scale up and post approval changes presentation

SUPAC

1. SUPAC Scale up and post approval changes

2. Overview ► Definition of supac : ► What are SUPAC documents ► Key SUPAC documents for quality assessment (FPPs) ► Basic uses of SUPAC documents Introduction to SUPAC IR guidance ► Main document ► Component and composition ► M anufacturing and process ► L imitation :

3. What is Supac In the process of developing the new product the batch size used in earliest human studies are small. The size of the batch is gradually increased (scale up ) the scale up and changes made after approval in the composition manufacturing process, manufaturing equipment and change of site have become known as scale up and post approval changes (supac )

4. Quality Assessment Manufacturing sciences Pharmaceutical engineering/pharmaceutical technology ( production methods and systems, facilities, equipment, etc. ) Pharmaceutical sciences Chemistry (organic, inorganic, physical, biochemical, analytical (e.g. methodology, validation, spectral analysis)) Pharmaceutical chemistry (study of drug design) Pharmaceutics (study of drug formulation) Pharmacognosy (study of drugs of natural origin) Other fields : Math/statistics, microbiology, GMP

5. What are SUPAC documents A series of documents issued by US FDA (CDER) to help applicants with post-approval changes Documents are categorized into SUPAC IR (immediate release) SUPAC MR (modified release) SUPAC IR/MR equipment addendum SS: Nonsterile semi-solids + equipment addendu m Various types of changes are described: ►Components and composition ► Manufacturing (equipment, process) ► Batch size ► Manufacturing site changes

6. SUPAC documents S ome premises before using SUPAC as supporting documents: Treat as supportive documents only ► to understand the significance of changes ► to assist in decision-making

7. Basic uses of SUPAC documents D etermining the importance of various changes: SU: scale-up during original dossier assessment Note t hat this is not SU during development. Consider changes made after the biobatch ► Components and composition ► Manufacturing (equipment, process) ► Batch size ► Manufacturing site changes

8. continue ...... PAC : post-PQ/post-approval, i.e. Variations Comparing the PQ’d/approved product to a changed product. In addition: This guideline can be used to determine whether strengths of a product can be considered proportional, if they are not strictly proportional (i.e. small changes in excipients between strengths). This allows for a decision as to whether in-vivo studies on only a single strength may be sufficient (proportional strength biowaiver).

9. Introduction to SUPAC IR guidance SUPAC guidelines define: 1. Levels of change 2. Recommended chemistry, manufacturing and controls (CMC) for each level of change 3. In-vitro and/or in-vivo requirements for each level of change 4. Required documentation to support the change

10. Introduction to SUPAC IR T wo key areas: ► Changes to components and composition ► Changes to manufacturing (equipment, process)

11. Components and composition Levels of change: likelihood of impact on formulation quality and performance Level 1: unlikely to have detectable impact on formulation quality and performance. Level 2: could have significant impact Level 3: likely to have significant impact

12. Components and composition Level 1 changes: quantitative only (except IR: colour, flavour, ink; MR: + preservative). Level 2 changes: quantitative > Level 1, plus any change in excipient grade (MR: + change in excipient specifications). Level 3 changes: quantitative > Level 2, plus addition or deletion of an excipient (except for a colour, flavour, ink).

13. Composition – Level 1 Changes Level 1 changes 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. [Note that total additive effect should not exceed 5% of total target FPP weight.]

14. Example PERCENT EXCIPIENT (w/w) OUT OF TOTAL Excipient TARGET DOSAGE FORM WEIGHT L1 L2 Filler ±5 ±10 Disintegrant Starch ±3 ±6 Other ±1 ±2 Binder ±0.5 ±1

15. Composition – Level 1/2 Changes Excipient % Excipient Lubricant L1 L2 Calcium (Ca) or Magnesium (Mg) Stearate ±0.25 ±0.5 Other ±1 ±2 Glidant Talc ±1 ±2 Other ±0.1 ±0.2 Film Coat ±1 ±2 TOTAL ADDITIVE EFFECT 5% 10%

16. Composition – Level 2 Changes L evel 2 changes 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. Changes in the technical grade of an excipient e.g. Avicel PH102 vs Avicel PH200 [Note that total additive effect should not exceed 10% of total target FPP weight.]

17. Composition – Level 3 Changes Any change beyond level 2 OR: Any level 2 change for a BCS class 4 (low solubility and low permeability) or narrow therapeutic drug Drugs not meeting the level 2 dissolution testing For both level 2 and level 3 changes, the therapeutic range, solubility and permeability are factors to consider.

18. Recommended documentation – L evel 1 ,Level2, Level 3 Stability testing: O ne batch on long-term stability data reported in annual report. Supportive dissolution data: Supportive in-vivo bioequivalence testing: Requirements for level 2 include stability testing, dissolution testing and possibly an in-vivo study (depending on the results of dissolution testing). IR guideline: the dissolution testing required depends on the BCS class of the API. Level 3 : Same as level 2 requirement

19. Manufacturing – Process Changes Level 1: changes to parameters (e.g. mixing times, operating speeds) within application/validation ranges Level 2: changes to parameters (e.g. mixing times, operating speeds) outside application/validation ranges Level 3: change in the type of process , such as from granulation technique to direct compression of dry powder

20. Manufacturing – Process Changes Recommended documentation: Level 1: one batch on long-term stability data reported in annual report. Level 2: stability, dissolution Level 3: stability, dissolution, and BE study

21. Manufacturing – Equipment Changes Equipment is categorized according to Class: operating principle Subclass: design characterization

22. Example class/subclass: Blending and Mixing Class: Diffusion (tumble) mixers: Subclasses: V-blenders Double Cone Blenders Slant Cone Blenders Cube Blenders Bin Blenders Horizontal/Vertical/Drum Blenders Static Continuous Blenders Dynamic Continuous Blenders

23. Example class/subclass: Blending and Mixing

24. Manufacturing – Equipment Changes Level 1: 1) C hange from non-automated or non-mechanical equipment to automated or mechanical equipment to move ingredients . 2) C hange to alternate equipment of the same design and operating principles of the same or of a different capacity. Level 2: C hange to equipment of different design and different operating principles

25. Manufacturing – Equipment Changes “ Applicants should carefully consider and evaluate on a case-by-case basis changes in equipment that are in the same class, but different subclass . In many situations, this type of change in equipment would be considered similar. For example, within the Blending and Mixing section, under the Diffusion Mixers Class, a change from a V-blender (sub-class) to a Bin tumbler (subclass) represents a change within a class and between sub-classes.”

26. SUPAC and Composition - Summary SUPAC does: ► discuss relative changes in formulation ► discuss supporting data to support a change ► give an idea of how to consider various changes by looking at the change coupled with the API characteristics SUPAC limitation : Formulation/Manufacturing does not discuss multiple changes does not directly cover same class, different subclass for equipment does not cover modified equipment ► must be used in conjunction with other references, e.g. excipient handbook