Berkeley Nutritional Mfg Corp. 1/31/17

2017 > Berkeley Nutritional Mfg Corp. 1/31/17

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San Francisco District 1431 Harbor Bay Parkway Alameda, CA 94502-7070

WARNING LETTER

January 31, 2017

Via UPS

Overnight Delivery Return Receipt Requested

Mr. Robert W. Matheson, President/CEO Berkeley Nutritional Manufacturing Corporation dba Protein Research 1852 Rutan Drive Livermore, CA 94551-7635 FEI: 2937236

Dear Mr. Matheson:

The U.S. Food and Drug Administration (FDA) conducted an inspection of your dietary supplement manufacturing facility, located at 1852 Rutan Drive, Livermore, CA http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2017/ucm539265.htm[2/7/2017 3:47:08 PM] 2017 > Berkeley Nutritional Mfg Corp. 1/31/17

94551-7635 from February 18, 2016 through March 4, 2016. We found serious violations of the Current Good Manufacturing Practice (CGMP) regulations for Manufacturing, Packaging, Labeling, or Holding Operations for Dietary Supplements, Title 21, Code of Federal Regulations (CFR), Part 111 (21 CFR Part 111). These violations cause your dietary supplement products identified below to be adulterated within the meaning of section 402(g)(1) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. § 342(g)(1)] in that the dietary supplements have been prepared, packed, or held under conditions that do not meet CGMP requirements for dietary supplements.

Additionally, we reviewed the labeling of dietary supplement products collected during the inspection of your facility. Based on our review, we found serious violations of sections 402(f) and 413(a) of the Act [21 U.S.C. § 342(f) and 350b(a)]], section 403 of the Act [21 U.S.C. § 343], sections 505(a) and 502(f)(1) of the Act [21 U.S.C §§ 355(a), and 352(f)(1)]. You can find the Act and FDA regulations through links on the FDA’s home page at http://www.fda.gov.

Unapproved New Drug Violations

This is to advise you that the Food and Drug Administration (FDA) reviewed the product labels for the Irvingia IGOB-131 + Cissus CQR-300 Weight Management Formula and Magnesium Malate products. The claims on the product labels establish that the products are drugs under section 201(g)(1)(B) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. 321(g)(1)(B)] because they are intended for use in the cure, mitigation, treatment, or prevention of disease. As explained further below, introducing or delivering these products for introduction into interstate commerce for such uses violates the Act.

Examples of some of the claims on the product labels that provide evidence that the products are intended for use as drugs include:

Irvingia IGOB-131 + Cissus CQR-300 Weight Management Formula

• “[M]anagement of obesity” • “[I]mprovements in…LDL cholesterol”

Magnesium Malate

• “[C]hronic muscle soreness”

The Irvingia IGOB-131 + Cissus CQR-300 Weight Management Formula and Magnesium Malate products are not generally recognized as safe and effective for the above referenced uses and, therefore, the products are “new drugs” under section 201(p) of the Act [21 U.S.C. 321(p)]. New drugs may not be legally introduced or

http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2017/ucm539265.htm[2/7/2017 3:47:08 PM] 2017 > Berkeley Nutritional Mfg Corp. 1/31/17

delivered for introduction into interstate commerce without prior approval from FDA, as described in sections 301(d) and 505(a) of the Act [21 U.S.C. 331(d), 355(a)]. FDA approves a new drug on the basis of scientific data and information demonstrating that the drug is safe and effective.

A drug is misbranded under section 502(f)(1) of the Act [21 U.S.C. 352(f)(1)] if the drug fails to bear adequate directions for its intended use(s). “Adequate directions for use” means directions under which a layperson can use a drug safely and for the purposes for which it is intended (21 CFR 201.5). Prescription drugs, as defined in section 503(b)(1)(A) of the Act [21 U.S.C. 353(b)(1)(A)], can only be used safely at the direction, and under the supervision, of a licensed practitioner.

The product Irvingia IGOB-131 + Cissus CQR-300 Weight Management Formula is intended for treatment of one or more diseases that are not amenable to self- diagnosis or treatment without the supervision of a licensed practitioner. Therefore, it is impossible to write adequate directions for a layperson to use your product safely for its intended purposes. Accordingly, Irvingia IGOB-131 +Cissus CQR-300 Weight Management Formula product fails to bear adequate directions for its intended use and, therefore, the product is misbranded under section 502(f)(1) of the Act [21 U.S.C. 352(f)(1)]. The introduction or delivery for introduction into interstate commerce of this misbranded drug violates section 301(a) of the Act [21 U.S.C. 331(a)].

Dietary Supplement CGMP Violations

The inspection revealed the following significant violations of the CGMP requirements for dietary supplements. These violations cause your dietary supplement products to be adulterated under section 402(g)(l) of the Act [21 U.S.C. § 342(g)(l)] in that they have been prepared, packed, or held under conditions which do not meet the CGMP regulations for dietary supplements.

We acknowledge the receipt and have reviewed your Form FDA 483 written response letter submitted on March 22, 2016. The written responses for the violations cited on the Form FDA 483 issued on March 4, 2016 appear to be inadequate. We are concerned of your failure to establish and implement effective corrective actions.

