Stability Information Month Results!

May was Stability Information Month, and the information sources did not disappoint. This month’s (June 2024) Newsletter carries the hot topics that emerged from StabilityHub’s Office Hours, the PSDG Meeting at KENX’s Laboratory University and the Science of Stability Conference in Barcelona, Spain. Take a moment to check these out and make a note to bring the ones that most concern your organization to your Stability Group, Stability Review Board or Quality organization to capitalize on the experience of others. One or more of these areas may be an opportunity for your staff members to manage a challenge as a value-added contribution toward a better performance appraisal or merit promotion.

We start with this report from the Science of Stability Conference (SOS), 13-14 May 2024, Barcelona.

The 8th SOS conference, sponsored by FreeThink Technologies, Inc. and Lhasa Limited, brought scientists together from around the world to discuss accelerated aging, degradation chemistry, and stability. Once again, the content-rich conference featured a packed schedule of scientific topics, including forced degradation best practices, kinetic models for assessing nitrosation risk in solid drug products, application of ASAP (Accelerated Stability Assessment Program) to oligo and peptide product development, and approaches for predicting changes in physical properties on stability, including dissolution slowdown and recrystallization of amorphous solid dispersions (ASDs). FreeThink was proud to have Patrick Kelleher, Ph.D., present the Application of ASAPprime® for predictive accelerated stability modeling of probiotics in packaging, and Oxygen sensitivity accelerated stability modeling. The full program, slide presentations, and updates on future SOS events can be accessed at www.stabilityconference.com.

At the KENX Laboratory University Meeting June 4-6 in Philadelphia, Accelerated Stability Programs figured prominently in both presentation and discussion, thoroughly exploring the concept of Isoconversion in general and the application of the ASAP program specifically. While still not yet fully embraced by regulatory authorities as a substitute for traditional stability programs, it is making steady progress as reliable supportive data for solid oral dose products, among others, and internally as a rapid assessment for packaging materials, desiccants, impact of excursions, and more.

The recently released ICH Q14 Guidance (Analytical Procedure Development) was front and center for panel discussion and 9 topic-related presentations covering potential impact to Analytical Lifecycle Management in multiple ways; the end goal being generation of analytical methods that are robust, reliable and fit-for-purpose.

Stability Statistics garnered several presentations as well, emphasizing that the foundation of any statistical report begins with defining the research question you want to answer in order to provide quantitative assessments for decision making. With many questions to answer and multiple statistical methods available, it’s easy for Stabilitarians to wander off-target. Understanding the process and partnering closely with your local statistician can avoid a lot of unnecessary delays and erroneous conclusions.

Auditing and preparation for inspections received a lot of scrutiny with the most common problem discussed being a widespread failure to maintain these activities as a high priority in the face of all the other demands placed on Stabilitarians. Inventory inaccuracies and inadequate SOPs along with failure to keep adequate documentation for preventive maintenance are among the top contenders for citations. Keeping after chronic problems and maintaining a high level of compliance intelligence to anticipate stability pitfalls are key. Artificial Intelligence will figure prominently in predicting, catching and remediating problems. As noted below, the FDA is fully engaged along these lines.

Artificial Intelligence is a smart bet to revolutionize most aspects of the Stability function, especially mining and melding databases to quickly assemble works like phase-appropriate, regionally compliant, lean, and green protocols, among others. Constructing product pedigrees for packaging, excipients, APIs and manufacturing procedures, predicting chamber space requirements for next year’s stability studies, and putting an accurate price tag on everything needed in your departmental budget are easy-peasy for this emerging technology. The FDA is already on board, using AI to pinpoint organizations most likely in need of extra compliance attention. Expect an FDA AI Guidance this year while industry committees focus on new AI applications and best practices.

Telling the Stability Story was a standout topic of the meeting, emphasizing that Stability is a complex, trifold (technical, regulatory, and compliance) activity generating data from Long Term and Accelerated studies, Annual Commercial batches, Discrepancy studies, Cumulative expiry, Temperature Cycling, Photostability, Reconstitution, In-use, and Comparability studies. There is an army of Stability Stakeholders who provide input to the process as well as rely on the output. The Stabilitarian must know their audience, purpose, and message to successfully tell the Stability Story.

