SUPAC GUIDELINES

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SUPAC GUIDELINES for Technology Transfer

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SUPAC (scale up and post approval changes) GUIDELINES:

SUPAC (scale up and post approval changes) GUIDELINES SUMIT KUMAR MITTAL (M.PHARM) DEPARTMENT OF QUALITY ASSURANCE ISF COLLEGE OF PHARMACY, MOGA 1

Guidance for Industry:

Guidance for Industry SCALE-UP AND POSTAPPROVAL CHANGES FOR IMMEDIATE RELEASE SOLID ORAL DOSAGE FORMS INCLUDES :- CHEMISTRY, MANUFACTURING, AND CONTROLS. IN VITRO DISSOLUTION TESTING. IN VIVO BIOEQUIVALENCE DOCUMENTATION. 2

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I .THE PURPOSE OF GUIDELINE :- The guidence provide recommendation for the sponsers of New drug application (NDA’s). Abriviated new drug application (ANDA’s). Abriviated antibiotic application (AADA’s) For the manufacturer who intend, during the post approval period, to change:- 1)The components or composition. 2)The site of manufacture. 3)The scale up/scale down of manufacture. 4)The manufacturing(process and equipment) of an immediate release oral formulation. 3

THE GUIDANCE CAME INTO BEING DUE TO THE FOLLOWING EFFORTS:-:

THE GUIDANCE CAME INTO BEING DUE TO THE FOLLOWING EFFORTS:- A workshop on scale-up of immediate release drug products conducted by the American Association of Pharmaceutical Scientists (AAPS) in conjugation with the United States Pharmacopoeial convention and the food and drug Administration(FDA). Research conducted by the University of Maryland at Baltimore on the chemistry ,Manufacturing and the controls of immediate release drug products under the FDA /University of Maryland Manufacturing research contract. The drug categorization research conducted at the University of Michigan and the university of Uppsala on the permeability of drug substances. 4

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SCALE UP AND POST APPROVAL CHANGES (SUPAC) Task Force which was established by the Centre for Drug Evaluation and Research (CDER) Chemistry, Manufacturing and Controls Coordinating Committee. II. 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. 5

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C. Dissolution Testing Case A: Dissolution of Q = 85% in 15 min in 900 ( 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. A surfactant may be used with appropriate justification. 6

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D. Drug Product: E. Drug Substance: 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 J. Operating Principle: Rules or concepts governing the operation of the system. 7

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K. Pilot Scale The manufacture of either drug substance or drug product by a procedure fully representative of and simulating that used for full manufacturing 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, which ever is larger (as reported in the FEDERAL REGISTER of Thursday, September 22, 1994, 59 FR 48754-59). 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. 8

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N. Scale-up The process of increasing the batch size. O. Scale-down The process of decreasing the batch size . P. 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. Q. 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. 9

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III. COMPONENTS AND COMPOSITION This section of 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:- 1. Adding a new excipient or 2. Deleting an excipient are defined at Level 3 (defined below), except as described below. 10

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A. Level 1 Changes Definition of Level 1 changes are those that are unlikely to have any detectable impact on formulation quality and performance. Example: a. Deletion or partial deletion of an ingredient intended to affect the color or flavor of the drug product; or change in the ingredient of the printing ink to another approved ingredient. b. Changes in excipients , expressed as percentage (w/w) of total formulation, less than or equal to the following percent ranges: 11

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EXCIPIENT EXCIPIENT PERCENT (w/w) OUT OF TOTAL TARGET DOSAGE FORM WEIGHT Filler ±5 Disintegrant :- Starch ±3 Other ±1 Binder ±0.5 Lubricant:- Calcium or Magnesium Stearate ±0.25 Other ±1 Glidant :- Talc ±1 Other ±0.1 Film Coat ±1 12

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These percentages are based on the assumption that the drug substance in the product is formulated to 100% of label/potency. The total additive effect of all excipient changes should not be more than 5%. Example: In a product consisting of active ingredient A, lactose, microcrystalline cellulose and magnesium stearate , the lactose and microcrystalline cellulose should not vary by more than an absolute total of 5% (e.g. lactose increases 2.5% and microcrystalline cellulose decreases by 2.5%) relative to the target dosage form weight if it is to stay within the Level 1 range. 13

