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April 20, 2023

WARNING LETTER
WL #643600

Dear Ms. Whitney:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Accra-Pac, Inc. dba Voyant Beauty, FEI 1818911, at 1919 Superior Street, Elkhart, Indiana, from August 23 to September 2, 2022.

This warning letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations (CFR), parts 210 and 211 (21 CFR parts 210 and 211).

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).

Furthermore, during the inspection, FDA investigators collected a sample of (b)(4), distributed by your customer (b)(4). The results of the FDA laboratory testing of this sample demonstrate that this drug product manufactured at your facility is adulterated within the meaning of section 501(a)(2)(B) of the FD&C Act (21 U.S.C. 351(a)(2)(B)), in that contamination with the impurity benzene at unacceptable levels demonstrates that the quality assurance within your facility is not functioning in accordance with CGMP requirements.

Drug CGMP Violations

We reviewed your September 26, 2022, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

During our inspection, our investigators observed specific violations including, but not limited to, the following.

1. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).

Your firm manufactures over-the-counter (OTC) topical aerosol drug products as well as cosmetic products for numerous customers using shared equipment. Your firm failed to perform adequate investigations into benzene contamination in your drug products as high as 13.3 parts per million (ppm). After obtaining information, including data from your customers, indicating that your finished drug products manufactured with isobutane propellants were contaminated with benzene, your propellant investigation was limited to isobutane propellants. However, you failed to expand your investigation to other propellants, such as dimethyl ether, when you received information from a customer that your cosmetic products using dimethyl ether as the propellant also contained unacceptable levels of benzene. We note that you also use dimethyl ether as a propellant in drug products. Your investigation, focused on isobutane’s role in the benzene contamination, was therefore flawed because it failed to account for other potential root causes when unacceptable levels of benzene were found in your finished cosmetic products manufactured using a different propellant on equipment shared with your drug products.

Because the root cause of the benzene contamination is not well understood, the scope of your product impact investigation was also inadequate. As part of the joint investigation conducted by you and your customers, you and your customers selectively tested reserve samples of finished drug products with higher propellant concentrations but failed to adequately test other reserve samples to identify if all drug product batches were impacted.

Your response is inadequate. Your sampling and testing approach for risk assessment is based on tracing propellant batches used in finished product batches. However, your ability to accurately trace propellant is undermined by your failures to test for benzene in each batch of the incoming propellants and to routinely test for benzene in your propellant storage tanks because you use non-dedicated tanks for hydrocarbon propellants. Therefore, your risk assessment may underestimate the numbers of impacted drug product batches. We acknowledge that you are now testing each batch of propellant prior to use. However, your response states, “the heels of each (propellent) blend that remained in the (storage) tanks were blended with propellant with a result of ≤1.0 ppm, then retested, assuring the final result met specification.” Based on your response, it is unclear if your procedure allows you to blend non-conforming propellant with conforming propellant. The practice of blending non-conforming lots with other lots for the purpose of meeting specifications is not acceptable. Verify in response to this letter that no propellant containing benzene above a scientifically sound and appropriate specification is permitted to be blended with any other propellant for use on site.

In response to this letter, provide:

• A comprehensive assessment of your overall system for investigating deviations, discrepancies, complaints, OOS results, and failures. Provide a detailed action plan to remediate this system. Your action plan should include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, corrective action and preventive action (CAPA) effectiveness, quality unit oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.
• Test results of all reserve samples for finished products that were not subject to recall and are currently on the U.S. market within expiry, using a suitable method for testing for benzene in finished products.
• A detailed description of the method you establish to test for benzene in finished products prior to release, until you have demonstrated you have a comprehensive understanding of the root cause of the benzene contamination and have implemented adequate controls to prevent such contamination of your drug products.
• A report of periodic assessments of the implementation and effectiveness of CAPAs.
• A detailed description of your current sampling and testing procedure of each batch of incoming propellants before or after it is transferred to your storage tanks.

