SUPAC-IR,MR,SS

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By: kavinaga (77 month(s) ago)

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-: Prepared by :-Vora vipulDepartment of pharmaceutics,Atmiya Institute of pharmacy,Rajkot. : 

-: Prepared by :-Vora vipulDepartment of pharmaceutics,Atmiya Institute of pharmacy,Rajkot. GUIDELINES FOR SCALE UP AND POST APPROVAL CHANGES 1 SUPAC/M.Pharm sem-II/Vora Vipul

Content : : 

Content : Purposes of the guideline The guideline defines SUPAC-IR: Immediate release solid oral dosage forms SUPAC-MR: Modified Release Solid Oral Dosage Form SUPAC-SS:nonsterile semisolid dosage forms 2 SUPAC/M.Pharm sem-II/Vora Vipul

PURPOSE OF GUIDELINE : 

PURPOSE OF GUIDELINE who intend, during the postapproval period, to change NDA ANDA AADA changes The components or compositions The site of manufacture Manufacturing (Process and equipment) of an immediate release dosage form The scale up/down of manufacturer 3 SUPAC/M.Pharm sem-II/Vora Vipul

The guidance defines : 

The guidance defines 1)Levels of change 2)Recommended chemistry, manufacturing, and controls tests 3)In-vitro and/or in-vivo tests for each level 4)Documentation that should support the change. 4 SUPAC/M.Pharm sem-II/Vora Vipul

The guideline defines : 

The guideline defines 5 SUPAC/M.Pharm sem-II/Vora Vipul

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6 SUPAC-IR: Immediate release solid oral dosage forms Guideline SUPAC-IR Nov. 1995 Post Approval Changes based on Risks SUPAC/M.Pharm sem-II/Vora Vipul

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7 SUPAC - IR United states pharmacopoeial convention University of Maryland University of Uppsala and university of Michigan CDER SUPAC/M.Pharm sem-II/Vora Vipul

Components And Compositions changes : 

Components And Compositions changes 1)Focus on the changes in amount of excipients in the drug product 2)Not focus on change in the amount of the drug substance 8 SUPAC/M.Pharm sem-II/Vora Vipul

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Level 1 Changes Those changes that are unlikely to have any detectable impact on formulation quality and performance. Example Changes in the color, flavors Changes In the excipient express as the percentage (w/w) of total formulation, less than or equal to the following range 9 SUPAC/M.Pharm sem-II/Vora Vipul

Level 1 Changes : 

Test documentation Chemistry documentation Application/compendial release requirements stability testing (One batch long term) Dissolution Documentation None beyond the compendial requirements In vivo bioequivalence documentation None Filling documentation Annual reports (all information including long-tem stability data) Level 1 Changes 10 SUPAC/M.Pharm sem-II/Vora Vipul

Level 2 Changes : 

Changes are those that could have significant impact on the formulation quality and performance Example Changes in the technical grade of excipient (Avicel PH102 vs. Avicel PH200) Changes expressed as percent (w/w of total formulation) Level 2 Changes 11 SUPAC/M.Pharm sem-II/Vora Vipul

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Level 2 Changes Test Documentation Chemistry documentation Level 1 + 1 batch with 3 month accelerated stability study Dissolution documentation Case A – High permeability, High solubility Case B – low permeability, High Solubility Case C – High permeability, Low Solubility Drugs In vivo Bioequivalence documentation None Filing documentation – As level 1 + Accelerated stability study 12 SUPAC/M.Pharm sem-II/Vora Vipul

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Level 3 Changes Level 3 changes are those that are likely to have significant impact on formulation quality and performance Example Any qualitative or quantitative excipient changes to a narrow therapeutic drug beyond the range for level 1 All other drug not meeting the dissolution criteria as level 2 13 SUPAC/M.Pharm sem-II/Vora Vipul

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Level 3 Changes Test documentation Chemistry Documentation – Level 1 + 1 month accelerated stability of 1 batch (SBOIA) or 3 batches (SBOINA) Dissolution documentation – Case B In vivo Bioequivalence – Full bioequivalence study. Except IVIVC verified. Filing documentation – prior approval supplement , annual report. 14 SUPAC/M.Pharm sem-II/Vora Vipul

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Site Changes It includes the changes in location of the site of manufacturing facilities for both company owned and contract manufacturer. It do not include scale up 15 SUPAC/M.Pharm sem-II/Vora Vipul

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Level 1 Site change within a single facility where same equipment, SOP, Environment condition and common personnel Test document Chemistry, dissolution are according to compendial and In vivo BE not required. Filing the annual report 16 SUPAC/M.Pharm sem-II/Vora Vipul

