WARNING LETTER

Profounda, Inc. MARCS-CMS 642595 — February 01, 2023

Delivery Method:: VIA Electronic Mail
Product:: Drugs

Recipient:: Recipient Name

Mr. Todd E. MacLaughlan; Recipient Title

Chief Executive Officer; Profounda, Inc.; 10501 South Orange Ave., STE 124
Orlando, FL 32824
United States; todd@profounda.com

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

DATE: 2/1/2023

Case #: 642595

WARNING LETTER

Dear Mr. MacLaughlan:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Profounda, Inc., FEI 3011873350, at 10501 South Orange Ave., STE 124, Orlando, from August 3 to August 9, 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).

We reviewed your August 17, 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 establish written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess. (21 CFR 211.100(a)).

Your firm failed to provide data to demonstrate that you have validated manufacturing processes for your over-the-counter (OTC) drug products, including but not limited to “Rhinase D.” Your firm lacked qualification protocols, reports, or studies to determine if manufacturing processes were in a state of control and appropriate acceptance criteria were met.

In your response, you state that you will complete a validation report for “Rhinase D” that will include results for “Rhinase” drug product.

Your response is inadequate. You have not demonstrated that your manufacturing processes are designed, controlled, and reproducibly yield batches of uniform character and quality. Notably, “Rhinase” does not contain the same active ingredient as “Rhinase D.”

You also fail to provide detailed process performance qualification protocols for the validation of your different OTC drug product manufacturing processes and corrective actions.

Process validation evaluates the soundness of design and state of control of a process throughout its lifecycle. Each significant stage of a manufacturing process must be designed appropriately and assure the quality of raw material inputs, in-process materials, and finished drugs. Process qualification studies determine whether an initial state of control has been established.

Successful process qualification studies are necessary before commercial distribution. Thereafter, ongoing vigilant oversight of process performance and product quality is necessary to ensure you maintain a stable manufacturing operation throughout the product lifecycle.

See FDA’s guidance document Process Validation: General Principles and Practices for general principles and approaches that FDA considers appropriate elements of process validation at https://www.fda.gov/files/drugs/published/Process-Validation--General-Principles-and-Practices.pdf.

In response to this letter, provide:

A list of all products released by your firm, including examples of labeling. Also include a thorough and independent evaluation of all products released by your firm that remain within expiry, to determine if they are drugs, as defined by the FD&C Act.
A detailed summary of your validation program for ensuring a state of control throughout the product lifecycle, along with associated procedures. Describe your program for process performance qualification and ongoing monitoring of both intra-Page batch and inter-batch variation to ensure a continuing state of control. Also, include your program for qualification of your equipment and facility.
Include your process performance protocol(s) and written procedures for qualification of equipment and facilities.
A timeline for performing appropriate process performance qualification (PPQ) for each marketed drug product you manufacture.
An assessment of each drug product process to ensure that there is a data-driven and scientifically sound program that identifies and controls all sources of variability, such that your production processes will consistently meet appropriate specifications and manufacturing standards. This includes, but is not limited to, evaluating suitability of equipment for its intended use, sufficiency of detectability in your monitoring and testing systems, quality of input materials, and reliability of each manufacturing process step and control.

2. Your firm failed to establish 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)).

Your firm failed to establish an adequate stability program and determine appropriate expiration dates for the OTC drug products that you manufacture. For example, you assigned a five-year expiry period to “Rhinase D” drug product batch 1J02 (30g). At the time of inspection, only (b)(4) of real-time and accelerated data were available. You lacked sufficient stability data to substantiate the “Rhinase D” five-year expiry period.

In your response, you explain that your five-year expiry date is based on the stability of “Rhinase,” a different drug product that does not contain oxymetazoline hydrochloride, the active ingredient used in “Rhinase D.” Furthermore, you indicated that it was your assumption that your product would be stable and (b)(4). In addition, you commit to labeling “… future batches only with (b)(4) data or longer but only if [you] have real time stability data.”

Your response is inadequate. You fail to provide data to demonstrate that the chemical and microbiological properties of your drug products will remain within specification throughout their labeled expiry period. You also fail to provide interim measures to address whether your drug products that remain on the market have adequate stability data. For products without appropriate stability studies, there is insufficient scientific evidence to support that drug products will meet established specifications and retain their quality attributes through their labeled expiry.

In response to this letter, provide:

A comprehensive independent assessment and corrective action and preventive action (CAPA) plan to ensure the adequacy of your stability program. Your remediated program should include, but not be limited to:

o Stability indicating methods
o Stability studies for each drug product in its marketed container-closure system before distribution is permitted
o An ongoing program in which representative batches of each drug product are added each year to the program to determine if the shelf-life claim remains valid
o Detailed definition of the specific attributes to be tested at each station (timepoint)

All procedures that describe these and other elements of your remediated stability program.