2. Your firm failed to conduct, for each batch of drug product, appropriate laboratory testing, as necessary, required to be free of objectionable microorganisms (21 CFR 211.165(b)).

You failed to test many of your topical drug products for critical microbiological attributes. Without testing each batch prior to release, you did not have scientific evidence that all drug product batches were free of microbial contamination that is objectionable in view of its intended use.

In your response, you note that you are a contract manufacturer, and that per your quality agreements, your customers determine the test plans and specifications. You also state that you would evaluate the water content of the products and conduct risk assessment for all your drug products that are not being evaluated for microbiological attributes.

Your response is inadequate. You are responsible for the quality of drugs you produce as a contract facility, regardless of agreements in place with product owners. In addition, the water activity, and not water content, of a product can provide useful information about the potential for a product to support microbial growth. It is also well established that many microorganisms are known to survive and persist even in drug products that typically have minimal water activity.

In response to this letter, provide:

• A list of microbiological specifications (i.e., total counts, objectionable microorganisms), including test methods, used to analyze each lot of your drug products before a lot disposition decision.
• A summary of all results obtained from testing retain samples from each batch. If such testing reveals substandard quality drug products, take rapid corrective actions, such as notifying customers and product recalls.

3. Your firm failed to conduct at least one test to verify the identity of each component of a drug product (21 CFR 211.84(d)(1)).

You failed to adequately test the incoming components used to manufacture your drug products. Specifically, your component identity testing does not include a limit test for diethylene glycol (DEG) and ethylene glycol (EG) on all lots of glycerin before use in the manufacture or preparation of drug products. You manufacture multiple drug products that contain glycerin.

In your response, you provided conforming DEG and EG test results of reserve samples for glycerin lots used to manufacture drug products. However, you did not test for DEG and EG in glycerin item (b)(4), which was used to manufacture sunscreen products for children, as it appears that your inventory for glycerin item (b)(4) is depleted. You also failed to provide a risk assessment for finished products on the market and within expiry manufactured with glycerin item (b)(4).

In response to this letter, provide:

• A summary of test results for reserve samples of all finished product lots manufactured with glycerin item (b)(4).
• A description of how you will test each component lot for conformity with all appropriate specifications for identity, strength, quality, and purity. If you intend to accept any results from your supplier’s Certificates of Analysis (COA) instead of testing each component lot for strength, quality, and purity, specify how you will robustly establish the reliability of your supplier’s results through initial validation as well as periodic re-validation. In addition, include a commitment to always conduct at least one specific identity test for each incoming component lot. In the case of glycerin, we note that this includes the performance of parts A, B, and C of the United States Pharmacopeia (USP) monograph.
• A comprehensive review of the components used in your drug products to ensure appropriate identity tests are performed.

The use of glycerin contaminated with DEG has resulted in various lethal poisoning incidents in humans worldwide. For more information, see FDA’s guidance document Testing of Glycerin for Diethylene Glycol at https://www.fda.gov/media/71029/download

FDA Tested Drug Samples

During the inspection, FDA investigators collected samples of three drug products. FDA laboratory testing of these samples found the following:

Product Name	Customer Lot Number	Expiration Date	Benzene Test Results (ppm)
(b)(4)	(b)(4)	(b)(4)	6
(b)(4)	(b)(4)	(b)(4)	3
(b)(4)	(b)(4)	(b)(4)	1

* Not distributed in the United States

Manufacturers should not use benzene in the manufacture of drugs because it is a known human carcinogen that causes leukemia and other blood disorders. FDA has alerted all drug manufacturers to the known risk factors for contamination with benzene. For more information see https://www.fda.gov/drugs/pharmaceutical-quality-resources/fda-alerts-drug-manufacturers-risk-benzene-contamination-certain-drugs

On (b)(4), FDA recommended your customer, (b)(4), consider removing the adulterated batch of (b)(4) drug product from the U.S. market.

