The 2023 PSDG Meeting was conducted within the KENX Laboratory University Event in San Diego, CA, May 9-11, bringing together dozens of Stabilitarians, Analysts, and Quality personnel to explore the latest challenges in the Stability Arena. This month’s StabilityHub Newsletter focuses on these topic areas with a summary of each and an invitation to all our readers to further the discussion, raise questions of their own, and share some of the approaches they have successfully used to overcome their toughest hurdles. Most of all, challenge your group to evaluate where it stands regarding these subjects. Last month, we reviewed topics 1-17 and all 6 Focus topic sessions. Today’s discussion reviews topics 18-34 to complete the series.

CHAMBER MONITORING, RESPONDING TO EXCURSIONS, AND BEST MAINTENANCE PRACTICES

Chris Latoz, Manager, Stability Services, Hollister Inc.

Chris made the case for the importance of all operations surrounding Stability Chambers with a review of chamber-related FDA citations, highlighting the need for best practices in risk assessments, control strategies, preventive maintenance, monitoring, and response to excursions. In many of our companies, heavy focus on studies de-emphasizes healthy attention to critical aspects of chamber operations, which could eventually lead to negative impact to the studies they support. Are we vigilant in addressing all necessary aspects of our chambers?

METHOD LIFECYCLE MANAGEMENT

Samuel Seal, Waters

Sam made the case that analytical testing helps us understand process dynamics, drives critical decisions, and helps us to understand and control variability in analytical methods. He reviewed the following stages of the method life cycle:

  • Method Lifecycle Management
  • Method Development, Validation, Transfer, Verification & Scaling
  • Routine Use and Method Performance Monitoring
  • Method Migration

While Stabilitarians are seldom involved directly with analytical methods, when anything goes amiss in the method lifecycle, stability studies are impacted, most commonly in the form of reporting an outdated method in association with stability data. Do you regularly check and update method references associated with your studies? The method development folks should be among those with whom you communicate the most.

MANAGE DATA INTEGRITY INSPECTIONS AND RESPOND TO FINDINGS

Matthew LaPierre, Jackson Scott Consulting

Matthew covered in depth the various steps involved with managing data integrity to gain a realistic understanding of the entire system and accurate assessment of associated risk. How responses are made are as important as their content.

  • Contain the issue: Ensure all NEW systems are brought in with the right requirements. Create a URS standard to use that MUST be completed before users shop for systems.
  • Finish your assessments: Show you understand the system and the risks to it by creating comprehensive process maps. If you can’t finish your assessments before an inspection, prioritize the critical systems.
  • Document short-term & long-term remediation plan for all gaps: Both short and long-term remediation are important. Ensure accountability and tracking against metrics.
  • Show progress: The agency realizes there is much work to do. Often, they’ll give the feedback, “Too many assessments, not enough remediation.”

While Data Integrity has matured as a quality concern, how would you evaluate your ability to manage an inspection in this area? It’s a system that can present acceptability on the surface while problems can go undetected beneath. How vigorously have we focused on Data Integrity and what will we do in response to regulatory findings?

EFFECTIVE USE OF LIMS AND ELN FOR STABILITY

Annabelle Pratt, Lab Informatics, Practice Lead, Sagax Team

Annabelle brought to life the overall importance of Laboratory Information Systems to the success of various aspects of Stability Operations and the advantages gained through Electronic Laboratory Notebooks. In particular she reviewed the construction and important stages in selecting and building an effective LIMS.

Pain Points Without LIMS:

  • Overwhelming documentation challenges
  • Inability to Trend and Improve
  • Data Integrity and Accountability
  • Scalability Issues
  • Failure to Adhere to Protocol
  • Disparate Testing, Inventory, Planning
  • Paper Based or Excel Management

Several decades after the first LIMS emerged, industry is still struggling to get it right in using LIMS to their greatest advantage. How does your company measure up in this regard? What actions are currently in place to optimize your LIMS and/or Electronic Laboratory Notebooks?

CONDUCT A RISK-BASED ASSESSMENT FOR ANALYTICAL TEST METHOD VALIDATION – A Practical Example

Dr. David Vincent, Chief Scientific Officer (CSO), B.Sc., MPH. Ph.D. VTI Life Science, Inc.

David led the audience through a brief review of the Test Method Life Cycle and zeroed in on assessment of method validation, showing a practical risk-based approach.

The purpose of risk assessment for AMV studies is to provide successful measurable results for:

  • The level of method performance needed as manifested in the AMV protocol acceptance criteria.
  • To develop a strategy to determine the desired amount of formal validation to be executed.

In great depth, each step was covered for the various analytical qualification classes including typical pitfalls and remediations. Are we assured that our companies conduct risk-based assessments adequate to meet industry best practices and regulatory standards?

