Dealing With Post Approval Changes-Supac: Wasim Raja.S Sri Venkateswara College of Pharmacy

DEALING WITH POST APPROVAL CHANGES- SUPAC
1 | Wasim Raja.S
Sri Venkateswara College of Pharmacy
Overview
What are SUPAC documents
Key SUPAC documents for quality assessment Finished Pharma Products (FPPs)
Basic uses of SUPAC documents

Introduction to SUPAC IR guidance
Main document Equipment addendum
Examples
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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
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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
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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.)
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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
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PAC: post-PQ/post-approval, i.e. Variations
Comparing the PQd/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).
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Immediate Release Solid Oral Dosage Forms
Scale-Up and Post approval Changes: Chemistry, Manufacturing, and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation (1995)
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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)
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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
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Introduction to SUPAC IR
Two key areas:
Changes to components and composition
Changes to manufacturing (equipment, process)
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Components and composition
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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
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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).
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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.]
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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 vs Avicel 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.]
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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)
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Composition Level 1/2 Changes

Excipient
L1 Filler 5 Starch 3
% Excipient
L2 10 6
Disintegrant Other
Binder
1
0.5
2
1
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Excipient Lubricant Calcium (Ca) or Magnesium (Mg) Stearate Other Glidant Talc Other Film Coat
TOTAL ADDITIVE EFFECT
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% Excipient L1 0.25 1 1 0.1 1 5% L2 0.5 2 2 0.2 2 10%


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.
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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
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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.
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Requirements for level 3 include stability testing, dissolution testing and an in-vivo study.
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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%
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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
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Excipient % Excipient
L2
Lubricant L1 Calcium (Ca) or Magnesium (Mg) Stearate 0.25 Other 1 Glidant Talc 1 Other 0.1 Film Coat 1
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0.5 2 2 0.2 2

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.
29 | Wasim Raja.S
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)
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Manufacturing
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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
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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
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Manufacturing Equipment Changes

Equipment is categorized according to
Class: operating principle
Subclass: design characterization
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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
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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
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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
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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.
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Example class/subclass: Blending and Mixing
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Equipment categorization
Example: Gemco slant cone blender
Unit operation: blending and mixing Class: diffusion (tumble) mixer Subclass: slant cone blender
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Level 1: 1) change from non-automated or nonmechanical 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
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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.
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Recommended documentation:
Level 1: one batch on long term stability
Level 2: stability, dissolution
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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)
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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.
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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.
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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
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SUPAC limitations
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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
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Conclusion
For new (to you) and unique situations:
Consult! Those with related experience Senior assessors BE assessors
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Availability
Go to: www.fda.gov
Drugs Guidance, Compliance & Regulatory Information OR directly:
http://www.fda.gov/Drugs/GuidanceComplianceRegulatory
Information/Guidances/default.htm
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Thank You
52 | Wasim Raja.S

Dealing With Post Approval Changes-Supac: Wasim Raja.S Sri Venkateswara College of Pharmacy

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DEALING WITH POST APPROVAL CHANGES- SUPAC

Basic uses of SUPAC documents

What are SUPAC documents

Sri Venkateswara College of Pharmacy

SUPAC documents for quality assessment

SUPAC IR/MR equipment addendum

Sri Venkateswara College of Pharmacy

Not official documents for PQP.

Basic uses of SUPAC documents

scale-up during original dossier assessment.

Note that this is not SU during development.

Basic uses of SUPAC documents

Introduction to SUPAC IR guidance

Sri Venkateswara College of Pharmacy

Introduction to SUPAC IR guidance

Introduction to SUPAC IR guidance

Changes to manufacturing (equipment, process)

Sri Venkateswara College of Pharmacy

Components and composition

Sri Venkateswara College of Pharmacy

Components and composition

Level 1: unlikely to have detectable impact

Level 2: could have significant impact

Sri Venkateswara College of Pharmacy

Components and composition

Composition Level 1 Changes

Sri Venkateswara College of Pharmacy

Composition Level 2 Changes

Sri Venkateswara College of Pharmacy

Grades (when provided)

Composition Level 1/2 Changes

Sri Venkateswara College of Pharmacy

Composition Level 1/2 Changes

% Excipient L1 0.25 1 1 0.1 1 5% L2 0.5 2 2 0.2 2 10%

Composition Level 3 Changes

Recommended documentation level 1

Sri Venkateswara College of Pharmacy

Recommended documentation level 2

Sri Venkateswara College of Pharmacy

Sri Venkateswara College of Pharmacy

Sri Venkateswara College of Pharmacy

Recommended documentation level 3

Sri Venkateswara College of Pharmacy

Formulation changes - Example

Sri Venkateswara College of Pharmacy

Formulation changes - Example

Lactose 4.05% - filler - within level 1

Talc 1.94% - glidant within level 2

Sri Venkateswara College of Pharmacy

Composition Level 1/2 Changes

Formulation changes - Example

Sri Venkateswara College of Pharmacy

SUPAC and Composition - Summary

Sri Venkateswara College of Pharmacy

Manufacturing Process Changes

Sri Venkateswara College of Pharmacy

Manufacturing Process Changes

Level 3: stability, dissolution, and BE study

Sri Venkateswara College of Pharmacy

Manufacturing Equipment Changes

Subclass: design characterization

Sri Venkateswara College of Pharmacy

Manufacturing Equipment Changes