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1. Test Documentation:- a. Chemistry Documentation:- Application/ compendial release requirements and stability testing. Stability testing: one batch on long-term stability data reported in annual report. b. Dissolution Documentation:- None beyond application/ compendial requirements. c. In Vivo Bioequivalence Documentation:- None. d. Filing Documentation:- Annual report (all information including long-term stability data). 14

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B. Level 2 Changes 1. Definition of Level Level 2 changes are those that could have a significant impact on formulation quality and performance. Tests and filing documentation for a 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. 15

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High solubility drugs are those with a dose/solubility volume of less than or equal to 250 mL. Example: Compound A has as its lowest solubility at 37 + 0.5°C, 1.0 mg/ mL at pH 7, and is available in 100 mg,200 mg and 400 mg strengths. This drug would be considered a low solubility drug as its dose/solubility volume is greater than 250 mL (400 mg/1.0 mg/ mL =400 mL ). Permeability ( Pe , centimeter per second) is defined as the effective human jejunal wall permeability of a drug and includes an apparent resistance to mass transport to the intestinal membrane. High permeability drugs are generally those with an extent of absorption greater than 90% in the absence of documented instability in the gastrointestinal tract, or those whose permeability attributes have been determined experimentally). 16

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Examples of Level 2 Changes : Change in the technical grade of an excipient . Example: Avicel PH102 vs. Avicel PH200.) b. 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 (which represent a two fold increase over Level 1 changes): EXCIPIENT EXCIPIENT PERCENT (w/w) OUT OF TOTAL TARGET DOSAGE FORM WEIGHT Filler ±10 Disintegrant :- ±5 Starch ±6 Other ±2 17

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These percentages are based on the assumption that the drug substance in the drug product is formulated to 100% of label/potency. The total additive effect of all excipient changes should not change by more than 10%. EXCIPIENTS EXCIPIENT PERCENT (w/w) OUT OF TOTAL TARGET DOSAGE FORM WEIGHT Binder ±1 Lubricant:- Ca or Mg Stearate ±0.5 Other ±0.5 Glidant :- Talc ±2 Other ±0.2 Film Coat ±2 18

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2 . Test Documentation:- a. 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. b. Dissolution Documentation:- Case A: High Permeability, High Solubility Drugs Dissolution of 85% in 15 minutes in 900 mL of 0.1N HCl . If a drug product fails to meet this criterion, the applicant should perform the tests described for Case B or C (below). 19

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Case B: Low Permeability, High Solubility Drugs 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. The dissolution profile of the proposed and currently used product formulations should be similar. Case C : High Permeability, Low Solubility Drugs Multi-point dissolution profiles should be performed in water, 0.1 N 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. A surfactant may be used, but only with appropriate justification. The dissolution profile of the proposed and currently used product formulations should be similar. 20

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c. 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. 3. Filing Documentation Prior approval supplement (all information including accelerated stability data); annual report (long-term stability data). 21

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C. Level 3 Changes 1. Definition of Level Level 3 changes are those that are likely to have a significant impact on formulation quality and performance. Tests and filing documentation vary depending on the following three factors: therapeutic range, solubility, and permeability. Examples: a. Any qualitative and quantitative excipient changes to a narrow therapeutic drug beyond the ranges noted in Section III.A.1.b. b. All other drugs not meeting the dissolution criteria under Section III.B.2.b. c. Changes in the excipient ranges of low solubility, low permeability drugs.III.A.1.b. d. Changes in the excipient ranges of all drugs beyond those in Section III.B.1.b. 22

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2. Test Documentation a. 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 reported in supplement; one batch on long-term stability data reported in annual report. 23

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b. Dissolution Documentation Case B dissolution profile as described in Section III.B.2.b. c. In Vivo Bioequivalence Documentation Full bioequivalence study. The bioequivalence study may be waived with an acceptable in vivo/in vitro correlation has been verified. 3. Filing Documentation Prior approval supplement (all information including accelerated stability data); annual report (long-term stability data). 24

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IV. SITE CHANGES Site changes consist: C hanges 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. 25

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Level 1 Changes Definition of Level Level 1 changes consist of site changes within a single facility where 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, except for administrative information and the location of the facility. Common is defined as employees already working on the campus who have suitable experience with the manufacturing process. 26

