrane.

Changes : 

Changes Change in the technical grade of an excipient. Changes in excipients, expressed as percent (w/w) of total formulation, greater than those listed above for a Level 1 change but less than or equal to the following percent ranges.

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The total additive effect of all excipient changes should not change by more than 10%.

Test Documentation : 

Test Documentation Chemistry Documentation Application/compendial release requirements and batch records. Stability testing: 1 batch with 3 months accelerated stability data in supplement and 1 batch on long-term stability. Dissolution Documentation Case A: High Permeability, High Solubility Drugs Case B: Low Permeability, High Solubility Drugs Case C: High Permeability, Low Solubility Drugs In Vivo Bioequivalence Documentation None: if the situation does not meet the description in Case A, Case B or Case C, refer to Level 3 changes. Filing Documentation Prior approval supplement (all information including accelerated stability data); annual report (long-term stability data).

Level 3 Changes- likely to have a significantimpact on formulation quality and performance. : 

Level 3 Changes- likely to have a significantimpact on formulation quality and performance. Tests and filing documentation vary depending on the following three factors therapeutic range, solubility, and permeability. Any qualitative and quantitative excipient changes to a narrow therapeutic drug beyond the ranges All other drugs not meeting the dissolution criteria under Case A,B,C. Changes in the excipient ranges of low solubility, low permeability drugs beyond those listed in Table 1. Changes in the excipient ranges of all drugs beyond those listed in Table2.

Test Documentation : 

Test Documentation Chemistry Documentation Application/compendial release requirements and batch records. Significant body of information available: One batch with three months accelerated stability data reported in supplement; one batch on long-term stability data reported in annual report. Significant body of information not available: Up to three batches with three months accelerated stability data. one batch on long-term stability data reported in annual report. Dissolution Documentation Case B dissolution profile. In Vivo Bioequivalence Documentation Full bioequivalence study. The bioequivalence study may be waived with an acceptable in vivo/in vitro correlation has been verified. Filing Documentation Prior approval supplement (all information including accelerated stability data); annual report (long-term stability data).

SITE CHANGES : 

SITE CHANGES Site changes consist of changes in location of the site of manufacture for both company-owned and contract manufacturing facilities and do not include any scale-up changes, changes in manufacturing (including process and/or equipment), or changes in components or composition.. New manufacturing locations should have a satisfactory current Good Manufacturing Practice (CGMP) inspection.

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Level 1 Changes- site changes within a single facility here the same equipment, standard operating procedures (Sop's), environmental conditions (e.g., temperature and humidity) and controls, and personnel common to both manufacturing sites are used, and where no changes are made to the manufacturing batch records,. Test Documentation Chemistry Documentation None beyond application/compendial release requirements. Dissolution Documentation None beyond application/compendial release requirements. In Vivo Bioequivalence Documentation None. Filing Documentation Annual report.

. : 

. Level 2 Changes -consist of site changes within a contiguous campus, or between facilities in adjacent city blocks, where the same equipment, SOP's, environmental conditions (e.g., temperature and humidity) and controls, and personnel common to both manufacturing sites are used, and where no changes are made to the manufacturing batch records, except for administrative information and the location of the facility Test Documentation Chemistry Documentation Location of new site and updated batch records. None beyond application/compendial release requirements. One batch on long-term stability data reported in annual report. Dissolution Documentation None beyond application/compendial release requirements. In Vivo Bioequivalence Documentation None. Filing Documentation Changes being effected supplement; annual report (long term stability test data).

