May one color be replaced with another by placing the batch on concurrent stability and reporting it in the annual report?
A change from one color to another should be submitted as a prior approval supplement.
Can color be changed under SUPAC-IR?
Yes. A change in color, either in amount or from one color to another, is a level 3 component and composition change which calls for a prior approval supplement. However, if the color is merely being removed, it is a level 1 change and can be reported in the next annual report.
What is the full definition of a change in 'technical grade" of an excipient? Does this only mean a change in excipient specifications that may impact functionality or does it include a change in supplier even if all applicable specifications remain the same?
Technical grades of excipients differ in their specifications and intended use. Technical grades may differ in: 1) specifications and/or functionality; 2) impurities; and 3) impurity profiles. If a supplier of an excipient changes but its technical grade AND specifications remain the same, the agency should be notified in an annual report.
How does one apply SUPAC-IR to multifunctional excipients, e.g., starch?
SUPAC-IR composition changes are based on being able to define the use or action of the particular excipient in the product. This rationale should be included by the applicants as part of their original applications. Not all multifunctional excipients are listed in the guidance. However, if an excipient was utilized to provide multiple functions such as pregelatinized starch as a filler, starch as a disintegrant, starch paste as a binder, then the most conservative recommended change should be followed (e.g., for an excipient that is a filler, disintegrant and binder, the recommended limit for a Level 2 change is " 0.5 percent,). An applicant may wish to add an explanation of how the change will affect other functions of the excipient in the product. If this information was not included in the original application, the review division should be consulted before filing such a SUPAC change, either through a CBE or annual report.
What is the reference source for defining the action of an inactive ingredient, for example, lubricant versus glidant? What if the action is defined differently in two sources?
An applicant should be able to justify the choice and the basis for the selection of a particular excipient, i.e., its expected function in the drug product. It may be useful to cite a source. The action may depend on the specific product.
Does SUPAC-IR cover changes in granulating solution volume outside the range in an application?
Changes in granulating solution volume are not covered under SUPAC-IR. Minor changes are considered as normal operating procedure and should be included in the executed batch record. However, if this represents a permanent change, such a change may be described in the annual report along with the data to justify that the formulation quality and performance (i.e., drug product is within the approved specifications) was not altered.
To what category does a change in granulation solvent in a wet granulation process belong?
A change in granulating solvent (e.g., alcohol to water) would alter the composition of the drug product, both qualitatively and quantitatively, even though it may be removed during manufacture of the drug product. Because such a change may have significant impact on formulation quality and performance, it is a level 3 composition change that needs a prior approval supplement.
The NDA includes validated/approved ranges for excipients in the formulation. We would like to move the target formula amount of one of the fillers to the upper value in the range. Will this be a level 1 change in composition?
All changes are predicated on the target approved in the original application or through a prior approval supplement for a formulation change. For products approved with only a range for an excipient, the target may be assumed to be the mid-point of the approved range. If the new target is within the validated range, the change will be a level 1 or 2 change depending on the specific excipient changed and the percent change (see the SUPAC-IR guidance document). The target originally approved remains the target of record; i.e., Level 1 or Level 2 component changes made under SUPAC- IR do not change the target. If the new target is not within the validated range, the proposed target will need a prior approval supplement.
When microcrystalline cellulose is increased by 5%, the tablet weight increases. Can this still be a level 1 change?
After the SUPAC-IR change, if the new target weight is still within the range in the approved original application, it is a level 1 change. Otherwise, it is a Level 2 or 3 change, both of which are to be submitted as a prior approval supplement.
If one component in a formulation is decreased, must another be increased so that the final weight can remain the same?
No. The amount of a single component in the formulation may be changed independent of any other changes. (See 9 above)
It is my understanding that the development report should cover ranges of processing parameters. Further, the validation report should cover the target parameters for production. If this is true, when level 1 changes are made, how can the validation cover range? For future validation reports, is it acceptable to vary processing parameters to prepare for future SUPAC changes?
The validation report should cover the target production parameters; however, it is not restricted to these only. If a range is specific, it needs to be validated. This can involve manufacturing batches of product at the extremes of the desired range(s), with appropriate testing to assure that the extreme range batches continue to meet all quality attributes, including dissolution and possibly in vivo bioequivalence tests. For future validation reports, it is acceptable to vary processing parameters. However, it should be understood that the Center's chemists do not review validation data collected by applicants, post-approval, on the first three production batches, because such information is checked by the Field investigators as part of the cGMP requirements. Thus, a summary of validation data on the test (bioavailability/bioequivalence) batch(es) submitted in the original application for approval is the basis for setting acceptable ranges of processing parameters for manufacture of the IR dosage form. These data may include parameters such as mixing time, mixing speed, and blend assays. Thus, for future level 1 SUPAC-IR changes, applicants should use the approved validation ranges as described in the application.
What is the guidance to determine if a new drug falls into the category of narrow therapeutic range?
Appendix A of the SUPAC-IR guidance lists a number of such drugs. In addition, 21 CFR 320.338 describes how to determine if a drug falls into this category.
Is a change in gelatin capsule size considered a SUPAC-IR component and composition change?
Issues related to empty gelatin capsules are not covered in the SUPAC-IR guidance. Only the component categories discussed in the document are covered. Changes for other components should be submitted in accordance with the provisions of 21 CFR 314.70.
When making a component or composition change according to SUPAC-IR, and the approved application has a range and target for a specific component, does the range move when the target changes?
No. The range remains the same even when the target changes. Such changes are predicated on the target approved in the original application or through prior approval supplement for a formulation change. Changes to the approved range should be made by prior approval supplements in accordance with the provisions of 21 CFR 314.70.
Are wetting agents covered under SUPAC-IR?
No. Only components included in categories spelled out in the guidance qualify as SUPAC-IR changes. Thus, wetting agents are not covered.
Can inks be changed under SUPAC-IR? If so, how?
If the new ink has been used in other approved products the change is allowed under SUPAC-IR as a level one change. Alternatively, if all of the components of the ink have been used in approved drug products, the switch also can be made under SUPAC-IR. A justification should be given; reference should be made to the approved product(s) where the ink and/or the components are already used.
Can inks be eliminated under SUPAC-IR?
Ink can be eliminated as a level 1 change.