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WARNING LETTER

August 30, 2023

 

Reference #659891

Dear Bart D. Shrode,

The United States Food and Drug Administration (“FDA”) inspected your powdered infant formula manufacturing facility located at 5023 Venture Drive, Eau Claire, Wisconsin 54703 (“the Gateway facility”), from March 6 through April 26, 2023.

Based on the information you provided to FDA investigators during the most recent inspection, Perrigo Company PLC (“Perrigo”) purchased the Gateway facility from Nestle on November 1, 2022. The acquisition included the facility along with the U.S. and Canadian rights to the Good Start infant formula brands. Nestle remains responsible for Nestle’s current WIC contracts, with Perrigo supplying product through the Gateway facility for those contracts. Both Perrigo and Nestle have indicated they will be working closely together in the transitional period following the purchase of the Gateway facility.

During our inspection of the Gateway facility, FDA investigators found significant violations of Title 21, Code of Federal Regulations, Part 106 (21 C.F.R. Part 106), Infant Formula Requirements Pertaining to Current Good Manufacturing Practice, Quality Control Procedures, Quality Factors, Records and Reports, and Notifications (“the Infant Formula Rule”). At the conclusion of the inspection, the FDA investigators issued a Form FDA-483, Inspectional Observations (“Form FDA-483"), listing the deviations found at your facility. Based on the inspectional findings, FDA has determined that your actions have violated the Federal Food, Drug, and Cosmetic Act (“the Act”) and the Infant Formula Rule. See Sections 402(a)(4), 412(a)(3), and 301(a) of the Act [21 U.S.C. §§ 342(a)(4), 350a(a)(3), and 331(a)]. You may find the Act and FDA regulations, including 21 C.F.R. Part 106, through links on FDA’s website at www.fda.gov.1

You submitted a corrective action response, dated May 16, 2023, which includes descriptions of your firm’s ongoing corrective actions. After thoroughly reviewing your submission, FDA is issuing you this letter to advise you of the Agency’s concerns and bring to your attention areas that still require corrective actions.

1. You did not establish a system of process controls covering all stages of processing that was designed to ensure that infant formula does not become adulterated due to the presence of microorganisms in the formula or in the processing environment, as required by 21 C.F.R. § 106.55(a). Specifically:

a. You identified Cronobacter spp. in the following finished products:

i. During a continuous production campaign that ran from October 23, 2022, to November 2, 2022, two (2) products tested positive for Cronobacter spp. The positive products were identified as Parent’s Choice Infant Formula Milk-Based Powder with Iron, which was spray dried on October 26, 2022, and packaged on October 27-28, 2022, and Parent’s Choice Infant Formula Milk-Based Powder with Iron, which was spray dried on November 2, 2022, and packaged on November 2, 2022.

Prior to the initiation of this production campaign, on October 21, 2022, to October 23, 2022, you conducted a major clean-in-place (CIP)/Top Down 4-Step Cleaning. On November 2, 2022, when you received notification of the positive Cronobacter spp., you ceased production and packaging operations, placed all products on hold, and immediately initiated cleaning and sanitation activities, which entailed a major CIP/Top Down 4-Step Cleaning. Our investigator’s review of your sanitation records indicated that there were no intervening sanitation breaks during this production campaign.

Your firm’s Exceptional Release/Unblock Request Form (dated 11/7/2022), which includes your root cause analysis, concluded that “the root cause could not be directly determined however it was likely due to cross-contamination between the dryer environment and the product contact equipment.” You did not identify a probable source of contamination, and yet your root cause analysis did not include further investigation, such as Whole Genome Sequencing (WGS), of the finished product isolates or the environmental isolates recovered from the facility. Your immediate action of conducting cleaning and sanitation activities without first conducting any environmental, pre-clean swabbing to try to determine whether the same pathogen was present within the processing environment limited your ability to conduct a comprehensive investigation into the root cause of the contamination.

