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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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Jubilant HollisterStier General Partnership 2/20/13


Department of Health and Human Services logoDepartment of Health and Human Services

Public Health Service
Food and Drug Administration
 Silver Spring, MD  20993 


Warning Letter
WL: 320-13-08
CERTIFIED MAIL                                                                        
February 20, 2013
Mr. Jean-Francois Hebert
Vice President Operations
Jubilant HollisterStier General Partnership
16751 Rte Trans Canada            
Kirkland, Québec, Canada H9H 4J4
Dear Mr. Hebert:
During our March 19-26, 2012 inspection of your pharmaceutical manufacturing facility, Jubilant HollisterStier General Partnership, located at 16751 Rte Trans Canada, Kirkland, Québec, Canada, investigator(s) from the U.S. Food and Drug Administration (FDA) identified significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals, Title 21, Code of Federal Regulations, Parts 210 and 211. These violations cause your drug product(s) to be adulterated within the meaning of Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 351(a)(2)(B), in that the methods used in, or the facilities or controls used for, their manufacture, processing, packing, or holding do not conform to, or are not operated or administered in conformity with, CGMP. 
Our inspection also revealed that your firm failed to fulfill its registration obligations under Section 510(i)(1) of the Act, and its listing obligations under Sections 510(i)(2) and 510(j), which are prohibited acts under Section 301(p), 21 U.S.C. 360(i)(1) and (2), 360(j), and 331(p).
We have conducted a detailed review of your firm’s response dated April 13, 2012, and note that it lacks sufficient corrective actions.  We also acknowledge receipt of your firm's additional correspondence dated May 16, 2012, June 1, 2012, and August 9, 2012. 
Our investigator(s) observed specific violations during the inspection, 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). 
For example, on multiple occasions, you failed to perform failure investigations for rejected batches or implement any preventive actions. 
The inspection found that your firm failed to perform an investigation for the failure of (b)(4) Injection (b)(4) mg/ml lot (b)(4) to meet in-process pH requirements. This failing pH result was confirmed by your QC laboratory.  Additionally, you rejected filled (b)(4) Injection lot (b)(4) when sub-lots failed to meet the particle in-process acceptance criteria, but did not conduct an adequate investigation into that failure. In your response, you stated that the “…process is known to generate occasional out of limit in-process (b)(4) aggregate particle density results…” However, you did not provide your determination of actual root cause for this failure to meet in-process limits. Additionally, you noted that the sponsor of this product is planning (b)(4) activities for this process and will target consistent particle results as part of the validation of the new process. Please note that your firm is expected to conduct thorough investigations for each failure to meet specifications, regardless of future plans for validation. 
In your response to this letter, provide a copy of your revised procedure requiring a thorough failure investigation when in-process or finished product testing shows that your product fails to meet established specifications. 
In addition, our investigator found that you do not determine and implement corrective and preventive actions (CAPAs) in a timely manner to prevent recurrence of manufacturing deviations.  For example, the inspection noted that some CAPAs remained open for approximately 500-700 days (one was open for 761 days) without implementation of corrections. Your firm’s response stated that you have now completed these CAPAs.  However, you failed to address why you had not completed these CAPAs in a timely manner to prevent repetition of manufacturing problems. We are concerned that your response corrects the FDA 483 observation, but does not provide for a systematic and sustainable correction to ensure timely and effective CAPAs.
In response to this letter, provide updated information on all CAPAs related to manufacturing operations and quality control that you initiated since March 1, 2012.  Provide a brief summary explaining whether your delay in implementing timely CAPAs to resolve root causes of problems affected the quality of the released product. 
  1. Your firm does not have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specification for the drug product, including identity and strength of each active ingredient, prior to release (21 CFR 211.165 (a)). Your firm also failed to establish acceptance criteria for the sampling and testing conducted by the quality control unit that are adequate to assure that batches of drug products meet each appropriate specification and appropriate statistical quality control criteria as a condition for their approval and release (21 CFR 211.165(d)). 
For example, your firm released multiple lots of finished (b)(4) products despite the failure of these lots to meet acceptance criteria during 100% visual inspection.  
The inspection revealed that (b)(4) Injection lots #(b)(4), #(b)(4), and #(b)(4), and (b)(4) lots #(b)(4), #(b)(4), and #(b)(4) failed to meet the visual inspection specification of ≤ (b)(4)% and ≤ (b)(4)%, respectively, for major defects. Nonetheless, you released these batches for distribution without re-evaluating them to ensure that none of the vials you released contained (b)(4) defects, glass particles, or other foreign material which could impact product performance (e.g., reconstitution, stability) or pose a hazard to its consumers.  Regarding lot #(b)(4), your firm had a compressor failure (due to a power outage) during the (b)(4) operation that resulted in a 34oC increase above the target temperature at that stage of the cycle. This excessive deviation was measured on at least two shelves and resulted in unacceptable (b)(4) appearance. During final visual inspection, more than 2500 vials were inspected out of the batch due to the temperature deviation.  On the basis of this visual inspection, you allowed the remainder of the batch (over (b)(4) vials) to be released.  Please explain this decision in your response, and include a discussion of whether it is feasible for your operators to visually detect and sort out all affected units of a batch following such a significant temperature deviation in the (b)(4) cycle.
