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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GSK (GlaxoSmithKline) recently received a Health Canada inspection report on July 3, 2014, almost a month (6/12/14) following FDA’s issuance of a Warning Letter for the same facility.  While Health Canada did not release specifics of the involved issues, it did indicate some of the findings were similar to those Observations noted by the FDA.  As you may recall from the previous Blog on this subject, FDA Investigators found Gram negative bacteria in the Purified Water systems and an on-going issue with Out of Trend (OOT) results for endotoxin. Health Canada is currently writing a summary report which will be issued upon completion.

Health Canada gave GSK a “Compliant” rating which indicates that the problems do not pose an immediate risk to the citizens of Canada.  Even with a “Compliant” rating, corrective actions were required.

The FDA noted that 21% of the plant’s production in 2014 could not be released to market because of GSK’s various problems.  The Ste. Foy facility is contracted to produce 53% or 6.36 million of the roughly 12 million seasonal flu vaccine doses that Canada has ordered for 2014-15.  Another 23 million does is anticipated for delivery to the U.S.

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ID Biomedical Corp, a subsidiary of GSK Biologicals, located in Quebec, Canada was audited by the FDA from March 31 through April 9, 2014.  The FDA Investigators documented deviations from CGMP in the manufacture of their biological drug product, Flulaval and its intermediates.  Significant objectionable conditions included:

  1. You failed to assure that appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile, are established and followed. Such procedures include validation of all aseptic and sterilization processes [21 CFR 211.113(b)]. Specifically, deviation #200217121 was initiated March 5, 2012 to investigate out of trend (OOT) results for endotoxin. The average endotoxin in the first 20 seasonal (b)(4) monovalent lots for 2012 was higher than the first 20 in 2010, and 2011. The investigation concluded that the endotoxin results have been atypical since May 2011.


What is interesting within this particular citation is that the FDA indicated that the endotoxin results were OOT, not necessarily failing – but definitely atypical and should have been corrected, not an on-going issue.  However when one views the next Observation, one recognizes that the Purified Water (PW) systems have had on-going issues for several years, and that the Client has not been able to satisfactorily cleanse the system and maintain it in an acceptable state.  With the variety of Gram negative bacteria that were encountered, it may be somewhat surprising that the Client only had OOT and not OOS results.

  1. Controls for the purified water system at your facility are inadequate to prevent bioburden and endotoxin excursions.
  2. The 2012 Annual Product Quality Review report for water indicates that there were many bioburden excursions in purified water system (b)(4)(Loop (b)(4). Water from Loop (b)(4) is used in part to humidify air in (b)(4). Different types of bacteria were found, but in the majority of cases, the microorganisms found were Ralstonia picketti and Achromobacter spp.
  3. The 2013 Annual Product Quality Review report for water concludes that four alert limits and one action limit were reached for water system (b)(4) (Loop (b)(4). Water from Loop (b)(4) is used in part for equipment washing. Organisms isolated from these five excursions included Ralstonia picketti and Achromobacter xylosoxidans. Achromobacter xylosoxidans and other water borne gram negative bacteria have been implicated in product contamination issues at you facility as far back as 2011. 
  4. There is not set schedule for disinfection of your water system. The system is only disinfected on (b)(4). The system was disinfected twice in 2011, five times in 2012, four times in 2013 and once in 2014 to date. In addition the water system is circulated (b)(4) temperature and is cleaned with (b)(4). No (b)(4) is used in the system.


During 2012, 2013 and 2014 (to audit date), a number of bioburden and endotoxin excursions occurred. The bacteria found were those Gram negatives that are typically found in Purified Water (PW) Systems that are not maintained in a controlled state. Please note that while the specification for PW is 100 CFU/mL, when one finds a predominate number of a few species, and those species can be classified as “in-house” Gram negative isolates, it suggests that the PW system is not in control.

When PW is used for equipment washing, and the PW is contaminated, there is a high probability that the final product produced will have a high likelihood of being contaminated as well. Ideally, any equipment that will have contact with the final product should not be washed, and never rinsed, with anything other than Water for Injection (WFI).

Within the Warning Letter, it was also observed that the PW system was only disinfected twice (2011), five times (2012), four times (2013) and once (to date, 2014). It also appears that the FDA had an issue with the temperature maintained and what was used for cleaning. However, this information was redacted.

The FDA suggested that the SOPs governing disinfection of the water system was “weak” and that the SOPs should either suggest a schedule or provide guidance based upon testing. The author’s experience with both PW and WFI systems suggests that it is not difficult to control the bacterial count through the use of temperature control – either with continuous or intermittent heating.

