White & Blue Lion, Inc, City of Industry, CA recently recalled all lots of tattoo inks and tattoo needles due to pathogenic bacterial contamination.  The recall indicated that the “use of these products may cause bacterial infection and can lead to sepsis, a potentially life-threatening complication of an infection.  The recall includes all tattoo ink, tattoo needles, tubes, ink cups and kits…”

FDA laboratory testing has found bacterial contamination in both the inks and needles.

A variety of potentially pathogenic microorganisms were isolated from the tattoo kits (ink and needles) to include:  Gram negative bacteria, Gram positive rods and cocci, which were identified as Bacillus spp., Sphingomonas paucimobilis, Micrococcus lutes, Corynebacterium spp., Clostridium botulinum and other Clostridium spp.  The recall made a point that no mycobacteria were isolated.

A variety of potentially pathogenic organisms were also isolated and identified from the ink sets.  These included Gram negative bacteria, Gram positive rods and cocci which were further identified as Bacillus spp., Acinetobacter spp., Staphylococcus haemolyticus, and Sphingomonas paucimobilis.

This recall was made with the knowledge of the US Food and Drug Administration.

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Between October 29 and November 1, 2013, the FDA inspected Marck Biosciences Ltd., Kheda, India.  As a consequence of this audit, the FDA issued six extensive Observations.  This Blog only reviews Observation 5 (a) and 5 (b).

  1. “Your firm failed to maintain the buildings used in the manufacture, processing, packing, or holding of a drug product in a clean and sanitary condition and keep them free of infestation by rodents, birds, insects, and other vermin (21 CFR 211.56(a)).


Other sections of 21 CFR 211.56 are included below. These sections continue to amplify the issues found within the facilities. 

21 CFR 211.56(b) states that “there shall be written procedures assigning responsibility for sanitation and describing in sufficient detail the cleaning schedules, methods, equipment, and materials to be used…

21 CFR 211.56(c) states there shall be written procedures for use of suitable rodenticides, insecticides, fungicides, fumigating agents, and cleaning and sanitizing agents. Such written procedures shall be designed to prevent the contamination of equipment, components, drug product, containers, closures, packaging, labeling materials or drug products and shall be followed….”

  1. During the inspection, investigators noted significant mold growth in the washroom located at the entry to the sterile manufacturing area.  The ceiling of this room had been allowed to deteriorate to such an extent that it caved in.  This room shares a common mezzanine with the adjacent sterile processing rooms.

Your response does not identify any efforts to identify the mold growth or relate it to environmental monitoring data from the neighboring sterile suite, nor does it discuss the potential effect on the microbial quality of products made in your facility.  Your response also does not discuss why this deterioration was permitted by your management until our inspection of the facility. In response to this letter, describe your investigation into the extent of mold within your facility, including within your HVAC system.  Describe any additional findings of mold, corrective measures, and your investigation into the effect of any findings on product quality.


It appears that the facilities’ management chose not to perform any remediation of the area containing mold until the FDA arrived. When mold becomes visible to the naked eye, and no one automatically performs remediation, this suggests significant neglection of responsibilities. Also, the FDA Guidance for Industry (2004) Sterile Drug Products, requires any microorganisms isolated from such areas to be identified. 

We note that a recent MHRA report of a December 2013 audit conducted at your facility discussed the findings of fungus growth within a large volume parenteral product manufactured at your facility.  Please provide a full accounting of this incident and a copy of your investigation into the matter, along with corrective and preventive actions taken.


Because the various regulatory agencies interact with one another and share information, it is not surprising that this event became available to others. Finding fungal growth within LVP (large volume parenterals) within the ISO 5 environment begs the question as to the root source of the fungal masses. Fungal masses within LVP often are obvious to the naked eye.

  1. The investigators noted numerous dead insects in the “Sample Pass Through” Room, located approximately (b)(4) from the Sterile Filling Line #(b)(4) of the small volume parenterals facility.  In addition, dead and decaying frogs were found next to the product exit dock. Your response states that these pest infestation issues would be corrected.  It also includes a commitment to remove the manufacturing waste near the entrance to the facility and to fill in the swamp-like perimeter that appeared to be serving as a harborage for vermin.  Your response does not address why the observed conditions were permitted to exist in and around the manufacturing facility.  In response to this letter, discuss this issue and provide details of your pest prevention program.