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Level 2 Site change within a contiguous campus, or between facilities in adjacent city blocks. Test documentation – level 1 + one batch long term stability in chemistry documentation Filing documentation – annual report 17 SUPAC/M.Pharm sem-II/Vora Vipul

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Level 3 Site change to a different campus Test documentation Chemistry documentation One batch for accelerated stability (3 Months) + One batch for long term stability for SBOIA Or 3 batches for accelerate and long term stability (SBOINA) Dissolution testing – Case B No BE required Filing documentation – annual reports 18 SUPAC/M.Pharm sem-II/Vora Vipul

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Change in the batch size Post approval changes in the size of a batch from the pivotal/pilot scale biobatch material to larger or smaller production . Scale down below 1,00,000 dosage units is not covered by this guideline. Scale up changes should be properly validated and if needed, inspected by appropriate agency personnel. 19 SUPAC/M.Pharm sem-II/Vora Vipul

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Level 1 Changes in the batch size up to and including factor of 10 times the size of the pilot / biobatch where The equipment is of same design and principle Both manufacturer. According to the CGMP compliance. Same SOP’s followed Test and filing documents are same as of the level 2 of the site changes requirement. 20 SUPAC/M.Pharm sem-II/Vora Vipul

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Level 2 Change Changes in the batch size beyond the factor of 10 Test documentation As per level 1 + one batch with three months accelerated stability + Case B dissolution testing. 21 SUPAC/M.Pharm sem-II/Vora Vipul

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Manufacturing Changes A. Equipment Level 1 change This consist of Change from non-automated to automated or vice versa to move ingredients Change to alternative equipment of same design and the operating principle of the same or different capacity Test and filing documentation – as per level 1 of batch size change 22 SUPAC/M.Pharm sem-II/Vora Vipul

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Level 2 Change Change in equipment to a different design Test and filing documentation As per level 3 of the site change except Case C dissolution instead of Case B. 23 SUPAC/M.Pharm sem-II/Vora Vipul

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Manufacturing Changes B. Process changes Level 1 change This changes includes process changes like mixing times and operating speed within application/validation range Test and filing document as per level 1 of site change 24 SUPAC/M.Pharm sem-II/Vora Vipul

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Level 2 Change This changes includes process changes like mixing times and operating speed outside the application/validation range Test and filing documentation – as per the level 2 changes in site changes 25 SUPAC/M.Pharm sem-II/Vora Vipul

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Level 3 Change Change in the type of the process used in the manufacture of the product, such as a change in from the wet granulation to the direct compression of dry powder. Documentation – As per the level 3 changes of components and composition changes. 26 SUPAC/M.Pharm sem-II/Vora Vipul

Slide 27: 

SUPAC-MR Modified Release Solid Oral Dosage Forms 27 SUPAC/M.Pharm sem-II/Vora Vipul

List of Content : 

List of Content General stability consideration Components and Composition-Nonrelease controlling excipient Components and Composition-Release controlling excipient Site changes Changes in batch size (Scale-up/Scale-down) Manufacturing equipment changes Manufacturing process changes 28 SUPAC/M.Pharm sem-II/Vora Vipul

General stability considerations: : 

General stability considerations: Applicant required to refer FDA guideline for submitting documentation of stability of human drug and biologics. Stability data from pilot scale batches will be acceptable to support the proposed change. Submission of historical accelerated and available long-term data would facilitate review and approval of the supplement. 29 SUPAC/M.Pharm sem-II/Vora Vipul

Components and composition-Nonrelease controlling excipient: : 

Components and composition-Nonrelease controlling excipient: Focuses on changes to nonrelease controlling excipients. Changes in components or composition that have the effect of adding a new excipient or deleting an excipient are defined at level 3. 30 SUPAC/M.Pharm sem-II/Vora Vipul

Slide 31: 

Definition: “Changes are unlikely to have any detectable impact on formulation quality and performance.” Examples: Deletion or partial deletion of ingredients intended to affect the color or flavor of the drug product or change in printing ink to another approved ingredient. Changes in non release controlling excipients ,expressed as percentage (W/W) of total formulation, less than or equal to the following changes. Level 1 Changes 31 SUPAC/M.Pharm sem-II/Vora Vipul

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32 SUPAC/M.Pharm sem-II/Vora Vipul

Slide 33: 

These percentage are based on the assumption that the drug substance in the product is formulated to 100% of label /potency. The total effect of non release controlling excipient changes should not be more than 5%. The total weight of the dosage form should still be within the original approved application range. 33 SUPAC/M.Pharm sem-II/Vora Vipul

