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August 6, 2021

Case # 610102

WARNING LETTER

Dr. Reid:

You registered your facility with the U.S. Food and Drug Administration (FDA) as an outsourcing facility under section 503B of the Federal Food, Drug, and Cosmetic Act (FDCA) [21 U.S.C. § 353b]¹ on March 23, 2018, and most recently on January 22, 2020. From February 19, 2020, to February 28, 2020, an FDA investigator inspected your facility, Maitland Labs of Central Florida, located at 7972 Forest City Road, Orlando, FL 32810. During the inspection, the investigator noted that drug products you produced failed to meet the conditions of section 503B of the FDCA necessary for drugs produced by an outsourcing facility to qualify for exemptions from certain provisions of the FDCA. In addition, the investigator noted serious deficiencies in your practices for producing sterile drug products, which put patients at risk.

FDA issued a Form FDA 483 to your facility on February 28, 2020. FDA acknowledges receipt of your facility’s response, dated March 16, 2020. Based on this inspection, it appears you produced drugs that violate the FDCA.

A. Compounded Drug Products under the FDCA

Under section 503B(b) of the FDCA, a compounder can register as an outsourcing facility with FDA. Drug products compounded by or under the direct supervision of a licensed pharmacist in an outsourcing facility qualify for exemptions from the drug approval requirements in section 505 of the FDCA [21 U.S.C. § 355(a)], the requirement in section 502(f)(1) of the FDCA [21 U.S.C. § 352(f)(1)] that labeling bear adequate directions for use and the Drug Supply Chain Security Act requirements in section 582 of the FDCA [21 U.S.C. § 360eee-1] if the conditions in section 503B of the FDCA are met.²

An outsourcing facility, which is defined in section 503B(d)(4) of the FDCA [21 U.S.C. § 353b(d)(4)], is a facility at one geographic location or address that — (i) is engaged in the compounding of sterile drugs; (ii) has elected to register as an outsourcing facility; and (iii) complies with all of the requirements of this section. Outsourcing facilities must comply with other applicable provisions of the FDCA, including section 501(a)(2)(B) [21 U.S.C. § 351(a)(2)(B)], regarding current good manufacturing practice (CGMP), and section 501(a)(2)(A) [21 U.S.C. § 351(a)(2)(A)], regarding insanitary conditions. Generally, CGMP requirements for the preparation of drug products are established in Title 21 of the Code of Federal Regulations (CFR) parts 210 and 211.

In addition, for a compounded drug product to qualify for the exemptions under section 503B, the labeling of the drug must include certain information (section 503B(a)(10) of the FDCA [21 U.S.C. §353b(a)(10)]).

Further, for a compounded drug product to qualify for the exemptions under section 503B, it must be compounded in an outsourcing facility that is in compliance with the registration and reporting requirements in section 503B(b) including the requirement to submit adverse event reports to FDA “in accordance with the content and format requirements established through guidance or regulation under section 310.305 of title 21, Code of Federal Regulations (or any successor regulations)” (sections 503B(a)(1) and (b)(5) of the FDCA [21 U.S.C. §§353b(a)(1) and (b)(5)]).³

B. Failure to Meet the Conditions of Section 503B

During the inspection, the FDA investigator noted that drug products produced by your facility failed to meet the conditions of section 503B. For example, the investigator noted:

1. Some of your facility’s drug products, for example Nalbuphine 10 mg/mL in 0.2% Saline, did not include the following statements on the label: the established name of the drug and the dosage form as required by section 503B(a)(10)(A)(iii) of the FDCA. Some of your facility’s drug products, for example Nalbuphine 10 mg/mL in 0.2% Saline, did not include the following information on the container: a list of active and inactive ingredients identified by established name, and the quantity or proportion of each ingredient as required by section 503B(a)(10)(B)(i) of the FDCA.

2. Your facility’s drug products were not compounded in an outsourcing facility that is in compliance with the requirements of section 503B(b) (see section 503B(a)(1) of the FDCA). Specifically, your facility does not comply with section 503B(b)(5) of the FDCA, which as noted above, requires an outsourcing facility to “submit adverse event reports to …[FDA] in accordance with the content and format requirements established through guidance or regulation under section 310.305 of title 21, Code of Federal Regulations (or any successor regulations).” Specifically, your facility’s procedures for reporting adverse events are inadequate. For example, your documented procedures do not advise employees to maintain records relating to adverse event reports for 10 years and do not advise employees to submit adverse event reports by utilizing either the Safety Reporting Portal (SRP) or Electronic Submission Gateway (ESG).