The presence of “numerous dead insects in the “Sample Pass Through” Room, located approximately (b)(4) from the Sterile Filling Line #(b)(4) of the small volume parenterals facility” again questions why management was not aware of this condition.   Similarly, the presence of “dead and decaying frogs” gives pause as to why this firm was not immediately placed on “Import Alert”.

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After the Warning Letter for Zhejiang Jiuzhou Pharmaceutical Co. was published in a recent Blog (8/20/14), several of my colleagues sent me comments regarding this Chinese Active Pharmaceutical Ingredient (API) source. They were particularly intrigued by the Blog because one had observed an Import Alert that was issued by the FDA on March 18, 2014, but could find no information to support it. Another individual indicated that the FDA may issue an Import Alert if there appears to exist through an inspection so many critical findings that immediate action is required.

A somewhat similar Blog in 2011 was written wherein H&P Industries had two rather significant FDA Form 483s in 2011, never was issued a Warning Letter, but rather had product seized several months later and then several months after that was issued a Consent Decree.  When the FDA deems that significant harm may occur to the general population, they may take rapid action.

Another colleague purchases upstream compounds to use as starting materials.  The question raised by this individual was “If API manufacturer(s) purchase materials from this company, could it cause problem?”

For an answer to this question, I refer to ICH Q7.  Within ICH Q7,

7.1 General Controls

7.10 There should be written procedures describing the receipt, identification, quarantine, storage, handling, sampling, testing and approval or rejection of materials

7.11 Manufacturers of intermediates and/or APIs should have a system for evaluating the suppliers of critical materials

7.13 If the supplier of a critical material is not the manufacturer of that material, the name and address of that manufacturer should be known by the intermediate and/or API manufacturer

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Zhejiang Jiuzhou Pharmaceutical Co., Ltd. (China) was inspected from October 21-24, 2013 at their active pharmaceutical ingredient manufacturing facility.  Deviations from CGMP were noted in the manufacture of the API.

  1. “Failure to implement an effective system of managing quality and failure to transfer all quality or regulatory information received from the API manufacturer to your customers.

Your trading company, hereafter referred to as Zonebanner, purchased APIs from an outside supplier and relabeled them without the oversight of a quality unit.  The information from the original certificate of analysis, generated by the actual manufacturer, was transferred to a new certificate of analysis on Zhejiang Jiuzhou Pharmaceutical Co. letterhead with no information about the original manufacturer or analytical laboratory performing the analyses.  In addition, a new label identifying Zhejiang Jiuzhou Pharmaceutical Co. as the manufacturer was added to drums.  In doing so, your firm essentially obscured the supply chain of these APIs.

Zonebanner had no quality system in place for the relabeling operations.  In addition, we note that in at least one instance of a lot of gabapentin shipped to the U.S., the retest date from the original manufacturer’s certificate of analysis (November 2013) was changed to an expiration date listed as eleven months later (October 2014) on the new certificate of analysis…

In response to this letter, provide details of the proposed quality system to be implemented at Zonebanner.  Describe procedures and provide examples that demonstrate that traceability is maintained for currently distributed APIs and that information sent to customers includes an accurate representation of the manufacturer and analytical testing laboratory.  In addition, provide your rationale for the expiry extension of the gabapentin lot described above.  If this or other similar extensions were unsupported, then describe your intended actions for the lot(s) in question.”


Unfortunately, this is not the first of these kinds of issues arising within China. Transferring of information to a new certificate of analysis on Zhejiang Jiuzhou Pharmaceutical Co. letterhead with no information about the original manufacturer or analytical laboratory performing the analyses obscures the supply chain of APIs. In addition, changing the original manufacturer’s certificate of analysis to an expiration date listed as eleven months later on a new certificate of analysis.


