DEALING WITH POST APPROVAL CHANGES- SUPAC

1 | Wasim Raja.S
Sri Venkateswara College of Pharmacy

Overview
What are SUPAC documents
Key SUPAC documents for quality assessment Finished Pharma Products (FPPs)

Basic uses of SUPAC documents

Introduction to SUPAC IR guidance
Main document Equipment addendum

Examples
2 | Wasim Raja.S
Sri Venkateswara College of Pharmacy

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

3 | Wasim Raja.S

Sri Venkateswara College of Pharmacy

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

4 | Wasim Raja.S

Sri Venkateswara College of Pharmacy

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.)
5 | Wasim Raja.S
Sri Venkateswara College of Pharmacy

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
6 | Wasim Raja.S
Sri Venkateswara College of Pharmacy

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).
7 | Wasim Raja.S
Sri Venkateswara College of Pharmacy

Introduction to SUPAC IR guidance

Immediate Release Solid Oral Dosage Forms
Scale-Up and Post approval Changes: Chemistry, Manufacturing, and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation (1995)

8 | Wasim Raja.S

Sri Venkateswara College of Pharmacy

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)
9 | Wasim Raja.S
Sri Venkateswara College of Pharmacy

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
10 | Wasim Raja.S
Sri Venkateswara College of Pharmacy

Introduction to SUPAC IR
Two key areas:
Changes to components and composition

Changes to manufacturing (equipment, process)

11 | Wasim Raja.S

Sri Venkateswara College of Pharmacy

Components and composition

12 | Wasim Raja.S

Sri Venkateswara College of Pharmacy

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

13 | Wasim Raja.S

Sri Venkateswara College of Pharmacy

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).
14 | Wasim Raja.S
Sri Venkateswara College of Pharmacy

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.]

15 | Wasim Raja.S

Sri Venkateswara College of Pharmacy

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.]

16 | Wasim Raja.S

Sri Venkateswara College of Pharmacy

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)
17 | Wasim Raja.S
Sri Venkateswara College of Pharmacy

Composition Level 1/2 Changes

Excipient
L1 Filler 5 Starch 3

% Excipient
L2 10 6

Disintegrant Other
Binder

1
0.5

2
1

18 | Wasim Raja.S

Sri Venkateswara College of Pharmacy

Composition Level 1/2 Changes

Excipient Lubricant Calcium (Ca) or Magnesium (Mg) Stearate Other Glidant Talc Other Film Coat
TOTAL ADDITIVE EFFECT
19 | Wasim Raja.S

% Excipient L1 0.25 1 1 0.1 1 5% L2 0.5 2 2 0.2 2 10%

Sri Venkateswara College of Pharmacy

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.
20 | Wasim Raja.S
Sri Venkateswara College of Pharmacy

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

21 | Wasim Raja.S

Sri Venkateswara College of Pharmacy

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.

22 | Wasim Raja.S

Sri Venkateswara College of Pharmacy

23 | Wasim Raja.S

Sri Venkateswara College of Pharmacy

24 | Wasim Raja.S

Sri Venkateswara College of Pharmacy

Recommended documentation level 3

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

25 | Wasim Raja.S

Sri Venkateswara College of Pharmacy

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%

26 | Wasim Raja.S

Sri Venkateswara College of Pharmacy

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

27 | Wasim Raja.S

Sri Venkateswara College of Pharmacy

Composition Level 1/2 Changes

Excipient % Excipient
L2

Lubricant L1 Calcium (Ca) or Magnesium (Mg) Stearate 0.25 Other 1 Glidant Talc 1 Other 0.1 Film Coat 1
28 | Wasim Raja.S

0.5 2 2 0.2 2
Sri Venkateswara College of Pharmacy

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.

29 | Wasim Raja.S

Sri Venkateswara College of Pharmacy

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)
30 | Wasim Raja.S
Sri Venkateswara College of Pharmacy

Manufacturing

31 | Wasim Raja.S

Sri Venkateswara College of Pharmacy

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

32 | Wasim Raja.S

Sri Venkateswara College of Pharmacy

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

33 | Wasim Raja.S

Sri Venkateswara College of Pharmacy

Manufacturing Equipment Changes

Equipment is categorized according to
Class: operating principle

Subclass: design characterization

34 | Wasim Raja.S

Sri Venkateswara College of Pharmacy

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
35 | Wasim Raja.S
Sri Venkateswara College of Pharmacy

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

36 | Wasim Raja.S

Sri Venkateswara College of Pharmacy

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
37 | Wasim Raja.S
Sri Venkateswara College of Pharmacy

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.
38 | Wasim Raja.S
Sri Venkateswara College of Pharmacy

Example class/subclass: Blending and Mixing

39 | Wasim Raja.S

Sri Venkateswara College of Pharmacy

Equipment categorization
Example: Gemco slant cone blender
Unit operation: blending and mixing Class: diffusion (tumble) mixer Subclass: slant cone blender

40 | Wasim Raja.S

Sri Venkateswara College of Pharmacy

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

41 | Wasim Raja.S

Sri Venkateswara College of Pharmacy

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.
42 | Wasim Raja.S

Sri Venkateswara College of Pharmacy

Manufacturing Equipment Changes

Recommended documentation:
Level 1: one batch on long term stability

Level 2: stability, dissolution

43 | Wasim Raja.S

Sri Venkateswara College of Pharmacy

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)
44 | Wasim Raja.S
Sri Venkateswara College of Pharmacy

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.
45 | Wasim Raja.S
Sri Venkateswara College of Pharmacy

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.
46 | Wasim Raja.S
Sri Venkateswara College of Pharmacy

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
47 | Wasim Raja.S
Sri Venkateswara College of Pharmacy

SUPAC limitations

48 | Wasim Raja.S

Sri Venkateswara College of Pharmacy

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
49 | Wasim Raja.S
Sri Venkateswara College of Pharmacy

Conclusion
For new (to you) and unique situations:
Consult! Those with related experience Senior assessors BE assessors

50 | Wasim Raja.S

Sri Venkateswara College of Pharmacy

Availability
Go to: [Link]
Drugs Guidance, Compliance & Regulatory Information OR directly:

[Link]
Information/Guidances/[Link]

51 | Wasim Raja.S

Sri Venkateswara College of Pharmacy

Thank You

52 | Wasim Raja.S

Sri Venkateswara College of Pharmacy