SUPAC guidelines: Pilot plant scale-up techniques Industrial Pharmacy Notes
SUPAC Definition
The scale-up process and the changes made after approval in the composition, manufacturing process, manufacturing equipment, and change of site have become known as Scale-Up and Post-approval Changes, or SUPAC.
Changes are being made in the manufacturing process and chemistry of a drug product following approval and continuing throughout its life. Depending upon foreseen (or unforeseen) requirements, there can be changes in the raw materials, process, equipment or manufacturing site, and batch size which ultimately affect the quality attributes of a drug or finished product. Therefore, there is a need to anticipate and fully evaluate the impact of any kind of change on the quality of a drug or finished product. The intensity of the adverse effect produced by a particular change depends on the type of dosage form.
Purpose of Guidance
This guidance provides recommendations to sponsors of new drug applications (NDA’s), abbreviated new drug applications (ANDA’s), and abbreviated antibiotic applications (AADA’s) who intend, during the post-approval period, to change:
- The components or composition
- The site of manufacture
- The scale-up/scale-down of manufacture
- The manufacturing (process and equipment) of an immediate release oral formulation.
The guidance defines:
- Levels of change
- Recommended chemistry, manufacturing, and controls tests for each level of change
- In-vitro dissolution tests and/or in vivo bioequivalence tests for each level of change
- Documentation that should support the change. For those changes filed in a “changes being effected supplement’’ [21 CFR 314.70 (c)], the FDA may, after a review of the supplemental information, decide that the changes are not approvable
This guidance thus sets forth application information that should be provided to CDER to assure continuing product quality and performance characteristics of an immediate release solid oral dose formulation for specified post-approval changes
I. Site Changes
Site changes consist of changes in the location of the site of manufacture for both company-owned and contract manufacturing facilities and do not include any scale-up changes, changes in manufacturing (including process and/or equipment), or changes in components or composition. Scale-up is addressed in Section V of this guidance. New manufacturing locations should have a satisfactory current Good Manufacturing Practice (CGMP) inspection
Level 1 changes
Definition: 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. Common is defined as employees already working on the campus who have suitable experience with the manufacturing process
Test Documentation
- Chemistry Documentation: None beyond application/compendial release requirements.
- Dissolution Documentation: None beyond application/compendial release requirements.
- In Vivo Bioequivalence Documentation- None.
Filing Documentation-Annual report.
Level 2 changes
Definition: 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.
Test Documentation
a. Chemistry Documentation Location of new site and updated batch records. None beyond application/ compendial release requirements. One batch on long-term stability data reported in annual report.
b. Dissolution Documentation None beyond application /compendial release requirements.
c. In Vivo Bioequivalence Documentation- None.
Filing Documentation
Changes being effected supplement; annual report (long term stability test data).
Level 3 changes
Definition:
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. To qualify as a Level 3 change, the same equipment, SOPs, environmental conditions, and controls should be used in the manufacturing process at the new site, and no changes may be made to the manufacturing batch records except for administrative information, location and language translation, where needed
Test Documentation
Chemistry Documentation Location of the new site and updated batch records. Application/ compendial release requirements. Stability: Significant body of data available: One batch with three months of accelerated stability data is reported in the supplement; one batch of long-term stability data is reported in the annual report. A significant body of data not available: Up to three batches with three months of accelerated stability data reported in the supplement; up to three batches of long-term stability data reported in the annual report.
Dissolution Documentation Case B: Multi-point dissolution profile should be performed in the application/compendia medium at 15, 30, 45, 60 and 120 minutes or until an asymptote is reached. The dissolution profile of the drug product at the current and proposed site should be similar.
In Vivo Bioequivalence Documentation- None.
Filing Documentation
Changes being effected supplement; annual report (long-term stability data)
2. Changes in Batch Size (Scale-Up/Scale-Down)
Post-approval changes in the size of a batch from the pivotal/pilot scale biobatch material to larger or smaller production batches call for the submission of additional information in the application. Scale-down below 100,000 dosage units is not covered by this guidance. All scale-up changes should be properly validated and, where needed, inspected by appropriate agency personnel.
Level 1 Changes
Definition of Level: 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 is of the same design and operating principles;
2) The batch is manufactured in full compliance with CGMP;
3) The same standard operating procedures (SOPs) and controls, as well as the same formulation and manufacturing procedures, are used on the test batch and on the full-scale production batch.
Test Documentation
Chemistry Documentation Application/ compendial release requirements. Notification of change and submission of updated batch records in the annual report. One batch on long-term stability reported in
annual report.
Dissolution Documentation None beyond application/compendial release requirements.
In Vivo Bioequivalence-None.
Filing Documentation
Annual report (long- term stability data).
Level 2 Changes
Definition of Level Changes in batch size beyond a factor of ten times the size of the pilot/biobatch, where:
- The equipment used to produce the test batch is of the same design and operating principles;
- The batch is manufactured in full compliance with CGMP’S; and
- The same SOP’s and controls as well as the same formulation and manufacturing procedures are used on the test batch and on the full-scale production batch.
Test Documentation
- Chemistry Documentation Application/ compendial release requirements. Notification of change and submission of updated batch records. Stability testing: One batch with three months of accelerated stability data and one batch on long-term stability.
- Dissolution Documentation-Case B testing.
- In Vivo Bioequivalence-None.
Filing Documentation
Changes being effected supplement; annual report (long-term stability data).
3. Manufacturing Equipment
Manufacturing changes may affect both equipment used in the manufacturing process and the process itself.
Level 1 Changes
Definition of Change This category consists of:
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.
