WARNING LETTER
King Bio Inc.
MARCS-CMS 567480 —
March 20, 2019
Product:
Drugs
Recipient:
Recipient Name
Dr. Frank King, Jr
Recipient Title
President
King Bio Inc.
3 Westside Drive
Asheville
,
NC
28806
United States
Issuing Office:
Division of Pharmaceutical Quality Operations II
4040 North Central Epressway, Suite 300
Dallas
,
TX
75204-3128
United States
DATE 3/20/2019
Case # 564578
WARNING LETTER
VIA UPS EXPRESS
Dr. Frank King, Jr - President
King Bio, Inc.
3 Westside Drive
Asheville, NC, 28806
Dear Dr. King:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, King Bio, Inc., FEI 1053442, at 3 Westside Drive, Asheville, NC, from July 9 to 20, 2018.
This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See 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).
During our inspection, FDA collected samples of finished homeopathic drug products manufactured by King Bio, Inc. FDA test results revealed inordinately high microbiological contamination.
In addition, based on our review, your products “Cold Sores & Herpes,” “Adrenal Burnout,” and “Lymph Detox,” are misbranded drugs under sections 503(b) of the FD&C Act, 21 U.S.C. 353(b).
We reviewed your August 10, 2018, response in detail and acknowledge receipt of your subsequent correspondence.
During our inspection, our investigators observed specific violations including, but not limited to, the following.
CGMP Charges
1.    Your firm failed to establish an adequate quality control unit with the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging materials, labeling, and drug products (21 CFR 211.22(a)).
Your quality unit failed to assure that homeopathic drug products met all required specifications prior to release and distribution, and to take appropriate action in response to failing test results.
You manufacture and distribute hundreds of drugs including those intended for infants, children, pregnant women, and immunocompromised individuals. Over multiple years, your firm obtained recurring test results for water used as a component of your drugs, as well as results for finished homeopathic drug products, outside of microbiological limits. This testing revealed extremely high levels of microbiological contamination, including results that were Too Numerous to Count (TNTC), and identified the presence of significant opportunistic pathogens in your drugs. Furthermore, your tests of retained samples and customer complaint bottles found objectionable microbiological contamination in already distributed lots.
FDA laboratory testing also revealed exceedingly high levels of ­­microbiological contamination in multiple homeopathic drugs produced by your drug company.
Significantly, you failed to take actions to prevent consumer exposure to marketed drug product lots known by your firm to contain microbiological contamination. For example:
–     You released Dr. King’s Lymph Detox, lot 010118BE, on April 11, 2018. This lot failed Microbial Limits Testing (MLT) and failed Antimicrobial Effectiveness Testing (AET). Although these microbiological quality failures were reported on April 23, 2018, you continued to distribute this drug product lot.
–     You also did not remove failing drug products from distribution when laboratory testing showed very high levels of microbial contamination in Dr. King’s Natural Products ShinglePlex, lot 010118Q, and Dr. King’s Advanced Arnica, lot 080917C.
Your firm recalled these three contaminated lots only after FDA contacted you regarding the microbiological contamination of your drug products.
Your firm also lacked adequate investigations into failing drug products, poor water quality, and customer complaints. More specifically, in numerous instances, your quality unit failed to investigate out-of-limit microbial results from your purified water system used to manufacture water containing drugs. Failures of finished product testing and retention samples also lacked meaningful and effective investigations. In addition to these total count failures, you identified objectionable microorganisms (such as
Burkholderia multivorans)
in multiple drug products but lacked investigations.
You did not take effective actions to investigate root causes, and correct flaws, in your manufacturing operations and quality management systems to prevent recurrence of these serious quality failures. Ultimately, you did not ensure timely and effective corrective and preventative actions to prevent exposure of consumers to contaminated product. While you continued to obtain microbiological test results outside of acceptable limits on a recurring basis, you did not initiate recalls until the FDA identified these serious issues in our inspection and relayed safety concerns to you.
Executive management must support a quality unit that assures product quality and patient safety, and not undermine the steps needed to prevent production and distribution of hazardous products. Our inspection findings indicate that your quality unit was not able to fully exercise its authority or responsibilities. In at least one instance, your Quality Assurance Manager recommended a drug product recall due to microbial contamination, but your firm failed to remove the adulterated drug product from the market. In addition, while the “OOS Log” includes certain laboratory results, it did not appear to ensure prompt and consistent reporting of every OOS (Out of Specification) laboratory result to quality assurance (QA) for appropriate review.
