Stand-alone packaging site changes may be made under SUPAC-IR with CBE supplement, FDA advises.

STAND-ALONE PACKAGING SITE CHANGES MAY BE SUBMITTED AS CHANGE-BEING-EFFECTED supplement under FDA's Scale-up and Post-Approval Changes Guidance for Immediate Release products, FDA said in a Feb. 18 letter to application holders. The agency has reconsidered its previous position that only packaging site changes that were part of a complete manufacturing operation are covered by SUPAC-IR, the letter states.

For the stand-alone packaging site change to require a change-being-effected supplement, it must use containers and closures included in the approved application and have a satisfactory Good Manufacturing Practices profile. FDA added that the CBE should contain "a commitment to place the first production batch of the product on long-term stability studies using the approved protocol and to submit the resulting data in annual reports."

"If the facility has not received a satisfactory cGMP inspection within the previous two years for the type of packaging operation involved, a prior-approval supplement with the same commitment for stability is recommended," FDA said.

Another reassessment by FDA that has "been of great concern and interest to industry" is for a stand-alone analytical testing laboratory site changes, FDA said. Such changes may also now be made with a change-being-effected supplement under SUPAC-IR. In addition to meeting cGMPs, the site must use the same standard operating procedures and test methods employed in the approved application. Again, if the facility has not had a satisfactory GMP inspection within the previous two years, "a prior approval supplement is recommended."

The letter includes a question-and-answer list covering questions about SUPAC- IR "that have been asked most frequently" or that FDA considers most significant.

The questions on manufacturing site changes include: "Must the inspection which is required for a site transfer have been conducted for the same dosage form?" and "Is moving to/between contract manufacturers covered by SUPAC-IR?" To both, FDA answers in the affirmative. Another question asks: "Is it possible to have a site change covered under SUPAC-IR when the change results in different/revised SOPs?" FDA responds that "if SOPs are different, the implication is that the manufacturing process has also changed. Thus this site change is not covered under SUPAC-IR" and "a prior approval supplement is required."

A question under component and composition changes asks whether color may be changed under SUPAC-IR. FDA states that a change in color may be made under the guidance and clarifies that "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." FDA adds, however, that "if the color is merely being removed, it is a level 1 change and can be reported in the next annual report."

The letter to industry is the latest effort by FDA to clarify SUPAC-IR requirements. The agency held a SUPAC-IR training last February and sent a letter to industry in April on implementation of the guidance ("The Pink Sheet" Feb. 26, 1996, T&G-5 and April 22, 1996, T&G-10).

FDA has further clarified the requirements of SUPAC-IR with the release of a draft manufacturing equipment addendum to the guidance on Feb. 3. The addendum was developed by FDA and the International Society of Pharmaceutical Engineering as an aid in determining what documentation should be submitted to the agency for manufacturing equipment changes.

The addendum organizes equipment by class (operating principle) and subclass (design characteristic) under broad categories of unit operation such as blending and mixing, drying, particle size reduction and separation, granulation, unit dosage, coating and printing, and soft gelatin capsule encapsulation. FDA is requesting comments on the addendum by April 3.