2-2 Supporting-Documents SUPAC

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|
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|
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|
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|
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|

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
Manufacturing (equipment, process)
Batch size
Manufacturing site changes
7|

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).
8|

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|

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 |

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 |
Introduction to SUPAC IR
Two key areas:
Changes to components and composition
Changes to manufacturing (equipment, process)
12 |
13 |

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 |

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 |
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 |

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 |
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 |
Composition Level 1/2 Changes

Excipient
% Excipient
L1
Filler
L2
5
10
Starch
Other
0.5
Disintegrant
Binder
19 |

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%
20 |

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 |
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 |

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 |
24 |
25 |

Requirements for level 3 include stability testing,
dissolution testing and an in-vivo study.
26 |
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 |

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 |

Excipient
Lubricant
Calcium (Ca) or
Magnesium (Mg) Stearate 0.25
Other
Glidant
Talc
Other
Film Coat
29 |
% Excipient
L1
L2
0.5
1
0.1
1
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.
30 |
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 |
Manufacturing
32 |
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 |
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 |
Manufacturing Equipment Changes

Equipment is categorized according to
Class: operating principle
Subclass: design characterization
35 |
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 |

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 |
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 |
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 |
Example class/subclass:
Blending and Mixing
40 |
Equipment categorization
Example: Gemco slant cone blender
Unit operation: blending and mixing
Class: diffusion (tumble) mixer
Subclass: slant cone blender
41 |

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 |

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 |

Recommended documentation:
Level 1: one batch on long term stability
Level 2: stability, dissolution
44 |
Equipment change - Example

Biobatch:
Stokes tablet press and ribbon blender
Proposed production:
Gerteis roller compactor and Gallay inbin blender
Granulation:
same class (dry granulation), different subclass
Blending:
different class (convection vs diffusion)
45 |

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 InBin 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 |

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 |
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 |
SUPAC limitations
49 |
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 |
Conclusion
For new (to you) and unique situations:
Consult!
Those with related experience
Senior assessors
BE assessors
51 |
Availability
Go to: www.fda.gov
Drugs
Guidance, Compliance & Regulatory Information
OR directly:
http://www.fda.gov/Drugs/GuidanceComplianceRegulatory
Information/Guidances/default.htm
52 |
Questions?
53 |

2-2 Supporting-Documents SUPAC

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Assessment Workshop

Copenhagen January 2011

Lynda Paleshnuik | January 2011

Lynda Paleshnuik | January 2011

Lynda Paleshnuik | January 2011

What are SUPAC documents

Lynda Paleshnuik | January 2011

SUPAC documents for quality assessment

Lynda Paleshnuik | January 2011

Lynda Paleshnuik | January 2011

Basic uses of SUPAC documents

scale-up during original dossier assessment

Note that this is not SU during development.

Lynda Paleshnuik | January 2011

Basic uses of SUPAC documents

Lynda Paleshnuik | January 2011

Introduction to SUPAC IR guidance

Lynda Paleshnuik | January 2011

Introduction to SUPAC IR guidance

Lynda Paleshnuik | January 2011

Introduction to SUPAC IR guidance

2. Recommended chemistry, manufacturing and controls

Lynda Paleshnuik | January 2011

Lynda Paleshnuik | January 2011

Components and composition

Lynda Paleshnuik | January 2011

Components and composition

likelihood of impact on formulation quality

Level 1: unlikely to have detectable impact

Lynda Paleshnuik | January 2011

Components and composition

Lynda Paleshnuik | January 2011

Composition Level 1 Changes

Lynda Paleshnuik | January 2011

Composition Level 2 Changes

Lynda Paleshnuik | January 2011

Grades (when provided)

Lynda Paleshnuik | January 2011

Composition Level 1/2 Changes

Lynda Paleshnuik | January 2011

Composition Level 1/2 Changes

Lynda Paleshnuik | January 2011

Composition Level 3 Changes

Lynda Paleshnuik | January 2011

Recommended documentation level 1

Lynda Paleshnuik | January 2011

Recommended documentation level 2

Lynda Paleshnuik | January 2011

Lynda Paleshnuik | January 2011

Lynda Paleshnuik | January 2011

Recommended documentation level 3

Lynda Paleshnuik | January 2011

Formulation changes - Example

Lynda Paleshnuik | January 2011

Formulation changes - Example

Lynda Paleshnuik | January 2011

Composition Level 1/2 Changes

Lynda Paleshnuik | January 2011

Formulation changes - Example

Lynda Paleshnuik | January 2011

SUPAC and Composition - Summary

Lynda Paleshnuik | January 2011

Lynda Paleshnuik | January 2011