OSRX, Inc. - 701889 - 04/23/2025

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WARNING LETTER
WL # 701889

April 23, 2025

Dear Ms. Frost:

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 October 28, 2023, and most recently on October 25, 2024. From October 16, 2024, to October 25, 2024, an FDA investigator inspected your facility, OSRX, Inc., located at 1120 Kensington Ave, Missoula, Montana 59801. During the inspection, the investigator collected evidence indicating 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 drug products intended or expected to be sterile, which put patients at risk.

FDA issued a Form FDA 483 to your facility on October 25, 2024, and issued an amended Form FDA 483 on November 4, 2024. FDA acknowledges receipt of your facility’s response, dated November 15, 2024. 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)]).

B. Failure to Meet the Conditions of Section 503B

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

1. Your facility’s drug products, such as Prednisolone Phosphate 1% Moxifloxacin 0.5% 5ml Sterile Ophthalmic Solution and Atropine Sulfate 0.025% 3.5ml Sterile Ophthalmic Solution, did not include the following on the label: a list of active and inactive ingredients, identified by established name and the quantity or proportion of each ingredient.

2. Your facility’s drug products, such as such as Prednisolone Phosphate 1% Bromfenac 0.075% 5ml Sterile Ophthalmic Solution and Moxifloxacin 0.5% Bromfenac 0.075% 5ml Sterile Ophthalmic Solution, did not include the following information on the container: (1) information to facilitate adverse event reporting: www.fda.gov/medwatch and 1-800-FDA-1088; and (2) directions for use, including, as appropriate, dosage and administration.

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 that drug products intended or expected to be sterile were prepared, packed, or held under insanitary conditions, whereby they may have become contaminated with filth or rendered injurious to health, causing your drug products to be adulterated under section 501(a)(2)(A) of the FDCA. For example, the investigator observed:

1. Your firm failed to perform adequate smoke studies under dynamic conditions to demonstrate unidirectional airflow within the ISO 5 classified critical area. Therefore, your products intended to be sterile are produced in an environment that may not provide adequate protection against the risk of contamination. Specifically, you did not include (b)(4) operators working inside the ISO 5 (b)(4) Biosafety Cabinet (BSC) simultaneously to perform check weighing, filling, and capping activities, as per your production activities.

2. You did not perform adequate product evaluation and take appropriate corrective action after microbial contamination was recovered within the ISO 5 aseptic processing area.

The FDA investigator also 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 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)).

2. 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).

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

4. Your firm failed to establish and follow adequate control procedures to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product (21 CFR 211.110(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.³ 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.⁴ The introduction or delivery for introduction into interstate commerce of these products therefore violates section 301(a) of the FDCA. Further, it is also a prohibited act under section 301(k) of the FDCA 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. We are unable to fully evaluate some of your corrective actions due to lack of adequate supporting documentation:

1. Regarding your firm’s failure to simulate the worst-case scenarios of your production process during Aseptic Simulation Process (APS), your firm did not provide your ASP demonstrating simulated worst-case scenarios to include largest number of container units aseptically filled, longest filling duration, performance of identified interventions and aseptic filling operators who are deemed as “Full Qualification”.

2. Regarding your firm’s failure to incubate all integral media fill units, your firm states as part of a corrective action you opened CAPA OEPA-2024-00771.1 and closed it on October 16, 2024, and submitted in your response SOP-CC-0003 titled “Aseptic Process Simulation – Media Fills, Effective Date: Oct 9, 2024”. You stated you would submit a revised SOP-CC-0003, however we received SOP-CC-003 with an effective date of October 9, 2024, which is prior to the FDA inspection. In addition, you failed to provide a revised media fill master batch production record to reflect that all APS media fill units will be incubated and documentations for the reasons why units are rejected.

3. Regarding your firm’s failure to establish a gowning qualification program for operators entering the ISO classified areas, your firm provided Document Change Request Number DCR-2024-0114, approved on November 3, 2024, to address a lack of gowning qualification program at your facility for entry to Cleanroom Suite 100, room number (b)(4)(ISO 7) and room number (b)(4) (ISO 7), from the gowning in airlock (room number (b)(4)) ensuring sterile gowning is donned without contamination. However, changes to procedures FRM-CC-004.1, SOPCC-0023, TRAIN-0005, FRM-CC-0007.2, FRM-CC-0005.2, and FRM-CC-0023.1 remain pending with an estimated completion date of first quarter 2025 as stated in your response.

4. Regarding your firm’s failure to establish a dynamic smoke study report/video simulating (b)(4) employees inside the ISO 5 (b)(4) Biosafety Cabinet (BSC) performing check weights, filling and capping activities, your firm committed to repeat the OSRX smoke study video in December 2024. However, you did not provide the revised dynamic smoke study report/video.

5. Regarding your firm’s failure to thoroughly investigate microbial contamination in the ISO 5 BSC during production, your response failed to ensure a thorough investigation is performed for any microbial recovery in the ISO 5 environment. Your investigations did not include environmental trending reports for each personnel performing work inside the ISO 5 classified area when microorganisms were recovered inside the ISO 5BSC from active viable air sampling plates.

