Publications

A team of American scientists report on some recent developments in the realm of pharmaceutical stress testing, or forced degradation, practices relating to solid dosage forms, bringing some valuable clarity for drug developers.

Audits • Quality

Distinctive strategies for doing remote audits successfully. Keywords: Prepare, Communication, Sharing

Best Practices • Shelf-Life

Stability studies are an integral part of the drug development process for any drug product. In addition to monitoring chemical degradation, the physical stability of a drug product must also be evaluated to ensure that the drug release and performance is not affected by storage. In this study, directly compressed tablets of 16 different formulations were exposed to an accelerated stability program to quantify changes in tablet breaking force, porosity, contact angle and disintegration time. Tablets were exposed to five different storage conditions from 37∘C/30% relative humidity (RH) to 70∘C/75%RH with testing after 2 and 4 weeks of storage. Each formulation contained two different fillers (47% w/w each), a disintegrant (5% w/w) and magnesium stearate (1% w/w). The results show that tablets stored at high humidity show increases in porosity and decreases in tensile strength, particularly if they contain a highly hygroscopic filler such as microcrystalline cellulose (MCC). For tablets stored at high temperature, the most commonly affected property was the tablet wettability, measured by sessile drop contact angle measurements. These results are considered in combination with the performance-controlling disintegration mechanism (Maclean et al., 2021) to identify the critical properties which influence the performance after storage.

Best Practices • Packaging • Secondary

The growth of global counterfeiting has risen rapidly in the 21st century and accounts for more than 3% of world trade, or over $500 Billion USD. While the topic of counterfeit products may first call to mind Rolex watches or Gucci purses, the fact is, fake drugs represent a multi-billion-dollar global market. Why? Follow the money. Counterfeit pharmaceuticals are the most lucrative sector of the global trade in illegally copied goods.

Audits • Compliance • Quality

A short summary with data table showing various types and numbers of observations related to stability in 2021.

Key words: Inspection, Observation, Regulation

Best Practices • Best Practices • Data Analysis • Determination • Extrapolation • Reports • Shelf-Life • Statistics

Abstract: Conventional laboratory information management systems (LIMS) have been largely deficient in addressing these challenges, primarily because of the unique nature of stability data and how it is collected and analyzed. This paper details the development and implementation of a strategy for leveraging SAS technologies to address the analytical needs of a stability monitoring program, and its impact on day-to-day operations for a stability testing laboratory in a major pharmaceutical company.

Closure Integrity • Packaging • Primary

As the biologics market continues to grow, drug manufacturers are looking for packaging solutions that maintain integrity during processing and freezing, are easy to scale up to larger volumes, and remain robust throughout the temperature-controlled supply chain. However, finding the right containment system requires more than looking over a spec sheet. Here are some important considerations to keep in mind when choosing packaging for a biologic drug substance.

Best Practices • Determination • Extrapolation • Shelf-Life

Abstract: Long-term stability of monoclonal antibodies to be used as biologics is a key aspect in their development. Therefore, its possible early prediction from accelerated stability studies is of major interest, despite currently being regarded as not sufficiently robust. In this work, using a combination of accelerated stability studies (up to 6 months) and first order degradation kinetic model, we are able to predict the long-term stability (up to 3 years) of multiple monoclonal antibody formulations. More specifically, we can robustly predict the long-term stability behaviour of a protein at the intended storage condition (5 °C), based on up to six months of data obtained for multiple quality attributes from different temperatures, usually from intended (5 °C), accelerated (25 °C) and stress conditions (40 °C). We have performed stability studies and evaluated the stability data of several mAbs including IgG1, IgG2, and fusion proteins, and validated our model by overlaying the 95% prediction interval and experimental stability data from up to 36 months. We demonstrated improved robustness, speed and accuracy of kinetic long-term stability prediction as compared to classical linear extrapolation used today, which justifies long-term stability prediction and shelf-life extrapolation for some biologics such as monoclonal antibodies. This work aims to contribute towards further development and refinement of the regulatory landscape that could steer toward allowing extrapolation for biologics during the developmental phase, clinical phase, and also in marketing authorisation applications, as already established today for small molecules.

Best Practices • Testing

Given the rapid emergence of gene therapies based on recombinant adeno-associated virus (rAAV), there is a great need for appropriate analytical tools to support every lifecycle stage of these products.

