- Valeant Pharmacueticals International
- Issuing Office:
- New York District Office
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New York District
158-15 Liberty Ave
Jamaica, NY 11433
November 3, 2016
WARNING LETTER NYK-2017-1
VIA UNITED PARCEL SERVICE
DELIVERY SIGNATURE REQUESTED
Mr. Joseph C. Papa, Chairman and CEO
Valeant Pharmaceuticals International
400 Somerset Corporate Blvd.
Bridgewater, New Jersey 08807
Dear Mr. Papa:
During an inspection of your firm located in Rochester, NY, on August 23, 2016 through September 1, 2016, an investigator from the United States Food and Drug Administration (FDA) determined that your firm is a specification developer and distributor of the Small Particle Size Aerosol Generator, (SPAG-2), a nebulizer pneumatic flow system for the administration of Virazole (ribavirin) aerosol and the OraPharma ONSET Mixing Pen, a high precision compounding and dispensing device for mixing two solutions together. 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 any function of the body.
We received your response dated September 21, 2016 to the observations noted on Form FDA 483, List of Inspectional Observations that was issued to you at the close of our inspection. We address your responses below, in relation to each of the noted violations. These violations include, but are not limited to, the following:
Quality System Violations
This inspection revealed that your “SPAG-2” and “ONSET Mixing Pen” 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, its manufacture, packing, storage, or installation are not in conformity with the current good manufacturing practice requirements of the Quality System regulation found at Title 21, Code of Federal Regulations (CFR), Part 820. These violations include, but are not limited to, the following:
1. Failure to establish and maintain procedures for validating the device design, as required by 21 CFR 820.30(g). Specifically,
a) Design validation activities for SPAG-2 were not documented in the Design History File (DHF). Your firm stated that clinical testing (validation) of the product was conducted as part of the initial device design prior to the product being acquired by your firm, however, there is no such documentation of this validation testing and/or documentation supporting why this design validation is no longer relevant or needed in the DHF or design file for the product.
b) Design validation was not performed in response to executing design changes that affect the labeling for the usable life of the ONSET Mixing Pen. Your firm now stipulates on your labeling that the product should be replaced after 18 months of use. This instruction was added based on a review of data for a dosing mechanism component evaluated by an outside party. Your firm did not validate whether this usability timeframe was suitable to your specific ONSET Mixing Pen product.
We reviewed your firm’s response and concluded that it is not adequate. We acknowledge your response states you will revise Design Control SOPs NSOP 4.1.4, 4.1.5, 4.1.6 to include a DHF and DMR checklist for the review of acquired, or transferred legacy products to ensure compliance with 21 CFR Part 820.30 and current Valeant Design Control requirements. We also acknowledge your plans to revise 26.1.1-NREF-4 (Guidance for Post-Transfer Design Change) to require documented justification and rationale regarding the applicability of design control requirements as it relates to the adequacy of historical supporting verification and validations. Finally, we acknowledge that you plan to apply design controls to SPAG 2, ONSET Mixing Pen, and all other Valeant Rochester, NY devices where Valeant is the specification developer/owner. However, these corrections are still in progress and we will need to assess successful training and implementation of this procedure during our next inspection.
2. Failure to establish and maintain procedures for the identification, documentation, validation or where appropriate verifications, review and approval of design changes before their implementation, as required by 21 CFR 820.30(i). Specifically, the ONSET Mixing Pen product underwent a design change; however, design change procedures did not assure that design validation activities occurred for this product. For example, Quality Change Request 307426 for the ONSET Mixing Pen determined incorrectly that design validation was not required with respect to the design change of the device giving the product a defined 18 month shelf life.
We reviewed your firm’s response and concluded that it is not adequate. We acknowledge your response states although Valeant believes this was an isolated incident regarding QCR 307426, Valeant will confirm its preliminary conclusion by performing a retrospective review of Valeant Rochester, NY Medical Devices QCRs from calendar year 2015 to September 22, 2016 to verify that the design change question was answered correctly and appropriate action will be taken. We also acknowledge the promised corrections to design control procedures; however the corrections remain in progress and we will need to assess successful training and implementation of these procedures during our next inspection.
3. Failure to establish and maintain procedures for implementing corrective and preventive action, as required by 21 CFR 820.100(a). Specifically,
a) Corrective and preventive actions surrounding field action for the ONSET Mixing Pen were incomplete in that they did not address or document how their actions affected existing product in inventory. The field action for ONSET Mixing Pens initiated on 1/26/16 requested users to stop the use of the device if it has been used for more than 18 months and included a determination to replace the pen after 18 months of use. Subsequent to the field action, multiple additional lots in inventory were shipped to customers without these field action notifications. Lots distributed included (b)(4) for a total of 4,237 units. Additionally, investigation activities surrounding the ONSET Mixing Pen that ultimately led to the decision to require an 18 month usage period were inadequate in that they there was a lack of understanding and documentation of how users will determine the start day (i.e. day 0) so they can make appropriate replacement at the end of the dictated 18 month usage period.
b) Procedures addressing corrections and removals, critical action committees and health hazard evaluations as they relate to corrective and preventive actions are lacking for defining the recall initiation date to assure the FDA is notified in appropriate time frames. Additionally, procedures do not define when a Health Hazard Evaluation is required including what is required to be assessed for determining risk.
