Jackie Eysol – Certified Quality Auditor

For Immediate Release (Indianapolis, Indiana August 22, 2017). Performance Validation (PV) is pleased to recognize Ms. Jackie Eysol’s certification as an American Society for Quality Certified Quality Auditor (CQA).

Jackie is a Senior Validation Engineer with Performance Validation.  A Senior Validation Engineer is responsible for demonstrating a sound knowledge, application, and proper implementation of technical, quality and scientific principles necessary to meet industry regulatory, and customer requirements with respect to commissioning, qualification, and Validation. As a CQA Jackie will also be responsible as a member of PV’s quality system to perform internal audits and to help the company meet its commitment to continuous improvement.

The Certified Quality Auditor is a professional who understands the standards and principles of auditing and the auditing techniques of examining, questioning, evaluating and reporting to determine a quality system’s adequacy and deficiencies. The Certified Quality Auditor analyzes all elements of a quality system and judges its degree of adherence to the criteria of industrial management and quality evaluation and control systems.  Certification is obtained by successfully completing a 150 question examination administered by the American Society for Quality.

503B Guidance

With the passage of the Compounding Quality Act, Drug Quality and Security Act of 2013 FDA defined two categories of compounding pharmacies: 503A and 503B.  This blog post is to provide 503B Guidance.

NEW – Now Available in Limited Quantities – Get yours Now!
GMP Book

Performance Validation has printed a limited number of Pocketbook compliance guides that include 21 CFR Part 210 and 211, and the FDA’s Compliance Policy Guide which addresses the FDA inspection methodology.

No need to guess what the FDA inspector will be looking for during the inspection, now you can be in the know.

To obtain the pocketbook and information about Performance Validation simply complete the contact form.

Click here to jump to the USFDA Regulatory Policy Information page that lists all the compounding facility draft and final guidance documents.

FDA’s Human Drug Compounding Progress Report: Three Years After Enactment of the Drug Quality and Security Act (January 2017) is available from the FDA here.

FDA Investigation into Compounded Products

The FDA website posted the summary of their investigation into two serious adverse events associated with ImprimisRX’s compounded curcumin emulsion product for injection.

The full summary is available on the FDA website, click here.

The short version:

Two patients were administered infusions of curcumin (a component of the spice tumeric) compounded with polyethene glycol (PEG) 40 castor oil.

One patient a female 30-year old experienced cardiac arrest, the patient suffered depleted oxygen brain injury and subsequently died.  The second patient a 71-year old male developed a hypersensitivity reaction, he was transferred to a nearby emergency room where he was treated and released.

FDA’s investigation into the adverse events associated with ImprimisRx’s curcumin emulsion product for injection highlights some of the risks associated with compounded drugs, particularly those that use non-pharmaceutical grade components and ingredients lacking a USP monograph. The risks illustrated in this case include:

  • the absence of a label warning about hypersensitivity reactions associated with the PEG 40 castor oil;
  • the use of an ungraded inactive ingredient, i.e., PEG 40 castor oil, that is not suitable for human consumption or therapeutic use and may contain impurities such as DEG; and
  • the IV administration of curcumin, despite the fact that its safety profile by this route of administration has not been established, nor has its effectiveness in treating eczema or thrombocytopenia.

Pharmacy error statistics as posted by the Hannon Legal Group:

  • Medication errors account for approximately 7000 deaths annually in hospitals alone and tens of thousands more in outpatient facilities.
  • It is estimated that between 2.2 million and 3.7 million medication dispensing errors have occurred in the U.S. in each of the past eight years which caused serious health problems or death.
  • According to the FDA, over 1.3 million people are injured each year due to medication mistakes.
  • Preventable adverse drug events (ADEs) cost the healthcare system $2 billion every year.

Isomeric Pharmacy Solutions

As posted on FDA’s website.  U.S. District Judge Robert J. Shelby entered a consent decree of permanent injunction yesterday between the United States and Isomeric Pharmacy Solutions.

According to the complaint for permanent injunction, Isomeric manufactured and distributed purportedly sterile drug products, including injectable and ophthalmic drugs that were adulterated because the drugs were made under insanitary conditions and in violation of current good manufacturing practice requirements under the FD&C Act. Drugs prepared, packed, or held under insanitary conditions may have been contaminated with filth or otherwise harmful if given to patients. The complaint also alleges that Isomeric manufactured and distributed unapproved drugs and drugs that were misbranded because their labeling did not bear adequate directions for use.

“Isomeric endangered the public health by manufacturing injectable drugs under poor conditions that compromised their required sterility and put patients at risk,” said FDA Commissioner Scott Gottlieb, M.D. “We will continue taking strong enforcement actions against compounders who violate the Drug Quality and Security Act and put patients at risk by failing to produce sterile drugs in compliance with the law.”

FDA’s post provides links to prior inspections of this registered outsourcing facility.  A 483 was issued August 2015, a second 483 issued June 2016, a warning letter posted Dec 2016, followed by a third 483 issued March 2017.

In the March 2017 483, Observation 2 identifies that 33 customer complaints were received since the previous inspection yet NONE were investigated.