Any microbial contamination in the ISO 5 area is considered an insanitary condition and is a serious concern. Upon recovery, your firm should immediately assess the impact on drug products produced. This assessment should include a thorough evaluation of how contamination could have entered this critical area, and over what period of time the contamination could have existed, as well as drug products that remain on the market that could be affected.

6. Regarding your firm’s failure to investigate labeling inspection failures that exceeded your specification limits, your investigation document QE-2024-0133 into labeling visual inspection failures, due to wrinkled labels on the bottles, did not include documented training records of all visual inspection personnel for reporting production quality events (deviations/investigations).

7. Regarding your firm’s failure to perform viable surface sampling in the ISO 5 (b)(4) during filling of a drug product, your response included CAPA QEPA-2024-0121.1, approved on October 22, 2024, which states all compounding and environmental monitoring personnel were trained emphasizing the requirements for surface sampling with each compounded lot. However, you did not provide documentation of retraining of all compounding and environmental monitoring personnel with the requirements set forth under SOP-CC-0026 titled “Routine Environmental Monitoring Cleanroom 100, Effective date Jul 15, 2024”.

8. Regarding your firm’s failure to provide justification for sampling (b)(4) units from two totes to examine for visual inspection as a form of an Acceptable Quality Limit (AQL), your response states your AQL visual inspection samples are selected from a batch (b)(4) from two totes, with (b)(4) samples selected from one tote, and (b)(4) samples from the other, thus representative of the entire batch. You did not provide a scientific rational for selecting the two totes to be sampled; furthermore, you did not provide the revised master batch records for all your drug products.

Some of your corrective actions appear deficient:

1. We acknowledge that you stated in your response that you will revise SOP-CC-0026 titled “Routine Environmental Monitoring Cleanroom 100 to address a change in the action limit for the number of Colony Forming Units (CFUs) to (b)(4) CFUs, however, your estimated completion date is (b)(4). Furthermore, you failed to implement an interim corrective action to address the reclassification of the action limit to (b)(4) CFU for the ISO5 classified areas.

2. We acknowledge your commitment to retraining operators to conduct fingertip sampling, however, you did not provide a justification why it would be completed first quarter 2025. Furthermore, your SOP states to use (b)(4) fingers instead of five when applying pressure to the agar plate.

3. We acknowledge that you provided SOP-INSP-0003 titled “Visual Inspector Qualification, Effective Date May 20, 2024” but did not address how you intend to qualify your visual inspection sample defect library/kits used for operator visual inspection training of topical ophthalmic solutions nor provide an approved procedure as to how you establish and maintain your sample defect library/kits.

4. You reference USP <1790> Visual Inspection of Injections and you did not commit to performing 100% visual inspection of all drug products including your sterile topical ophthalmic solutions contained in opaque droptainers and sterile injectable intraocular solution contained in glass vials.

USP <771> Ophthalmic Products – Quality Tests considers the 100%-unit inspection as the complete nondestructive inspection of the container-closure system and its contents. The 100%-unit inspection is applied to all ophthalmic products: topical, intraocular injections or ophthalmic products used in association with a surgical procedure, and extraocular injections. An evaluation of the package and fill acceptability methodology is discussed in the Visible Particulates in Injections <1790> for your reference. Furthermore, the acceptance limits for visible particles should be based your process capability as established during product development. The recommendation is to study and trend the particle burden of the product solution and the container–closure contribution, develop a reasonable life-cycle control strategy, and establish limits based on risk assessment.

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).]

Furthermore, regarding issues related to the conditions of section 503B of the FDCA, some of your corrective actions appear adequate. Specifically, you state that “OSRX is in the process of updating its SOP-DST-0002 to include a step for labeling the clear plastic container with a label… that contains the information required under 503B(a)(10)(B).” However, no corrective actions have been provided to the agency to address label issues concerning a list of active and inactive ingredients, identified by established name and the quantity or proportion of each ingredient.

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. In particular, this review should assess your aseptic processing operations. A third party consultant with relevant sterile drug manufacturing expertise should assist you in conducting this comprehensive evaluation.

E. Conclusion

The violations cited in this letter are not intended to be an all-inclusive statement of 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 any violations. Failure to adequately address any violations may result in legal action without further notice, including, without limitation, seizure and injunction.

Within fifteen (15) working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to address any violations. Please include an explanation of each step being taken to prevent the recurrence of violations, 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 your products are not in violation of the FDCA, include your reasoning and any supporting information for our consideration. If you cannot completely address this matter within fifteen (15) working days, state the reason for the delay and the time within which you will do so.

All correspondence should refer to the Warning Letter Number above (# 701889) and include a subject line that clearly identifies the submission as a Response to Warning Letter. If you have questions regarding the contents of this letter, please contact compoundinginspections@fda.hhs.gov.

Sincerely,
/S/

F. Gail Bormel, JD, RPh
Director
Office of Compounding Quality and Compliance
Office of Compliance
Center for Drug Evaluation and Research

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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 The specific products made by your firm are drugs within the meaning of section 201(g) of the FDCA [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.

4 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).