RAPID MICROBIOLOGICAL METHODS: QUALIFICATION CONSIDERATION

Anthony Grilli, MS, Laboratory Director CEO, FOCUS Laboratories

Anthony laid out the regulatory and compendial basis for microbiological testing and then discussed the current technology available in obtaining the most accurate and speedy results along with their advantages and limitations. Included in the presentation were validation techniques for alternative methods when sponsors made innovative discoveries ahead of their time. Ultimately, all aspects of microbiological testing were explained. As Stabilitarians, we often view Micro testing as a black box that turns out a pass or fail result. As with analytical testing, we need to expand our knowledge and understanding of our organization’s microbiological test operations.

PREPARING FOR AN AUDIT

John O’Neill, Facilitator PSDG, Editor StabilityHub

John presented a perspective of audits as an unseen strength, involving a network of stakeholders that support the focal point of the audit and a broad risk assessment of the ancillary systems as well as the central.

  • Reveal hidden need for improvement.
  • Allow a glimpse into current industry weaknesses
  • Ensure compliance and inspire better performance
  • Improve our programs and hence our data
  • Strengthen inter-departmental relationships
  • Train our staff members
  • Prevent observations and citations
  • Save expenditures of resources in regulatory response & remediation
  • Protect the Company
  • Protect the Patient

Do we embrace audit preparation as a routine function of Stability Operations? Do you budget time and resources in preventive measures before they become exponential expenditures in the aftermath of an audit? It is well worth the cost.

MONITORING ORGANIC IMPURITIES: THE DYNAMIC IMPACT OF <476>, <477> & <1086>

Antonio Hernandez-Cardoso, Senior Principal Scientist, USP

Antonio brought the USP perspective for monitoring organic impurities that can arise from many stages of our development process and can often manifest themselves during stability studies of Components, API’s, and Products. Thresholds, limits and reporting and control are key features in latest USP organic impurity developments.

How well-versed are we in how and where impurities arise. Do we participate in their detection and reporting during the stability process?

ANALYTICAL METHOD DEVELOPMENT USING QbD

David Lavrich, Ph.D., Senior Principal Scientist, Merck, Inc

David presented the application of Quality by Design principles to the development of analytical methods. Making a case for the benefits gained by careful planning, risk reduction and implementation.

Benefits of Early Planning of an Analytical QbD Approach:

  • The Need to reduce risk in method development and validation
  • The promise of QbD-building quality into test methods
  • Structure of QbD and how it applies to analytical procedure lifecycle management
  • Understanding measurement processes (Measurement System Analysis)

Successful Implementation of Risk-based Verification Strategy:

  • Improving test method robustness using DOE
  • Measurement quality- Gauge R&R
  • Measurement Process Control-continued Test Method Verification
  • Effective use of graphical methods to visualize and understand variations

Has Quality by Design aged out of our consciousness, or should we regularly circle back to evaluate our programs and process considering QbD?

OPTIMIZING PREPARATION FOR YOUR LAB INSPECTIONS

Laure L. Larkin, Associate Director Global Product Stability, Ethicon R&D Analytical Evaluation

Laure contributed a thoughtful analysis of typical laboratory inspection observations, defining each category and providing an example for each. In addition, she cited the pet peeves of inspectors and the low hanging fruit that often greets them during inspections.

Top 10 findings categories from recent data:

  • SOPs
  • Missing Data
  • Deviations
  • Traceability/Segregation
  • OOS Dispositions
  • Doc/Data/Sample Retention
  • Management Resourcing
  • Test Method Validation
  • Training
  • Data Review

When was the last time you checked these categories for any deficiencies in your operations?

IDENTIFYING ERROR BY CONDUCTING AN EFFECTIVE INVESTIGATION

Kenneth R. Miller, Ph.D. Director, Stability & Data Management, BioMarin Pharmaceutical, Inc.

Ken outlined the need for and components of effective investigations. They are well-documented, timely, unbiased, and thorough. He explored common problems with laboratory investigations as noted in 483 observations and warning letters; what’s entailed in developing a comprehensive investigation methodology, the tools needed for performing root cause analysis, and how to best document investigations.

EVALUATE THE PERFORMANCE OF THE MARKETED STABILITY PROGRAM

Sherilyn Campie, Director of QC Stability, Coherus Biosciences

Sherilyn relayed the essence of marketed product stability programs in deriving product quality under recommended storage at time of expiry and demonstrating product quality is consistent with primary batches through ongoing studies, annual studies, post-approval changes, shelf-life extension, and special studies.

Is this phase of Product Stability in your company up to best practice standards? A number of regulatory observations reveal that our diligence can drop off at this stage once regulatory approval is achieved.

