SUPAC Guideline Purpose
SUPAC Guideline, This guideline provide recommendation mainly to those sponsors of 1.0 New Drug Applications (NDA’s), 2.0 Abbreviated New Drug Applications (ANDA’S), And 3.0 Abbreviated Antibiotic Applications (AADA’s) who want to change during the post approval period
1.0 The components or composition;
2.0 The site of manufacture of an immediate release oral formulation.
3.0 Scale-up/scale-down of manufacture; and/or(Batch Size Change)
4.0 Manufacturing (Process and Equipment)
This guidance (SUPAC Guideline) has been deprived or resulted from the workshop on scale-up of immediate release drug products directed by AAPS(American Association of Pharmaceutical Scientists) in conjunction with the USPC (United States Pharmacopoeial Convention) and FDA (Drug Administration).
SUPAC Guideline mainly focused on
[][]Levels of change,
[][]Each level of change for recommended chemistry, manufacturing, and controls tests
[][]In vivo bioequivalence tests/or in vitro dissolution tests,
[][]Documentation that should support the changes.
SUPAC Guideline doesn’t comment if compliance/inspection documentation doesn’t affected. Except as specified in this guideline, no post approval changes are affected. These guidelines do not comment on or affect compliance/verification documents issued by the CDER Compliance Office or the FDA Regulatory Authority.
Some useful definitions for SUPAC Guideline
Batch
A certain amount of drug or other ingredient is produced according to a of production order and during the same production cycle, it is intended to maintain consistent character & quality within certain limits.
Dissolution Testing
[][]Case A:
Dissolve Q = 85% in 900 mL (mL) for 15 minutes use of 0.1N Hydrochloride (HCl), USA Pharmacopoeia (USP) <711> Apparatus 1 at 100 rpm or Apparatus 2 at 50 rpm.
[][]Case B:
The multipoint dissolution profile in the application/summary interval is 15, 30, 45, 60, 120 minutes or until the asymptote is reached for the proposed and now accepted formula.
[][]Case C:
Water, 0.1N HCl, And pH 4.5, 6.5 and 7.5 USP buffers (5 separate Profile) Proposed and currently accepted pharmaceutical formulation where Multi-point dissolution profiles performed. Proper sampling should be done in the following locations: Up to 90% of the drug 15, 30, 45, 60 and 120 minutes Resolved from medicines or asymptote Reached. Surfactants can be used with suitable agents Justification.
Validation
Establishing a high level of security with documented evidence Producing a product that consistently meets that requirement for a particular process Given specifications and quality features. Verified the manufacturing process is a process that has been proven to carry out what it claims to be or is represented as. Proof of verification is obtained by If possible, process-based data collection and evaluation from the development phase to the production phase. Verification inevitably involves process certification ( Not only materials, equipment, systems, buildings, personnel) Includes control over the entire process of repeated batches or executions.
1.0 Components and Composition
This section of the guidance focuses on changing pharmaceutical additives. Changes in the amount of active substance are not covered in this guideline. Ingredients or compositional changes that cause the addition of new additives or the removal of additives are defined at Level 3 (defined below), except as described below.
SUPAC Guideline: Levels of change
Level 1 Change
Level 1 changes are unlikely to have detectable impact on product quality and performance.
Level 1 Change, Example
[][]Example 1
Removal or partial removal of an element intended to affect the color or odor of the drug product, Or change printing ink material on another approved material.
Example 2
[][]Changes in excipients, expressed as a percentage of (w/w) Total composition below the next percentage area:
[][]The above mentioned percentage has been demonstrated that the drug substance has been formulated to 100% of label/potency.
[][]Total additive shall not be more than 5%( If a product formulated with Active Ingredient I, Microcrystalline cellulose, lactose, magnesium stearate. Then Microcrystalline cellulose, lactose total quantity shall not be more than 5%.
[][]If any component increases 2.5%, other component shall be decrease at 2.5%; if we increase microcrystalline cellulose 2.5% then Lactose shall be decrease to 2.5% & this is vice versa which is relating to target dosage weight.
[][]Mentioned active and excipients in the formulation shall be multiple targets as it represents the nominal composition for the drug product where any future changes shall be in the dug product based. Based on approved composition allowable changes shall be made.