Because your compounded drug products have not met all of the conditions of section 503B, they are not eligible for the exemptions in that section from the FDA approval requirements of section 505, the requirement under section 502(f)(1) that labeling bear adequate directions for use, and the Drug Supply Chain Security Act requirements described in section 582 of the FDCA.

Specific violations are described below.

C. Violations of the FDCA

Adulterated Drug Products

The FDA investigator noted CGMP violations at your facility that caused your drug products to be adulterated within the meaning of section 501(a)(2)(B) of the FDCA. The violations include, for example:

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).

2. Your firm failed to establish and follow an adequate written testing program designed to assess the stability characteristics of drug products and to use results of stability testing to determine appropriate storage conditions and expiration dates (21 CFR 211.166(a)).

3. Your firm failed to conduct laboratory testing to determine whether each batch of drug product purporting to be sterile and pyrogen-free conforms to such requirements (21 CFR 211.167(a)).

Outsourcing facilities must comply with CGMP requirements under section 501(a)(2)(B) of the FDCA. FDA’s regulations regarding CGMP requirements for the preparation of drug products have been established in 21 CFR parts 210 and 211. FDA intends to promulgate more specific CGMP regulations for outsourcing facilities. FDA has issued a revised draft guidance, Current Good Manufacturing Practice — Guidance for Human Drug Compounding Outsourcing Facilities under Section 503B of the FD&C Act. This draft guidance, when finalized, will describe FDA’s expectations regarding outsourcing facilities and the CGMP requirements in 21 CFR parts 210 and 211 until more specific CGMP regulations for outsourcing facilities are promulgated.

Under section 301(a) of the FDCA [21 U.S.C. § 331(a)], the introduction or delivery for introduction into interstate commerce of any drug that is adulterated is a prohibited act. Further, it is a prohibited act under section 301(k) of the FDCA [21 U.S.C. § 331(k)] to do any act with respect to a drug, if such act is done while the drug is held for sale after shipment in interstate commerce and results in the drug being adulterated.

Unapproved New Drug Products

You do not have any FDA-approved applications on file for drug products that you compound.⁴ Under sections 505(a) and 301(d) of the FDCA [21 U.S.C. §§ 331(d)], a new drug may not be introduced into or delivered for introduction into interstate commerce unless an application approved by FDA under section 505 of the FDCA is in effect for the drug. Marketing of these products, or other applicable products, without an approved application violates these provisions of the FDCA.

Misbranded Drug Products

You compound drug products that are intended for conditions not amenable to self-diagnosis and treatment by individuals who are not medical practitioners; therefore, adequate directions for use cannot be written so that a layman can use these products safely for their intended uses. Consequently, their labeling fails to bear adequate directions for their intended uses causing them to be misbranded under section 502(f)(1) of the FDCA.⁵

Under section 502(a) of the FDCA [21 U.S.C. § 352(a)], a drug product is misbranded if its labeling is false or misleading in any particular. Evidence collected during the inspection established that your drug product, Nalbuphine HCl 10 mg/mL in 0.2% Saline, contains 0.063% citric acid anhydrous. However, the container label states it contains 0.63% citric acid anhydrous. Additionally, evidence collected during the inspection established that Nalbuphine HCl 10 mg/mL in 0.2% Saline is to be stored at a temperature of 15 to 30 degrees Celsius, 59 to 86 degrees Fahrenheit; cannot be frozen; and needs to be protected from light. However, your product label and container label for Nalbuphine HCl 10 mg/mL in 0.2% Saline states only that the product be “store[d] at room temperature (60-80 Fahrenheit).” It does not state that this product cannot be frozen and needs to be protected from light. These misleading representations of the ingredient concentration and of the storage and handling instructions on the labeling cause the product to be misbranded under section 502(a) of the FDCA.

The introduction or delivery for introduction into interstate commerce of these products therefore violates section 301(a) of the FDCA [21 U.S.C. § 331(a)]. Further, it is also a prohibited act under section 301(k) of the FDCA [21 U.S.C. § 331(k)] to do any act with respect to a drug, if such act is done while the drug is held for sale after shipment in interstate commerce and results in the drug being misbranded.