Slide 34: 

Test documentation Chemistry documentation:-Application/compendial product release requirement Stability: First production batch-Long term stability data Dissolution documentation: None Bioequivalence documentation: None Filing documentation Annual report- all information including long term stability data. 34 SUPAC/M.Pharm sem-II/Vora Vipul

Slide 35: 

Level 2 change: 1) Defination “Level 2 changes are those that could have a significant impact on formulation quality and performance”. Example: A change in the technical grade and/or specifications of a non release controlling excipients. Changes in non release controlling excipient expressed as percentage (w/w) of total formulation. (two folded increase over level 1 changes). 35 SUPAC/M.Pharm sem-II/Vora Vipul

Slide 36: 

2) Test documentation Chemistry documentation Application/compendial product release requirements and updated executed batch records. Stability: One batch with three month accelerated stability data reported in prior approval supplement and long term stability data of first production batch reported in annual report. Dissolution documentation Extended release Multipoint dissolution profile in 0.1N HCl and USP buffer media at pH 4.5 and 6.8 for the changed drug product and the bio batch or marketed batch (unchanged drug product). 36 SUPAC/M.Pharm sem-II/Vora Vipul

Slide 37: 

Adequate sampling at 1, 2 and 4 hours and every two hours there after until either 80% of the drug from the drug product is released or an asymptote is reached. Surfactant may be used with appropriate justification. Delayed release: D.T. performed in 0.1N HCl for 2 hours (acid stage) followed by USP buffer media with range of pH 4.5-7.5 (buffer stage) under standard test condition and two additional agitation speed. Apparatus-1: 50,100 and 150 rpm. Apparatus-2: 50,75 and 100 rpm. Adequate sampling at 15,30,45,60 and 120 min until 80% of the drug releases from drug product or an asymptote is reached. 37 SUPAC/M.Pharm sem-II/Vora Vipul

Slide 38: 

c) Bioequivalence documentation: None Filing documentation Prior approval supplement (accelerated stability data) annual report (long term stability data). 38 SUPAC/M.Pharm sem-II/Vora Vipul

Slide 39: 

Level 3 change Definition “Level 3 changes are those that are likely to have a significant impact on quality and performance.” Example: Changes are as level 2 changes example (b). The total weight of the dosage form may be within or outside the approved original application range. 39 SUPAC/M.Pharm sem-II/Vora Vipul

Slide 40: 

Test documentation: Chemistry documentation: Application/ compendial product release requirements and updated executed batch records. Stability: Significant body of information available: One batch with three months accelerated stability data reported in prior approval supplement and long term stability data of first three production batches reported in annual report. 40 SUPAC/M.Pharm sem-II/Vora Vipul

Slide 41: 

Significant body of information not available: Three batches with three months accelerated stability data reported in prior approval supplement and long term stability data of first three production batches reported in annual report. Dissolution documentation: Extended release: Same as level 2 changes. Delayed release: Same as level 2 changes. 41 SUPAC/M.Pharm sem-II/Vora Vipul

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Bioequivalence documentation: A single dose bioequivalence study. The bioequivalence study may be waived in presence of an established in vitro/in vivo correlation. Filing documentation: Same as level 2 changes. 42 SUPAC/M.Pharm sem-II/Vora Vipul

Components and composition-Release Controlling Excipients : 

Definition The sponsor should provide appropriate justifications (i.e. mechanism of drug release and manufacturing process) for claiming any excipient as a release controlling excipient in the formulation of the modified release solid oral dosage form. Level 1 changes: Same as non release controlling excipient. Components and composition-Release Controlling Excipients 43 SUPAC/M.Pharm sem-II/Vora Vipul

Slide 44: 

Level 2 changes: Same as non release controlling excipient. Test documentation for a level 2 changes would vary depending on whether the product could be considered to have a narrow therapeutic range. 2. Test documentation: Chemistry documentation: same as non release controlling excipient. Stability: Non narrow therapeutic range drugs: One batch with three months accelerated stability data reported in prior approval supplement and long term stability data of first production batch reported in annual report. 44 SUPAC/M.Pharm sem-II/Vora Vipul

Slide 45: 

Narrow therapeutic range drugs: Three batches with three months accelerated stability data reported in prior approval supplement and long term stability data of first three production batches reported in annual report. Dissolution documentation: Same as non release controlling excipient for both non narrow and narrow therapeutic range drugs. c. Bioequivalence documentation Non narrow therapeutic range: None Narrow therapeutic range drugs: Same as non release controlling excipient. 45 SUPAC/M.Pharm sem-II/Vora Vipul

