Author: Brandon Miller

IVDR & In Vitro Diagnostics

Posted on by Brandon Miller

In Vitro Diagnostics Regulation (IVDR) Changes

 

Listen to this In Vitro Diagnostics highlight from RCA Radio where Seyed Khorashahi breaks down the EU’s move from list-based IVD device classifications to a rule-based IVDR medical device classification, resulting in four new device classes.
 
 

 

Listen to the entire episode where we go over all of the important things happening in the Medical Device industry here.

 

 

Device Classification Changes

  • List-based Classification to a Rule-Based 
    • Class A (lowest risk) to class D (highest risk), where class B, C, and D would require Notified Body (NB) involvement.
  • MDGC 202- 16 Guidance on Classification for in vitro diagnostic Medical Devices under Regulation (EU) 2017/746.

 

Lifecycle Approach

  • Establishment and Demonstration of effective Quality Management Systems (QMS).
  • More stringent requirements for clinical evidence that demonstrates conformity.
  • Post-Market Performance monitoring and reporting requirements.
  • Introduction of Unique Device Identifiers (UDIs) for improved traceability.

 

Supply Chain Oversight

  • Regulations covering the entire supply chain.
    • Economic Operators
      • Importers
      • Distributors
      • Authorized Representatives
  • Notified Bodies have discretionary authority to audit suppliers and subcontractors

 

To begin the Regulatory Compliance Associates scoping process today, please enter your information in the blue form below and click the submit button at the bottom of the webpage. You may also email us at [email protected].

FDA Guidance: Continuous Manufacturing

Posted on by Brandon Miller

continuous manufacturingThe U.S. Food and Drug Administration (FDA) recently updated its pharmaceutical manufacturing guidance on Continuous Manufacturing (CM), including elaborating on established industry best practices.

 

Examples of new insights provided by FDA include clarification of the differences between continuous manufacturing modes and manufacturing approaches. The intended purpose behind the guidance is to continue industry harmonization efforts between ICH guidance and FDA regulatory & statutory requirements.

 

Continuous Manufacturing

 

Continuous manufacturing involves the process of uninterrupted materials being steadily added into the manufacturing process. The in-process ingredients are then manufactured and simultaneously developed into output materials during manufacturing. The updated FDA guidance focuses on facets of a continuous manufacturing system where multiple steps of operation are connected as continuous flow manufacturing.

 

The intended seamless procedure is considered by many industry experts as more efficient and helps reduce human error. By comparison, batch manufacturing lines may not use the same types of automated monitoring nor leverage as many predictive maintenance data points.

 

Factors of Production

 

The FDA guidance provides a deeper explanation of the underlying continuous manufacturing factors of production. A description of these characteristics by the Agency expands upon continuous flow production themes, including types of technology, options for dosage form, or molecule type.

 

Topics that are broadly applicable to a continuous production system and batch manufacturing are not included in the updated guidance scope. FDA recommends to the reader to revisit other existing ICH Q7 guidance as needed and appropriate for the medical manufacturer.

 

Control Strategy

 

Continued process performance and product quality are two primary elements described in the scientific approach to continuous manufacturing. State of control relies on the continuous production process and unique parameters (e.g. process parameters, quality attributes, etc.) that are designed to stay within an appropriate pre-set range.

 

Further, the guidance specifically calls out the importance of identifying the root cause of drift. FDA continuous manufacturing examples highlighted for employees to closely monitor include variation of inputs, equipment fatigue, and aging of materials.

 

Process Dynamics

 

Understanding transient events and the various impacts they can have on the continuous production system is a critical facet of FDA Control Strategy. Further, the FDA guidance elaborates that this includes transient events that are both planned (e.g., process start-up, process shutdown or a manufacturing pause) and unplanned (e.g. production disturbance).

 

Residence Time Distribution (RTD)

 

One key takeaway from the FDA guidance for industry is understanding how process dynamics are characterized when output material quality is affected. Additionally, using measures like residence time distribution can help medical manufacturers differentiate between the time available for material transport and transformation. 

