Source: https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2013/ucm369127.htm
Timestamp: 2019-01-17 04:55:09
Document Index: 154977907

Matched Legal Cases: ['arts 210', 'arts 210', '§ 351', '§ 211', '§ 211', '§ 211', '§ 211', '§ 211', '§ 211', '§ 211', '§ 211', '§ 334']

Lloyd Inc. of Iowa 8/30/13
KAN-2013-16
William Eugene Lloyd, D.V.M., Ph.D
604 W. Thomas Avenue
Shenandoah, Iowa 51601-1744
Dear Dr. Lloyd:
During an inspection of your firm located at 604 W. Thomas Avenue, Shenandoah, Iowa on March 18 through April 16, 2013, investigators from the U.S. Food and Drug Administration (FDA) documented significant violations of the Current Good Manufacturing Practice (CGMP) regulations for Finished Pharmaceuticals, Title 21, Code of Federal Regulations, Parts 210 and 211 [21 CFR, Parts 210 and 211]. This letter concerns your firm’s deviations from CGMP related to your manufacturing of animal drugs. These deviations cause animal drug products manufactured at your facility 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)], which provides that a drug is adulterated “if the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to … current good manufacturing practice to assure that such drug meets the requirements of this Act as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess.”
We acknowledge your written responses dated May 7 and June 17, 2013, addressing our investigators’ observations that were presented to you on the FDA Form 483, List of Inspectional Observations. The violations we observed, along with our comments regarding your responses to the FDA Form 483 include, but are not limited to, the following:
1. Failure to have master production and control records that justify variation in the amount of components necessary for the preparation of the dosage form [21 CFR § 211.186(b)(4)].
Specifically, your firm has not provided an adequate rationale for the (b)(4)% overage used in the manufacture of Levothyroxine products canine formulations PID and PIJ. Your batch records are formulated at (b)(4)% (+/- (b)(4)%) of label claim without justification or an assessment on product impact. This (b)(4)% overage failed to assure the canine Levothyroxine drug products you manufactured have the strength they purport to possess (b)(4)% (+/- (b)(4)%).
We acknowledge your decision to recall the affected lots of Levothyroxine drug products from the market. We also note your firm has (b)(4) and no longer plans to manufacture (b)(4) drug products.
Your May 7 and June 17, 2013 responses fail to provide documented scientific justification to explain why the excess API was necessary when charging the APIs used in manufacturing your canine Levothyroxine PID or PIJ at (b)(4)% (+/- (b)(4)%) of label claim. Your process is not considered to be in an adequate state of control when excess API is routinely used by your firm. To ensure proper formulation, you must justify excess amounts of a component in each batch record.
Regarding canine Levothyroxine PIJ and your planned reformulation, we acknowledge your corrective actions to hire an independent consultant, reconfirm loss during manufacturing, and complete two validation SOPs. However, we have concerns regarding your determination of appropriate API charge and process validation. Your responses failed to include 1) what information from past batches will determine planned overage amounts, 2) information regarding ongoing process verification to ensure the manufacturing process continues to be reproducible, and 3) when you plan to manufacture and distribute the reformulated Levothyroxine PIJ.
2. Failure to establish 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)].
Specifically, you failed to conduct process validation studies for all strengths of each of your canine Levothyroxine products. There is no assurance of the quality of these products, including critical attributes such as uniformity of active (and inactive) ingredients. There is no assurance of batch to batch uniformity. The following strengths of canine Levothyroxine products lack process validation studies:
Canine Levothyroxine PIJ formulation strengths 0.2 mg, 0.3 mg, 0.4 mg, 0.6 mg, 0.7 mg, and 1.0 mg.
Canine Levothyroxine PID formulation strengths 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, and 0.7 mg.
Your May 7 and June 17, 2013 responses fail to include important information regarding your validation plans. Please address the following questions:
- What information is included in an “engineering study”?
- Are the engineering studies/validation activities performed at your firm with the same equipment used for manufacturing?
- Are you changing in-process material (i.e., components/APIs)?
- Have you established key quality attributes and process parameters for your validation studies?
- What is the timeframe for completion of your validation activities?
Be advised that the degree of validation sampling (e.g., number and frequency) and testing should be more extensive (than routine production) to provide sufficient statistical confidence of quality within a batch and between batches.