D. Corrective Actions

We have reviewed your facility’s response to the Form FDA 483, dated March 16, 2020. Some of your corrective actions appear adequate. However, we cannot fully evaluate the adequacy of the following corrective actions described in your response because you did not include sufficient information or supporting documentation:

1. In response to Observation 2a of the Form FDA 483, you stated that, “A form FOR-9.018 will be generated and investigated to see if this will require a CAPA...” However, you have not provided any updates regarding the status of any investigation if applicable per SOP-9.018. Further, during the inspection, it was noted that you have proposed per the SOP #PRO-7.052 entitled, “Inspection Checks for Parenteral Products”, Section 6.4.10 that, “(b)(4).” However, you did not provide a justification on how this limit was established. Drug products intended for parenteral administration should be prepared in a manner designed to exclude particulate matter. Administration of an injectable product with particulates may lead to severe health consequences. In addition, you have not provided the revised SOP #PRO-7.052 for our review.

2. In response to Observation 3b of the Form FDA 483, we acknowledge your commitment to work with your contract testing laboratory to perform container closure integrity testing (CCIT). However, you have not provided documentation to demonstrate that CCIT has been performed. Before a batch is released, CCIT is expected to be completed on samples aged to or beyond the desired expiration date to ensure that sterility is maintained over that time period. This is of particular concern as during our inspection, it was noted that 21 vials ((b)(4) vials produced) failed to meet general appearance attributes (crimp caps and stoppers came off during the (b)(4) cycle).

3. In response to Observation 3c of the Form FDA 483, you have stated that you will work with your contract testing laboratory to determine if the (b)(4) method used for the assay/potency test of Nalbuphine HCL is stability-indicating. You have not provided an update whether the (b)(4) assay/potency method used for testing Nalbuphine HCL is stability indicating and can detect impurities and that no degradants co-elute with active pharmaceutical ingredient or excipients.

Further, your (b)(4) testing method is inadequate to be used for identification testing as the method does not have good discriminative ability. In general, identification testing should establish the identity of the drug substance(s) in the drug product and should be able to discriminate between compounds of closely related structure which are likely to be present. Identity tests should be specific for the drug substance, e.g., infrared spectroscopy. Identification solely by a single chromatographic retention time, for example, is not regarded as being specific. However, the use of two chromatographic procedures, where the separation is based on different principles, or combination of tests into a single procedure, such as high-performance liquid chromatography (HPLC)/UV diode array, HPLC/Mass Spectrometry (MS), or gas chromatography (GC)/MS, is generally acceptable.

4. In response to Observation 5 of the Form FDA 483 regarding sterility testing, we have reviewed the documentation provided by your contract testing laboratory. You have not provided the supporting validation documentation for sterility testing to demonstrate that the sterility method is adequate for its intended use. Additionally, we acknowledge your commitment to “look at finding a discreet and stable table or stand for the (b)(4) in the near future as time permits.” However, you have not provided an update on the progress of this corrective action. Regarding the (b)(4) location during the inspection, you stated in your response that, “If there are any types of vibrations, they are minor and we don’t consider this a possible risk, certainly not one that would affect operations or test results.” However, you did not provide evidence to support this statement. Therefore, we remain concerned about this potential impact on endotoxin testing results used to release product to market.

In addition, the following corrective actions appear deficient:

1. In response to Observation 2b of the Form FDA 483, you stated you acknowledge that per your firm’s existing procedure, a Form FOR-9.018 should have been generated as well as “an impact analysis of this batch to determine risk.” However, you have not provided documentation to demonstrate that you have completed the impact analysis or any further investigation. Furthermore, during the inspection, you indicated that the batch passed the test for sterility and that the (b)(4) alerts related to exhaust rate too fast and unsealed door had no impact on product quality. However, this justification is not acceptable. Facilities producing purportedly sterile drug products should not rely upon or cite a passing sterility test result as an indication of product sterility. These procedures are not by themselves designed to ensure that a batch of product is sterile or has been sterilized. This is accomplished primarily by validation of the sterilization process. It is essential that robust equipment design and upstream process controls are employed to assure the quality of each lot throughout processing to prevent contamination. Additionally, you did not provide evidence demonstrating that you have performed a re-validation of the (b)(4) after the replacement of the required (b)(4) parts.

