Pharma Industry Contends with Contamination-Based Recalls

With curtailed on-site inspection activities for manufacturing facilities in the past year as a result of the COVID-19 pandemic, regulatory authorities such as FDA have had a challenging time. However, maintenance of quality and safety for regularly produced pharmaceuticals remains a priority. The past year especially saw the challenge of a slew of drug recalls caused by the detection of nitrosamine contamination. A roundup of voluntarily initiated recalls due to this contamination is summarized below.

Metformin

Metformin had the largest number of recalls throughout 2020 and at the start of 2021 with FDA citing nitrosamine contamination as the primary cause of the recalls. Nearly every month, starting in May 2020, drugmakers were announcing/reporting product recalls. In May 2020, Amneal Pharmaceuticals issued a voluntary recall of its metformin hydrochloride (HCl) extended release tablets, USP, in 500 mg and 750 mg strengths because of N-nitrosodimethylamine (NDMA) impurities detected in the products (1). FDA had notified Amneal of the impurity detection after seven lots of the products showed the presence of NDMA in amounts above acceptable levels and recommended the recall. Also in May 2020, Apotex issued a voluntary recall of its metformin hydrochloride extended-release tablets, USP 500 mg, when FDA tested one lot and found NDMA levels above the acceptable limits (2).

June 2020 saw several other companies issuing recalls for their metformin products. Marksans Pharma, Teva Pharmaceuticals USA, and Lupin Pharmaceuticals all issued voluntary recalls for their respective metformin products based on NDMA contamination. Marksans Pharma recalled metformin HCl extended-release tablets, USP 500 mg, lot no. XP9004 (3); Teva recalled 14 lots of metformin HCl extended-release tablets, USP 500 mg and 750 mg, in 100- and 1000-count bottles (4); and Lupin Pharmaceuticals recalled metformin HCl extended-release tablets, USP (generic equivalent of Fortamet), 500 mg, lot G901203 (5).

In July 2020, Lupin Pharmaceuticals issued another recall, this time for all batches of metformin HCl extended-release tablets, USP 500 mg and 1000 mg as a part of FDA’s “ongoing assessment” and the continuation of a dialog between company and agency under which additional analysis showed that certain tested batches exceed acceptable limits of NDMA. Lupin Pharmaceuticals decided to issue the July recall “out of an abundance of caution,” the company stated in its announcement at the time (6). In the same month, Granules Pharmaceuticals voluntarily recalled 12 lots of metformin HCl extended-release tablets, USP 750 mg in 100- and 500-count bottles (7).

In August and September of 2020, Bayshore Pharmaceuticals and Sun Pharmaceutical Industries, respectively, issued voluntary recalls for their metformin products. Bayshore recalled one lot, lot no. 18641, of metformin HCl extended-release tablets, USP 500 mg, in 1000-count bottles and one lot, lot no. 18657, of metformin HCl extended-release tablets, USP 750 mg, in 100-count bottles after testing found NDMA levels in excess of acceptable limits (8). Sun Industries recalled one lot, lot no. AB06381, of its Riomet ER (metformin HCl for extended-release oral suspension), 500 mg per 5 mL (9). Meanwhile, later in October 2020, Marksans Pharma expanded its earlier recall to include an additional 76 unexpired lots of metformin HCl extended-release tablets, USP 500 mg and 750 mg, out of an abundance of caution after testing unexpired identified marketed lots (10).

Nostrum Laboratories issued multiple voluntary recalls towards the end of 2020 and in early 2021. In November 2020, the company voluntarily recalled two lots of metformin HCl extended-release tablets, USP 750 mg (11), and two lots of metformin HCl extended release tablets, USP 500 mg (12). Following these announcements, the company issued further recalls in January 2021 for two more lots of metformin HCl extended-release tablets, USP 750 mg (13,14).