ESTABLISHING A PROGRAM FOR LABORATORY DISASTER MANAGEMENT

Chris Latoz, Manager, Stability Services, Hollister Inc.

Chris made the case for the necessity of preserving samples, data and equipment while reducing stress and anxiety. He took the audience through the steps of a Hazard Vulnerability Assessment.

Key Elements to Consider for Program for Laboratory Disaster Management, leading to effective disaster management.

  • Create a Laboratory Disaster Plan
    • Hazard Vulnerability Assessment (HVA)
    • Mitigation
    • Preparedness
    • Response
    • Recovery
  • Test, Train, and Exercise the Plan
  • Distribute, Maintain, and Update the Plan

The pharmaceutical industry can fall victim to complacence during prolonged periods of success and stability. How would you rate your current state of preparedness and how often do you revisit and evaluate this area?

EVALUATION OF STABILITY DATA PER ICH Q1E: Application of Guidance to Drive Statistical Strategies

Laura Pack, Sr. Director, QC & Statistics, Rezolute, Inc.

Laura did a masterful job of un-packing ICH Q1E, pointing out that when it comes to statistics, Stabilitarians and Statisticians can be speaking different languages using the same terms, but having different meanings. Laura covered and interpreted the provisions of the guidance, pointing out typical pain points, and methods of successful application.

With statistics being the basis of the shelf-life and storage stories we want to tell about our product in convincing regulatory authorities, do we maximize our relationships and interaction with our statisticians, or have we underestimated the critical role they play in our process?

DATA INTEGRITY COMPLIANCE; CREATE YOUR CUSTOM QC LAB AUDIT CHECKLIST

Dr. David Vincent, MPH. PhD/CEO VTI Life Science, Inc.

David reviewed the role played by Data Integrity in today’s regulatory inspections and laid out a strategy for success, along with a detailed checklist to certify that data integrity within your program meets all expectations.

Audit Strategy:

  • Starts with a specific result (or record).
  • Re-create the sequence of events that occurred at the time the result (or record) was generated using the electronic (meta) data.
  • The auditor will want to know:
    • WHO performed the analysis?
    • WHAT equipment was used to perform the analysis?
    • WHEN the analysis was performed?
    • WHY the analysis was performed?
    • WHERE the electronic (meta) data is stored?

How do you stand with regard to Data Integrity permeating your entire process? DI ranks near the top of the list as a quality concern when Inspectors arrive at your door.

UNDERSTANDING STABILITY CHAMBERS SELECTION, VALIDATION AND CALIBRATION (from the viewpoint of a long-time user)

John O’Neill, Facilitator PSDG, Editor StabilityHub

John gave an introductory primer on all aspects of acquiring, qualifying, and maintaining stability chambers along with extensive examples of what goes wrong and why, along the way.

A Study is only Valid if the Chamber Stays Within Calibration and Performance Specifications. An invalid chamber casts doubt on the validity of a stability study, which casts doubt on:

  • Product shelf life and storage requirements
  • Gaining approval by regulatory authorities
  • Viability of the company
  • Prognosis of the patient

How tight is your chamber program? Do you have thorough Preventive Maintenance and Re-Qualification programs? Can you project your chamber needs and costs three years out? Are these responsibilities at the top of someone on your team’s job description?

QC LAB DATA INTEGRITY PROGRAMS / DATA INTEGRITY PROCESS MAPPING- IDENTIFY AND MITIGATE DATA GAPS

Nanda Subbarao, Sr. Consultant, Biologics Consulting Group, Inc.

Nanda provided the audience with a detailed walk-through of how to initiate a thorough data mapping process and follow up with careful analysis and mitigation.

Data Process Mapping of Laboratory Data:

  • Why do we need Data Integrity in Pharma/biologics laboratories
  • Why should we prepare and analyze analytical data maps?
  • Data mapping for different types of analytical methods
  • Steps in data mapping
  • Identification of Data Integrity gaps
  • Mitigation of Data Gaps:
  • Case study: Consequences of an incomplete chromatography system process map
  • Mitigation of an incomplete process map
  • Short term, intermediate term, and long-term mitigation of data integrity risks
  • Challenges presented by new modalities
  • Challenges presented by an evolving data storage environment

As seen by the popularity of this topic at the PSDG / KENX event, it is critical to our process and can be a huge stumbling block if not carefully handled. How do you stack up in your efforts to analyze and control data integrity within your organization?

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A stabilitarian encounters new situations every day. StabilityHub’s discussion forums give Stabilitarians an opportunity to ask questions and offer solutions to specific scenarios. Join in the conversations with other Stabilitiarians and share your knowledge!