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September 27, 2022

WARNING LETTER
WL #629019

Dear Mr. Flynn:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Sterling Pharmaceutical Services, LLC, FEI 3009705561, at 109 S 2nd Street, Dupo, Illinois, from February 7 to 18, 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).

In addition, the FDA reviewed the product labels for (b)(4) “(b)(4),” “(b)(4),” “(b)(4),” “(b)(4),” “(b)(4),” “(b)(4),” “(b)(4),” “(b)(4),” “(b)(4),” “(b)(4),” “(b)(4),” “(b)(4),” and “(b)(4),” collected during an inspection of your facility between February 7, 2022 and February 18, 2022. Based on our review, these products are unapproved new drugs under section 505 of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 355. Introducing or delivering these products for introduction into interstate commerce violates sections 301(d) and 505(a) of the FD&C Act, 21 U.S.C. 331(d), 355(a). In addition, your firm has significant violations of CGMP regulations. Your firm’s poor manufacturing practices are particularly concerning because many of your products, such as (b)(4) “(b)(4),” “(b)(4),” “(b)(4),” “(b)(4),” “(b)(4),” “(b)(4),” “(b)(4),” “(b)(4),” “(b)(4),” “(b)(4),” “(b)(4),” “(b)(4),” and “(b)(4),” are ophthalmic and directed for use in young children.

We reviewed your March 14, 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 is a contract manufacturer of sterile over-the-counter and homeopathic ophthalmic drug products utilizing aseptic processing. You identified your aseptic processing lines as Restricted Access Barrier Systems (RABS). However, your systems permitted access to the processing line (e.g., use of (b)(4)) without the design of rigid wall enclosures. Furthermore, you lacked other fundamental elements of a valid RABS design including glove ports which are employed to reduce or eliminate direct operator interventions into the ISO 5 critical area. These glove ports and infrequent door openings provide the foundation for the overall design and control concept of a RABS that reduces the hazard of ingress of contamination from the surrounding aseptic processing cleanroom environment. Your processing lines lacked basic design features to enable them to be categorized as a RABS.

You did not adequately investigate the excursions above your action limit, including an adverse trend of microbiological contamination from your aseptic processing line environment. For example, from January 1 to December 31, 2021, your environmental monitoring (EM) program repeatedly recovered microorganisms from production line ISO 5 areas (air, surface, and personnel) in your facility.

Your EM results from January 1 to February 16, 2022, including ISO 5 areas and aseptic processing operator glove samples, showed an adverse trend that revealed compromised environmental control of your aseptic processing operation. You continued ophthalmic drug production without adequate investigation and preventive measures to address the persistent microbiological contamination in your ISO 5 environments that posed a risk to product sterility.

Specific incident investigations into these contamination risks routinely identified poor aseptic behavior by personnel and concluded there was a “very low” risk to drug products. Your investigations were inadequate because they did not thoroughly address the persistent adverse trend of microorganisms recovered from ISO 5 areas, including spore-forming bacteria and fungi.

Environmental monitoring of your cleanrooms also recovered gram negative bacterial contamination.

Moreover, on July 7, 2021, your firm detected a sterility failure for (b)(4), lot (b)(4), contaminated with Herbaspirillum aquaticum, a gram-negative bacterium. Non-sterile ophthalmic drugs pose unacceptable risks to patients. We acknowledge that you rejected this lot, however your investigation failed to consider that this sterility failure, in conjunction with your adverse EM trends, may be indicative of contamination risks from the basic design of your processing lines and could impact other batches.

It should be noted that a sterility test, while a critical quality control for aseptically processed products that purport to be sterile, cannot be solely relied upon as justification to release drug product batches as the test is only the last in a series of design provisions and controls intended to protect the consumer from distribution of an unsafe batch. Any finished product positive sterility test results represent a serious CGMP issue requiring prompt and comprehensive investigation. Furthermore, your firm’s absence of strict adherence to proper design, aseptic methods, and environmental controls undermine your daily assurance of consistent sterile manufacturing.

