Alarm Management

21 CFR 211.192 requires a thorough review of any unexplained discrepancy whether or not the batch has been distributed.  Lack of / or poor Alarm management was identified by the FDA during an inspection of a 503B Outsourcing Facility (Observation 2, Form 483).

The firms Building Maintenance System had logged ~766 alarms since March 8, 2016 (the inspection was August/September 2016) and the firm had not documented deviations nor performed investigations on any of the alarms in conjunction with batch release.  All of the alarms at the time of inspection were deemed critical by the firm.

In the posted warning letter, the FDA reviewed the Firms corrective actions.  The Firm’s response identified that the alarm records contained within the facilities Building Management System were not reviewed concurrently with the production batch records prior to release because most of the 766 alarms were not actually critical.  However, the alarms were considered critical at the time of the inspection and the firm did not supply a rational for which alarms are critical and which are not.

Alarm and alarm management should be used as part of the control strategy to ensure the operators are informed when a Critical Process Parameter is approaching or is out of specification.  There should be a difference between a warning, an alert, and an alarm with different operator actions to restore (if necessary) the system to controlled operation.  The alarm management strategy should be developed by the firm based on understanding of the quality target product profile, the Critical Quality Attributes which have an influence on product quality and the critical process parameters that may influence CQA’s and ultimately impact product quality (ICHQ8R2).

Alarm management may be evaluated using the risk management tools contained in ICHQ9.  This will aid the facility in insuring each alarm has a purpose in terms of the overall control strategy.  Having a control strategy that generates hundreds or thousands of nuisance alarms can desensitize the operator resulting in slow or no response to an actual critical condition.

Have a question on Alarm Management? Please use our “Contact Us” form and one of PVs quality professionals will be in touch.

 

 

Validation

In a recently posted FDA Warning Letter, USFDA provided a clear expectation concerning the purpose of validation:

The purpose of validation is to determine whether your processes can operate within established parameters to assure consistent batch uniformity, integrity, and drug quality. Reliable and well-documented batch operations are essential to ensuring process control and drug quality.

The firm that received the warning letter was cited for 21 CFR 100(a) – and could not provide process qualification batch records and quality control documentation.  According to the warning letter, the firm was only provided a protocol and summary report with insufficient data.

As part of the warning letter, FDA requested:

  • A data-driven and scientifically sound program that identifies and controls all known sources of variability, such that your production and packaging processes will consistently meet appropriate parameters. This includes, but is not limited to, evaluating suitability of equipment for its intended use, assuring quality of input materials, and determining the capability and reliability of each manufacturing process step and control.
  • Revised procedures that establish an ongoing program for monitoring process control and detecting variation throughout the product lifecycle.
  • An updated master batch record for manufacturing sterile [redacted] that requires specific processing details in order to fully document each significant manufacturing step.

This is a good warning letter to learn from as the above items relate back to each of the 3 stages of process validation.

In Stage 1 – Process Design is based on building and capturing process knowledge and understanding (identification of the Critical Quality Attributes and Critical Process Parameters (CQA/CPP), which leads to the establishment of a strategy for process control.

In Stage 2 – Process Qualification  is based on design of the facility and qualification of the equipment and utilities.  Completion of this phase leads to process performance qualification where the facility demonstrates that operators, equipment, procedures, and systems work together to produce compliant product.

And finally in Stage 3, Continued Process Verification where routine monitoring of the process using statistical tools can verify the manufacturing process is operating in a state of control.

Equipment

The cGMPs are pretty explicit when it comes to equipment used in the manufacturing, holding, and packaging of drugs.

21 CFR 211.67(a) states that equipment and utensils shall be cleaned, maintained, and, as appropriate for the nature of the drug, sanitized and/or sterilized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements.

In a recently posted warning letter at a compounding pharmacy FDA investigators identified that hoods used in compounding of drug products were not cleaned (observation of a white powder residue in the joints between the plastic front panel, pivot hinges, and between the work surface and the back panel.  Additionally, the FDA investigators observed the firms operator manually filling gelatin capsules using a worn plastic store club card – certainly not appropriate pharmaceutical filling equipment.  Lastly in terms of the equipment citations, the investigators identified a cabinet surrounding the utensil dishwasher was in a poor state of repair, potentially contaminating cleaned utensils.

