During an FDA investigation of SKB in Cork, Ireland, the FDA encountered an unusual situation where the pharmaceutical waste tank was found to have contaminated various other tankage used to manufacture APIs. Part of the rationale provided by SKB was that no reason existed to suspect contamination and, therefore, the analyst did not look for any. Please read through the entire Blog to learn more about this unusual Warning Letter. It certainly should be shared with your Quality Control personnel.

During an October 18-23, 2013 inspection of a SKB pharmaceutical manufacturing facility, SmithKline Beecham (Cork) Ltd., located at Currabinny, Carrigaline, Cork, Ireland, investigator(s) from the U.S. Food and Drug Administration (FDA) identified deviations from current good manufacturing practice (CGMP) for the manufacture of active pharmaceutical ingredients (APIs).

The firm discovered that the (b)(4) used to manufacture (b)(4) batches of (b)(4) and (b)(4) batches of (b)(4) was contaminated with material from their pharmaceutical waste tank, which contained APIs, intermediates, and solvents…..Your firm became aware of this contamination in January 2012 and completed risk assessments to determine the impact on the quality of (b)(4) manufactured using the contaminated solvents on April 19, 2013. Your firm distributed (b)(4) shipments of (b)(4) potentially contaminated (b)(4) batches after becoming aware of this significant deviation. In contrast, (b)(4) batches made with the contaminated (b)(4) were rejected.

Quality impact assessments were made for both (b)(4) and (b)(4), but was noted that the approach taken in the two assessments was different. For instance, the (b)(4) assessment noted that the standard release testing did not detect significant quantities of contaminants in the potentially impacted (b)(4) batches, but that additional testing on (b)(4) from (b)(4) showed the impacted batches were exposed to significant amounts of (b)(4). The assessment states that the sample preparation used in the (b)(4) sample release testing appears to be incapable of complete extraction of the potential contaminants, and it therefore relied on results obtained from the additional testing from the (b)(4) of (b)(4) product to demonstrate that the (b)(4) batches were impacted by the pharmaceutical waste contamination event.

Your firm’s SOP regarding communication of significant deviations states that your firm must communicate to the receiving site information concerning deviations having a potential quality impact on the product. During the inspection, your personnel informed the investigator that your firm determined that there was no potential to impact the quality of the affected products manufactured with (b)(4) and chose not to “escalate” the deviation by notifying your customers.

In your response to this letter, please address the concerns outlined above. Please also describe why the quality assessments appear to assume uniform distribution of contaminants following addition of (b)(4) to the waste stream and before the backflow of contaminants into the (b)(4) tank. Provide a revised quality assessment for (b)(4) that clearly describes all calculations used to support the conclusions, and clearly describe any altered conclusions after addressing the issues described in this letter. For each analytical method used to support your conclusions, provide method qualification information, including the limit of detection for each potential contaminant. Also, provide a quality impact assessment for your (b)(4) product, which was also manufactured using (b)(4) around the time of the initial contamination in the (b)(4) tank. Describe any contact you have had with the customers of the potentially affected products and your plans with respect to the disposition of any potentially affected batches that remain within expiry.

In addition, your firm tested solvent from the (b)(4) tank in September 2011 and October 2011 to look for potential (b)(4) contamination via a gas chromatographic method. The chromatograms from both samples show large peaks for (b)(4) as well as small but detectable levels of at least ten other contaminants. These unexpected peaks should have indicated to your firm that the (b)(4) tank had been contaminated with pharmaceutical waste, as described above. Instead, your laboratory personnel ignored these unexpected peaks and conducted no investigation into what gave rise to them. As a result, your firm did not notice the (b)(4) tank contamination until a third sample from the tank was tested in January 2012.

In your response to the Form FDA-483, you stated that there was no reason to expect (b)(4) contamination and therefore the analyst did not notice the (b)(4) peak. Your response does not address why the analyst did not notice the numerous other detected contaminants in the chromatogram, nor did it address why a second reviewer did not notice the unexpected peaks in the chromatograms.

Posted in FDA Compliance, Regulatory Compliance, Warning Letters | Tagged , , , , , , , , , , | Leave a comment



Each fiscal year the FDA issues the various FDA 483 Observations from the various Centers to include CBER, CDER, CDRH, etc.  This Blog focuses only upon those issued by Center for Drug Evaluation and Research (CDER) and will concentrate upon those found within 21 CFR Part 211.  Interestingly, while the order of the Observations has remained constant within the top four, the number of Observations has markedly increased in numbers (from 340 in 2012 to 491 in 2013).  Of particular interest to my readers should be 21 CFR 211.113 (b) which pertains to the manufacture of sterile drug products.  In 2012 this Observation was considerably lower in terms of numbers of Observations noted (<43).

