Inspections, Compliance, Enforcement, and Criminal Investigations
Ion Labs, Inc. 7/31/09
Department of Health and Human Services
|Public Health Service
Food and Drug Administration
|555 Winderley Pl., Ste. 200
Maitland, Fl 32751
RETURN RECEIPT REQUESTED
July 31, 2009
William Oliver Jr., President
Ion Labs, Inc.
5459 115th Ave N.
Clearwater, Florida 33760
Dear Mr. Oliver:
An inspection of your drug manufacturing facility located at 5459 115th Ave N., Clearwater, Florida, 33760 conducted by our Food and Drug Administration (FDA) investigator from November 24, 2008 through December 31, 2008, determined that you are a manufacturer of human and veterinary drug products and dietary supplements. The inspection revealed significant deviations from the Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals, Title 21, Code of Federal Regulations (CFR), Parts 210 and 211, with regard to the manufacture of pharmaceutical products by your facility. The deviations reported by the investigator cause your finished drugs to be adulterated within the meaning of Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. § 351(a)(2)(B)].
In addition, this inspection also revealed that your firm is manufacturing and/or marketing unapproved drugs in violation of Section 505(a) of the Act [21 U.S.C. § 355(a)] and the drugs are also misbranded in violation of Section 502(o) of the Act [21 U.S.C. § 352(o)] because they have not been listed as required by Section 510(j) of the Act, [21 U.S.C. § 360(j)].
We received your response, dated February 9, 2009, concerning our investigator's observations noted on the Form FDA 483, List of Inspectional Observations, that was issued to you at the conclusion of the inspection. We address this response below, in relation to each of the noted violations. The violations include, but are not limited to, the following:
1. Your firm has not established test procedures or other laboratory control mechanisms that are designed to assure that drug products conform to appropriate standards of identity, strength, quality, and purity and to assure that any deviation from the written test procedures or laboratory control mechanisms are recorded and justified [21 CFR § 211.160(a) & 211.160(b)]. For example, no written and approved procedures were available for dissolution and uniformity of dosage unit testing of drug products, prior to release. Specifically, the following drug products lacked these tests: Acetaminophen 500 mg tablets; Influend Severe Cold and Cough tablets; Influend Severe Cold and Flu tablets; Super Pain Express Plus Caffeine capsules (Pain Plus), and; Guai-Aid tablets (400 and 600 mg).
Your response stated "We will implement new procedures to be specific for assay approval including dissolution and uniformity specifications." This response is inadequate because it fails to describe if all drug products will he covered with this SOP and does not state when the SOP will be implemented.
This is a repeat observation from the June 2007 inspection.
2. Your firm has not established and followed scientifically sound and appropriate specifications, standards sampling plans, and test procedures designed to assure that drug products conform to appropriate standards of identity, strength, quality and purity [21 CFR § 211.160(b)]. For example,
a) For the testing of incoming components, your firm failed to conduct HPLC system qualification using certified standards and validated procedures. Your firm stated that it used the active pharmaceutical ingredient (API) guaifenesin as a standard to qualify the High Pressure Liquid Chromatographic (HPLC) system, prior to testing of drug product samples. Your laboratory failed to certify guaifenesin against a primary standard from an accredited institution and/or to fully characterize the material as a standard.
b) Chorpheniramine maleate USP (lot 66050) was used as a standard for the assay testing of the final blend and for stability (room temperature and accelerated) testing, although it was not a certified standard. These tests were performed for Influend Jr Severe Cold and Cough liquid Batch 800076.
c) The API lidocaine HCL was used as a standard to test the same batch of Jungle Juice (batch 800113) finished drug product; however, this standard was not characterized.
We note the commitment in your response to use certified standards from an accredited institution. However, your response states "Ion Labs will review all IQ, OQ and PQ for all instruments that are currently in the Laboratory and will amend those that will need to be more complete." This response is inadequate in that you do not specifically commit to requalification of the HPLC system. Further, your response states "There will be a procedure written to specify lab testing methods and specifications that are ingredient or API specific." This. response is inadequate because it does not state when the SOP will be implemented.