A review of the FDA Inspections Observations for FY 2016 identified 180 citations per the following distribution:

The top 3 categories of findings attributable to subpart D include:

  • Approximately 46% of the findings were attributed to 21 CFR 211.67(b) – failure to establish and/or follow written procedures for the cleaning and maintenance of equipment.
  • Approximately 36% of the findings were attributed to 21 CFR 211.67(a) – failure to clean, maintain, or sanitize at appropriate intervals to prevent malfunctions and/or contamination that would alter the safety, identify, strength, quality or purity (SISPQ) of the drug product.
  • Finally approximately 7.2% of the findings were attributed to 21 CFR 211.67(c) – failure to keep adequate records for the maintenance, cleaning, sanitizing, and/or inspection of equipment.

A review of FDA Turbo data identifies that there has been a slight increase in the number of equipment related inspection observations from 2006 to 2016:

Have a question about 21 CFR 211.67, Subpart D – Equipment?  Contact Dr. Van Doel, or use PV’s Contact Us form to submit your question.

Pharmakon Update

As reported by Inside Indiana – The former compliance director of Pharmakon, Caprice Bearden, has pleaded guilty to multiple federal charges, that include introducing adulterated drugs into interstate commerce and conspiracy to defraud the U.S.

As quoted by Minkler the US Attorney, “this defendant distributed serious drugs to hospitals in Indiana and around the country, knowing that the drugs were significantly under or over the strength they were supposed to be. She put greed and the reputation of her company ahead of the health and safety of our most vulnerable patient populations.”

The indictment from the US DOJ for Paul Elmer (Owner) and Caprice Bearden (Compliance Officer) is available here.

As reported by Fox59, The Owner of Pharmakon Paul Elmer, also indited in a 10-count indictment.

A video of the June 22, 2017 DOJ announcement of the charges against Paul Elmer and Caprice Bearden from Fox 59 News is provided below.

 

U.S. attorney, FDA officials announce charges against compound…

The Department of Justice and FDA are announcing charges against a Noblesville compounding pharmacy.

More here: http://via.fox59.com/5CRLo

Posted by FOX59 News on Thursday, June 22, 2017

Winter Temperature Mapping

Winter Temperature Mapping

The Winter season is fast approaching!  USP guidelines require extreme seasonal temperature mappings to be performed where product temperatures are critical.  PV can assist you in meeting your Winter temperature mapping needs.

Have you had increasing internal or external requests to demonstrate adequate temperature and/or humidity control within your facility?

Performance Validation has the resources and experience necessary to help provide a documented temperature mapping analysis of your facility, cold room, warehouse, refrigerator, or freezer.

Take a look at our most recent annual temperature mapping studies to see how Performance Validation has assisted multiple clients with there mapping needs.

Have a question, need information or a quote?  Contact Neil Enlow, PV’s Manager of our mapping services or use our contact us form.

 

Digital Pill

Several months ago we blogged about the use of digital sensors, to help monitor family members activity in and around the home, and the use of these digital sensors embedded in medication, basically a digital pill, to help monitor patient compliance in taking medication.

For example, a sensor embedded in a chair that would inform caregivers or patient family if the individual did not get up or was not active.  A sensor on the fridge door that would inform when it was opened, or if it was not opened to help verify if the individual was eating.
One of the  more exciting options were tablets with an embedded sensor, a digital pill, that would activate based on contact with stomach fluids to inform caregivers and/or patient family that the individual had taken their medication.  One of the big issues with elderly patients is medication compliance.  Patients who forget and do not take their their medication at all, patients who do not take it at or about the same time every day which can lead to reduced effectiveness, or patients who forget they have taken their medication and inadvertently overdose.
Per the Device Daily Bulletin, the FDA just approved the first prescription pill containing a sensor, the digital pill, that verifies ingestion via electronic detection.
If widely adopted in other medication, the ability to remote monitor medication compliance in a loved one by a family member, or patient by a care giver could provide a significant advantage in monitoring medication compliance.  With more consistent dosing, this may lead to better healthcare outcomes for the patient.

PV’s Southeast Team – Habitat for Humanity

PV’s Southeast Team (L-R) Erin, Clarence, Kim, and Brian

Saturday, November 4th, members of the Southeast Performance Validation Team participated in a wonderful opportunity – Habitat for Humanity. They spent the day learning about trusses, roofing, and design alongside members of the community as well as the future homeowners of the house!

