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Warning Letter #636044

June 08, 2023

Dear Mr. Boyd:

The U.S. Food and Drug Administration (FDA) inspected your wholesale drug distribution facility, Safe Chain Solutions, LLC (Safe Chain), FEI 3009729473, at 822 Chesapeake Drive, Cambridge, Maryland from April 11 to May 11, 2022.

The Drug Supply Chain Security Act (DSCSA) (Title II of Public Law 113-54), enacted by Congress on November 27, 2013, added Section 582 to the Federal Food, Drug, and Cosmetic Act (FD&C Act). Section 582 of the FD&C Act (21 U.S.C. 360eee-1) states the requirements that certain entities in the pharmaceutical distribution supply chain (including wholesale drug distributors) must follow related to product tracing, verification, and authorized trading partners. This warning letter summarizes significant violations of the requirements found in section 582(c) of the FD&C Act. These requirements are intended to help preserve the security of the supply chain for certain prescription drug products, thereby protecting patients from exposure to drugs that may be counterfeit, stolen, contaminated, or otherwise harmful.

FDA issued a Form FDA 483 to Safe Chain at its Cambridge, MD headquarters on May 10, 2022. FDA reviewed your firm’s response, dated June 1, 2022.

FDA has observed that Safe Chain did not have adequate verification systems in place in violation of section 582(c)(4)(A) & (B) of the FD&C Act. FDA observed that Safe Chain failed to maintain records regarding suspect product investigations in violation of section 582(c)(4)(A)(iii) of the FD&C Act, and failed to respond to a notification of illegitimate product in violation of section 582(c)(4)(B)(iii) of the FD&C Act. In addition, Safe Chain engaged in transactions with unauthorized trading partners in violation of section 582(c)(3) of the FD&C Act. Failure to comply with any of the requirements under section 582 of the FD&C Act is a prohibited act under section 301(t) of the FD&C Act (21 U.S.C. 331(t)).

DSCSA Violations

During FDA’s inspection, our investigators observed that your firm failed to comply with various requirements of the DSCSA. Specific violations include, but may not be limited to, the following:

1. Your firm failed to have systems in place to enable compliance with the verification requirements of the DSCSA (FD&C Act Section 582(c)(4)(A) & (B)).

Under section 582(c)(4)(A) & (B) of the FD&C Act, wholesale drug distributors must have systems in place to enable the wholesale distributor to comply with the verification requirements of the DSCSA.

Your firm was not able to demonstrate systems that would enable Safe Chain to comply with a number of verification requirements required by the DSCSA. For example, your document, “Standard Operating Procedure for Suspect & Illegitimate Product” (Suspect & Illegitimate Product SOP) (re-issue date 3/15/21) lacked sufficient detail or instruction to enable Safe Chain to adequately:

o Identify suspect product,¹
o Conduct an investigation (including validating any applicable transaction history and transaction information) to determine whether a suspect product is an illegitimate product in coordination with trading partners,
o Handle an illegitimate product notification,
o Handle a request for verification of a suspect product from FDA,
o Make notifications of cleared product, and
o Maintain adequate records relating to the investigation of suspect product or the disposition of illegitimate product.

Your firm’s failure to establish and implement systems to enable your compliance with these DSCSA requirements may have resulted in suspect product entering the supply chain rather than the product being quarantined as required by section 582(c)(4)(A)(i)(I) of the FD&C Act. For example, an email from February 6, 2021 from the California Board of Pharmacy to Safe Chain, explains that Safe Chain distributed Gentek lot CCXKVA (discussed in more detail in section 2 below) to White Cross Pharmacy and that this lot lacked the required (b)(4) and the original induction seal had been removed and replaced with a non-genuine seal.² A physical examination of the product may have prevented the lot from being distributed.

Your firm’s Suspect & Illegitimate Product SOP also contained information inconsistent with the DSCSA. Specifically, the SOP stated that if “SCS [Safe Chain Solutions] receives confirmation the product is illegitimate or potentially fraudulent an FDA form 3911 will be filed. Disposition of the product will depend on guidance received from the FDA.” As written, this SOP indicated that the firm is expecting guidance from FDA upon submission of a 3911, and disposition of the product depends on such guidance. However, disposition of illegitimate product is your responsibility and is not dependent on FDA’s response to a FDA Form 3911. (FD&C Act section 582(c)(4)(B)).