 

This type of quality metric strategy is specific to the continuous manufacturing process an often includes:

 

  • Product composition
  • Product formulation
  • Material properties
  • Equipment design
  • Equipment configuration

 

Operating Range

 

Each planned operating range should be based on the process dynamics and characterized by the planned over the planned ranges and anticipated input. Further, the FDA clearly states that material variability should use scientifically justified approaches for measuring quality against process dynamics that illustrate the variation during material transport and transformation.

 

Material Characterization

 

The FDA guidance goes on to list material feeding, process dynamics and output material quality as crucial continuous manufacturing elements that negatively impact material characterization. The FDA guidance lists a materials characterization facility as important to increasing production quality. Finally, realizing the predictability of material attribute variability on process performance and product quality is significant to the control strategy.

 

Solid Dosage Form

 

While analyzing the continuous manufacturing material flow process in a solid dosage form, the FDA guidance lists the following considerations that can impact powder feeding:

 

  • Particle size
  • Cohesiveness
  • Adhesiveness
  • Hygroscopicity
  • Static charge
  • Surface area of drug substances and excipients

 

Chemically Synthesized

 

While analyzing the material flow process in a chemically synthesized drug substance, the continuous manufacturing FDA guidance lists the following considerations that can impact flow properties:

 

  • Viscosity
  • Concentration
  • Multi-phase feed

 

Monoclonal Antibody

 

While analyzing the material flow process in a therapeutic protein (e.g. monoclonal antibody) substance, the FDA guidance lists the following continuous manufacturing considerations that can impact cell culture performance, process performance, or process consistency:

 

  • Lot-to-lot variability
  • Cell culture media
  • Different types of feed components

 

System Integration

 

The FDA guidance goes into depth about integrated systems characteristics and how equipment design can influence continuous manufacturing performance:

 

  • Design configuration
    • Maximum run time compatibility
    • Parts geometry impacting transformation
    • Integration and transfer steps
  • Design interface
    • Surge tanks
    • Mass flow rate
  • Material diversion and sampling
    • Diverter valve
    • Sampling probe
    • Material flow
    • Material transformation

 

The guidance continues to elaborate on equipment selection and how the equipment design, if executed properly, can help with process simplification.

 

Process Monitoring

 

Process monitoring and maintaining a state of control during production increases the understanding of real-time system performance. The FDA guidance states that these common approaches to process monitoring and control are also applicable to continuous manufacturing:

 

  • Established target setpoints
  • Established control limits
  • Design space
  • Measurement specifications

 

Process Analytical Technology

 

The FDA guidance also elaborates on why process analytical technology is suitable for continuous manufacturing. Examples provided by the agency for industry employees include:

 

  • In-line ultraviolet (UV) flow cells
  • Monitoring therapeutic protein concentration
  • In-line near-infrared spectroscopy
  • Assessing blend uniformity or water content
  • High-performance liquid chromatography
  • Monitoring the conversion of chemical reactions

 

To begin the Regulatory Compliance Associates scoping process today, please enter your information in the blue form below and click the submit button at the bottom of the webpage. You may also email us at [email protected].

Quality Culture & The Role of Management

Posted on by Brandon Miller

In the pharmaceutical and medical device industries, quality culture plays an essential role in profit generation, product safety and approval from regulatory bodies. As a result, organizations must prioritize maintaining product and process quality. One significant aspect of quality control is data integrity — a company’s data should be complete, consistent and accurate in both paper and electronic forms.

 

The adoption of electronic record keeping systems has led to a resurgence in data integrity citations. In response, many regulatory agencies — including the Food and Drug Administration (FDA), the Medicines and Healthcare Products Regulatory Agency (MHRA), the Pharmaceutical Inspectorate Consortium (PICS) and the World Health Organization (WHO) — have released guidance on data integrity. Many of these reports discuss quality culture as a key part of maintaining data integrity in life sciences.