3. Your firm has not conducted adequate calibration of instruments, apparatus, gauges, and recording devices at suitable intervals in accordance with an established written program containing limits for accuracy and precision [21 CFR § 211.160(b)(4)]. For example,
a) Your firm failed to conduct injector and detector performance testing for the (b)(4) HPLC system. For example, no HPLC injector and detector testing for linearity, accuracy, and precision were conducted, such as: 1) various injection volumes and standard concentration testing; 2) evaluation of detector for noise/drift; and 3) carryover testing to evaluate response at low levels to determine the detection of possible interferences that may affect peaks of interest.
b) The laboratory pH meter was not calibrated on days of use, as required by SOP 800.7. Drug products that require pH testing include Genetuss 2, Orasep Spray, Sorbutuss, and Brontuss SF.
4. Your firm has not thoroughly investigated the failure of a batch or any of its components to meet its specifications whether or not the batch has already been distributed [21 CFR 211.192]. For example, unexplained discrepancies were not investigated and/or incomplete investigations were conducted or documented for the following:
a) Acetaminophen 500 mg (Batch 800081) was compressed into tablets on April 4, 2008; however, this batch of tablets was reprocessed due to a problem with compressing the tablets. In an attempt to correct the compression problem, additional inactive ingredients were added to this batch (b)(4) additional powder A and (b)(4) additional powder B) without justification or an assessment on product impact. Also, your firm increased specifications for individual tablet weight. This batch was released for distribution on, April 30, 2008. There was no record of this incident in batch records and your firm failed to document an investigation of this incident, including the root cause and corrective actions for this suspect batch.
b) Uniformity of blend testing conducted on March 28, 2008 for content of dextromethorphan HBr and phenylephrine HCI in lnfluend Severe Cold and Cough tablets (Validatiion Batch 800074) revealed OOS assay results. All four samples from different locations in the blender revealed assay results that were less than 73.0% of label claim for the dextromethorphan HBr ingredient. Also, all four phenylephrine HCI samples were greater than 141.0% of label claims. No documentation for the OOS results was noted, nor any corrective actions. This batch was shipped on May 5, 2008, prior to release.
Your response states "Ion Labs will establish a procedure to evaluate suspect or out-of-specification (OOS) test result(s)." However, your response is inadequate because it fails to include any details on handling investigations such as what errors or incidents would result in a full-scale OOS investigation.
Please note that it is the responsibility of your firm to investigate the cause of the failure of a batch of a drug product to meet its specifications and to include conclusions and follow-up measures to prevent recurrence of these events.
5. Your firm has not established written procedures for production and process control designed to assure that drug products have the identity, strength, quality and purity that they are represented to possess [21 CFR § 211.100(a)]. For example, your firm has not established written procedures for, or conducted, appropriate process validation studies for the following drug products: a) Acetaminophen tablets; b) Orasep Spray; c) Australian Dream; d) Brontuss SF liquid; and e) K-9 Aspirin tablets.
In addition, validation protocols for three drug products (e.g., Guai-Aid 600 mg tablets; Sorbutuss liquid; and Influend Severe Cold and Cough tablets) are inadequate. For example, your protocol for Guai-Aid 600 mg tablets addresses weighing and mixing, but does not address compression and demonstrating control of the tabletting process. Also, your firm uses a "general Protocol" for all products. Validation studies must be conducted according to protocols specific to each product and process. The critical controls and processing
parameters must be known, shown to be in control and a demonstration of process reproducibility with objective measures must be made. Your sampling plans are not explained or justified. You have not justified why the results of the sampling and testing you conduct (assuming the results are acceptable) can be extrapolated to all the dosage units in the lot. You have not conducted any analysis comparing data between :your validation batches. Also, this "general Protocol" under Section 4, states "The following will necessitate the
revalidation of a process: 3. any; batch failure." If the test samples fail, your validation protocol [?] does not require determining root cause. Further, your validation protocol fails to include any indication that the critical manufacturing steps impacting product quality are understood and properly controlled so that it can be assured that each dosage unit in the lot will meet its specification and quality attributes.
