Supporting Documents SUPAC

5/25/2018 Supporting Documents SUPAC

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Assessment Workshop

CopenhagenJanuary 2011

Supporting

Documents:

SUPAC


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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


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Quality Assessment

Manufacturing sciencesPharmaceutical 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


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What are SUPAC documents

A series of documents issued by US FDA (CDER) to helpapplicants 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 supportivedocuments only

to understand the significance of changes

to assist in decision-making

Not official documents for PQP.

Should notbe 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 notSU during development.

Consider changes made after the biobatch


Manufacturing (equipment, process)

Batch sizeManufacturing site changes


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PAC:post-PQ/post-approval, i.e. VariationsComparing the PQd/approved product to a changed product.

In addition:

This guideline can be used to determine whether strengths of aproduct 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 onlya single strength may be sufficient (proportional strength

biowaiver).


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Immediate Release Solid Oral Dosage Forms

Scale-Up and Postapproval Changes: Chemistry,

Manufacturing, and Controls, I n Vitro Dissolution

Testing, and I n Vivo BioequivalenceDocumentation(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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Levels of change: likelihood of impact on formulation qualityand 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 excipientspecifications).

Level 3 changes: quantitative > Level 2, plus addition

or deletion of an excipient (except for a colour, flavour,ink).


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CompositionLevel 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 (expressedas 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. AvicelPH102 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 bediluent change, when formulation uses it as binder)


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CompositionLevel 1/2 Changes

Excipient % Excipient

L1 L2

Filler 5 10

DisintegrantStarch 3 6

Other 1 2

Binder 0.5 1


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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%


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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 toconsider.


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Recommended documentationlevel 1

Stability testing: one batch on long-term stability datareported 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 dependson the BCS class of the API.

MR guideline: the dissolution testing depends on the

type of releaseof 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 betweenthe 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 thelubrication stage

Assessors consider excipients as follows:

Lactose 4.05% - filler - within level 1 Magnesium stearate 0.49% - lubricantwithin level 2

Talc 1.94% - glidantwithin level 2

Colloidal SiO2lubricant - 1.62% - within level 2


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Excipient % ExcipientLubricant 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


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The API in the product was low solubility, therefore inaddition to the above, the number of changes should be

troubling, and three changes are level 2.

The lubricant magnesium stearate is hydrophobic andknown 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.


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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 changesby looking at the change coupled with the API

characteristics

SUPAC does not:

substitute for critical thinking (e.g. formulationchanges for modified release products)


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Manufacturing


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ManufacturingProcess Changes

Level 1: changes to parameters (e.g. mixing times,operating speeds) withinapplication/validation ranges

Level 2: changes to parameters (e.g. mixing times,

operating speeds) outsideapplication/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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ManufacturingProcess 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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ManufacturingEquipment 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 categorizedaccording to class (operating principle) and

subclass(design characteristics)

gives concise descriptions in context of otherclasses/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

E l l / b l


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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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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 non-mechanical equipment to automated or mechanical

equipment to move ingredients; and 2) change to

alternate equipment of the same design and operating

principlesof 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 acase-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 Mixingsection, 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 isnot 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 sizeusing a Gallay In-Bin blender and Gerteis Roller

Compactor is required in order to gain approval. Executed batch

records, comparative dissolution studiesin 0.5% sodium lauryl

sulfate and two additional media, and a certificate of analysis are

required in order to meet this requirement. Data should becomparedto that generated from the lot used in biostudies.


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As no batches have been manufactured using the proposedcommercial equipment, in order to obtain approval, you may

provide blank master manufacturing documentationwhich

proposes the use of equipmentas 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 thefuture.


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Equipment addendumSemi-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 limitationsFormulation/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 otherreferences, 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
http://www.fda.gov/http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryhttp://www.fda.gov/Drugs/GuidanceComplianceRegulatoryhttp://www.fda.gov/


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Questions?

Supporting Documents SUPAC

Documents

Transcript of Supporting Documents SUPAC