WARNING LETTER

Sure-Biochem Laboratories, LLC MARCS-CMS 646619 — March 24, 2023

Delivery Method:: Via Email
Product:: Drugs

Recipient:: Recipient Name

Tiffany Heigler; Recipient Title

President and CEO; Sure-Biochem Laboratories, LLC; 1000 Atlantic Ave
Camden, NJ 08104
United States

Issuing Office:: Division of Pharmaceutical Quality Operations I; United States

Warning Letter #646619

March 24, 2023

Dear Ms. Heigler:

The U.S. Food and Drug Administration (FDA) inspected your contract testing laboratory, Sure-Biochem Laboratories, LLC, FEI 3023533273, at 1000 Atlantic Ave., Camden, NJ, from September 28 to October 7, 2022. Our inspection determined that you are a contract testing laboratory conducting microbial testing including, but not limited to, finished drugs.

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, the drugs you tested 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 October 27, 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 follow required laboratory control mechanisms and to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity (21 CFR 211.160(a) and 211.160(b)).

You failed to adequately establish and follow procedures for growth promotion testing of your microbiological media to assure suitability before use, including failing to establish appropriate challenge conditions and acceptance criteria to ensure the media could support appropriate growth. For example, your growth promotion testing conducted on July 13, 2022, for Salmonella media lot number (b)(4), identified light and moderate growth for the challenge organisms including Escherichia coli. You accepted the lot for use without noting the deviation as required by your established procedure that specifies the growth of Escherichia coli should be inhibited. Further, you also failed to conduct growth promotion for each lot of media received.

Additionally, you did not validate your alternative microbial methods used to test drug products to assure the methods were equivalent to or better than USP methods. Specifically, you failed to adequately establish that your microbiological testing methods can reliably detect objectionable microorganisms. For example, Lab Numbers (b)(4) and (b)(4) were samples of (b)(4) drug products marketed for pre- and post-surgical oral care and intended for use with patients who are particularly susceptible to infection.

Your microbial method failed to detect Burkholderia cepacia complex (Bcc), and you reported “Not Detected” to your client. Subsequently, you sent microbial subcultures from these samples to another external laboratory that detected Burkholderia contaminans in both samples, a species that is part of Bcc. The ability of microbial testing methods to detect objectionable microorganisms in the presence of each drug product to be tested must be established and validated.

In your response, you commit to performing growth promotion for every lot of purchased media and revising your growth promotion procedure to ensure media can support acceptable growth. You also acknowledge that your alternative method used to test drug products was insufficient to detect Bcc, and state that you will develop a procedure for the USP <60> test method. However, your response is inadequate because it does not address how you will review the validity of previous results using your alternative methods, or how you will communicate with your clients about these potentially noncompliant analyses. You also state that you will perform method suitability verifications for each type of product, but do not detail the actions you would take if suitability verifications are found inadequate.

Your clients rely on your laboratory data for critical information about the quality of their drugs. Thus, it is important that your test methods are properly verified or validated, and that you use appropriate test methods to enable your clients to make proper decisions (e.g., lot disposition). Results generated using unverified or unvalidated methods can mislead customers and may put consumers at risk.

In response to this letter, provide:

A comprehensive, independent assessment of your laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system.
A retrospective assessment of prior testing to assure 'suitability' of your methods for the last (b)(4) years of testing, and a commitment to notify customers of any deficiencies. Include any revised testing results provided to your clients with incorrect enumeration calculations.
A comprehensive investigation into the extent of the inaccuracies in data, records, and reporting, including results of the data review for drugs tested. Include a detailed description of the scope and root causes of your data integrity lapses.
A procedure to establish a quantitative, acceptance criteria rather than qualitative growth entries (e.g., (b)(4)) included in your growth promotion testing.
Raw data from inoculation studies of your drugs to ensure appropriate identification of objectionable microorganisms including, but not limited to Bcc.

2. Your firm failed to establish an adequate quality unit and the responsibilities and procedures applicable to the quality control unit are not in writing and fully followed (21 CFR 211.22(a) and 211.22(d)).