Your response to the Form FDA! 483 states "ION Labs will separate the report section of the existing Validation Protocol and create a separate binder with written review and comments, for validation processes and procedures used during validation. The Validation Report will discuss the validation batches, as required by the validation procedures for solid dosage and liquid finished products." FDA is unclear how your response will fully address our process validation concerns because it does not establish manufacturing controls,
critical components, and critical process parameters for all products manufactured at your firm. Finally, your response lacks specific timeframes for completion.
This is a repeat observation from the June 2007 inspection.
6. Your firm has not conformed to written specifications and testing procedures for in-process materials [21 CFR § 211.160(b)(2)]. For example, your firm failed to document hardness testing of tablets in order to ensure resistance of the tablets to chipping, abrasion or breakage under conditions of storage, transportation and handling before usage.
Your response states "All in-process testing results including hardness testing will be documented in the new Batch Production Records." This response is inadequate because an implementation date was not included in your response.
7. Your firm does not have laboratory records that include complete data derived from all tests necessary to assure compliance with established specifications and standards, including examinations and assays such as a statement of the results of tests and how the results compare with established standards of identity, strength, quality, and purity for the component, drug product container, closure, in-process material, or drug product tested [21 CFR § 211.194(a)]. For example,
a) Your firm does not use primary standards from an accredited institution such as USP. Also, no testing has been performed to certify any of your laboratory standards as secondary standards (e.g., testing against USP primary standards) or fully characterized to be used as a standard.
b) API, Phenylephrine HCl assay laboratory testing was conducted without a primary standard from an accredited institution (e.g., USP). Also, your firm's certified secondary standard was not tested against a primary standard, or a standard that was purified arid fully characterized. Therefore, the assay testing results for Lot 51202 cannot be verified as being reliable.
c) Your firm's laboratory records:lack the following information: 1) a statement of methods used for the testing of samples, 2) a statement of how test results compare with specifications, and 3) a complete record of all data secured in the course of each test. For example, records for your Sorbutuss and Extussive batch test on May 13, 2008 lacked documentation stating what test method(s) was used and how: the results documented as % LC (label claim) compare with specifications.
Your response stated that your firm has purchased standards from an accredited institution and all components and finished product testing is now tested using these certified standards; however, you failed to identify the name of the accredited institution.
8. Your firm has not tested or examined, as appropriate, each lot of components drug product containers and closures [21 CFR § 211.84]. The written and approved test procedures, specifications, and testing practices performed for API components used to manufacture finished drug products are not adequate. Your API components have not been tested for conformity with all appropriate written and approved specifications for quality, purity, and strength nor identity tested after the reliability of supplier's analyses have
been verified (i.e. full COA testing at certain intervals). There is no assurance that any of your API components used to manufacture drug products, meet adequate purity, strength, and quality criteria. For example,
a) There are no written and approved testing procedures or specifications for testing impurities or related; compounds in APIs.
b) Regarding the (b)(4) your firm stated the supplier was not qualified and no testing was performed, per SOP 900.1. Yet, this lot was used as a component to manufacture Influend Jr Severe Cold and Cough liquid (batch 800076). Also, this API was used as a standard to test batch 800076, which was distributed. Your firm has no written and approved laboratory testing methods and specifications, specific for the API, (b)(4).
Your response for this item is inadequate because you failed to include what testing will be conducted to qualify your API vendors. Also, you did not state what abbreviated testing is to be conducted after your vendor/supplier has been verified. Further, you did not include implementation date(s) of this additional proposed testing.