List of documents required to implement the Level 1 change
Chemistry Documentation
[][]Application / official release requirements and Stability Testing Report.
-Stability test: batch containing long-term stability data Reported in the annual report for one batch
[][]Dissolution Documentation
-Nothing goes beyond the application/official requirements.
[][]n Vivo Bioequivalence Documentation
-None/Nothing else.
[][]Filing Documentation
-Annual report (all information including data on long-term stability).
Level 2 Change
[][]Level 2 changes are changes that can have a significant impact on the quality and performance of the formulation. List of documentation depends on three factors for level 2 documentation. Therapeutic range, solubility and permeability. The range of treatment is defined as narrow or not narrow.
[][]Change in the excipient technical grade (i. e. Avicel PH102 vs. Avicel PH200.)
[][]Excipients changes has been demonstrated as w/w for the respective formulation which is greater than the Level I changes but it shall be equal to or less than the mentioned range demonstrated below.
Table 2: Level 2 Change
[][]The above mentioned percentage has been demonstrated that the drug substance has been formulated to 100% of label/potency.
[][]Total additive shall not be more than 10%( If a product formulated with Active Ingredient I, Microcrystalline cellulose, lactose, magnesium stearate. Then Microcrystalline cellulose, lactose total quantity shall not be more than 10%.
[][]If any component increases 5%, other component shall be decrease at 5%; if we increase microcrystalline cellulose 5% then Lactose shall be decrease to 5% & this is vice versa which is relating to target dosage weight.
List of documents required to implement the Level 2 change
Chemistry Documentation
[][]Application/ official release requirements and batch records.
[][]Stability testing: 1 lot with 3 months accelerated stability data and 1 lot for long-term stability data
[][]Dissolution Documentation
Case A, Case B & Case C required for 1.0 High Permeability, High Solubility Drugs, 2.0 Low Permeability, High Solubility Drugs, 3.0 High Permeability, Low Solubility Drugs.
[][]In Vivo Bioequivalence Documentation
-If the situation is not as described See Case A, Case B, or Case C, the refer to Level 3 Changes.
[][]Filing Documentation
Pre-approval supplement (accelerated stability data with all information) Annual report (long term stability data)
Level 3 Changes
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: Solubility, Permeability and therapeutic range.
Examples: Level 3 Changes
[][]Changes of excipient quantity for a narrow therapeutic drug over the above mentioned Table 1.
[][]Changes of excipient quantity of all drugs beyond those listed in Section Table 2.
[][]Changes of excipient quantity for low solubility, low permeability drug over the above mentioned Table 1.
List of documents required to implement the Level change
Chemistry Documentation
[][]Application/ official release requirements and batch records.
>>Stability test: One batch 3 month accelerated stability data & One batch long-term stability data Reported in one year report.
[][]Dissolution Documentation
>>Case B dissolution profile
[][]In Vivo Bioequivalence Documentation
>>Can be waived with the accepted verified in vivo/in vitro study.
[][]Filing Documentation
>>Pre-approval supplement (accelerated stability data with all information) Annual report (Long term stability data).
2.0 Site Changes
Changes in the site which is owned by company or site of contact manufacturing . No scale up batches, changes in component or composition batch shall not be mentioned/ include here. Selected site shall be possessed cGMP.
Level 1 Changes
Definition of Level
This is really a site to site change where actually no basic changes are made only administrative information are changes all of the control parameter like SOP, Environment, Equipment’s, Facility etc. are same and manpower is fully experienced on the new site in a single facility.
Documentation
[][]Chemistry Documentation
>>No special requirements
[][]Dissolution Documentation
>>No special requirements
[][]In Vivo Bioequivalence Documentation
>>None.
[][]Filing Documentation
>>Only Annual report
Level 2 changes
In the adjacent city blocks where the same equipment’s, environment, SOP’s etc. are used & no change are made except administrative information and the location of the site.
[][]Test Documentation
>>Chemistry Documentation
>>New site Location and updated batch records.
>>Batch long-term stability data reported in annual report.
[][]Dissolution Documentation
>>Official Requirements only
[][]In Vivo Bioequivalence Documentation
>>No issue
[][]Filing Documentation
>>Annual report (long-term stability test data), Changes being effected supplement;
Level 3 changes
[][]Level 3 changes comprise of an adjustment of assembling site to an alternate grounds. An alternate grounds is characterized as one that isn’t on similar unique adjoining site or where the offices are not in contiguous city blocks.