Lifting those Trusses

One of the challenges that they faced during the day was getting the trusses on the roof without a crane. Each truss was hand lifted from the ground to the roof, where it was then positioned and erected. This required a great amount of safety awareness and precision!

Erin on the chop saw

Another challenge they faced was the limiting factor of resources. This called for some critical thinking – Can any measurements be split into multiple pieces? Can certain materials be re-purposed? They were able to assist the Habitat leads and provide suggestions to be as efficient as possible and complete the task at hand.

Many thanks to the PV Southeast Team for their community outreach through Habitat for Humanity, helping to build community in our Augusta GA area, and participation in a wonderful team building exercise!  Great Job Team!

Outreach SE United States

This past week, Performance Validation continued our outreach within the life science sectors of Georgia and South Carolina by sponsoring and exhibiting at the 2017 annual events of GA & SC Bio.

On Tuesday, October 24, 2017 Rick Van Doel and Brian Larmon attended the 16th annual GA Bio Innovation Summit in Atlanta, GA. The Summit provided a forum for professionals from industry, academia and government to discuss major trends and issues, including topics related to scientific research, product development, financing, business development and public policy. The event was kicked-off by Keynote speaker Greg Simon of the Biden Cancer Initiative who spoke about the need to double the efforts towards disease research, funding, staffing etc. As a cancer survivor himself, the insight Greg provided was especially personal.

On Wednesday – Thursday, October 24-26 Kimberly Lee and Rick Van Doel attended 2017 SCBio Annual Conference in Charleston, SC. SCBio – South Carolina Bio – is a non-profit organization that charges themselves with “Building the Business of Life Sciences in South Carolina” (www.scbio.org), which was the theme of this year’s event. Attendees consisted of a mixture between academia, research, state representatives, manufacturing executives, and service providers for the life sciences industry.

Highlights from the SC Bio event included a Gubernatorial Address from South Carolina Governor Henry McMaster who spoke to the vision for growth of the life science industry in South Carolina along with sessions including University Presidents from the Medical University of South Carolina, University of South Carolina, and Clemson University. Additional panelist shared their professional stories of company startups and revealed their lessons learned. The event fostered an environment of power networking by providing roundtable discussions with company executives that included a one-on-one. Additional networking events took place around the city at local restaurants allowing attendees to meet in a more personalized setting while enjoying some of the South’s most delectable cuisine.

Both of these events provided an outreach opportunity for Performance Validation, to share on PV’s life science expertise and capabilities  to the Georgia and South Carolina Life Science Companies.

Performance Validation’s (PV) core business is providing commissioning, qualification and validation services to the pharmaceutical, biotech, and medical device industries. PV has a group of team members located in Columbia, South Carolina and the Augusta, Georgia area with experience in commissioning and qualifying of facilities, utilities, and equipment for the pharmaceutical industry.

For examples of project that PV has completed please see our project summary webpage. For examples of the types of services we offer within each of our skill disciplines please see the services page (Commissioning, Qualification, Validation, Building Commissioning, Environmental Mapping, Computer Systems Validation, and Medical Device-QSR Support. For questions on our service offerings or to request a quote please contact PV at 855-PERFVAL or use our contact us webpage.

Commissioning and Qualification – Planning

Prior to starting commissioning and qualification activities, a plan should be developed. The plan may be commonly referred to as a Commissioning Plan, Commissioning and Qualification Plan, Qualification Plan or Validation Plan. The name changes based on the overall intent of the activity, but the documents all serve the same purpose – to help guide your team through the execution of the commissioning or qualification activities. It is written at the start of the project and defines the project’s scope and goals.

Although unique, each Plan document typically contains the following basic elements:

 

Scope

  • Defines the facilities, system , or equipment to be included in the project

Objective

  • Defines the goals of the project

System(s) Overview

  • A high-level overview of a system and its components within the scope of the project.
  • Provides a process description that speaks to the mechanical and automated functions of the systems and equipment.

