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Warning letters, 483s, Recalls, Import Alerts, Audit observations

Updated on April 10, 2023

Apotex Inc had to recall 4 lots of Drospirenone and Ethinyl Estradiol Tablets (3 mg/0.03 mg) due to contraceptive tablets out of sequence or missing or incorrect tablet placement in March 2019. The tablets were manufactured by Oman Pharmaceutical Products LLC. The packaging errors include blisters with no inert (Placebo) tablets, missing active tablets inert tablet in active tablets row.

Recall details: 4 lots, (7DY008A, 7DY009A, 7DY010A, 7DY011A, Exp. 08/2020); 82,705 cartons
Drospirenone and Ethinyl Estradiol Tablets, USP, 3 mg/0.03 mg, 28 Tablets per Blister (NDC 60505-4183-1), packaged as 3 blisters per carton – 84 tablets per carton (NDC 60505-4183-3)

(Outer Carton contains three inner Cartons; Inner Carton contains 1 blister with 21 active yellow color tablets and 7 placebo white color tablets).

Manufactured by: Oman Pharmaceutical Products Co. L.L.C., P.O. B1885, Postal Code 111, Seeb.

Manufactured for:  Apotex Corp., Weston, FL 33326;

The pack of 28 tablets in a blister has four rows of tablets. 3 rows of active Drospirenone and Ethinyl Estradiol Tablets, USP, 3 mg/0.03 mg with 7 tablets in each row (yellow tablets) and the 4th row with inert tablets (white tablets). This is a trypical calendar pack. Drospirenone and Ethinyl Estradiol Tablets, USP are estrogen/progestin tablets indicated for use by women to prevent pregnancy. The calendar pack help patient to follow the prescribed tablet intake pattern (first yellow tablet to be taken on the first day of menstrual period or on first sunday after onset of menstrual period; one yellow tablet to be taken daily for 21 days followed by white tablets for 7 days).  

Recall

The packaging errors included: Blisters with no inert (Placebo) tablets, Missing active tablet in a blister, Blister with inert tablet in active tablets row. The packaging errors can lead to a patient not taking a tablet due to a missing tablet in blister or that a patient takes a placebo (inert) tablet instead of an active tablet and thus loss of efficacy due to variation in the dosage consumed. 

Blister with no Placebo tablets
Missing active tablet in a blister
Blister with inert tablet in active tablets row
These blister packing of tablets are typically packed with multiphasic packing machines with different hoppers for active and inert tablets. The hoppers are typically topped up manually during packing. During such operation due to operator error, wrong tablets could be topped up in a hopper (e.g. – active tablets in inactive tablets hopper) leading to blisters with no inactive tablets. During packing operations due to machine errors (e.g. jerky run of the machine) tablets may jump from cavities out of blister (leading to empty pockets) or into other tablet pocket (leading to wrong placement of tablet).  Such packing errors may go undetected due to ineffective / erroneous camera / tablet inspection system (normally associated with packing machines). Lapses in manual blister inspection during packing (by “Checkers” on the packing line) also add on to such packing errors going undetected.

Multiphasic packing is a complex operation. Several procedural and engineering controls should be in place to prevent such packaging errors which lead to costly product recall and loss of reputation.

  • Each top up of the hoppers with tablets can have a double check by supervisor or an In Process Quality Assurance (IPQA) personnel with documentation in batch records (checklist for tables top up).
  • Ensure the blister packing machines have efficient tablet inspection system (camera). The system should be “taught” to detect all possible errors (like missing tablets, wrong tablets in blister pockets) and to reject such blisters. Track the number of such rejects in each batch (reconcile in the batch records), any spikes in rejects should be investigated.
  • Have an effective manual tablet inspection system. Even after having an efficient automated tablet inspection system, there could be rare occurrences of missing tablets / wrong tablet in a blister pocket due to machine errors (such as jerks) after the camera system. This should be caught by the manual blister inspection with trained and qualified checkers. The checkers should be periodically rotated (e.g. every two hours) to avoid fatigue. Also track and document the rejects  (number of rejects, type of rejects) during manual inspection, reconcile in the batch records; any spikes in rejects should be investigated. Periodically requalify the checkers through induced errors in packing; There should be 100% detection of the errors during such requalification by checkers.
  • Review the maintenance programme of the packing machine; link it with the defectives observed during batch packing (both Tablet inspection system rejects as well as manual rejects).
  • Recall of the batch(es) as it cause patients to consume wrong tablets, resulting in loss of efficacy of tablets and other adverse consequences.
  • Investigate the event thoroughly. Define scope of investigation – number of products and batches to be investigated. How is the cut off of potentially affected batches identified. This will require establishment of the root cause(s) and when such events would have most likely started.
    • For e.g. – after the last preventive maintenance or after some specific parts of the blister packing machine was changed.
    • Or else all distributed batches within expiry will be a suspect and considered for potential recall.
  • Implement effective corrective and preventive actions (CAPA) – efficient tablet inspection system (camera system), improving the manual inspection of blisters (training, qualification, periodic requalification, rotation of “Checkers” during the shift); procedural controls such as doer-checker controls during topping up of tablet hoppers.

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