[][]To qualify as Level 3 change, similar Equipment Setup, Environment circumstances SOP’s, and controls should be utilized in the assembling system at the new site, and no changes might be made to the Manufacturing batch records with the exception of regulatory data, area and language interpretation, where required.
Test Documentation
>>Chemistry Documentation
>>New site Location of & updated batch record.
>>Application/compendial release requirements.
Stability:
>>Stability test: One batch 3 month accelerated stability data & One batch long-term stability data Reported in one year report.
Dissolution Documentation
>>Case B: Multi-point dissolution profile ought to be achieved within the utility/compendial medium at 15, 30, 45, 60 and a hundred and twenty mins or till an asymptote is reached. The dissolution profile of the drug product on the contemporary and proposed site must be similar.
In Vivo Bioequivalence Documentation
None.
Filing Documentation
Annual report (long-term stability data).
Level 1 Changes
Change in batch size, as much as and which includes a thing of 10 times the scale of the pilot/biobatch, in which: 1) the system used to produce the take a look at batch is of the identical layout and working concepts; 2) the batch is manufactured in complete compliance with CGMP’s; and 3) the equal well known running processes (SOP’s) and controls, in addition to the same components and production tactics, are used on the take a look at batch and on the overall-scale production batch.
Test Documentation
[][]Chemistry Documentation
>>Similar or as of Application/compendial release requirements.
>>Notification for change & submission of updated batch records in annual report.
>>Long term stability reported in annual report (One batch)
[][]Dissolution Documentation
>>Similar as of application/compendial release requirements.
[][]In Vivo Bioequivalence
>>None.
[][]Filing Documentation
>>long-term stability data (Annual report).
3.0 Batch Size change
Level 1 Changes
Changes in batch length past a aspect of ten instances the scale of the pilot/biobatch, wherein: 1) the machine used to supply the take a look at batch is of the identical design and operating principles; 2) the batch is (are) produced in whole compliance with CGMP’S; and 3) the same SOP’s and controls as well as the identical formulation and manufacturing approaches are used at the take a look at batch and on the full-scale manufacturing batch.
Test Documentation
[][]Chemistry Documentation
>>Similar or as of Application/compendial release requirements.
>>Notification for change & submission of updated batch records in annual report.
>>Long term stability reported in annual report (One batch) & three months accelerated stability data for One batch
[][]Dissolution Documentation
>>Case B testing.
[][]In Vivo Bioequivalence
>>None.
[][]Filing Documentation
>>long-term stability data (Annual report).
4.0 Manufacturing
Manufacturing adjustments/Change might also affect each system used in the production process & the technique itself.
A. Equipment
Level 1 Changes
Definition of Change
This class includes: 1) alternate from non-automated or non-mechanical system to automatic or mechanical equipment to transport elements; and a couple of) trade to opportunity device of the identical layout and working ideas of the equal or of a distinct potential.
Test Documentation
[][]Chemistry Documentation
>>Similar or as of Application/compendial release requirements.
>>Notification for change & submission of updated batch records in annual report.
>>Long term stability reported in annual report (One batch)
[][]Dissolution Documentation
>>Similar as of application/compendial release requirements.
[][]In Vivo Bioequivalence Documentation
>>None.
[][]Filing Documentation
>>Long-term stability data (Annual report).
Level 2 Changes
[][]Definition of Level
>>Equipment Change to a different design & different operating principles.
[][]Test Documentation
[][]Chemistry Documentation
>>Similar or as of Application/compendial release requirements.
>>Notification of change and submission of updated batch records.
>>Long term stability reported in annual report (One batch) with 3 month accelerated stability data.
[][]Dissolution Documentation
>>Case C dissolution profile.
[][]In Vivo Bioequivalence Documentation
>>None.
[][]Filing Documentation
>>long-term stability data (annual report); Prior approval supplement with justification for change;
B. Process
Level 1 Changes
This class includes process adjustments along with adjustments consisting of blending instances and operating speeds within application/validation degrees.
Test Documentation
[][]Chemistry Documentation
Similar as of application/compendial release requirements.
