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WARNING LETTER

October 9, 2020

Dear Mr. Cox:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, RLC Labs Inc., FEI 3002523846, at 1850 E Riverview Drive, Phoenix, Arizona, from February 20 to March 5, 2020.

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).

Our inspection also revealed that your firm failed to fulfill its registration and listing obligations under section 510(j) of the FD&C Act, which is prohibited under section 301(p), 21 U.S.C. 360 and 331(p). As a result, your drugs are misbranded under section 502(o) of the FD&C Act, 21 U.S.C. 352(o).

Additionally, your WP Thyroid® and Nature-Throid® drug products are adulterated under section 501(b) of the FD&C Act, 21 U.S.C. 351(b), for failure to conform to compendial standards for strength, quality, or purity.

Information and records gathered during the course of the inspection, and information available on your website, www.getrealthyroid.com, reflect that your products are intended to treat a disease or condition. Therefore, your products are drugs as defined in section 201(g) of the FD&C Act [21 U.S.C. 321(g)]. Your products, which contain thyroglobulin (an alpha amino acid polymer with a specific defined sequence consisting of 2770 amino acids), are also biological products as defined in section 351(i)(1) of the Public Health Service Act (PHS Act) [42 U.S.C. 262(i)(1)] because they are a “protein” as defined in 21 C.F.R. 600.3(h)(6) or are “analogous” to a protein because the identified biological product (i.e., protein) component in these naturally derived mixtures is necessary for the activity of the product and contributes to achieving the intended therapeutic effect.

Please be advised that to lawfully market a drug that is a biological product, a valid biologics license must be in effect [42 U.S.C. 262(a)]. Such licenses are issued only after the sponsor shows that the product is safe, pure, and potent. While in the development stage, such products may be distributed for clinical use in humans only if the sponsor has an investigational new drug application (IND) in effect as specified by FDA regulations [21 U.S.C. 355(i); 42 U.S.C. 262(a)(3); 21 CFR Part 312]. None of your products are the subject of an approved biologics license application (BLA), nor is there an IND in effect for any of them. Based on this information, we have determined that your actions have violated the FD&C Act and the PHS Act.

We reviewed your March 26, 2020, response to our Form FDA 483 in detail.

During our inspection, our investigators observed specific violations including, but not limited to, the following.

CGMP Violations

1. Your firm’s quality control unit did not review and approve written procedures for production and process control, including any changes to them, designed to ensure that the drug products you manufacture have the identity, strength, quality, and/or purity they purport or are represented to possess (21 CFR 211.100(a)).

Your firm failed to provide data to demonstrate that your manufacturing processes, including the blending of active pharmaceutical ingredients (API) lots for your WP Thyroid and Nature-Throid drug products, have been validated. During the inspection you could not locate the process validation data to present to the investigators. In addition, critical equipment used to manufacture these drug products were not qualified.

Your response is inadequate. You did not provide the validation data requested at inspection. You proposed to re-initiate the process validation for your drug products. However, you failed to provide interim measures to ensure that your manufacturing processes are in a state of control. Regarding equipment qualifications, you stated that you have initiated qualification activities on some equipment and that you will correct deficient qualification on all drug production equipment. You failed to provide a Master Validation Plan, validation/qualification protocols, and specific timelines for completion.

FDA collected ten samples during the inspection, covering several different strengths of WP Thyroid and Nature-Throid. Six samples were found to be sub-potent for at least one of the two active ingredients. Thyroid Tablets outside of the USP acceptance criteria are adulterated within the meaning of 501(b) of the FD&C Act, 21 U.S.C. 351(b), in that their strength, quality, or purity falls below the standards set forth in an official compendium recognized in the FD&C Act.

Because of the narrow therapeutic range of this drug product, it is especially important to prevent patients with hypothyroidism from receiving insufficient or excessive doses. Appropriate controls and understanding of your manufacturing process is essential to ensuring a safe and effective drug product. We acknowledge that your firm agreed to voluntarily recall all lots of WP Thyroid and Nature-Throid with current expiry due to sub-potency.

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 robustly, controlled appropriately, and assure the ongoing quality of raw material inputs, in-process materials, and finished drugs.

