DOJ and Pharmakon

You may recall several of my blog posts concerning Pharmakon Pharmaceuticals, their FDA inspections, the resultant 483’s and their release of sub/super potent drugs.  This morning DOJ released a press release concerning the indictment of Pharmakon’s owner and director of compliance. DOJ and Pharmakon

Thursday, June 22, 2017

Pharmacy owner and director of compliance charged with defrauding United States and distributing adulterated drugs


Indianapolis – Josh J. Minkler, the United States Attorney, announced today the owner and director of compliance of an Indiana compounding pharmacy were charged criminally in connection with their distribution of over- and under-potent drugs, and defrauding the United States by interfering with and obstructing the lawful functions of the Food and Drug Administration (FDA).

J. Elmer, 64, of Fishers, Indiana, and Caprice R. Bearden, 62, of Carmel, Indiana, were charged in a 10-count indictment with one count of conspiracy to defraud the United States, three counts of distributing an adulterated drug in interstate commerce and six counts of adulterating drugs while held for sale after shipment of a drug component in interstate commerce. Elmer was arrested yesterday and had his initial court appearance in U.S. District Court in the Southern District of Indiana where he pleaded not guilty and was released under conditions imposed by the Court. Bearden was issued a summons to appear before the court. Trial has been scheduled for August 21, 2017 at 9:00 a.m.

“These defendants put greed and the reputation of their company ahead of the health and safety of our most innocent victims,” said Minkler. “Their actions put lives in danger and they will be held accountable.”

“The distribution of over- and under-potent drug products poses a serious risk of harm to patients,” said Acting Assistant Attorney General Chad A. Readler of the Justice Department’s Civil Division. “FDA’s efforts to ensure the safety of compounded drugs is critically important. Impeding FDA’s ability to do its job and uncover these types of safety concerns will not be tolerated. The Justice Department is committed to working with FDA to protect patients and ensure compounded drugs are safe.”

Elmer owned and was the President of Pharmakon Pharmaceuticals Inc. (Pharmakon), and Bearden was the company’s Director of Compliance. Pharmakon compounded drugs at a facility in Noblesville, Indiana for customers in Indiana and many other states.

The indictment alleges that from July 2013 through mid-February 2016, Bearden received approximately 70 potency test failure notices from companies used by Pharmakon to test for potency, indicating that drugs such as morphine sulfate and fentanyl were either under- or over-potent. According to the indictment, Bearden discussed the out-of-specification test results with Elmer, a licensed pharmacist, and until Pharmakon compounded over-potent morphine sulfate in February 2016, Elmer determined that Pharmakon should not contact any individuals or entities – including hospitals – who received the drugs, nor conduct any product recalls before FDA intervention.

On several occasions, according to the indictment, infants were injected with drugs compounded by Pharmakon that were significantly over-potent. For example, the indictment alleges that in early February 2016, Pharmakon distributed over-potent morphine sulfate, an opioid typically used for relief of moderate to severe acute and chronic pain, to a hospital in Indiana and a hospital in Illinois. As alleged in the indictment, three infants at the hospital in Indiana received the morphine sulfate which was nearly 25 times the strength indicated on its label, and one infant was taken by emergency helicopter to a nearby children’s hospital.

Further, as alleged in the indictment, during FDA inspections of Pharmakon in 2014 and 2016, Bearden lied about Pharmakon’s never having received any out-of-specification drug potency test results. According to the indictment, Elmer learned of Bearden’s lies during or shortly after the FDA’s inspections and took no action to correct her and to inform the FDA of the extent of Pharmakon’s drug potency failures. The indictment alleges further that Elmer and Bearden conspired to defraud the United States by interfering with and obstructing the lawful functions of the FDA, and obstructing, influencing and impeding FDA inspections. In addition, as alleged, during the 2016 inspection, Elmer directed at least one Pharmakon employee to backdate batch records of compounded drugs.

“Companies that do not meet federal manufacturing standards, especially when dealing with highly potent drugs like fentanyl meant for vulnerable populations, put the health and safety of American consumers at great risk,” said FDA Commissioner Scott Gottlieb, M.D. “The FDA and our Office of Criminal Investigations will continue to pursue and help bring to justice those companies who put the public health at risk.”

According to the indictment, during two inspections of Pharmakon in 2014, FDA observed conditions that did not comply with FDA regulations. The indictment alleges that Elmer and Bearden failed to investigate the root causes of the drug potency failures and otherwise failed to make changes in Pharmakon’s compounding operations to reduce the incidence of these failures. Instead, as alleged in the indictment, under the direction and supervision of Elmer and Bearden, Pharmakon continued to distribute under- and over-potent drugs, shipping these drugs before receiving the potency test results.