Test Documentation
i. Chemistry documentation application/ compendial release requirements. Notification of change and submission of updated batch records. Stability testing: One batch on long-term stability.
ii. Dissolution Documentation None beyond application/compendial release requirements.
iii. In Vivo Bioequivalence Documentation- None
Filing Documentation– Annual report (long- term stability data).
Level 2 Changes
Definition of Level
Change in equipment to a different design and different operating principles.
Test Documentation
Chemistry Documentation Application/ compendial release requirements. Notification of change and submission of updated batch records. Stability testing: Significant body of data available: One batch with three months of accelerated stability data reported in the supplement; one batch on long-term stability data reported in the annual report. A significant body of data not available: Up to three batches with three months of accelerated stability data reported in the supplement; up to three batches of long-term stability data reported in the annual report.
Dissolution Documentation-Case C dissolution profile.
In Vivo Bioequivalence Documentation- None.
Filing Documentation
Prior approval supplement with justification for change; annual report (long-term stability data).
4. Manufacturing Process
Level 1 Changes
Definition of Level This category includes process changes including changes such as mixing times and operating speeds within application/validation ranges.
Test Documentation
i. Chemistry Documentation None beyond application/compendial release requirements.
ii. Dissolution Documentation None beyond application/compendial release requirements.
iii. In Vivo Bioequivalence Documentation- None.
Filing Documentation-Annual report.
Level 2 Changes
Definition of Level This category includes process changes including changes such as mixing times and operating speeds outside of application/validation ranges.
Test Documentation
i. Chemistry Documentation Application/ compendial release requirements. Notification of change and submission of updated batch records.
Stability testing: One batch on long-term stability.
ii. Dissolution Documentation-Case B dissolution profile.
iii. In Vivo Bioequivalence Documentation- None.
Filing Documentation Changes being effected supplement; annual report (long term stability data).
Level 3 Changes
Definition of Level This category includes changes in the type of process used in the manufacture of the product, such as a change from wet granulation to direct compression of dry powder.
Test Documentation
Chemistry Documentation Application/ compendial release requirements. Notification of change and submission of updated batch records. Stability testing: Significant body of data available: One batch with three months of accelerated stability data reported in the supplement; one batch on long-term stability data reported in the annual report. A significant body of data not available: Up to three batches with three months of accelerated stability data reported in the supplement; up to three batches of long-term stability data reported in the annual report.
Dissolution Documentation – Case B dissolution.
In Vivo Bioequivalence Documentation In vivo bioequivalence study. The bioequivalence study may be waived if a suitable in vivo/in vitro correlation has been verified.
Filing Documentation
Prior approval supplement with justification; annual report (long-term stability data).
5. In-Vitro Dissolution
See current United States Pharmacopeia/ National Formulary, section <711>, for general dissolution specifications. All profiles should be conducted on at least 12 individual dosage units. Dissolution profiles may be compared using the following equation that defines a similarity factor (f2): f2 = 50 LOG {[1+1/n (R-T ) ] x 100} n 2 -0.5 t=1 t t where Rt and Tt are the percent dissolved at each time point. An f2 value between 50 and 100 suggests the two dissolution profiles are similar.
6. In-Vivo Bioequivalence Studies
Below is a general outline of an in vivo bioequivalence study. It is intended as a guide and the design of the actual study may vary depending on the drug and dosage form.
A. Objective: To compare the rate and extent of absorption of the drug product for which the manufacture has been changed, as defined in this guidance, to the drug product manufactured prior to the change.
B. Design: The study design should be a single dose, two-treatment, two-period crossover with an adequate washout period between the two phases of the study. Equal numbers of subjects should be randomly assigned to each of the two dosing sequences.
C. Selection of Subjects: The number of subjects enrolled in the bioequivalence study should be determined statistically to account for the intrasubject variability and to meet the current bioequivalence interval.
D. Procedure: Each subject should receive the following two treatments:
Treatment 1: Product manufactured with the proposed change.
Treatment 2: Product manufactured prior to the proposed change.
Following an overnight fast of at least 10 hours, subjects should receive either Treatments 1 or 2 above with 240 mL water. Food should not be allowed until 4 hours after dosing. Water may be allowed after the first hour. Subjects should be served standardized meals beginning at 4 hours during the study.
E. Restrictions: Prior to and during each study phase, water may be allowed ad libitum except for 1 hour before and after drug administration. The subject should be served standardized meals and beverages at specified times. No alcohol or xanthine- or caffeine-containing foods and beverages should be consumed for 48 hours prior to each study period and until after the last blood sample is collected.
F. Blood Sampling: Blood samples should be collected in sufficient volume for analysis of parent drug and active metabolite(s), if any. The sampling times should be such that it should be able to capture the Cmax and Tmax during the absorption period. Sampling should be carried out for at least three terminal elimination half- lives for both parent drug and active metabolite(s). Whole blood, plasma or serum, whichever is appropriate for the analytes, should be harvested promptly and samples should be frozen at -200C or -700C to maintain sample stability.
G. Analytical Method: The assay methodology selected should ensure specificity, accuracy, interday and intraday precision, linearity of standard curves, and adequate sensitivity, recovery, and stability of the samples under the storage and handling conditions associated with the analytical method.
H. Pharmacokinetic Analysis: From the plasma drug concentration-time data, AUC0-t, AUCo-infinity, Cmax, Tmax, Kel and t1/2 should be estimated.
I. Statistical Analysis: Analysis of variance appropriate for a crossover design on the pharmacokinetic parameters using the general linear models procedures of SAS or an equivalent program should be performed, with examination of period, sequence and treatment effects. The 90% confidence intervals for the estimates of the difference between the test and reference least squares means for the pharmacokinetic parameters (AUC0-t, AUCo- infinity, Cmax, Tmax) should be calculated, using the two one-sided t-test procedure.
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