In addition, your document “Standard Operating Procedures for Vendor and Transaction History Authentication” (re-issue date 4/1/21) contained information inconsistent with the DSCSA. The document indicated that in case of “(b)(4),” your firm should contact the Maryland Board of Pharmacy and the FDA within 3 days. However, the DSCSA requires a trading partner that determines a product in its possession or control is an illegitimate product to notify the FDA within 24 hours of making such a determination. (FD&C Act section 582(c)(4)(B)(ii)). (FDA understands “(b)(4).

Your lack of sufficient written procedures, or other systems related to compliance with the verification requirements of the DSCSA, rendered your firm unable to demonstrate compliance with the verification requirements of the section 582(c)(4) of the FD&C Act.

2. Your firm conducted transactions with trading partners that were not authorized (FD&C Act Section 582(c)(3)).

The DSCSA requires that trading partners of wholesale distributors meet the applicable requirements for being authorized trading partners. (FD&C Act Section 582(c)(3)). To be authorized, a wholesale drug distributor must have a valid license under State law or section 583 of the FD&C Act, in accordance with section 582(a)(6) of the FD&C Act, and comply with the licensure reporting requirements in section 503(e) of the FD&C Act. (FD&C Act Section 581(2)(B)). Under section 503(e)(2)(A) of the FD&C Act, wholesale distributors must report to FDA, on an annual basis, “each State by which the person is licensed and the appropriate identification number of each such license; the name, address, and contact information of each facility at which, and all trade names under which, the person conducts business;” and “any significant disciplinary actions.”

Your firm has a written procedure to verify a trading partner’s status, “Standard Operating Procedures for Trading Partner Validation” (re-issue date of 3/15/21) (Trading Partner Validation SOP). This procedure recognizes that (b)(4) as defined by the DSCSA. Your Trading Partner Validation SOP even goes so far as to provide the link to FDA’s publicly accessible database of WDDs and 3PLs that have reported their state licensure status to FDA: https://www.accessdata.fda.gov/scripts/cder/wdd3plreporting/index.cfm. Your firm, however, did not adhere to this SOP and failed to verify that all of your trading partners reported licensure information to FDA.

Between July, 2020 and March, 2021, your firm purchased drug products from wholesale drug distributors that were not authorized trading partners according to sections 581(2) and 503(e) of the FD&C Act. For example, your firm purchased prescription drug products from wholesale distributors Gentek and Boulevard 9229 LLC. However, FDA has no record of Gentek or Boulevard 9229 LLC ever submitting the required annual reports to FDA regarding state licensure as required by section 503(e) of the FD&C Act. In addition, Boulevard 9229 LLC provided your firm with a fraudulent license. Therefore, Boulevard 9229 LLC not only failed to report to FDA, but it was also never appropriately licensed as required by section 503(e)(1)(A) and 582(a)(6) of the FD&C Act.

The importance of the requirement that trading partners of wholesale distributors be authorized is highlighted by the fact that, on multiple occasions, your firm was notified that it had received prescription drug products containing different medication than was purported to be present based on the product labeling, making those products suspect product and unfit for distribution. For example, on multiple occasions your firm was notified by trading partners that patients reported receiving bottles of a product labeled as Biktarvy (bictegravir, emtricitabine and tenofovir alafenamide) that in fact contained different tablets instead of the Biktarvy tablets.

• Your firm purchased Biktarvy (lot CCXKVA) from Gentek on July 28, 2020. Subsequently, on July 29, 2020, your firm sold bottles from this lot to pharmacy trading partner White Cross. On November 23, 2020, Gilead Sciences, Inc., the manufacturer of Biktarvy, notified your firm that a bottle from lot CCXKVA that was dispensed by White Cross to a patient contained different tablets instead of Biktarvy tablets.
• On September 30, 2020, your firm purchased Biktarvy from Gentek (lot CDFYCA) and subsequently sold it to Medicine Shoppe Pharmacy #1802. On October 14, 2020, your firm was notified through an email from World Wide Pharma Sales that a patient returned a bottle of Biktarvy (lot CDFYCA) to the pharmacy because it contained a different medication than was purported to be present based on the product labeling. Furthermore, in another email from World Wide Pharma Sales, from November 24, 2020, you were notified of yet another patient complaint concerning lot CDFYCA. A second patient had retuned a bottle of Biktarvy (lot CDFYCA) to the same pharmacy because it also contained a different medication than was purported to be present based on the product labeling.
• On January 7, 2021, your firm purchased Biktarvy from Gentek for a third time (lot CCZCFA), having already been informed that two prior lots purchased from this firm contained bottles of a medication that was different than what was purported to be present based on the product labeling. Safe Chain subsequently sold the product to Medicine Shoppe Pharmacy #1802. Safe Chain discovered that the drug product purchased in this third lot also contained multiple tablets of a different product than should have been present based on the product’s label. A letter from Safe Chain to Gilead indicates that your firm knew of the issue with this third lot by February 12, 2021.
• On March 1, 2021, your firm purchased Biktarvy (lot CDSFFA) from Boulevard 9229 LLC. In a letter to your customer, dated March 27, 2021, Safe Chain reported a quality complaint regarding this product. The drug product purchased contained multiple tablets of a different product than should have been present based on the product’s label.

