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; and/or
- The manufacturing (process and equipment) of an immediate release oral formulation.
SU: Scale-up during original dossier assessment.
Note that this is not SU during development. Consider changes made after the Biobatch
PAC: Post-PQ/post-approval, i.e. Variations. Comparing the PQ’d/approved product to a changed product.
The guidance defines:
- Levels of change: Minor, Moderate and Major change
- Recommended chemistry, manufacturing, and controls tests for each level of change:
- Test: In vitro dissolution tests and/or in vivo bioequivalence tests for each level of change
- Filing: Documentation that should support the change (Annual, Change being effected supplement and Prior approval supplement).
Various types of changes are described in SUPAC:
- Components and composition
- Manufacturing (equipment, process)
- Batch size
- Manufacturing site changes
Components and composition:
This section of the guidance focuses on changes in excipients in the drug product. Changes in the amount of drug substance are not addressed by this guidance. Changes in components or composition that have the effect of adding a new excipient or deleting an excipient are defined at Level 3 defined below.
A. Level 1 Changes
Level 1 changes are those that are unlikely to have any detectable impact on formulation quality and performance.
Examples:
a. Deletion or partial deletion of an ingredient intended to affect the color or flavor of the drug product; or change in the ingredient of the printing ink to another approved ingredient.
b. Changes in excipients, expressed as percentage (w/w) of total formulation, less than or equal to the following percent ranges:
EXCIPIENT Percent Excipient (w/w) Out of total target dosage form weight
Filler ±5
Disintegrant
Starch ±3
Other ±1
Binder ±0.5
Lubricant
Calcium (Ca) or
Magnesium (Mg) Stearate ±0.25
Other ±1
Glidant
Talc ±1
Other ±0.1
Film Coat ±1
These percentages are based on the assumption that the drug substance in the product is formulated to 100% of label/potency. The total additive effect of all excipient changes should not be more than 5%. (Example: In a product consisting of active ingredient A, lactose, microcrystalline cellulose and magnesium Stearate, the lactose and microcrystalline cellulose should not vary by more than an absolute total of 5% (e.g. lactose increases 2.5% and microcrystalline cellulose decreases by 2.5%) relative to the target dosage form weight if it is to stay within the Level 1 range).
The components (active and excipients) in the formulation should have numerical targets which represent the nominal composition of the drug product on which any future changes in the composition of the product are to be based. Allowable changes in the composition should be based on the approved target composition and not on previous Level 1 changes in the composition.
Test Documentation:
a. Chemistry Documentation – Application/compendial release requirements and stability testing. Stability testing: one batch on long-term stability data reported in annual report.
b. Dissolution Documentation – None beyond application/compendial requirements
c. In Vivo Bioequivalence Documentation – None.
Filing Documentation:
Annual report (all information including long-term stability data).
B. Level 2 Changes
Level 2 changes are those that could have a significant impact on formulation quality and performance.
Tests and filing documentation for a Level 2 change vary depending on three factors: therapeutic range, solubility, and permeability. Therapeutic range is defined as either narrow or non-narrow. A list of narrow therapeutic range drugs is provided in Appendix A. Drug solubility and drug permeability are defined as either low or high. Solubility is calculated based on the minimum concentration of drug, milligram/milliliter (mg/mL), in the largest dosage strength, determined in the physiological pH range (pH 1 to 8) and temperature (37 + 0.5oC). High solubility drugs are those with a dose/solubility volume of less than or equal to 250 mL. (Example:
Compound A has as its lowest solubility at 37 + 0.5oC, 1.0 mg/mL at pH 7, and is available in 100 mg, 200 mg and 400 mg strengths. This drug would be considered a low solubility drug as its dose/solubility volume is greater than 250 mL (400 mg/1.0 mg/mL=400 mL). Permeability (Pe, centimeter per second) is defined as the effective human jejunal wall permeability of a drug and includes an apparent resistance to mass transport to the intestinal membrane. High permeability drugs are generally those with an extent of absorption greater than 90% in the absence of documented instability in the gastrointestinal tract, or those whose permeability attributes have been determined experimentally).
Examples:
a. Change in the technical grade of an excipient. (Example: Avicel PH102 vs. Avicel PH200.)
b. Changes in excipients, expressed as percent (w/w) of total formulation, greater than those listed above for a Level 1 change but less than or equal to the following percent ranges (which represent a twofold increase over Level 1 changes):
EXCIPIENT Percent Excipient (w/w) Out of total target dosage form weight
Filler ±10
Disintegrant
Starch ±6
Other ±2
Binder ±1
Lubricant
Calcium (Ca) or
Magnesium (Mg) Stearate ±0.5
Other ±2
Glidant
Talc ±2
Other ±0.2
Film Coat ±2
These percentages are based on the assumption that the drug substance in the drug product is formulated to 100% of label/potency. The total additive effect of all excipient changes should not change by more than 10%.
The components (active and excipients) in the formulation should have numerical targets that represent the nominal composition of the product on which any future changes in the composition of the product are to be based. Allowable changes in the composition should be based on the approved target composition and not on the composition based on previous Level 1 or Level 2 changes.