Data Integrity • Quality

In the podcast the speakers count down the top five data integrity issues when complying with GMP guidance. Data Integrity is a critical element to GMP compliance, and all life science manufacturers need to develop and maintain processes for managing their data, reducing the risk to the integrity of that data, and stored properly. Of course, this is all part of the Regulatory Guidelines which have been in place for years. Still, nearly half of all warning letters contain data integrity components.

Investigations • Quality • Study Design • Tools

Introduction: Critical thinking is an approach to learning that forms part of many university curricula as well as for wider society (1). However, all too often in the world of work the critical thinking approach seems to dissipate and this can have negative consequences in terms of decision making. Within pharmaceuticals and healthcare, this can result in weak root cause analysis, poorly set CAPAs, weakly thought-out change controls and so on.

This article is one of a three-part series about critical thinking in the context of pharmaceutical and healthcare organizations: Critical thinking #1: Why pharmaceuticals and healthcare needs more critical thinkers. Critical thinking #2: Reading research papers. Critical thinking #3: Self-questioning and questioning for a better outcome.

Closure Integrity • Laboratory Issues • Methods • Packaging • Primary • Testing

Opening Paragraph: Container Closure Integrity Testing (CCIT) in the pharmaceutical industry is such an important piece of the packaging puzzle, that more and more regulatory agencies around the globe are beginning to draft specific requirements for manufacturers. With the greater need to meet these requirements, product inspection companies are evolving their technology to meet the increased speed and efficiency demands of the packaging lines. An absolute truth in the CCIT space is that one single inspection technology cannot be used for every type of pharmaceutical product.

Authorities • Guidances • Regulations • Regulatory

Abstract: In consideration of the recent ICH Quality Discussion Group (QDG) recommended revision to the ICH series of stability guidelines, the IQ Consortium (International Consortium for Innovation and Quality in Pharmaceutical Development) Science- and Risk-based Stability Working Group conducted a comprehensive review of ICH Q1A, Q1B, Q1C, Q1D, Q1E, and Q5C to identify areas where the guidelines could be clarified, updated, and amended to reflect the potential knowledge gained from current risk-based predictive stability tools and to consider other science- and risk-based stability strategies in accordance with ICH Q8-12. The recommendations propose a holistic approach to stability understanding, utilizing historical data, prior knowledge, modeling, and a risk assessment process to expand the concept of what could be included (or would be acceptable) in the core stability data package, including type and amount of stability evidence, assignment of retest period and shelf-life for a new product, and assessment of the impact of post-approval changes.

Change Control • Quality • SOPS

Start with Why: Needing to develop or update your procedures? Are you sitting at your computer starting to write procedures for every subject discussed in regulations and standards, addressing each statement with a procedural step? Put the procedure template away. The first step to writing effective procedures is in understanding WHY you are writing that procedure.

Investigations • Quality • Tools

Introduction: One of the dilemmas facing the quality risk management function is with a series of completed risk assessments and a series of multiple outcomes that require addressing, in the context of limited resources or other scheduling issues. When faced with multiple risks, how are these to be prioritized? This represents that part of risk management that assessed what needs to be managed and how much effort should be focused towards achieving adequate performance and avoiding undesirable events.

Authorities • Guidances • Regulations • Regulatory

Highlights • The additions and revisions of the Chinese Pharmacopoeia 2020 edition general chapters are introduced. • The applications of advanced techniques have been expanded in the Chinese Pharmacopoeia 2020 edition. • The technical requirements will be better harmonized with ICH in the Chinese Pharmacopoeia 2025 edition. This article also appears in the Regulatory Information section of Stability Hub

Authorities • Guidances • Regulations • Regulatory • Submissions

Conclusion Paragraph: Recent changes in the organization, structure, and philosophy at the FDA are a positive sign for the pharmaceutical industry. The guidance contains a comprehensive Appendix that provides several practical examples to help classify the change type, which will be useful for reference and as a training tool when implementing the change assessment and notification process.

