Novartis International AG 11/18/11

Novartis International AG 11/18/11 Statistical equivalence between the (b)(4) as well as (b)(4) could possibly be demonstrated utilizing both parametric or perhaps non-parametric (based on distribution analysis) approaches (comparing implies and also variances). With Regard To example: This is actually a repeat violation in the August 2008 Warning Letter issued to the Wilson, North Carolina facility.

In the reaction for the FDA form 483 (Observation # 4a), anyone committed in order to update SOP P200.136 (Media Fills) in order to right the particular reconciliation discrepancy at each step in the media fill: filling, visual inspection, receipt at the microbiology laboratory, mid-incubation, along with final evaluation.

Donald DeGolyer, President Sandoz US Head Commercial Operations, North America Sandoz Inc. 506 Carnegie Center, Suite 400 Princeton, new Jersey 08540 Sincerely, Specific violations observed throughout the inspections include, yet aren't limited to, the particular following: b. Inside addition, you reference the Cpk values pertaining to processes using a (b)(4) versus your processes utilizing your (b)(4). Regarding example, via January to June 2011, you received 33 complaints with regard to crystallization/cloudy remedy regarding this product. Sandoz Canada Inc., Boucherville, Quebec, Canada This is truly a repeat observation from your July 2009 inspection at the Boucherville, Quebec facility.

1. your media fill Lot# (b)(4) (filling finish date October 30, 2009) shows that (b)(4) vials had been received for incubation as well as (b)(4) vials were evaluated.

VIA UPS We have reviewed your firm's responses regarding Might 31, 2011, July 13, 2011, and August 25, 2011, and also note they lack sufficient corrective action.

For example, investigators observed that numerous items of equipment, which includes your, (b)(4) remained dirty right after cleaning ended up completed as well as verified with a supervisor.. FDA expects Novartis to try a comprehensive as well as global assessment of your manufacturing

operations to make particular that drug items conform for you to FDA requirements. However, your current reaction didn't address the potential product top quality impact of using stoppers that have not really been appropriately evaluated for manufacturing sterile products.

You must consider prompt action to right the actual violations cited on this letter. Regarding 6 media fill lots manufactured from 2009 for you to 2011, your number of units filled didn't match the actual number becoming evaluated/incubated. However, your own firm failed to perform an adequate follow-up in order to correct this problem. Finally, the actual Agency is concerned in regards in order to the reaction associated with Novartis in order to this matter. The procedure, SOP P.200.136 (Media Fills), suggests that investigations will probably be initiated when there can be a discrepancy between your units received by the laboratory and the units received for incubation. In the event that you wish to continue to ship your goods or perhaps services from Sandoz Canada Inc., for the United States, it may become the responsibility of one's firm to be able to ensure compliance effortlessly United States Regarding America standards with regard to CGMP and all applicable Usa laws and regulations.

Within fifteen operating events of receipt associated with this letter, please notify this office in writing in the particular actions that will you have come to appropriate violations. These kind of lots were launched for distribution for the United States. Cpk analysis requires a normal underlying distribution along along with a demonstrated state involving statistical process control (ASTM E2281). A Person submitted a new field alert in order to FDA in August 05, 2011, following the conclusion associated with this inspection.

2. We will verify the particular implementation of one's revised investigation processes within a future inspection. a. include an explanation of each step being taken up avoid the recurrence regarding violations and copies involving supporting documentation. Your Own firm provides not really thoroughly investigated your failure of your batch or perhaps any 1 of its components to fulfill its specifications, if the actual batch has been distributed. Corporate management has got the responsibility to be sure the quality, safety, and integrity involving its products. Boucherville, Quebec facility ought in order to be sent towards the Meals & Drug Administration, Middle regarding Drug Evaluation and also Research, Workplace associated with Compliance, office of Manufacturing as well as Item Quality, Division involving International Drug Quality, White Oak Constructing 51, 10903 New Hampshire Avenue, Silver Spring, Maryland 20993, towards the interest of Maan Abduldayem, Compliance Officer.