The quality unit must be empowered to make final quality decisions. It is essential that the quality unit be enabled to provide timely oversight of all laboratory and manufacturing (including utilities) data that could impact product quality, whether or not lots have already been distributed. When making batch disposition decisions, the quality unit must be provided with all batch production and control records, including all deviations and test data, to enable a fully informed and appropriate decision regarding suitability for distribution.
In your response, you mention that you recalled some drug product lots, updated your quality control Standard Operation Procedure (SOP), and conducted a review of out-of-limit results since January 2018. However, your response is inadequate as you do not address the underlying issue of inadequate manufacturing and quality assurance, or the impact of such inadequacies on the quality and safety of your drugs. In addition, the limited period of your retrospective review lacked scientific justification.
In response to this letter, provide the following.
An independent, retrospective review of all OOS results and complaints since Jan. 1, 2015. This retrospective review should also evaluate all batches that remain in distribution to determine if your firm released batches that did not conform to established specifications or appropriate manufacturing standards.
A comprehensive assessment with corrective and preventive actions (CAPA) to ensure your Quality Unit (QU) is given the needed authority, responsibilities, and resources to effectively discharge its function. The assessment should include review and remediation of the QU function, including but not be limited to:
-  ensuring the QU conducts a complete and thorough final review of all production and control records for each batch prior to the disposition decision; performs oversight and approval of manufacturing and laboratory investigations; and fully discharges all other QU roles to assure identity, strength, quality, and purity of all products.
-  establishing methods to ensure quality and safety of all your products over the entire expected period of use. This includes, for example, ongoing evaluations for each product and its container closure system(s) to assure your labeled shelf-life remains valid. It also includes immediate notification of any potentially adverse product quality data (e.g., complaints, returns, retains, stability testing) related to all batches, whether or not they have already been distributed.
-  ensuring all procedures are appropriate and effective;
-  provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices;
Your plan for ongoing evaluations (at least annually) of the quality standards of each drug product to determine the need for changes in drug product specifications, manufacturing, or control procedures.
A comprehensive, independent assessment of your overall system for investigations of deviations, atypical events, complaints, out-of-specification results, and failures. Your CAPA should include but not be limited to improvements in investigation competencies, root cause analysis, written procedures, and quality unit oversight. Also include your process for evaluating CAPA effectiveness.
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 (21 CFR 211.100(a)).
You have not validated your manufacturing process used to produce homeopathic drug products distributed to the U.S. market. This is particularly worrisome because you manufacture various homeopathic drugs from ingredients that pose potentially toxic effects. For example, some of your drugs are manufactured from
Nux vomica
which contains strychnine, a highly toxic, well-studied poison that is used as a rodenticide.
In addition, your firm lacked adequate written procedures for production and control records, and you failed to adequately demonstrate antimicrobial effectiveness of your preservative systems.
Process Validation
Unvalidated processes lack scientific data to assure products are of acceptable quality, identity, strength, and purity. Especially for drugs that contain ingredients with potentially toxic effects, unvalidated processes could expose patients to unnecessary risks due to the lack of knowledge about and control over sources of variation. In addition, you produce many drug products that require especially careful design to prevent microbiological contamination and validation to demonstrate robust production of safe drug products.
During the inspection, your firm acknowledged that your production control records lack pertinent information such as hold times, location of manufacturing, and procurement of water for production. Each significant step of a manufacturing process must be controlled to assure that in-process materials and finished drugs meet appropriate quality attributes and specifications.
Antimicrobial Effectiveness
You also failed to adequately demonstrate antimicrobial effectiveness of your preservative systems. For example, you attempted to evaluate antimicrobial effectiveness of one of your liquid drugs and consider it suitable for its intended use in over several hundred other drugs with varying formulations. You lacked adequate studies to demonstrate the adequacy of your preservative systems and your firm has continued to identify very hazardous contamination levels in your products.
You should also note that preservative systems cannot be a substitute for current good manufacturing practices, including but not limited to, an adequately designed and controlled production process.
In your response, you commit to conducting validation studies for all products and “preservative systems.” You also commit to continue microbiological testing on your drugs and assert that your testing confirms the integrity of your product and manufacturing processes. However, your response is inadequate because testing is not a substitute for an adequately designed, controlled, and validated production process. In addition, you failed to address the potential effects of your failure to validate your manufacturing processes on the quality and safety of all products that you released for distribution in the United States remaining within expiry.
