INSPECTION TRACKER: DRUG MANUFACTURING ESTABLISHMENTS (CANADA)

 

Health Canada Begins Publishing Information Regarding Emerging Issues

As part of Health Canada’s ongoing commitment to openness and transparency, the Department recently began publishing information regarding emerging issues identified through the drug inspection program.

This tracker provides a snapshot of the potential health and safety issues Health Canada is tracking with companies that fabricate, package/label, test, wholesale, distribute or import drugs for sale in Canada. The information in the chart will expand to eventually include details about affected Canadian companies and products.

How the Inspection Tracker Works

  1. Health Canada responds to potential risks as soon as they learn about them whether from their own inspections, the companies themselves, adverse reaction reports or from various regulatory partners.
  2. The tracker highlights actions Health Canada is taking such as: requests for voluntary quarantine, stop sales, import restrictions, or product recalls. It also indicates those circumstances where no action has been warranted.
  3. Even if a company is listed on the tracker, it doesn’t necessarily mean there is an immediate risk to the health of Canadians. It means Health Canada is looking into a potential issue.
  4. Health Canada will continue to take action to manage risks identified to the health of Canadians using the most appropriate level of intervention, proportional to the risk to health.
  5. This tracker currently doesn’t list specific drugs and health products affected but links to Recalls & Safety Alerts if a risk has been linked to specific products on the Canadian market.
  6. This tracker is updated regularly.
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Sagent Pharmaceuticals Recall due to FDA Observations Pertaining to Aseptic and GMP Practices at the Manufacturer’s Site Potentially Impacting Product Sterility

Sagent Pharmaceuticals, Inc. Schaumburg, IL announced on February 23, 2015 the voluntary nationwide recall of two lots of Atracurium Besylate Injection, USP, 50mg/5mL single-dose vials (NDC 25021-659-05) and four lots of Atracurium Besylate Injection, USP, 100mg/10mL multi-dose vials (NDC 25021-672-10) manufactured by Emcure Pharmaceuticals Ltd. and distributed by Sagent.

Sagent has initiated this voluntary recall of Atracurium Besylate Injection, USP, 50mg/5mL and 100mg/10mL to the user level due to FDA observations pertaining to aseptic and GMP practices at the manufacturer’s site potentially impacting product sterility. Non-sterility of a drug administered via the intravenous route has the potential to result in infections, which could be fatal, especially in patients who are immunocompromised.

Sagent has transferred the manufacture of this product to its own facility and this product manufactured at the Sagent facility will not be impacted by the recall.

Sagent is not aware of any adverse patient events resulting from the use of the subject product lots.

The lot numbers being recalled are VATA012, VATA015 (50mg/5mL) and VATB012, VATB013, VATB014, VATB017 (100mg/10mL) which were distributed to hospitals, wholesalers and distributors nationwide from February 2014 through February 2015.

Atracurium Besylate Injection, USP, 50mg/5mL and 100mg/10mL is indicated, as an adjunct to general anesthesia, to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation, and is supplied in single-dose and multi-dose vials.

 

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2015 United States Pharmacopeia (USP) Microbiological Training Program — 9-Part Live Training Program Instructor: Barry A. Friedman Ph.D.

STARTS THURSDAY, MARCH 19, 2015

The United States Pharmacopeia (USP) contains a number of chapters relating to microbiology within its General and General Information Chapters. These Chapters present information that relate to both non-sterile and aseptic processing. Several of these chapters have been recently updated and all have been updated since 2009. Each of these Chapters has relevance to each other and provides a significant knowledge base of microbiological requirements. Several of these have also been harmonized and permit one to not only follow the USP, but simultaneously meet the requirements of both the European and Japanese Pharmacopeia.

This intensive 9-Part annual live training program on the topic of Microbiological General and General Information Chapters will consist of 9 live training sessions of 2 hour presentations followed by 30 minutes of live Q&A each. It will include over 22 hours of live presentation and Q&A delivered periodically over the course of five months. The method of delivery proves effective in providing trainees with ample time to absorb, process, and put to use the information learned, and then return to the next session with any questions, as opposed to condensing this intensive training program’s curriculum into a short seminar, and thereby saturating the audience with an overload of information. The design and preparation of this program’s content is a result of years of practical industry experience on the part of the presenter, Dr. Friedman, ensuring that trainees will be provided with the most up to date and practical information on the topic. This live training program is instructed by Dr. Barry Friedman, who has over thirty years of experience in pharmaceuticals, biotechnology and regulatory compliance. He has worked with both large and small pharmaceutical and biotechnology companies on various aspects of non-sterile and sterile microbiology to include auditing, method validation and regulatory compliance.