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Level 3 Changes consist of a change in manufacturing site to a different campus. A different campus is defined as one that is not on the same original contiguous site or where the facilities are not in adjacent city blocks. Test Documentation Chemistry Documentation Location of new site and updated batch records. Application/compendial release requirements. Stability: Significant body of data available: One batch with three months accelerated stability; one batch on long-term stability data reported in annual report. Significant body of data not available: Up to three batches with three months accelerated stability data, up to three batches on long- term stability data reported in annual report. Dissolution Documentation Case B: Multi-point dissolution profile should be performed in the application/compendial medium at 15, 30, 45, 60 and 120 minutes or until an asymptote is reached.. In Vivo Bioequivalence Documentation None. Filing Documentation Changes being effected supplement; annual report

CHANGES IN BATCH SIZE (SCALE-UP/SCALE-DOWN) : 

CHANGES IN BATCH SIZE (SCALE-UP/SCALE-DOWN) Postapproval changes in the size of a batch from the pivotal/pilot scale biobatch material to larger or smaller production batches call for submission of additional information in the application. Scale-down below 100,000 dosage units is not covered by this guidance. All scale-up changes should be properly validated and, where needed, inspected by appropriate agency personnel.

Level 1 Changes- in batch size, up to and including a factor of 10 times the size of the pilot/biobatch, : 

Level 1 Changes- in batch size, up to and including a factor of 10 times the size of the pilot/biobatch, the equipment used to produce the test batch(es) is of the same design and operating principles, the batch(es) is (are) manufactured in full compliance with CGMP's, the same standard operating procedures (SOP's) and controls, as well as the same formulation and manufacturing procedures, are used on the test batch(es) and on the full-scale production batch(es)

Test Documentation : 

Test Documentation chemistry Documentation Application/compendial release requirements. Notification of change and submission of updated batch records in annual report. One batch on long-term stability reported in annual report. Dissolution Documentation None beyond application/compendial release requirements. In Vivo Bioequivalence None. Filing Documentation Annual report (long-term stability data).

Level 2 Changes- Changes in batch size beyond a factor of ten times the size of thepilot/bio batch, : 

Level 2 Changes- Changes in batch size beyond a factor of ten times the size of thepilot/bio batch, the equipment used to produce the test batch(es) is of the same design and operating principles, the batch(es) is (are) manufactured in full compliance with CGMP'S, and the same SOP's and controls as well as the sameformulation and manufacturing procedures are used on the testbatch(es) and on the full-scale production batch(es).

Test Documentation : 

Test Documentation Chemistry Documentation Application/compendial release requirements. Notification of change and submission of updated batch records. Stability testing: One batch with three months accelerated stability data and one batch on long-term stability. Dissolution Documentation Case B testing. In Vivo Bioequivalence None. Filing Documentation Changes being effected supplement; annual report (long-term stability data).

MANUFACTURING -changes may affect both equipment used in the manufacturingprocess and the process itself. : 

MANUFACTURING -changes may affect both equipment used in the manufacturingprocess and the process itself. Level 1 Changes consists of: change from non-automated or non-mechanical equipment to automated or mechanical equipment to move ingredients, change to alternative equipment of the same design and operating principles of the same or of a different capacity.

Test Documentation : 

Test Documentation Chemistry Documentation Application/compendial release requirements. Notification of change and submission of updated batch records. Stability testing: One batch on long-term stability. Dissolution Documentation None beyond application/compendial release requirements. In Vivo Bioequivalence Documentation None. Filing Documentation Annual report (long-term stability data).

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Level 2 Changes in equipment to a different design and different operating principles. Test Documentation Chemistry Documentation Application/compendial release requirements. Notification of change and submission of updated batch records. Stability testing: Significant body of data available: One batch with three months accelerated stability data reported in supplement; one batch on long-term stability data reported in annual report. Significant body of data not available: Up to three batches with three months accelerated stability data; up to three batches on long-term stability data reported in annual report. Dissolution Documentation Case C dissolution profile. In Vivo Bioequivalence Documentation None. Filing Documentation Prior approval supplement with justification for change, annual report (long-term stability data).

Process : 

Process Level 1 Changes- includes process changes including changes such as mixing times and operating speeds within application/validation ranges. Test Documentation Chemistry Documentation None beyond application/compendial release requirements. Dissolution Documentation None beyond application/compendial release requirements. In Vivo Bioequivalence Documentation None. Filing Documentation Annual report.