Because the severity of these Observations, the Warning Letter requests that ID Biomedical and GSK arrange to have meetings with the FDA to discuss the issues cited as well as encourage frequent interaction between the Client and technical staff with FDA to move forward as rapidly as possible. ID Biomedical also has provided commitments of corrective and preventive actions. However, it appears that the FDA questions their abilities based upon their lackluster history.

Interestingly, the FDA has not placed any of their “boilerplate” verbiage re: Drug Shortages within the Warning Letter.   Does this suggest that sufficient other manufacturing resources exist for this biological?


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FDA Warning Letters – Their Relationship to Drug Shortages

The FDA has become keenly aware within the past several years of the impact that their audits have on the availability of drugs becoming available to the consuming public.  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 and illustrated the “FDA Response to Drug Shortages”.

Within his presentation, he discusses 1) shortages as a significant public health threat; 2) FDA’s role in drug shortages; 3) recent FDA activities; and 4) future FDA directions.  He noted that the three primary sources of drug shortages include Quality manufacturing issues of 1) Quality: facility remediation efforts (35%); 2) Quality: product manufacturing issues (31%), and 3) discontinuation of product (14%).  Examples of Quality manufacturing issues included sterility, particulates, crystallization, precipitation, etc.

For sterile injectables, he noted that the state of industry was an issue because a small number of manufacturers make up most of the market, a lack of redundant manufacturing, complex manufacturing processes, and very inexpensive products (in some situations).

It was noted that an Executive Order from President Obama directed the FDA to use its authorities to encourage early notification of potential shortages.  It became particularly obvious within any Warning Letters that were issued within the past several years.  As a result, close to 200 drug shortages were prevented in 2011 and more than 280 in 2012.  Injectables were a large percentage of those averted in the time frame of 2010-2013.  The two primary notification sources for sterile injectable drugs were manufacturers (40%) and FDA inspections (43%).

To review the Strategic Plan and learn of the Future of Drug Shortages, please review the following web site that contains all of the slides presented as well as illustrated graphics.  Please visit: http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM400503.pdf?source=govdelivery&utm_medium=email&utm_source=govdelivery

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TurboEIR is a FDA software program designed to standardize Form FDA 483s and Establishment Inspection Reports (EIR).  It was completely “rolled out” in October 2002. For each “Objectionable Condition” (FDA 483 Observation), TurboEIR requests the inspection team to choose a “canned” citation and then describe the details of the situation.  In addition, each “canned” citation contains a paraphrase of the underlying authority. Quite often the underlying authority is a regulation from Title 21, Code of Federal Regulations, but may also be a statutory reference.

TurboEIR is strongly encouraged by FDA management for the purpose of writing accurate, consistent, and complete reports and documents as well as increase the efficiency of report writing.

Each team member who has a TurboEIR laptop can independently work on the Form FDA 483 on their own.  However, because citations can only be used once per 483, significant communication and coordination is required.  In some cases the analysts will write each Observation, locate the regulation within the CFR for that specific Observation and then locate the citations on the TurboEIR website.  In these cases, the information is then provided to the Lead Investigator who will incorporate it into the Form FDA 483.

Investigators should be aware some of their Observations might duplicate manufacturing Observations of the same violated regulation.  In these situations, the Observations are grouped under one citation.  For many of the CFR regulations, there are multiple citations to choose from in TurboEIR, since there may be multiple ways for a firm to violate a given regulation.  Care must, however, be taken in selecting the best citation for the violation(s) observed.

Because of the opportunity for the Investigator is choose from multiple citations, the astute follower of Form FDA 483s recognizes that some of the citations and their subsequent examples don’t always appear to completely logically follow.  An excellent example of this relates to the use of 21 CFR 211.192 when 21 CFR 211.113 (a) or (b) should be used.  For example:

21 CFR 211.192 Production Record Review states:

All drug product production and control records, including those for packaging and labeling, shall be reviewed and approved by the quality control unit to determine compliance with all established, approved written procedures before a batch is released or distributed. Any unexplained discrepancy (including a percentage of theoretical yield exceeding the maximum or minimum percentages established in master production and control records) or the failure of a batch or any of its components to meet any of its specifications shall be thoroughly investigated, whether or not the batch has already been distributed. The investigation shall extend to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy. A written record of the investigation shall be made and shall include the conclusions and follow-up.

21 CFR 211.113(a)(b) Control of Microbiological Contaminations states:

(a)  Appropriate written procedures, designed to prevent objectionable microorganisms in drug products not required to be sterile, shall be established and followed.

