Publications

Audits • Quality

Introduction: Gearing up for a quality audit is no small feat. Whether it’s your organization’s first time being audited or the 100th, there’s always room for improvement when it comes to your quality management system. An internal quality audit is an important tool for any company that wishes to assess its quality procedures, compare performance against external standards, or prepare for an external audit. By conducting an internal audit, organizations can identify areas where they need to make changes or improvements. We'll review the benefits of and responsibilities within an internal audit, as well as the 4 steps you should follow to make sure your audit is successful. Key Words: Systematic, Planning, Corrective

Closure Integrity • Equipment • Packaging • Testing

Introduction: The quality and effectiveness of drugs significantly depends on their proper packaging: It needs to be unscathed and of the highest quality. Otherwise, serious consequences might occur. This was proven by a serious incident in the 1970´s: During this period, contaminated intravenous fluids packaged in glass bottles - which were typical at the time for packaging such dosage forms - caused an estimated 2,000 to 8,000 episodes of bloodstream infection, resulting in the deaths of about 10% of the patients. This severe package-integrity failure incident has triggered a heightened awareness of package integrity.

Change Control • Change Control • Data Integrity • Quality • SOPS • Systems • Tools

Key strategies for change control -Having a strong change control process in place is critical for compliance. -Developing a regulatory notification decision flowchart or matrix now can make your life much easier later. -Don’t forget to document everything! You’ll need to document every piece of the change control process from identification through to approval and implementation. -Using a software system for tracking the MANY moving pieces during a change control process can minimize chaos and ensure that steps are not skipped. -Quality or engineering cannot complete the change control process in a silo, it is a team effort that functions best when it has input from everyone. -Don’t forget the follow-up activities to make sure that the change was effective and didn’t introduce any other problems. Key Words: Risk, 9001, Regulation

Best Practices • Shelf-Life • Statistics

The role of sampling and measurement uncertainty in assessing production process capability is examined, using content uniformity testing as an example. An expanded components of variance model is proposed for consideration during risk assessment and mitigation studies, with emphasis that either empirical (“top-down”) or model-based (“bottom-up”) approaches to estimation of uncertainty can be equally valuable in completing an expanded production process characterization (PPC) study.

Closure Integrity • Equipment • Methods • Packaging • Testing

Automated laser-based headspace inspections systems are now implemented and validated for 100% container closure inspection of sterile pharmaceutical containers at production speeds. Such implementations give insight into the process, ensure the maintenance of sterility for finished product after capping, and can be seen as a tool for meeting current regulatory guidance. Download this White Paper to get an introduction to laser-based headspace inspection and the application to 100% container closure inspection of sterile pharmaceutical containers.

Best Practices • Data Analysis • Methods • Specifications • Submissions

This presentation, in light of ICH Q1/Q5C reviews a Predictive Stability Strategy implemented at AstraZeneca, including some recent developments and routine application. This is supported by four case studies across the stages of development. Key Words: Astra, Case, Q5C

Packaging • Parameters • Primary • Protocols • Sample Control • Storage • Study Design • Transit

In this three-part series, the author examines what causes protein aggregation and practical steps you can take to mitigate the risk. Key Words: Sterile, Prefilled, Vials

Auditing • Best Practices • Communications • Outsourcing

Opening Paragraph: When reviewing health agency citations, it is clear that a common area of focus by investigators during inspections is the stability program and the data that is generated by the program. Why is this? Obviously, there can be numerous reasons such as that stability studies are frequently on the critical path when seeking agency approval and the resource demands associated with stability testing and the competing priorities. But one of the issues, I believe, is that stability testing is commonly outsourced, which puts a focus on the vendor qualification/oversight program, along with the associated quality agreements, adding a complexity/risk that investigators are aware of.

Compliance • Guidances • Life Cycle • Parameters • Protocols • Quality • Regulatory • Study Design • Submissions

Abstract We have summarized five high impact issues related to the stability studies for drug substances that are documented in the Type II drug master files (DMFs) supporting Abbreviated New Drug Applications (ANDAs). We intend to provide the scientific considerations for the regulatory policies which bear upon such high-impact issues. We have also provided our perspective to avoid such issues, to reduce the DMF review time, and subsequently to accelerate the approvals of the supporting ANDAs.

Methods • Testing

Webinar

Best Practices • Storage • Transit

Introduction: Demand for viral vectors used for cell and gene therapies (CGT) is increasing dramatically as hundreds of these novel treatments advance through the clinic towards commercialization. Many challenges must be overcome to ensure the cost-effective manufacturing of these complex biomolecules, including selecting the right solutions for packaging, storage and transport of these expensive and potentially lifesaving products.

Best Practices • Best Practices • Sample Control

Summary: The problem of counterfeit medicines is becoming a tremendous burden to society. An edible security tag affixed to each medicine can provide track and trace measures with dose information and on-dose (in-dose) authentication. Furthermore, it serves as a last line of defense against illicit pharmaceutical products.

Equipment • Methods • Testing

Introduction: Lyophilization, or freeze-drying, is a process used to stabilize a pharmaceutical formulation and increase the shelf life by removing water from the drug product. During lyophilization, the drug formulation is first frozen and then the ice is removed by sublimation under vacuum during a primary drying phase. A secondary drying phase is then used to remove unfrozen water molecules at a temperature higher than that used for primary drying. Pharmaceutical freeze-drying cycles are designed to remove most of the loosely bound water and to achieve a pharmaceutically elegant cake. For biological materials, it is important to retain a high level of activity in the final product.