In your own response, you reiterated in which these specification failures had been attributed to end up being able to sample bias, and which you conducted further studies in order to appropriate with regard to this sampling bias. Inside your own response, your firm commits to implement a new procedure regarding microbiological screening associated with stoppers pertaining to endotoxin content material also to validate the reliability of your supplier's CoA. Such methods include validation in the sterilization process [21 CFR ยง 211.113(b)]. The firm did not validate the use regarding (b)(4) #8, and product manufactured on this (b)(4) stood a slower dissolution rate than product manufactured in (b)(4) #15. Because any results of this investigation, an individual proposed the next corrective actions: modify your sensor, boost documentation, and re-train personnel. Midway Blvd, Broomfield, Colorado; Sandoz Inc., located with 4700 Sandoz Dr., Wilson, North Carolina; as well as Sandoz Canada Inc., situated from 145 Jules-Leger Street, Boucherville, Quebec, Canada, investigators from your food along with Drug Administration (FDA) identified significant violations of the current Excellent Manufacturing Practice (CGMP) regulations pertaining to Finished Pharmaceuticals, Title 21, Code involving Federal regulations (21 CFR), Parts 210 and

also 211. facility within Boucherville, Quebec, Canada. We remind a person in which you might be in cost of making certain the firm's drug manufacturing operations comply with applicable requirements, which includes the actual CGMP regulations. five from eight lots (62.5%) of one's finished product (b)(4) Injectable ((b)(4) mg/mL) reviewed during the inspection contained crystals in the vials as follows: 36% rejection regarding lot (b)(4) ((b)(4) mL inside (b)(4) mL vials), 12% rejection involving lot (b)(4) ((b)(4) mL vials), 29% rejection of lot (b)(4) ((b)(4) mL vials), 43% regarding lot (b)(4) ((b)(4) mL in a (b)(4) mL vial), as well as 25% associated with lot (b)(4) ((b)(4) mL inside a (b)(4) mL vial). your firm will not need sufficient created methods pertaining to production and process controls made to assure the drug items anyone manufacture have the identity, strength, quality, as well as purity they purport as well as are generally represented to possess [21 CFR ยง 211.100(a)].

If, as a results of receiving this Warning Letter or possibly in general, you are contemplating generating a choice that may result inside a decreased variety of finished drug items as well as bulk drug substances produced by the manufacturing facility, FDA requests that you simply make contact with CDER's Drug Shortages program immediately, as you begin the internal discussions, from drugshortages@fda.hhs.gov to always be able to make certain that the action(s) doesn't adversely affect the public health.

Khalid Nasim Vice-President involving Technical Operations Sandoz Inc. 2555 West Midway Boulevard Broomfield, Colorado 80020-1632 Cc: Please provide just about any data/documentation offered by your investigations that will establishes reconcilability of most media fill units. The idea will be apparent that will Novartis International AG (Novartis) just isn't implementing global as well as sustainable corrective actions. your response will be inadequate because a new Cpk value on your own isn't an appropriate metric to demonstrate statistical equivalence. Total accountability of media fill units includes: units filled, rejected, received by simply microbiology department with regard to incubation, removed for positive controls, and also final inspection. Jimenez: /Steven Lynn/ Steven Lynn Acting Director Office regarding Manufacturing and product Quality Office involving Compliance Center pertaining to Drug Evaluation along with Research

In your response, an individual state we had been holding isolated instances as well as in which there's zero impact in order to product. ยง 355(k)]. A New re-inspection may end up being required in the Broomfield, Colorado, along with Wilson, North Carolina, and Boucherville, Quebec facilities.