1. Your firm failed to establish specifications for any point, step, or stage in the manufacturing process where control is necessary to ensure the quality of the dietary supplement, as required by 21 CFR 111.70:

a) You failed to establish an identity specification for each component used in the manufacture of a dietary supplement as required by 21 CFR 111.70(b)(1). Specifically, you did not establish identity specifications for the Biotin DCP Trit Powder and Dicalcium Phosphate Dihydrate components you use in the manufacture of the Super B with Mood Supporting Vitamins dietary supplement

http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2017/ucm539265.htm[2/7/2017 3:47:08 PM] 2017 > Berkeley Nutritional Mfg Corp. 1/31/17

product.

b) You failed to establish component specifications that are necessary to ensure that the specifications for purity, strength, and composition of dietary supplements manufactured using the components are met, as required by 21 CFR 111.70(b)(2). Specifically, you have not established specifications for the Biotin DCP Trit Powder and Dicalcium Phosphate Dihydrate components that ensure the Super B with Mood Supporting Vitamins dietary supplement product meets the final product specifications.

Once you have established component specifications and before using a component, you must conduct at least one appropriate test or examination to verify the identity of the dietary ingredient prior to its use, as required by 21 CFR .75(a)(1)(i), unless you petition the agency for an exemption under 21 CFR 111.75(a)(1)(ii) and the agency exempts you from such testing, and you must confirm the identity of other components and determine whether other applicable component specifications established in accordance with 21 CFR 111.70(b) are met , as required by 21 CFR 111.75(a)(2). A Certificate of Analysis may not be used in lieu of an identity test. You must also ensure that the tests and examinations that you use to determine whether the specifications are met are appropriate, scientifically valid methods, as required by 21 CFR 111.75(h)(1), and you must make and keep records of the specifications established, as required by 21 CFR 111.95(b)(1).

We have reviewed your response letter, dated March 22, 2016, and determined your response to be inadequate. Your response letter provided component specifications regarding identity, purity, strength, and composition for only some components used to manufacture the Super B with Mood Supporting Vitamins dietary supplement product. Your response did not include component specifications for the Biotin DCP Trit Powder and Dicalcium Phosphate Dihydrate.

Dietary Supplement Labeling Violations

The Green Superfood Cacao Chocolate Infusion dietary supplement product is misbranded under section 403 of the Act [21 U.S.C. §343] because the product does not comply with the labeling requirements for dietary supplements. The inspection revealed the following violations of labeling requirements for dietary supplements:

1. The Green Superfood Cacao Chocolate Infusion product is misbranded within the meaning of section 403(s)(2)(B) of the Act, 21 U.S.C. § 343(s)(2)(B) because the product label fails to identify the product using the term ”dietary supplement” in accordance with 21 CFR 101.3(g), which requires that a dietary supplement be identified by the term “dietary supplement” as part of the product’s statement of

http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2017/ucm539265.htm[2/7/2017 3:47:08 PM] 2017 > Berkeley Nutritional Mfg Corp. 1/31/17

identity, except the word “dietary” may be deleted and replaced by the name of the dietary ingredient in the product or an appropriately descriptive term.

2. The Green Superfood Cacao Chocolate Infusion product is misbranded within the meaning of section 403(s)(2)(C) of the Act [21 U.S.C. § 343(s)(2)(C)] )] because the label fails to identify the part of the plant (e.g., root, leaves) from which each botanical dietary ingredient in the product is derived, as required by 21 CFR 101.4(h)(1).

3. The Green Superfood Cacao Chocolate Infusion product is misbranded within the meaning of section 403(g)(1) of the Act [21 U.S.C. 343(g)(1)] because the product does not conform to the definition and standard for chocolate as noted in 21 CFR 163.110 (Requirements for Standardized Cacao Products). Your product label indicates the term “chocolate” in the product name as well as in the nutrition information with the listing of “chocolate blend”. We note the word “chocolate” in the phrase Cacao Chocolate Infusion is in a print size that is significantly larger than the phrase in which it appears, so as to give prominence to the word “chocolate.” We do note the listing of “natural chocolate flavoring” in the nutrition information. However, the product label listing of “chocolate blend” and “chocolate” appears to imply the product contains chocolate. The terms "chocolate flavored" or "natural chocolate flavored" rather than the term “chocolate” or “chocolate blend” must be used on the labeling of any nonstandardized food in which the consumer could reasonably expect a chocolate ingredient but which contains cocoa as the sole source of chocolate flavoring.

The above violations are not intended to be an all-inclusive list of violations at your facility or that exist in connection with your products or their labeling. You are responsible for investigating and determining the causes of the violations identified above and for preventing their recurrence or the occurrence of other violations. It is your responsibility to ensure that all the products you manufacture or distribute meet all of the requirements of the Act and its implementing regulations. You should take prompt action to correct the violations cited in this letter. Failure to promptly correct these violations may result in legal action without further notice, such as seizure and/or injunction.

Please be advised a description of the new drug approval process can be found on FDA's internet website at http://www.fda.gov/cder/regulatory/applications/default.htm. Any questions you may have regarding this process should be directed to the Food and Drug Administration, Division of Drug Information (HFD-240), Center for Drug Evaluation and Research, 5600 Fishers Lane, Rockville, Maryland 20857.