“In addition to violating CGMP, your firm shipped a misbranded active pharmaceutical ingredient to the U.S.  As described above, according to our inspection, your firm prepared a certificate of analysis (COA) for gabapentin on your firm’s letterhead, indicating that the product was manufactured by your firm, Zhejiang Jiuzhou Pharmaceutical Co., Ltd, when in fact it was not.  The gabapentin was manufactured by (b)(4).  In addition, the expiration date on your firm’s COA is not one supported by the COA from the original manufacturer, (b)(4).

Moreover, your firm relabeled gabapentin and included on the label an official stamp that identifies your firm, Zhejiang Jiuzhou Pharmaceutical Co., Ltd, as the manufacturer of the product, rather than the actual manufacturer, (b)(4).  Based on our findings, the active pharmaceutical ingredient, gabapentin, is misbranded within the meaning of Section 502(a) of the Act [21 U.S.C. 352(a)] in that its labeling is false or misleading in any particular. See also 21 CFR 201.1(h)(2).”


Including on the label an official stamp that identifies this firm as the manufacturer of the product, rather than the actual manufacturer constitutes misbranding within the meaning of the labeling as false or misleading.

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The FDA inspected the Trifarma S.p.A. pharmaceutical manufacturing facility, located at Via Pavese 2, Rozzano, Italy from January 27 – 29, 2014.  They identified significant deviations from current good manufacturing practice (CGMP) for the manufacture of active pharmaceutical ingredients (APIs).

Three Observations were noted (see below) that have historically been observed within other Warning Letters previously issued by the FDA.  It is surprising that this firm was not aware of several of those Warning Letters to include a Form FDA 483 received by another of their Italian plants.

“1.    Failure to maintain complete data derived from all testing and to ensure compliance with established specifications and standards pertaining to data retention and management.

Your firm did not retain complete raw data from testing performed to ensure the quality of your APIs. Specifically, your firm deleted all electronic raw data supporting your high performance liquid chromatography (HPLC) testing of all API products released to the U.S. market. In addition, your firm failed to retain basic chromatographic information such as injection sequence, instrument method or integration method for the tests. Your firm’s lack of data control causes us to question the reliability of your data.

In addition, your laboratory management was unaware of, and therefore did not follow, the written procedure detailing the review of analytical data. Furthermore, your management confirmed that the review of analytical data did not include evaluating the system suitability parameters to ensure proper column performance.

Your response states that your firm has been researching backup systems since July 2013 and will have a backup system online by the third quarter of 2014. Your response also states you have begun provisionally storing backup data on each computer, including the integration method as part of that data. However, you do not address the backup of the injection sequence, the instrument method or audit trails.  In addition, your response does not address how your firm will ensure that electronic files are not deleted prematurely from local computers.

In response to this letter, provide a comprehensive corrective action plan addressing the foregoing concerns. Include information regarding system-wide changes, revised procedures, and appropriate retraining of employees that will be implemented immediately to ensure retention of complete electronic raw data for all laboratory instrumentation and equipment.”


Deleting of electronic raw data, especially with HPLC, is not new.  Several firms to include Wockhardt’s Walui and Chikalthana Facilities, Maharasthtra Receive Warning Letter (11/25/13) (posted on 12/3/13) and Dr. Reddy’s Laboratories Indian Mexican API Facilities Cited by FDA in Warning Letter (posted 7/06/11) within recent years have been cited for the failure to retain basic chromatographic information. In addition, as noted within the Warning Letter ICH Q7 discusses the need to provide system suitability to assure proper column performance.  Also, responses to Observations need to be complete and comprehensive. 

“2.    Failure to prevent unauthorized access or changes to data and to provide adequate controls to prevent omission of data.

Your firm did not have proper controls in place to prevent the unauthorized manipulation of your laboratory’s raw electronic data.  Specifically, your laboratory systems did not have access controls to prevent deletion or alteration of raw data. The inspection noted that all laboratory employees were granted full privileges to the computer systems.

In addition, prior to January 7, 2014, HPLC and gas chromatograph (GC) computer software lacked active audit trail functions to record changes to data, including information on original results, the identity of the person making the change, and the date of the change.

Your response states your Agilent GC system and HPLC systems now have audit trails, with (b)(4) more GC systems to be upgraded by the second quarter of 2014. However, your response did not describe the audit trails for the processing of the data on your Agilent systems. Your response also states your firm has begun to retain electronic raw data on the local hard drive, but without proper safeguards to ensure they cannot be deleted prematurely. Such safeguards will not be implemented until the third quarter of 2014.