9. Your firm has not established a written testing program designed to assess the stability characteristics of drug products [21 CFR § 211.166(a)]. For example, there are no written and approved stability procedures that define for each drug product the specific tests to be performed, the frequency, and the acceptance criteria/specifications. Laboratory documentation states only active ingredient assay testing is being performed.
Your response for this item stated "Specific procedures will be implemented regarding stability with specific testing and appropriate specifications for finished products." This response is inadequate because you did not include what specific testing you will be conducting nor did you include an implementation date of your proposed stability testing.
10. Your firm's Quality Control Unit has not reviewed and approved all drug product production and control records before batches are released for distribution [21 CFR § 211.192]. Batches of drug products are not always approved and testing is not always completed prior to release.
a) Influend drug product: finished product (batches 800074, 800075, 800076, and 800077) were released on May 5, 2008; however, these batches were reviewed and approved between the dates of May 8, 2008 and May 12, 2008. In addition, Batches 800074, 800075, and 800076 were not tested for all active ingredients and Batches 800074 and 800075 had failing test results.
b) Jungle Juice (batch 80(113) was released on May 27, 2008 and May 30, 2008 and subsequently reviewed and approved on June 2, 2008.
c) Acetaminophen 500 mg Tablets (batch 800081) was released on April 25, 2008 and subsequently reviewed and approved on April 30, 2008.
Your response stated "A complete revision and rewrite of QA/QC SOP's, documentation as well [as a] cGLP training regimen will be implemented for all QA/QC members." This response is inadequate because it failed to: a) define what SOPs will be revised/rewritten; b) state when the SOPs will be implemented; c) describe what information is included in this training program; and d) include related CGMP training for respective personnel.
11. Your firm has not established a written record of major equipment cleaning, maintenance, and use [21 CFR § 211.182]. Specifically, no individual equipment log books were maintained documenting the date, time, product, and lot number of each batch of finished drug product processed with major non-dedicated product manufacturing equipment. No equipment use log books were available for the mixers including the V-blender; tanks; tablet compression machine, and; filling and packaging equipment.
Your response stated that the procedures and work instructions will be updated to include the requirement to have and use cleaning logs; however, this response is inadequate because it failed to state when use of the log books will be implemented.
Misbranded and Unapproved New Drugs
Based on the labeling collected during the inspection of your facility, the products Influend Cold and Cough tablets (with added Antioxidants and Immune system enhancers), Influend Severe Cold and Flu tablets (with added Antioxidants and Immune system enhancers), Influend JR. Cold and Cough Liquid (with added Antioxidants and Immune system enhancers), and lnfluend JR. Severe Cold and Flu (with added Antioxidants and Immune system enhancers), manufactured by your firm, 1 are drugs within the meaning of Section 201(g)(1)(B) of the Act, 21 U.S.C. § 321(g)(1)(B), because they are intended for use in the diagnosis,cure, mitigation, treatment, or prevention of disease, and under section 201(g)(1)(C) or the Act,21 U.S.C. § 321(g)(1)(C), because they are intended to affect the structure or any function of the body of man. Specifically, the products are labeled for the temporary Relief of certain cough and/or cold symptoms, and the labeling for these products prominently state, "Multi-system Relief with added ANTIOXIDANTS and IMMUNE SYSTEM ENHANCERS."
