Recipient: Lonza Walkersville, Inc. United States Issuing Office: Baltimore District Office United States

Baltimore District 6000 Metro Drive, Suite 101 Baltimore, MD 21215 Tel: (410) 779-5455 Fax: (410) 779-5705

WARNING LETTER

CMS #520239

April 21, 2017

Certified Mail

Return Receipt Requested

Alexandre Pasini, Head of Operations

Lonza Group Ltd

Muenchensteinerstrasse 38

CH-4002 Basel

Switzerland

Dear Mr. Pasini:

During an inspection of Lonza Walkersville, Inc., located at 8830 Biggs Ford Road, Walkersville, MD, conducted from January 18, 2017 through February 6, 2017 , investigators from the United States Food and Drug Administration (FDA) determined that your firm is a contract manufacturer of class II medical devices that include (b)(4). Under section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act), [21 U.S.C. § 321(h)], these products are devices because they are intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment, or prevention of disease, or are intended to affect the structure or function of the body.

You may find the Act and FDA’s regulations through links in FDA’s home page at www.fda.gov . This inspection revealed that these devices are adulterated within the meaning of section 501(h) of the Act, [21 U.S.C. § 351(h)], in that the methods used in, or the facilities or controls used for, their manufacture, packing, storage, or installation are not in conformity with the Current Good Manufacturing Practice (CGMP) requirements of the Quality System (QS) regulation found at Title 21, Code of Federal Regulations (CFR), Part 820.

Our investigators issued the Form FDA 483, List of Inspectional Observations, to your firm at the conclusion of the inspection on February 6, 2017. We received your response, dated February 28, 2017 concerning our investigator’s observations noted on the Form FDA 483 that was issued to your firm. We address this response below, in relation to each of the noted violations. These violations include, but are not limited to, the following:

1. Failure, where the results of a process cannot be fully verified by subsequent inspection and test, to validate the process with a high degree of assurance and to approve according to established procedures, as required by 21 CFR 820.75(a). Specifically, your procedure, “Lonza Walkersville Validation Master Plan,” Doc. No: (b)(4), Version 8.0, is not adequately established. This procedure covers cleaning validations, cleanroom qualifications, and HEPA filter certifications. For example,





A. Your firm uses the (b)(4) to aseptically fill (b)(4) liquid media products. However, the validation “(b)(4),” Doc. No. (b)(4), Dated April 2007 was not adequately performed. Specifically,





There were no predefined acceptance criteria or monitoring performed for viable organisms.

Sampling was inadequate for this validation. Normal production of (b)(4) uses (b)(4) on each (b)(4) in the ISO 5 cleanroom. For each run in this validation, only (b)(4) was taken from one of the (b)(4) .

Sampling was inadequate for this validation. While reviewing how your firm cleans the (b)(4) , a supervisor stated the (b)(4) .

This validation was inadequate because it did not cover the cleaning of the (b)(4) . Your firm performed an environmental sampling investigation on January 5, 2017 after receiving two confirmed complaints for sterility failures of (b)(4) product. (b)(4) were (b)(4) and your firm’s preliminary results show Pantoea organisms were identified in the (b)(4) . Pantoea organisms were also isolated from returned product samples from lots associated with the two confirmed complaints.

Since the (b)(4) were not covered in a cleaning validation, an adequate preventive maintenance (PM) program was not established to clean and monitor the (b)(4). The current PM system for the (b)(4) requires cleaning only the (b)(4) of any liquid or media residue. This PM does not require any monitoring to determine if the cleaning is effective.





B. Your firm uses the (b)(4) to formulate liquid media products in bulk. However, the validation “ (b)(4) ,” Dates of Study: March 2000, was not adequately performed. Specifically,





There were no predefined acceptance criteria or monitoring performed for viable organisms.

(b)(4) were taken. The (b)(4) samples are required to be (b)(4) , but there was no predefined acceptance criterion for the (b)(4) samples. According to a verbal statement from your firm’s management, the current specification for (b)(4) samples is (b)(4) . However, the March 2000 “ (b)(4) ,” documents the following rinse samples did not meet specification:





were taken. The Run 1, Sample 2, (b)(4) – (b)(4) ; TOC = 6.80 PPM

Run 2, Sample 23, (b)(4) – (b)(4) ; TOC = 11.3 PPM

Run 2, Sample 24, (b)(4) – (b)(4) ; TOC = 0.656 PPM

Run 3, Sample 23, (b)(4) – (b)(4) ; TOC = 4.27 PPM

C. There are no requirements in your master validation procedure for qualifying a clean room. There should be requirements in this procedure for how you are going to comply with the ISO 14644 standard and your quality system. These requirements include but are not limited to performing both viable and nonviable sampling at an operational status, demonstrating unidirectional airflow, and establishing key process parameters like HEPA air filter velocities to demonstrate you have adequate control of the cleanroom.