In response to this letter, provide your corrective action plan to prevent deletion and alteration of electronic data. In addition, describe with more detail your firm’s new archival process and provide assurance that it will consistently function to prevent the types of failures described above from recurring in the future.

We also note that your firm lacked electronic raw data supporting cleaning, method and process validations.  In response to this letter, provide a corrective action plan to review all related test methods associated with products distributed to the U.S. in light of the lack of supporting raw data. 


Laboratory electronic data systems require a hierarchy of access controls by users that include every level from no changes permitted to full access to change.  Again, the FDA has cited other firms for this same issue.  Please visit my Blog entitled “Failure to Protect Computerized Data – A Reminder of Sandoz and Cephazone Pharma’s FDA Warning Letter Issues (9/03/13)  Audit trails were also again noted in this Citation, and were more specific as to the FDA’s various concerns.

“3.    Failure to ensure that employees receive appropriate and documented training on the particular operations that the employee performs.

Your firm did not document any training of production employees on the production operations they perform. Specifically, operators in Synthesis Plant (b)(4) did not have any documented on-the-job training associated with the production operations they perform. In addition, your management was unaware that they should follow the SOP for the issuance of CoAs, which provides for a review of relevant analytical data. Without documented training, there is a lack of assurance that your employees can reliably execute their API manufacturing responsibilities requirements.

Your response states your firm had updated your training SOP in July 2013 to include on-the-job training along with CGMP training However, the current inspection revealed that your firm is not following this procedure.”


Observation #3 is self-explanatory.  In addition, the FDA found that the Client is not following the training SOP.  Unless SOPs that exist on one’s site are followed, the FDA will very likely cite that Client.


The FDA also reminded this firm that their Ceriano Laghetto, Italy plant received similar deficiencies to those cited in this Form FDA 483 and subsequent Warning Letter. “It is essential that your firm implement a robust global quality system.”

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Health Canada recently issued a summary report of their recent audit of ID Biomedical (GSK).  Within this report, they presented summaries of both their 2012 and 2014 Inspections.  Enclosed are copies of selected sections of both Inspections as well as my additional comments.


Health Canada’s 2012 regular GMP inspection of the Sainte-Foy facility concentrated on laboratory activities. This included assessing how solutions were prepared, how vials were filled and labelled, and visual inspections of finished products.

While the inspection did not identify any critical observations (classified as risk 1) that required immediate action to protect the health and safety of Canadians, it did identify two major observations (classified as risk 2) related to staff practices in areas that are maintained in such a way as to restrict the growth of microorganisms in the environment, prevent contamination and ensure sterility. Inspectors made other observations (classified as risk 3) that were related to incomplete standard operating procedures, analysis methods, and minor deficiencies in the visual inspection program.

The facility was given an overall compliant rating based on the review of all observations made during the inspection. As part of the normal inspection process, the facility submitted a corrective action plan to respond to the observations. Health Canada reviewed the plan and found it addressed the observations in a timely manner to the Department’s satisfaction. Assessment of the implementation and effectiveness of these corrective measures were verified during the 2014 inspection.”


While it is difficult to determine the exact Observations from what was stated in the summary, the comment regarding “to restrict the growth of microorganisms in the environment, prevent contamination and ensure sterility” are some of the same items noted within the 2014 FDA Warning Letter. These comments made by Health Canada would raise the interest level of FDA Investigators.


Manufacturing Controls

…It was observed that previous changes made to the water quality systems did not address reoccurring issues with respect to microbial contamination. An additional observation related to the efficacy of one of the disinfecting products used to cleanse certain microorganisms which had not been assessed regularly.”


Please note that a similar comment was made within the recent FDA Warning Letter. Also, any time that sequential Form FDA 483s occur, and that the Observation is recurring, this recurrence is likely to cause the issuance of a Warning Letter. Health Canada acknowledged a repetition of similar Observations during both 2012 and 2014, but did not increase the severity of the Citations beyond a “Major”. Often when Regulatory organizations find several “Major” Citations, they will elevate the combination of Citations to a “Critical”.

