WARNING LETTER

Health Plus Inc. MARCS-CMS 616877 — December 29, 2021

Delivery Method:: Via Email
Product:: Drugs

Recipient:: Recipient Name

Ms. Rita Mediratta; Recipient Title

President; Health Plus Inc.; 13837 Magnolia Avenue
Chino, CA 91710
United States; ritam@healthplusinc.com

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

WARNING LETTER

December 29, 2021

Dear Ms. Mediratta:

The U.S. Food and Drug Administration inspected your drug manufacturing facility, Health Plus Inc., FEI 2027164, at 13837 Magnolia Avenue, Chino, California, from June 23 to July 1, 2021.

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 product is 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 July 20, 2021 response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

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

1. Your firm failed to ensure that returned drugs meet appropriate standards of safety, identity, strength, quality and purity prior to redistributing (21 CFR 211.204).

Your firm’s handling of returned drug product before its redistribution is inadequate. For example, during the inspection, you were not able to provide documentation of adequate inspection and investigation of the returned product confirming the label conditions under which the returned drug product was held, stored, or shipped before its return and before redistributing. Furthermore, you failed to perform adequate testing to ensure the safety, identity, strength, quality, and purity of the returned product. Organoleptic examination alone is not sufficient to ensure that a product maintains its safety, identity, strength, purity, and quality after it has been in a situation where it may have been exposed to improper storage conditions.

Before redistribution, you combined returned capsules from various lots into new batches with new lot numbers. These new lots did not have uniform character and quality, including capsules that would expire in less than three years. However, you then assigned these comingled batches new lot numbers and granted them an additional three-year shelf life. The new expiration dates are not supported by stability data and, in some instances, exceeded the expiration date of the returned product by up to 18 months. Your batch production records did not indicate you performed testing on these comingled batches before their redistribution.

Your practices of conducting organoleptic examination on the returned product that was subjected to unknown conditions before return, making comingled batches by combining returned drug product with various lot numbers and expiration dates, and assigning a new product shelf life disregarding the expiration dates of the returned product are unacceptable.

In response to this letter, provide the following:

• A comprehensive, independent assessment and remediation plan to ensure the adequacy of your returned drug product handling and processing for redistribution. Provide a detailed action plan and associated procedures that should include, but not be limited to, the following:
o Documentation of the conditions under which returned drug products have been held, stored, or shipped before, during and after return, reason for the return, quantity returned, date of disposition, and ultimate disposition, including procedures for destruction if doubt exists as to drug quality.
o A procedure for ensuring the conditions under which returned drug products were held, stored, or shipped did not adversely affect the safety, identity, strength, quality or purity of the drug products.

• Provide your action plan to address any product quality risks associated with the redistributed batches in the United States, including potential customer notifications and recalls.

2. Your firm failed to establish adequate 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, and your firm’s quality control unit did not review and approve those procedures, including any changes (21 CFR 211.100(a)).

Your firm did not adequately validate the process used to manufacture your over-the-counter drug product Super Colon Cleanse Stimulant Laxative. Your firm changed the formulation of your Super Colon Cleanse Stimulant Laxative in December 2017, including the removal of multiple components. You did not issue a process validation protocol and associated analytical testing report until November and December 2018, respectively, a year after your reformulation. Additionally, the only data supporting your November 2018 validation protocol, dated October 21, 2014, was from a test of the previous formulation and does not reflect the current drug product formulation. Since the December 2017 formulation change, your firm has manufactured and released at least (b)(4) batches of the drug product which you distributed to the U.S. market with inadequate process validation data.

In your response, you stated that you would create a new standard operating procedure (SOP) for process validation and would document and review the results of the process validation study. Additionally, you indicated that you would commence manufacturing the first process validation batch in August 2021.

Your response is inadequate because failure to conduct process validation studies can result in product quality attribute failures. You also failed to address your justification for continuing to manufacture the drug product when you have not adequately demonstrated that your manufacturing processes are reproducible and controlled to yield a drug product of uniform character and quality.

In response to this letter, provide the following:

• 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 for your marketed drug product.

• 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, and 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.

• 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 (QU). Your change management program should also include provisions for determining change effectiveness.

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/regulatory-information/search-fda-guidance-documents/process-validation-general-principles-and-practices.

3. Your firm failed to establish and document the accuracy, sensitivity, specificity, and reproducibility of its test methods (21 CFR 211.165(e)).

You did not adequately validate the method for assay used for your Super Colon Cleanse laxative drug product release specification. Specifically, per your specifications, the (b)(4) Spectrophotometer method for assay is to be conducted at the wavelength of (b)(4) as indicated in your finished drug product specifications. However, according to the data in the validation report you used the wavelength of (b)(4). In addition, the method validation report did not include system suitability, nor did it demonstrate that your modified method is fit for purpose.