D. The (b)(4) liquid media products are filled in Media Fill Room (b)(4) , Filling Area (b)(4) ; however, your qualification, “Qualification of Media Fill Room (b)(4) and Surrounding Areas (Rooms (b)(4) ) per ISO Standard 14644-1,” Validation ID # (b)(4) , Revision #1 was not adequately performed.



Key process parameters such as HEPA filter air velocities were not adequately established. The qualifications did not determine a specification for air velocities for the HEPA filters to adequately control the process.

There was no evidence that unidirectional air flow was obtained through a smoke study.

Total particulate air monitoring was only performed at a rest state. There was no monitoring at an operational state.

There was no viable particulate monitoring.

We have reviewed your response dated February 28, 2017 to this violation and have determined that the adequacy of the response cannot be determined at this time. We acknowledge the corrective actions listed in your response, to include the development of a separate Cleaning Master Validation Plan and the creation of a validation protocol containing instructions and acceptance criteria for performing static and dynamic smoke studies. Additionally, the Validation Master Plan will be revised to include predefined acceptance criteria, monitoring of viable organisms, appropriate sampling sites, worse case cleaning of the filling process, and qualification and requalification requirements for how your firm intends to comply with ISO 14644 and your quality system.



2. Failure to develop, conduct, control, and monitor production processes to ensure that a device conforms to its specifications, as required by 21 CFR 820.70(a). Where deviations from device specifications could occur as a result of the manufacturing process, the manufacturer shall establish and maintain process control procedures that describe any process controls necessary to ensure conformance to specifications. For example,



Your procedure, “Aseptic Process Simulation Program: (b)(4) ,” Doc. No. (b)(4) , Version 8, is not adequately established. Specifically,



A. There is no definition of what an intervention is for performing activities that are not considered routine and need to be assessed when performing an aseptic process simulation (APS).



B. Interventions that were performed and approved during APSs are not written in a procedure; therefore operators do not know what interventions they can perform during routine production unless they review previous APSs.



C. During normal production of (b)(4) , (b)(4) were used, each with its own (b)(4) where sterile product goes through after (b)(4) . An APS performed in 2016 demonstrated an intervention where (b)(4) were exchanged, for a total of (b)(4) ; however, it is unclear if these (b)(4) were exchanged for the same reason as the potential mechanical issues experienced in production. Several lots manufactured exceeded this intervention. The following lots exceeded this intervention and were associated with confirmed complaints of sterility failures:



(b)(4) Lot (b)(4) , manufactured on (b)(4) , involved the usage of (b)(4) and a fill time of (b)(4) .

Lot (b)(4) Lot (b)(4) , manufactured on (b)(4) , involved the usage of (b)(4) and a fill time of (b)(4) .



Your firm’s July 2016 APS states the duration of fill time is (b)(4) and the October 2016 APS includes a total fill of (b)(4) . (b)(4) Lots (b)(4) and (b)(4) exceeded these fill times. Additionally, your procedure, “Aseptic Process Simulation Program: (b)(4) ,” Doc. No. (b)(4) , Version 8, states each operator must remain in the cleanroom no more than six hours without exiting or regowning. There is no study performed during your firm’s July 2016 or October 2016 APSs to validate the requirement that operators can remain in the cleanroom no more than six hours without exiting and regowning. The APSs did not study what the maximum amount of time personnel can remain in the filling area and your firm does not monitor or document how long personnel remain in the cleanroom.





D. This procedure does not require interventions during production to be documented in device history records, therefore there is no information to determine if the interventions performed during production are similar to those being performed during APSs. There was no documentation why these (b)(4) were changed for these lots but your firm’s management stated it was most likely due to potential mechanical issues. It is not documented in the 2016 APS whether the (b)(4) were changed due to potential mechanical issues.



We have reviewed your firm’s February 28, 2017 response to this violation and concluded that it is partially adequate. We acknowledge the corrective actions listed in your response, to include the revision of the APS procedure to include requirements for simulating interventions, additional interventions based on the process history, the procedure will clearly define approved routine interventions, what constitutes a non-routine intervention, and the steps to assess the impact of the non-routine intervention during an Aseptic Process Simulation. However, your response did not address the maximum amount of time personnel can remain in the filling area. Furthermore, Attachment 4 of your response, “ (b)(4) ,” did not take into account all interventions that were exceeded or were never adequately established.