In addition to the above violations, we have the following comments:

The presentation of nutrition information in the supplement facts label for the Green

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Superfood Cacao Chocolate Infusion product is not in accordance with 21 CFR 101.9 and 101.36. For example:

• The headings of “Calories”, “Total Carbohydrate” and “Protein” should not be indented

• “Dietary Fiber” should be indented under “Total Carbohydrate”

Please respond to this letter in writing within fifteen (15) working days from your receipt of this letter. Your response should outline the specific steps you are taking to correct the violations listed above and to prevent similar violations in the future. Your response should include any documentation necessary that would assist us in evaluating your corrections. If you cannot complete all corrections before you respond, you should explain the reason for your delay and state when you will correct any remaining violations.

Section 743 of the Act [21 U.S.C. 379j-31] authorizes FDA to assess and collect fees to cover FDA’s costs for certain activities, including reinspection-related costs. A reinspection is one or more inspections conducted subsequent to an inspection that identified noncompliance materially related to a food safety requirement of the Act, specifically to determine whether compliance has been achieved. Reinspection- related costs means all expenses, including administrative expenses, incurred in connection with FDA’s arranging, conducting, and evaluating the results of the reinspection and assessing and collecting the reinspection fees [21 U.S.C. 379j-31(a) (2)(B)]. For a domestic facility, FDA will assess and collect fees for reinspection- related costs from the responsible party for the domestic facility. The inspection noted in this letter identified noncompliance materially related to a food safety requirement of the Act. Accordingly, FDA may assess fees to cover any reinspection-related costs.

Your written response should be sent to Lawton W. Lum, Director of Compliance at the address noted above and reference unique identifier 500324. If you have any questions concerning this letter, please contact Compliance Officer Lance De Souza at (510) 337-6873.

Sincerely, /S/ Darla R. Bracy Acting District Director San Francisco District

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Hospira Inc 2/14/17

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Kansas City District Office 8050 Marshall Drive - Suite 205

Lenexa, Kansas 66214-1524 913-495-5100

February 14, 2017

WARNING LETTER

Ref: CMS Case: 506761 DELIVERY VIA UPS

Mr. Ian C. Reed Chairman and CEO Pfizer Inc. 235 East 42nd St. New York, NY 10017

Dear Mr. Reed:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Hospira Inc., a Pfizer Company at 1776 Centennial Drive, McPherson, Kansas, from May 16 to June 8, 2016.

This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See 21 CFR, parts 210 and 211. https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2017/ucm542587.htm[2/28/2017 3:49:11 PM] 2017 > Hospira Inc 2/14/17

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 June 29, 2016, 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.

1. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).

During our inspection, we reviewed reports from multiple investigations that you conducted into complaints regarding the presence of visible particulates in several of your sterile injectable products. The presence of visible particulates in sterile injectable products is an indication of a significant loss of control in your manufacturing process and represents a severe risk of harm to patients. We documented that your investigations into these product quality defects were inadequate and failed to spur appropriate corrective actions and preventive actions.

Vancomycin Hydrochloride for Injection For example, on December 31, 2015, you received a complaint of particulate matter in a vial of vancomycin hydrochloride for injection, lot 565003A. After examining the vial and your retain samples, on January 11, 2016, you determined that the contaminant was cardboard. You concluded that the most probable source of contamination was related to the handling of your vial stoppers. However, on February 8, 2016, you closed the investigation without a comprehensive evaluation of the extent of the contamination and without taking further corrective actions.

On February 24 and April 15, 2016, you received additional complaints of particulate matter, also confirmed to be cardboard, in other vials of the same lot without taking any further action.

The presence of multiple foreign particulates in your products is unacceptable. Extrinsic contaminants, such as cardboard, pose a significant risk to patients and

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indicate that your process for manufacturing sterile injectable products is out of control.

Although you recalled lot 565003A on May 6, 2016, you did not do so until more than four months after receiving the initial product complaint and determining that products in the lot had been contaminated with cardboard. Moreover, you received additional complaints about the same problem in the intervening time period but failed to take further action.

Ketorolac Tromethamine Injection On September 16, 2015, you received a complaint about particulate matter in an unspecified number of vials of ketorolac tromethamine injection, 30 mg/mL, lot 46205DD. You confirmed the presence of particulate matter in the returned product complaint samples and then found that 190 out of (b)(4) your retention samples from this lot also contained visible particulates.

Your investigation into this matter was inadequate. For example, your investigation report indicates that “[t]en representative [retention] samples were sent to the Particle Lab for further evaluation.” Your report does not provide a scientific rationale for selecting only (b)(4) vials for testing, nor does it explain the nature and purpose of the testing and examination you conducted as part of the investigation. Furthermore, although your investigation indicates that you found brown agglomerates during production of lot 46205DD, you concluded that this was “most likely . . . caused by the (b)(4) during the mixing process based on a previous assessment.” Although your investigation indicates that the particles are similar to particles found in other lots of the same product, you failed to determine the specific identity and source of the particles in lot 46205DD. You released lot 46205DD because “the presence of (b)(4) was found to be intrinsic to the manufacturing process.” However, you did not determine whether the same problem may have affected other lots, nor did you document any corrective actions taken in response to the deviation.