Your quality unit (QU) lacked adequate control over your testing operations and failed to ensure that you had suitable procedures. For example, your QU failed:

To adequately retain documentation for the review, approval, or rejection, of laboratory testing materials such as buffers, reagents, and media. There is a lack of assurance that testing materials used to conduct microbial testing meet all appropriate specifications before use of an incoming lot, and include evaluation of certificates of analysis (COA).
To ensure procedures were followed to document and retain records such as laboratory investigations, corrective action and preventive action plans (CAPA), and change controls. You told our investigators that you were not following a number of your standard operating procedures (SOPs).
To establish an adequate CGMP training program. You lacked appropriate resources to perform QU related functions and our inspection revealed basic CGMP violations.

In your response, you admit to not adhering to your SOPs and state that you will document receipt of all incoming testing materials and retain the associated documentation. You also committed to hiring a quality consultant to develop a CGMP training program and perform quality functions. However, your response is inadequate because you did not commit to conducting a retrospective review to ensure materials used for drug product testing were suitable for their intended use. In addition, you state that your lab technician will attend “21 CFR 820 training,” which is applicable to medical devices, but does not address the lack of CGMP training for drugs.

Your firm’s quality systems are inadequate. See FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations for help implementing quality systems and risk management approaches to meet the requirements of CGMP regulations 21 CFR, parts 210 and 211 at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070337.pdf .

In response to this letter, provide:

A retrospective review of records for testing using received materials to assure correct materials were used and acceptable.
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 lot and its related information before the QU disposition decision
o Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products

A comprehensive, independent assessment of your change management system. This assessment should include, but not be limited to, your procedure(s) to ensure changes are justified, reviewed, and approved by your QU. Your change management program should also include provisions for determining change effectiveness.
An independent summary of your retrospective review of records for (b)(4) years of testing using received materials to assure correct materials were used and acceptable.

3. Your firm failed to ensure that laboratory records included complete data derived from all tests necessary to ensure compliance with established specifications and standards (21 CFR 211.194(a)).

Your laboratory records do not include complete testing data to support the analysis performed. For example, your records lack a statement of methods used for testing, a statement of the results of tests and how they compare to the established specifications, a record of all critical equipment used, and confirmation of compliance with testing conditions. Furthermore, you were unable to provide raw data to support the suitability of your alternative methods for each drug tested.

All CGMP-related data must be retained by all laboratories, including contract testing laboratories, to enable appropriate assessments and decisions by the QU and customers, and to demonstrate ongoing control.

In your response, you state that you will revise your records to include the missing information. Your response is inadequate because you make no commitment to retrospectively review prior testing for completeness, validity, or for errors.

In response to this letter, provide:

A comprehensive independent assessment of documentation practices used throughout your laboratory operations to determine where documentation is 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.
An independent assessment that summarizes the potential impact on product quality of the inadequate documentation.

Responsibilities of a Contract Testing Lab

FDA considers contractors as extensions of the manufacturer’s own facility. Your failure to comply with CGMP may affect the quality, safety, and efficacy of the drugs you test for your clients. It is essential that you understand your responsibility to operate in full compliance with CGMP when performing analytical work for your customers. Your laboratory role is critical to the pharmaceutical supply chain, and it is essential that you meet all CGMPs related to your function. As part of this responsibility, it is essential that you provide prompt, complete, and transparent analytical information to your customers (e.g., manufacturers) to enable them to handle their quality responsibilities related to batch evaluation and contractor oversight. This responsibility includes, but is not limited to, conveying to the customer any out-of-specification (OOS) investigations performed by your firm.

For additional information refer to FDA Guidance for Industry Contract Manufacturing Arrangements for Drugs: Quality Agreements (https://www.fda.gov/media/86193/download).

CGMP Consultant Recommended

Based upon the nature of the violations we identified at your firm, we strongly recommend engaging a consultant (i.e., an independent third party) qualified as set forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements. Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for resolving all deficiencies and systemic flaws to ensure ongoing CGMP compliance.

Data Integrity Remediation

Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you test. See FDA’s guidance document Data Integrity and Compliance With Drug CGMP for guidance on establishing and following CGMP compliant data integrity practices at https://www.fda.gov/media/119267/download.

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.
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 send your electronic reply to Yvette Johnson, Compliance Officer, at Yvette.Johnson@fda.hhs.gov and ORAPHARM1_RESPONSES@fda.hhs.gov. Identify your response with FEI# 3023533273.

Sincerely,
/S/

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