These instances are especially concerning from a public health perspective given that Biktarvy is indicated to treat a serious health condition, HIV-1 infection, and the recommended dosage for adult and pediatric patients is one pill daily. As explained in the Patient Counseling Information section of the Prescribing Information for Biktarvy, “it is important to take BIKTARVY on a regular dosing schedule with or without food and to avoid missing doses as it can result in development of resistance.” Patients who receive the wrong drug product from the pharmacy may not be able to take the prescribed dose in a timely manner which can cause serious adverse health consequences. In addition, FDA-approved Biktarvy bears a boxed warning, commonly referred to as a “black box warning,” which is the strongest warning FDA requires, indicating that the drug carries a significant risk of serious and even life-threatening adverse effects. The boxed warning addresses risks including post treatment acute exacerbation of Hepatitis B.

Your firm continued to purchase product from the same unauthorized trading partners, which resulted in acquiring more suspect product from those entities after they had previously sold you suspect product. This is extremely concerning from a public health perspective given the serious health condition Biktarvy is indicated for. In FDA’s 2016 final guidance Drug Supply Chain Security Act Implementation: Identification of Suspect Product and Notification, FDA warns trading partners that purchasing from a source that a trading partner knows or has reason to believe has engaged in questionable business practices could significantly increase the chance of suspect product entering the pharmaceutical distribution supply chain.

3. Your firm failed to maintain records of suspect product investigations (FD&C Act Section 582(c)(4)(A)(iii)).

The DSCSA requires that wholesale distributors maintain records of investigations of suspect product for not less than 6 years. (FD&C Act section 582(c)(4)(A)(iii)). Your firm was both unable to provide any written documentation of what products were held in or released from quarantine, and unable to provide records explaining how suspect product was quarantined. In addition, while you were able to produce some correspondence pertaining to the various lots of suspect product, you were unable to provide records about when and how investigations took place to determine whether suspect product was illegitimate.

For example, in a letter from Safe Chain’s outside counsel to Gilead, dated February 12, 2021, you indicate that you would quarantine Biktarvy lot CCZCFA when it was returned to you by the dispenser. The letter explains that Safe Chain notified your immediate trading partner, but does not clarify whether you were referring to a dispenser trading partner or your supplier, Gentek. Your letter also explains that Gentek advised you to destroy the product. However, you were not able to produce records demonstrating that you quarantined the product, any notice you shared about the suspect product with Gentek or other immediate trading partners, or records of the disposition of the product.

Also, your firm could not produce adequate records pertaining to three other suspect product investigations for which Safe Chain made notifications of illegitimate product to the FDA using Form FDA 3911. These Form FDA 3911s were submitted on March 25, 2021 (lots CCXKVA and CDFYCA), March 27, 2021 (lot CDSFFA), and April 7, 2021. (Lot CCZCFA was included on the March 25, 2021 Form FDA 3911 as well.) While these FDA Form 3911s provide some insight into actions Safe Chain claims to have taken, you were not able to provide documentation supporting these actions. As a result, FDA is unable to determine if, or at what point, the drugs referred to in the FDA Form 3911s were appropriately quarantined, as required by section 582(c)(4)(A)(i)(I) of the FD&C Act, and whether investigations were conducted in coordination with trading partners, as required by section 582(c)(4)(A)(i)(II) of the FD&C Act.

4. Your firm failed to respond to a notification of illegitimate product (FD&C Act Section 582(c)(4)(B)(iii)).

Upon receiving a notification of illegitimate product, a wholesale distributor must identify all illegitimate product subject to such notification in its possession or control, including any product that is subsequently received. (FD&C Act section 582(c)(4)(B)(iii)). You are also required to quarantine such product within your possession or control from product intended for distribution (FD&C Act sections 582(c)(4)(A)(i)(I) and 582(c)(4)(B)(i)(I)) and investigate the product as suspect product (FD&C Act sections 582(c)(4)(A)(i)(II) and 582(c)(4)(B)(iii)). You were not able to provide evidence that you appropriately responded to notifications of illegitimate product.