Further, your Exceptional Release/Unblock Request Form (dated 11/7/2022) included a proposal and rationale on product disposition for products produced from October 23, 2022 through November 2, 2022. This proposal initially identified batches of product that were marked for rejection, partial release, and release. When you made these initial disposition decisions, you did not evaluate or consider the lack of intervening sanitation breaks as a factor regarding the impacted product within this production campaign. Upon evaluation of your sanitation records and additional discussion with FDA, on March 16, 2023, your firm confirmed that all product produced from October 23, 2022, through November 2, 2022 remained within your control and no product had been distributed to consumers or customers. Following further discussion with FDA, you committed to destroying all products produced from October 23, 2022 through November 2, 2022.

ii. During a continuous production campaign that ran from January 3, 2023 through January 18, 2023, a batch of your Gerber Good Start Soothe Pro powder product tested positive for Cronobacter spp. The positive product was spray dried on January 11, 2023 and packaged on January 12, 2023.

Prior to the initiation of this production campaign, on December 31, 2022 to January 2, 2023, you conducted a major CIP of the dryer equipment and a Top Down 4-Step Cleaning of the packaging equipment. On January 18, 2023, when you received notification of the positive Cronobacter spp., you ceased production and packaging operations, placed all products on hold, and immediately initiated cleaning and sanitation activities, which entailed a major CIP/Top Down 4-Step Cleaning. Our investigator’s review of your sanitation records indicated that there were no intervening sanitation breaks during this production campaign.

Your firm’s Exceptional Release Unblock Request Form (dated 1/25/23), which includes your root cause analysis, stated in part that, “The packaging line had down time due [to] multiple scoop jams during the production of the batch.” While you identified a potential source of contamination resulting from the maintenance of the packaging line, we note that your root cause analysis did not include further investigation, such as WGS, of the finished product isolate or the environmental isolates recovered from your facility. Your immediate action of conducting cleaning and sanitation activities without further investigation, such as first conducting any environmental, pre-clean swabbing to try to determine whether the same pathogen was present within the processing environment, limited your ability to conduct a comprehensive investigation into the root cause of the contamination.

In response to the Cronobacter spp. finished product finding, you destroyed the batch of Gerber product in the campaign run that tested positive for Cronobacter spp. and three additional batches flanking the positive batch (two batches prior to the positive batch and one batch subsequent to the positive batch). However, you released the remaining 20 batches of product produced within this campaign. Your firm’s rationale for the release included negative test results of the remaining batches of finished product and an assertion that your root cause investigation, “did not find an ongoing condition that [led] to the Cronobacter finding that would impact these batches.” However, without performing WGS or any pre-investigational swabbing, you were not able to determine whether ongoing environmental contamination could have contributed to this product positive. We also note that your root cause analysis did not evaluate or consider the lack of intervening sanitation breaks as a factor regarding the impacted product within this production campaign.

Following FDA’s evaluation of your sanitation records and subsequent discussions with the Agency, on March 17, 2023, your firm conducted a voluntary recall of the impacted batches of the Gerber Good Start Soothe Pro product that was manufactured during your continuous production campaign and that you had previously released into U.S. commerce.

iii. During a continuous production that ran from March 26, 2023 through April 5, 2023, a batch of your Gerber Good Start Plus Iron and Calcium Fortified Milk-Based (“Gerber Good Start Plus”) powder product tested positive for Cronobacter spp. The positive product was spray dried on March 26, 2023 and packaged on March 27, 2023.

Prior to the initiation of this production campaign, on March 22, 2023 to March 26, 2023, you conducted a major CIP of the dryer equipment and a Top Down 4-Step Cleaning of all tote areas and the packaging room. On April 5, 2023, when you received notification of the positive Cronobacter spp., you ceased production and packaging operations, placed all products on hold, and immediately initiated cleaning and sanitation activities, which entailed a major CIP/Top Down 4-Step Cleaning. Our investigator’s review of your sanitation records indicated that there were no intervening sanitation breaks during this production campaign.