Silver Spring, MD 20993 Your firm failed for you to submit the Area Alert Statement (FAR) regarding any kind of bacteriological contamination, as well as any kind of significant chemical, physical, or another change or even deterioration in the dispersed drug product, or just about any failure of one as well as a lot more dispersed batches regarding drug product in order to meet the specifications set up because associated with it within the application within 3 working times [21 CFR ยง 314.81(b)(1)(ii) and also ยง 505(k) with the Act [21 U.S.C. Box 25087, 6th avenue & Kipling Street, Denver, Colorado 802250087, for the interest regarding Nancy G. The reaction signifies that you simply had zero crystallization problems just before 2009 and that there are already minor changes within the incoming materials and method parameters inside the final a couple of years. Your Own response, however, is inadequate simply because you are generally doing not really adequately address the must prospectively assess the adequacy of those controls via achievement associated with effective procedure validation studies.

Department associated with health as well as Human Services Joseph Jimenez Chief Executive Officer Novartis International AG Forum 1, Novartis Campus CH-4056 Basel, Switzerland b) you failed to follow together with your own processes for validation involving aseptic processing.

In the event that anyone can't complete corrective motion inside fifteen operating days, state the major reason for that delay and in addition the date by simply that you may have completed the actual correction. The Particular intent in the 21 CFR ยง 314.81(b)(1) regulation would become to set up a young warning system in order that significant complaints are brought to the Agency's attention by simply applicant holders so as for you to avoid possible safety hazards through drug goods currently throughout distribution.

Your failure for you to implement proper corrective actions as well as avoid future recurrence is indicative involving an ineffective top quality system.

A. The Particular number of media fill vials sent with regard to manual visual inspection has been furthermore inconsistent with the quantity of units sent to the microbiology laboratory. i. Also, inside Attachment VI of one's response, anyone try to demonstrate the actual equivalence with the (b)(4) processes through providing data obtained using your "SAS" system which contains

projected expiry information. Within addition, your current reply to the Warning Letter regarding Sandoz Canada, Inc. In The Particular Program Of media fill studies, a person failed for you to establish proper criteria with regard to reconciliation of filled vials (total units evaluated/incubated as compared for the total variety of units filled) resulting in inconsistent as well as inaccurate media fill results. The firm offers certainly not conducted no less than 1 certain identity test and it has not necessarily established the longevity of the supplier's analyses through appropriate validation in the supplier's test results at proper intervals [21 CFR ยง 211.84(d)(2)].

Please make contact with your CDER's office of Manufacturing and Item quality (OMPQ) within 5 times of receipt regarding this letter in order to timetable a regulatory meeting to be able to discuss the proposed corrective actions and period frames, also as your arrange for ensuring timely as well as meaningful involvement of corporate senior executive management through Novartis, Sandoz Inc., as well as Sandoz Canada Inc. However, anyone failed in order to adequately decide the main trigger of this crystallization problem, including whether or even not really the significant frequency associated with crystallization inside your existing batches arrives towards the changes since 2009.

In your own response, an individual state which you can easily find controls in destination to control variability in the process as well as within the final product. In-process specification regarding (b)(4) uniformity was not achieved for three validated processes including: (b)(4) mg capsules (lots (b)(4), (b)(4)), (b)(4) mg/(b)(4) mg (b)(4) tablets (lots (b)(4) as well as (b)(4)) as well as (b)(4) mg tablets (lots (b)(4) and (b)(4)). Please identify your reaction along with appropriate FEI # regarding each and also every location.

We are worried that the firm lacks method knowing to always be able to consistently manufacture (b)(4) Injectable ((b)(4) mg/mL). Making Use Of a new (b)(4) when products were validated on a (b)(4) wasn't inside your approved validation procedure, and anyone also had zero information to demonstrate equivalence of the different (b)(4).

