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  5. Kari Gran Inc. - 640035 - 11/30/2022
  1. Warning Letters


Kari Gran Inc. MARCS-CMS 640035 —

Delivery Method:

Recipient Name
Ms. Kari R. Gran
Recipient Title
President and Co-founder
Kari Gran Inc.

1735 Westlake Ave N, #110
Seattle, WA 98109
United States

Issuing Office:
Division of Pharmaceutical Quality Operations IV

United States


November 30, 2022

Dear Ms. Gran:

The U.S. Food and Drug Administration inspected your drug manufacturing facility, Kari Gran Inc., FEI 3015320016, at 1735 Westlake Ave N, #110, Seattle, from July 5 to July 8, 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 July 28, 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 have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release. Your firm also failed to establish and 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 211.165(a) and 21 CFR 211.166(a)).

You failed to perform adequate release testing for each batch of your drug product prior to distribution. Your firm released multiple batches of over-the-counter (OTC) SPF sunscreen drug products to the U.S. market without adequate testing of zinc oxide, the active ingredient in the finished drug products. You only test the initial drug batches, and do not conduct routine finished product testing, including assay, on subsequent batches. When assay testing is conducted, batches are released prior to receiving the test results. In addition, you failed to perform microbiological testing on each batch of finished drug product.

Drug product batches must be tested for identity, strength, quality, and purity prior to release. Testing is an essential part of ensuring the drug products you manufacture conform to all pre-determined quality attributes and are appropriate for their intended use, including microbiological specifications. Without adequate testing, you lack basic data to support that each drug product batch conforms to appropriate specifications before release. Additionally, you did not have appropriate stability data to demonstrate that the chemical and microbiological properties of your drug products met established specifications and remain acceptable throughout their assigned shelf-life.

In your response, you stated that you sent your existing batches for zinc oxide assay testing and will implement this assay testing for (b)(4). Additionally, you claimed to have created a written testing program to assess the stability characteristics of drug products.

Your response is inadequate. You did not provide your updated procedures including a stability protocol.

In response to this letter, provide the following:

• A list of chemical and microbial specifications, including test methods, used to analyze each batch of your drug products before a batch disposition decision.
  o An action plan and timelines for conducting full chemical and microbiological testing of retain samples to determine the quality of all batches of drug product distributed to the United States that are within expiry as of the date of this letter.
  o A summary of all results obtained from testing retain samples from each batch. If such testing reveals substandard quality drug products, take rapid corrective actions, such as notifying customers and product recalls.
• 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 and a 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.

2. Your firm failed to conduct at least (b)(4) to verify the identity of each component of a drug product. Your firm also failed to validate and establish the reliability of your component supplier’s test analyses at appropriate intervals (21 CFR 211.84(d)(1) and (2)).

You failed to adequately test your incoming components for identity before using them to manufacture your drug products. Identity testing for each component lot used in drug product manufacturing is required, and you can only rely on certificates of analysis (COA) for other component attributes by validating the suppliers’ test results at appropriate intervals. During the inspection you also acknowledged that you have not qualified your supplier, yet you relied on their COA for attributes of the components.

In your response, you stated that incoming lots of components will be tested and released by the quality control unit.

Your response is inadequate. You did not provide the procedures for testing the components. By not adequately analyzing your components for identity, purity, strength, and quality, you failed to ensure your incoming components meet appropriate specifications.

In response to this letter, provide the following:

• 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 re-validation. In addition, include a commitment to always conduct at least one specific identity test for each incoming component lot.
• A summary of results obtained from testing all components to evaluate the reliability of the COA from each component manufacturer. Include your Standard Operating Procedure (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.

3. 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. Your firm also failed to prepare batch production and control records with complete information relating to the production and control of each batch of drug product produced (21 CFR 211.100 (a) and 21 CFR 211.188).

Process Validation

You failed to adequately validate your manufacturing processes for your OTC drug products, which would provide assurance that you are capable of consistently delivering a quality product. Specifically, your protocol lacked details on critical manufacturing variables including, but not limited to, mixing time and temperature. You did not demonstrate that your manufacturing processes were controlled to consistently yield a drug product of uniform character and quality.

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.

Without adequate process validation, incorporating all manufacturing inputs and parameters that can affect product quality, your firm lacks basic assurance that you can reproducibly deliver products that meet specifications. See FDA's guidance for industry, Process Validation: General Principles and Practices for general principles and approaches that the FDA considers appropriate elements of process validation at https://www.fda.gov/media/71021/download.

