- Delivery Method:
- VIA Electronic Mail
Recipient NameBobby J. King, Jr.
- Sircle Laboratories, LLC
P.O. Box 238
Ridgeland, MS 39158
- Issuing Office:
- Office of Pharmaceutical Quality Operations, Division II
September 21, 2021
Case #: 615098
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Sircle Laboratories, LLC, FEI 3011772828, at 105 Lexington Drive, Suite J, Madison, Mississippi, from April 13 to 26, 2021.
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).
We reviewed your May 11, 2021, response to our Form FDA 483 in detail.
During our inspection, our investigator observed specific violations including, but not limited to, the following.
1. Your firm’s quality control unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity. (21 CFR 211.22)
Your firm lacks appropriate oversight and procedures to manage contract manufacturing organizations (CMOs) used on behalf of your firm for the manufacturing, packaging, and distribution of your drug products. You are ultimately responsible for CGMP activities you perform.
Your firm has failed to follow your established quality unit (QU) procedures, as well as commitments documented in quality agreements (QA). In your response, you maintained that you have CGMP responsibilities, including, but not limited to, having written procedures for your quality unit, handling of consumer complaints, release of drug products, and qualifying and approving of your CMOs. QU deficiencies include:
Inadequate QU oversight of your CMOs
Your QU lacked adequate oversight and controls for your CMOs, which led to your use of sub-standard CMOs. Since 2017, FDA has taken the following actions in response to CGMP violations found at your CMOs.
For example, (b)(4), was issued a Warning Letter on (b)(4), that included, but not limited to, violations for the failure to establish appropriate time limits for each stage of production, and failure to thoroughly investigate out-of-specification (OOS) results.
In your response, you stated that you are in the process of developing procedures that address the approval process for your CMOs. Your response is inadequate because you did not conduct a retrospective review of the lack of QU oversight of your CMOs and product distribution which may impact the identity, strength, quality, and purity of your drug products.
In response to this letter, provide a comprehensive assessment plan to ensure that suppliers are suitably qualified and appropriate oversight is maintained. This assessment should include, but not be limited to:
• Supplier qualification selection and management procedures that encompass all functions of CGMP activities your CMOs perform on your behalf.
• Suitability of your suppliers and key elements of your requalification program (e.g., audit).
Failure to establish and follow QU procedures
• Lack of batch release procedures
Your firm failed to establish adequate written responsibilities and procedures for reviewing batches made by your CMO. You also failed to review production records for each batch for disposition (i.e., reject or approve) per your QA with (b)(4). You are ultimately responsible for approving or rejecting drug product batches manufactured for you by a contract facility. Determining the suitability of each batch for release is an essential component of your quality unit responsibility.
In your response, you confirmed that you do not have a written procedure specifying release of drug products from CMOs and stated that you are developing procedures. Your response is inadequate because you did not provide details on what these procedures entail or how they will be applied.
Failure to follow change control procedures
Your QU failed to ensure your firm follows your change control procedure. For example, since the last FDA inspection in March 2019, your firm implemented changes to your consumer complaints and drug product recalls procedures without following your change control procedure. In addition, you approved changes to your drug product labeling without following your change control procedure. In each of these instances, your firm did not adequately justify or document these changes as required in your change control procedure.
In your response, you acknowledge that you have not been following your change control procedure for the changes your firm has implemented. Your response is inadequate in that the forms provided did not include an assessment of the impact of the changes, including changes to your labeling materials.
In response to this letter, provide a comprehensive, independent assessment of your change management system. This assessment should include, but not be limited to, your procedures to ensure changes are justified, reviewed, and approved by your quality unit. Your change management program should also include provisions for determining change effectiveness.
Your response is inadequate because you did not conduct a retrospective review of the failure to establish and follow QU procedures, which may impact the identity, strength, quality, and purity of your drug products.
• In response to this letter, provide a comprehensive assessment and remediation plan to ensure your QU is given the authority and resources to effectively function. The assessment should also include, but not be limited to:
o A determination of whether procedures used by your firm are robust and appropriate.
o Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices.
o A complete and final review of each batch and its related information before the QU disposition decision. Include a retrospective review of all batches currently in the U.S. market and within expiry as of the date of this letter and a report summarizing the findings of the analysis.
o Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products.
2. Your firm failed to follow establish and follow adequate written procedures describing the handling of all written and oral complaints regarding a drug product (21 CFR 211.198(a)).