 

What Is a Quality Culture?

 

Within an organization, quality culture is a working environment in which the risk of noncompliant and erroneous data and records is minimized. Creating a quality culture requires that all members of an organization encourage the open reporting of errors, omissions and other threats to data integrity and product quality.

 

As the WHO and other regulatory agencies have noted, management must be involved with the creation of a quality culture. Quality control should not be limited to the quality management team, but rather flow across all levels of leadership. Managers and other business leaders must be just as accountable for data integrity as everyone else.

 

How Can Management Contribute?

 

As awareness about the importance of quality increases, pharmaceutical companies are likely to see more requests for documentation demonstrating a commitment to quality and data integrity. Quality is also likely to impact a company’s finances — organizations with highly developed quality cultures may spend around $350 million less fixing mistakes every year.

 

To remain competitive, every business must consider the role of management in quality culture. Here are four ways leaders can contribute to quality in pharmaceutical, medical device, biologics and other organizations:

 

  • Lead by example: Quality culture must be encouraged from the top down. If managers and leaders demonstrate a commitment to quality, people throughout the company will follow.
  • Update reporting procedures: Managers should review and update their companies’ reporting procedures to elevate and address issues with data systems when they arise.
  • Review your audit schedule: While regulators don’t require internal audits, they are an important part of upholding data integrity. Review your audit schedule and ensure you are also auditing contract manufacturers and other outside parties.
  • Act on audit results: When an audit reveals gaps in data integrity, act immediately to address the problem. This shows you take quality seriously. You can address issues independently or seek help from experts like those at Regulatory Compliance Associates.

 

Learn More About Data Integrity and Quality Culture

 

The management role in quality culture is a hot topic in the life sciences industry. To learn more about data integrity and quality, contact Regulatory Compliance Associates or listen to the RCA Radio podcast. In the latest episode, host and RCA’s own, Erika Porcelli and Susan Schniepp discuss the history of data integrity and how management can integrate quality into the product lifecycle.

 

To begin the Regulatory Compliance Associates scoping process today, please enter your information in the blue form below and click the submit button at the bottom of the webpage. You may also email us at [email protected].

Medical Device Testing

Posted on by Brandon Miller

In the world of medical device testing, manufacturers should seek to identify key characteristics that set a high-quality laboratory aside from the rest. A successful medical device testing relationship should be built on trust, quality, and integrity. Some potential consequences for choosing an incapable third-party testing partner include inaccurate results, legal liability, regulatory compliance issues, wasted resources, and more. Most importantly, failure to achieve FDA approval or regulatory approval can lead to timely delays, wasted products, and the loss of business opportunities. 

 

How to identify a medical device testing partner

 

While the cost of medical device testing is often a determining factor, it’s essential to consider the cost of quality when selecting a testing partner. Additionally, assessing the laboratory’s ability to deliver testing results within required timelines without compromising quality is an advantage. It is critical not to be misled into unrealistic turnaround times or lower costs that could lead to re-testing and/or delays due to unreliable data driven by a lack of competence in testing. High-quality reliable data you can trust comes with appropriate timelines required to support critical sample preparation, strict quality control measures, and complex analysis.

 

In addition to cost and turnaround time, be sure to look for the following criteria when choosing a medical device testing laboratory to support your products:

 

A strong quality system

 

Quality management systems (QMS) are essential to ensure the reliability of all aspects of testing. From safeguarding the accuracy and confidence of results to the implementation of quality control measures, a strong QMS contributes to greater trust in 3rd party testing. One that has been regularly audited by the FDA is favorable.

 

Actively participates in standard development

 

Continued involvement at industry meetings including standard development keeps testing laboratories at the forefront of regulatory science and enables them to help you make the right testing decisions that are compliant and widely accepted. Technical expertise and experience go a long way in the proper support and understanding of the ever-evolving world of standards.