You did not conduct a comprehensive assessment of the particulate matter observed in the distributed vials and retention samples, including its specific identity and whether other lots were affected. You failed to provide either a scientific rationale for the conclusions you reached in your investigations or information on the methodologies used during your testing.

In response to this letter, provide:

your rationale for not conducting chemical analysis of the particulates observed in ketorolac tromethamine injection, 30 mg/mL, lot 46205DD, and implementing appropriate actions to prevent recurrence of this event; updates on your root cause analysis of the particle contamination events and your corrective action and preventive action (CAPA) plan;

https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2017/ucm542587.htm[2/28/2017 3:49:11 PM] 2017 > Hospira Inc 2/14/17

an evaluation of the nature and extent of particulates present in retain samples for all distributed lots of your sterile drug products that remain within expiry and for which you have received one or more complaints of particulate matter; an evaluation of any lots that were found to contain intrinsic or extrinsic particulate matter during manufacturing but were subsequently released; and the corrective actions you propose to initiate against compromised products that remain on the market. 2. Your firm failed to establish valid in-process specifications (21 CFR 211.110(b)).

You routinely manufacture sterile injectable products without defect (alert or action) limits for both semi-automated and fully-automated in-process visual inspections. For example, your visual inspection procedures instruct operators to ignore or discount established in-process defect limits whenever you make a change to your manufacturing process, including changes to your visual inspection program. Our investigator noted many complaints related to particulate matter in sterile injectable products manufactured at your facility, indicating that the lack of defect limits for visual inspections may have resulted in the release of products that otherwise would not have been distributed.

In response to this observation, you committed to:

performing a retrospective review of released batches by comparing the observed in- process visual inspection reject data against previously established historical limits; applying historical in-process visual inspection rejection limits to currently manufactured batches until you can establish and implement revised limits; and revising in-process visual inspection procedures to clarify the requirements for when new in-process visual inspection reject limits will be established in response to changes to the manufacturing process including changes to materials used in the manufacturing process. Your response is inadequate because you did not indicate whether these changes apply to both products manufactured under your label and products you manufacture under contract for your customers.

3. Your firm failed to follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes (21 CFR 211.113(b)).

During the inspection, our investigators observed multiple examples of practices that represent significant risks to the sterility of your finished products.

https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2017/ucm542587.htm[2/28/2017 3:49:11 PM] 2017 > Hospira Inc 2/14/17

Poor Aseptic Technique During the inspection, our investigator observed operators manufacturing hydromorphone lot 651903A. The investigator observed the introduction of a bottle of sterile water with a shrink- wrapped plastic tamper-resistant seal into the (b)(4) isolator material transfer chamber. Inserting bottles with intact tamper seals into the chamber is specifically prohibited by your firm’s (b)(4) isolator SOP MF0732.00. The isolator uses (b)(4) to sterilize objects placed inside the chamber, but the (b)(4) cannot penetrate plastic seals. If a water bottle is inserted into the chamber with an intact seal, only the exposed surfaces of the bottle would be rendered sterile. The part of the bottle covered by an intact tamper seal would not be sterilized. Removal of the seal could compromise the sterility of the surrounding aseptic manufacturing environment.

Our inspection documented that at least two, and possibly four, of your operators observed the presence of this sealed bottle in the chamber, despite the explicit prohibition in the SOP. Our investigator identified this issue during production, and you were unable to explain why your operators did not recognize this problem.

In response to this letter, provide an assessment of how this poor aseptic practice may have affected the quality of your products.

Poor Personnel Monitoring Technique Our investigators observed personnel in aseptic manufacturing areas using (b)(4) to sanitize their hands immediately before they touched personnel contact plates. Sanitizing hands immediately before conducting personnel monitoring significantly reduces the likelihood of detecting microbiological contamination in the aseptic manufacturing environment. Indeed, your own training procedures note that employees should not use (b)(4) immediately before performing personnel monitoring.

In your response, you committed to observing operators during personnel monitoring, revising your aseptic processing training, and conducting additional aseptic processing training for personnel who work in aseptic processing areas. Your response is inadequate because you only reviewed the microbiological environmental monitoring data for two lots of product: Nimbex NX20 lot 65105DD filled on line (b)(4) and vancomycin M-6535 lot 65090DD, filled on line (b)(4) You did not evaluate environmental data from other lots that may have been affected by similar poor sampling techniques.

In response to this letter, provide a summary and assessment of personnel monitoring and environmental data for other lots aseptically filled on lines (b)(4) and (b)(4). Also indicate the changes you will make to your environmental monitoring program procedures to ensure that samples taken accurately reflect the level of environmental control present during manufacturing.

https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2017/ucm542587.htm[2/28/2017 3:49:11 PM] 2017 > Hospira Inc 2/14/17

4. Your firm failed to control rejected in-process materials under a quarantine system, to prevent their use in manufacturing or processing operations for which they are unsuitable (21 CFR 211.110(d)).

Your procedure MF0502.00 (b)(4) Inspection Machines for the online semi-automated visual inspection of vials allows (b)(4) to reinspect rejected units and place them with acceptable units. This procedure does not require operators to quarantine initially rejected units for later reinspection, account for the number of units that are subjected to reinspection, or document the difference between the initial inspection results and reinspection results. Accordingly, the procedure is inadequate to ensure that potentially defective or otherwise unsuitable (b)(4) units are not reintroduced into the manufacturing process.