2. In response to Observation 3a of the Form FDA 483, you stated you believe that humidity control is not required for stability studies for products packaged in impermeable containers such as glass per your SOP# QAL-9.020v1, Standardized Stability Study Procedures and the statement from your (b)(4) quality person. However, the justification you provided is not acceptable as impermeable containers are “containers that provide a permanent barrier to the passage of gasses or solvents, e.g., sealed aluminum tubes for semisolids, sealed glass ampoules for solutions.” Hence, your product is not packaged in containers that provide permanent barrier to the passage of solvents or gases, but rather packaged in glass vials sealed and crimped. Therefore, our expectation is that you evaluate the impact of humidity on your drug products during long term stability studies.

In addition to the issues discussed above, you should note that CGMP requires the implementation of quality oversight and controls over the manufacture of drugs, including the safety of raw materials, materials used in drug manufacturing, and finished drug products. See section 501 of the FDCA. If you choose to contract with a laboratory to perform some functions required by CGMP, it is essential that you select a qualified contractor and that you maintain sufficient oversight of the contractor’s operations to ensure that it is fully CGMP compliant. Regardless of whether you rely on a contract facility, you are responsible for assuring that drugs you produce are neither adulterated nor misbranded [See 21 CFR 210.1(b), 21 CFR 200.10(b).].

Regarding observations related to the requirements for adverse event reporting in section 503B(b)(5) of the FDCA, we are unable to fully evaluate the corrective actions with respect to your facility’s procedures due to lack of adequate supporting documentation: You verbally stated during the inspection that you would update your facility’s procedures for reporting adverse events, but you did not provide a copy of such updated procedures

Furthermore, your corrective actions regarding observations related to the labeling requirements of section 503B(a)(10) of the FDCA and misbranding provisions of 502(a) of the FDCA appear deficient. You state that “all of the…observations [related to drug product and container labels] were corrected prior to the end of the inspection on 2/29/20.” However, the revised labels provided during the inspection lack the dosage form and still contain certain false or misleading statements with respect to storage and handling instruction.

Should you continue to compound and distribute drug products that do not meet the conditions of section 503B, the compounding and distribution of your drugs would be subject to the new drug approval requirement, the requirement to label drug products with adequate directions for use, and the Drug Supply Chain Security Act requirements.

FDA strongly recommends that your management undertake a comprehensive assessment of operations, including facility design, procedures, personnel, processes, maintenance, materials, and systems. A third-party consultant with relevant sterile drug manufacturing expertise should assist you in conducting this comprehensive evaluation.

E. Conclusion

The issues cited in this letter are not intended to be an all-inclusive list of potential violations 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. It is your responsibility to ensure that your firm complies with all requirements of federal law, including FDA regulations.

You should take prompt action to address the issues cited in this letter. Failure to promptly address these issues may result in legal action, including, without limitation, seizure and injunction.

Within 15 (fifteen) working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to address the issues identified. Please include an explanation of each step being taken to prevent the recurrence, as well as copies of related documentation. This letter notifies you of our concerns and provides you an opportunity to address them. If you believe that your products are not in violation of the FDCA, include your reasoning and any supporting information for our consideration. If you cannot address these issues within fifteen (15) working days, state the reason for the delay and the time within which you will finish addressing them.

Please identify your response with FEI 3013854204. Send your electronic reply to Dr. Shawn Larson – Compliance Officer at [email protected] and [email protected].

If you have questions regarding the contents of this letter, please contact Dr. Larson at 214-253-5216.

Sincerely,
/S/

CDR John W. Diehl, M.S
Acting Program Division Director
Office of Pharmaceutical Quality Operations,
Division II

_________________________

1 See Pub. L. No. 113-54, § 102(a), 127 Stat. 587, 587-588 (2013).

2 We remind you that there are conditions, other than those discussed in this letter, that must be satisfied to qualify for the exemptions in section 503B of the FDCA.

3 For additional information, see FDA’s guidance, “Adverse Event Reporting for Outsourcing Facilities Under Section 503B of the Federal Food, Drug, and Cosmetic Act,” which can be found at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM434188.pdf.

4 The specific products made by your firm are drugs within the meaning of section 201(g) of the Act, [21 U.S.C. § 321(g)] because they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of diseases and/or because they are intended to affect the structure or any function of the body. Further, they are “new drugs” within the meaning of section 201(p) of the FDCA [21 U.S.C. § 321(p)] because they are not generally recognized as safe and effective for their labeled uses.

5 Your compounded drug products are not exempted from the requirements of section 502(f)(1) of the FDCA by regulations issued by the FDA (see, e.g., 21 CFR 201.115).