[][]Dissolution Documentation
Similar as of application/compendial release requirements.
[][] In Vivo Bioequivalence Documentation
None.
[][]Filing Documentation
Annual report.
Level 2 Changes
Definition of Level
This category includes process changes including changes such as mixing times and operating speeds outside of application/validation ranges.
Test Documentation
[][]Chemistry Documentation
>>Similar as of Application/compendial release requirements.
>>Change notification & updated batch records to be submit.
>>Stability testing: Long-term stability for One batch.
[][]Dissolution Documentation
>>Case B Study: Dissolution profile.
[][]In Vivo Bioequivalence study
>>None.
[][]Filing Documentation
>>Long-term stability (Annual Report); Changes being affected supplement;
Level 3 Changes
Application/compendial release requirements.
Change Notification & updated batch records submission.
[][]Stability testing:
Significant body of data available:
three months accelerated stability data for One batch reported in supplement; long-term stability data reported in annual report for one batch.
[][]Dissolution Documentation
Case B dissolution profile.
[][]In Vivo Bioequivalence Documentation
May be waived if a suitable in vivo/in vitro correlation has been verified/established.
[][]Filing Documentation
Prior approval supplement with justification; long-term stability data (Annual report).
[][]In Vitro Dissolution
As per USP/NF Section<711>, to be conducted for 12 individual dosages.
In Vivo Bioequivalence Studies
In vivo bioequivalence study has been demonstrated as below. The actual design style may vary as it can be treated as an intended design guide for drug and dosage form.
[][]Objective:
The drug product which manufacture has been changed its rate and extent of absorption shall be compare.
[][]Design:
The study layout must be a single dose, two-treatment, two-period crossover with adequate washout period among the 2 phases of the study.
[][]Selection of Subjects:
The range of subjects enrolled inside the bioequivalence observe need to be decided statistically to account for the intrasubject variability and to satisfy the modern bioequivalence interval.
[][]Procedure:
>>Each subject should obtain the subsequent remedies:
Treatment 1: Product produced with the proposed change.
Treatment 2: Product produced prior to the proposed change.
>>Following an overnight speedy of at least 10 hours, subjects must get hold of both Treatments 1 or 2 above with 240 mL water. Food ought to now not be allowed until four hours after dosing. Water can be allowed after the primary hour. Subjects must be served standardized food beginning at 4 hours at some stage in the look at.
[][]Restrictions:
>>Prior to and at some stage in each observe section, water can be allowed ad libitum except for 1 hour before and after drug administration. The issue ought to be served standardized food and drinks at unique instances.
List of Narrow Therapeutic Range Drugs: SUPAC Guideline
[][]Aminophylline Tablets, ER Tablets
[][]Carbamazepine Tablets, Oral Suspension
[][]Clindamycin Hydrochloride Capsules
[][]Clonidine Hydrochloride Tablets
[][]Clonidine Transdermal Patches
[][]Dyphylline Tablets
[][]Disopyramide Phosphate Capsules, ER Capsules
[][]Ethinyl Estradiol/Progestin Oral Contraceptive Tablets
[][]Guanethidine Sulfate Tablets
[][]Isoetharine Mesylate Inhalation Aerosol
[][]Isoproterenol Sulfate Tablets
[][]Lithium Carbonate Capsules, Tablets, ER Tablets
[][]Metaproterenol Sulfate Tablets
[][]Minoxidil Tablets
[][]Oxtriphylline Tablets, DR Tablets, ER Tablets
[][]Phenytoin, Sodium Capsules (Prompt or Extended), Oral Suspension
[][]Prazosin Hydrochloride Capsules
[][]Primidone Tablets, Oral Suspension
[][]Procainamide Hydrochloride, Capsules, Tablets, ER Tablets
[][]Quinidine Sulfate Capsules, Tablets, ER Tablets
[][]Quinidine Gluconate Tablets, ER Tablets
[][]Theophylline Capsules, ER Capsules, Tablets, ER Tablets
[][]Valproic Acid Capsules, Syrup
[][]Divalproex, Sodium DR Capsules, DR Tablets
[][]Warfarin, Sodium Tablets
SUPAC Guideline, here by apply for the above mentioned & SUPAC Guideline shall be followed for the same.