In your response, you propose to rewrite procedure MF0502.00 to create an indeterminate status after detecting “anomalous” units (b)(4) semi-automated visual inspection process. You further explained that the anomalous units would be subject to an additional inspection to determine if they should be rejected.

Your response is inadequate because you have not provided a justification for retaining units that fail your firm’s visual inspection requirements.

5. Your firm failed to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity (21 CFR 211.160(b)).

You lack scientifically sound and appropriate sampling plans for inspection and analytical activities conducted at your facility. For example, you do not inspect all reserve samples from each lot selected for the yearly visual examination to identify any evidence of drug product deterioration. There is no scientific justification for the number of reserve samples you select for examination. You also lack appropriate statistical sampling plans for the inspection of (b)(4) paper label rolls as described in your Monograph Y-011-AM. Statistically appropriate sampling plans provide assurance that the samples you select for inspection or analysis are representative of the lot or batch from which they are drawn.

In response to this letter, provide your detailed assessment and justification for each statistical sampling plan used for materials, processes, and products at your facility.

Post-Market Reporting Violations

https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2017/ucm542587.htm[2/28/2017 3:49:11 PM] 2017 > Hospira Inc 2/14/17

The inspection also revealed that Hospira Inc. failed to submit field alert reports to FDA as required by section 505(k) of the FD&C Act, 21 U.S.C. 355(k), 21 CFR 314.81(b)(1) (new drug applications), and 21 CFR 314.98 (abbreviated new drug applications). For example, you failed to submit a field alert report after discovering extensive label deterioration. You received numerous complaints indicating label adhesion and deterioration defects, and performed retention sample evaluations between April 20, 2015, and June 25, 2015 in connection with such complaints. For example, your investigation of azithromycin ADD-Vantage, lot 49335DD, determined that 148 out of (b)(4) retain samples had varying degrees of adhesion defects. Further, your investigation showed at least 8 different lots of different products had significant label deterioration. Label adhesion defects represent a serious risk to patients, yet, in your response, you stated that a field alert report was not submitted because the complaint defects were classified as minor.

Repeat Violations at Multiple Sites

FDA cited similar CGMP violations at other facilities in your company’s network.

1. Hospira Healthcare India Pvt., Ltd. FEI 3008386908: Warning Letter 320-13-18 was issued May 28, 2013. Charges included failure to follow appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile. 2. Hospira, Inc., FEI 1021343 and FEI 1048698: Warning Letter 10-ATL-12 wasissued for two U.S. facilities on April 12, 2010. Charges included failure to have adequate written procedures for production and process controls designed to assure that drug products have the identity, strength, quality, and purity they purport or are represented to possess. 3. Hospira Australia Pty, Limited, FEI 3001174929: Warning Letter 320-14-15 was issued on September 26, 2014. Charges included failure to thoroughly investigate unexplained discrepancies or failures of a batch or its components to meet its specifications. 4. Hospira S.p.A., FEI 3004640070: Warning Letter 320-15-08 wasissued for your Italy facility on March 31, 2015. Charges included failure to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile.

These repeated failures at multiple sites demonstrate that your company’s oversight and control over the manufacture of drugs is inadequate.

Your executive management remains responsible for fully resolving all deficiencies and ensuring ongoing CGMP compliance. You should immediately and comprehensively assess your company’s global manufacturing operations to ensure that systems and processes, and ultimately, the products manufactured, conform to FDA requirements.

https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2017/ucm542587.htm[2/28/2017 3:49:11 PM] 2017 > Hospira Inc 2/14/17

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 in all your facilities.

If you are considering an action that is likely to lead to a disruption in the supply of drugs produced at your facility, FDA requests that you contact CDER’s Drug Shortages Staff immediately, at [email protected], so that FDA can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Staff also allows you to meet any obligations you may have to report discontinuances or interruptions in your drug manufacture under 21 U.S.C. 356C(b) and allows FDA to consider, as soon as possible, what actions, if any, may be needed to avoid shortages and protect the health of patients who depend on your products.

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.

Send your electronic reply to [email protected] or mail your reply to:

Miguel Hernandez Compliance Branch Director U.S. Food and Drug Administration Kansas City District Office 8050 Marshall Drive, Suite 205 Lenexa, Kansas 66214

Please identify your response with FEI 1925262.

Sincerely,

https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2017/ucm542587.htm[2/28/2017 3:49:11 PM] 2017 > Hospira Inc 2/14/17

/S/ Cheryl A. Bigham District Director Kansas City District Office of Regulatory Affairs

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https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2017/ucm542587.htm[2/28/2017 3:49:11 PM] 2017 > Humco Holding Group, Inc 1/26/17

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Home  Inspections, Compliance, Enforcement, and Criminal Investigations  Compliance Actions and Activities  Warning Letters  2017

Humco Holding Group, Inc 1/26/17

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Dallas District Office 4040 N. Central Expressway,

Suite 300 Dallas, Texas 75204

January 26, 2017

2017-DAL-WL-09

Warning Letter

UPS OVERNIGHT MAIL

Gregory C. Pulido, Chairman and CEO Humco Holding Group, Inc. 7400 Alumax Rd. Texarkana, Texas 75501-0282

Dear Mr. Pulido:

During our June 25, 2015 to July 1, 2015 inspection of your pharmaceutical manufacturing facility, Humco Holding Group, Inc., located in Texarkana, Texas, investigators from the Food and Drug Administration (FDA) identified significant https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2017/ucm541308.htm[2/21/2017 11:31:04 AM] 2017 > Humco Holding Group, Inc 1/26/17

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 or Act), 21 U.S.C. 351(a)(2) (B).

