Changes as per SUPAC Guideline Part -I (components or composition)
Changes as per SUPAC Guideline Part -I (components or composition)
During the post-approval period, to change:
1) The components or composition
2) The site of manufacture
3) The scale-up/scale-down of manufacture.
4) The manufacturing (process and equipment) of an immediate release oral formulation.
The guidance defines:
1) Levels of change
2) Recommended chemistry,manufacturing, and controls tests for each level of change
3) in-vitro dissolution tests and in-vivo bio equivalence tests for each level of change.
4) 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 regarding 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.
CHANGE IN COMPONENTS AND COMPOSITION:
- Changes in excipients in the drug product.
- Changes in components or composition that have the effect of adding a new excipient or deleting an excipient.
A. Level 1 Changes:
Definition of Level – Changes 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 lactose, micro-crystalline cellulose and magnesium stearate, the lactose and micro-crystalline cellulose should not vary by more than an absolute total of 5% (e.g. lactose increases 2.5% and micro-crystalline 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 Bio-equivalence Documentation
- None.
3. Filing Documentation
Annual report (all information including long-term stability data).
B. Level 2 Changes
Definition of Level
The changes 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
- 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) an temperature (37 + 0.5 C).
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 + 0.5 C, 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 two fold 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
- Drug 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 Bio-equivalence Documentation
- None
- If the situation does not meet the description in Case A, Case B or Case C, refer to Level 3 changes.
3. Filing Documentation
- Prior approval supplement (all information including accelerated stability data)
- Annual report (long-term stability data).
C. Level 3 Changes
Definition of Level
The changes 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
- Permeability.
Examples:
a. Any qualitative and quantitative excipient changes to a narrow therapeutic drug beyond the ranges noted in Section Level 1 Changes (Refer -Examples-b).
b. All other drugs not meeting the dissolution criteria under Section Level 2 Changes (Refer -b. Dissolution Documentation).
c. Changes in the excipient ranges of low solubility, low permeability drugs beyond those listed in Section Level 1 Changes (Refer -Examples-b).
d. Changes in the excipient ranges of all drugs beyond those listed in Section Level 2 Changes (Refer -Examples-b).
2. 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 Level 2 Changes (Refer -Examples-b).
c. In-Vivo Bio-equivalence Documentation
Full bio-equivalence study.
The bio-equivalence study may be waived with an acceptable in-vivo/in-vitro correlation has been verified.
3. Filing Documentation
- Prior approval supplement (all information including accelerated stability data).
- Annual report (long-term stability data).