The "added ANTIOXIDANTS and IMMUNE SYSTEM ENHANCERS" (emphasis added) appear to refer to some of the purported "inactive ingredients" listed on the products' labeling (e.g., arabinogalactan, olive leaf extract, elderberry extract, vitamin c), because the combinations of ingredients listed as "active" in the labeling for these products for the temporary relief of certain cough and/or cold symptoms are acceptable under the final monograph for Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Drug Products for OTC use, 21 CFR part 341 (OTC Cold Cough Monograph), and there are no additional ingredients identified as "active" in the labeling. Even though these additional, purportedly "inactive" ingredients could be marketed separately as dietary supplements, the presence of dextreimethorphan hydrobromide, phenylephrine hydrochloride, chlorpheniramine maleate, acetaminophen, and diphenhydramine hydrochloride in these products, with their intended uses to mitigate or treat cough and/or cold symptoms, renders the entirety of each product a drug. Under section 201(g)(1)(D) of the Act, 21 U.S.C. § 321(g)(1)(D), the purported "inactive ingredients" that your firm claims are "antioxidants and immune system enhancers" are also drugs, even in the absence of any claims that they treat, mitigate, or prevent cough or cold symptoms, because they are components of the finished drug product. See CFR § 21 0.3(b)(3). And, based on the antioxidants and immune system enhancers claim in the labeling of this product, they are also "active" drug ingredients within the meaning of 21 CFR § 201.66(b)(2).
Moreover, based on the combination of these active drug ingredients (e.g., dextromethorphan hydrobromide, phenylephrine hydrochloride, chlorpheniramine maleate, arabinogalactan, olive leaf extract and vitamin c), as described above, the products Influend Cold and Cough tablets, Influend Severe Cold and Flu tablets, Influend JR. Cold and Cough Liquid, and Influend JR. Severe Cold and Flu are new drugs within the meaning of section 201 (p) of the Act arid 310.3(h), because they are not generally recognized as safe and effective for their labeled uses. These products are not subject to FDA's OTC Drug Review, because no product formulated with these active ingredients and labeled for these intended uses has previously been commercially marketed, and the agency has never proposed that such a product be included in that review. In order for OTC cough and/or cold products to be generally recognized as safe and effective and not misbranded for their labeled uses, and thus be marketed without an approved NDA, they must meet the requirements of the OTC Cold Cough Monograph. In addition, regardless of the active ingredients, there are no provisions in that monograph for including antioxidant and immune system enhancing claims on the labeling of OTC cough and cold drug products.
Under sections 301(d) and 505(a) of the Apt, 21 U.S.C. §§ 331(d) and 355(a), a new drug may not be introduced or delivered for introduction into interstate commerce unless an FDA-approved application is in effect for it. Based on our information, you do not have any FDA-approved applications on file for these drug products. Because the products described above are unapproved new drugs that do not have approved applications, their introduction and delivery into interstate commerce violates these provisions of the Act.
These products are also misbranded under Section 502(o) of the Act, 21 U.S.C. § 352, because they have not been listed as required by Section 510(j) of the Act, 21 U.S.C. § 360(j).
The issues discussed in this letter and on the Form FDA 483 are not intended to be an all inclusive statement of the objectionable conditions that exist at your facility. You are responsible for investigating and determining the causes of the objectionable conditions identified above and for preventing their recurrence or the occurrence of other objectionable conditions. It is your responsibility to assure that your firm complies with all requirements of the Act and FDA regulations.
Within 15 working days of receipt of this .letter please notify this office in writing of the specific steps you have taken to correct violations. Include an explanation of each step taken to prevent recurrence of similar violations as well as copies of related documentation. If you cannot complete corrective action within fifteen working days, state the reason for the delay and the time within which you will complete the correction. If you no longer manufacture or market ally products, your response should so indicate, include the reasons for, and the date on which you ceased production.
You should take prompt action to correct the violations addressed in this letter. Failure to promptly correct these violations may result in regulatory action being initiated by the Food and Drug Administration without further notice. These actions include, but are not limited to, seizure and injunction. Other federal agencies may take this warning letter into account when considering the award of contracts.
Please send your reply to the U.S. Food and Drug Administration, Attention: Winston R. Alejo, Compliance Officer, 555 Winderley Place, Suite 200, Maitland, Florida, 32751. If you have questions regarding any issues in this letter, please contact Mr. Alejo at (407) 475-4731.
Emma R. Singleton
Director, Florida District
1 Evidence that we collected during our inspection indicated that you were marketing these products at the time of the inspection of your firm. We understand that you subsequently recalled these products in April 2009.