When significant variability is observed in a drug manufacturing process or its input materials, it is essential that executive management support and promptly implement effective actions to address the source(s) of the variation and ensure a continued state of control.
Your firm lacks an ongoing program for monitoring process control to ensure stable manufacturing operations and consistent drug quality. 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/downloads/drugs/guidances/ucm070336.pdf
.
In response to this letter, provide the following.
Provide a risk assessment for distributed drug products on the market within expiry that you manufactured using an unvalidated process or inadequate preservative system. This should include, but not be limited to an evaluation of the potential effects of your lack of validation on all products intended for vulnerable populations, such as infants and children, distributed within the United States, and still within expiry.
Establish a data-driven and scientifically sound program that identifies and controls all sources of variability, such that your production and packaging processes will consistently meet appropriate manufacturing standards and parameters. This includes, but is not limited to, evaluating suitability of equipment for its intended use, assuring quality of input materials, and determining the capability and reliability of each manufacturing process step and control.
Detail your validation plan for ensuring a state of control throughout the product lifecycle. Include a timeline for performing appropriate process performance qualification (PPQ) for each of your drug products, and describe your program for vigilantly monitoring batch-to-batch variation to ensure an ongoing state of control. Also include your process performance protocol(s) and your written procedures for qualification of equipment and facilities.
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).
You failed to adequately design, validate, and control the purified water systems used to manufacture drugs. You tested water samples over an extended period and identified recurring excessive levels of bioburden in your process water, including Too Numerous To Count (TNTC) results and other results far in excess of your
(b)(4)
CFU/ml limit. Despite knowing your water was unsuitable for use as a component of your homeopathic drug products, you continued to manufacture and distribute drugs using this purified water system. The unacceptable water quality used by your firm for drug manufacturing posed an unacceptable risk to public health.
Your purified water system contains many design features that foster microbial proliferation and biofilm formation, such as dead-legs and ball valves. Dead-legs and ball valves impede water circulation and allow water to stagnate. Water in turbulent motion is essential to prevent accumulation of microbial contamination on internal surfaces (e.g. pipes, pumps, cross-connections, areas of poor slope) while stagnant water can harbor microorganisms and provide a starting point for biofilms which sporadically slough off organisms, creating non-uniform contamination.
In addition to the water system in Building 3, our inspection observed that there are similar design flaws with the water system in Building 150. If this water system is used for any pharmaceutical production, you should fully remediate the inadequate design flaws.
Your purified water system is inadequate for additional reasons, including but not limited to a lack of:
Robust design
Procedures for monitoring, control, and maintenance
Final signature of validation report for approval by the operations and quality assurance managers responsible for oversight of the water system
Your testing results show that you were aware that your purified water system was out of control. For example, your firm had several out-of-limit bioburden results in March 2017. By May 2017, you shut down the water system due to contamination with bioburden at levels at TNTC and began purchasing purified water for production. Your water testing results in June 2017 were also outside of microbial limits and as of July 2017, your firm had multiple failing water system bioburden results that were TNTC. In October 2017, you attempted to conduct a water system validation, but you still had recurrent bioburden results outside allowable limits and even started using
(b)(4)
filters because of these failures. You continued to get test results out of allowable limits through June 2018. In addition, FDA testing of a Dr. King’s Kids Bedwetting and Teething Advanced Formula manufactured November 2017 (tested September 2018) showed inordinately high levels of microbiological contamination.
We note that you use
(b)(4)
filters downstream in your system. Use of
(b)(4)
filters are not a replacement for upstream proper design and control prior to filtration, as confirmed by your failing test results.
A major part of adequate control of your water system requires understanding the intended use of the product and intended patient population. An adequate water system must start with a robust design. A state of control is then assured by vigilant oversight of the system including but not limited to ongoing maintenance, a daily monitoring program, vigilant review of test results, summary data, effective investigations, and responsive systems to promptly address indications of deficient system control.
Although you commit to several corrective actions, including validating a new purified water system, your response is inadequate because it lacks a detailed explanation of the new system design, enhanced system controls, and other associated remediations. You failed to consider the impact to your already distributed product until the FDA recommended that you conduct a voluntary recall of your water-containing drugs. You also claim that your conforming microbial tests indicate the integrity of your products and manufacturing operation. However, as the foregoing shows, microbial testing cannot be relied upon as sole justification to release drug product batches, as contamination is not uniformly distributed in a system and any given sample may not be representative of the type or level of contamination.