The conspiracy charge carries a statutory maximum sentence of five years in prison and a fine of $250,000 or twice the gross gain or gross loss from the offense. The charges of distributing an adulterated drug in interstate commerce and adulterating drugs while held for sale after shipment of a drug component in interstate commerce each carry a statutory maximum punishment of one year in prison and a fine of $100,000 or twice the gross gain or gross loss from the offense.

Acting Assistant Attorney General Readler and U.S. Attorney Minkler commended the FDA Office of Criminal Investigations, which conducted the investigation. The case is being prosecuted by Assistant U.S. Attorney Cindy J. Cho, of the U.S. Attorney’s Office for the Southern District of Indiana and Trial Attorney David A. Frank of the Civil Division’s Consumer Protection Branch.

For more information about the Consumer Protection Branch, visit its website at For more information about the U.S. Attorney’s Office for the Southern District of Indiana, visit its website at

An indictment is only a charge and is not evidence of guilt. A defendant is presumed innocent and is entitled to a fair trial at which the government must prove guilt beyond a reasonable doubt.


2017 Compounding Pharmacy Update

The following is a 2017 Compounding Pharmacy Update.

Compounding Pharmacies continue to be in the spotlight at FDA.   A review of posted warning letters by USFDA identify the following frequency of occurrence through early June for each of the past 4-years:

The 4 year average January 1 to ~June 4 is ~15 warning letters.  With 14 warning letters issued to compounding pharmacies issued thus far in 2017, industry performance seems comparable to the past 4 years.  Will this trend continue for the rest of the year? Will the FDA change the level of oversight based on congressional intervention?

Nine of the 14 warning letters contained specific cGMP deficiencies and the top 5 findings included:

21 CFR 211.28(a), 5 findings: The firm failed to ensure that manufacturing personnel wore clothing appropriate to protect drug product from contamination.

21 CFR 211.113(b), 4 findings: The firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes.

21 CFR 211.167(a), 4 findings: The firm does not have, for each batch of drug product purporting to be sterile and/or pyrogen-free, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product.

21 CFR 211.42(c)(10)(v), 4 findings: The firm failed to establish an adequate system for cleaning and disinfecting the room and equipment to produce aseptic conditions.

21 CFR 211.42(c)(10)(iv), 3 findings: The firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas.

With 2017 nearly half gone, will the 2017 compounding pharmacy performance improve, remain the same, or worsen when compared to the historical averages?




How to be placed on an Import Alert

Quick way to get on an import alert.

In a recently posted warning letter, a Chinese firm inspected by FDA Feb 13-17, 2017 identified a number of GMP deficiencies.  This included:

  1. Manufacturing and shipping drugs to the USA when the manufacturing firm has no quality management system.
  2. Have no written procedures for testing and sampling of incoming materials, and where the “warehouse employees accounted for incoming raw material handling, sampling, and testing ‘in their heads’.” As reported by the firms management.
  3. Test the same lot multiple times, recording the value only on the last sample, which was used to generate a Certificate of Analysis and release the API.
  4. Re-use process parameter values from previous batches to complete batch records.

The firm was placed on an Import Alert 66-40, May 4, 2017, and recommended to retain a cGMP consultant to assist in bringing the firm into compliance.

Ebola is Back

As reported by the World Health Organization Ebola is back.  Since April 22, there have been 9 suspected cases of Ebola including 3 deaths in the Democratic Republic of Congo.  The last Ebola outbreak in the Democratic Republic of the Congo was August 2014 in Boendi, this was during the largest outbreaks of Ebola in West Africa.  As reported by Fox news during the 2014-2015 outbreak more than 11,000 people died from Ebola in Guinea, Liberia, and Sierra Leone.  Another source cited a total of 21,296 Ebola virus disease (EVD) cases, including 13,427 laboratory-confirmed EVD cases reported from the three most affected countries (Guinea, Liberia, and Sierra Leone).

WHO declared the 2014-2015 outbreak of Ebola over in January 2016. There is no FDA approved cure for Ebola.  However, ZMapp  an anti-Ebola monoclonal antibody cocktail was used under humanitarian conditions.  A trial in 71 patients in Guinea, Sierra Leon, Liberia, and the U.S. failed to conclusively demonstrate efficacy, although the small numbers did suggest benefit as reported by Additional therapies were reported in Treatment of ebola virus disease (Kilgore, Grabenstien, Salim, and rybak, 2015).

Perhaps a bigger question for the world is now that Ebola is back, will the world unite to find a cure or vaccine?  Will the outcomes be different this time?  Or will we see another tens of thousands of Ebola infections, and a similar number of deaths from this disease?


