Assessment Workshop
Copenhagen – January 2011
Supporting
Documents:
SUPAC
1|
Lynda Paleshnuik | January 2011
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
2|
Lynda Paleshnuik | January 2011
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
3|
Lynda Paleshnuik | January 2011
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
4|
Lynda Paleshnuik | January 2011
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
5|
Lynda Paleshnuik | January 2011
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.)
6|
Lynda Paleshnuik | January 2011
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
7|
Lynda Paleshnuik | January 2011
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).
8|
Lynda Paleshnuik | January 2011
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)
9|
Lynda Paleshnuik | January 2011
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)
10 |
Lynda Paleshnuik | January 2011
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
11 |
Lynda Paleshnuik | January 2011
Introduction to SUPAC IR
Two key areas:
► Changes to components and composition
► Changes to manufacturing (equipment, process)
12 |
Lynda Paleshnuik | January 2011
Components and composition
13 |
Lynda Paleshnuik | January 2011
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
14 |
Lynda Paleshnuik | January 2011
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).
15 |
Lynda Paleshnuik | January 2011
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.]
16 |
Lynda Paleshnuik | January 2011
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.]
17 |
Lynda Paleshnuik | January 2011
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)
18 |
Lynda Paleshnuik | January 2011
Composition – Level 1/2 Changes
Excipient
% Excipient
L1
L2
±5
±10
Starch
±3
±6
Other
±1
±2
±0.5
±1
Filler
Disintegrant
Binder
19 |
Lynda Paleshnuik | January 2011
Composition – Level 1/2 Changes
Excipient
% Excipient
Lubricant
L1
Calcium (Ca) or
Magnesium (Mg) Stearate ±0.25
Other
±1
Glidant
Talc
±1
Other
±0.1
Film Coat
±1
TOTAL ADDITIVE EFFECT
5%
20 |
Lynda Paleshnuik | January 2011
L2
±0.5
±2
±2
±0.2
±2
10%
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.
21 |
Lynda Paleshnuik | January 2011
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
22 |
Lynda Paleshnuik | January 2011
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.
23 |
Lynda Paleshnuik | January 2011
24 |
Lynda Paleshnuik | January 2011
25 |
Lynda Paleshnuik | January 2011
Recommended documentation – level 3
 Requirements for level 3 include stability testing,
dissolution testing and an in-vivo study.
26 |
Lynda Paleshnuik | January 2011
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%
27 |
Lynda Paleshnuik | January 2011
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
28 |
Lynda Paleshnuik | January 2011
Composition – Level 1/2 Changes
Excipient
% Excipient
Lubricant
L1
Calcium (Ca) or
Magnesium (Mg) Stearate ±0.25
Other
±1
Glidant
Talc
±1
Other
±0.1
Film Coat
±1
29 |
Lynda Paleshnuik | January 2011
L2
±0.5
±2
±2
±0.2
±2
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.
30 |
Lynda Paleshnuik | January 2011
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)
31 |
Lynda Paleshnuik | January 2011
Manufacturing
32 |
Lynda Paleshnuik | January 2011
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
33 |
Lynda Paleshnuik | January 2011
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
34 |
Lynda Paleshnuik | January 2011
Manufacturing – Equipment Changes
Equipment is categorized according to
 Class: operating principle
 Subclass: design characterization
35 |
Lynda Paleshnuik | January 2011
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
36 |
Lynda Paleshnuik | January 2011
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
37 |
Lynda Paleshnuik | January 2011
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
38 |
Lynda Paleshnuik | January 2011
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.
39 |
Lynda Paleshnuik | January 2011
Example class/subclass:
Blending and Mixing
40 |
Lynda Paleshnuik | January 2011
Equipment categorization
Example: Gemco slant cone blender
Unit operation: blending and mixing
Class: diffusion (tumble) mixer
Subclass: slant cone blender
41 |
Lynda Paleshnuik | January 2011
Manufacturing – Equipment Changes
 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
42 |
Lynda Paleshnuik | January 2011
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.”
43 |
Lynda Paleshnuik | January 2011
Manufacturing – Equipment Changes
Recommended documentation:
Level 1: one batch on long term stability
Level 2: stability, dissolution
44 |
Lynda Paleshnuik | January 2011
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)
45 |
Lynda Paleshnuik | January 2011
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.
46 |
Lynda Paleshnuik | January 2011
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.
47 |
Lynda Paleshnuik | January 2011
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
48 |
Lynda Paleshnuik | January 2011
SUPAC limitations
49 |
Lynda Paleshnuik | January 2011
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
50 |
Lynda Paleshnuik | January 2011
Conclusion
For new (to you) and unique situations:
 Consult!
● Those with related experience
● Senior assessors
● BE assessors
51 |
Lynda Paleshnuik | January 2011
Availability
Go to: www.fda.gov
► Drugs
► Guidance, Compliance & Regulatory Information
OR directly:
http://www.fda.gov/Drugs/GuidanceComplianceRegulatory
Information/Guidances/default.htm
52 |
Lynda Paleshnuik | January 2011
Questions?
53 |
Lynda Paleshnuik | January 2011