Guidances • Pharmacopoeia • Regulations

Abstract: Lecture Notes: Unit: III Testing of natural products and drugs: Effect of herbal medicine on clinical laboratory testing, Adulterant Screening using modern analytical instruments, Regulation and dispensing of herbal drugs, Stability testing of natural products, protocol. Monographs of Herbal drugs: Study of monographs of herbal drugs and comparative study in IP, USP, Ayurvedic Pharmacopoeia, British herbal Pharmacopoeia, Siddha and Unani Pharmacopoeia, WHO guidelines in quality assessment of herbal drugs.

Best Practices • Chambers • Compliance • Excursions • Investigations • Quality

Abstract The purpose of a Stability Program is to support the expiration dating of pharmaceutical products, medical devices, and biologics and recommend storage conditions. These products are manufactured and placed in special environmental chambers (stability chambers) with specific temperature and humidity conditions according to the ICH Q1A (R2) guideline. Samples are then withdrawn and tested at various time intervals, according to specifications. Stability data are generated throughout the product lifecycle to support development, commercialization, distribution, and even transportation. The stability data sets are part of regulatory submissions; thus, any deviation or investigation may cause sample integrity concerns. According to the FDA, WHO, and various global guidelines, the temperature and humidity of the stability chambers must be accurately controlled to specific tolerances. Excursions must be evaluated and investigated if they exceed 24 hours in duration and if there is any impact on the quality of the products, additional actions may be necessary. This paper will provide some key factors to consider regarding how temperature and humidity excursions to stability samples should be investigated and what data is needed to support conclusions about sample viability. This article may also be of interest to the chamber management group of the Stability Program and those involved with facility management. Various suggestions can be incorporated into a company’s internal standard operating procedure (SOP) to handle deviations and protect the integrity of products stored.

Audits • Quality

Conclusion: Working from home has become a common occurrence for many companies. Restricted access to visitors is also more prevalent than in previous years. This has necessitated finding new ways to accomplish old tasks. Use of remote or virtual audits may be one of the tools available. Prior to implementing remote audits, it is important for companies to consider the various risks and difficulties in performance or participation in a virtual audit. Key Words: Pandemic, Virtual, Travel

Investigations • Laboratory Issues • Resources • Testing

Introductory Paragraph: In the pharmaceutical and biotech industries, delays in getting products to market cost companies revenue and inhibit patient access to their medications. CAI clients often seek help in closing open investigations, but ignore the source of these investigations, even while product sits quarantined. Where clients really need help is in cutting human error off at the source. Industry average deviation costs generally range from $25,000 to $55,000, yet they can top $1,000,000 per deviation if product loss is involved. Investigating one deviation alone can cost a company thousands of dollars. When considering the cost of heroic efforts to produce and release batches, subsequent employee turnover, and potential downtime, cost increases exponentially.

Compliance • Data Integrity • Laboratory Issues • LIMS • Quality • Testing

Introduction: “If it is not written down, it did not happen.” That is the foundation on which contemporaneous data and data integrity are built upon. Contemporaneous, by definition, means “existing, occurring, or originating during the same time.” [1] When this concept is applied to laboratory settings, it refers to recording data, whether it is a time, measurement, or observation when the work is being completed. It is considered unacceptable to record the data using a different means (e.g., a loose piece of paper) then transfer said data later to the appropriately...

Best Practices • Best Practices • Equipment • Sample Control • Storage • Testing

Temperature control is critical to many molecular and cellular experiments, but managing sample temperature requires either the use of secondary measuring equipment or long, imprecise incubations in freezers or refrigerators. These inefficient methods lengthen processing time for even the simplest experiments – increasing workload, time pressures, and the risk of human error. With the development of new thermochromic science, product scientists at Labcon have created a series of centrifuge tubes and microcentrifuge tubes that give a rapid, real-time visual cue when the contents in a sample tube have reached a desired temperature.

Audits • Authorities • Compliance • Guidances • Quality • Regulations • Regulatory

Introductory Paragraph: As health authorities around the world wrestle with how to conduct manufacturing inspections during the 2020 global pandemic, as well as with shrinking resources and the need to better leverage them, mutual recognition agreements (MRAs) between the authorities are providing some relief.

This article is also included in the "Regulations" section of StabilityHub.