Ranitidine

Ranitidine was another drug plagued with NDMA impurities last year. In January 2020, Appco Pharma and Denton Pharma, Inc. dba Northwind Pharmaceuticals, an affiliate of Northwind Pharmaceuticals, issued voluntary recalls for ranitidine products. Appco recalled all quantities and lots, within expiry, of ranitidine HCl capsules in 150 mg and 300 mg strengths (15). Denton Pharma also recalled all unexpired lots of ranitidine tablets, 150 mg and 300mg, in response to the manufacturer’s recall of all unexpired lots of ranitidine tablets, 150 mg and 300 mg, which Denton Pharma had repackaged (16).

Later in February 2020, American Health Packaging recalled 11 lots of ranitidine tablets, USP 150 mg, 100-count unit dose blisters. The company initiated its recall in response to the manufacturer’s (Amneal Pharmaceuticals) recall, which included affected lots that were repackaged by American Health Packaging (17).

Other nitrosamine-based recalls

Besides metformin and ranitidine, some other solid-dose products were also affected by NDMA contamination. In January 2020, Mylan, via its US-based business, Mylan Pharmaceuticals, issued a recall of three lots of nizatidine capsules, USP 150 mg and 300 mg strengths. The recall was based on the detection of trace amounts of NDMA in the API, nizatidine, USP, which was manufactured by Solara Active Pharma Sciences (18).

Other contamination-based recalls

In addition to NDMA contamination, the pharmaceutical industry has had to contend with other contamination-based recalls in the past year. Taro recalled one lot, lot no. 331771, of lamotrigine 100 mg tablets in 100-count bottles in January 2020. The lot was found to have been cross contaminated with a small amount of enalapril maleate, another drug substance that is used to manufacture a different product at the same facility (19).

In May 2020, MasterPharm recalled one lot of Finasteride Plus 1.25mg capsules when an independent testing laboratory found undeclared minoxidil, an antihypertensive drug, in the product at levels that exceed FDA limits. According to a company statement, consumption of undeclared minoxidil would likely result in low blood pressure, rapid heartbeat, and salt and water retention, which leads to swelling, and could put patients at risk for developing heart failure or other heart damage (20).

Recalls prompted by failed results

Aside from contamination, some solid-dose drugs were recalled because of failure to meet certain specifications. In April 2020, Avet Pharmaceuticals recalled eight lots of tetracycline HCl capsules, USP 250 mg and 500 mg, in 100-count bottles because of low out-of-specification dissolution test results (21).

Similarly, Torrent Pharmaceuticals recalled one lot, lot no. BFD1G001, of anagrelide capsules, USP 1 mg in 100-count bottles also due to dissolution test failure that was detected during routine quality testing. Failed dissolution would likely result in a slower rate and extent of drug release, meaning that less anagrelide would be available in the body (22).

In a separate situation, certain thyroid medications were recalled due to potency issues. In May 2020, Acella Pharmaceuticals recalled 13 lots of 30-mg, 60-mg, and 90-mg NP Thyroid (thyroid tablets, USP, composed of levothyroxine and liothyronine) when testing found those lots to be superpotent, containing potentially up to 115% of the labeled amount of liothyronine, one of the APIs (23).

In September 2020, RLC Labs recalled 483 lots of Nature-Throid and WP Thyroid (thyroid tablets, USP, composed of liothyronine and levothyroxine) in all strengths and all counts of product, including 30-, 60-, 90-, 100-, and 1000-count bottles. Potency was also an issue in this recall; FDA tested samples from six lots and found them to be sub potent (24). Similarly, Acella also recalled one lot, lot no. M327E19-1, of 15-mg and one lot, lot no. M328F19-3, of 120-mg NP Thyroid in September 2020 also because testing found these lots to be sub potent (25).