3. Failure to ensure in-process specifications are consistent with drug product final specifications [21 CFR § 211.110(b)].
Specifically, since 2009, your in-process final blend assay specification range is (b)(4)% - (b)(4)% with (b)(4)% overage for canine Levothyroxine PIJ formula tablets. This specification range is not consistent with the narrower final tablet specification of (b)(4)% - (b)(4)% (USP label claim). Further, your historical data (based on (b)(4) production batches) revealed that only (b)(4)% of the Levothyroxine active ingredient is lost during manufacturing. Your final blend assay specification range would allow the release of blend between (b)(4)% and (b)(4)% (accounting for the (b)(4)% overage), which would allow tablets to be compressed above the USP final specification range, even accounting for the purported (b)(4)% historical loss.
Your May 7 and June 17, 2013 responses state your corrective action would include completing appropriate engineering studies to establish an adequate and robust in-process sampling methodology. However, these responses failed to include specific information on how you plan to determine your in-process blend specification for canine Levothyroxine PIJ formula tablets. For example, you did not state if historical data will be included with data from engineering studies to determine your revised in- process specification .
4. Failure to ensure samples of in-process materials taken for determination of conformance to specifications are representative [21 CFR § 211.160(b)(2)].
Specifically, you have not shown that your in-process sampling procedure for the canine Levothyroxine final blend (formulations – PIJ, PID) of taking a sample from the (b)(4) for your final mix assay prior to tableting is representative of the entire blend. For example, you have not been able to consistently obtain reproducible in-process final mix assay results from the same locations within each (b)(4).
Your May 7 and June 17, 2013 responses states that your firm will: “Complete engineering studies to establish an adequate and robust in-process sampling methodology.” These responses are insufficient because they fail to include 1) what sampling information is part of your engineering studies, 2) if blend uniformity testing will be conducted, and 3) how many batches will be tested as part of the studies.
5. Failure to follow procedures describing the handling of all written and oral complaints regarding a drug product [21 CFR § 211.198(a)]. Failure of your Quality Control Unit (QCU) to conduct complaint investigations or include a written record of the reasons that an investigation was found not to be necessary [21 CFR § 211.198(b)(3)].
Specifically, despite your SOP’s own procedural requirements for handling complaints, you failed to complete investigations into the following:
Seven of 9 consumer complaints received since 2012 for canine levothyroxine PIJ formulation, for example:
Complaint T4-2012-14 for lack of effectiveness, received July 11, 2012 and still open at the time of the inspection.
Complaint T4-2012-17 for multiple lots of bottles distributed without lot numbers and/or expiry dates, received August 6, 2012 and still open at the time of the inspection
Eleven of 16 complaints received since 2012 for canine levothyroxine PID formulation, for example:
Complaint T4-2012-10 for “low TT4 (assay result) in the last 5-6 dogs on this strength,” received August 20, 2012 and still open at the time of the inspection
Your response dated June 17, 2013 states your firm revised your complaint handling process to include your contract formulator in your firm’s process to investigate and close out complaints. Please ensure that the complaint investigation process includes 1) a root cause determination and a corrective action plan and, 2) the findings of the investigation and follow up. Your June 17, 2013 response also states that you have been initiating action to close your open complaints. Also, you state that eight veterinary drug product consumer complaints are currently open and will be investigated and closed in 30 days. However, we are concerned about the length of time your firm required to properly handle complaints, especially complaints that may be attributed to thyroid related issues. You have been aware of our concerns regarding inadequate complaint handling at your firm since year 2000.
6. Failure to perform a thorough investigation and make a record of the conclusions and follow-up of an unexplained discrepancy [21 CFR § 211.192]. For example, your firm failed to properly investigate 9 lots of canine PID Levothyroxine tablets recalled (6 lots since last FDA inspection); 13 reports of manufacturing (blend) OOS reports (9 since 2011); and an FDA 3-day Field Alert stability failure.
Finding of “leak test failure on a bottle” for components used to manufacture Thyro-Tabs 0.8 mg Lot VKB34212 on December 14, 2012. Exception Report ER-018-2012 was opened on December 14, 2012, and remained open during the inspection.
Finding of “leak test failure on a bottle” for components used to manufacture Thyro-Tabs 0.4 mg Lot KA00813 on January 25, 2013. Exception Report ER-010-2013 was opened January 25, 2013, and remained open during the inspection.