For example, you emailed Gilead regarding Biktarvy Lot CDGXKA in October 2020. You were informed in an email response from Gilead to Safe Chain dated October 9, 2020, that the transaction history in your records was inconstant with Gilead’s records and that Gilead considers the product to be illegitimate product. You were not able to provide any further information about Lot CDGXKA and whether your firm investigated or quarantined the product.

Your Response to the FDA Form 483

FDA has reviewed your June 1, 2022 response to our Form FDA 483 in detail and your response is inadequate for the following reasons:

• FDA understands that your firm hired a third-party consulting firm after FDA’s inspection to assist in reviewing and enhancing all the company’s SOPs. However, your firm’s new SOP, “Handling and Reporting Suspect and/or Illegitimate Products” (effective 5/5/22) contains information not consistent with the DSCSA. For example, the SOP indicates that immediate trading partners be notified (b)(4) after Safe Chain makes a determination that product in its possession or control is illegitimate product. FDA reiterates that the DSCSA requires immediate trading partners to be notified within 24 hours of an illegitimate product determination. (FD&C Act section 582(c)(4)(B)(ii)). FDA notes that the revised SOP you provided, “Vendor and Transaction History Authentication” (effective 5/9/15) is updated with the correct time-frame. However, the inconsistency between the two SOPs creates the potential for significant confusion and untimely notification.
• In your response you state that you have: “…NEVER knowingly purchased illegitimate products from any of our Vendors…” (emphasis in original). You explain that you continued to purchase products from Gentek, and did not cease sales of the product, even after becoming aware of issues with product received from the firm because the products were part of an ongoing investigation and you believed the issue was at the retailer/pharmacy level.

Your response is inadequate because you failed to provide any documentation demonstrating the rationale for your belief that the issue was at the retailer/pharmacy level. If your firm had conducted the required investigations, which would have included your firm’s knowledge of reported issues with the drug, you may have recognized the inherent risk of these Gentek products to the supply chain. Furthermore, your response appears to acknowledge that your efforts to look into the problematic product was limited to Safe Chain and Safe Chain’s attorneys. If this is the case, this is inadequate because the DSCSA requires that investigations of suspect product take place in coordination with trading partners. (FD&C Act section 582(c)(4)(A)(i)(II)).

DSCSA Resources

As explained above, your firm has failed to comply with a number of DSCSA provisions. Please see the FDA guidance documents listed below for additional information about the DSCSA requirements noted above:³

• Drug Supply Chain Security Act Implementation: Identification of Suspect Product and Notification, Final Guidance, June 2021, https://www.fda.gov/media/88790/download
• Definitions of Suspect Product and Illegitimate Product for Verification Obligations Under the Drug Supply Chain Security Act, Final Guidance for Industry, March 2023, https://www.fda.gov/media/111468/download.
• Verification Systems Under the Drug Supply Chain Security Act for Certain Prescription Drugs, Draft Guidance for Industry, March 2022, https://www.fda.gov/media/117950/download.
• Identifying Trading Partners Under the Drug Supply Chain Security Act, Draft Guidance for Industry, July 2022, https://www.fda.gov/media/159621/download.

Conclusion

Safe Chain’s response to FDA Form 483 does not indicate that sufficient remediation efforts have been taken. FDA is sending this compliance letter to Safe Chain because of the inherent risk to the supply chain when firms do not comply with the provisions of the DSCSA.

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.

Correct any violations promptly. Failure to promptly and adequately address these violations may result in regulatory or legal action without further notice, including seizure and injunction.

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 send your electronic reply to ORAPHARM1_Responses@FDA.HHS.GOV and “cc” Compliance Officer, Emmanuel Ramos (Emmanuel.Ramos@fda.hhs.gov). Your written notification should refer to the Warning Letter #636044 and include FEI number 3009729473.

If you have questions regarding the contents of this letter, please contact Emmanuel Ramos, Compliance Officer, via email at Emmanuel.Ramos@fda.hhs.gov or by telephone at 240-507-7119.

Sincerely,
/S/

Lisa Harlan
Program Division Director
Office of Pharmaceutical Quality Operations, Division I
U.S. Food & Drug Administration

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1 “Suspect product” and “illegitimate product” are defined in sections 581(21) and (8) of the FD&C Act, respectively.

2 Trading partners should be mindful of product that is missing required information or security features, as that may indicate the product should be considered suspect. See FDA’s 2016 final guidance Drug Supply Chain Security Act Implementation: Identification of Suspect Product and Notification.

3 Draft guidances, when finalized, will represent the agency's current thinking on the topic.