Quality Control Systems:

“Observations regarding the management of some quality control systems were also noted. An observation pertained to the management of the environmental program for the production areas and the need for improvement to ensure that they are sterile at all times. It was noted that a piece of filling equipment was not being sufficiently monitored to detect microbial levels. There were also gaps in how complaints concerning potentially defective products were evaluated and investigated. In addition, deficiencies were noted in the way the facility documented what the impact of deviations from established procedures or standards was on the quality of the products. Lastly, the facility runs a simulation of its production line. It was noted that the facility did not compare the rejection rate between the actual product line and the simulation.”


An observation “pertained to the management of the environmental program for the production areas and the need for improvement to ensure that they are sterile at all times”. This particular observation could be significant since the issue of lack of sterility would potentially cause the manufacture of non-sterile product. The comparison of “the rejection rate between the actual product line and the simulation” is difficult to discern as to its meaning. It appears that this does not relate to sterility, but to all of the vials that may have been removed for a variety of AQL reasons.


“Due to the short timeframe between the U.S. FDA and the Health Canada inspection, ID Biomedical Corporation of Quebec was unable to implement all of the corrective actions it proposed in response to the U.S. FDA observations before the initiation of the Health Canada inspection. Health Canada will continue to exchange information and results with the U.S. FDA on the GMP practices at the ID Biomedical Corporation of Quebec.

ID Biomedical Corporation of Quebec has been cooperative throughout the inspection process, moving quickly to address the observations of the inspectors. GSK is requested to provide by August 4, 2014 its corrective action plan to Health Canada to outline how it will address all of the observations identified at the time of the Health Canada inspection. Health Canada will actively monitor the implementation of the action plan at the Sainte-Foy facility…”

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FDA Warning Letters – Their Relationship to Drug Shortages — An Interesting Counterpoint

Recently (June 12, 2014) I authored a Blog re: “FDA Warning Letters – Their Relationship to Drug Shortages”.  This Blog elicited several very interesting comments.  Within this Blog, I noted that Douglas C. Throckmorton, MD, Deputy Director for Regulatory Affairs, CDER, FDA recently presented at the ISPE meeting on June 4, 2014 where he discussed this topic and illustrated the “FDA Response to Drug Shortages”.

A private communication that subsequently arrived looked at this issue from a different vantage point.  This vantage point discusses how many drugs that have had import alerts, seizures, consent decrees and other judicial actions have required the drugs to be removed from the market without any apparent regard for medical necessity.  In all fairness to the FDA, the Agency does attempt to have replacements available.  However, when they are not available, perhaps the FDA needs to consider what will happen when that patient, often cancer related, cannot receive a medication for several months.  I am not advocating non-sterile products be introduced into the product stream, but, as noted below, will a few particulates harm anyone who may otherwise be critically harmed before the medication is again available?

Please read the note below.  As always, your comments are appreciated.

“WOW! This discussion has hit so many points it could easily be broken down into a dozen different threads. However, the major concern I have with these types of discussion is that there really is no completely right or wrong answers given as people focus on answering a part and don’t address the whole issue. It is also interesting to see how “data” can be manipulated, i.e., FDA working with early notification has prevented some 200+ shortages. How about the other side of the coin where the remaining large number of shortages not prevented by the FDA was being created due to over interpretation of regulations by any investigator who happens to “believe” that something is wrong – even if there is no data to prove it.  How many hundreds of lots and tens of thousands of dosages with absolute MINIMUM potential for medical harm (virtually non-existent) have been “lost” to patients?  In these non-critical medical recalls, why hasn’t the FDA gotten “with it” and worked out these issues with risk analyses regulatory discretion resolutions as well?  Sorry – but I do not see the needs of patients being helped more by holding back or withdrawing these products from the marketplace. In a personal discussion with a cancer patient well respected in our industry and known to most – when I asked if it was a question of “possibly getting a particle injected OR not getting the drug at all – the reply was “not even a decision to be given a second thought – GIVE ME THE DRUG!!!” Stopping the problems in the industry – particularly with some notorious firms – is absolutely needed – but we can’t do it while causing more harm than good.”

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