FDA Inspection Results May 2017

Summary of FDA Inspection Results May 2017, CDER

In a recent warning letter, a US API manufacturer was cited for providing Certificate of Analysis (COA) that repeatedly omitted the name and address of the original API manufacturer, and failed to provide a copy of the original batch certificate.  When providing the COA’s no secondary review of the certificate was performed to ensure accuracy of information.

The manufacturer was cited for lack of written SOPs for numerous quality functions.  Additionally, products were released for distribution prior to receipt and review of results from the drug-testing laboratory.

The final citation addressed the use of shared equipment where the manufacturer has not performed any validation testing to verify the cleaning procedures are adequate to remove drug residues.

In a recent warning letter, an Indian drug manufacturing facility was cited for delaying a pre-announced FDA inspection by informing FDA that the facility workers had gone on strike.  However, FDA obtained evidence that the firm was actively manufacturing products during this time.  Eventually the FDA inspection did occur.  However, the firm limited access to FDA.  During the inspection, the lights in the facility were off which resulted in FDA walkthroughs of the facility in the dark with a flashlight.  Even under these poor lighting conditions, FDA inspectors were able to ascertain the facility was in an unkempt condition.


Data Integrity

Data integrity
In a recently posted warning letter a number of issues were identified concerning data integrity of laboratory results.  These results included:
Laboratory personnel used a software function “inhibit integration” without scientific justification. As identified in the warning letter:

Inhibiting integration at various points during release testing for commercial batches is not scientifically justified. It can mask identification and quantitation of impurities in your API, which may result in releasing API that do not conform to specifications.

The FDA identified that audit trail functionality had been enabled the day prior to the FDA inspection. Additionally, there were no procedures in place for Quality to review and evaluate the audit trail data.
Records requested by FDA (audit trail data) were provided in the form of excel spreadsheets rather than direct exports from the chromatographic software. As reported in the warning letter:

…were not the original records or true copies, and showed signs of manipulation. The records you did provide contained highlighting, used inconsistent date formats, and lacked timestamp data; these features are inconsistent with original data directly exported from chromatographic testing software.
Our investigators and their supervisor explained at least twice that the data you provided was not representative of actual audit trail data from the chromatographic systems, and requested that you provide the original, unmodified records.

Lastly, the FDA stated, “Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture. We acknowledge that you are using a consultant to audit your operation and assist in meeting FDA requirements.” This section concludes with a substantial listing of information the company is to provide to FDA in response to the warning letter.

Have a question on Data Integrity?  The ISPE Great Lakes Chapter will be providing a one day training session on Data Integrity June 15, 2017 in Indianapolis.  Click here for more information and registration.


In a recently released study by Johns Hopkins, 67% of mutations that cause cancer are random, unpredictable copying mistakes.  Other studies show that 40% of cancers can be prevented based on avoiding unhealthy enviornments or life-style choices.  Cancers initiated by random, unpredictable copying mistakes (or Luck) will occur regardless of the enviornment or life-style choices.

However, the 60/40 split is not common across all cancers.  32 different cancer types were studied.  For example as identified in the study (Johns Hopkins Medicine, 2017):

In other cancer types, such as those of the prostate, brain or bone, more than 95 percent of the mutations are due to random copying errors.

Lung cancer, they note, presents a different picture: 65 percent of all the mutations are due to environmental factors, mostly smoking, and 35 percent are due to DNA copying errors. Inherited factors are not known to play a role in lung cancers.

Looking across all 32 cancer types studied, the researchers estimate that 66 percent of cancer mutations result from copying errors, 29 percent can be attributed to lifestyle or environmental factors, and the remaining 5 percent are inherited.

So luck (good or bad) has a great deal of influence on your health.

Johns Hopkins Medicine. (2017). Most cancer mutations are due to random DNA copying ‘mistakes’. ScienceDaily. Retrieved March 30, 2017 from

Brexit and EMA

As reported by Raps (Brennan, 2017) the UK set in motion Britian’s exit from the EU with a departure over the next two years. EMA’s headquarters will leave London for another EU country. Bresit and the EMA could be interesting.

Will reloaction of EMA headquarters to another EU country result in a relocation of the existing EMA staff? Will the EU replace all or a core group of the London EMA staff? Will this potential change in staff and EMA leadership change its focus, approach, methods? What impact will the relocation have on the approval pipeline? Interesting times ahead.

2017 Society of Quality Assurance Annual Meeting

Are you planning to attend the 2017 Society of Quality Assurance Annual Meeting March 26-31, in National Harbor, Maryland?