In your response to the FDA 483, you committed to modifying the visual inspection procedure used at the conclusion of manufacturing.  However, your written response does not adequately address the quality of the product that was released to the market. In your response, please provide a risk assessment for marketed product.  Also, provide information regarding your scientific rationale as to whether the (b)(4)% vial rejection specification is an appropriate level to trigger an investigation of serious defects (e.g., glass particles, foreign materials, container-closure integrity defects) in a given lot of your parenteral drug products. In addition, provide the scientific rationale for your newly proposed limits. In particular, discuss the incidence of critical defects that your firm considers tolerable from a risk standpoint in a parenteral drug batch and explain what capability is feasible in a well-controlled process.
  1. Your firm failed to establish adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, or purity they purport or are represented to possess (21 CFR 211.100 (a)). 
For example, SOP 1179 Version 03, entitled “Inspection of Vials of (b)(4) Products,” and SOP 1086 Version 02, entitled “Visual Inspection of (b)(4) Products” are deficient in the following ways: 
a. They include an acceptance rate for major vial defects of  (b)(4)% and ≤ (b)(4)% for (b)(4) and (b)(4) products, respectively, but do not provide for a corrective and preventive action to be taken if the acceptance criterion is exceeded.
b. They do not provide for a second inspection or additional evaluation when the product fails to meet its specification.
Our inspection documented that (b)(4) lots #(b)(4), #(b)(4), and #(b)(4) exceeded the acceptance criteria, but that you released them for distribution with no additional evaluation (e.g., 100% inspection or AQL inspection) to assure that the quality and purity of the entire lot was not compromised.  Your firm informed the investigator that, based on the procedure detailed in SOP 1179, your firm only inspects lots once regardless of the number of defective vial rejection rate. As a result, you released to the market (b)(4) Lots #(b)(4), #(b)(4), and #(b)(4) despite their (b)(4)%, (b)(4)%, and (b)(4)% major defect rejection rates, respectively.      
Your firm’s SOP for (b)(4) product visual inspection, SOP 1086 Version 02, entitled “Visual Inspection of (b)(4) Injectable Products” is similarly deficient. It does not require corrective and preventive action if the acceptance criterion is exceeded, nor does it provide for a second inspection or other appropriate additional evaluation when the product fails to meet its specification.  Despite a visual inspection acceptance rate for major defects of  ≤ (b)(4), you released (b)(4) Lots #(b)(4), #(b)(4), and #(b)(4) with (b)(4)%, (b)(4)%, and (b)(4)% major defect rates, respectively.  You did not conduct any acceptance quality limit (AQL) inspection or a second 100% visual inspection.
You indicate in your initial response to the FDA 483 that you made changes to these procedures, including introduction of an AQL inspection limit and a 100% reinspection under certain circumstances. In your response, you also proposed possible root causes for the failure of the six cited lots to meet acceptance criteria. We are concerned, however, with your risk assessment, which suggests that the failure of these products to meet acceptance criteria for defects during the 100% inspection has no bearing on the quality of the released units. Please provide detailed information regarding how you reached your conclusion.
You also did not address the risk posed by any other lots that may have also failed to meet the visual acceptance criteria. In your response to this letter, provide an updated and thorough risk assessment, and describe how you intend to manage the risk posed by all lots, released and within expiry, which failed to meet visual acceptance criteria. 
The inspection also noted water running on the floor of the equipment wash room that was  tracked into the dirty equipment staging room and further, into the pharmaceutical corridor leading to the sterile production hallway, the (b)(4) line, and the vial filling area. Please be mindful that it remains your responsibility to have appropriate design, control and vigilant supervisory oversight of the facility where you manufacture sterile products.  In response to this letter, please provide an explanation of the measures you have taken to assure that the facility is designed and operated to assure that water from other areas will not be introduced into the aseptic filling area.
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.
If, as a result of receiving this warning letter or for other reasons, you are considering a decision that could reduce the number of finished drug products or active pharmaceutical ingredients produced by your manufacturing facility, FDA requests that you contact CDER's Drug Shortages Program immediately, as you begin your internal discussions, at drugshortages@fda.hhs.gov 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 Program also allows you to meet any obligations you may have to report discontinuances in the manufacture of your drug 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 be able to take corrective action without interrupting supply, or to shorten any interruption, thereby avoiding or limiting drug shortages.
Until all corrections have been completed and FDA has confirmed corrections of the violations and your firm’s compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as a drug product manufacturer. In addition, your failure to correct these violations may result in FDA refusing admission of articles manufactured at Jubilant HollisterStier General, 16751 Rte Trans Canada, Kirkland, Québec, Canada into the United States under Section 801(a)(3) of the Act, 21 U.S.C. 381(a)(3). The articles are subject to refusal of admission pursuant to Section 801(a)(3) of the Act, 21 U.S.C. 381(a)(3), in that the methods and controls used in their manufacture do not appear to conform to CGMP within the meaning of Section 501(a)(2)(B) of the Act, 21 U.S.C. 351(a)(2)(B). 
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 and prevent the recurrence of violations, and provide copies of supporting documentation. If you cannot complete corrective actions within fifteen working days, state the reason for the delay and the date by which you will have completed the corrections. Additionally, if you no longer manufacture or distribute the drug product(s) at issue, provide the date(s) and reason(s) you ceased production. Please identify your response with FEI # 3001623073.
Please send your reply to:
Rafael Arroyo, Compliance Officer
U.S. Food and Drug Administration
Center for Drug Evaluation and Research
Office of Manufacturing and Product Quality
Division of International Drug Quality
White Oak, Building 51, Room 4237
10903 New Hampshire Ave.
Silver Spring, MD 20993
Tel:     (301) 796-4839
Fax:     (301) 847-8741
Michael Smedley
Acting Director
Office of Manufacturing and Product Quality
Office of Compliance
Center for Drug Evaluation and Research