A comprehensive independent assessment of all drug products in the U.S. market to determine if you have data to support that they conform to specifications throughout their shelf-life, including evaluating storage conditions, differences in each formulation, packaging configurations, and all historical stability studies that have been performed. If there are gaps in the data needed to scientifically support that your drug products retain their quality attributes through their labeled shelf-life, provide a CAPA plan which will include an impact assessment for any batches that remain within their shelf-life in the market.
A summary of results from testing retain samples within expiry for all drug product batches not currently in your existing stability program. Testing of each batch should be completed within 60 days of this letter. You should test all appropriate quality attributes including, but not limited to, identity and strength of active ingredients as well as microbiological quality (total counts; identification of bioburden to detect any objectionable microbes) of each batch. If testing yields an out-of-specification (OOS) result, indicate the corrective actions you will take, including notifying customers and initiating recalls.

3. Your firm failed to use equipment in the manufacture, processing, packing, or holding of drug products that is of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance (21 CFR 211.63).

Your purified water system used to manufacture drug products was not designed and maintained appropriately for its intended use. For example, your water system included a dead leg and was not continuously circulating, which could foster the development of biofilms. When the water was not in use, it sat stagnant in the system except when the (b)(4) points-of-use (POUs) were opened.

In your response, you discuss the current controls in place for your water system and the use of testing data from your “validation report.” In addition, you also indicate you employ the use of (b)(4) during production on a (b)(4) basis. You commit to increase the testing frequency to include each batch of water produced for OTC drug products and to (b)(4).

Your response is inadequate. You fail to describe how your water system maintenance, cleaning process, seasonal variations, and other actual conditions of use were considered during your “validation” efforts and to provide adequate justification for the sampling frequency. Your response also fails to address that you do not perform (b)(4) testing on the (b)(4) that you use during production.

In response to this letter, provide:

A comprehensive assessment and remediation plan for the design, control, and maintenance of the water system.
Validation report for the water system obtained after all identified system design issues have been fully remediated and any maintenance repairs have been completed. Include the system validation protocol, the complete test results, and the final validation report.
Your total microbial count limits to monitor whether this system is producing water suitable for the intended use for each of your products.
A detailed risk assessment addressing the potential effects of the water system on the quality of all drug product lots currently in the U.S. within expiry. Specify actions that you will take in response to the risk assessment, such as customer notifications and product recalls.
A procedure for your water system monitoring that specifies routine microbial testing of water to ensure its acceptability for use in each batch of drug products produced by your firm. In addition, your response should describe how your sampling method will be improved to ensure purified water collection is performed in a manner that is representative of actual manufacturing conditions and does not compromise detection of microbes.
The current action (and alert, if any) limits for total counts and objectionable organisms used for your purified water system. Ensure that the total count limits for your purified water are appropriately stringent in view of the intended use of each of the products produced by your firm.

4. Your firm failed 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(b)).

Your firm had inadequate laboratory controls. For example:

Microbiological methods used for determining the quality of purified water and finished drug products were deficient. Specifically, you failed to perform growth promotion testing on every batch of ready-to-use media and to verify microbiological method suitability for each drug product you manufacture.
Your firm failed to conduct appropriate laboratory testing for each batch of drug product that is required to be free of objectionable microorganisms (21 CFR 211.165(b)). In particular, your firm failed to conduct testing for Burkholderia cepacia complex (BCC) for numerous non-sterile aqueous-based dosage form drug products at release and on stability.

For further information regarding the significance of BCC and other objectionable contamination of non-sterile, water-based drug products, see FDA’s advisory notice posted on July 7, 2021, at https://www.fda.gov/drugs/drug-safety-and-availability/fda-advises-drug-manufacturers-burkholderia-cepacia-complex-poses-contamination-risk-non-sterile.

In your response, you state that quality control of media is performed by your supplier, who also performed a shipping study, and that positive and negative controls are not necessary. Additionally, you commit to initiating testing for BCC.

Your response is inadequate. You fail to address the full scope and impact of the CGMP deficiencies as well as the associated risks to drug product quality, including batches in distribution. Without appropriate testing of media you cannot ensure your drug products meet appropriate microbial quality specifications.

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 comprehensive, independent assessment of the design and control of your firm’s manufacturing operations, with a detailed and thorough review of all microbiological hazards.
A detailed risk assessment addressing the hazards posed by distributing drug products with potentially objectionable contamination. Specify actions you will take in response to the risk assessment, such as customer notifications and product recalls.
Complete investigations into all batches with potential objectionable microbial contamination. The investigations should detail your findings regarding the root causes of the contamination.
Appropriate microbiological batch release specifications (i.e., total counts, identification of bioburden to detect objectionable microbes) for each of your drug products.
All chemical and microbial test methods used to analyze each of your drug products.
A gap assessment to ensure that all of your drug products referenced in the United States Pharmacopeia meet compendial criteria.
A list of chemical and microbial specifications, including test methods, used to analyze each batch of your drug products before a batch disposition decision.