 

Upholds proper accreditation (ISO 17025)

 

The first sign of technical competence is accreditation to ISO 17025 which specifies the general requirements to carry out tests and/or calibrations, including sampling. Compliance with the FDA’s ASCA program is also desirable in addition to other industry-specific organizations. Accreditation demonstrates 3rd party testing compliance with international standards and ensures the credibility of lab testing services.

 

Robust regulatory resources

 

Internal subject matter experts who understand the complexities of globally regulated manufacturers will lead to more successful testing outcomes. Selecting a third-party laboratory that offers in-house expertise in this area can help reduce the regulatory feedback burden.

 

Customer-driven

 

Reliable and accurate medical device testing results are essential for maintaining customer satisfaction. Since a test report is often the final product provided by a testing laboratory, the overall customer success should be highlighted as critical to the overall success of the laboratory.

 

By specifically evaluating these factors, you can identify a strong third party testing partner that meets your specific testing needs and standards of quality, reliability, and competence.

 

To begin the Regulatory Compliance Associates scoping process today, please enter your information in the blue form below and click the submit button at the bottom of the webpage. You may also email us at [email protected].

 

FDA Expands Virtual Audit Guidance

Posted on by Brandon Miller

The US Food and Drug Administration (FDA) has recently expanded on its clarification of a virtual audit, and how new manufacturing protocols in the COVID-19 environment will evolve. Travel constraints continue to impact the industry, especially in countries like India where a tremendous outbreak of COVID cases erupted in April 2021.

 

“This does show that indeed, we are very much interested in doing these remote interactive investigations, you know, especially the ones with video streaming technology.” said Michael Kopcha, director of the Office of Pharmaceutical Quality in the agency’s Center for Drug Evaluation and Research.

Looking for help preparing for the new guidance? Contact Us Now →

After reviewing recommendations from the European Medicines Agency (EMA) and the UK Medicines and Healthcare Regulatory products Agency (UK MHRA), the FDA continues to address the questions many pharmaceutical companies and partners have voiced during the pandemic. FDA officials commented that, due to these early learnings from other global regulatory bodies, they have recently expanded their recommendations for virtual audit best practices and new criteria of considering when to conduct a remote inspection.

 

Two of the initial primary use cases for virtual pharmaceutical inspections mentioned by the FDA include records requests and on-site inspectional work. While developing the new virtual audit process is still ongoing, one recommendation is Pharmaceutical companies should choose a proven regulatory partner to assist with the audit. Agency executives explained they will not be engaging vendors to perform virtual audits on behalf of the FDA.

virtual audit

 

One looming issue to be remedied is will virtual audits be allowed for facilities with serious good manufacturing practice (GMP) violations. FDA officials have expanded on their risk-based approach to prioritization in deciding which sites may qualify. An expanded virtual audit strategy continues to be a work-in-progress by agency officials including defining which companies qualify for an FDA virtual inspection and, more importantly, in what order the virtual audits may happen.

 

GMP violations involve either FDA warning letters or action-indicated site classifications based on the possible corrective actions needed. If the corrective actions needed for a facility can be successfully addressed remotely, it may become more likely that the number of hybrid virtual inspections authorized by the FDA will continue to grow. However, agency official commentary concluded that each facility will be examined by the FDA team on an individual basis with consideration of potential violations involved being a primary decision-making driver.

 

The good news for Pharmaceutical industry executives is it appears the FDA is willing to learn from international regulatory experiences and potentially even collaborate using technology in new ways to increase the FDA’s ability to continue operations. Global travel limitations will more than likely impact every industry for the foreseeable future in 2021 until the COVID-19 vaccine becomes more widely administered.

 

To begin the Regulatory Compliance Associates scoping process today, please enter your information in the blue form below and click the submit button at the bottom of the webpage. You may also email us at [email protected].