References

1. FDA, “Amneal Pharmaceuticals LLC Issues Voluntary Nationwide Recall of Metformin Hydrochloride Extended Release Tablets, USP, 500 mg and 750 mg, Due to Detection of N-Nitrosodimethylamine (NDMA) Impurity,” Company Announcement, www.fda.gov, June 1, 2020.
2. FDA, “Apotex Corp. Issues Voluntary Nationwide Recall of Metformin Hydrochloride Extended-Release Tablets 500mg Due to the Detection of N-nitrosodimethylamine (NDMA),” Company Announcement, www.fda.gov, June 5, 2020.
3. FDA, “Marksans Pharma Limited Issues Voluntary Nationwide Recall of Metformin Hydrochloride Extended-Release Tablets, USP 500mg, Due to the Detection of N-Nitrosodimethylamine (NDMA),” Company Announcement, www.fda.gov, June 5, 2020.
4. FDA, “Teva Pharmaceuticals USA, Inc. Initiates Voluntary Nationwide Recall of Metformin Hydrochloride Extended-Release Tablets USP 500 mg and 750 mg Due to Detection of N-Nitrosodimethylamine (NDMA),” Company Announcement, www.fda.gov, June 5, 2020.
5. FDA, “Lupin Pharmaceuticals, Inc. Issues Voluntarily Nationwide Recall of One Lot of Metformin Hydrochloride Extended-Release Tablets USP, 500mg Due to the Detection of N-Nitrosodimethylamine (NDMA),” Company Announcement, www.fda.gov, June 11, 2020.
6. FDA, “Lupin Pharmaceuticals, Inc. Issues Voluntarily Nationwide Recall of Metformin Hydrochloride Extended-Release Tablets, 500mg and 1000mg Due to the Detection of N-Nitrosodimethylamine (NDMA) Impurity,” Company Announcement, www.fda.gov, July 8, 2020.
7. FDA, “Granules Pharmaceuticals, Inc. Issues Voluntary Nationwide Recall of Metformin Hydrochloride Extended-Release Tablets USP, 750 mg Due to the Detection of N-Nitrosodimethylamine (NDMA) Impurity,” Company Announcement, www.fda.gov, July 6, 2020.
8. FDA, “Bayshore Pharmaceuticals, LLC Issues Voluntary Nationwide Recall of Metformin Hydrochloride Extended-Release Tablets USP, 500 mg and 750 mg Due to the Detection of N-Nitrosodimethylamine (NDMA) Impurity,” Company Announcement, www.fda.gov, Aug. 20, 2020.
9. FDA, “Sun Pharmaceutical Industries, Inc. Issues Voluntary Nationwide Recall of RIOMET ER (Metformin Hydrochloride for Extended-Release Oral Suspension) Due to N-Nitrosodimethylamine (NDMA) Content Above the Acceptable Daily Intake (ADI) Limit,” Company Announcement, www.fda.gov, Sept. 23, 2020.
10. FDA, “Marksans Pharma Limited Issues Expansion of Voluntary Nationwide Recall of Metformin Hydrochloride Extended-Release Tablets, USP 500mg & 750mg, Due to the Detection of N-Nitrosodimethylamine (NDMA),” Company Announcement, www.fda.gov, Oct. 5, 2020.
11. FDA, “Nostrum Laboratories, Inc. Issues Voluntary Nationwide Recall of Metformin HCl Extended Release Tablets, USP 750 mg, Due to N-Nitrosodimethylamine (NDMA) Content Above the Acceptable Daily Intake (ADI) Limit,” Company Announcement, www.fda.gov, Nov. 2, 2020.
12. FDA, “Nostrum Laboratories, Inc. Issues Voluntary Nationwide Recall of Metformin HCl Extended Release Tablets, USP 500 mg, Due to N-Nitrosodimethylamine (NDMA) Content Above the Acceptable Daily Intake (ADI) Limit,” Company Announcement, www.fda.gov, Nov. 3, 2020.
13. FDA, “Nostrum Laboratories, Inc. Expands Voluntary Nationwide Recall of Metformin HCl Extended Release Tablets, USP 750 mg, Due to N-Nitrosodimethylamine (NDMA) Content Above the Acceptable Daily Intake (ADI) Limit,” Company Announcement, www.fda.gov, Jan. 4, 2021.
