Top Banner

of 33

Welcome message from author
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript

  • SUPACSUPAC

    Scale-Up and Post Approval Changes

  • What are SUPAC documentsWhat are SUPAC documents 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

  • SUPAC documents for quality SUPAC documents for quality assessmentassessment

    SUPAC IR (immediate release)

    SUPAC MR (modified release)

    SUPAC IR/MR equipment addendum

    SUPAC IR Q&A

    SS: Nonsterile semi-solids + equipment addendum

  • SUPAC documentsSUPAC documentsTreat as supportive documents only

    to understand the significance of changes to assist in decision-making

    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).

  • Introduction to SUPAC IR guidanceIntroduction 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

  • Introduction to SUPAC IRIntroduction to SUPAC IR

    Two key areas: Changes to components and composition

    Changes to manufacturing (equipment, process)

  • Components and compositionComponents and composition

  • Components and Components and compositioncomposition

    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

  • Components and compositionComponents 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).

  • Excipients - NoteExcipients - 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)

  • Composition Level 1/2 Composition Level 1/2 ChangesChanges

    Excipient % Excipient L1 L2

    Filler 5 10Disintegrant

    Starch 3 6Other 1 2

    Binder 0.5 1

  • Composition Level 1/2 Composition Level 1/2 ChangesChanges

    Excipient % Excipient Lubricant L1 L2

    Calcium (Ca) orMagnesium (Mg) Stearate 0.25 0.5Other 1 2

    GlidantTalc 1 2Other 0.1 0.2

    Film Coat 1 2TOTAL ADDITIVE EFFECT 5% 10%

  • Composition Level 3 ChangesComposition 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 testingFor both level 2 and level 3 changes, the therapeutic range, solubility and permeability are factors to consider.

  • Recommended documentation level 1Recommended 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

  • Recommended documentation level 2Recommended 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.

  • Recommended documentation level 3Recommended documentation level 3

    Requirements for level 3 include stability testing, dissolution testing and an in-vivo study.

  • SUPAC and Composition - SummarySUPAC 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)

  • ManufacturingManufacturing

  • Manufacturing Process ChangesManufacturing 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

  • Manufacturing Process ChangesManufacturing 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

  • Manufacturing Equipment ChangesManufacturing Equipment Changes

    Equipment is categorized according to

    Class: operating principle

    Subclass: design characterization

  • Equipment categorizationEquipment 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

  • ManufacturingManufacturing Equipment Changes 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

  • Example class/subclass:Example class/subclass:Blending and MixingBlending 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

  • Equipment categorization exampleEquipment 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.

  • Example class/subclass:Example class/subclass:Blending and MixingBlending and Mixing

  • Manufacturing Equipment ChangesManufacturing 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

  • Manufacturing Equipment ChangesManufacturing Equipment Changes

    Recommended documentation:Level 1: one batch on long term stabilityLevel 2: stability, dissolution

  • SUPAC limitationsSUPAC limitations

  • SUPAC limitations SUPAC limitations Formulation/ManufacturingFormulation/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

  • ConclusionConclusion

    For new (to you) and unique situations:

    Consult! Those with related experience Senior assessors BE assessors

  • AvailabilityAvailability

    Go to: www.fda.gov Drugs Guidance, Compliance & Regulatory

    InformationOR directly:http://www.fda.

    gov/Drugs/GuidanceComplianceRegulatory

    Information/Guidances/default.htm

    SUPACWhat are SUPAC documentsSUPAC documents for quality assessmentSUPAC documentsIntroduction to SUPAC IR guidanceIntroduction to SUPAC IRComponents and compositionComponents and compositionComponents and compositionExcipients - NoteComposition Level 1/2 ChangesComposition Level 1/2 ChangesComposition Level 3 ChangesRecommended documentation level 1Recommended documentation level 2Recommended documentation level 3SUPAC and Composition - SummaryManufacturingManufacturing Process ChangesManufacturing Process ChangesManufacturing Equipment ChangesEquipment categorizationManufacturing Equipment ChangesExample class/subclass: Blending and Mixing Equipment categorization exampleExample class/subclass: Blending and MixingManufacturing Equipment ChangesManufacturing Equipment ChangesSUPAC limitationsSUPAC limitations Formulation/ManufacturingConclusionAvailability