In your response, you stated that your process qualification studies are ongoing.

Your response is inadequate. You have not demonstrated that your manufacturing processes are designed, controlled and reproducible to yield a product of uniform character and quality. Failure to perform adequate process validation can result in product quality attribute failure.

Batch Production Records

Your batch production records do not include adequate production details, including but not limited to, critical steps in your manufacturing processes such as critical parameters (e.g., mixing times, holding times, temperature), manufacturing instructions and actual measured weights of each ingredient in a batch. This documentation is necessary to establish that manufacturing processes are consistently followed and are reproducible.

During the inspection, our investigator identified that your batch production records contained the use of white-out correction liquid and crossed-out data entries, including entries for raw material lot number and supplier information. Our investigator also identified several entries that were written over and crossed out without a signature, date, or explanation.

Complete and accurate batch production and control records are necessary to ensure that manufacturing processes are consistently followed and reproducible. Additionally, incomplete manufacturing records deprive you of the ability to adequately investigate deviations and batch failures.

In your response, you proposed document controls over your batch production records.

Your response is inadequate. Your firm failed to provide details on how you will complete and document your production records.

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 (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.
• 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.
• A remediation plan that assures ongoing management oversight throughout the manufacturing lifecycle of all drug products. Provide a more data-driven and scientifically sound program that identifies sources of process variability, and assures that manufacturing (including both production and packaging) operations meet appropriate parameters and quality standards. This includes, but is not limited to, evaluating suitability of equipment for its intended use, ensuring quality of input materials, determining the capability and reliability of each manufacturing process step and its controls, and vigilant ongoing monitoring of process performance and product quality.
• Revised master production records for all your drug products to demonstrate that, when executed, they fully document each manufacturing step.
• Procedures you have implemented to ensure production records are completed as required and reviewed by your quality unit before release of products for distribution.

4. Your firm’s quality control unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22).

Your quality unit (QU) did not provide adequate oversight for the manufacture of your OTC drug products. For example, your QU failed to ensure the following:

• An adequate written procedure for annual product review.
• An adequate written procedure for complaint handling.
• An adequate written procedure for labeling finished products. In addition, our investigator identified that a finished product batch was missing the unique lot number and expiration date.

An adequate QU overseeing all manufacturing operations is necessary to consistently ensure drug quality. Your firm’s quality systems are inadequate. See FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations for help in 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/media/71023/download.

In your response, you stated that written procedures have been established for annual product review to include complaints, recalls, returned or salvaged drug products, and investigations. You also committed to tracking written logs (in addition to electronic correspondence) for unexplained discrepancies related to your drug products. You stated that effective July 11, 2022, all 15 ml Essential SPF 30 bottles have been labeled with an affixed expiration date.

Your response is inadequate. You did not provide the procedures as evidence or indicate how your QU will provide oversight of your operations.

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 comprehensive, independent assessment of your overall system for investigating deviations, discrepancies and complaints, OOS results, and failures. Provide a detailed action plan to remediate this system. Your action plan should include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, CAPA effectiveness, QU oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.

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.

Data Integrity Remediation

Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture. See FDA’s guidance document Data Integrity and Compliance With Drug CGMP for guidance on establishing and following CGMP compliant data integrity practices at https://www.fda.gov/downloads/drugs/guidances/ucm495891.pdf. We strongly recommend that you retain a qualified consultant to assist in your remediation. In response to this letter, provide the following.

A. A comprehensive investigation into the extent of the inaccuracies in data records and reporting including results of the data review for drugs distributed to the United States. Include a detailed description of the scope and root causes of your data integrity lapses.

B. A current risk assessment of the potential effects of the observed failures on the quality of your drugs. Your assessment should include analyses of the risks to patients caused by the release of drugs affected by a lapse of data integrity and analyses of the risks posed by ongoing operations.

C. A management strategy for your firm that includes the details of your global CAPA plan. The detailed CAPA should describe how you intend to ensure the reliability and completeness of all data generated by your firm including microbiological and analytical data, manufacturing records, and all data submitted to the FDA.


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 the FDA to withhold issuance of Export Certificates. The 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 deviations 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.

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

Please identify your responses with the unique identifier: CMS 640035

If you have questions regarding the contents of this letter, please contact Andrew Haack, compliance officer by telephone at 206-340-8212 or email at Andrew.Haack@fda.hhs.gov.

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

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