We reviewed your firm’s response and concluded that it is partially adequate. With respect to observation 3a, we acknowledge that you re-evaluated activities associated with your ONSET Mixing Pen field action to include widening the scope of your actions to include the lots documented above, therefore providing consignees with the corrective action information for those affected devices. We also acknowledge the following promised corrective actions: defining the 18 month usage period for consignees, further defining your CAC procedure and then retrospectively evaluate all existing CACs and recalls against this procedure. However, the promised corrections remain in progress and will need to be assessed during a follow up inspection. With respect to violation 3b, we acknowledge the promised corrections and improvements to your existing recalls, health hazard analysis and critical action committee procedures; however we will need to assess successful training and implementation of the changes to these procedures during our next inspection.
4. Failure to establish and maintain procedures for to control product that does not conform to specified requirements, as required by 21 CFR 820.90(a). Specifically, nonconformance investigation activities are not always completely documented to demonstrate appropriate containment of potentially affected materials and segregation or disposition in accordance with procedures. For example, NC 521798 initiated for SPAG-2 lacked complete documentation of the problem and incomplete documentation of lot containment actions. An additional SPAG-2 lot (b)(4) was identified as being affected as part of your critical action committee and there was no documentation of the handling of this lot through your nonconformance process. NC508502 initiated for SPAG-2 documented initial risk assessment ratings; however the record lacks any reference as to what was reviewed associated with the risk rating.
We reviewed your firm’s response and concluded that it is not adequate. We acknowledge you intend to train employees on your SOPs for handling nonconformances and associated corrective and preventative actions, conduct a retrospective review of nonconformance files at the Rochester site and develop/revise work instructions and aides. We also acknowledge that NC 521798 will be updated to complete the documentation of the problem, including, how the problem was identified, the scope of the containment investigation, containment actions, and to add affected materials. However, these corrections are still in progress and the adequacy of the response cannot be assessed.
5. Failure to establish and maintain an adequate organizational structure to ensure that devices are designed and produced in accordance with the requirements of this part, as required by 21 CFR 820.20(b). Specifically, the organizational structure has not assured that acquired products are adequately integrated into your quality management system. The responsibility for reviewing and authorizing work performed under your quality management system has not assured that necessary activities have occurred prior to approving. For example, SPAG-2 and ONSET Mixing Pen products have not been adequately integrated into your Quality Management System (QMS) under design controls, production & process controls and corrective and preventative action (CAPA) controls. This is evidenced by the above violations pertaining to violations with design validation, corrective and preventative actions and nonconforming product evaluation, dispositioning and approval.
We reviewed your firm’s response and concluded that it is not adequate. We acknowledge you will develop a SOP detailing how to manage integrating purchased products/companies into your QMS and that you state this SOP will include developing change plans for acquisitions including phase reviews with senior level management with cross-functional departments to provide input into the change management process. We acknowledge that the SOP for how to manage integrating purchased products will be retrospectively applied to Valeant’s acquired products listed where Valeant Rochester is now the specification developer/owner. We acknowledge the Directive on Change Management 26.1-NDIR will be changed to require detailed change plans for acquired products and to define the functions that must provide input into the change process and that a gap assessment required and approved by quality leadership, at a minimum, will be required prior to product release under the Valeant QMS. However, these procedural changes have not been implemented to date and the retrospective review of purchase products has not been completed. Thus the adequacy of the response cannot be assessed.
Your firm should take prompt action to correct the violations addressed in this letter. Failure to promptly correct these violations may result in regulatory action being initiated by the FDA without further notice. These actions include, but are not limited to, seizure, injunction, and civil money penalties. Also, federal agencies may be advised of the issuance of Warning Letters about devices so that they may take this information into account when considering the award of contracts. Additionally, premarket approval applications for Class III devices to which the Quality System regulation violations are reasonably related will not be approved until the violations have been corrected. Requests for Certificates to Foreign Governments will not be granted until the violations related to the subject devices have been corrected.
Please notify this office in writing within fifteen business days from the date you receive this letter of the specific steps your firm has taken to correct the noted violations, as well as an explanation of how your firm plans to prevent these violations, or similar violations, from occurring again. Include documentation of the corrections and/or corrective actions (which must address systemic problems) that your firm has taken. If your firm’s planned corrections and/or corrective actions will occur over time, please include a timetable for implementation of those activities. If corrections and/or corrective actions cannot be completed within fifteen business days, state the reason for the delay and the time within which these activities will be completed. Your firm’s response should be comprehensive and address all violations included in this Warning Letter.
Your written response should be sent the Food and Drug Administration; Attention:
CDR Catherine Beer
U. S. Food and Drug Administration
One Winners Circle, Suite 110
Albany, NY 12205
If you have any questions about the content of this letter please contact: CDR Catherine Beer at (518) 453-2314 x1015.
Finally, you should know that this letter is not intended to be an all-inclusive list of the violations at your firm’s facility. It is your firm’s responsibility to ensure compliance with applicable laws and regulations administered by FDA. 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. Your firm should investigate and determine the causes of the violations, and take prompt actions to correct the violations and bring the products into compliance.
Matthew R. Palo
Lieutenant Commander, U.S. Public Health Service
District Director (acting)
New York District
Cc: Mr. Joseph C. Papa, Chairman and CEO
Valeant Pharmaceuticals International
1400 North Goodman Street
Rochester, New York 14609
Cc: Mr. Stephen B. Haight, Vice President Quality
Valeant Pharmaceuticals International
1400 North Goodman Street
Rochester, New York 14609
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