If YES, please plan to stop by Booth 315 to meet Kevin Marcial of the Performance Validation team.

Performance Validation is a Value Added Reseller of the Adaptive GRC solution. Adaptive GRC Solution, which is a cost-effective approach to Governance, Regulation, and Compliance.  Adaptive GRC offers a suite of flexible, FDA compliant, and cloud‐based software suite to manage audit, risk, compliance, and quality activities. The solution can be implemented enterprise‐wide out of the box or configured for your specific requirements.

Adaptive GRC Key Capabilities:

Vendor Risk Management, IT/Information Security & Risk Compliance Oversight, Quality (CAPA) & Deviation Management, Enterprise Risk Management, Document Management, and Audit Management.

AdapativeGRC was originally built from experience in the Life Sciences sector. It has full Part 11 audit trail and electronic signature capabilities. It also has a baseline set of IT controls to allow more rapid use and deployment. Using AdapativeGRC can help to get gaps identified and analyzed with less effort. No local installation is required (operates over a standard web browser). You can get access to a full eGRC system for a much lower cost than was previously possible.

Adaptive GRC Demo Video

Temperature Mapping and WHO

There are a number of industry regulations from all around the world that explicitly and implicitly require temperature mapping as a documented process to demonstrate adequate temperature conditions are maintained for storage of temperature-sensitive pharmaceutical products.  However, most of those regulations provide little guidance as to the specifics on how an appropriate temperature mapping should be performed. In recent years, USP, ISPE and PDA have all begun to provide some specific mapping guidance and best practices to the industry with recommendations for mapping duration, frequency, locations, etc.

In May 2015 the World Health Organization (WHO) issued Supplement 8, “Temperature mapping of storage areas” to their own WHO Technical Report Series, No. 961, 2011.  Several regulatory authorities,  particularly European agencies such as the HPRA, refer to these WHO guidelines.  Supplement 8 is specific to temperature-controlled storage areas designed for long-term or short-term storage of temperature-sensitive products including freezer rooms, cold rooms, temperature-controlled storage areas, quarantine areas and receiving and loading bays.  The supplement provides the following guidance for a temperature mapping protocol that should be reviewed and approved to ensure the mapping study is correctly carried out:

  • Approval page and change control history
  • Acronyms and glossary
  • Description and rationale – describe the installation to be mapped
  • Scope – define the purpose of the mapping study and if there is a need for seasonal mappings
  • Objectives – plan to measure temperature variations (door openings, day of the week/time of day, heating, cooling, ventilation, airflow variations), identifying acceptable and non-acceptable         storage areas, locations for routine monitoring.
  • Methodology – mapping sensor specifications, drawing of the area being mapped (including racking, heating and cooling components, existing temperature sensors), acceptance criteria, and mapping locations.  Mapping sensors should be arranged in a grid fashion along the width    and length of the area so that the area is reasonably covered with sensors located every 5-10       meters (20-30 meters for very large facilities).  At each point in the grid, sensors should be     placed at high, medium, and low levels (or bottom, multiple middle, and top locations for tall                areas).  Mapping should be run for a minimum of 7 consecutive days for warehouse and                 ambient storage areas and for between 24 and 72 hours for freezer rooms and cold rooms to    include operation of duplicate refrigeration units running separately.
  • Mapping report template – include introduction, summary, conclusions and recommendations
  • Annexes as needed – raw data, graphs, deviation reports/CAPAs, mapping sensor calibration certificates.

Most, if not all, of the above items would be provided in a typical validation protocol for a mapping study.  Often the protocol and report formats are “as specified” by the customer.  However, if the facility is subject to/ or may be inspected by organizations following the WHO supplement, ensuring these elements are included at the start of the study may eliminate questions during an inspection.

Have a need for or questions about mapping studies?   Neil Enlow is Performance Validation’s responsible manager for this service.  Temperature Mapping is one of Performance Validation’s core areas of expertise.  In the last 20 years, we have executed hundreds of mapping studies, covering all spectrums of size and ranges, from cryogenic storage freezers to depyrogenation tunnels, from reach-in chambers to warehouses.  PV owns and maintains a large inventory of calibrated and validated mapping equipment, including Vaisala VL-2000, VL-1000, VL-1416 data loggers, and Kaye Validator systems and we also have experience with most other temperature monitoring systems used within the industry (i.e. Ellab, Hobo, TempTales, Kaye AVS, Kaye ValProbes, etc.).

Source: WHO Technical Report Series, No. 992, Annex 5, Supplement 8


For Additional information please contact

Neil Enlow
Principal Validation Engineer
Performance Validation, LLC