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“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……”
Michigan an Uppsala ◘ International Society of Pharmaceutical Engineering (equipment addenda) .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.
• The are many advantages to using SUPAC !! • SUPAC relates to filings in place with FDA. • A company may make changes by filing a supplement using the existing regulations under 21 CFR 314. This offers significant advantages with regard to planning and resource allocation. • SUPAC may present challenges when dealing with loosely structured NDAs!! • Companies may make changes to existing filings with a greatly reduced approval time.70(b)(2). • In many cases changes may be made using an annual report.Various features • SUPAC is only a guidance and NOT a regulation. .
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 .
plus addition or deletion of an excipient (except for a colour. ink). MR: + preservative). ink. flavour.Components and composition • Level 1 changes: quantitative only (except IR: colour. • Level 3 changes: quantitative > Level 2. . plus any change in excipient grade (MR: + change in excipient specifications). flavour. • Level 2 changes: quantitative > Level 1.
– A level 2 change allows a range of +10% – Changes beyond +10% are considered level 3. the SUPAC-IR guidance defines change in quantity as percentage (weight / weight) of total release-controlling excipients.SUPAC-IR Excipient Levels • For the release controlling excipients. For these: – A level 1 change means that the total additive effect of all RCE should not be more than +5%. .
Other . 2.Higher than SUPAC-IR Level 2 Excipient ranges II III .0% +/.Lubricant: Ca/Mg Strt.0% +/.2.0% +/. Other .6.Binder .1.Glidant: Talc. +/.Binder .1. +/-2.SUPAC-IR Excipient Levels Level I Excipients % Change (w/wtotal) Allowed +/. 1.3.0%.Disintegrant: Starch. +/.1% +/.25%.Film Coat .0% +/.5% +/.Filler .Disintegrant: Starch.10.0% +/.Glidant: Talc.5.0. +/-1.1. Other .2.0% +/.0%. Other .0.0.0.Film Coat .0%. Other .5%. Other .0% +/.2% +/.Lubricant: Ca/Mg Strt.0%.0% +/.0.Filler .0% .
] FILING DOCUMENTS • Stability testing: one batch on long-term stability data reported in annual report.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. • Supportive dissolution data: none • Supportive in-vivo bioequivalence testing: none .
] FILING DOCUMENTS Requirements for level 2 include stability testing. not just grade changes [Note that total additive effect should not exceed 10%of total target FPP weight.g. • Changes in the technical grade of an excipient e. dissolution testing and possibly an in-vivo study (depending on the results of dissolution testing).Composition – Level 2 Changes Level 2 changes • Changes greater than level 1 but less than the following table (level 2 column). . Avicel PH102 vs Avicel PH200 • BEWARE TRADE NAME CHANGES – some are actually qualitative changes.
4 BCS classes are: 1 = HS. 85% in 30 minutes. LP. 4 = LS. If dissolution is this rapid across the pH range. i. absorption not dissolution rate limited. HP.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. 2 = 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. and dissolution. intestinal permeability. HP.. . BCS defines rapid dissolution.e. 3 = HS.
Dissolution data .
. solubility and permeability are factors to consider. dissolution testing and an in-vivo study.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. FILING DOCUMENTS Requirements for level 3 include stability testing.
g.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.SUPAC and Composition . formulation changes for modified release products) .
• . such as from granulation technique to direct compression of dry powder FILING DOCUMENTS :. Stability testing: One batch on long-term stability.Stability Dissolution BE study • .g.g. mixing times. Dissolution Documentation: Case B dissolution profile Level 3: change in the type of process.Manufacturing – Process Changes • Level 1: changes to parameters (e. operating speeds) outside application/validation ranges FILING DOCUMENTS:Notification of change and submission of updated batch records. Level 2: changes to parameters (e. operating speeds) within application/validation ranges FILING DOCUMENTS :-None beyond application/ compendial release requirements. mixing times.
Dissolution study case c . FILING DOCUMENTS • Chemistry Documentation :Application/ compendial release requirements. • Stability testing: One batch on long-term stability LEVEL 2 • Change in equipment to a different design and different operating principles. FILING DOCUMENTS :Stability. and 2) change to alternative equipment of the same design and operating principles of the same or of a different capacity.Manufacturing – Equipment Changes LEVEL 1 • 1) change from non-automated or non-mechanical equipment to automated or mechanical equipment to move ingredients. • Notification of change and submission of updated batch records.
environmental conditions (e. FILING DOCUMENTS • Location of new site and updated batch records • One batch on long-term stability data reported in annual report.SITE CHANGES • Level 1 changes consist of site changes within a single facility where the same equipment. and personnel common to both manufacturing sites are used.. except for administrative information and the location of the facility FILING DOCUMENTS :-None beyond application/ compendial release requirements. .g. environmental conditions (e.. SOP's. • Level 2 changes consist of site changes within a contiguous campus. except for administrative information and the location of the facility. where the same equipment. and where no changes are made to the manufacturing batch records. or between facilities in adjacent city blocks.g. and personnel common to both manufacturing sites are used. standard operating procedures (SOP's). and where no changes are made to the manufacturing batch records. temperature and humidity) and controls. temperature and humidity) and controls.
• Accelerated study and long term stability study according to data available • Dissolution Documentation : Case B Multi-point dissolution profile .SITE CHANGES • Level 3 changes consist of a change in manufacturing site to a different campus. Application/ compendial release requirements. 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.
and 3) the same standard operating procedures (SOP's) and controls.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. 2) the batch(es) is (are) manufactured in full compliance with CGMP's. where: 1) the equipment used to produce the test batch(es) is of the same design and operating principles. as well as the same formulation and manufacturing procedures. FILING DOCUMENTS • Notification of change and submission of updated batch records in annual report. • One batch on long-term stability reported in annual report. are used on the test batch(es) and on the full-scale production batch(es).
• . 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). 3 Dissolution Documentation : Case B testing. 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.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.
I. D. E.IN VIVO BIOEQUIVALENCE STUDIES • • • • • • • • • A. B. C. F. G. Objective Design Selection of Subjects Procedure Restrictions Blood Sampling Analytical Method Pharmacokinetic Analysis Statistical Analysis . H.
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