Your firm’s Exceptional Release/Unblock Request Form (dated 4/4/23), which includes your root cause analysis, concluded that, “Potential contamination was introduced into the packaging line during increased dry cleaning interventions.” While you identified a probable source of contamination, we note that your root cause analysis did not include further investigation, such as WGS of the finished product isolates or the environmental isolates recovered from the facility. Your immediate action of conducting cleaning and sanitation activities without first conducting any environmental, pre-clean swabbing to try to determine whether the same pathogen was present within the processing environment limited your ability to conduct a comprehensive investigation into the root cause of the contamination. You also did not evaluate or consider the intervening sanitation breaks as a factor regarding the impacted product within this production campaign. However, we acknowledge that you rejected and destroyed all batches made within this continuous production campaign.

In reviewing each of the three above contamination events and your corresponding Exceptional Release/Unblock Request Forms documenting the actions you have taken in response to your finished product positives as discussed above, which also contain information pertaining to your investigation into the events, root cause analyses, corrective actions, and proposals with rationales for product dispositions, the Agency has identified gaps within your root cause investigations that should be addressed in order to help mitigate the risk for future product contamination. The Agency has the following areas of concern:

• Your root cause analyses do not include an investigation of the finished product isolates or the environmental isolates recovered from your facility. Further investigation of these isolates, such as conducting WGS, would have provided more information about the potential role of your facility in contributing to the contamination events by indicating whether or not the strain of Cronobacter found in finished product matched a strain of Cronobacter previously detected at your facility. WGS results could also indicate whether the same strain of Cronobacter may be contributing to multiple contamination events, which would then inform the type of corrective action and verification activities you would need to perform to sufficiently remediate the contamination from your facility following an intrusion event. We advised you of the importance of performing WGS on finished product and environmental isolates and comparing these results as part of a thorough root cause analysis via FDA’s Letter to Industry on March 8, 2023.

• Your firm’s Exceptional Release/Unblock Request Form, which contains your root cause analysis, shows that as part of your corrective action response you immediately conduct cleaning and sanitation activities after notification of a finished product positive test result. The goal of a corrective action plan is to prevent affected product from entering the market and to determine the root cause of the problem to prevent recurrence. Effective corrective action plans often involve conducting a root cause investigation (i.e., performing an investigation to determine the source of the contamination) to inform appropriate containment and corrective action activities. When you detect a finished product positive, your immediate response is to initiate sanitation activities on suspected environmental and/or equipment surfaces and then collect samples from these surfaces to verify sanitation effectiveness. This approach, without conducting any pre-clean, investigational swabbing, may limit your ability to determine whether those surfaces initially contributed to the contamination event. We encourage firms conducting a root cause investigation to thoroughly investigate the potential sources of contamination by collecting environmental samples before performing sanitation activities, in addition to performing other root cause investigation activities.

• Upon further evaluation of your sanitation activities for each of these contamination events, your records demonstrate that you conducted cleaning activities before and after each continuous production campaign, which included the application of sanitizer to food contact surfaces. However, during your continuous production campaigns, your cleaning activities were either not performed or were limited to dry cleans that did not include the application of a sanitizing treatment to all food contact surfaces. You did not provide adequate information or data to demonstrate that your dry clean procedures were sufficient to mitigate microbiological contamination from your system. Furthermore, you did not evaluate or consider the lack of intervening sanitation breaks as a factor in making your disposition decisions regarding the impacted product within each of the contaminated production campaigns.