One should also be aware that the FDA, and CDER, in particular, use an internal electronic system to assist in positioning an Observation.  This system called TURBO EIR is designed to provide the most pertinent Observation vs. the information collected by the FDA auditor.  While this system is “painted” by the FDA as providing the most fool-proof method of providing the correct citation, it is especially notable within the area of microbiology that this often does not occur and one should question the number of microbiological citations, i.e., 21 CFR 211.113 (a)/(b) – especially when one studies 21 CFR 211.192 and recognizes that several of citations should not have been “192”, but 211.113(b).

Ref   No


Short   Description

21 CFR 211.22(d)


Procedures not  in writing,   fully followed
21 CFR 211.192


Investigations of discrepancies,   failures
21 CFR 211.100(a)


Absence of Written Procedures
21 CFR 211.160(b)


Scientifically sound laboratory   controls
21 CFR 211.67(b)


Written procedures not   established/followed
21 CFR 211.113(b)


Procedures for sterile drug   products
21 CFR 211.67(a)


Cleaning / Sanitizing /   Maintenance
21 CFR 211.165(a)


Testing and release for   distribution
21 CFR 211.110(a)


Control procedures to monitor and   validate performance
21 CFR 211.166(a)


Lack of written stability program
21 CFR 211.100(b)


SOPs not followed / documented
21 CFR 211.68(a)


Calibration/Inspection/Checking   not done
21 CFR 211.188


Prepared for each batch, include   complete information
21 CFR 211.84(d)(2)


Reports of Analysis (Components)
21 CFR 211.63


Equipment Design, Size and   Location
21 CFR 211.25(a)


Training–operations, GMPs,   written procedures
21 CFR 211.198(a)


Complaint Handling Procedure
21 CFR 211.113(b)


Validation lacking for sterile   drug products


Posted in FDA Compliance, Regulatory Compliance | Tagged , , , , , | Leave a comment



Canton Laboratories, India was found to have reported analytical results without having performed the testing.  C of A’s stated that the data conformed to specifications; however, multiple personnel confirmed that the testing was not performed.  Similar data was observed in July 2008 with other testing.  Please read below to learn more about another Indian example of data falsification and adulteration.                 

 1.      Failure to perform laboratory testing of APIs to ensure conformance to specifications and to accurately report results on Certificates of Analysis (CoA).   

Your firm reported microbial limits results on CoAs for three API batches without performing these tests.  Specifically, your firm has no raw data for the microbial limits tests reported on the CoAs for (b)(4) USP lots (b)(4), and (b)(4). Your quality unit approved the release of these API batches without data to support that release specifications were met. While your CoAs state that microbial limits conformed to specifications, the inspection found that no testing was done.  Multiple personnel confirmed that your firm did not perform the microbial tests reported on the CoAs.

Similarly, our inspection found other examples where your firm did not have raw data, yet reported testing as acceptable on your CoAs.  For example, your firm released (b)(4) USP (for use in (b)(4)) and (b)(4) USP (for use in (b)(4)) without supporting documentation for metallic impurities testing.

Your firm’s response to this observation stated that your firm has revised relevant SOPs and performed training on these SOPs.  We note that the previous inspection in July 2008 found a similar observation. That inspection found that your firm did not retain raw data and documentation for Karl Fischer titration, Assay, Specific Gravity, solubility, clarity, and pH of (b)(4), USP. Your firm’s response to the 2008 observation, similar to your response to the current findings, was to correct this issue through retraining and document revision. It is very concerning that your firm has not taken the proper actions to address the underlying issues.

In your response, provide a complete corrective action plan that begins with a retrospective review of the analytical data and batch records for all products that remain within expiration.  It is essential that this investigation includes all products manufactured at your site. In addition, provide details of the systemic actions taken to prevent recurrence of these fundamental deficiencies in laboratory data integrity and COA authenticity.                                        


Posted in FDA Compliance, Microbiological Issues, Permanent Injunction, Regulatory Compliance, Warning Letters | Tagged , , , , , , | Leave a comment




Baxter International Inc initiated a recall for a single lot of DIANEAL PD-2 Peritoneal Dialysis Solution with 1.5% Dextrose.  While the recall is due to non-integrity of the container-closure, it appears that complaints of particulate matter, identified as mold, were growing within the 6000 mL bags from the leak to the container.  Based on the comments within the recall, it appears that more than one complaint has been filed.  Please see the entire recall notice below.

FOR IMMEDIATE RELEASE - March 5, 2014 – DEERFIELD, Ill.,– Baxter International Inc. announced today it has initiated a voluntary recall in the United States of a single lot of DIANEAL PD-2 Peritoneal Dialysis Solution with 1.5% Dextrose 6000mL (Ambu-Flex II) to the hospital/user level. The recall is being initiated as a result of complaints of particulate matter, identified as mold, resulting from a leak in the container.