3. Failure to establish and maintain procedures for implementing corrective and preventive action (CAPA) as required by 21 CFR 820.100(a). Specifically, your procedure, “Corrective and Preventive Action Program,” Doc. No: (b)(4) , Version 11.0, is not adequately established. For example,



The following CAPAs had inadequate corrective actions:





A. CAPA # (b)(4) was opened on February 5, 2016 for a number of observations found in the (b)(4) filling area of Cleanroom Room (b)(4) where the (b)(4) liquid media products are made. The CAPA states there is inadequate separation between operators and the filling zone. This CAPA was closed for this observation without accessing if these products could be made at your facility’s other clean rooms or production could halt.

B. CAPA PR# (b)(4) was opened on June 10, 2015 because the heat sealers used to create a sterile barrier for the (b)(4) were not adequately validated. The heat sealers are hand held sealers and cannot be validated because there are no parameters to control except time. In addition, there was inadequate testing performed to show seal integrity was met. Your firm realized these issues and researched other sealers but did not stop manufacturing of (b)(4) liquid media products and has not yet found a solution.



We have reviewed your firm’s February 28, 2017 response to this violation and determined that it is partially adequate. We acknowledge the corrective actions listed in your response, to include updating the CAPA procedure to include requirements for objective evidence to support closure. In addition, effectiveness checks will be required for all medical device CAPAs, a retrospective review of closed CAPAs will be performed, and your firm will confirm that the risk score required by procedure is appropriate. We also acknowledge that your firm ceased manufacturing the liquid media products in January 2017 and will resume manufacturing after the corrective actions are achieved. You also stated that an alternate sealer has been identified that can be validated. However, your response states, “At the time the CAPA (b)(4) was closed, there was rationale to support continued filling. Specifically, in the year prior to the CAPA closure, the APS for this process had been successful, there had been no sterility failures, and environmental monitoring demonstrated that the facility was in a state of control.” FDA believes, in order for your rationale to continue filling to be adequate, you should perform adequate environmental monitoring during operation and at the point of fill in the ISO 5 filling areas and perform adequate personnel monitoring during each run.





4. Failure to adequately establish procedures to control environmental conditions as required by 21 CFR 820.75(c).



Specifically, your procedure, “ (b)(4) ,” Doc. No (b)(4) , Version 10.0, is not adequately established. It requires (b)(4) . Sampling is required to take place when the operators are actually gowning or as determined by your cleanroom monitoring program based off your risk assessment per ISO Standard 14644-2. You do not have a cleanroom risk assessment.

We have reviewed your firm’s response dated February 28, 2017 to this violation and have determined that the adequacy of the response cannot be determined at this time. We acknowledge the corrective actions listed in your response, to include conducting a documented cleanroom risk assessment for media cleanrooms, and based on those results, your firm will revise your two procedures associated with this violation.

We also note that your firm failed to test numerous product lots for sterility based on USP or an equivalent method. You instead used a surrogate sterility test that lacks a representative sample of the batch and is insufficiently sensitive. We acknowledge that your firm commits to testing sterility of finished products based on USP in the future. It should be noted, however, that a passing sterility test alone is insufficient to support release of products unless the manufacturing operation is designed to robustly and reproducibly assure batch sterility.71>71>

The deviations identified above are not intended to be an all-inclusive list of deficiencies at your establishment. It is your responsibility to ensure that all products marketed by your firm comply with the FD&C Act and its implementing regulations. You must take prompt action to correct these violations. Failure to promptly correct these deviations may result in administrative and/or regulatory action without further notice including, but not limited to, seizure, injunction, and/or prosecution.

You should notify this office in writing of the steps you have taken to bring your firm into compliance with the law within fifteen (15) working days of receiving this letter. Your response should include each step that has been taken or will be taken to correct the violations and prevent their recurrence. If corrective action cannot be completed within fifteen (15) working days of receiving this letter, state the reason for the delay and the time frame within which the corrections will be completed. Please include copies of any available documentation demonstrating that corrections have been made.

Your written response should be sent to Ms. Cherlita Honeycutt, Compliance Officer, U.S. Food and Drug Administration, 6000 Metro Drive, Suite 101, Baltimore, Maryland 21215. If you have any questions about this letter, please contact Ms. Honeycutt at (410) 779-5412 or via e-mail at Cherlita.Honeycutt@fda.hhs.gov

Sincerely,

/S/

Evelyn Bonnin

District Director

Cc:

John Mosack

Senior Site Director

Lonza Walkersville, Inc.

8830 Biggs Ford Road

Walkersville, MD 21793

Michele Jones

Director of QA

Lonza Walkersville, Inc.

8830 Biggs Ford Road