In your response you indicate that you conducted a retrospective evaluation of all microbiological monitoring results between January 2021, and March 2022, and concluded that there was no impact to the lots previously released. Your response is inadequate as your retrospective review relied on third-party sterility testing, smoke studies, personnel training, and processes, but failed to consider that persistently deficient environmental controls are likely rooted in fundamental facility or equipment design flaws. In addition to line design hazards that fundamentally compromise aseptic processing, you performed makeshift line modification within the ISO 5 areas using materials that can harbor bioburden (e.g., (b)(4)).

A vigilant ongoing EM program is essential to detect and respond to potential product contamination hazards in your manufacturing environment in a timely manner. Loss of environmental control in an aseptic manufacturing facility can ultimately pose a serious hazard to patients.

In response to this letter, provide:

• A comprehensive, independent risk assessment of all contamination hazards with respect to your aseptic processes, equipment, and facilities including, but not be limited to:
  o All human interactions with the ISO 5 area
  o Equipment placement and suitability, including ergonomics for each human interaction
  o Air quality in the ISO 5 area, and surrounding room including, but not limited to, air volume, air flow, and microbial/particulate levels
  o Facility layout
  o Personnel flows and material flows throughout all rooms used to support and conduct sterile operations
  o Building management systems

• A detailed remediation plan with timelines to address the findings of the contamination hazards risk assessment. Describe specific tangible improvements to be made to aseptic processing operation design and control at your facility and explain how this CAPA will robustly remediate your deficient sterile manufacturing operation. Include comprehensive changes/improvements in the design of both your aseptic processing lines and cleanrooms. Also describe your plans for qualification and validation of your extensively remediated operations.

• Your CAPA plan to implement routine, vigilant operations management oversight of facilities and equipment. This plan should ensure, among other things, prompt detection of equipment/facilities performance issues, timely upgrades to equipment and facilities, adherence to appropriate preventive maintenance schedules, effective execution of repairs, and improved systems for ongoing management review.

• A comprehensive and independent assessment of your ongoing use of a rapid sterility testing method for ophthalmic drug products produced on an aseptic line that requires frequent human intervention. Include the independent assessment to evaluate whether the method is equivalent to or better than USP <71> sterility test.

• A summary of your program for qualifying and overseeing the contract laboratory performing testing of drug products you manufacture. Include a detailed assessment to determine if the laboratory is qualified to do the tests and all batch testing performed on your behalf is satisfactory.

• A summary of results from testing retain samples of all drug product batches within expiry. You should test all appropriate quality attributes including, but not limited to, sterility testing via compendial method of each batch. If testing yields an out of specification result or unexplained discrepancy, indicate the corrective actions you will take, including notifying customers and initiating recalls.

• An independent assessment of your EM program including, but not limited to, investigating deviations from microbiological limits. Include your plan for implementing the recommendations in the assessment.

2. Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas (21 CFR 211.42(c)(10)(iv)).

Your EM program (including personnel monitoring) was inadequate for classified areas used for the production of sterile ophthalmic drug products. We observed instances during production of two lots of sterile eye drops in which your firm failed to ensure adequate monitoring of non-viable particulates (NVP).

Furthermore, personnel monitoring was insufficient. Monitoring was limited to operators’ gloved hands following aseptic interventions. Because of the significant gaps within your EM program, you have insufficient information to assess the quality of the aseptic processing environment.

Your response is inadequate because you did not provide the recovered NVP data and describe how you recovered the data (which you stated during the inspection was unrecoverable). You also did not determine how many batches may have been affected by your identified root cause.

Further, your response indicated that you made procedural changes to incorporate occasional monitoring of arms and hoods of personnel gowns based on your risk assessment (V22-00602.RA). However, your response is inadequate because it fails to consider potential basic design issues with your aseptic processing line as supported by the nature and frequency of personnel aseptic interventions, manually intensive activities, EM data, aseptic breaches, and line maintenance manipulations. For example, in your response, you failed to include justification for omitting samples of personnel goggles and chest as well as aseptic processing line (b)(4) from EM. Environmental monitoring should promptly identify potential routes of contamination, allowing for implementation of corrections before product contamination could occur.