System Boundaries

  • A limit drawn around the system(s) to logically define what is and is not included in the system. The boundaries clearly define what elements (e.g. process equipment, facilities, instrumentation, utilities, etc.) makeup the system. Predetermined system boundaries help to define the scope of C&Q activities
    • For larger projects, this section may identify a methodology that would be used to identify the boundaries of direct and indirect systems with a goal of ensuring that critical components are only associated with direct impact systems.
    • For smaller projects, this section may include the actual boundary output (e.g. the marked up project drawings identifying the system boundaries).

Roles and Responsibilities

  • A RACI (responsible, accountable, consulted and informed) chart or diagram is a matrix of all deliverables/activities on the project and the corresponding action or responsibility of each person/role on the project. This chart or diagram provides an organizational structure for the team members of the project, helps to reduce overlapping of responsibilities, and optimizes resource usage.

Deliverables

  • The Plan should provide a listing of all of the documents to be generated in order to fully commission or qualify the system or equipment This may include:
    • User Requirements
    • Risk Management (e.g. FMEA, System/Component Classification)
    • Design Review/Qualification
    • Commissioning (Installation Verification and Functional Testing)
    • Qualification (Installation Qualification, Operational Qualification, and Process Performance Qualification)
    • Summaries/Final Reports
    • Traceability Matrices

Schedule

  • A schedule should be included, listing activities such as system turnover and document development and execution for each system and/or major piece of equipment.
    • The schedule may consist of a high-level milestone schedule and reference a project schedule created and maintained outside of the plan document.
    • Alternatively, the detailed schedule may be held within the planning document. With the understanding that every change would require review/and approval of the planning document.

Approval and Changes

The Plan should be approved prior to commencing subordinate tasks. Approvers may include client representatives from Design, Construction, Engineering, Quality, Validation, and End-User management. Changes to the plan should be reviewed by the original approvers and a revision history maintained.

Have a question about commissioning, qualification, and/or validation planning. Please use our Contact us form to ask your questions or to inquire as to how Performance Validation may assist you with your project needs.

Audit Trail Review – A Data Integrity Issue

Data integrity demands a great amount of attention in the life science industry. This is now truer than ever with increased focus from the FDA, EU, and industry standards on data integrity issues and best practices. Audit trails for computerized systems are required for all FDA / EU regulated systems. It must capture the creation, modification, and deletion of regulated electronic records. Who created and when the record must be captured, as well as who, when and why the record was modified or deleted – as relevant. When a system is validated, an audit trail should be verified to ensure accuracy and that it meets all applicable regulatory and organizational requirements. Once the system is validated and in production, the audit trail should not be forgotten. A formal process to examine the audit trail to ensure data integrity is needed in the regulated environment. Let us consider audit trail review – how to approach it and a few items of interest.

Audit trail review refers to the process of periodically examining an audit trail based on a variety of factors. It is valuable to define audit trail review based on system risk. ISPE – as recommended by ISPE in the Records and Data Integrity Guide. Place a risk level on a system just as one would for any other computerized system risk assessment using criteria such as impacts to patient safety, drug/product efficacy, quality system, business risks, complexity/criticality etc. How often and to what degree the audit trail review occurs can then be assigned. Do include all system stakeholders in the criteria and assessment process including IT, QA, and business process owners.

It is important to develop procedures and processes for audit trail review or incorporate them into a Validation Master Plan and/or Quality Management System. The review itself might only be a spot check for a very low risk system or it could be a comprehensive analysis and tracing of data and metadata. Metadata is one aspect that should not be overlooked. The audit trail review cannot be adequate (in most cases) if information that makes the data meaningful (metadata) is not available. This is a time when putting on an investigator or QA “hat” is imperative. Audit trail review should (again, based on risk level) look with scrutiny at reruns and fails of data capture and modification. Procedurally and scientifically, it may be acceptable for rerunning and failing instrument runs, for example. However, does the audit trail capture these events? If so, how and is it complete? Again, risk is key, but these are questions and answers that are important. This is also an opportune time to review training records, access controls, and general system security – as applicable.

Audit trail review is an essential component to data integrity for any computerized system. There are guidelines and industry best practices out now which are very helpful in developing a process to manage the reviews. Yet it is important to understand the system’s risk and criticality so as to approach the assessment process efficiently. Use the audit trail review to put the pieces of data capture, modification, and deletion together – using metadata to give scale and meaning to the data and information. An audit trail review may be easy to overlook or curtail, but its contribution to overall data integrity and thus patient safety is very significant.