In your response to this letter provide the following.
A comprehensive, independent evaluation of the water system design, as well as a thorough corrective action and preventive action plan (CAPA) to install and validate a suitable water system. The CAPA should include, but not be limited to:
o   Detailed plans for sustainable remediation activities for your purified water system in Building 3, including its redesign and associated schematic, control, and validation. Provide a list of components in the system and materials of construction as well. You should also make the same remediations to your purified water system in building 150 if used for drug production.
o   An effective program for ongoing control, maintenance, and monitoring that ensures the system consistently produces water that meets the purified water USP monograph specifications and appropriate microbial limits. Regarding the latter, include both your alert and action limits.
o   Include all significant control parameters (e.g., water temperature, flow rate, sanitization frequency, sampling points and frequency).
Data to evaluate whether the system consistently produces the desired water quality limits over time. Intensive monitoring at various points in the system, including testing of feedwater, is an integral part of determining if seasonal variations or other changes in other elements of the system are adversely affecting water quality.
A detailed risk assessment of the potential effects of the observed water system failures on the quality of each of your drug product lots within expiry that were not recalled, and notification to your customers of these significant deviations.
A description of your future plans for drug production using water from both Building 3 and Building 150. In addition, provide a list of all drugs made since January 1, 2016 using production water from building 150 including clarification of which drug products (whether intermediate or finished stages) are being, or have been, produced with the water system in building 150.
Inadequate Quality Oversight
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.
See FDA’s guidance document,
Quality Systems Approach to Pharmaceutical CGMP Regulations
, for help implementing modern 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/GuidanceComplianceRegulatoryInformation/Guidances/UCM070337.pdf
.
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 evaluate the completion and effectiveness of your corrective actions and preventive actions. Particular attention should be paid to engaging a qualified consultant with experience in microbiology and water purification.
Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for fully resolving all deficiencies and ensuring ongoing CGMP compliance.
Recall & Cessation of Manufacturing
We acknowledge that you recalled all water-containing drugs after the FDA contacted you via telephone on August 23, 2018.
On October 11, 2018, via telephone, you agreed to notify the FDA before you resume manufacturing water-containing drugs.
Misbranded Homeopathic Drugs
Your firm’s products, including, but not necessarily limited to “Cold Sores & Herpes,” “Adrenal Burnout,” and “Lymph Detox” are drugs under section 201(g)(1) of the FD&C Act, 21 U.S.C. 321(g)(1), because they are intended to diagnose, cure, mitigate, treat, or prevent disease, and/or intended to affect the structure or any function of the body. Examples of claims on your website www.drkings.com, where you take orders for products, that establish the intended use for your products above include, but may not be limited to, the following:
Cold Sores & Herpes
:
The product name, “Cold Sores & Herpes”
On your webpage entitled “Sensational Skin for Every Season” you state that “Homeopathy Can Help” directly above a picture of your “Cold Sores & Herpes” product. This website also states:
o    “[H]erpes [is] caused by the herpes simplex virus and [is] contagious in the active phase. [It is] very common . . . and anyone can get [it], no matter how clean. In fact, people with the herpes virus never know they have it, because they never have symptoms.”
o   “There are two kinds of herpes virus: HSV-1, which is usually not a sexually transmitted disease (STD) and occurs on the lip (a cold sore). Up to 80% of the population has HSV-1. This virus may also be transmitted to the genitals, and about 40% of genital herpes is caused by HSV-1. HSV-2, which usually causes
herpes genitalis
, is an STD in the genital area. Both viruses can be transmitted by saliva, body secretions or oral sex. Up to 22% of sexually active adults have genital herpes caused by HSV-2. Homeopathy Can Help[photo of Cold Sores & Herpes product].”
o    “Dr. King’s Cold Sores & Herpes is formulated to relieve . . .tingling and itching from herpes.”
Adrenal Burnout
:
The document accessible from your website, entitled, “How You Can Monitor & Manage Your Adrenal & Thyroid Health” states:
“Statistics show that 28% of the population suffers from diagnosed hypothyroidism. They’re given medication and told there’s no cure… and that they’ll need these meds for the rest of their lives. … 28% diagnosed with hypothyroidism. … My Recommendations to Patients with Thyroid Insufficiency . . . take our homeopathic ‘Adrenal Burnout…’” “Adrenal Burnout helps fix the underlying causes of a fried nervous system and burnt-out glandular system . . . it addresses a broad spectrum of symptoms associated with adrenal and thyroid fatigue.”