14. FDA, “Nostrum Laboratories, Inc. Expands Voluntary Nationwide Recall of Metformin HCl Extended Release Tablets, USP 750 mg, Due to N-Nitrosodimethylamine (NDMA) Content Above the Acceptable Daily Intake (ADI) Limit,” Company Announcement, www.fda.gov, Jan. 25, 2021.
15. FDA, “Appco Pharma LLC Issues Voluntary Nationwide Recall of Ranitidine Hydrochloride Capsules 150 mg and 300 mg Due to an Elevated Amount of Unexpected Impurity, N-Nitrosodimethylamine (NDMA),” Company Announcement, www.fda.gov, Jan. 7, 2020.
16. FDA, “Denton Pharma, Inc. dba Northwind Pharmaceuticals Voluntarily Recalls All Unexpired Lots of its Ranitidine Tablets and Ceases Distribution, Due to Possible Presence of N-nitrosodimethylamine (NDMA) Impurity,” Company Announcement, www.fda.gov, Jan. 8, 2020.
17. FDA, “American Health Packaging Issues Voluntary Nationwide Recall of Ranitidine Tablets, USP 150 mg, 100 Count Unit Dose Blisters Due to the Detection of N-nitrosodimethylamine (NDMA) Impurity,” Company Announcement," www.fda.gov, Feb. 27, 2020.
18. FDA, “Mylan Initiates Voluntary Nationwide Recall of Three Lots of Nizatidine Capsules, USP, Due to the Detection of Trace Amounts of NDMA (N-Nitrosodimethylamine) Impurity Found in the Active Pharmaceutical Ingredient Manufactured by Solara Active Pharma Sciences Limited,” Company Announcement, www.fda.gov, Jan. 8, 2020.
19. FDA, “Taro Pharmaceuticals U.S.A., Inc. Issues Voluntary Nationwide Recall of Lamotrigine Tablets USP, 100 mg, 100 Count Bottles,” Company Announcement, www.fda.gov, Jan. 10, 2020.
20. FDA, “MasterPharm, LLC. Issues Voluntary Nationwide Recall of Finasteride Plus 1.25mg Due to the Presence of an Undeclared Antihypertensive Drug,” Company Announcement," www.fda.gov, May 11, 2020.
21. FDA, “Avet Pharmaceuticals Inc. Issues Voluntary Nationwide Recall of Tetracycline HCl Capsules USP, 250 mg and 500 mg Due to Failed Dissolution Specifications,” Company Announcement, www.fda.gov, April 16, 2020.
22. FDA, “Torrent Pharmaceuticals Limited Issues Voluntary Nationwide Recall of Anagrelide Capsules, USP Due to Dissolution Test Failure,” Company Announcement, www.fda.gov, Dec. 9, 2020.
23. FDA, “Acella Pharmaceuticals, LLC Issues Voluntary Nationwide Recall of Certain Lots of NP Thyroid (Thyroid Tablets, USP) Due to Super Potency,” Company Announcement, www.fda.gov, May 22, 2020.
24. FDA, “RLC Labs, Inc., Issues Voluntary Nationwide Recall of All Lots of Nature-Throid and WP Thyroid with Current Expiry Due to Sub Potency,” Company Announcement, www.fda.gov, Sept. 3, 2020.
25. FDA, “Acella Pharmaceuticals, LLC Issues Voluntary Nationwide Recall of Two Lots of NP Thyroid, Thyroid Tablets, USP Due to Sub Potency,” Company Announcement, www.fda.gov, Sept. 17, 2020.

About the author

Feliza Mirasol is the science editor for Pharmaceutical Technology.

Article Details

Pharmaceutical Technology
Supplement: Solid Dosage Drug Development and Manufacturing
April 2021
Pages: s32–s34

Citation

When referring to this article, please cite it as F. Mirasol, “Pharma Industry Contends with Contamination-Based Recalls,” Pharmaceutical Technology’s Solid Dosage Drug Development and Manufacturing Supplement (April 2021).