3. your media fill Lot# (b)(4) (filling finish date July 1, 2010) exhibits which (b)(4) vials were filled and only (b)(4) vials had been incubated. These kinds of controls along with variability needs in order to have been prospectively assessed via conclusion regarding productive procedure validation studies. An Individual failed for you to extend investigations with other batches regarding the same item and other products that could happen for you to be connected with just about all the failure, as well as your firm's created investigation records failed in order to incorperate your conclusions and also follow-up [21 CFR ยง 211.192]. Neither upper management in Novartis nor from Sandoz Inc., nor from Sandoz Canada Inc., ensured global, adequate, as well as timely resolution with the concerns at these sites.

2. ยง 355(k)]].

Field Alert Record (FAR) Violation In your own response, an individual state which you may find controls in destination to control variability in the method as well as inside the final product. your firm should have submitted these FARs in regards to end up being able to the continuing crystallization complaints within three operating days.

Sandoz Canada Inc., Boucherville, Quebec, Canada iv. you did not file FARs pertaining to those two specification failures regarding approximately 3 months and after the investigation closed. The firm can not have sufficient created procedures

regarding production and also method controls built to assure the drug items you manufacture hold the identity, strength, quality, and purity they will purport or perhaps are usually represented to be able to possess [21 CFR ยง 211.100(a)].

WL: 320-12-05

B. Schmidt, Compliance Officer. ยง 351(a)(2)(B)] in that the techniques utilized in, or the facilities or perhaps controls employed for, their particular manufacture, processing, packing, or even holding do not really conform to, as well as usually are generally not controlled or even administered within conformity with, CGMP. This can end up being a repeat observation from your July 2009 inspection in the Boucherville, Quebec facility. iii. Notably, the firm will not routinely test with regard to endotoxin upon incoming stopper lots, as well as lacks justification with regard to certainly not conducting this testing. The firm provides not necessarily cleaned and also maintained equipment from appropriate intervals in order to stop contamination that would alter the safety, identity, strength, or company's drug product [21 CFR ยง 211.67(a)].

Dear Mr. Pertaining To the actual lots which were distributed, your root cause of the failure had been identified as sample bias. However, your reaction is actually inadequate since you had released product to the industry depending on stratified sampling without having adequate scientific justification. However, this can be a repeated violation in the August 2008 Warning Letter issued to the Wilson, North Carolina facility. These kind of violations cause the drug products to become adulterated inside madness regarding section 501(a)(2)(B) of the Federal Food, Drug, and also Beauty Act (the Act) [21 U.S.C. Fourteen out of 79 (18%) laboratory investigations lacked documentation involving either an investigation in to various other connected batches as well as products, or a corrective action.

Until most corrections happen to be completed as well as FDA offers confirmed corrections of the violations and your firm's compliance together with CGMP, FDA could withhold approval associated with any new applications or even supplements listing your own firm as a drug product manufacturer. for example: The August 2011 inspection in addition said that Sandoz Canada Inc. The Actual content is topic to always be able to refusal regarding admission pursuant to section 801(a)(3) in the Act [21 U.S.C. Additionally, the reaction must state if you no more manufacture or perhaps distribute the drug product(s) manufactured at this facility, and supply the date(s) and also reason(s) a person ceased production. your media fill Lot# (b)(4) (filling finish date November 18, 2010) shows that (b)(4) vials were received regarding incubation and only (b)(4) vials had been evaluated.

During our April 19 to be able to Might 6, 2011, June 6 to 22, 2011, along with July 26 in order to August 4, 2011 inspections of one's pharmaceutical manufacturing facilities, Sandoz Inc., situated in 2555 W. Your Own firm features certainly not proven or perhaps followed proper created treatments designed to avoid microbiological contamination associated with drug goods purporting being sterile. Your slower dissolution rate resulted inside a recall involving 16 a lot of Triamterene

Hydrochlorothiazide 50/25 mg manufactured throughout (b)(4) #8.

