SUPAC Documents: Supporting Quality Assessment in Pharmaceutical Manufacturing

1. Assessment WorkshopCopenhagen – January 2011 Supporting Documents: SUPAC

2. Overview • What are SUPAC documents • Key SUPAC documents for quality assessment (FPPs) • Basic uses of SUPAC documents • Introduction to SUPAC IR guidance ► Main document ► Equipment addendum • Examples

3. 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

4. What are SUPAC documents A series of documents issued by US FDA (CDER) to help applicants with post-approval changes • Documents are categorized into IR, MR and SS (FPPs) • Various types of changes are described: ►Components and composition ► Manufacturing (equipment, process) ► Batch size ► Manufacturing site changes

5. SUPAC documents for quality assessment • SUPAC IR (immediate release) • SUPAC MR (modified release) • SUPAC IR/MR equipment addendum • SUPAC IR Q&A • SS: Nonsterile semi-solids + equipment addendum

6. SUPAC documents Some premises before using SUPAC as supporting documents: Treat as supportive documents only ► to understand the significance of changes ► to assist in decision-making Not official documents for PQP. Should not be considered definitive. Nothing substitutes for critical thinking. (Guidelines address simplified situations.)

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

8. Basic uses of SUPAC documents • 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 Immediate Release Solid Oral Dosage Forms Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation (1995)

10. Introduction to SUPAC IR guidance ► Prepared by SUPAC expert working group (CDER) ► Result of: ◘ scale-up workshop by American Assoc of Pharmaceutical Scientists/USP convention/FDA ◘ research from universities of Maryland, Michigan an Uppsala ◘ International Society of Pharmaceutical Engineering (equipment addenda)

11. 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

12. Introduction to SUPAC IR Two key areas: ► Changes to components and composition ► Changes to manufacturing (equipment, process)

13. Components and composition

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

15. 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).

16. Composition – Level 1 Changes Level 1 changes • Addition or deletion of a colour or flavour, or change in an ink excipient (or preservative (MR)) • Changes less than the following table level 1 column (expressed as percentage of the total formulation): [Note that total additive effect should not exceed 5% of total target FPP weight.]

17. Composition – Level 2 Changes Level 2 changes • Changes greater than level 1 but less than the following table (level 2 column). • Changes in the technical grade of an excipient e.g. Avicel PH102 vsAvicel PH200 • BEWARE TRADE NAME CHANGES – some are actually qualitative changes, not just grade changes [Note that total additive effect should not exceed 10%of total target FPP weight.]

18. Excipients - Note Know your excipients: • Description • Grades (when provided) • Use in the formulation (e.g. MCC change stated to be diluent change, when formulation uses it as binder)

19. Composition – Level 1/2 Changes Excipient% Excipient L1L2 Filler ±5 ±10 Disintegrant Starch ±3 ±6 Other ±1 ±2 Binder ±0.5 ±1

20. Composition – Level 1/2 Changes Excipient% Excipient Lubricant L1L2 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%

21. 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.

22. Recommended documentation – level 1 • Stability testing: one batch on long-term stability data reported in annual report. • Supportive dissolution data: none • Supportive in-vivo bioequivalence testing: none

23. Recommended documentation – level 2 • 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. MR guideline: the dissolution testing depends on the type of release of the FPP.

26. Recommended documentation – level 3 • Requirements for level 3 include stability testing, dissolution testing and an in-vivo study.

27. Formulation changes - Example Antimalarial product with formulation changes between the biolot and the proposed production lots • Lactose 4.05% (anh or monohydrate?) • Magnesium stearate 0.49% • Talc 1.94% • Colloidal silicon dioxide (SiO2) 1.62%

28. Formulation changes - Example • Applicant states: “quantitative changes were only at the lubrication stage” Assessors consider excipients as follows: • Lactose 4.05% - filler - within level 1 • Magnesium stearate 0.49% - lubricant – within level 2 • Talc 1.94% - glidant – within level 2 • Colloidal SiO2 – lubricant - 1.62% - within level 2

29. Composition – Level 1/2 Changes Excipient% Excipient Lubricant L1L2 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

30. Formulation changes - Example • The API in the product was low solubility, therefore in addition to the above, the number of changes should be troubling, and three changes are level 2. • The lubricant magnesium stearate is hydrophobic and known to have a potential significant effect on dissolution (even used as control release agent in some formulations) and it is at the border of level 2, in addition to the changes in both glidants.

31. 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 does not: ► substitute for critical thinking (e.g. formulation changes for modified release products)

32. Manufacturing

33. 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

34. 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

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

36. Equipment categorization SUPAC equipment addenda: ◘ aid for considering equipment changes ◘ provides information on equipment categorized according to class (operating principle) and subclass (design characteristics) ◘ gives concise descriptions in context of other classes/subclasses

37. Manufacturing – Equipment Changes Divided by unit operation: • Blending and mixing • Drying • Particle size reduction/separation • Granulation • Unit dosing (tabletting, encapsulating, powder filling) • Coating and printing • Soft gelatin capsule encapsulation

38. 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

39. Equipment categorization example Class (operating principles) diffusion/tumble mixers: Particles are reoriented in relation to one another when they are placed in random motion and interparticular friction is reduced as the result of bed expansion (usually within a rotating container); Subclasses (design characteristics) for diffusion mixers are distinguished by geometric shape/positioning of axis of rotation.

40. Example class/subclass:Blending and Mixing

41. Equipment categorization Example: Gemco slant cone blender Unit operation: blending and mixing Class: diffusion (tumble) mixer Subclass: slant cone blender

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

43. 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.”

44. Manufacturing – Equipment Changes Recommended documentation: Level 1: one batch on long term stability Level 2: stability, dissolution

45. Equipment change - Example Biobatch: Stokes tablet press and ribbon blender Proposed production: Gerteis roller compactor and Gallay in‑bin blender Granulation: same class (dry granulation), different subclass Blending: different class (convection vs diffusion)

46. Equipment change - Example The equipment used to manufacture the bioequivalence batch is not considered representative of the equipment proposed for commercial manufacture. In order to establish that the equipment/process differences do not have an effect on the quality of the proposed full-scale tablets, the manufacture of one lot of at least pilot size using a Gallay In‑Bin blender and Gerteis Roller Compactor is required in order to gain approval. Executed batch records, comparative dissolution studies in 0.5% sodium lauryl sulfate and two additional media, and a certificate of analysis are required in order to meet this requirement. Data should be compared to that generated from the lot used in biostudies.

47. Equipment change - Example As no batches have been manufactured using the proposed commercial equipment, in order to obtain approval, you may provide blank master manufacturing documentation which proposes the use of equipment as used to manufacture the lot used for bioequivalence studies (i.e. Stokes tablet press and ribbon blender). A process validation protocol specific for these manufacturing documents should be provided. You are also requested to provide a commitment to submit a Variation containing information on executed batches should you wish to use the Gallay In-Bin Blender and Gerteis Roller Compactor in the future.

48. Equipment addendum – Semi-solids Equipment categorization differs from that for IR products: Unit operations: Particle size reduction/separation Mixing: low/high shear convection, roller (mill), static mixers (vs IR/MR: diffusion, convection, pneumatic) Emulsification (dispersion of one liquid phase into another) Deaeration Transfer Packaging: holding, transfer, filling and sealing

49. SUPAC limitations

50. SUPAC limitations – Formulation/Manufacturing SUPAC: ► has not been updated (1995/97 for main guides, 1998/99 for equipment addenda) ► 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