The Quality Lowdown: Yes, The US FDA Expects You To Heed Import Alerts And Testing Requirements

PCCA repackaged adulterated APIs, Allay failed to understand processes, ShangRao and Mexican firms peddled subpotent, sometimes methanol-tainted ethanol.

 

Questions around active pharmaceutical ingredient imports continued to dominate recent US Food and Drug Administration enforcement news as the agency continued to enforce good manufacturing practices despite little ability to conduct site visits.

It’s a reminder that the agency’s ability to block adulterated imports may be one of its more pandemic-resistant authorities.

That said, one border-related warning letter was made possible by an inspection in Texas that preceded coronavirus shutdowns by a few months. It’s a particularly important warning letter because of the outsize impact it could have on the domestic compounding pharmacy sector.

And another warning letter stemmed from a rare pandemic inspection in Florida that provides a reminder of the way FDA investigators can deeply examine manufacturing processes when they can access facilities, as they will in great numbers once COVID-19 fades, no doubt.

Meanwhile, border testing continued to identify dangerous contamination of alcohol-based hand sanitizers with deadly methanol.

PCCA Warned About Adulterated API Suppliers

By comparing company records against import data, the US FDA found during a recent inspection that Professional Compounding Centers of America Inc., Houston, Texas, distributed active pharmaceutical ingredients that were adulterated, coming as they did from a supplier that was under an active import alert and that had not resolved concerns raised in a warning letter related to refusing an FDA inspection and destroying batch records, among other things.

What’s more, the comparison also showed the FDA that PCCA obtained APIs from another 23 suppliers the agency had placed on import alert or issued warning letters to or both.  The import alerts were for GMP compliance failures or for refusing, denying or delaying FDA inspections.

The concerns raised in the October 2019 inspection were not resolved by PCCA’s November 2019 response and led the FDA to send the company a warning letter on 27 January.

In the warning letter, the FDA requested lot numbers, distribution dates and recipients of the APIs. The agency also demanded to know which shipments, if any, had occurred after the APIs had been added to import alerts and before they had been removed, or after warning letters had been issued but before they had been closed out.

For any APIs distributed during those periods, PCCA would have to alert the customers that the APIs were adulterated – and include a copy of the notification in PCCA’s response to the FDA.

The agency also requested a plan for how PCCA would strengthen its supply chain to avoid buying and selling adulterated drugs.

PCCA plays a major role in the US compounding pharmacy sector, supplying more than 3,900 compounding pharmacies with ingredients, equipment, education and consulting services. The company also advocates for the sector, often commenting on FDA regulatory proposals and doing some congressional lobbying.

Noting that PCCA repackages and distributes glycerin USP as an excipient or other component of drug products, the FDA said PCCA’s glycerin does not conform to USP requirements for identity testing.

The problem was that PCCA’s test method is unable to detect diethylene glycol, a deadly adulterant that has found its way into glycerin in the past. (Also see "Seeking a More Trustworthy Global Supply Chain" - Pink Sheet, 31 Mar, 2008.) (Also see "FDA Global Supply Chain Concerns Prompt Glycerin DEG Testing Guidance" - Pink Sheet, 7 May, 2007.)

The FDA took issue in the warning letter with PCCA’s response to the glycerin-related inspectional observation, in which the company asserted that testing of incoming glycerin for diethylene glycol and ethylene glycol impurities is “superfluous and simply not required.”

It is not enough to rely on a supplier’s assertions in such matters, the agency told PCCA: they must be independently verified.

PCCA also relabeled tramadol, fentanyl, buprenorphine and morphine API lots that it had repackaged without identifying the API suppliers in the labeling, as required.

Allay Pharmaceuticals Warned Over Lack Of Process Understanding

One of the rare drug GMP inspections the US FDA conducted during the pandemic led the agency on 27 January to issue a warning letter to Allay Pharmaceuticals LLC, Hialeah, FL.

The 5-15 May 2020 inspection uncovered subpotent active pharmaceutical ingredients and found that process validation, investigation and stability testing activities were inadequate.

There was a lack of content uniformity related, apparently, to inadequate blending, which the FDA noted could lead to segregation, high moisture levels, particle aggregation and inconsistent flow characteristics.

The FDA rejected as inadequate a plan put forth in Allay’s 6 June response to the Form 483 report to perform concurrent validation to assess product behavior “as you do not appear to have a high degree of understanding of the sources of variation in your manufacturing processes,” the FDA told the company.

The warning letter also said Allay failed to investigate out-of-specification assay results the FDA had obtained from one lot of tablets Allay manufactured for a product owner.

The active ingredient may have met the specification established by Allay and the product owner – but it was required to meet a different USP specification, which it did not.

The FDA said it also raised this issue in a separate warning letter to the product owner.

Allay did not adequately investigate the OOS result, for example by addressing the 13 other lots within expiry that exceeded the assay specification during release or stability testing, the FDA said.

The FDA also found major problems with Allay’s stability program. For example, it did not place certain validation batches involving a new API supplier on stability until nearly a year after they were manufactured.

The agency also gave Allay’s quality unit poor marks. For example, the unit failed to adequately investigate a 7.8% discrepancy in API assay results between the supplier’s certificate of analysis and Allay’s own testing.

Allay agreed to recall certain lots and destroy another.

The company notes on its web site that it recently established a branch office in Dhaka, Bangladesh.