Intraperitoneal administration of a product contaminated with mold could result in life-threatening fungal peritoneal infection or sepsis. Baxter has received reports of adverse events for this lot of DIANEAL PD Solution; no causal relationship has been established between the events and this recall to date.

DIANEAL is a peritoneal dialysis (PD) solution for use in chronic renal failure patients being maintained on PD therapy. The one affected lot is C903799, expiration 05/15 (product code L5B9710), NDC 00941-0411-11. Product affected by this recall was packaged in flexible plastic containers and distributed to dialysis centers, facilities, distributors and patients in the United States.

Baxter notified customers by recall letter to instruct customers to locate and remove any affected product from their facility. All patients who received product from the affected lot also were contacted by recall letter and provided instructions to arrange for product return. Dialysis centers, facilities, distributors and patients should stop use and return to place of purchase.

The affected lot was distributed to customers between May 2013 and January 2014. Unaffected lot numbers can continue to be used according to the instructions for use. Healthcare providers who received affected product should return it to Baxter for credit by contacting Baxter Healthcare Center for Service at 1-888-229-0001, Monday through Friday, between the hours of 7:00 a.m. and 6:00 p.m., Central Time. Unaffected lots of product are available for replacement.

Posted in FDA Compliance, Microbiological Issues, Recall, Regulatory Compliance | Tagged , , , , , , | Leave a comment



The Mentholatum Co. recently issued a Recall for several different eye drops that were manufactured in Vietnam.  Similar eye drops manufactured in Japan were not included within this Recall.  The Recall was initiated due to a manufacturing review at the Vietnam production facility and involved sterility controls.  The Company indicated that there exists no evidence that the product does not meet specification and that this action is strictly a precautionary measure.  It remains of interest that this represents the first Recall that has been observed originating in Vietnam. 

Recall — Firm Press Release

 The Mentholatum Company Issues Voluntary Nationwide Recall of Rohto® Eye Drops Made in Vietnam

FOR IMMEDIATE RELEASE - Orchard Park, NY – January 16, 2014 – The Mentholatum Company announced today it is conducting a voluntary recall to the retail level of Rohto® Arctic, Rohto® Ice, Rohto® Hydra, Rohto® Relief and Rohto® Cool eye drops Made in Vietnam. This recall includes ONLY lots of product that were manufactured in Vietnam and DOES NOT include eye drops made in Japan. The lot numbers for products made in Vietnam will include the letter “V,” for example, “Lot 3E1V,” and will be located on the bottom panel of the carton, and on the bottom of the eye drop bottle. Products manufactured in Japan are not included in this recall and continue to be available to consumers.

The Mentholatum Company is initiating the recall due to a manufacturing review at the production facility in Vietnam involving sterility controls. To date, there has been no evidence indicating that product does not meet specifications; however, the company is taking this action as a precautionary measure.

The product is sold nationwide over-the-counter at pharmacies and retail stores. This recall affects Rohto® Arctic, Rohto® Ice, Rohto® Hydra, Rohto® Relief and Rohto® Cool eye drops that were made in Vietnam only, which can be identified by the words “Made in Vietnam” on the side carton panel under the company name and address information, as well as on the back label of the bottle.


Posted in FDA Compliance, Microbiological Issues, Recall, Regulatory Compliance | Tagged , , , , , , | Leave a comment


The U.S. Food and Drug Administration today notified Ranbaxy Laboratories, Ltd., that it is prohibited from manufacturing and distributing active pharmaceutical   ingredients (APIs) from its facility in Toansa, India, for FDA-regulated drug products. The Toansa facility is now subject to certain terms of a consent decree of permanent injunction entered against Ranbaxy in January 2012.

The decree contains, among other things, provisions to ensure compliance with current good manufacturing practice (CGMP) requirements at Ranbaxy facilities in Paonta Sahib and Dewas, India, as well as provisions to address data integrity issues at those facilities. In September 2013, the FDA added Ranbaxy’s Mohali facility to the CGMP provisions of the decree.

Under the decree, the FDA has issued an order prohibiting Ranbaxy from:

  • distributing in the United States drugs manufactured using API from Toansa, including drugs made by Ranbaxy’s Ohm Laboratories facility in New Jersey;
  • manufacturing API at its Toansa facility for FDA-regulated drug products;
  • exporting API from Toansa to the United States for any purpose; and
  • providing API from Toansa to other companies, including other Ranbaxy facilities, making products for American  consumers.

