FDA Perspectives: An Initial Report of CDER's Recall Root Cause Research Project (Part II) - Pharmaceutical Technology

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FDA Perspectives: An Initial Report of CDER's Recall Root Cause Research Project (Part II)
The authors discuss how their research will help FDA in its identification of areas of emphasis in pre- and postapproval evaluation of products and processes.

Pharmaceutical Technology
Volume 35, Issue 1, pp. 66-69

Examples of root-cause analysis

With that brief background on RCA, the following hypothetical but realistic examples may be useful to illustrate the typical output of our RCAs5 and how persistently asking the question "why" can lead to a specific answer:
RCA Example 1.
Who: Tim's PharmCo
What: Tim's PinkApple tablets
Where: Springfield, MO
When: 4/1/2005
Why: Some tablets contain no active ingredient.

The question to ask in this situation is "Why is there no active ingredient in the tablet?"

During the investigation it was determined that tablet lots manufactured on a Plover 78 press since Mar. 19, 2005, lacked API and instead "pink layer only" tablets were produced. (The "pink layer" provides bulk, color, and acts as a barrier to the other layers. When only the pink layer is present, this signifies that the active layer is missing.)

The next question should logically be, "Why are 'pink layer only' tablets not detected?"

The deviation appeared to be due to an intermittent manufacturing equipment malfunction. So, the authors would ask, "Why is there a malfunction?"

There is incomplete rejection of "pink layer only" tablets during routine sampling at the compression stage.

Why is there incomplete rejection of "pink layer only" tablets?

The physical act of sampling interferes with the synchronicity in the compression operation.

Why does sampling interfere with compression?

The operator stops the machine to take a sample.

Why does the operator stop the machine?

The automated sampling shoot does not always work; it is intermittent.

What is the recall root cause?

Fundamentally, a grave coating-process operational flaw must be corrected to assure the presence of active ingredient. The further failure of final QC checks to detect this serious defect is due to a loss of compression machinery synchronization with a sampling chute that needs repair.

RCA Example 2.
Who: Enervite Pharmaceuticals
What: EstraStick Oral solution 0.03 mg/day
Where: New York, NY
When: 10/14/2003
Why: Labeling issue

The patient booklet contained in each calendar-pack of nine systems does not include the required current black box warning for the key ingredient as contained in the approved NDA labeling. The black-box warning was updated in August 2003.

Why is the black-box warning not included in the patient booklet?

The firm's label control program did not assure that the patient booklet reflected the latest warning associated with the product.

Why was the booklet not updated?

Following approval of the new patient packaging insert (PPI) black-box labeling, the firm put new labeling into use for the pharmacy shelf box. However, the firm did not properly update the packaging bill of materials and resulting packaging orders to replace patient booklets with the new PPI.

Why were the packaging bill of materials and packaging order not properly updated?

Jounne Smythe was out on sick leave and his replacement, Mack T. Nive, did not know to update the packaging bill of materials and the packaging order.

Why didn't Mack know to do the update?

The standard operating procedure (SOP) did not describe how to do the updates.

Why didn't the SOP describe how to do the update?

Jounne was the only person ever to do updates and the procedure had never been documented.

What is the recall root cause?

The firm needs to write an SOP and train the staff to ensure that packaging materials are updated and obsolete labeling is not used.


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