Thyro-Tabs 0.8 mg Lot VKA34212 had an OOS of (b)(4)% of USP Label Claim at the 3 month stability interval. A 3-day Field Alert was subsequently issued on April 15, 2013 for this canine Levothryoxin PIJ drug product.
Your May 7 and June 17, 2013 responses outline new and revised procedures for investigations and corrective and preventive actions and indicate you have been initiating action to close your open investigations. You indicate you would complete open investigations including determination of root cause and implementation of corrective action in July, 2013. Please indicate whether your review of these open investigations revealed process related deficiencies (i.e., findings from leak test failures). In addition, please include information on the follow up regarding your recalled lots, OOS reports and FDA field alerts. Timely assessment of quality indicators, such as out-of-specification findings and complaints, is essential to detecting and determining the scope of product or process deficiencies. You have been aware of our concerns regarding inadequate investigations at your firm since 1999.
7. Failure to follow written procedures to evaluate, at least annually, the quality standards of each drug product to determine the need for changes in drug product specifications or manufacturing or control procedures [21 CFR § 211.180(e)].
For example, despite the requirements in SOP 13-059, your QCU has not completed annual product reviews (APRs) that include a review of approved and rejected batch records, complaints, recalls, returns, and investigations conducted on any of the animal drug products manufactured in 2012. Specifically, you failed to document completion of APRs for:
PIJ formulation, all strengths, for the year 2012.
PID formulation animal levothyroxine products, all strengths, for the year 2012.
Prednisolone animal products, 5mg and 20mg strengths, for the year 2012.
In your May 7, 2013 response you indicate that you have committed to a schedule for conducting annual product reviews. We will confirm that you are implementing this schedule and adequately conducting APRs at the next inspection. You have been aware of our concerns regarding annual product reviews since 2004.
Over the past 10 years, FDA’s inspections of your firm have continued to find repeated deficiencies in your quality system. These observations suggest that your firm has failed to implement adequate global and sustainable corrective actions, and that you continue to manufacture and distribute pharmaceutical product without upholding your legal obligation to comply with CGMP. We highly recommend that appropriate resources be used to conduct a thorough retrospective evaluation of past deficiencies and that appropriate permanent changes be implemented to ensure that your firm manufactures pharmaceutical products using a sustainable quality platform. Fundamental to this responsibility is your assurance of investigation and resolution of the issues, prevention of distribution of defective product, and implementation of an effective quality management system across all facets of your pharmaceutical manufacturing operations.
This letter is not intended as an all-inclusive list of violations at your facility. It is your responsibility to ensure that your facility and all products manufactured or distributed by your firm are in compliance with the Act and its implementing regulations. The specific violations noted in this letter and in the Form FDA 483, List of Observations, issued at the end of this inspection may be symptomatic of serious problems in your firm’s quality assurance and laboratory systems.
You should investigate and determine the causes of the violations, and take prompt action to correct the violations and bring your products into compliance. Failure to promptly correct these violations may result in enforcement action being initiated by the Food and Drug Administration without further notice. These actions include, but are not limited to, seizure and/or injunction. The Federal Food, Drug, and Cosmetic Act provides for the seizure of illegal products (Section 304) and for injunction against the manufacturers and distributors of illegal products (Section 302) [21 U.S.C. §§ 334 and 332].
Please respond in writing within fifteen (15) working days of the receipt of this letter, as to the specific additional steps you will take, or have taken, to correct the violations identified in this letter and any other violations of the Act, and to assure that similar violations do not occur. Your response should include an explanation of each step being taken to achieve and maintain compliance with the regulations. Include copies of any available documentation demonstrating that corrections have been made. If your planned corrections will occur over time, please include a timetable for implementation of those corrections. If corrective action cannot be completed within fifteen (15) working days, state the reason for the delay and the timeframe within which the corrections will be completed.
Your reply to this Warning Letter should be sent to Amy E. Devine, Compliance Officer, Food and Drug Administration, Kansas City District, 8050 Marshall Drive, Suite 205, Lenexa, KS 66214-1524. If you have any questions about the contents of this letter, please contact Ms. Devine at 913-495-5147.
Page Last Updated: 09/23/2013