SCALE UP & POST APPROVAL CHANGES (SUPAC)

SUPAC RATIONALE
For years the Agency has had difficulty developing a regulatory policy, based on solid pharmaceutical principles for scaling-up solid oral dosage form batch sizes. The published scientific literature does not presently provide a sufficiently rich source of data to enable such regulatory policy formation. Additionally, the process should be controlled by employment of a validation protocol which defines the critical parameters and also establishes the acceptance criteria for the granulation or blend which may include sieve analysis, flow, density, uniformity, compressibility, moisture content, etc

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)

Various features
SUPAC is only a guidance and NOT a regulation. A company may make changes by filing a supplement using the existing regulations under 21 CFR 314.70(b)(2). The are many advantages to using SUPAC !! SUPAC relates to filings in place with FDA. SUPAC may present challenges when dealing with loosely structured NDAs!! Companies may make changes to existing filings with a greatly reduced approval time. In many cases changes may be made using an annual report. This offers significant advantages with regard to planning and resource allocation.

SUPAC documents for quality assessment

SUPAC IR (immediate release) SUPAC MR (modified release) SUPAC IR/MR equipment addendum SUPAC IR Q&A SS: Non sterile semi-solids + equipment addendum

General Aspects: (Change) Variables Covered

Components and Composition Non

Release Controlling Controlling

Release

Site

Batch Size (Scale-Up/Scale-Down)

Manufacturing Equipment Process

General Aspects: Supporting Data

Level of Change

Level I (Minor) change Level II (Moderate) change Level III (Major) change Chemistry (A/C test, Stability) In Vitro dissolution/release In Vivo bioequivalence test / IVIVC Annual report Change being effected supplement Prior approval supplement

Tests

Filing

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).

SUPAC-IR Excipient Levels

For the release controlling excipients, the SUPAC-IR guidance defines change in quantity as percentage (weight / weight) of total release-controlling excipients. For these: A level 1 change means that the total additive effect of all RCE should not be more than +5%. A level 2 change allows a range of +10% Changes beyond +10% are considered level 3.

SUPAC-IR Excipient Levels

Level
I

Excipients

% Change (w/wtotal) Allowed

+/- 1.0%; +/- 0.1% +/- 3.0%; 1.0% +/- 0.5% +/- 0.25%; +/-1.0% +/- 5.0% +/- 1.0% +/- 2.0%; +/- 0.2% +/- 6.0%; 2.0% +/- 1.0% +/- 0.5%; +/-2.0% +/- 10.0% +/- 2.0%

- Glidant: Talc; Other - Disintegrant: Starch; Other - Binder - Lubricant: Ca/Mg Strt; Other - Filler - Film Coat - Glidant: Talc; Other - Disintegrant: Starch; Other - Binder - Lubricant: Ca/Mg Strt; Other - Filler - Film Coat - Higher than SUPAC-IR Level 2 Excipient ranges

II

III

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.] FILING DOCUMENTS

Stability testing: one batch on long-term stability data reported in annual report. Supportive dissolution data: none Supportive in-vivo bioequivalence testing: none

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.]

FILING DOCUMENTS

Requirements for level 2 include stability testing, dissolution testing and possibly an in-vivo study (depending on the results of dissolution testing).

Dissolution data
BCS takes into account three major factors that govern the rate and extent of drug absorption from IR solid oral dosage forms: solubility, intestinal permeability, and dissolution. 4 BCS classes are: 1 = HS, HP; 2 = LS, HP; 3 = HS, LP; 4 = LS, LP Different formulations of rapidly dissolving BCS class 1 product can be given biowaiver if they show rapid and similar dissolution profiles over the physiological pH range.

BCS defines rapid dissolution, i.e., 85% in 30 minutes. If dissolution is this rapid across the pH range, absorption not dissolution rate limited.

Dissolution data

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

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)

Manufacturing Process Changes

Level 1: changes to parameters (e.g. mixing times, operating speeds) within application/validation ranges FILING DOCUMENTS :-None beyond application/ compendial release requirements. Level 2: changes to parameters (e.g. mixing times, operating speeds) outside application/validation ranges FILING DOCUMENTS:Notification of change and submission of updated batch records. Stability testing: One batch on long-term stability. Dissolution Documentation: Case B dissolution profile Level 3: change in the type of process, such as from granulation technique to direct compression of dry powder FILING DOCUMENTS :- Stability Dissolution BE study

Manufacturing 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 alternative equipment of the same design and operating principles of the same or of a different capacity. FILING DOCUMENTS Chemistry Documentation :Application/ compendial release requirements. Notification of change and submission of updated batch records. Stability testing: One batch on long-term stability LEVEL 2 Change in equipment to a different design and different operating principles. FILING DOCUMENTS :Stability, Dissolution study case c

SITE CHANGES

Level 1 changes consist of site changes within a single facility where the same equipment, standard operating procedures (SOP's), environmental conditions (e.g., temperature and humidity) and controls, and personnel common to both manufacturing sites are used, and where no changes are made to the manufacturing batch records, except for administrative information and the location of the facility FILING DOCUMENTS :-None beyond application/ compendial release requirements. Level 2 changes consist of site changes within a contiguous campus, or between facilities in adjacent city blocks, where the same equipment, SOP's, environmental conditions (e.g., temperature and humidity) and controls, and personnel common to both manufacturing sites are used, and where no changes are made to the manufacturing batch records, except for administrative information and the location of the facility. FILING DOCUMENTS Location of new site and updated batch records One batch on long-term stability data reported in annual report.

SITE CHANGES
Level 3 changes consist of a change in manufacturing site to a different campus. A different campus is defined as one that is not on the same original contiguous site or where the facilities are not in adjacent city blocks FILING DOCUMENTS Location of new site and updated batch records. Application/ compendial release requirements. Accelerated study and long term stability study according to data available Dissolution Documentation : Case B Multi-point dissolution profile

CHANGES IN BATCH SIZE (SCALE-UP/SCALE-DOWN)

Level 1 Change in batch size, up to and including a factor of 10 times the size of the pilot/ biobatch, where: 1) the equipment used to produce the test batch(es) is of the same design and operating principles; 2) the batch(es) is (are) manufactured in full compliance with CGMP's; and 3) the same standard operating procedures (SOP's) and controls, as well as the same formulation and manufacturing procedures, are used on the test batch(es) and on the full-scale production batch(es). FILING DOCUMENTS Notification of change and submission of updated batch records in annual report. One batch on long-term stability reported in annual report.

CHANGES IN BATCH SIZE (SCALE-UP/SCALE-DOWN)

Level 2
Definition of Level : Changes in batch size beyond a factor of ten times the size of the pilot/biobatch, where: 1) the equipment used to produce the test batch(es) is of the same design and operating principles; 2) the batch(es) is (are) manufactured in full compliance with CGMP'S; and 3) the same SOP's and controls as well as the same formulation and manufacturing procedures are used on the test batch(es) and on the full-scale production batch(es). FILING DOCUMENTS 1 Notification of change and submission of updated batch records. 2 Stability testing: One batch with three months accelerated stability data and one batch on long-term stability. 3 Dissolution Documentation : Case B testing.

IN VIVO BIOEQUIVALENCE STUDIES

A. B. C. D. E. F. G. H. I.

Objective Design Selection of Subjects Procedure Restrictions Blood Sampling Analytical Method Pharmacokinetic Analysis Statistical Analysis

THANKS