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Level 2 Changes - includes process changes including changes such as mixing times and operating speeds outside of application/validation ranges. Test Documentation Chemistry Documentation Application/compendial release requirements. Notification of change and submission of updated batch records. Stability testing: One batch on long-term stability. Dissolution Documentation Case B dissolution profile. In Vivo Bioequivalence Documentation None. Filing Documentation Changes being effected supplement; annual report (longtermstability data).

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Level 3 Changes - includes change in the type of process used in the manufacture of the product, such as a change from wet granulation to direct compression of dry powder. Test Documentation Chemistry Documentation Application/compendial release requirements. Notification of change and submission of updated batch records. Stability testing: Significant body of data available: One batch with three months accelerated stability data; one batch on long-term stability data reported in annual report. Significant body of data not available: Up to three batches with three months accelerated stability data; up to three batches on long-term stability data reported in annual report. Dissolution Documentation Case B dissolution. In Vivo Bioequivalence Documentation In vivo bioequivalence study. The bioequivalence study may be waived if a suitable in vivo/in vitro correlation has been verified. Filing Documentation Prior approval supplement with justification; annual report (long-term stability data).

IN VITRO DISSOLUTION : 

IN VITRO DISSOLUTION general dissolution specifications. All profiles should be conducted on at least 12 individual dosage units. Dissolution profiles may be compared using the following equation that defines a similarity factor (f2): f2 = 50 LOG {[1+1/n Σn t=1 (Rt-T ) 2] 0.5 x 100} where Rt and Tt are the percent dissolved at each time point. An f2 value between 50 and 100 suggests the two dissolution profiles are similar.

IN VIVO BIOEQUIVALENCE STUDIES : 

IN VIVO BIOEQUIVALENCE STUDIES A general outline of an in vivo bioequivalence study. It is intended as a guide and the design of the actual study may vary depending on the drug and dosage form. Objective: To compare the rate and extent of absorption of the drug product for which the manufacture has been changed, as defined in this guidance, to the drug product manufactured prior to the change. Design: The study design should be a single dose, two-treatment, two-period crossover with adequate washout period between the two phases of the study. Equal numbers of subjects should be randomly assigned to each of the two dosing sequences

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Selection of Subjects: The number of subjects enrolled in the bioequivalence study should be determined statistically to account for the intrasubject variability and to meet the current bioequivalence interval. Procedure: Each subject should receive the following two treatments: Treatment 1: Product manufactured with the proposed change. Treatment 2: Product manufactured prior to the proposed change. Following an overnight fast of at least 10 hours, subjects should receive either Treatments 1 or 2 above with 240 mL water. Food should not be allowed until 4 hours after dosing. Water may be allowed after the first hour. Subjects should be served standardized meals beginning at 4 hours during the study.

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Restrictions: Prior to and during each study phase, water may be allowed ad libitum except for 1 hour before and after drug administration. The subjectshould be served standardized meals and beverages at specified times. No alcohol or xanthine- or caffeine-containing foods and beverages should be consumed for 48 hours prior to each study period and until after the last blood sample is collected. Blood Sampling: Blood samples should be collected in sufficient volume for analysis of parent drug and active metabolite(s), if any. The sampling times should be such that it should be able to capture the Cmax and Tmax during the absorption period. Sampling should be carried out for at least three terminal elimination half-lives for both parent drug and active metabolite(s). Whole blood, plasma or serum, whichever is appropriate for the analytes, should be harvested promptly and samples

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Analytical Method: The assay methodology selected should ensure specificity, accuracy,interday and intraday precision, linearity of standard curves, and adequate sensitivity, recovery, and stability of the samples under the storage and handling conditions associated with the analytical method. Pharmacokinetic Analysis: From the plasma drug concentration-time data, AUC0-t, AUC0-inf, Cmax, Tmax, Kel and t1/2 should be estimated. Statistical Analysis: Analysis of variance appropriate for a crossover design on the pharmaco-kinetic parameters using the general linear models procedures of SAS or an equivalent program should be performed, with examination of period, sequence and treatment effects. The 90% confidence intervals for the estimates of the difference between the test and reference least squares means for the pharmacokinetic parameters (AUC0-t, AUC0-inf, Cmax) should be calculated, using the two one-sided t-test procedure.