Your May 16, 2023 corrective actions submitted in response to the Form FDA-483 provided additional information about the contamination events and your rationale behind your disposition decisions. However, your corrective action responses did not indicate that you will evaluate your sanitation activities in making product disposition decisions if future product testing detects a pathogen. Your corrective action response states that, “PWI has updated its finished product release procedures, 5765-SOP-QA-0055 Quality-Batch Review and Product Disposition, to now hold the entire campaign of products (which is defined by sanitation breaks at the start and end of production) until all microbiological testing for pathogens has been completed. Product will be released only after confirmation that there are no Cronobacter positives in any of the line or finished product samples. To better manage the amount of product impacted as well as balance release time to our customers, PWI has also increased the frequency of sanitation breaks to minimize the amount of product on hold.” The Agency urges you to clearly incorporate an evaluation of your sanitation and hygienic control activities in making product disposition decisions if future product testing detects a pathogen. For instance, in each of the four (4) finished product positive events discussed above, a definitive root cause was not identified by your investigation activities per your Exceptional Release/Unblock Request Forms. However, you assumed that cross-contamination events had occurred between personnel and/or the environment with either food contact surfaces or the product stream within high hygiene zones of the dry production areas. You described each of these cross-contamination events resulting from various line intervention activities. A review of your sanitation and hygienic control procedures and practices, and an identification of areas for improvement, would appear warranted as a part of your corrective actions for each of these contamination events to determine whether the design and implementation of your procedures are sufficient to maintain control of your processing environment. We will assess the adequacy of your corrective actions during our next inspection of your facility.

b. You identified Cronobacter spp. in the following environmental samples:

i. FDA’s inspection included the collection of 125 environmental swabs on March 7, 2023, and March 8, 2023. Our analysis found that two (2) of the swabs were positive for C. sakazakii. These swabs were collected from non-food contact surface locations in high hygiene areas on a vacuum surface located on (b)(4) of the dryer tower and from a wall under the vent near the floor in the Utensil room off the (b)(4) Dryer Tower area. Additionally, in parallel to the FDA swabbing, you collected sister swabs, which isolated Cronobacter spp. from two (2) swabs located from a wall under the vent near the floor in the Utensil room off the (b)(4) Dryer Tower area and near a floor/footing juncture below the first-floor landing near the sifter overs collection on (b)(4) of the Dryer Tower area.

This was not the first time the Agency has found C. sakazakii in environmental samples collected at this facility. During FDA’s previous inspection of this facility from March 5, 2022 through April 14, 2022, FDA collected 231 environmental swabs. Our analysis found that six (6) swabs collected from (b)(4) areas of the processing environment were positive for C. sakazakii. Additionally, in parallel to the FDA swabbing, sister swabs were collected, which isolated C. sakazakii from four (4) swabs. Observations pertaining to C. sakazakii positive findings within the environment were discussed in Form FDA-483, issued on April 14, 2022, and were discussed in a regulatory meeting conducted on September 14, 2022, and were again discussed during a firm phone call with the Agency on April 4, 2023.

FDA conducted whole genome sequencing (WGS) on the C. sakazakii isolates that we obtained from our environmental samples collected during our current inspection. Based on the results of the WGS analysis, the two (2) isolates comprise two (2) different strains of C. sakazakii. Of particular significance, these two (2) strains each matched environmental isolates that FDA had previously collected from this facility in March 2022.The presence of the same strains of C. sakazakii over this period of time is indicative of resident pathogens or harborage sites in your facility since 2022. We advised you of the importance of these WGS results via a conference call on April 4, 2023.

The detection of C. sakazakii in your facility across multiple independent inspections is significant in that it demonstrates your sanitation procedures have been inadequate to significantly minimize or prevent the presence of C. sakazakii in your facility. Once C. sakazakii is established in a production area, personnel or equipment can facilitate the pathogen’s movement and contamination of food contact surfaces and finished product. It is essential to identify the areas of the food processing plant where this organism can survive, and to take corrective actions as necessary to eradicate the organism by rendering these areas unable to support the survival and growth of the organism and prevent the organism from being re-established in such sites. We recommend that you continue to identify potential harborage sites and sources of the organism in your processing environment and implement the necessary hygienic controls to ensure C. sakazakii does not continue contaminating your environment or your powdered infant formula products.