Packaging • Sterile

Summary: This week, Stacey welcomes back Bernard Hsu and Paul Pluta to talk about the curious case of death by black licorice. Unanticipated illness and even death due to unexpected effects of ingredients in the foods or medicine we consume occurs all too often. Sometimes these are deliberate, with people consuming more than prescribed or mixing medications. The IVT Network recently published a blog post Unexpected Toxicity From Drug Products on this very topic. Today we will discuss this case and many more as we discover the associated science with two of the authors. Bernard Hsu and Paul Pluta.

Best Practices • Packaging • Sterile

Roberta Goode talks about patient safety and how medical packaging is a key component of that. She discusses the nuts and bolts around “Selecting medical device packaging materials and sterilization methods to achieve appropriate sterility assurance levels and sterile barrier integrity throughout the labeled shelf life.”

Determination • Shelf-Life • Submissions

Introductory Paragraph: Beyond Use Date (BUD) is very different from expiration date. USP Chapter 797 defines BUD as the date or time after which a compounded sterile preparation (CSP) may not be stored or transported and is calculated from the date or time of compounding. Expiration date is a manufacturer defined term based on very specific testing used for commercially available products. A CSP cannot be labeled with the term “expiration date” or any variance thereof. It must be labeled with a different phrase such as, “do not use after” or “use before” etc.

Data Integrity • Quality

This is an incomplete link, but may enable the user to find an alternative article or another source from the available infomration.

Planning • Quality • Resources • Tools

Introduction: Challenges impacting validation -- Industry had not experienced or expected a full-blown global pandemic until COVID-19 dur the past year. Not only has this widespread terrifying event created a significant number of challenges for all functional areas including validation, it has also challenged the production, staffing, economic, and distribution activities as well as cleaning and sanitization efforts. Work arrangements such as remote working and staggered staffing have created several challenges for validation teams.

Best Practices • Closure Integrity • Methods • Packaging • Testing

Summary • Know your package and what attributes can effect your product over the product life time. • Current Guidance for CCI points towards Deterministic Test Methods • No Golden All Encompassing Test Method to cover all package/product combinations. • Understanding the risks over the product life cycle and mitigating those risks through strategy/ analysis is key.

Determination • Extension • Extrapolation • Shelf-Life • Statistical • Statistics

This webinar describes a new procedure added to Statgraphics 19 for analyzing data from stability studies. Stability studies are commonly used by pharmaceutical and other types of companies to estimate the rate of product degradation and to establish shelf life. Measurements are typically made on samples from multiple batches at different points in time. Of primary interest is estimating the time at which the prediction limits from the degradation model cross the specification limits for the product.

Audits • Quality • Regulatory • Submissions • Tools

Conclusion: The current paper-based on-site inspections present challenges to the efficient and effective utilization of FDA and industry resources for verification and enhancement of quality and compliance. Travel restrictions presented by COVID-19 further exacerbate the challenges of continuing the current construct. Digitally enabled remote inspections would reduce administrative burden, allowing both the agency and inspected entities to focus more effort on addressing gaps, continuous improvement, and implementation of best practices. Standardized output and communications would reduce time to understand opportunities, set action plans, and implement improvements that provide benefits to FDA, inspected entities, and enhanced quality and safety to patients.

In and beyond the COVID -19 pandemic, the need for a transparent method of evaluating and communicating quality management maturity is acute and critical (5). Using technological solutions, manufacturers can demonstrate the rigorous oversight of their systems. Their supervision should demonstrate understanding and control over their manufacturing processes. When regulators such as the FDA can observe the rigor and maturity of a corporate QMS, they can exercise a more flexible regulatory approach. Such a flexible approach should create opportunities that are genuinely aligned with the notion of partners in public health, reduce the need for “extensive regulatory oversight,” and encourage continual improvement of manufacturing processes. One can expect that a formal rating system to measure and rate quality management maturity will need to emerge soon. Now is the time that firms seriously consider investing in technologies that contribute to maturity and oversight of their QMS and enable drawing a distinction from others with less mature systems.

Best Practices • Methods • Planning • Resources • Testing

Testing may be required for antimicrobial preservatives to protect non-sterile dosage forms from microorganism growth.

Best Practices • Extension • Quality • Regulatory • Shelf-Life • Submissions • Tools

Abstract: Post-approval changes (PACs) are inevitable and necessary throughout the lifecycle of pharmaceutical products - to implement new knowledge, maintain a state of control, and drive continual improvement.