Please provide the summary report of one's evaluation of finished item complaints regarding crystals, which includes investigations conducted to decide the root cause, any identified triggers which could cause the item in order to crystallize, as well as corrective actions implemented to be able to optimize the actual process. Inside addition, failure to right these violations may bring about FDA refusing admission regarding content articles manufactured from Sandoz Canada Inc., 145 Jules-Leger Street, Boucherville, Quebec, Canada in to the United States. However, the data a person present for your "projected expiry" associated with (b)(4) mg doesn't confirm that the 2 processes are generally equivalent; instead, this information demonstrates your variability inside your method and the expected failure of lot (b)(4), asset #(b)(4), produced making use of the actual (b)(4). Pertaining To your lots which were destroyed, you failed for you to extend your current investigation directly into other associated batches or establish any root cause.

For example, method validation regarding numerous drug products (e.g.,(b)(4) mg; (b)(4) mg; (b)(4) mg; and also (b)(4) mg) had not really been adequate. your media fill Lot# (b)(4) (filling end date December 14, 2010) exhibits that (b)(4) vials had been received regarding incubation and just (b)(4) vials had been evaluated.

1. your firm provides not really completely investigated the particular failure of the batch or even any of its components to satisfy its specifications whether your batch has already been distributed [21 CFR ยง 211.192].

Jon Rushord Vice-President associated with Technical Operations Sandoz Inc. 4700 Sandoz Dr. Wilson, North Carolina 27893-8143 3. Regarding example: Further, your reaction attempts in order to demonstrate equivalence in the (b)(4) and also (b)(4) processes via uniformity along with dissolution data, although you didn't supply just about any data regarding (b)(4) or perhaps (b)(4) parameters. during the inspection, our investigator identified at least 4 goods regarding which usually method validation has been performed using a (b)(4) ; however, these four tablet goods had been furthermore getting manufactured using the (b)(4).

Sandoz Inc., Broomfield, Colorado Facility November 18, 2011 For example, an individual used a pair of (b)(4) #8 and #15, interchangeably for your manufacture of multiple drug items without having validating the method making use of both bits of equipment with regard to all of the particular products. An Individual conducted process validation pertaining to six of one's drug goods using just (b)(4) #15. We will verify the implementation and effectiveness involving this corrective motion throughout a future inspection of one's facility. v. The media fill Lot# (b)(4) (filling finish date August 20, 2009) shows in which (b)(4) ampoules had

been received for incubation and (b)(4) ampoules were evaluated. a) Your Own media fill studies were insufficient to establish the aseptic method is at control. Sandoz Inc., Wilson, North Carolina Facility Our investigation revealed that you did not submit FARs within 3 times concerning tendencies of complaints regarding (b)(4) Injectable that will could signal chemical, physical, or other changes or even deterioration within the dispersed batches of that product. When (b)(4) #15 ended up being removed coming from support in 2007, anyone continued to manufacture these 6 drug products utilizing (b)(4) #8. We are worried that will the firm may be cited pertaining to inadequate cleaning within a quantity of previous inspections, and also that will you've promised corrective actions however our inspections carry on to reveal problems on this area involving CGMP. ii. It is extremely important that will your firm's investigation treatments make certain that a full investigation, such as almost all related lots as well as root cause identification, is performed prior to distribution. Although (b)(4) #8 and #15 had been identical inside the construction regarding their own external (b)(4), these people contained various internal configurations. your response for you to Observation #1 does not utilize possibly of these approaches, along with lacks the appropriate analysis to aid the conclusion in which simply no significant distinctions existed between both (b)(4) processes.

Your reply towards the Warning Letter relating to Broomfield, Colorado as well as Wilson, North Carolina facilities should be sent from this source for the Meals & Drug Administration, Denver District Office, building 20-Denver Federal Center, P.O. Please contact Keith Olin, Project Management Officer, OMPQ, with (301) 796-0962 or perhaps keith.olin@fda.hhs.gov, to end up being able to routine a meeting in CDER headquarters.