Slide 46: 

Filing documentation: Prior approval supplement (accelerated stability data) Annual report (long term stability data). Level 3 changes Affecting all the therapeutic ranges. Same as non release controlling excipient. 46 SUPAC/M.Pharm sem-II/Vora Vipul

Site Changes : 

Site Changes It consist of changes in location of the site of manufacture, packaging operations, and/or analytical testing laboratory for both company owned and contract manufacturing facilities. They 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 had a satisfactory cGMP inspection. A stand alone packaging operations site change and laboratory changes, may be submitted as a Changes Being Effected Supplement 47 SUPAC/M.Pharm sem-II/Vora Vipul

Slide 48: 

Level 1 changes: Definition “It consist of site changes within a single facility where the same equipment, standard operating procedures (SOPs), environmental conditions (e.g., temperature and humidity) and controls, and personnel common to both manufacturing sites are used Test documentation and filing documentation are same as non release controlling excipient. 48 SUPAC/M.Pharm sem-II/Vora Vipul

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Level 2 changes: Definition “It consist of site changes within a contiguous campus, or between facilities in adjacent city blocks.” Test documentation Chemistry documentation Notification of location of new site and updated executed batch records. None beyond application/compendial product release requirements. 49 SUPAC/M.Pharm sem-II/Vora Vipul

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Stability: One batch with three months accelerated stability data reported in Changes Being Effected supplement and long-term stability data of first production batch reported in annual report. Dissolution documentation and Bioequivalence documentation Same as non release controlling excipient. 3. Filing documentation: Changes being effected supplement (accelerated stability data) Annual report ( long term stability data) 50 SUPAC/M.Pharm sem-II/Vora Vipul

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Level 3 changes: Definition It consist of a change in manufacturing site to a different campus. 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. 51 SUPAC/M.Pharm sem-II/Vora Vipul

Slide 52: 

Test documentation Chemistry documentation Notification of location of new site and updated executed batch records. Application/compendial product release requirements. Stability: Same as non release controlling excipient. Dissolution documentation, bioequivalence documentation and filing documentation also same 52 SUPAC/M.Pharm sem-II/Vora Vipul

Changes In Batch Size (Scale up/Scale down) : 

Post approval 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 to 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. Changes In Batch Size (Scale up/Scale down) 53 SUPAC/M.Pharm sem-II/Vora Vipul

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Level 1 changes Definition Change in batch size, up to and including a factor of ten times the size of the pilot/biobatch Test documentation Chemistry documentation Application/compendial product release requirements. Notification of change and submission of updated executed batch records in annual report. Other documentation remains same as non release controlling excipient. 54 SUPAC/M.Pharm sem-II/Vora Vipul

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Level 2 changes Definition Changes in batch size beyond a factor of ten times the size of the pilot/biobatch. Test documentation Notification of change and submission of updated batch records. Other documentation remains same as non release controlling excipient. 55 SUPAC/M.Pharm sem-II/Vora Vipul

Manufacturing equipment changes : 

Manufacturing equipment changes Manufacturing changes may involve the equipment used in the manufacturing process (critical manufacturing variable). If manufacturer wishes to use manufacturing equipment that is not identical in every respect to the original manufacturing equipment used in the approved application, appropriate validation studies should be conducted to demonstrate that the new equipment is similar to the original equipment. 56 SUPAC/M.Pharm sem-II/Vora Vipul

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Level 1 change Definition It consists of (1) change from nonautomated or nonmechanical equipment to automated or mechanical equipment to move ingredients and (2) change to alternative equipment of the same design and operating principles of the same or of a different capacity. Test documentation and filing documentation remains same as non release controlling excipient. 57 SUPAC/M.Pharm sem-II/Vora Vipul

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Level 2 change Definition Change in equipment to a different design and different operating principles. Test documentation and filing documentation remains same as non release controlling excipient. 58 SUPAC/M.Pharm sem-II/Vora Vipul

Manufacturing process changes : 

Manufacturing process changes Changes involve the manufacturing process itself. Validation studies should be conducted in case of process changes. For purposes of categorizing the level of changes, process change may be considered only to affect a release controlling excipient when both types of excipients (i.e., nonrelease and release controlling) are present during the unit operation undergoing a change. 59 SUPAC/M.Pharm sem-II/Vora Vipul

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Level 1 change Definition Process changes involving adjustment of equipment operating conditions such as mixing times and operating speeds within original approved application ranges affecting the non release controlling and/or release controlling excipient. 60 SUPAC/M.Pharm sem-II/Vora Vipul