In response to this letter, provide:

• A comprehensive independent review of your personnel and EM program, including but not limited to:
  o A plan to fully remediate these programs. For example, describe changes to equipment, procedures and practices that will ensure meaningful ongoing data is collected to promptly detect and respond to emerging microbiological trends from your classified areas. Provide an updated timeline for implementation of your improved program, including procedural changes.
  o A risk assessment based on a retrospective review of personnel and EM data since you initiated sterile manufacturing of ophthalmic drug products. This assessment should include a review of all batches likely affected by gaps in NVP data.

3. Your firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes (21 CFR 211.113(b)).

Your firm had not established adequate procedures designed to prevent microbiological contamination risks in your facility. For example, your firm did not routinely document interventions performed by aseptic processing area operators during production. In addition, our investigators observed poor aseptic behaviors.

Investigators observed operators repeatedly exhibiting poor aseptic behaviors during filling operations of (b)(4), Lot (b)(4). To perform interventions during aseptic operations, the design of your filling line required personnel to reach through a (b)(4) placed in front of the aseptic processing equipment where open processing of finished product occurred. Operators were also observed contacting the (b)(4) with their goggles and chest area of their gowns while leaning into the ISO 5 zone to perform aseptic interventions. Additionally, operators did not sanitize the (b)(4) with sterile (b)(4), although it was required by your procedures for interventions. Among other factors, adequate separation, proper line design and control, robust sterilization and disinfection, a vigilant EM program, and strict personnel adherence to aseptic practices are essential to prevent contamination.

Our investigators also observed that non-routine interventions performed by aseptic operators were not recorded. The exclusion of this data inhibits adequate quality evaluations and investigations into deficiencies and compromises your ability to ensure media fills accurately simulate the number and type of interventions that occur during commercial manufacturing.

Your response includes changes to batch record documentation and procedures for qualification of aseptic operators along with applicable training. However, your response fails to acknowledge potential design issues (e.g., equipment ergonomic flaws that influence operator behaviors), excessive need for manual manipulations, and insufficiency of barrier protection to provide adequate separation from surrounding areas.

In response to this letter, provide:

• Your plan to ensure appropriate aseptic practices and cleanroom behavior during production. Include steps to better assure routine and effective supervisory oversight for all production batches. Also describe the frequency of quality assurance oversight (e.g., audit) during aseptic processing and other operations.

• A thorough risk assessment that evaluates how poor aseptic technique and cleanroom behavior, such as those observed during the inspection, may have affected quality and sterility of your drugs.

Unapproved New Drugs

Statements on the product labels that provide evidence of the intended uses of these products include, but are not limited to, the following:

“(b)(4)” Sterile Eye Drops
• “Temporarily Relieves: ● (b)(4) ● (b)(4) ● (b)(4)”
“(b)(4)” Sterile Eye Drops
• “Temporarily Relieves: ● (b)(4) . . . ● (b)(4)”
“(b)(4)” Sterile Eye Drops
• “Supports: ● (b)(4)”
“(b)(4)” Sterile Eye Drops
• “Temporarily Relieves: ● (b)(4)”
“(b)(4)” Sterile Eye Drops
• “Temporarily Relieves: ● (b)(4) ● (b)(4) ● (b)(4)”
“(b)(4)” Sterile Eye Drops
• “Temporarily Relieves: ● (b)(4) ● (b)(4) ● (b)(4)”
“(b)(4)” Sterile Eye Ointment
• The product name “(b)(4),” which is located together on the label with “Drug Facts . . . Directions . . . (b)(4).”
“(b)(4)” Sterile Eye Drops
• “Temporarily Relieves: ● (b)(4) ● (b)(4) . . . ● (b)(4)”
“(b)(4)” Sterile Eye Ointment
• The product name “(b)(4),” which is located together on the label with “Drug Facts . . . Directions . . . (b)(4).”
“(b)(4)” Sterile Eye Drops
• “Temporarily Relieves: ● (b)(4) ● (b)(4) ● (b)(4)”
“(b)(4)” Sterile Eye Drops
• “Temporarily Relieves: ● (b)(4) ● (b)(4) ● (b)(4)”
“(b)(4)” Sterile Eye Drops
• “Temporarily Relieves: ● (b)(4) ● (b)(4) ● (b)(4)”
“(b)(4)” Sterile Eye Ointment
• The product name “(b)(4),” which is located together on the label with “Drug Facts . . . Directions . . . (b)(4).”

