8/15/2020
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`Hospira Inc - 506761 - 02/14/2017 | FDA
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`CLOSEOUT LETTER
`Hospira Inc
`MARCS-CMS 506761 — FEBRUARY 14, 2017
`
`Recipient:
`Mr. Ian C. Reed
`Hospira Inc
`235 East 42nd St.
`New York,, NY 10017
`United States
`
`Issuing Oce:
`Kansas City District Oce
`United States
`
` 
` 
`
` 
`
` 
`
`
`
`February 14, 2017
` 
`
` 
`
` 
`
`Kansas City District Oce
`8050 Marshall Drive - Suite 205
`Lenexa, Kansas 66214-1524
`913-495-5100
`
`WARNING LETTER
`
` 
`Ref: CMS Case:  506761
`DELIVERY VIA UPS
` 
`Mr. Ian C. Reed Chairman and CEO Pzer 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 Pzer Company at 1776 Centennial
`Drive, McPherson, Kansas, from May 16 to June 8, 2016.
` 
`This warning letter summarizes signicant violations of current good manufacturing practice (CGMP) regulations for nished
`pharmaceuticals. See 21 CFR, parts 210 and 211.
`https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/hospira-inc-506761-02142017
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`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).
` 
`The inspection also revealed that Hospira Inc. failed to submit eld 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).
` 
`We reviewed your June 29, 2016, response in detail and acknowledge receipt of your subsequent correspondence.
` 
`During our inspection, our investigators observed specic violations including, but not limited to, the following.
` 
`1.    Your rm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its
`specications, 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 signicant 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 conrmed 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 signicant
`risk to patients and 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 unspecied number of vials of ketorolac tromethamine
`injection, 30 mg/mL, lot 46205DD. You conrmed 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 scientic 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 specic 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 specic identity and whether other lots were affected. You failed to provide either a scientic 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
`
`https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/hospira-inc-506761-02142017
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`recurrence of this event;
`
`updates on your root cause analysis of the particle contamination events and your corrective action and
`preventive action (CAPA) plan;
`
`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 rm failed to establish valid in-process specications (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 rm 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 signicant risks to the sterility of your nished
`products.
` 
`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 specically prohibited by your rm’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 identied 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
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`https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/hospira-inc-506761-02142017
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`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 signicantly 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 lled on line (b)
`(4) and vancomycin M-6535 lot 65090DD, lled 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 lled
`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 reect the level of environmental control present during manufacturing.
` 
`4.    Your rm 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 justication for retaining units that fail your rm’s visual inspection
`requirements.
` 
`5.    Your rm failed to establish laboratory controls that include scientically sound and appropriate specications, 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 scientically 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 scientic justication 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 justication for each statistical sampling plan used for materials, processes,
`and products at your facility.
` 
`Post-Market Reporting Violations
` 
`The inspection also revealed that Hospira Inc. failed to submit eld 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 eld 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 signicant label
`deterioration. Label adhesion defects represent a serious risk to patients, yet, in your response, you stated that a eld alert report was not
`submitted because the complaint defects were classied as minor.
` 
`Repeat Violations at Multiple Sites
` 
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`https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/hospira-inc-506761-02142017
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`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 specications.
`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 deciencies 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.
` 
`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  drugshortages@fda.hhs.gov (/node/360930), 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 certicates.
` 
`After you receive this letter, respond to this oce 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  Miguel.Hernandez@fda.hhs.gov or mail your reply to: (mailto:Miguel.Hernandez@fda.hhs.gov)
` 
`Miguel Hernandez
`Compliance Branch Director
`U.S. Food and Drug Administration
`Kansas City District Oce
`8050 Marshall Drive, Suite 205
`Lenexa, Kansas 66214
` 
`Please identify your response with FEI 1925262.
`  
` 
`Sincerely,
`/S/
`Cheryl A. Bigham
`District Director
`
`https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/hospira-inc-506761-02142017
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`Hospira Inc - 506761 - 02/14/2017 | FDA
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`8/15/2020
`Kansas City District
`Ofce of Regulatory Affairs
`Close Out Letter
`Hospira Inc - Close Out Letter 6/27/18 (/ucm614613)
`
` More Warning Letters (/inspections-compliance-enforcement-and-criminal-investigations/compliance-actions-and-activities/warning-letters)
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`https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/hospira-inc-506761-02142017
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