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Test documentation Chemistry documentation None beyond application/compendial product release requirements. Notification of the change and submission of the updated executed batch records. Other documentation remains same as non release controlling excipient. 61 SUPAC/M.Pharm sem-II/Vora Vipul

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Level 2 change Definition This category includes process changes involving adjustments of equipment operating conditions such as mixing times and operating speeds outside of original approved application ranges. Other documentation remains same as non release controlling excipient. 62 SUPAC/M.Pharm sem-II/Vora Vipul

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Level 3 change This category 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. Other documentation remains same as non release controlling excipient. 63 SUPAC/M.Pharm sem-II/Vora Vipul

Slide 64: 

SUPAC-SS:Nonsterile semisolid dosage forms 64 SUPAC/M.Pharm sem-II/Vora Vipul

SUPAC – SS : 

SUPAC – SS Components and composition Change in excipients preservatives manufacturing Equipment process Batch size Manufacturing site In vitro release test In vivo bioequivalence studies 65 SUPAC/M.Pharm sem-II/Vora Vipul

Components and composition : 

Components and composition 66 SUPAC/M.Pharm sem-II/Vora Vipul

Components and composition : 

Components and composition 67 SUPAC/M.Pharm sem-II/Vora Vipul

Components and composition : 

Components and composition 68 SUPAC/M.Pharm sem-II/Vora Vipul

Components and compositionPreservative : 

Components and compositionPreservative 69 SUPAC/M.Pharm sem-II/Vora Vipul

Components and compositionPreservative : 

Components and compositionPreservative 70 SUPAC/M.Pharm sem-II/Vora Vipul

Components and compositionPreservative : 

Components and compositionPreservative 71 SUPAC/M.Pharm sem-II/Vora Vipul

Manufacturing equipment : 

Manufacturing equipment 72 SUPAC/M.Pharm sem-II/Vora Vipul

Manufacturing equipment : 

Manufacturing equipment 73 SUPAC/M.Pharm sem-II/Vora Vipul

Manufacturing Process : 

Manufacturing Process 74 SUPAC/M.Pharm sem-II/Vora Vipul

Manufacturing process : 

Manufacturing process 75 SUPAC/M.Pharm sem-II/Vora Vipul

Batch size : 

Batch size 76 SUPAC/M.Pharm sem-II/Vora Vipul

Batch size : 

Batch size 77 SUPAC/M.Pharm sem-II/Vora Vipul

Manufacturing site change : 

Manufacturing site change 78 SUPAC/M.Pharm sem-II/Vora Vipul

Manufacturing site change : 

Manufacturing site change 79 SUPAC/M.Pharm sem-II/Vora Vipul

In vitro release testing : 

In vitro release testing In vitro surrogate tests are often used to assure that product quality and performance are maintained over time and in the presence of change. In vitro release testing are used to assure consistent delivery of the active component(s) from semisolid products. 80 SUPAC/M.Pharm sem-II/Vora Vipul

In vitro release testing : 

In vitro release testing Use of open chamber diffusion cell system – Franz cell system. Use of synthetic membrane – polysulfone, cellulose acetate/nitrate mixed ester, polytetrafluoroethylene Receptor medium – aqueous buffer for water soluble drugs and hydro-alcoholic medium for sparingly soluble drugs Number of samples – six are recommended 81 SUPAC/M.Pharm sem-II/Vora Vipul

In vitro release testing : 

In vitro release testing Sample applications – to prevent solvent evaporation and compositional changes. Sampling time – at least 5 times over an appropriate time period Sample analysis – specific and sensitive analytical procedure is required. In vitro release rate : A plot of the amount of drug released per unit membrane area (mcg/cm ) versus square root of time yield a straight line. The slope of the line (regression) represents the release rate of the product. 82 SUPAC/M.Pharm sem-II/Vora Vipul

In vivo Bioequivalence studies : 

In vivo Bioequivalence studies Design is dependent on the pharmacological activity of the drug and dosage form, nature of the active drug. The bioequivalence study can be a comparative skin blanching study or a comparative clinical trial or any other appropriate validated bioequivalence study. 83 SUPAC/M.Pharm sem-II/Vora Vipul

QUESTIONS: : 

QUESTIONS: What are SUPAC guidelines for IR, MR and non sterile SS? (Gujarat university 2005, 2007) 84 SUPAC/M.Pharm sem-II/Vora Vipul

REFERENCE : : 

REFERENCE : http://www.fda.gov 85 SUPAC/M.Pharm sem-II/Vora Vipul

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87 SUPAC/M.Pharm sem-II/Vora Vipul

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