The above claims for (b)(4) “(b)(4),” “(b)(4),” “(b)(4),” “(b)(4),” “(b)(4),” “(b)(4),” “(b)(4),” “(b)(4),” “(b)(4),” “(b)(4),” “(b)(4),” “(b)(4),” and “(b)(4)” demonstrate that they are drugs under section 201(g)(1) of the FD&C Act, 21 U.S.C. 321(g)(1), because they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease, and/or intended to affect the structure or any function of the body. Moreover, these products are “new drugs,” as defined by 201(p) of the FD&C Act, 21 U.S.C. 321(p), because they are not generally recognized as safe and effective for use under the conditions prescribed, recommended, or suggested in their labeling. With certain exceptions not applicable here, new drugs may not be introduced or delivered for introduction into interstate commerce without an approved application from FDA in effect, as described in sections 505(a) and 301(d) of the FD&C Act, 21 U.S.C. 355(a) and 331(d). No FDA-approved application pursuant to section 505 of the FD&C Act, 21 U.S.C. 355, is in effect for these products. Accordingly, these products are unapproved new drugs marketed in violation of sections 301(d) and 505(a) of the FD&C Act, 21 U.S.C. 331(d) and 355(a).

We recognize that (b)(4) “(b)(4),” “(b)(4),” “(b)(4),” “(b)(4),” “(b)(4),” “(b)(4),” “(b)(4),” “(b)(4),” “(b)(4),” “(b)(4),” “(b)(4),” “(b)(4),” and “(b)(4)” are labeled as homeopathic drugs with active ingredients measured in homeopathic strengths. Under section 201(g)(1) of the FD&C Act, 21 U.S.C. 321(g)(1), the term “drug” includes articles recognized in the official Homeopathic Pharmacopeia of the United States (HPUS), or any supplement to it. Homeopathic drug products are subject to the same statutory requirements as other drugs; nothing in the FD&C Act exempts homeopathic drugs from any of the requirements related to adulteration, misbranding, or approval.

Ineffective Quality System

Significant findings in this letter demonstrate that your firm does not operate an effective quality system in accord with CGMP. In addition to the lack of effective production operations oversight to ensure reliable facilities and equipment, we found your quality unit is not enabled to exercise proper authority and/or has insufficiently implemented its responsibilities. You should immediately and comprehensively assess your company’s global manufacturing operations to ensure that systems, processes, and the products manufactured conform to FDA requirements.

Responsibilities as a Contractor

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. See FDA’s guidance document Contract Manufacturing Arrangements for Drugs: Quality Agreements at https://www.fda.gov/media/86193/download.

CGMP Consultant Recommended

We acknowledge you engaged a consultant 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.

Additional Guidance on Aseptic Processing

See FDA’s guidance document Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice to help you meet the CGMP requirements when manufacturing sterile drugs using aseptic processing at https://www.fda.gov/media/71026/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 address your reply via email to: ORAPHARM3_RESPONSES@fda.hhs.gov

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

Your written notification should refer to the Warning Letter Case Number above (#629019). If you have questions regarding the contents of this letter, please contact Dr. Garthwaite at (612) 758-7132.

Sincerely,
/S/

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

cc: (b)(4)