“We are taking swift action to prevent substandard quality products from reaching U.S. consumers,” said Carol Bennett, acting director of the Office of Compliance in the FDA’s Center for Drug Evaluation and Research. “The FDA is committed to ensuring that the drugs American consumers receive – no matter where they are produced – meet quality standards and are safe and effective.”

The FDA exercised its authority under a provision in the consent decree which permits the agency to extend the decree’s terms to any Ranbaxy-owned or operated facility if an FDA inspection finds the facility in violation of the Federal Food, Drug, and Cosmetic Act or FDA regulations, including CGMP requirements. CGMP requirements serve as the primary regulatory safeguard over drug manufacturing and must be followed by companies to ensure manufacturing quality. The FDA also acted under a separate provision in the decree which permits the agency to order additional corrective actions that FDA determines are necessary to achieve compliance with the law or the decree.

The FDA’s inspection of the Toansa facility, which concluded on Jan. 11, 2014, identified significant CGMP violations. These included Toansa staff retesting raw materials, intermediate drug products, and finished API after those items failed analytical testing and specifications, in order to produce acceptable findings, and subsequently not reporting or investigating these failures.

The agency is evaluating potential drug shortage issues that may result from this action. If the FDA determines that a medically necessary drug is in shortage or at risk of shortage, the FDA may modify this order to preserve patient access to drugs manufactured under controls that are sufficient to assure quality, safety and effectiveness.

As a result of this action, Ranbaxy is now prohibited from manufacturing API for FDA-regulated drugs at the Toansa facility and from introducing API from that facility into interstate commerce, including into the United States, until the firm’s methods and controls used to manufacture drugs at the Toansa facility are established, operated and administered in compliance with CGMP.

Ranbaxy is required to hire a third-party expert to thoroughly inspect the Toansa facility and certify to the FDA that the facility and its methods and controls are adequate to ensure continuous compliance with CGMP. Ranbaxy will not be permitted to resume manufacturing and distributing API for FDA-regulated drugs from the Toansa facility until the agency is satisfied that Ranbaxy has addressed its manufacturing quality issues at that facility.

The FDA recommends that patients not disrupt their drug therapy because this could jeopardize their health. Patients who are concerned about their medications should talk with their health care professional before discontinuing treatment.

Posted in 483, Consent Decree, FDA Compliance, Import Alert, Import Ban, Regulatory Compliance | Tagged , , , , , , , , , | Leave a comment


The U.S. Food and Drug Administration is alerting hospitals, health care professionals, and patients of a voluntary recall of all non-expired drug products produced and distributed for sterile use by Abrams Royal Compounding Pharmacy in Dallas, Texas. The recalled products include injectable medications, intravenous (IV) injections, eye drops, pellet implants, nasal sprays, inhalation solutions, and eye ointments that were distributed between June 17, 2013 and Dec. 17, 2013.

Contaminated sterile drugs put patients at risk of serious infection. Health care professionals who have received the affected products should stop using them and follow Abrams’ recall instructions.

The FDA is aware of one adverse event associated with mineral IV injection produced by Abrams’ lot number 11142013@74. A patient who received this product was admitted to a hospital in California and had blood cultures that tested positive for Stenotrophomonas maltophilia, a gram-negative bacterium that can cause many types of infections. These include respiratory infections such as pneumonia, bloodstream infections and meningitis. In addition, Abrams identified a similar gram-negative bacterium in the same lot of mineral IV injection.

“Patient safety is our top priority, and giving a patient a contaminated drug could result in a serious infection,” said Howard Sklamberg, director of the Office of Compliance in the FDA’s Center for Drug Evaluation and Research.   “Using these products puts patients at an unacceptable risk, and we urge health care professionals to follow recall instructions issued by the firm.”

Patients who were administered any sterile drug products produced and distributed by Abrams and have concerns should contact their health care professional.


An   adverse event notification was provided to the FDA for a single product,   mineral IV injection, produced by Abrams’, Lot number 11142013@74.  Blood cultures tested positive for   Stenotrophomonas maltophilia, a gram-negative bacterium.  Abrams identified a similar gram-negative bacterium in the same lot of mineral IV injection.

One may   ask the question why ALL non-expired drug products produced and distributed   for sterile use by Abrams was being recalled.    Because S. maltophilia is often found within Purified Water, and, because it appears that most if not all of these products used a water source that may have been derived from Purified Water that was present in their   facilities and/or the facilities were cleaned with Purified Water, then the bacterium would have the ability to contaminate their facilities.  If Water for Injection were used for the manufacture of the final product, the equipment used to manufacture the water would have killed this bacterium.  Thus, while a Root Cause analysis will determine the actual cause, speculation at this time suggests that the problem would have come from Purified Water.


Posted in FDA Compliance, Microbiological Issues, Recall, Regulatory Compliance | Tagged , , , , , , , , , , | Leave a comment