StabilityHub conducted its first on-line Office Hours event, featuring an all-star panel of Stability Function SMEs fielding questions from an array of stability stakeholders who brought their most perplexing challenges. A selection of these is posted here.

What to do with a large gap between date of manufacture and date on stability?

Minimize time intervals as much as possible through careful scheduling and marshaling resources, then justify the required time, applying knowledge of your product’s shelf life budget and utilizing appropriate re-releases and Time Zero tests.

How should we best address Use Testing Requirements? How would it apply to single use products?

There are some specific recommendations within guidances regarding the number of batches to be used and where in the shelf life of the product that the tests should be conducted. There is almost nothing written about dose withdrawal to define the test. Product and patient knowledge should be applied to justify the nature of the process, especially with single use products.

Has continuous stability chamber validation/qualification replaced periodic qualifications and if not, how often should chambers be requalified?

Not yet, but with the purchase or rental of qualified equipment, it is possible. How to handle the immense amount of resulting data is the biggest challenge for those who take this route. The most common interval in use for periodic requalification is two years (listed in a Guidance) but any significant change in chamber components or loading patterns should trigger an on the spot requalification and reset the two year clock.

What are the best applications for Isoconversion measures? (such as ASAP Prime) and conversely, what applications are not optimal?

Generating quick (30-60 day) studies to produce predictive supportive data for longer term traditional studies to follow. Solid oral dose products best fit the Isoconversion model as well as for selection of packaging materials, desiccants, etc and determining the impact of cumulative temperature excursions. While further applications are under development, most biologicals and liquids do not fit the model.

What should we do in preparation for applying Artificial Intelligence to the Stability process?

Start with an updated Stability Process map and complete list of stability stakeholders. Envision together where AI can be applied to the process, cross-linked with the input/output of the stability stakeholders, and take that vision to your corporate or contracted AI Development Team (This exercise would be analogous to the development and implementation of a Laboratory Information Management System)

What are the most important steps to take in preparing for an audit of the Stability area?

There is a plethora of preparations, but here are 5 to start with: Take note of what issues from previous audits and inspections are still lingering in any measure. Test yourself against recent industry Warning Letters and 483’s. Caucus with your Stability Stakeholders to uncover any disconnects between departments and procedures. Conduct regular walkthroughs, including interviews and questions of personnel. Confirm that statistical trending is up to date.

What’s emerging in the use of Contract Organizations for Stability Storage, Testing and Disaster Recovery?

Competition has skyrocketed and the digital age has made the transfer of data more efficient and easier to achieve. Quality and Service Agreements are more important than ever and should ensure transparency and timeliness in communications.

What steps can we take to bullet proof our sample inventory process?

Institute a double verification program which includes chamber inventories as well as chain of custody for samples on the move. Limit those who can authorize any unplanned withdrawals to those who can and will document the changes properly (especially in systems such as LIMS) and maintain a safe supply of surplus samples. Minimize extensive counting and subsequent errors by packing porous (“breathable”) sample bins with known convenient quantities (such as units of 10’s or 100’s) and placing a tamper-evident seal on the bin. Do a quick count (ex. “one, two, three hundred and 37”) every time there is a sample pull and have the receiving individual also count and confirm. This would complete a 100% on-going inventory over the course of a year and avoid disruptive periodic inventory programs.

What time limits should we impose on our Pull, Testing, and Data Review windows?

Windows for each vary by company, product type, and even test category. You should record a justification for what you do. A conservative rule of thumb (with appropriate exceptions) is to pull samples within two business days after the scheduled due date, complete all testing (except microbiology) within 30 days after pull, and complete data review through the Quality approval step within 10 days of testing completion. Many have more liberal windows if they’ve never been challenged by authorities.

We hope you’ve found the Hot Topics list useful in raising the quality and compliance levels in your own operations. We’d love to receive your further topic nominations for expanding the list by contacting us, or better yet, post them for comment in the Discussion Forum on StabilityHub.