Lymph Detox
:
Your firm’s website, www.drkings.com, contains links to “The Healing Revolution Podcast” at https://www.drkings.com/en/healing-revolution-podcast/. In the episode entitled “Preventing Cancer” from 5/20/17, you advise listeners to go to your website, www.drkings.com, for detox remedies and specifically recommend “Lymph Detox” (among other things) to prevent cancer.
We recognize that “Cold Sores & Herpes,” “Adrenal Burnout,” and “Lymph Detox” are labeled as homeopathic drugs with active ingredients measured in homeopathic strengths. Under section 201(g)(1) of the FD&C Act (21 U.S.C. 321(g)(1)), the term “drug” includes articles recognized in the official Homeopathic Pharmacopeia of the United States (HPUS), or any supplement to it. Homeopathic drugs are subject to the same regulatory requirements as other drugs; nothing in the FD&C Act exempts homeopathic drugs from any of the requirements related to adulteration, labeling, misbranding, or approval.
We acknowledge that many homeopathic drugs are manufactured and distributed without FDA approval under enforcement policies set out in the FDA’s Compliance Policy Guide entitled,
Conditions Under Which Homeopathic Drugs May be Marketed
(CPG 400.400). As its title suggests, the CPG identifies specific conditions under which homeopathic drugs may ordinarily be marketed; thus, in order to fall under the enforcement policies set forth in the CPG, a homeopathic product must meet the conditions set forth in the CPG. One of those conditions is compliance with section 503(b) of the FD&C Act. The CPG states that homeopathic products intended solely for self-limiting disease conditions amenable to self-diagnosis (of symptoms) and treatment may be marketed OTC. Homeopathic products offered for conditions not amenable to OTC use must be marketed as prescription products.
Section 503(b)(1) of the FD&C Act, 21 U.S.C. 353(b)(1), identifies criteria for determining the prescription status of a product. Your above products are prescription drugs as defined in section 503(b)(1)(A) of the FD&C Act, 21 U.S.C. 353(b)(1)(A), because in light of their toxicity or other potentiality for harmful effect, or the method of their use, or the collateral measures necessary to their use, they are not safe for use except under the supervision of a practitioner licensed by law to administer such drugs. Therefore, these products are misbranded under section 503(b)(4) of the FD&C Act, 21 U.S.C. 353(b)(4), in that their labels fail to bear the symbol, “Rx only.”
[1]
The introduction or delivery for introduction of these misbranded drugs into interstate commerce is a violation of section 301(a) of the FD&C Act, 21 U.S.C. § 331(a).
Conclusion
Violations cited in this letter are not intended as an all-inclusive list. You are responsible for investigating these violations, for determining the causes, for preventing their recurrence, and for preventing 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.
Until these violations are corrected, we may withhold approval of pending drug applications listing your facility. We may re-inspect to verify that you have completed your corrective actions. We may also refuse your requests for export certificates.
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.
Electronically mail a signed copy of your written response to Shawn Larson - Compliance Officer, at
Shawn.Larson@fda.hhs.gov
and
ORAPHARM2_RESPONSES@fda.hhs.gov
. Your written notification should refer to
Case #
564578.
If you have questions regarding the contents of this letter, you may contact Shawn Larson via phone 214-253-5216 or
Shawn.Larson@fda.hhs.gov
.
Sincerely,
/S/
Charles Brown
Acting Program Division Director
Office of Pharmaceutical Quality Operations,
Division 2
Cc firm’s counsel at:
Abhishek K. Gurnani
100 S. Wacker Dr.
Suite 2000
Chicago, IL 60606
[1]
CPG 400.400 states that, in accordance with 503(b)(1) of the FD&C Act, homeopathic drug products offered for conditions that require diagnosis or treatment by a licensed practitioner must bear the prescription legend, “Caution: Federal law prohibits dispensing without prescription.” This CPG was issued by the agency in 1988. In 1997, Congress enacted the Food and Drug Administration Modernization Act (FDAMA); section 126 of FDAMA amended 503(b)(4) of the FD&C Act to require that the label of a prescription drug must bear, at a minimum, the symbol “Rx only.”
Content current as of:
03/26/2019
Regulated Product(s)
Drugs