This One-Voice-Of-Quality (1VQ) paper is part of a series of industry case studies intended to demonstrate the standard application of the principles outlined in the publication “Effective Management of Post-Approval Changes in the Pharmaceutical Quality System (PQS) - Through Enhanced Science and Risk-Based Approaches Industry; One-Voice-of-Quality (1VQ) Solutions” in PDA Journal of Pharmaceutical Science and Technology, 2020.

Furthermore, this 1VQ paper provides a practical application of the concepts described in ICH Q9, Quality Risk Management, ICH Q10, Pharmaceutical Quality System, and ICH Q12, Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management to shelf-life extensions for pharmaceutical products.

In this case study, the risk associated with the extension of shelf-life was evaluated. The conclusion drawn is that shelf-life extension changes when controlled effectively as described in this paper, present a low risk to product quality, and therefore can be downgraded from a prior-approval to notification or annual reportable and managed in the PQS with immediate implementation.

Data Integrity • Quality • Systems

This podcast is to help listeners better understand how to establish criteria around “critical data” and managing it within the data integrity programs of our own business.

What is critical data, and why is it important to define it? What are the first steps in establishing the criteria desired to identify critical data? Once we definite critical data, how fully integrate it into our data integrity program? How does “critical” data impact validation? What are some key considerations in critical data collection, and what are the biggest mistakes made here? Given that critical and non-critical data can be stored and maintained in the same database, what special protections of records controls do we need to be mindful of? What are the biggest challenges around critical data, and record controls? Can you highlight a couple of examples where data collection or storage failures have happened? Thinking about critical data reviews in your SOPs, review frequency and risk assessments. What are regulators expectations around critical data during an audit trail review? What are the most common failures or findings during these reviews?

Change Control • Data Integrity • Quality

Abstract: In drug manufacturing, quality is viewed as a required objective to be achieved through the management of the production process. Data are the results of the production process, and the way this process is performed affects data accuracy. The set of control procedures applicable to data integrity must be sufficiently comprehensive to provide evidence of operational and quality system activities. Data integrity covers data entry or collection, data storage, data transmission, and data processing. Data provenance is the assurance of the data source systems. Data validity is about the correctness and reasonableness of data conforming to the syntax and structure defined by the business requirements. Instead of regulated companies emphasizing data integrity, it is suggested companies concentrate on data quality to meet quality requirements, as contained in the respective medicine manufacturing practices regulations.

Best Practices • Equipment • Laboratory Issues

Abstract: Post-approval changes are inevitable and necessary throughout the lifecycle of pharmaceutical products to implement new knowledge, maintain a state of control, and drive continual improvement.

This One-Voice-of-Quality (1VQ) position paper is part of a series of industry case studies intended to demonstrate the standard application of the principles outlined in the publication “Effective Management of Post-Approval Changes in the Pharmaceutical Quality System (PQS) - Through Enhanced Science and Risk-Based Approaches Industry; One-Voice-of Quality (1VQ) Solutions” in PDA Journal of Pharmaceutical Science and Technology, 2020.

Furthermore, this 1VQ position paper provides a practical application of the concepts described in ICH Q9, Quality Risk Management [2], ICH Q10, Pharmaceutical Quality System [3], and ICH Q12, Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management [4] to changes to analytical equipment/instrumentation that are deemed to be equivalent.

This paper describes changes to analytical equipment that are considered ‘like for like’ or equivalent. The conclusion drawn from this case study is that such changes present a low risk, and therefore can be downgraded from a prior-approval and managed only within the company’s PQS.

Education • Investigations • Laboratory Issues • Quality • Tools • Training

Abstract: This article is concerned with error risk reduction, centered on illustrative case studies. Human error has long been identified as a contributing factor to incident causation, and pharmaceuticals and healthcare is no exception. Human error is a cause of substantial variation across the pharmaceutical and healthcare sectors. To a degree it can be prevented by analyzing process for failure modes and implementing better training, clearer documentation and by increasing automation. To do so requires an understanding of human behaviors and motivations, and ensuring that the 'human factor' is adequately assessed in the design of systems and processes. Human error is frequent topic of regulatory inspections. Error risk reduction is associated foremost with human error and the ways to reduce the impact of human error on procedures and processes. With this approach, it is important that the people carrying out the assessment should have an understanding of the different types of failure and the factors that make them more or less likely to occur.