Yves Moinard, Vice President associated with Technical Operations Sandoz Canada Inc. 145 Jules-Leger Street Boucherville, Quebec J4B 7K8 Canada Public health Service Food along with Drug Administration

In addition, you failed to file FARs inside 3 working days for two plenty of (b)(4) Injectable, (b)(4) mg/mL (lot (b)(4) along with lot (b)(4)) that will failed particulate characterization in the original and twelve month stability stations. Throughout addition, please provide your own revised procedure to ensure timely initiation regarding investigations when significant adverse styles tend to be observed.

WARNING LETTER We note that CGMP violations detailed within this letter contain multiple repeated violations through

individuals cited inside the August 2008 Warning Letter issued for you to Sandoz Inc.'s Wilson, North Carolina facility along with repeated observations via prior inspections from the Sandoz Canada Inc. other federal agencies usually takes this Warning Letter into consideration when it arrives to the particular award associated with contracts. The reaction indicated that an investigation has been conducted for media fill lot# (b)(4) in July 23, 2010.

For example, your current firm accepts and also relies upon your certificate involving Analysis (CoA) out regarding your stopper suppliers with out conducting sufficient vendor qualification. Failure in order to promptly right these violations at the Broomfield, Colorado, and Wilson, North Carolina facilities might result in legal motion without having further notice including, with out limitation, seizure and also injunction. Therefore, we locate your current response inadequate to deal with our concerns relating in order to your failure to always be able to validate the above-noted items around the (b)(4) equipment.

This is a repeat observation in the July 2009 inspection at the Boucherville, Quebec facility.

1. Your Own firm lacked a new justification with regard to these discrepancies. Without Having this data, the actual acceptability associated with the above media fill runs and furthermore the capability involving the process accustomed to manufacture sterile drugs in these times is questionable. Anyone are responsible for investigating and identifying the actual causes of the violations identified above and then for preventing their recurrence as well as the occurrence regarding some other violations, and for assuring compliance effortlessly needs regarding federal law as well as FDA regulations. ยง 351(a)(2)(B)].

For example, the inspection revealed that your firm failed for you to perform a satisfactory investigation with the crystallization associated with the perfect remedy is inside your finished item (b)(4) Injectable ((b)(4) mg/mL). Please supply your firm's evaluation of the influence on products produced throughout this period.

Sandoz Canada Inc., must develop and implement an SOP as well as appropriate coaching of relevant employees detailing the procedure and also responsibilities for handling FARs. However, 2 further incidents (November 18, 2010 and December 14, 2010) occurred following the implementation of those corrective actions.

C. The Actual quantity of units evaluated/incubated in some media fill runs had been smaller sized than what ended up filled, and in additional media fill runs, the number of units evaluated/incubated has been higher than had been filled. An applicant is required to end up being able to submit, inside 3 operating days of receipt, info relating to virtually any bacteriological contamination, or perhaps any kind of significant chemical, physical, or another alter or even deterioration within the dispersed drug product, or perhaps just about any failure of 1 as well as more dispersed batches involving drug item for you to satisfy the specifications established because involving it in the application.

This is a repeat violation in the August 2008 Warning Letter issued for the Wilson, North Carolina facility.

CGMP Violations The violations cited within this letter aren't intended to be an all-inclusive statement regarding violations which exist at your facilities. Additionally, FDA could withhold approval involving requests pertaining to export certificates, or perhaps approval regarding pending drug programs listing your own facility, until the above violations tend to be corrected. failed in order to submit NDA field Alert

Studies (FARs) to FDA inside compliance using 21 CFR ยง 314.81(b)(1)(ii), as necessary through section 505(k) with the Act [21 U.S.C. in addressing significant issues within the future. ยง 381(a)(3)], in that the techniques along with controls used within their manufacture do not necessarily appear to conform to CGMP within the meaning involving section 501(a)(2)(B) in the Act [21 U.S.C