(b)  Appropriate written procedures, designed to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed.  Such procedures shall include validation of all aseptic and sterilization processes

While these two citations appear completely different, they are often used interchangeably by Investigators.  (Please see the author’s Blog entitled “Hemofarm  A.D., Vrsac, Serbia Received Warning Letter (6/20/12) for Aseptic Processing Issues” which was posted on December 9, 2012.  This represents an excellent example of a “cross-over” where one might question the use of 21 CFR 211.192 in lieu of 21 CFR 211.113.

Some Investigators that perform several inspections within a year will often print out the main or often used citations.  Doing this allows the Investigator to read the citation on paper and discuss it with other Investigators whereas doing all on the computer may prove to become more cumbersome.

Please review the two following Blogs for the most frequently cited 2012 (April 24, 2013) and 2013 (March 20, 2014) Observations noted by FDA CDER.  Please note that 21 CFR 211.192 is within the top five most frequently listed. One wonders how many of these “192” citations should have been “113”?

Additional information on this subject may be obtained by attending the author’s Pharmawebinar sponsored by Tungstenshield.com on Wednesday, June 18, 2014 at 1 PM (EDST). The title for this webinar is “Deconstructing Warning Letters“ – Using Warning letters to Illustrate the FDA and Health Canada CFRs


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This Blog site periodically provides 483s and Warning Letters as well as commentary as a service to its clientele. A question frequently asked is “when is a 483 issued as well as what are the implications of a 483”. The FDA has recently issued a “FDA Form 483 Frequently Asked Questions” on their web site that addresses many of these questions and more. Since a 483 may also lead to a Warning Letter, management wants to know if the 483 that I just received may potentially lead to such. This is also covered within this FDA Q & A. Recent Blog postings also include the most frequent FDA CDER Observations for FY 2012 and 2013. Please read the posting below to assist you with answers on this important topic.

Q: When is an FDA Form 483 issued?

A: An FDA Form 483 is issued to firm management at the conclusion of an inspection when an investigator(s) has observed any conditions that in their judgement may constitute violations of the Food Drug and Cosmetic (FD&C) Act and related Acts. FDA investigators are trained to ensure that each observation noted on the FDA Form 483 is clear, specific and significant. Observations are made when in the investigator’s judgement, conditions or practices observed would indicate that any food, drug, device or cosmetic has been adulterated or is being prepared, packed, or held under conditions whereby it may become adulterated or rendered injurious to health.

Q: What is the purpose of an FDA Form 483?

A: The FDA Form 483 notifies the company’s management of objectionable conditions. At the conclusion of an inspection, the FDA Form 483 is presented and discussed with the company’s senior management. Companies are encouraged to respond to the FDA Form 483 in writing with their corrective action plan and then implement that corrective action plan expeditiously.

Q: Is the FDA Form 483 intended to be an all-inclusive list of every possible deviation from law and regulation?

A: No, it’s not. The FDA Form 483 is a report which does not include observations of questionable or unknown significance at the time of the inspection. There may be other objectionable conditions that exist at the firm that are not cited on the FDA Form 483. FDA investigators are instructed to note only what they saw during the course of the inspection. Companies are responsible to take corrective action to address the cited objectionable conditions and any related non-cited objectionable conditions that might exist.

Q: How is the FDA Form 483 shared with the company?

A: FDA Form 483s are discussed with a company’s management at the conclusion of the inspection. Each observation is read and discussed so that there is a full understanding of what the observations are and what they mean.

Q: What are the implications of the FDA Form 483 for agency enforcement and what happens next?

A: The FDA Form 483 does not constitute a final Agency determination of whether any condition is in violation of the FD&C Act or any of its relevant regulations. The FDA Form 483 is considered, along with a written report called an Establishment Inspection Report, all evidence or documentation collected on-site, and any responses made by the company.   The Agency considers all of this information and then determines what further action, if any, is appropriate to protect public health.


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Barry A Friedman, PhD has been publishing a variety of Regulatory Actions including information regarding Warning Letters, Recalls, and other regulatory activities for over three years.

These 140+ Regulatory Actions often include FDA related activities that are not readily found within the FDA web sites. In addition to these various Regulatory Actions, the Blog includes over 800+ “Key Search” terms where one might focus upon various Regulatory Actions. All of this may be found at: http://barryafriedmanphdllc.wordpress.com/

For those of you that may be interested in Dr. Friedman’s on-going webinars that complement these Regulatory Compliance issues, please visit Pharma Webinars at: http://www.tungstenshield.com/course-list-barry-friedman

Posted in 483, Consent Decree, Dietary Supplements, FDA Compliance, Import Alert, Import Ban, Microbiological Issues, New Guidances for Industry, Recall, Regulatory Compliance, Seizure, Warning Letters, Webinar | Tagged , , , , , | Leave a comment