The complete course agenda detailing each individual session can be found below at:  http://www.pharmawebinars.com/usp-microbiological-training-program-9 

http://www.pharmawebinars.com/usp-microbiological-training-program-9

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MICRO LABS LIMITED, VERNA, INDIA RECEIVES WARNING LETTER (01/09/15)

The FDA inspected Micro Labs Limited, located at Plot No. S-155 to S-159, Phase III, Verna Industrial Estate, Verna, India, between May 5-10 and 12-13, 2014. Investigators 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. In September 2014, the FDA subsequently issued an Import Alert banning the shipment of all products from this firm into the United States. This Warning Letter is a follow-up to all of the previous activities between Micro Labs Limited and the FDA.

A series of four Observations were presented within the Warning Letter.  One of the most substantial Observations (#1) indicated that the firm:

“…firm failed to ensure that laboratory records included complete data derived from all tests necessary to assure compliance with established specifications and standards (21 CFR 211.194(a))”. 

The FDA’s inspection identified laboratory test records that Micro Labs did not review and evaluate in making batch release decisions.  These records contained uninvestigated, out of specification (OOS) data.  Your firm did not include the data described below when calculating test results that was used to release finished product. Your firm also failed to identify, investigate, and determine the significance of the OOS results discussed below until the FDA investigators identified the excluded records during our inspection.

Your response states that you have initiated investigations into such extra data, together with data integrity audits. The FDA note that your response does not address the testing you have performed on active pharmaceutical ingredients, in-process goods, and validation samples tested by your QC laboratories.  In addition, your response does not include a complete review of all “trial” data (including samples and standards) generated by your firm to ensure that all of the OOS results have been identified and investigated.  As part of your response discussed below under “Summary,” please include the results of such a review, including steps taken to fully understand the scope and significance of this practice.

Observation #2 stated:

Your firm failed to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records, or other records (21 CFR 211.68(b)). 

“FDA investigators discovered a lack of basic laboratory controls to prevent changes to electronically stored data. The following examples show that you (Micro Labs) lack effective control of the integrity of instrument output data:

  1. a)    The ten Shimadzu HPLC instruments in the QC “commercial” laboratory were configured to send acquired injection data to PCs without audit trails.
  2. b)    There was a lack of controls to prevent substitution or overwriting of data. The (b)(4) audit trail dated January 6, 2014, for HPLC MLG/QC/12/026 and the (b)(4) audit trail dated January 15, 2014, for HPLCs MLG/QC/12/031 and MLG/QC/12/027 each showed sample injections marked with the same small graphic symbol.  For each of these entries, you replaced the original injection sequence data with data from a single manual injection and failed to save the original sequence data.”

COMMENT 

Audit trails represent a very basic element of Good Manufacturing Practice (GMP). 21 CFR Part 11 speaks to the issue of being able within the laboratory to track all data. Forwarding data to PCs without audit trails suggests a deliberate manipulation and ability to falsify data.  

In addition, the substitution or overwriting of data with data from manual injections and the failure to save the original sequence again suggests data falsification.

  1. Your firm failed to record and justify any deviations from required laboratory control mechanisms (21 CFR 211.160(a)).  

According to your management, a new standard operating procedure (SOP) was approved in February 2014, in order to eliminate your “trial” sample injection practices. However, during our inspection, we observed that your analysts continued these “trial” injection practices after the approval of your new SOP, and that your quality system and your management failed to detect and correct these deviations from the new procedure (see, e.g., Example 1(a)(5) above).

COMMENT

When new Standard Operating Procedures (SOPs) are implemented, aside from providing training on the SOPs, management needs to assure that the users are following the amended SOPs.  To have the FDA become the Quality Unit and find that the analysts continued to use “trial” injections, strongly suggests that the Micro Labs need to determine the capabilities of that Quality Unit and what kinds of management and oversight skills be implemented.