You acknowledge that while you use CMOs on your behalf, you maintain associated CGMP responsibilities, including, but not limited to, handling customer complaints and inquiries. However, your firm failed to adequately establish and follow your established complaint handling procedure. For example, your procedure stipulated responsibilities for the handling and investigating of consumer complaints to your “Drug Safety Specialist” and “Chief Scientific Officer.” During the inspection, these titles and staff positions did not exist at your firm.
Further, your QA with (b)(4) states that you will notify (b)(4) of complaints that are likely to result in a field alert and/or recall, and that (b)(4) will conduct and complete the complaint investigation. All quality-related complaints, beyond those likely to result in a field alert and/or recall, must be investigated per 211.198.
In your response, you stated that you revised the complaint handling procedure by removing the non-existent titles and replacing these job titles to “Chief Operating Officer.” Your response is inadequate because you did not provide evidence demonstrating that this individual follows the complaint handling procedure and performs reviews to determine whether a complaint represents a serious and unexpected adverse drug event.
In response to this letter, provide the following:
• Your retrospective assessment of complaints received by Sircle that were or should have been shared with your CMOs, including quality-related complaints that may not have been likely to result in a field alert and/or recall.
• A list of complaints received by Sircle from all sources, including those received by your CMOs where you handle customer complaints and inquiries.
• Procedure(s) detailing how you will share quality-related complaints with your CMOs
3. Your firm failed to establish and follow written procedures designed to assure that correct labels, labeling, and packaging are used for drug products. (21 CFR 211.130)
Your firm reviews and approves the labeling for the drug products manufactured by your CMOs. Your procedure for reviewing and approving the labels is inadequate. For example, your procedure does not require the verification of all elements on the labels, such as storage conditions and dispensing volumes. Moreover, your procedure does not include a review or comparison of drug product labels against an approved master or reference label.
In your response, you stated that you use master labels and that you are in the process of revising your label review procedure by July 1, 2021. Your response is inadequate.
You did not provide evidence that your firm uses master or reference labels when reviewing and approving your drug product labels. In addition, you have not provided your updated procedure in response to this observation. Further, your response lacks a retrospective review to ensure appropriate labeling is on all products currently in distribution.
In response to this letter, provide the following:
• Your corrective action and preventive action (CAPA) plan to improve labeling operations including adequate procedures for labeling review and approval, management oversight, and any other needed actions.
• A complete assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient. Include a detailed CAPA plan that comprehensively remediates your firm’s documentation practices to ensure you retain attributable, legible, complete, original, accurate, contemporaneous records throughout your operation.
Repeat Violations at Facility
In previous inspections, dated August 2015, and March 2019, FDA cited similar CGMP observations. You proposed specific remediation for these observations in your responses. These repeated violations demonstrate a failure of your executive management to exercise proper oversight and control over the manufacture of drugs. You should immediately and comprehensively assess all of your firm’s manufacturing operations to ensure that systems, processes, and ultimately, products conform to FDA requirements.
In response to this letter, provide the following:
• Describe how top management supports quality assurance and reliable operations, including but not limited to, timely provision of resources to proactively address emerging manufacturing/quality issues and to assure a continuing state of control.
• An independent assessment and remediation plan for your CAPA program. Provide a report that evaluates staff with proper investigation competencies, effectively conducts root cause analysis, assures CAPA effectiveness, regularly reviews investigations trends, implements improvements to the CAPA program when needed, ensures appropriate quality unit decision rights, and is fully supported by executive management.
Use of Contract Manufacturers
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.
As stated in your response, confirm that your CMO, (b)(4), is performing microbial testing on all batches of drug products manufactured by them for your firm.
You are responsible for the quality of your drugs regardless of agreements in place with your contract facilities. You are required to ensure that drugs are made in accordance with section 501(a)(2)(B) of the FD&C Act to ensure safety, identity, strength, quality, and purity. See FDA’s guidance document Contract Manufacturing Arrangements for Drugs: Quality Agreements at https://www.fda.gov/media/86193/download.
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 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 since our inspection to correct your 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.
Your written notification should refer to case # 615098.
Please electronically submit your reply, on company letterhead, to Rebecca Asente, Compliance Officer, at ORAPHARM2_RESPONSES@fda.hhs.gov. In addition, please submit a signed copy of your response to John Diehl, Compliance Branch, via firstname.lastname@example.org.
If you have questions regarding the contents of this letter, you may contact Rebecca Asente via (504) 846-6104 or Rebecca.email@example.com.
Tamala P. Bogan
Acting Program Division Director
Office of Pharmaceutical Quality Operations,