Failure to implement adequate process validation can result in insufficient understanding of process variables or failure to detect a drift in capability, which increases the risk of drug quality defects.

See FDA’s guidance document Process Validation: General Principles and Practices for general principles and approaches that FDA considers to be appropriate elements of process validation at https://www.fda.gov/media/71021/download.

In response to this letter, provide:

• 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-batch and inter-batch variation to ensure a continuing state of control.
• A timeline for performing appropriate process performance qualification (PPQ) for each of your marketed drug products.
• Include your process performance protocol(s), and written procedures for qualification of equipment and facilities.
• Provide a detailed program for designing, validating, maintaining, controlling and monitoring each of your manufacturing processes that includes vigilant monitoring of intra-batch and inter-batch variation to ensure an ongoing state of control. Also, include your program for qualification of your equipment and facility.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 follow a 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)).

You lack an adequate stability program for your WP Thyroid and Nature-Throid drug products, labeled with two- and three-year expiry periods respectively. During the inspection you provided stability data for drug product manufactured in your previous facility and with an API manufactured by a different supplier. No stability studies have been conducted for these drug products manufactured at your current facility with API from your current supplier.

In response to this observation, you acknowledged expiry dating was based on stability data from 2012 and from drug products manufactured at your previous facility. You proposed to engage a third-party laboratory to perform accelerated and real time stability studies for your drug products. In addition, you committed to test random retain samples of batches.

Your response is inadequate because it lacks stability protocols.

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 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.

3. Your firm failed to test samples of each component for conformity with all appropriate written specifications for purity, strength, and quality (21 CFR 211.84(d)(2)).

There is no assurance that the incoming API used to manufacture WP Thyroid and Nature-Throid drug products conforms with appropriate specifications to ensure that it meets the purported purity, strength, and quality. The inspection documented the use of at least (b)(4) different assay specifications for Liothyronine (T3) and Levothyroxine (T4). Individual API lots are received and mixed to produce a master blend that is then used to formulate your drug products.

Thyroid hormone drug products have a narrow therapeutic index and require a well-controlled API blend to ensure that finished drug products match their labeled strength. Without adequately established specifications for the API there is a lack of assurance that you can consistently manufacture drug product that meets quality attributes.

In your response, your firm committed to establishing specifications. However, you failed to include a timeline for when specifications would be established or adequate interim measures.

In response to this letter, provide:

• 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 Certificates of Analysis (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 re-validation. In addition, include a commitment to always conduct at least one specific identity test for each incoming component lot.
• The chemical and microbiological quality control specifications you use to test and release each incoming lot of component for use in manufacturing. Provide the justification for any specification established.
• 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.

4. Failure to establish an adequate quality control 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) failed to ensure that you have adequate procedures and did not provide adequate oversight of your manufacturing activities. For example:

• You lacked adequate systems to ensure proper documentation of manufacturing activities and for change management.
• Cleaning validation was not performed to demonstrate that cleaning agents are able to safely remove all drug product residues after manufacturing higher dosage products to lower dosage products.
• You lacked a CGMP training program for your employees engaged in CGMP operations.
• You failed to perform and establish procedures for annual product reviews and supplier qualification.
• You failed to establish appropriate procedures for the handling of rejected materials.

In addition, your quality personnel were unaware of complaint spreadsheets being maintained outside of the quality unit and these complaints were not investigated by the quality unit. Complaints documented in your spreadsheets involving WP Thyroid and Nature-Throid drug products noted many concerns about drug product potency, which were reflected by the failing samples mentioned earlier.

In your response you promised to establish and expand your quality unit, hiring qualified individuals and establishing SOPs. However, you failed to provide sufficient detail or adequate supporting documentation to support your CAPA. No interim measures or procedures were provided.

Significant findings in this letter indicate that your quality unit is not able to fully exercise its authority and/or responsibilities. Your firm must provide the quality unit with the appropriate authority and sufficient resources to carry out its responsibilities and consistently ensure drug quality.

In response to this letter, provide:

• 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 batch and its related information before the QU disposition decision
    o Oversight and approval of investigations and discharging all other QU duties to ensure identity, strength, quality, and purity of all products

Also describe how top management supports quality assurance and reliable operations, including but not limited to timely provision of resources to proactively address emerging manufacturing/quality issues and to assure a continuing state of control.