The inspection also revealed that your firm manufactures and distributes unapproved new drugs in violation of section 505(a) of the Act [21 U.S.C. § 355(a)]. Additionally, FDA has determined that some of the drugs that you manufacture are also misbranded in violation of sections 502 and 503 of the Act [21 U.S.C. §§ 352 and 353].

Unapproved New Drug Violations

Based on the information collected during the recent inspection, you manufacture and/or distribute an unapproved new drug in violation of sections 301(d) [21 U.S.C. §§ 331(d)], and 505(a) of the Act [21 U.S.C. § 355(a)].

The following unapproved new drugs were identified on inspection include:

Humco Cherry Flavored Potassium Chloride Oral Solution 10% (NDC 0395-2300) Shohl’s Solution (Modified), Sodium Citrate and Citric Acid Oral Solution (NDC 0802-3962) The above product are drugs within the meaning of section 201(g)(1) of the Act [21 U.S.C. § 321(g)(1)], because they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in humans and intended to affect the structure or any function of the body of man or other animals. Further, as labeled, these drugs are “new drugs” within the meaning of section 201(p) of the Act [21 U.S.C. § 321(p)] because they are not generally recognized, among experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, as safe and effective for use under the conditions prescribed, recommended, or suggested in their labeling.

Under sections 301(d) and 505(a) of the Act, a new drug may not be introduced or delivered for introduction into interstate commerce unless an application approved by FDA under either section 505(b) or (j) of the Act [21 U.S.C. § 355(b) or (j)] is in effect for the drug. There are no FDA-approved applications on file for the drugs listed above. The marketing of these drugs, or other new drugs, without an approved application constitutes a violation of the Act.

Misbranded Drugs Under the FD&C Act

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A. Prescription Drug Products

1. Section 502(f)(1)

Your Humco Cherry Flavored Potassium Chloride Oral Solution 10% and Humco Shohl’s Solution are misbranded under section 502(f)(1) of the Act [21 U.S.C. § 352(f)(1)].

The Humco Cherry Flavored Potassium Chloride Oral Solution 10% and Humco Shohl’s Solution are “prescription drugs” as defined in section 503(b)(1)(A) of the Act [21 U.S.C. § 353(b)(1)(A)], because, in light of their toxicity or potential for harmful effects, the method of their use, or the collateral measures necessary for their use, they are not safe for use except under the supervision of a practitioner licensed by law to administer them.

Because these drugs are not safe for use except under the supervision of a practitioner licensed by law to administer them, adequate directions cannot be written so that a layman can use them safely for their intended uses. Consequently, the labeling of your firm’s unapproved prescription drug product fails to bear adequate directions for their intended uses, causing it to be misbranded under section 502(f)(1) of the Act.

Because your product lacks the required approved applications, they are not exempt under 21 CFR 201.115 from the requirements of section 502(f)(1) of the Act. The introduction or delivery for introduction into interstate commerce of these misbranded products therefore violates section 301(a) of the Act [21 U.S.C. § 331(a)].

2. Section 503(b)(4)(A)

Humco Cherry Flavored Potassium Chloride Oral Solution 10%, Humco Shohl’s Solution, and Humco Strong Iodine Solution (Lugol’s Solution) (NDC 0395-2775) are prescription drugs, and therefore they are required to bear the symbol “Rx only.” These three prescription products are misbranded because the products’ labels fail to include the “Rx only” symbol that is required under section 503(b)(4)(A) of the Act [21 U.S.C. § 353(b)(4)(A)]). The introduction or delivery for introduction into interstate commerce of these drugs violates section 301(a) of the Act.

3. Section 502(a)

The label collected during the inspection for your Humco’s Cherry Flavored Potassium Chloride 10% Oral Solution claims that the product is to be used as “As a flavoring agent and a potassium source in compounding.” This label is false or misleading, causing the product to be misbranded under section 502(a) of the Act [21 U.S.C. § 352(a)]. While we note that the 16 fluid ounces presentation for this product is no

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longer listed with FDA, your firm’s response to the FDA 483 stated that your firm plans to continue to market this product in a gallon container.

The 16 fluid ounce product was labeled as both a flavoring agent for compounding and as a source of potassium, an active ingredient. Labeling this product either in the 16 fluid ounce or gallon container as both an excipient and as an active ingredient is confusing and may result in the inadvertent delivery of therapeutic doses of potassium chloride when the product is used to flavor a drug. Your firm also markets a Cherry Syrup product (NDC 0395-2662) which is labeled as a “Pharmacy Compounding Syrup Vehicle” and is used in compounding as a flavoring agent, raising the likelihood that these two products could be mistaken for one another. As a result, the label for the Humco’s Flavored Potassium Chloride 10% Oral Solution’s 16 fluid ounces is false or misleading, causing the product to be misbranded under section 502(a) of the Act [21 U.S.C. § 352(a)]. The introduction or delivery for introduction into interstate commerce of this drug therefore violates section 301(a) of the Act [21 U.S.C. § 331(a)] .