5. Your firm failed to withhold from use each lot of components, drug product containers, and closures until the lot had been sampled, tested, or examined, as appropriate, and released for use by the quality control unit (21 CFR 211.84(a)).

You lacked testing for every shipment of every lot of components used in the manufacture of your drug products. Specifically, you lacked a specific identity test to detect diethylene glycol (DEG) and ethylene glycol (EG) in all shipments, containers, and lots of glycerin before use in manufacturing drug products. DEG contamination in glycerin has resulted in various lethal poisoning incidents in humans worldwide. In addition, we note that both glycerin and propylene glycol are ingredients used in your drug products. As a drug manufacturer, you are responsible for performing specific identity tests for all incoming shipments of component lots prior to release for use in manufacturing.

In your response, you indicated that your firm reviewed the COA for DEG testing. You also committed to immediately begin testing glycerin for DEG using an independent outside laboratory and consider “appropriate action” in the event an OOS occurs.

Your response is inadequate. As previously mentioned, you fail to address the full scope and impact of the CGMP deficiencies as well as the associated risks to drug product quality, including addressing batches already in distribution. With respect to your glycerin-containing products, you have not addressed if your evaluation will include all lots of glycerin for each drug product batch you manufactured and that remains within shelf-life in the U.S. market. Without appropriate testing of components and ingredients, you cannot ensure the quality and safety of your drug products.

See FDA’s guidance document Testing of Glycerin for Diethylene Glycol to help you meet the CGMP requirements when manufacturing drugs containing glycerin, or other ingredients at risk for DEG or EG contamination, at https://www.fda.gov/regulatoryinformation/search-fda-guidance-documents/testing-glycerin-diethylene-glycol.

In response to this letter, provide:

A comprehensive, independent review of your material system to determine whether all suppliers of components, containers, and closures are each qualified and the materials are assigned appropriate expiration or retest dates. The review should also determine whether incoming material controls are adequate to prevent use of unsuitable components, containers, and closures.
The chemical and microbiological quality control specifications you use to test and release each incoming lot of components for use in manufacturing.
A description of how you will test each component lot for conformity with all appropriate specifications for identity, strength, quality, and purity. If you intend to accept any results from your supplier’s COA instead of testing each component lot for strength, quality, and purity, specify how you will robustly establish the reliability of your supplier’s results through initial validation as well as periodic revalidation. In addition, include a commitment to always conduct at least one specific identity test for each incoming component batch.
A summary of results obtained from testing all components to evaluate the reliability of the COA from each component manufacturer. Include your SOP that describes this COA validation program.
A summary of your program for qualifying and overseeing contract facilities that test the drug products you manufacture.
Within 30 days, provide the results of tests for DEG and EG in retain samples of all glycerin lots used in production of your glycerin-containing drug products. Indicate whether DEG or EG are present in any glycerin lots used to manufacture your drug products, some of which are intended for use in pediatrics. In addition, perform testing of all lot retain samples of any other drug product ingredients used by your firm that are at risk for DEG or EG contamination.
Provide a full risk assessment for drug products that contain glycerin (and any other ingredient at risk for DEG or EG contamination) and are within expiry in the U.S. market. Take prompt and appropriate actions to determine the safety of all lots of the ingredient(s) and any related drug product that could contain DEG or EG, including customer notifications and product recalls for any contaminated lots. Identify additional appropriate corrective actions and preventive actions that secure supply chains in the future, including but not limited to ensuring that all incoming raw material lots are from fully qualified manufacturers and free from unsafe impurities. Detail these actions in your response to this letter.

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/regulatoryinformation/search-fda-guidance-documents/contract-manufacturing-arrangements-drugs-quality-agreements-guidance-industry.

CGMP Consultant Recommended

Based upon the nature of the violations if your firm intends to resume manufacturing drugs for the U.S. market, we strongly recommend engaging a consultant qualified as set forth in 21 CFR 211.34 to assist your firm in meeting drug 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.

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.

If you are considering an action that is likely to lead to a disruption in the supply of drugs produced at your facility, FDA requests that you contact CDER’s Drug Shortages Staff immediately, at drugshortages@fda.hhs.gov, so that FDA can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Staff also allows you to meet any obligations you may have to report discontinuances or interruptions in your drug manufacture under 21 U.S.C. 356C(b). This also allows FDA to consider, as soon as possible, what actions, if any, may be needed to avoid shortages and protect the health of patients who depend on your products.

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.

Your written notification should refer to case # 642595.

Please electronically submit your reply, on company letterhead, to Dayna I. Martinez, Compliance Officer, at ORAPHARM2_RESPONSES@fda.hhs.gov. In addition, please submit a signed copy of your response to dayna.matinez@fda.hhs.gov

If you have questions regarding the contents of this letter, you may contact Dayna I. Martinez via phone at (787) 729-8608 or email at dayna.martinez@fda.hhs.gov

Sincerely,
/S/

Monica R. Maxwell
Program Division Director
Office of Pharmaceutical Quality Operations,
Division II