2 2 Supporting Documents SUPAC

Lynda Paleshnuik | January 20111 |

Assessment WorkshopCopenhagen – January 2011

Assessment WorkshopCopenhagen – January 2011

Supporting

Documents:

SUPAC


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


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


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


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


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.)


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


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).


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)



► 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)



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


Introduction to SUPAC IRIntroduction to SUPAC IR

Two key areas:

► Changes to components and composition

► Changes to manufacturing (equipment, process)


Components and compositionComponents and composition

User

Complexity of formulationsnmi handbook 900 pagesmulti-functional nmis



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



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).


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.]



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.]


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)


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




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%



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.


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



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.





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


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%



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




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



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.


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)


ManufacturingManufacturing


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


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


Manufacturing – Equipment ChangesManufacturing – Equipment Changes

Equipment is categorized according to

Class: operating principle

Subclass: design characterization


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



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


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


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.





Equipment categorizationEquipment categorization

Example: Gemco slant cone blender

Unit operation: blending and mixing

Class: diffusion (tumble) mixer

Subclass: slant cone blender



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



“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.”



Recommended documentation:

Level 1: one batch on long term stability

Level 2: stability, dissolution


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)



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.



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.


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


SUPAC limitationsSUPAC limitations


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


ConclusionConclusion

For new (to you) and unique situations:

Consult!

● Those with related experience

● Senior assessors

● BE assessors


AvailabilityAvailability

Go to: www.fda.gov

► Drugs

► Guidance, Compliance & Regulatory Information

OR directly:

http://www.fda.gov/Drugs/GuidanceComplianceRegulatory

Information/Guidances/default.htm


Questions?Questions?

2 2 Supporting Documents SUPAC

Documents

stokes tablet

gerteis roller

lubricant

total additive

dissolution

bin blender

operating

lynda paleshnuik