Biomedical News

Issue 3

Data Integrity for 21 CFR Part 11 Compliance: Instron’s Partnership with Xybion for ComplianceBuilder™

Data integrity and regulatory compliance have been a major focus for international regulatory agencies across the globe, such as the US Food and Drug Administration (FDA), the Medicine and Healthcare Products Regulatory Agencies (MHRA), and the World Health Organization (WHO). With each passing year, these regulatory bodies have increased their scrutiny levels to ensure the quality, safety, and efficacy of medical & food products being released into the market.  Guided by regulations such as FDA 21CFR Part 11 and GxP, in the context of laboratories, data integrity refers to the generation, transformation, and maintenance of data to assure the completeness, accuracy, and consistency of the data over its entire lifecycle. 

According to recent data from FDA reports, the pharmaceutical, medical device, and food industries continue to deal with challenges resulting from FDA audits as shown in the graph below: 

483 Observations with cGMP Violations

There has been a 5% rise in the number of FDA Form 483’s issued to the pharmaceutical industry and a whopping 21% increase in FDA Form 483 observations in 2015.

In the medical device industry, 64% of the FDA Form 483’s issued in 2015 were due to quality system deficiencies, mainly in Corrective and Preventive Action (CAPA) and Production and Process Controls (PP&C).

FDA Form 483 Observations Chart

Most of these CAPA’s have been issued due to lack of controls in compliance with laboratory and other production and process control systems.  Some of the common data integrity issues have been:

  • User identification
  • Traceability of complete data
  • Data lost or deleted
  • Data accessibility with no control
  • Data recorded in validated systems

For the past ten years, Instron has partnered with Xybion Corporation, to provide Bluehill users with ComplianceBuilder™, enabling users to meet the requirements of CFR Part 11. The table below provides details of some of the key requirements for CFR Part 11 Compliance, which helps build data integrity, and are addressed by ComplianceBuilder™:

CFR Part 11 Requirements   ComplianceBuilder™ Functionality
  • Validation of systems maintaining or managing essential records
  • Ability to generate accurate and complete copies of records in legible and electronic form suitable for inspection and review
  • Protection of records and recovery mechanism
  • Limiting system access to authorized and qualified users with suitable demonstrated training records
  • Use of secure, computer-generated, time-stamped audit trails
  • Use of operational system checks to enforce SOP driven workflows, sequencing of steps
  • ComplianceBuilder™ is a fully validated system
  • Recovers version controlled files even if they are deleted at source location
  • Generates audit trails for raw data and metadata
  • Configures electronic signatures
  • Provides user access control
  • Tracks changes across all IT subsystems including file systems, databases, and laboratory equipment
  • Monitors spreadsheets, documents, text, and Bluehill files for changes, including additions, deletions, and file modifications
  • Provides device and authority checks that limit access to authorized personnel
Our partnership has supported companies globally, both large and small across many industries including medical device, pharmaceutical, biotech, and others providing CFR Part 11 Compliance.  ComplianceBuilder™ is usually installed in the PC workstation connected to the Instron system to provide data integrity and facilitate real-time compliance monitoring of all the data generated in Bluehill. Several large corporations have expanded their use of ComplianceBuilder™ to enable compliance for other lab equipment and systems through Xybion’s server or site licenses. The server license provides compliance across all the lab equipment in addition to Instron systems.

As data Integrity and regulatory compliance continue to be major focuses for international regulatory agencies across the globe, it is imperative that laboratories increase their scrutiny to ensure the quality, integrity, and efficacy of test data over its entire lifecycle.

Residual Seal Force (RSF) Testing of Parenteral Products

Parenteral products contained in vial package systems require a robust seal at the interface between the glass vial and the elastomeric closure to prevent contamination and product leakage. The seal is established in the manufacturing process, but must withstand a variety of handling, processing, and storage conditions. 

The vial seal is comprised of three major parts: the glass vial, a rubber stopper, and an aluminum cap that secures the rubber stopper in the vial. The aluminum cap must be crimped onto the vial and stopper with a compressive force that will ensure sufficient mating of the glass and rubber surfaces. Closure variables of major importance include dimensional characteristics and tolerances, and mechanical properties of the three components including modulus and hardness. The initial force with which the closure compresses the vial is a function of the vertical and horizontal crimping forces applied during the aluminum cap application. However, due to the viscoelastic relaxation behavior of rubber, the force of the closure pressing against the vials decays as a function of time. In addition, the elastomer composition and various processing procedures will affect the viscoelasticity of the rubber. 

Residual Seal Force Test        Residual Seal Force Test

Manufacturers of parenteral vials are required to have a quantitative method for measuring the force exerted on the vial after the initial seal is made. Obtaining quantitative force data enables laboratories to optimize seal parameters to guarantee seal efficacy throughout the shelf life of the product. This force is defined as the residual seal force.  

Measuring the residual seal force can be done by testing vials in compression. As shown above, a specialized compression fixture is used. The lower fixture is customized to the vial body diameter while the upper fixture is customized to the vial cap diameter. The upper fixture is spherically seated to ensure even loading on the vial cap and contacts the vial outer diameter to ensure the force reading is at the vial seal. 

The compression curves below can be explained as a combination of metal seal and elastomeric closure stress-deformation response. 

Residual Seal Force Graph

 Load at Residual Seal
Specimen 1  3.9 lbf
Specimen 2  4.3 lbf
Specimen 3  3.6 lbf
Specimen 4  3.7 lbf
Specimen 5  3.9 lbf
Specimen 6  3.4 lbf
Specimen 7  4.1 lbf
Specimen 8   3.2 lbf
Mean  3.7 lbf
Standard Deviation   0.37 lbf

Instron's Laboratory Equipment Validation, Maintenance, Verification and Calibration Services

Equipment validation per FDA 21 CFR 820.72 is done to ensure that a particular piece of equipment is suitable for its intended purpose and is capable of producing a valid result.

An installation qualification (IQ) process is designed to establish that the system has been installed correctly. This documentation should include factual information such as installation conditions, operational safety features, all system manuals, environmental conditions, and all information on proper training and maintenance of the equipment. An operation qualification (OQ) process is designed to verify the proper operation of the testing system and its ability to produce valid results. A validation plan should include a functional check of the software to validate all necessary measurements and calculations. 

The Instron Professional Services group provides on-site support of IQ/OQ documentation for a variety of test types including tension, compression, torsion, and flexural testing. Also, validation of a variety of calculations within Instron’s Bluehill® 3 Software. 

In addition to IQ/OQ, laboratories should have a plan for equipment preventative maintenance (PM). Equipment maintenance is typically outlined in a manual provided by the equipment supplier. Maintenance can be as simple as machine cleaning and proper equipment storage, to more complex tasks such as transducer verification and calibration. 

Verification and calibration services include checking force, strain, speed, and displacement to a known standard. For medical device companies, it is imperative to perform routine verification and calibration in order to confirm the accuracy of the system’s measurements.

Webinar: Common Sources of error in biomedical testing

In the medical device and pharmaceutical industries, data accuracy is incredibly important.  Watch the webinar below for the most common areas overlooked in testing that could lead to inaccurate or misleading results.
View Webinar

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