lynda paleshnuik | january 2011 1 |1 | assessment workshop copenhagen – january 2011 supporting...
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Lynda Paleshnuik | January 20111 |
Assessment WorkshopCopenhagen – January 2011
Assessment WorkshopCopenhagen – January 2011
Supporting
Documents:
SUPAC
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OverviewOverview
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 AssessmentQuality 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 documentsWhat 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 assessmentSUPAC 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 documentsSUPAC 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 documentsBasic 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 documentsBasic 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).
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Introduction to SUPAC IR guidanceIntroduction 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)
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Introduction to SUPAC IR guidanceIntroduction 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 guidanceIntroduction 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 IRIntroduction to SUPAC IR
Two key areas:
► Changes to components and composition
► Changes to manufacturing (equipment, process)
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Components and compositionComponents and composition
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Components and compositionComponents 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 compositionComponents 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 ChangesComposition – 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 ChangesComposition – 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 - NoteExcipients - 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 ChangesComposition – 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 ChangesComposition – 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 ChangesComposition – 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 1Recommended 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 2Recommended 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 3Recommended documentation – level 3
Requirements for level 3 include stability testing, dissolution testing and an in-vivo study.
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Formulation changes - ExampleFormulation 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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Formulation changes - ExampleFormulation 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
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Composition – Level 1/2 ChangesComposition – 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 - ExampleFormulation 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 - SummarySUPAC 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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ManufacturingManufacturing
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Manufacturing – Process ChangesManufacturing – 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 ChangesManufacturing – 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 ChangesManufacturing – Equipment Changes
Equipment is categorized according to
Class: operating principle
Subclass: design characterization
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Equipment categorizationEquipment 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 ChangesManufacturing – 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
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 exampleEquipment 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
Example class/subclass:Blending and Mixing
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Equipment categorizationEquipment 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 ChangesManufacturing – 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 ChangesManufacturing – 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 ChangesManufacturing – Equipment Changes
Recommended documentation:
Level 1: one batch on long term stability
Level 2: stability, dissolution
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Equipment change - ExampleEquipment 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 - ExampleEquipment 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 - ExampleEquipment 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-solidsEquipment 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 limitationsSUPAC limitations
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SUPAC limitations – Formulation/ManufacturingSUPAC 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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ConclusionConclusion
For new (to you) and unique situations:
Consult!
● Those with related experience
● Senior assessors
● BE assessors
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AvailabilityAvailability
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?Questions?