Lynda Paleshnuik

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Assessment Workshop
Copenhagen January 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 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

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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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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



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Basic uses of SUPAC documents
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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Introduction to SUPAC IR guidance
Immediate Release Solid Oral Dosage Forms
Scale-Up and Postapproval Changes: Chemistry,
Manufacturing, and Controls, I n Vitro Dissolution
Testing, and I n Vivo Bioequivalence Documentation
(1995)

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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)

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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
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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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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



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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).
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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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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 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 % Excipient
L1 L2
Filler 5 10
Disintegrant
Starch 3 6
Other 1 2
Binder 0.5 1

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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%
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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.
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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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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.

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Recommended documentation level 3
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 (SiO
2
) 1.62%

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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 SiO
2
lubricant - 1.62% - within level 2

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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
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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.
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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 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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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
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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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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


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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.
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Manufacturing Equipment Changes
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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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.
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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.

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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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Questions?