AccuReg: What is SUPAC?

The Regulatory Clinic - August, 1997

Dear Clinic:

Our company, a manufacturer of generic drugs, has recently undergone a merger with a much larger firm. Now my supervisor has begun talking about SUPAC. What does this stand for, what does it mean, and how will it affect me and my company?

Signed, "Not Ready for Prime-Time," Minneapolis, MN

Dear "Prime-Time":

The acronym "SUPAC" stands for "Scale-Up and Post-Approval Changes". It refers to the FDA-recommended testing and filing actions to be taken by a pharmaceutical firm when it changes the manufacturing processes of a drug product that has been approved via a New Drug Application (NDA), an Abbreviated New Drug Application (ANDA), or an Abbreviated Antibiotic Drug Application (AADA). The Agency has provided its recommendations to industry in the form of Guidances.

As you may be aware, 21 CFR 314.70 already provides instructions for how changes to approved manufacturing process should be reported to the Agency. Specifically, depending on the magnitude of the change and the possibility that the change could negatively affect the product, the Code provides that notification should be accomplished in one of three ways:

Via a supplement that requires approval by the FDA prior to implementation of the change;
Via a supplement that does not require approval by the FDA prior to implementation of the change ("changes being effected");
Via an annual report.

Unfortunately, the instructions indicating which type of changes fall into what notification category can be broadly interpreted and are sometimes difficult to follow. Luckily, the regulations [21 CFR 314.70(a)] also indicate that less burdensome routes of notification may be followed if those routes are published in the Federal Register (FR). That is the main purpose of the SUPAC Guidances - to provide industry with clear, streamlined (i.e., "less burdensome") ways to test and report manufacturing changes. (Note: As required by 21 CFR 314.70(a), the documents are issued via the FR.)

Why do the SUPAC Guidances offer an advantage over the regulations?

The documents are specific for particular dosage forms. This approach was taken since some product types are more complicated than others, and as such, will likely require more complicated controls. To date, two Guidances have been finalized. They are:

Guidance for Industry: Immediate Release Solid Oral Dosage Forms---Scale-Up and Post-Approval Changes: Chemistry, Manufacturing and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation (November 1995)

Guidance for Industry: Nonsterile Semisolid Dosage Forms---Scale-Up and Post-Approval Changes: Chemistry, Manufacturing and Controls; In Vitro Dissolution Testing and In Vivo Bioequivalence Documentation (May 1997)

In addition, SUPAC documents covering other dosage forms (e.g., extended-release products, transdermals, parenteral solutions), as well as a related document(s) for bulk active substances, are at various stages of development.

The FDA and industry have been working very closely to prepare these documents. Industry supplies its input at meetings and workshops as well as through written comments.

Although these SUPAC documents are not regulations, the FDA is working to ensure that the Guidances are as consistently interpreted and applied by both the Agency and industry as possible. To this end, the Agency has undertaken a rather comprehensive training program, providing in-house training for its personnel and public workshops for others. Furthermore, although the main thrust of the training is provided at the time a Guidance is issued, the Agency has been diligent in ensuring that subsequent, ongoing interpretation and application of the recommendations remain consistent. In fact, as recent as February 1997, the FDA issued two documents discussing how to properly utilize the SUPAC-IR Guidance for Industry (issued November 1995). These documents are:

Manufacturing Equipment Addendum to the Guidance for Industry for Scale-Up and Post Approval Changes: Immediate Release Products (SUPAC-IR), Draft Guidance for Industry. Released on February 3, 1997.
Letter to industry from Dr. Roger L. Williams, Deputy Center Director for Pharmaceutical Science, CDER, dated February 18, 1997. This letter discussed how industry should interpret stand alone packaging operation site changes and stand alone analytical site changes based upon the Agency's re-assessment of these issues. In addition, it provided the answers to significant questions frequently asked by industry.

Finally, you asked how these Guidances affect you and your company, specifically. That depends on what types of products you manufacture, and your job responsibilities in the company. If you are involved in regulatory affairs submission work, scale-up activities, process validation, or analytical testing, you may be affected, assuming your company manufactures immediate release oral dosage forms and nonsterile semisolid dosage forms. (As indicated above, only these two types of products are currently covered by SUPAC Guidances.) If you manufacture another product type, SUPAC won't affect you now; your company must still interpret and follow 21 CFR 314.70. But even if that is the case, keep an eye out for future SUPAC Guidances that could affect your product -- they may be coming soon.

Susan M. Fromm, RAC
AccuReg, Inc.

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