  • 11-complaints were related to infection, pain, swelling or knotting at the injection site.
  • 6-complaints from clumping in the finished product.
  • 5-complaints associated with particles, fragments, or coring.

Have a question concerning the cGMPs or the FDA inspection process?

Performance Validation has printed a limited number of Pocketbook compliance guides that include 21 CFR Part 210 and 211, and the FDA’s Compliance Policy Guide which addresses the FDA inspection methodology.

No need to guess what the FDA inspector will be looking for during the inspection, now you can be in the know.

To obtain the pocketbook and information about Performance Validation simply complete the contact form.

Pharmacies

Compounding Pharmacies were well represented in this week’s digest of Recently Posted Warning Letters.  Four of the nine letters posted were associated with compound pharmacies.

All 4 of the warning letters identified the pharmacies failed to receive valid prescriptions for individually identified patients. As we know, compounding without a valid individual prescription does not meet the conditions of 503A.  Section 503A of the FDCA describes the conditions under which human drug products compounded by a licensed pharmacist in a State licensed pharmacy or a Federal facility, or a licensed physician, qualify for exemptions from three sections of the FDCA.

Specific observations identified by the FDA in the posted warning letters include (listed in numerical order of the CFR):

  • 21 CFR 211.28(a) Inappropriate clothing worn to protect the drug product from contamination Cited 1
  • 21 CFR 211.42(b): Inadequate design of the facility to prevent contamination or mix-ups Cited 1
  • 21 CFR 211.42(c)(10(iv): Failed to establish a system to monitor environmental conditions in the aseptic processing area Cited 2
  • 21 CFR 411.42(c)(10)(v): Failed to establish a system for cleaning and disinfecting the room and equipment to produce aseptic conditions) Cited 2
  • 21 CFR 211.42 (c)(10)(vi): Failure to establish a system for maintaining equipment used to control the aseptic conditions Cited 1
  • 21 CFR 211.67(a): Failed to sanitize and/or sterilize equipment and utensils Cited 1
  • 21 CFR 211.113(b): Failed to establish and follow procedures to minimize microbiological contamination Cited 2
  • 21 CFR 211.165(a): Failure to test each batch to verify the drug product meets final specifications prior to release Cited 2
  • 21 CFR 211.165(f): Failed to reject drug product that did not meet established standards or specifications, or any other relevant quality control criteria Cited 1
  • 21 CFR 211.166(a): No Stability testing program Cited 1
  • 21 CFR 211.167(a): Failure to test each batch to verify the drug product meets final specifications for sterility and/or pyrogen Cited 1
  • 21 CFR 211.192: Failed to investigate any unexplained discrepancy Cited 1

The warning letters are available on the FDA website.  A link to each warning letter is provided below:

Please note that there is approximately a year or more between the facility inspection and posting of the warning letter.  The warning letter identified the conditions that were observed during the inspection and may not represent current conditions.

Alex Whittaker – Certified Quality Auditor

For Immediate Release (Indianapolis, Indiana; July 21, 2017). 

Performance Validation is pleased to announce that Ms. Alex Whittaker has successfully completed certification as a Certified Quality Auditor.

Alex is a Validation Specialist with Performance Validation and is responsible to assist in the implementation, monitoring, and continuous improvement of our Quality Management System at a divisional level.

The Certified Quality Auditor is a professional who understands the standards and principles of auditing and the auditing techniques of examining, questioning, evaluating and reporting to determine a quality system’s adequacy and deficiencies. The Certified Quality Auditor analyzes all elements of a quality system and judges its degree of adherence to the criteria of industrial management and quality evaluation and control systems.  Certification is obtained by successfully completing a 150 question examination administered by the American Society for Quality.

Co-Manufacturing

In a recently posted warning letter, the manufacturer of over-the-counter (OTC) oral rinses and oral moisturizing drug products received a citation concerning 21 CFR 211.42.

The firm used the same manufacturing equipment to manufacture the GMP over-the-counter oral rinses and oral moisturizing drug products and numerous non-pharmaceutical materials (Co-Manufacturing) in your facility, including an industrial car care product, [redacted] polish and sealant.  As noted in the warning letter, the car care product is paraffin-based and labeled as “Harmful or fatal if swallowed” and “Keep out of reach of children.”  Additionally – the company manufactures leather treatments [redacted] Leather Care, [redacted] Leather Lotion) and sealants [redacted] Poly Sealant, using the same mixing tank and filling line used for OTC oral drug products (co-manufacturing).

This firm was also cited for failure to have adequate laboratory testing 21 CFR 211.165b.  As identified in the warning letter the firm released 24 batches of OTC drug products between 2013 and 2015 without performing analyses to assess whether they met all microbiological finished product specifications.

Lastly – the firm was cited for not having an adequate quality control unit 21 CFR 211.22a.  In this case the firm’s oversight of drugs manufactured by the firm, and testing provided by the contract laboratory was inadequate.  The FDA identified the contact testing laboratory had not validated the test method used to detect Burkholderia Cepacia. This inspection occurred in July of 2016.  However, the firm had similar issues identified by FDA in inspections conducted in 2013 and 2016  which only supports the inference that the firm’s quality unit is not adequate.