• 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 quality unit. Your change management program should also include provisions for determining change effectiveness.
• Appropriate improvements to your cleaning validation program, with special emphasis on incorporating conditions identified as worst case in your drug manufacturing operation. This should include but not be limited to identification and evaluation of all worst-case:

    o drugs with higher toxicities
    o drugs with higher drug potencies
    o drugs of lower solubility in their cleaning solvents
    o drugs with characteristics that make them difficult to clean
    o swabbing locations for areas that are most difficult to clean
    o maximum hold times before cleaning

In addition, describe the steps that must be taken in your change management system before introduction of new manufacturing equipment or a new product.

• A summary of updated SOPs that ensure an appropriate program is in place for verification and validation of cleaning procedures for products, processes, and equipment.

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/Guidances/UCM070337.pdf.

Unapproved Biological Product Violations

Please be advised that to lawfully market a drug that is a biological product, a valid biologics license must be in effect [42 U.S.C. 262(a)]. Such licenses are issued only after the sponsor shows that the product is safe, pure, and potent. While in the development stage, such products may be distributed for clinical use in humans only if the sponsor has an IND in effect as specified by FDA regulations [21 U.S.C. 355(i); 42 U.S.C. 262(a)(3); 21 CFR Part 312]. None of your products are the subject of an approved BLA, nor is there an IND in effect for any of them. Based on this information, we have determined that your actions have violated the FD&C Act and the PHS Act.

Misbranding Violations

FDA’s inspection dated February 20 to March 5, 2020, revealed that RLC Labs Inc. at 1850 E Riverview Dr, Phoenix, Arizona manufactures, labels and distributes porcine-derived thyroid drug tablets for human use under the brand names of WP Thyroid and Nature-Throid.

Section 510(j) of the FD&C Act and 21 Code of Federal Regulations (CFR) Part 207 outline the requirements for establishment registration and listing of drug products. Your firm has failed to maintain its establishment registration and submit drug listing information to the FDA for the drugs manufactured at the above facility, including WP Thyroid and Nature-Throid.

Under section 510(j) of the FD&C Act, your firm failed to fulfill its listing obligations, which is a prohibited act under section 301(p), [21 U.S.C. 360(j) and 331(p)]. In addition, your firm’s failure to fulfill its registration obligations misbrands the product(s) you manufacture at this facility under section 502(a) of the FD&C Act, and your firm’s failure to fulfill its drug listing obligations misbrands the product(s) under section 502(o) of the FD&C Act. Introduction or delivery for introduction into interstate commerce of a misbranded product is a prohibited act under section 301(a) (21 U.S.C. 352(o) and 331(a)).

CGMP Consultant Recommended

Based upon the nature of the violations we identified at your firm, we strongly recommend engaging a consultant 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.

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 these violations and for preventing their recurrence or the occurrence of other violations.

Correct the violations cited in this letter promptly. Failure to promptly correct these violations may result in legal action without further notice including, without limitation, seizure and injunction. Unresolved violations in this warning letter may also prevent other Federal agencies from awarding contracts.

FDA may also withhold approval of requests for export certificates and approval of pending new drug applications or supplements listing your facility as a supplier or manufacturer until the above violations are corrected. We may re-inspect to verify that you have completed your corrective actions.

After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done since our inspection to correct your violations and to prevent their recurrence. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion. If you believe that your products are not in violation of the FD&C Act or you have complied with FDA regulations, include your reasoning and any supporting information for our consideration.

Please send your electronic reply to ORAPharm4_Responses@fda.hhs.gov or mail your reply to:

CDR Steven E. Porter, Jr.
Director, Division of Pharmaceutical Quality Operations IV
19701 Fairchild Road
Irvine, CA 92612-2506

Please identify your response with unique identifier CMS 607596.

If you have questions regarding any issues in this letter, please contact William V. Millar, Compliance Officer via email at william.millar@fda.hhs.gov or by phone at (503) 671-9711 Ext. 30.

Sincerely,
/S/

CDR Steven E. Porter, Jr.
Director, Division of Pharmaceutical Quality Operations IV