We further note that Humco’s Lugol’s Solution label contains a directions section which uses an apothecary measurement no longer recommended for use by FDA. The directions section states that the “Dosage: Usual Dose; 4-1/2 minims 3 times a day,” this section also states “Usual Dose Range: 1-1/2 to 15 minims daily.” In FDA’s Draft Guidance for Industry entitled: “Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors” dated April, 2013,[1]the Agency outlines several important recommendations to firms to help avoid medication errors through product labeling. Specifically, with regard to product strength, the guidance recommends expressing dose in metric units of measure, such as mL, mg and mcg rather than apothecary measurements to avoid miscalculation of medication doses when converting from one unit of measure to another. Minims is a form of measurement no longer in common use and should be updated to reflect a metric unit of measurement to avoid potential errors and safety concerns.

4. Section 502(o)

Section 510 of the Act and 21 CFR 207, subject to certain limited exceptions, require establishment owners and operators (registrants) upon first engaging in the manufacture, preparation, propagation, compounding, or processing of drugs to register their establishments and submit listing information for all drugs in commercial distribution. Any drugs not included in the initial registration must be included with subsequent listing updates, either in June or December; whichever first occurs after the product has initially been marketed. In addition, any changes to a previously listed drug (including labeling) must be reported to the agency in June or December of the same year.

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Although in commercial distribution, listing obligations under section 510(j) of the Act were not satisfied for Humco Shohl’s Solution (NDC 0802-3962), which is a prohibited act under section 301(p) of the Act [21 U.S.C. 360(j) and 331(p)]. An incomplete drug listing paper form 2657 was submitted to FDA in 1992 but the deficiency in the data was not addressed. Your firm’s failure to fulfill its listing obligations misbrands the product under section 502(o) of the Act [21 U.S.C. 352(o)], introduction or delivery for introduction into interstate commerce of a misbranded product is a prohibited act under section 301(a) of the Act [21 U.S.C. 331(a)].

B. Humco’s “(b)(4)” Over-the-Counter Drug Product

(b)(4), is a drug within the meaning of section 201(g)(1) of the Act [21 U.S.C. § 321(g) (1)], because it is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in humans and intended to affect the structure or any function of the body of man or other animals.

For the reasons described below, “(b)(4)” is misbranded under sections 502(a) and 502(j) of the Act [21 U.S.C. §§ 352(a) and 352(j)] because it is false or misleading and also because it is a danger to health when used in the dosage or manner prescribed, recommended, or suggested in the labeling.

The principal display panel (PDP) for this drug bears an image of a baby (b)(4), however, the directions for use in populations younger than 12 years old direct consumers to “ask a doctor.” Using the image of “(b)(4)” on the labeling renders the drug product false or misleading because it suggests that this product may be used in infants.

While there is language on the labeling indicating that children or teenagers recovering from chickenpox or other ailments should not take (b)(4), the precaution is not sufficient to prevent administration to infants given its potentially deadly complications. (b)(4), a (b)(4) infant developed salicylate toxicity requiring hospitalization in the pediatric intensive care unit (PICU) as a result of continued [2] administration of (b)(4). The parents reported that they had chosen (b)(4) based on the picture of a baby on the front of the package.

Carton labels and product names should communicate information that is critical to the safe use of the medicine. For example, an image of a child on the PDP should be representative of the age group identified under “Directions” in the Drug Facts label (e.g., a product labeled for use in children twelve years of age or older should not show a picture of an infant on the PDP). The product logo, “(b)(4),” and the photograph depicting a baby, impede the safe use of “(b)(4).” For these reasons, this product is also misbranded under section 502(j) of the Act [21 U.S.C. § 352(j)] because it is dangerous to health when used in the dosage or manner, or with the frequency or duration prescribed, recommended, or suggested in the labeling. The

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introduction or delivery for introduction into interstate commerce of this drug therefore violates section 301(a) of the Act [21 U.S.C. § 331(a)].

Good Manufacturing Practice Deviations

We have completed a review of your written responses dated July 21, 2015 and August 31, 2015 to the FDA 483 and we acknowledge your promised corrective actions to correct the observations identified during the inspection of your firms. As your facilities work on corrective actions, please continue to update this office and provide associated records to support the completion of your corrective actions.

Should we observe the deficiencies identified on the above mentioned FDA 483, or similar deficiencies in the future; regulatory action (e.g., seizure, injunction, and civil money penalties) may be taken without further notice.

Our investigators observed specific violations, including, but not limited to, the following:

1. Your firm failed to establish 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)).

Failure to Validate Drug Manufacturing Processes

You have not validated the manufacturing processes for (b)(4) drug products you manufacture, including, but not limited to, Lugol’s Solution, Shohl’s Solution, Potassium Chloride, and (b)(4). You were previously cited for failing to validate manufacturing processes at the conclusion of our 2012 inspection of your facility.

Your July 21, 2015 response states that you have traditionally validated your processes through “historical review” and (b)(4) product reviews. You have not shown how these “historical reviews” support the validity of your manufacturing processes, nor have you provided documented retrospective or continuous verification activities for approximately (b)(4) of your drug manufacturing processes.