ShangRao Warned Over Alcohol Testing Failure

Border testing and disclosure via teleconference led the US FDA to put a Chinese manufacturer’s products on import alert and issue a warning letter.

FDA border testing found that hand sanitizer ShangRao Chunyu Technology Co. Ltd. sought to export to the US contained only 57% ethanol, which was below the 60% threshold in the tentative final monograph for antiseptic drug products and well below the 75% label claim, the agency said in a 3 February warning letter to the company based in Shangrao, a city in China’s Jiangxi Province.

ShangRao Chunyu was using an unsuitable device for release testing, the FDA said it learned during an 8 September 2020 teleconference with the company and its registered agent, Pragmatic Compliance LLC, leading to citation in the warning letter of the 211.160(b) release testing procedures requirement in the drug good manufacturing practices regulations in title 21 of the code of federal regulations.

The FDA on 6 November placed all drugs manufactured by the company on its import alert 66-78 for drugs that appear to be adulterated due to analytical testing results. (Also see "The Quality Lowdown: COVID-19's Pressures On Drug Quality" - Pink Sheet, 13 Aug, 2020.) (Also see "Deadly COVID-19 Hand Sanitizer Production Surge Prompted US FDA's New Import Alert Category" - Pink Sheet, 17 Sep, 2020.)

More Mexican Hand Sanitizer Warning Letters

The FDA issued several more warning letters to Mexican makers of alcohol-based hand sanitizer based on border testing results.

AAA Cosmetica

On 3 February, the FDA warned AAA Cosmetica, SA de CV, Tlalnepantla, Mexico, after finding 78% to 81% of toxic methanol and none of the labeled active ingredient, ethanol, in testing of alcohol-based hand sanitizer batches detained at the border.

After a 2 July teleconference with AAA Cosmetica and its registered US agent, ISC Forwarders Inc., the FDA on 6 July warned the public not to use the sanitizer products. On 14 July, the company began recalling one of the products, but not the others.

The company told the FDA in a 13 August email that when it previously tested hand sanitizers for ethanol, it misinterpreted the methanol peak.

The FDA placed AAA Cosmetica’s drug products on import alert 66-78. The agency said it had concerns about corrective action plans the company proposed between 24 July and 7 December, concluding that if the company wants to export to the US, then it will have to request a regulatory meeting to talk about appropriate corrective actions.

The agency included a copy of the warning letter to AAA Cosmetica’s outside counsel, David Rosen of the Washington law firm Foley & Lardner.

Simex Logistics

On 28 January, the FDA warned Simex Logistics S.A. de C.V., Celaya, Mexico, after finding that product detained at the border were only 51% ethanol, not the labelled 70% and below the minimum 60% allowed by the OTC monograph for such products. The third party Simex used for testing found results improved after mixing, indicating the gel formulation lacks uniform character and quality. Simex issued product recalls on 25 November, two weeks after the FDA had notified the public about the company’s subpotent hand sanitizer, and a week after the agency added the company to its import alert 66-78.

Botanicals Internacional

A 3 February warning letter said Botanicals Internacional S.A. de C.V., Cuautitlán Izcalli, Mexico, attempted to export its inatek hand sanitizer to the US that was labelled as 70% ethanol, but actually contained 75% methanol and only 0.2% ethanol, according to FDA testing. Because the FDA caught the problem in time, no recall was needed, but the agency went ahead and added the company to its import alert 66-78.

In 17 July correspondence, Botanicals Internacional told the FDA that it had separately discovered the methanol contamination, which it isolated to one supplier, but failed to exercise adequate control to prevent release for US distribution.

Precision Analitica

Alcohol-based hand sanitizer from Precision Analitica Integral S.A. de C.V., Mexico City, that the FDA detained at the US border turned out to contain 40% ethanol and 28% methanol rather than the labelled 75% ethanol, according to a 5 February warning letter.

After a 6 August teleconference with the company and its US agent, ESPMEX, LLC, the FDA on 7 August warned the public about the company’s methanol-tainted hand sanitizer. But Precision Analitica never recalled any of it.

The FDA copied the warning letter to Precision Analitica’s outside counsel, Benjamin England of Benjamin England & Associates.

Recent drug GMP import alerts

The US FDA has recently red-listed several manufacturing facilities on its Import Alert 66-40 due to drug good manufacturing practices concerns:

• 16 February, Shilpa Medicare Ltd., Polepally, India, with exclusions for azacitidine injection, cyclophosphamide capsules and erlotinib tablets;

• 27 January, Sierra Pharmaceuticals Inc. Sa De Cv, Mexicali, Mexico;

• 25 January, Howard Medical International, Nassau, Bahamas; and

• 12 January, Nanomateriales Sa De Cv, Apodaca, Mexico.

The Lowdown is a recurring Pink Sheet column offering quick takes on manufacturing quality and compliance policy. Some previous editions:

• (Also see "The Quality Lowdown: Warning Letters Suggest How The FDA Set Priorities During COVID-19" - Pink Sheet, 8 Sep, 2020.)
• (Also see "The Quality Lowdown: What Happens When The US FDA Must Choose Between Risks" - Pink Sheet, 28 Aug, 2020.)
• (Also see "Quality Lowdown: FDA Defends Nitrosamine Testing Methods While US, EU Enforcement Continues" - Pink Sheet, 22 Jul, 2020.)