Test Documentation
a. Chemistry Documentation – Application/compendial release requirements and batch records. Stability testing: 1 batch with 3 months accelerated stability data in supplement and 1 batch on long-term stability.
b. Dissolution Documentation
Case A: High Permeability, High Solubility Drugs Dissolution of 85% in 15 minutes in 900 mL of 0.1N HCl. If a drug product fails to meet this criterion, the applicant should perform the tests described for Case B or C (below).
Case B: Low Permeability, High Solubility Drugs Multi-point dissolution profile should be performed in the application/compendial medium at 15, 30, 45, 60 and 120 minutes or until an asymptote is reached. The dissolution profile of the proposed and currently used product formulations should be similar.
Case C: High Permeability, Low Solubility Drugs Multi-point dissolution profiles should be performed in water, 0.1 N HCl, and USP buffer media at pH 4.5, 6.5, and 7.5 (five separate profiles) for the proposed and currently accepted formulations. Adequate sampling should be performed at 15, 30, 45, 60, and 120 minutes until either 90% of drug from the drug product is dissolved or an asymptote is reached. A surfactant may be used, but only with appropriate justification. The dissolution profile of the proposed and currently used product formulations should be similar.
c. In Vivo Bioequivalence Documentation
None: if the situation does not meet the description in Case A, Case B or Case C, refer to Level 3 changes.
Filing Documentation
Prior approval supplement (all information including accelerated stability data); annual report (long-term stability data).
C. Level 3 Changes
Level 3 changes are those that are likely to have a significant impact on formulation quality and performance. Tests and filing documentation vary depending on the following three factors: therapeutic range, solubility, and permeability.
Examples:
a. Any qualitative and quantitative excipient changes to a narrow therapeutic drug beyond the ranges noted in Section III.A.1.b.
b. All other drugs not meeting the dissolution criteria under Section III.B.2.b.
c. Changes in the excipient ranges of low solubility, low permeability drugs beyond those listed in Section III.A.1.b.
d. Changes in the excipient ranges of all drugs beyond those listed in Section III.B.1.b.
Test Documentation
a. Chemistry Documentation – Application/compendial release requirements and batch records.
- Significant body of information available: One batch with three months accelerated stability data reported in supplement; one batch on long-term stability data reported in annual report.
- Significant body of information not available: Up to three batches with three months accelerated stability data reported in supplement; one batch on long-term stability data reported in annual report.
b. Dissolution Documentation – Case B dissolution profile as described in Section III.B.2.b.
c. In Vivo Bioequivalence Documentation – Full bioequivalence study. The bioequivalence study may be waived with an acceptable in vivo/in vitro correlation has been verified.
Filing Documentation
Prior approval supplement (all information including accelerated stability data); annual report (long-term stability data).
MANUFACTURING (equipment, process):
Manufacturing changes may affect both equipment used in the manufacturing
process and the process itself.
Process Changes:
Level 1: Within the existing process ranges supported by the current NDA, filed AR, normal testing.
Level 2: Outside the existing ranges, filed CBE, long term stability and dissolution profile testing.
Level 3: Different process, filed PA, all the above plus accelerated testing and biostudy or IVIV correlation.
Older Products
These will require careful review to identify critical process parameters, adequate specifications, clear manufacturing directions and a critical review of the product history. Although SUPAC offers an opportunity to improve our procedures the cost of dealing with incomplete data must be considered a risk. At the least they must be validated within recent process history
New Products
These offer the best opportunity for change since past history is clear in development reports and validation. Review may be simplified to examination of the related development documentation.
Equipment Change:
Level 1: Change to an automated or mechanical material handling system, or equipment of the same design and operating principle, filed AR(annual report), long term stability and normal testing.
Level 2: Change to a different design and operating principle, filed PA (prior approval), all the above plus accelerated stability and dissolution profile.
The class defines equipment that has the same operating principles, while sub class defines variation in design.
Equipment changes within a class are defined as the same (level 1), changes to another class are different (level 2).
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 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: Scale-up to ten times the Biobatch, filed AR, long term stability and normal testing as per NDA.
Level 2: Scale-up beyond ten times the Biobatch, filed as a CBE, all the above plus accelerated stability and dissolution profile testing.
MANUFACTURING SITE CHANGES:
Site changes consist of changes in 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 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.
These changes can be addressed through annual report.
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.
These changes can be addressed through CBE and annual report (long term stability data)
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, SOP’s, 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.
These changes can be addressed through CBE and annual report (long term stability data)
SUPAC GUIDELINES FOR DIFFERENT FORMULATIONS:
- SUPAC guidelines for different formulation for quality assessment are as follows;
- SUPAC IR (Immediate Release): Chemistry, Manufacturing and Controls, In vitro dissolution testing and In vivo Bioequivalence documentation.
- SUPAC MR (Modified Release): Chemistry, Manufacturing and Controls, In vitro dissolution testing and In vivo Bioequivalence documentation.
- SUPAC IR/MR equipment addendum
- SUPAC SS: Nonsterile semi-solids + equipment addendum