In response to this letter provide details, including timeframes, on how you will validate manufacturing processes for all of your drugs.

FDA’s guidance document on Process Validation: General Principles and Practices may help you understand our current thinking on approaches to process validation. The guidance is available at UCM070336.pdfhttp://www.fda.gov/downloads/Drugs/Guidances/.

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Failure to Validate Purified Water System

You have not validated the purified water system that you have been using for at least three years to manufacture products that are ingested, inhaled, or applied topically. Some of these products are indicated to treat irritated tissues or wounds that may be more vulnerable to infection. Although you partially documented the results of validation activities you conducted in 2013 following relocation of your water system in a report dated April 28, 2014, your report does not include the results of microbiological tests, (b)(4) tests, or (b)(4) tests that you performed during your validation activities. The same report states the microbial load of your purified water system steadily increased following the (b)(4)-day validation period in May, 2013, and that additional maintenance activity was required to address the increased microbiological load. You failed to validate the purified water system after completing the required maintenance activities.

Additionally, on multiple occasions, components of the water system failed. At least one of these incidents resulted in the water system operating without (b)(4). For example, on February 26, 2015, the (b)(4) of the (b)(4) failed and the system was(b) (4) until the (b)(4) was rebuilt on March 4, 2015. You did not conduct an investigation to evaluate the effects of this or other failures on the quality of the products you manufactured and released for distribution during this time.

Your August 31, 2015, response states you have contracted with a third party company to conduct a full validation of your water system. In response to this letter, provide the validation protocol and the final validation report.

2. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).

You received a complaint from a customer that Mecuroclear lot 542639 was contaminated with Gram negative bacteria commonly found in water, Burkholderia sp., and unspecified yeast and mold. This product is intended to be used as a first aid antiseptic to prevent infection in wounds. During the inspection, you provided a retrospectively written document that outlined the narrow and limited investigation you conducted into this complaint. Your investigation report failed to:

• evaluate whether Mecuroclear lot 542639 was contaminated with all of the microorganisms reported in the complaint; • include the results of all microbiological tests conducted; • identify a clear assignable cause; or • evaluate whether other lots or products were affected by the problem.

Your response states you will modify your recall and investigation procedures to

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require investigations even when products are discontinued. However, you have not addressed how you will ensure investigations extend to other lots or products that may have been affected by the same problem. Provide details on how your recall and investigation procedures will ensure that investigations are thorough and extend to other potentially affected lots of the drug product and other drug products. Additionally, provide microbiological testing results for products currently on the market to ensure that they are free of contamination.

Due to continuing CGMP issues at your firm, we recommend you engage a third party consultant with appropriate CGMP expertise to assess your firm’s facility, procedures, processes, and systems to ensure that the drugs you manufacture have their appropriate identity, strength, quality, and purity.

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 the violations identified above and for preventing their recurrence and the occurrence of other violations. It is your responsibility to ensure that your firm complies with all requirements of federal law and FDA regulations.

You should take prompt action to correct the violations cited in this letter, including immediately discontinuing the manufacture and distribution of the unapproved drugs at your facility. Failure to promptly correct these violations may result in legal action without further notice including seizure and injunction. Other federal agencies may take this Warning Letter into account when considering the award of contracts. Additionally, FDA may withhold approval of requests for export certificates, or approval of pending new drug applications listing your facility as a manufacturer until the above violations are corrected. A re-inspection may be necessary to verify corrective actions have been completed.

If, as a result of receiving this Warning Letter or for other reasons, you are considering a decision that could reduce the number of active pharmaceutical ingredients and/or finished products produced by your manufacturing facility, FDA requests that you contact CDER’s Drug Shortages Staff immediately, as you begin your internal discussions, at [email protected] so that we can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Staff also allows you to meet any obligations you may have to report discontinuances in your drug manufacture under 21 U.S.C. 356C(a)(1) and allows FDA to consider, as soon as possible, what actions, if any, may be needed to avoid shortages and protect the health of patients who depend on your products. In appropriate cases, you may take corrective action without interrupting supply, or to shorten any interruption, thereby avoiding or limiting drug shortages.

Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct violations. Include an explanation of

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each step being taken to prevent the recurrence of violations and copies of supporting documentation. If you cannot complete corrective action within fifteen working days, state the reason for the delay and the date by which you will have completed the correction. Additionally, your response should state if you no longer manufacture or distribute any of the drug products manufactured at this facility, and provide the date(s) and reason(s) you ceased production.

Your firm’s response should be sent to: Jeff R. Wooley, Compliance Officer, Dallas District Office, Food and Drug Administration, 4040 N. Central Expressway, Suite 300, Dallas, Texas 75204. If you have any questions about the contents of this letter, please contact: Mr. Wooley at (214) 253-5251.

The specific violations noted in this letter and in the Inspectional Observations, FDA 483, issued at the close of the inspection may be symptomatic of serious problems in your firm’s manufacturing and quality management systems. You should investigate and determine the causes of the violations, and take prompt actions to correct the violations and bring the products into compliance.

Sincerely, /S/ Gerald Bromley, Jr. Acting Dallas District Director

[1] See http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm349 [2] (b)(4) Salicylate toxicity (b)(4).