While a different scenario, the potential for cross contamination between industrial and GMP (co-manufacturing) is documented in the FDA’s Validation of Cleaning Processes (7/93):

One event which increased FDA awareness of the potential for cross contamination due to inadequate procedures was the 1988 recall of a finished drug product, Cholestyramine Resin USP. The bulk pharmaceutical chemical used to produce the product had become contaminated with low levels of intermediates and degradants from the production of agricultural pesticides. The cross-contamination in that case is believed to have been due to the reuse of recovered solvents. The recovered solvents had been contaminated because of a lack of control over the reuse of solvent drums. Drums that had been used to store recovered solvents from a pesticide production process were later used to store recovered solvents used for the resin manufacturing process. The firm did not have adequate controls over these solvent drums, did not do adequate testing of drummed solvents, and did not have validated cleaning procedures for the drums.

 

CDRH Calendar Year 2016 Data

Calendar year data for the Center for Devices and Radiological Heath data has been released and is available here.

Some highlights from the report:
  • There were 1450 Domestic and 725 Foreign inspections in 2016.
  • Overall 52% of the inspections resulted in NAI – No Action Indicated, 39% resulted in Voluntary Action Indicated, and 9% resulted in Official Action Indicated.
  • 854 FDA Form 483s, containing 3,027 citations for 21 CFR 820 were issued in 2016
  • Hot topics on all inspections for each of the quality system elements included:
    • CAPA 1017 observations 34%
    • Production and Process Controls 964 observations 32%
    • Design Control 382 observations 13%
    • Management 347 observations 11%
    • Document Controls 317 10%

Equipment Maintenance

In a recent warning letter, an Indian pharmaceutical manufacturer was cited for failure to maintain manufacturing equipment. The FDA during the facility inspection identified holes and corrosion in three pieces of equipment used in manufacturing. Previously, FDA received a compliant concerning metal embedded in a tablet from this manufacturer. Although the manufacturer replaced the equipment, they did not perform a retrospective review to determine the potential impact of the poorly maintained equipment on drugs manufactured and distributed prior to replacing the equipment.  21 CFR 211.67 addresses maintenance of the equipment to prevent malfunctions or contamination of the drug product.

Additionally, the firm admitted that they had not performed process validation for the manufacturing of Isoxsuprine hydrochloride tablets. Process validation is a requirement per 21 CFR 211.110a, yet a [redacted] number of batches of this product were shipped to the US that were manufactured using an un-validated manufacturing process. The firms formal response was that they “were not currently manufacturing” this product. Which of course the FDA took exception with as the firm had not provided any information on the validation of the manufacturing process, nor a retrospective risk assessment on the batches that were produced with an un-validated manufacturing process and subsequently released.

Based on the information in the warning letter, the firm apparently did not maintain the equipment properly which lead to metal contamination of the drug product that went undetected.

How do you do Risk Management?

ICH Q9 provides a simple process flow of a typical risk management process.  This process includes risk assessment (risk identification, risk analysis, and risk evaluation) which leads to risk control (risk reduction and risk acceptance). Figure 1 below, extracted from ICH Q9 illustrates this process flow.

Figure 1. Adapted from ICH Q9, Quality Risk Management, Nov 2005, retrieved from ICH.org

ICH Q9 provides information on typical risk management tools (Annex I) and how these tools may be used over the product quality life-cycle (Annex II).  One tool that is commonly used for risk assessment and control is the Failure Modes and Effects Analysis (FMEA).  Performance Validation recently completed a project with a biomedical research company to provide training on the use of FMEA.  However, it is important to remember that quality tools such as FMEA, FTA, FMECA, Fishbone diagrams, etc., are not risk management, but simply tools to help the organization understand what risks are present and the significance of these risks.   These risks are then analyzed to gain understanding of which of the identified risks are acceptable “as-is”, and which of these risks require further mitigation.

FMEA is a great tool and can be used alone or in conjunction with other quality tools to:

  • Identify and eliminate concerns early in the development of a process or design
  • Predict the likely effects for product performance
  • Identify critical steps/processes
  • Identify high risk areas
  • Prioritize risk
  • Prioritize remediation actions/solutions to maximize impact
  • Provide a methodology that facilitates process improvement
  • Prevent or minimize product manufacturing related quality issues
  • Improves internal and external customer satisfaction

How do you analyze your risk?  What quality tools does your organization use for risk assessment and control?  Do you have questions on how to implement ICH-Q9 or how these quality tools can be used to improve product quality, reduce waste, or manufacturing cycle time?  If so, PV can help.  We have American Society of Quality (ASQ) Certified Quality Engineers (CQE) who can provide FMEA training, help develop an FMEA work instruction or facilitate performing a FMEA.  We can also provide refresher training on complimentary quality tools that support the risk assessment and control process such as Ishikawa or fishbone diagrams, control charts, Pareto and process flow charts.

For more information on the use of quality tools in risk management please contact:

Holly Couch
Principal Validation Engineer
Certified Quality Engineer
Performance Validation, LLC