ii. The goal of a well-designed environmental monitoring program is to identify environmental pathogens, such as Cronobacter spp., and any harborage sites, if present, in your facility and to implement effective corrective actions to eliminate such environmental pathogens and harborage sites. In reviewing your firm’s environmental monitoring program, the Agency found that your firm did not detect Cronobacter spp. for multiple months before the notification of your finished product positive on November 2, 2022. After this notification, you switched your plant status to maximum control, which requires additional environmental testing pursuant to your procedures. During FDA’s review of your records pertaining to your firm’s environmental monitoring program at maximum control, we saw that you identified Cronobacter spp. in over twenty (20) locations of your facility, which included the Dryer Tower/Fluid Bed and in the tote dump/tote fill area. Of your positive findings, eight (8) locations were identified as being in (b)(4) locations, which you define as a ‘high potential for product contact.2  In response to these positive (b)(4) locations, you performed an investigation, which is documented in your Exceptional Release/Unblock Request Forms. Our review of your Exceptional Release/Unblock Request Forms indicates that you do not perform further investigation, such as WGS, on the environmental isolates recovered from your facility, as discussed above. Additionally, your environmental monitoring program does not clearly establish what corrective actions should be taken when a pathogen has been detected in your environment. This is further reflected in your Exceptional Release/Unblock Request forms, as your responses vary as to when investigational swabs are collected and in the details of your cleaning and sanitation activities. Lastly, it appears that you do not investigate any positive pathogen samples from (b)(4) areas of your facility, which would make it difficult to determine if, when, or how cross-contamination of bacteria is occurring in your facility from these sites and how to remediate and mitigate such cross-contamination.

iii. Environmental monitoring is an important verification measure to ensure that sanitation and hygiene controls are effectively preventing pathogens from entering or persisting in dry production areas. Your firm’s environmental monitoring program limits the collection of environmental samples for Cronobacter spp. to your (b)(4) locations, while relying heavily on monitoring for Enterobacteriaceae (“EB”) within the production area. Monitoring EB populations on environmental surfaces in dry production areas may serve as a useful indicator that unexpected water may have been introduced or some other breakdown of hygienic control may have occurred. However, FDA is not aware of sufficient data demonstrating a correlation between EB populations and the presence of Cronobacter spp. on environmental surfaces. Environmental samples collected by FDA investigators during your inspection recovered C. sakazakii from environmental surfaces where your firm was only conducting routine environmental testing for EB. A well-designed and implemented environmental monitoring program should provide information about the hygienic conditions at all stages of processing, while focusing the greatest amount of sampling on surfaces from which the risk of contamination to the product is highest. While testing environmental surfaces for EB provides some information on the conditions within the facility, the presence or absence of EB on environmental surfaces is not a reliable indicator for the presence of Cronobacter spp.

We acknowledge that your May 16, 2023 corrective actions submitted in response to the Form FDA-483 indicate that you have conducted investigational swabbing, performed cleaning and sanitizing activities, conducted environmental swabbing to verify the effectiveness of your cleaning, made plans to repair cracked floors, and stated that you will be conducting employee retraining activities. However, your response does not indicate that you are taking any proactive actions to address the resident strains of C. sakazakii present within the facility. We strongly encourage you to conduct a root cause analysis to identify any potential niche or harborage areas and to address facility practices or conditions that may contribute to the persistence of these harborage sites and potential routes of contamination. We will assess the adequacy of your corrective actions during our next inspection of your facility.

This letter is not intended to be an all-inclusive statement of violations that may exist in connection with your products. You are responsible for ensuring that your facilities operate in compliance with the Act, the Infant Formula Rule, and other applicable laws, and for investigating and determining the causes of any violations and for preventing their recurrence or the occurrence of other violations.

You should take prompt action to correct the violations noted in this letter. Failure to do so may result in legal action by the FDA without further notice, including, without limitation, seizure and injunction.

In addition to the above violations, we offer the following comment. To comply with 21 C.F.R. § 106.150, you must promptly notify FDA when infant formula product that may be adulterated leaves your establishment subject to your control as the manufacturer.