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SAGENT PHARMACEUTICALS INITIATES INJECTABLE RECALL DUE TO ASEPTIC AND GMP PRACTICES (2/23/15)

Sagent Pharmaceuticals Initiates a Nationwide Voluntary Recall of Atracurium Besylate Injection, USP, 50mg/5mL and 100mg/10mL due to FDA Observations Pertaining toAseptic and GMP Practices at the Manufacturer’s Site Potentially Impacting Product Sterility

Schaumburg, IL,Sagent Pharmaceuticals, Inc. announced on February 23, 2015 the voluntary nationwide recall of two lots of Atracurium Besylate Injection, USP, 50mg/5mL single-dose vials (NDC 25021-659-05) and four lots of Atracurium Besylate Injection, USP, 100mg/10mL multi-dose vials (NDC 25021-672-10) manufactured by Emcure Pharmaceuticals Ltd. and distributed by Sagent. Sagent has initiated this voluntary recall of Atracurium Besylate Injection, USP, 50mg/5mL and 100mg/10mL to the user level due to FDA observations pertaining to aseptic and GMP practices at the manufacturer’s site potentially impacting product sterility. Non-sterility of a drug administered via the intravenous route has the potential to result in infections, which could be fatal, especially in patients who are immunocompromised. Sagent has transferred the manufacture of this product to its own facility and this product manufactured at the Sagent facility will not be impacted by the recall.

Sagent is not aware of any adverse patient events resulting from the use of the subject product lots.

The lot numbers being recalled are VATA012, VATA015 (50mg/5mL) and VATB012, VATB013, VATB014, VATB017 (100mg/10mL) which were distributed to hospitals, wholesalers and distributors nationwide from February 2014 through February 2015. Atracurium Besylate Injection, USP, 50mg/5mL and 100mg/10mL is indicated, as an adjunct to general anesthesia, to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation, and is supplied in single-dose and multi-dose vials.

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Apotex Research Private Limited, Bangalore, India Receives Warning Letter (1/30/15)

During a June 23, 2014 through July 1, 2014, inspection of the Apotex Research Private Limited (ARPL) manufacturing facilities located at Plot #1 & 2, Bommasandra Ind. Area, 4th Phase, Jigani Link Road, Bangalore, India, investigators 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 caused their drug products 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 did not conform to, or are not operated or administered in conformity with, CGMP.

The FDA conducted a detailed review of the firm’s response dated July 22, 2014 and noted that it lacks sufficient corrective actions. They also acknowledged receipt of the firm’s additional correspondence dated August 11, 2014, August 29, 2014, September 30, 2014, October 31, 2014, December 5, 2014 and January 9, 2015.

The investigators observed specific violations during the inspection, including, but not limited to, the following:

  1.  Your firm failed to establish and follow appropriate written procedures, designed to prevent objectionable microorganisms in drug products not required to be sterile (21 CFR 211.113(a)).  

“On June 23, 2014, during the inspection of the QC Microbiology Laboratory, our investigators observed missing in-progress microbiological test plates for various finished drug products, in-process products, water, and media growth promotion samples. For example:

  1. Finished drug product (b)(4) Tablets (b)(4)mg batches (b)(4) and (b)(4) microbial sample plates/tubes were placed in the incubators on June 19-20, 2014, as documented in your LIMS computer system. The plates should have been incubated for (b)(4) days, per your procedures. On June 23, 2014, no plates/tubes for this batch were observed in any of the incubation chambers.
  2. Finished drug product (b)(4) Tablets (b)(4) mg Exhibit Batch (b)(4) sample for microbial testing was prepared on June 13, 2014. Your firm failed to provide the FDA investigator with the worksheet to document the incubation times and media used for the analysis. Your analyst described that the entire microbial test for this batch had already been completed the previous week but that the analyst had “forgotten” to document the details on the worksheet.

The FDA investigator noted other instances of missing samples/plates for in-process drug products, potable water, and growth promotion, even though records indicated that they were in the incubator.

As a result of the above observation, your firm initiated an investigation and reported that 290 (b)(4) plates and 36 media tubes under testing were missing, affecting 45 product sample batches, 12 growth promotion test batches, and 37 negative control plates.  Your firm also found discrepancies between the documentation and location of samples/plates and you indicated that the majority of the missing plates were found in the decontamination area for disposal.

In your response, you refer to an investigation and indicate that “…two analysts momentarily panicked (upon (1) learning that FDA Investigators were approaching the microbiology Lab and (2) seeing used petri plates from the weekend scattered throughout the laboratory)[sic] and directed the lab technician to immediately remove the petri plates from the microbiology lab … in an utterly misguided and ill-conceived attempt to clean up the microbiology lab prior to the start of the FDA inspection.”

Your response lacks a comprehensive risk assessment of your failure to follow procedures, your inadequate documentation system and your inadequate practices related to microbiological control. Your response failed to evaluate the effect of these violations on product quality, and did not include an assessment as to whether any other batches have been compromised.