FDA Updates Supply Chain Security Guidance

Posted on by Brandon Miller

The U.S. Food and Drug Administration (FDA) recently published multiple new guidance documents to help accelerate supply chain security and new product tracing requirements in the pharmaceutical industry. While most countries have implemented firmer regulations over the last decade, this new guidance is timely as domestic industry executives are reexamining security protocols in the wake of prominent cyberattacks.

 

The Drug Supply Chain Security Act (DSCSA) was originally designed as a framework for manufacturers, wholesalers, and dispensers to comply with laws that accomplish a safer, secure, and entrusted drug supply chain. A primary objective of DSCSA is to develop models and strategies to reduce the distribution of counterfeit, stolen, contaminated, or otherwise harmful drugs. These new FDA guidances include protocols for developing data architecture systems and how industry executives can optimize interoperability during the design and build phase. 

 

Need help with your Supply Chain? Talk to our Experts →

 

Drug Packaging

 

As part of the DSCSA, pharmaceutical manufacturers and repackagers are required to add a product identifier on drug packaging. The product identifier includes the product national drug code (NDC), serial number, lot number and expiration date for each package. It must be in both human- and machine-readable form (e.g. two-dimensional data matrix barcode). This is designed to help downstream partners (e.g. repackagers, wholesale distributors, and dispensers) associate the information encoded in the barcode with readable text used by Logistics teams. The updated human-readable format includes:

 

  • NDC: [insert product’s NDC]
  • SERIAL: [insert product’s serial number]
  • LOT: [insert product’s lot number]
  • EXP: [insert product’s expiration date]

 

Expiration Date

 

For select products where an expiration date includes only year and month due to space limitations, the drug’s actual expiration date is recommended to be the last day of the calendar month included in the human-readable expiration date on the drug package label.

 

Product Identifier

 

Each finished or unfinished drug is subject to regulatory listing requirements. The product identifier is a standardized graphic composed of an alphanumeric serial number (up to 20 characters) that helps identify the product and package configuration. Product identifiers must be affixed or imprinted on the smallest individual saleable unit of a product, which also includes all product sold to a dispenser.

 

National Drug Code

 

Each product identifier has a unique NDC. The NDC is a FDA-assigned 3-segment format (10 or 11-digit number) to identify its labeler, product, and package size and type. In select instances, the linear barcode requirements from 21 CFR 181 201.25 will stay in effect for additional FDA-regulated products and packaging. This digital fingerprint of data will be used to accelerate the regulatory learning process. 

 

Suspect/Illegitimate Products

 

The revised FDA guidance documents also now provide increased clarity regarding the FDA’s current interpretation of “suspect” and “illegitimate” products. “Suspect” and “illegitimate” products are defined as:

 

  • “counterfeit”
  • “diverted”
  • “stolen”
  • “fraudulent transaction”
  • “unfit for distribution”

 

Artificial Intelligence

 

As artificial intelligence and machine learning modernize the supply chain over time, it’s not unreasonable to imagine the new bar codes could detect medication errors in real time for healthcare professionals and pharmacists. This could provide alerts to validate industry professionals are:

 

  • Giving the right drug,
  • Via the right dose,
  • Via the right route of administration,
  • To the right patient,
  • At the right time.

 

Regulatory Agency Response

 

Specific scenarios designed for risk management of a suspect product entering the pharmaceutical supply chain are also referenced. The guidance provides examples of when manufacturers should notify the FDA of a high risk product that may be or is illegitimate. Industry executives are also encouraged to collaborate with the Agency to help refine existing processes for terminating notifications.

 

This new clarity provides pharmaceutical executives a further glimpse into the FDA’s interpretation of system attributes necessary for secure product tracing inside the marketplace. The language is noticeably more detailed at the package level and provides supporting commentary for avoiding supply chain disruptions and enhanced drug distribution security.

 

To begin the Regulatory Compliance Associates scoping process today, please enter your information in the blue form below and click the submit button at the bottom of the webpage. You may also email us at [email protected].