As discussed with you during your facility inspection, and as set forth in FDA’s March 8, 2023 letter to industry, when Cronobacter is detected in a finished infant formula product that is part of a continuous production run/campaign, all product prepared, packed, or held under the same insanitary conditions as the positive batch, whereby it may have become contaminated or rendered injurious to health, is deemed adulterated under section 402(a)(4) of the Act [21 U.S.C. § 342(a)(4)]. This would include all product produced before the contaminated lot going back to the last sanitation break unless the outcome of a root cause analysis or investigation can conclusively identify when the production system became contaminated, and that all product produced before this time was not subjected to the insanitary conditions created by the contamination event. Likewise, this would include all product produced after the contaminated lot until the next sanitation break unless some other sanitation/remediation procedures were conducted for which there is adequate information or data to demonstrate that the sanitation/remediation procedure is sufficient to mitigate the insanitary conditions created by the contamination event. As previously discussed, an adequate sanitation break requires either a full CIP cycle or the application of a sanitizing treatment (i.e., heat treatment or chemical treatment) to all food contact surfaces.

Releasing product that may be adulterated into interstate commerce without notifying FDA violates section of 21 C.F.R. § 106.150 and section 412(e)(1)(B) of the Act [21 U.S.C. § 350a(e)(1)(B)]. Specifically:

On January 18, 2023, your Gerber Good Start Soothe Pro Infant Formula powder product tested positive for Cronobacter spp. The Gerber Good Start Soothe Pro product was manufactured in a continuous production campaign that ran from January 2, 2023 through January 18, 2023. Upon FDA’s evaluation of your sanitation activities and batch records surrounding this production campaign during our inspection in March and April 2023, FDA determined that your firm released adulterated batches of your Gerber Good Start Soothe Pro powdered infant formula product. On March 17, 2023, your firm conducted a voluntary recall of these batches that had been previously released from within this production campaign. These batches of adulterated infant formula product had left control of your facility on March 9, 2023, and you did not notify FDA of this occurrence. (Based on recall effectiveness checks, FDA believes that your recall was effective and that you successfully removed these batches from the market.)

Please notify this office within fifteen working days of receipt of this letter as to the specific steps you have taken to correct the stated violations, including an explanation of each step being taken to identify violations and make corrections to ensure that similar violations will not recur. In your response, you should include copies of related documentation and any other useful information that would assist us in evaluating your corrections. If you cannot complete corrective actions within fifteen working days, state the reason for the delay and the time within which you will do so. If you believe that your products are not in violation of the Act, include your reasoning and any supporting information for our consideration.

Please send your written response to the U.S. Food and Drug Administration, Compliance Officer Boun Xiong, 250 Marquette Avenue, Suite 600 Minneapolis, MN 55401.

An emailed response is also acceptable. If you have questions regarding this letter, please contact Boun Xiong by telephone at 414-326-3976, or by email at Boun.Xiong@fda.hhs.gov.

Sincerely,
/S/
Ann M. Oxenham, JD
Director
Office of Compliance
Center for Food Safety and Applied Nutrition
U.S. Food and Drug Administration

/S/
Michael Dutcher, DVM
Acting Assistant Commissioner
Office of Human and Animal Food Operations U.S. Food and Drug Administration

Cc:
Dominik J. Paintner, Factory Manager
Perrigo Wisconsin, LLC
5023 Venture Dr, Eau Claire, WI 54703
DominikJohannes.Paintner@us.nestle.com

Kristi M. Knudtson, Senior Quality Manager
Perrigo Wisconsin, LLC
5023 Venture Dr, Eau Claire, WI 54703
kristi.knudtson@us.nestle.com

• 1See also FD&C Act Chapter IV: Food (Mar. 28, 2018), https://www.fda.gov/regulatory-information/federal-food-drug-and-cosmetic-act-fdc-act/fdc-act-chapter-iv-food; CFR - Code of Federal Regulations Title 21 (June 7, 2023), https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=106.
• 2Your E1 locations are the same as FDA Zone 2 sites, which are defined as non-contact food surfaces in a processing area directly adjacent to direct food contact surfaces (Zone 1 sites).