Guidances • Regulatory • Tools

Introduction: A revision to ICH Q9 Quality Risk Management (QRM) has been recently approved by the ICH Management Committee. ICH Q9 is a key document associated with change management and validation. The original ICH Q9 was issued more than 10 years ago. This topic was endorsed by the ICH Assembly in November 2019. Two primary activities are addressed: -Limited and specific adjustments to specific chapters and annexes in the current ICH Q9 -Specific training materials with examples to supplement current ICH Q9 and the proposed revisions. This document summarizes key points associated with the revision as expressed in ICH documents.

Determination • Guidances • Pharmacopoeia • Regulatory • Shelf-Life

United States Pharmacopeial Convention (USP) is continuing stakeholder engagement activities to foster input pertaining to beyond-use date (BUD) provisions in the compounding general chapters, and . These activities follow a final decision on formal appeals to these chapters, which recommended further engagement by the Compounding Expert Committee (CMP EC) with stakeholders on the issues raised pertaining to BUDs.

The Open Forum session was held on September 15, 2020. This was an open event, and USP invited all who wished to participate to register for the virtual event. Participants were able to ask questions, make comments and provide recommendations for 2020 – 2025 through a virtual discussion board.

USP and the CMP EC remain committed to moving forward in an open, transparent, balanced and timely manner. For any questions, please contact the USP Healthcare Quality and Safety staff at CompoundingSL@usp.org.

LIMS

Selecting the right LIMS (Laboratory Information Management System) software is a critical decision for any organization, as it directly impacts laboratory efficiency, data management, and regulatory compliance. This blog post discusses the importance of involving various stakeholders in the LIMS software selection process to ensure a comprehensive understanding of your organization's needs.

From lab managers to stability analysts and environmental monitoring personnel, each stakeholder brings unique insights into essential features such as multi-location lab management, remote worker accessibility, mobile application integration, sample tracking capabilities and more. Furthermore, this post explores cloud-based LIMS systems that offer reduced IT infrastructure risks while providing scalability for growing businesses.

Lastly, it delves into vendor demonstrations and evaluate potential LIMS solutions based on their ease of use and the adaptability of out of box workflows. By considering these factors during your LIMS software selection process can help you choose an optimal solution tailored to your specific requirements.

Laboratory Issues

The types of laboratory inefficiencies that a lean laboratory model can attempt to address include (2-4): Focus: Lack of control over the progress of individual samples. Organization: Different samples linked to samples for different markets are not necessarily tested in batches, leading to change over inefficiencies. Long lead times: The development of queues in front of each test can occur where individual samples wait until there are a sufficient number of other, similar samples arrive to activate the test run. This is not necessarily efficient. Variable lead times: Leading to a lack of predictability.

Investigations

Quality • Tools

Abstract: This paper highlights the practical benefits to the industry, of adopting the concept of the ‘Spectrum of Importance’ (SOFI) as proposed by O’Keeffe which presented an alternate approach to understanding and prioritizing process parameters. Their approach represented a move away from the current binary critical/non-critical one that is widely used by many companies today; instead, it involved positioning process parameters (and material attributes also) on a spectrum which reflects the relative importance of those parameters and attributes.

Quality • Tools

Abstract: Formality in Quality Risk Management (QRM) is an interesting concept. What makes a QRM activity ‘formal’ and what makes one ‘informal’? A simplistic viewpoint might be that formal is when a QRM tool is used to manage risks, and informal is when no such tool is used. But is it that simple? And are there different degrees of formality in QRM - is it a spectrum, or is it a binary concept? These questions are explored in this paper.

Determination • Guidances • Regulations • Regulatory • Shelf-Life • Study Design

From the article: Determining product shelf life is a regulatory requirement for pharmaceuticals and many other regulated consumer products. The shelf life of medicines is set following stringent regulations; therefore, efficient application of stability science is critical. The shelf life (expiration dating or expiry) is displayed on labels of pharmaceutical products to ensure the integrity, quality, and potency of the product when used within that time period. Shelf life is established using data that are generated to verify the label claim and approved by the regulatory agencies. An expiration date is required by regional laws to ensure the safety, efficacy, and quality of the drug products, and that these criteria are maintained throughout the labeled shelf life of the pharmaceutical product.