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2. Test Documentation a. Chemistry Documentation None beyond application/ compendial release requirements. b. Dissolution Documentation None beyond application/ compendial release requirements. c. In Vivo Bioequivalence Documentation None. 3. Filing Documentation Annual report. 27

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B. Level 2 Changes 1. Definition of Level: 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. 2. Test Documentation a. 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. 28

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b. Dissolution Documentation None beyond application/ compendial release requirements. c. In Vivo Bioequivalence Documentation None. 3. Filing Documentation Changes being effected supplement; annual report ( longterm stability test data). 29

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C. Level 3 Changes 1. Definition of Level: 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. To qualify as a Level 3 change, the same equipment, SOP's, environmental conditions, and controls should be used in the manufacturing process at the new site, and no changes may be made to the manufacturing batch records except for administrative information, location and language translation, where needed. 30

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2. Test Documentation a. Chemistry Documentation:- Location of new site and updated batch records.Application / compendial release requirements. b. 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. The dissolution profile of the drug product at the current and proposed site should be similar. 31

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c. In Vivo Bioequivalence Documentation:- None. 3. Filing Documentation:- Changes being effected supplement; annual report (long-term stability data). V. 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. 32

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A. Level 1 Changes Definition of Level: Change in batch size, up to and including a factor of 10 times the size of the pilot/ biobatch , where: 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 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 batches. 33

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2. 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. b. Dissolution Documentation None beyond application/ compendial release requirements. c. In Vivo Bioequivalence None. 3 . Filing Documentation:- Annual report (long-term stability data). 34

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B. Level 2 Changes Definition of Level: Changes in batch size beyond a factor of ten times the size of the pilot/ biobatch , where rest factors remain same as level 1. 2. 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. b. Dissolution Documentation Case B testing. c. In Vivo Bioequivalence None. 3. Filing Documentation Changes being effected supplement; annual report (long-term stability data). 35

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VI. MANUFACTURING Manufacturing changes may affect both equipment used in the manufacturing process and the process itself. Equipment Level 1 Changes a. Definition of Change This category consists of: 1) change from non-automated or non-mechanical 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. 36

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b. Test Documentation i . Chemistry Documentation:- Application/ compendial release requirements. Notification of change and submission of updated batch records. Stability testing: One batch on long-term stability. ii. Dissolution Documentation None beyond application/ compendial release requirements. iii. In Vivo Bioequivalence Documentation None. c. Filing Documentation Annual report (long-term stability data). 37

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2. Level 2 Changes a. Definition of Level:- Change in equipment to a different design and different operating principles. b. Test Documentation i . 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 reported in supplement; up to three batches on long-term stability data reported in annual report . 38

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ii. Dissolution Documentation Case C dissolution profile. iii. In Vivo Bioequivalence Documentation None. c. Filing Documentation Prior approval supplement with justification for change; annual report (long-term stability data). B. Process 1. Level 1 Changes a. Definition of Level This category includes process changes including changes such as mixing times and operating speeds within application/validation ranges. 39

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b. Test Documentation i . Chemistry Documentation: None beyond application/ compendial release requirements. ii. Dissolution Documentation None beyond application/ compendial release requirements. iii. In Vivo Bioequivalence Documentation None. c. Filing Documentation Annual report. 40

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2. Level 2 Changes a. Definition of Level:- This category includes process changes including changes such as mixing times and operating speeds outside of application/validation ranges. b. Test Documentation i . Chemistry Documentation:- Application/ compendial release requirements. Notification of change and submission of updated batch records. Stability testing: One batch on long-term stability. ii. Dissolution Documentation Case B dissolution profile. iii. In Vivo Bioequivalence Documentation None. 41

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c. Filing Documentation Changes being effected supplement; annual report ( longterm stability data). 3. Level 3 Changes a. Definition of Level 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. b. Test Documentation i . Chemistry Documentation Application/ compendial release requirements. Notification of change and submission of updated batch records. 42

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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 reported in supplement; up to three batches on long-term stability data reported in annual report. ii. Dissolution Documentation Case B dissolution. iii. 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 . c. Filing Documentation Prior approval supplement with justification; annual report (long-term stability data). 43

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