ARPL’s inability to prevent and detect poor recordkeeping practices raises serious concerns regarding the quality system in place at the time of the inspection. Appropriate controls are essential to assure that the information used for making decisions is trustworthy, accurate, and reliable.”

COMMENT:

When a firm fails with its procedures and recordkeeping practices, the Agency will consider these issues part of a larger problem to include Quality System issues. It is somewhat difficult to believe that the technician and the analysts panicked to such a degree that plates would be removed from the laboratory because the FDA Investigators were arriving. One would think that the entire facility would be aware of the FDA’s presence and continually maintain the facilities in a pristine condition. The failure to follow procedures, have good documentation practices and maintain microbiological control suggests a lack of training and proper internal management skills.

In addition, the dates of the incubation vs. the arrival of the FDA did not “hold water”. The FDA could readily review the dates of incubation to determine when plates and tubes would complete their incubation period based upon the Company’s SOPs and USP<61>. These forms of fabrication only cause the FDA to review the laboratory’s data in additional detail.

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NUTEK DISPOSABLES, INC ISSUES ALERT DUE TO POTENTIAL BACTERIA IN BABY WIPES (RECALL – 10/25/14)

FOR IMMEDIATE RELEASE — Oct. 25, 2014 — MCELHATTAN, PA — Nutek Disposables, Inc. of McElhattan, PA has initiated a nationwide voluntary product recall at the retail level of all lots of baby wipes that it manufactured under the brand names Cuties, Diapers.com, Femtex, Fred’s, Kidgets, Member’s Mark, Simply Right, Sunny Smiles, Tender Touch, and Well Beginnings, because some packages may contain bacteria. These wipes were distributed by Nutek prior to October 21, 2014 to the following retail stores: Walgreens, Sam’s Club, Family Dollar, Fred’s, and Diapers.com.

After receiving a small number of complaints of odor and discoloration, Nutek conducted microbial testing that showed the presence of a bacteria, called Burkholderia cepacia (B. cepacia), in some of these products. Soon after, on October 3, 2014 the company initiated a voluntary withdrawal of lots that had tested positive for the bacteria, as well as other baby wipes in the surrounding time frame. After some additional lots were tested, as a precautionary measure, Nutek believed it was a prudent decision to withdraw all its baby wipe products.

  1. B. cepacia poses little medical risk to healthy people. However, people who have certain health problems like weakened immune systems or chronic lung diseases, particularly cystic fibrosis, may be more susceptible to infections with B. cepacia. If you believe you have a weakened immune system or chronic lung disease and you have used one of the affected wipe products, you should call your doctor promptly for medical advice.

As of October 3, 2014, the date of the original withdrawal, the company had received only one report of irritation. Numerous reports of complaints have since been received by the company that include rash, irritation, infections, fever, gastro-intestinal issues, and respiratory issues, though these reports have not been confirmed to be related to the use of these products.

The company has not identified the cause of the problem, but is continuing to investigate. In the interim, Nutek has stopped shipping baby wipes manufactured at the facility.

Nutek takes the safety of consumers and the quality of its products very seriously and is taking all appropriate steps to address the issue and ensure this does not happen again.

The company is working with the U.S. Food & Drug Administration and the affected retailers and distributors throughout this process to address the issue.

COMMENT:

An article called “Burkholderia cepacia: The Decision is Overdue” was written by Torbeck et al in October 2011.  Within this article they discuss B. cepacia and the various microbiological problems that may be encountered within medical devices and drugs.  They note that water sources remain an excellent source of the bacterium which may survive in water for weeks, but only days on solid surfaces.

Within the Recall the Company (Nutek) had not identified the cause of the problem, but was continuing to investigate.  I would encourage Nutek to review this article from 2011 and consider the following potential causes that they list.

They include:

  • Inadequate cleaning procedures
  • Use of unsuitable grade of water (g., use of potable water to clean the process equipment)
  • Poor water system control (g., lack of proper sanitization, failure to validate and lack of scheduled maintenance)
  • Poor water systems design (g., stagnant water allowed biofilm development
  • Inadequate testing and specification (e.g., inadequate microbiological analysis, contaminated raw materials, incomplete/incorrect testing for antimicrobial effectiveness)

The authors proceed to indicate that water was implicated within six recalls, while contaminated raw materials were implicated three recalls and inadequate testing before distribution was implicated in two recalls.

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