On (b)(4), (b)(4) expanded an ongoing voluntary nationwide recall to include the contaminated batch of (b)(4) due to the presence of benzene above 2 ppm.

The contamination with benzene in a drug product manufactured in your facility, in addition to the significant violations documented in the inspection, demonstrate that the quality assurance within your facility is not functioning in accordance with CGMP requirements under section 501(a)(2)(B) of the FD&C Act.

Quality Agreement

Drugs must be manufactured in conformance with CGMP. FDA is aware that many drug manufacturers use independent contractors such as production facilities, testing laboratories, packagers, and labelers. FDA regards contractors as extensions of the manufacturer.

You are responsible for the quality of drugs you produce as a contract facility, regardless of agreements in place with product owners. You are required to ensure that drugs are made in accordance with section 501(a)(2)(B) of the FD&C Act for safety, identity, strength, quality, and purity. For more information, see FDA’s guidance document Contract Manufacturing Arrangements for Drugs: Quality Agreements at https://www.fda.gov/downloads/drugs/guidances/ucm353925.pdf.

SULFATRIM^TM PEDIATRIC SUSPENSION Production Ceased

We acknowledge your commitment to cease production of SULFATRIMTM PEDIATRIC SUSPENSION at this facility. In response to this letter, clarify whether you intend to resume manufacturing this drug at this facility in the future.

Cosmetic Products

In addition, we note that some of the products you manufacture may be regulated as cosmetics, as defined in section 201(i) of the FD&C Act. A cosmetic is adulterated under section 601(a) of the FD&C Act, 21 U.S.C. 361(a), if it bears or contains any poisonous or deleterious substance, such as benzene, which may render it injurious to users under the conditions of use prescribed in the labeling thereof, or, under such conditions of use as are customary or usual. Some of the practices that cause the OTC drug products you manufacture to be contaminated with benzene may also cause the cosmetic products you manufacture to be contaminated with benzene. We note that under section 301(a) of the FD&C Act, 21 U.S.C. 331(a), it is a prohibited act to introduce or deliver for introduction into interstate commerce a cosmetic product that is adulterated.

Conclusion

The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility. You are responsible for investigating and determining the causes of any violations and for preventing their recurrence or the occurrence of other violations.

If you are considering an action that is likely to lead to a disruption in the supply of drugs produced at your facility, FDA requests that you contact CDER’s Drug Shortages Staff immediately, at [email protected], so that FDA can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Staff also allows you to meet any obligations you may have to report discontinuances or interruptions in your drug manufacture under 21 U.S.C. 356C(b). This also allows FDA to consider, as soon as possible, what actions, if any, may be needed to avoid shortages and protect the health of patients who depend on your products.

Correct any violations promptly. Failure to promptly and adequately address this matter may result in regulatory or legal action without further notice including, without limitation, seizure, and injunction. Unresolved violations may also prevent other Federal agencies from awarding contracts.

Failure to address violations may also cause FDA to withhold issuance of Export Certificates. FDA may withhold approval of new applications or supplements listing your firm as a drug manufacturer until any violations are completely addressed and we confirm your compliance with CGMP. We may re-inspect to verify that you have completed corrective actions to address any violations.

This letter notifies you of our findings and provides you an opportunity to address the above deficiencies. After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done to address any violations and to prevent their recurrence. In response to this letter, you may provide additional information for our consideration as we continue to assess your activities and practices. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.

Please address your reply via email to: [email protected]

Attention: Brian D. Garthwaite, Ph. D.
Compliance Officer
U.S. Food and Drug Administration
Division of Pharmaceutical Quality Operations III

Your electronic reply should refer to the Warning Letter Case Number above (#643600). If you have questions regarding the contents of this letter, please contact Dr. Garthwaite at (612) 758-7132.

Sincerely,
/S/

CDR Jeffrey D. Meng
Program Division Director
Division of Pharmaceutical Quality Operations III