In your response, you stated that the method validation for assay was conducted at the correct wavelength. Your response is inadequate as follows.

• It lacked supporting documentation to support your claim that the method validation for assay was conducted at the correct wavelength.

• It did not provide a risk assessment for the drug product released using the assay method that was not adequately validated nor a justification for continuation of the drug product currently on the market.

In response to this letter, provide the following:

• 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 all test methods to ensure that they are adequately validated and suitable for their intended purposes.

• A retrospective assessment of reserve samples for all finished drug products that are currently on the market, using an adequately validated test method, to ensure that your drug products conform to the drug product specification.

• A review of the completeness, consistency, accuracy of data from your use of uncontrolled documents (e.g., legal pads) to document the data.

• A review of applicable compendial methods for your product.

Refer to FDA’s guidance documents Q2(R1) Validation of Analytical Procedures and Analytical Procedures and Methods Validation for Drugs and Biologics for general principles and approaches for method validation at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q2r1-validation-analytical-procedures-text-and-methodology-guidance-industry and https://www.fda.gov/regulatory-information/search-fda-guidance-documents/analytical-procedures-and-methods-validation-drugs-and-biologics, respectively.

4. 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)).

Your firm’s stability program is inadequate. Specifically, you only placed (b)(4) of your Super Colon Cleanse Stimulant Laxative drug product on stability and failed to perform any stability testing since at least September 2017. Furthermore, you did not have any stability data for drug product manufactured using the new formulation. Therefore, you lack sufficient stability data to substantiate the (b)(4) expiration of this drug product.

In your response, you stated that the delay in conducting a stability study was because of restrained resources for the QU. You stated that you will initiate long-term stability testing for ongoing (b)(4) stability testing and accelerated stability testing for the determination of the expiration dating period of the drug product.

Your response is inadequate because your firm has been aware of the inadequacy of your stability program since the 2013 inspection. Subsequent inspections in 2015, 2018, and 2021, all had identical or similar observations in your stability program. Your response lacked information on what you did between 2013 and the current inspection to remediate your stability program.

In response to this letter, provide the following:

• A comprehensive assessment and corrective action and preventive action (CAPA) plan to ensure the adequacy of your stability program. Your CAPA plan 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.

Refer to FDA’s guidance document Q1A(R2) Stability Testing of New Drug Substances and Products for general principles and approaches for stability testing at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q1ar2-stability-testing-new-drug-substances-and-products.

5. Your firm’s quality control unit failed to approve or reject all procedures or specifications impacting on the identity, strength, quality, and purity of the drug product (21 CFR 211.22(c)).

You failed to establish, review, and approve all procedures, including those which may impact the safety, identity, strength, quality, and purity of your drug product. Specifically, your QU failed to implement SOPs that are critical to ensure the quality of the drug product, such as the SOPs for operating the equipment used to manufacture the drug product.

In your response, you stated that you will create and revise corresponding SOPs. Your response is inadequate because you failed to provide supporting documentation (e.g., draft SOPs, training). Additionally, you provided similar responses to repeat or similar observations in the 2012, 2013, and 2018 inspections. Therefore, we have no assurance that your corrective actions will be implemented.

In response to this letter, provide the following:

• 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 of all other QU duties to ensure identity, strength, quality, and purity of all products

• A complete assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient. Include a detailed CAPA plan that comprehensively remediates your firm’s documentation practices to ensure you retain attributable, legible, complete, original, accurate, contemporaneous records throughout your operation.

• Your action plan to address any product quality or patient safety risks for your drug product in U.S. distribution, including potential customer notifications and recall.

Refer to FDA’s guidance document: Quality Systems Approach to Pharmaceutical CGMP Regulations for general principles and approaches at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/quality-systems-approach-pharmaceutical-current-good-manufacturing-practice-regulations.

Quality Unit Authority

Your inspectional history and significant findings in this letter indicate that your QU is not fully exercising its authority and/or responsibilities. Your firm must provide the QU with the appropriate authority and sufficient resources to carry out its responsibilities and consistently ensure drug quality.

Repeat Observations at Facility

In a previous inspection conducted in 2018, FDA cited similar CGMP observations. You proposed specific remediation for these observations in your response. Repeated failures demonstrate that executive management oversight and control over the manufacture of drugs is inadequate.

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. We also recommend that the qualified consultant perform a comprehensive audit of your entire operation for CGMP compliance, and that the consultant evaluates the completion and efficacy of your CAPA before you pursue resolution of your firm’s compliance status with FDA.

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.

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.

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
U.S. Food & Drug Administration
19701 Fairchild Road
Irvine, California 92612-2506

Please identify your response with unique identifier 616877.

If you have any further questions, please contact Nayan Patel, Compliance Officer, by email at Nayan.Patel1@fda.hhs.gov or by phone at (303) 236-3010.

Sincerely,
/S/

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