Best Practices • Equipment • Methods • Testing

Introduction: The recently published USP General Chapter [1] describes the specific methods that pharmaceutical companies will use to calibrate, qualify, and use water activity instruments in their testing protocols. It is water activity measurements, not total water content, that correlate to critical product quality attributes. USP includes a description of tunable diode laser absorption spectroscopy which is the only method to reliably and accurately measure water activity when the sample contains other volatile compounds. This article summarizes the importance of water activity and how laser-based headspace analysis can be used for water activity determination.

Closure Integrity • Equipment • Methods • Packaging • Primary • Testing

Pharmaceutical QC laboratories working with oxygen-sensitive formulations benefit greatly from using LIGHTHOUSE FMS-Oxygen Headspace Analyzers. Replacing traditional destructive methods that use electrochemical sensors, gas chromatography, or invasive sensors with accurate non-destructive laser-based headspace analysis saves valuable product samples for other tests and avoids product disposal and contamination issue.

Audits • Best Practices • Compliance • Guidances • Investigations • Laboratory Issues • Quality • Regulations • Regulatory • Testing

Introduction: On May 16, 2022, the FDA’s Center for Drug Evaluation and Research (CDER) released Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production - Level 2 revision Guidance for Industry. The purpose of this guidance is to provide the FDA’s current thinking on how to evaluate out-of-specification (OOS) test results, including the responsibilities of laboratory personnel, the laboratory phase of the investigation, additional testing that may be necessary, when to expand the investigation outside the laboratory, and the final evaluation of all test results.

Chain of Custody • Sample Control • Transit

Closing Paragraph: Ultimately, the increasing complex protocols that attend modern clinical trials, coupled with the needs and preferences of the patients involved and the logistical challenges introduced by the pandemic, have made direct-to- and direct-from-patient shipping crucial tools for providers and trial sponsors alike. Data to date shows that DCTs boast a somewhat higher enrollment rate than traditional clinical trials; retention and compliance among patients is also frequently improved by offering home health services in place of a trial site. As the demand for temperature-sensitive samples and therapeutics continues to rise, facilitating these solutions through a supplier with the expertise and experience needed to grow alongside development is integral to advancing the biopharmaceutical industry’s impact and reach.

Chain of Custody • Storage • Transit

Introduction: Many companies have worked overtime to expand their ultra-cold chain operations, resulting in new challenges for their shipping operations, both in terms of scale and handling. These challenges extend to home collection shipping, particularly direct-from-patient tissue samples, which are becoming more common with the current surge in decentralized clinical trials (DCTs). The damage that can result from improper transport of these cells makes cold chain storage a crucial part of their handling.

Sample Control • Storage

Vaporized liquid nitrogen is currently the only workable means of maintaining the ultra-cold temperatures necessary for certain therapeutics and tissue samples. While dry ice is a feasible solution for keeping packages between -20 and -80 C°, colder applications often necessitate the use of liquid nitrogen. This paradigm has resulted in a number of logistical challenges for biopharmaceutical companies, clinical trial sponsors, and healthcare providers, as both the temperature requirements for COVID-19 vaccines and the increasing proliferation of temperature-sensitive biotherapeutics has made ultra-cold storage capacity more critical than ever.

Best Practices • Chambers • Facilities • Systems

CONCLUSION Water, HVAC filter and Utility monitoring software, that is designed to remediate risk, focuses on automation to enforce process controls (SOP/Workflow). A system which enforces best practices will substantially reduce risks associated with water and utility monitoring processes. Using dedicated water and utility monitoring software provides the ability to discern adverse trends early, allowing companies to act quickly to correct issues, while the product is being made. Implementation of a computerized, paperless, best-practices solution, to control water and utility monitoring, provides an immediate and tangible ROI. The key benefit is the real-time availability of reliable data that can effectively and accurately provide documented evidence supporting product quality, product release and ensuring regulatory compliance.

Guidances • Methods • Pharmacopoeia

From the Article: The problem is, “no internationally harmonised guidance on E&L assessment and control exists” that specifically outlines the identification, qualification and reporting thresholds for E&Ls in multiple therapeutic modalities and dosage forms, including addressing safety assessment, the International Council for Harmonisation (ICH) highlighted in 2020. This, ICH noted, creates uncertainty for industry and regulators that could result in regulatory and patient-access delays.

In October 2021, the Product Quality Research Institute (PQRI) Parenteral and Ophthalmic Drug Products (PODP) L&E Working Group submitted recommendations for E&Ls in parenteral drug products (PDP) to the US Food and Drug Administration (FDA). These recommendations, the culmination of more than a decade of work by the group’s members and collaborators, are now available for the industry.

Parameters • Planning • Protocols • Study Design

Introduction: Stability is defined as the extent to which a product retains, within specified limits, the same properties and characteristics that it possessed at the time of its manufacture and release throughout its period of storage and use (i.e., its shelf-life). All specification limits thus apply during stability studies and during the whole shelf life of the drug product until the end of the labeled expiry date (APIs: re-test period / retest date). Every pharmaceutical product on the market shall be so constituted that, if stored as directed, it will meet all applicable pharmacopoeial requirements and manufacturer's specifications until its expiration date. But which parameters need to be tested for medical cannabis during stability studies? And which requirements apply? Useful information in relation to these questions is provided in the following sections.

Methods • Testing

Introduction: Potency is one of the CQAs for GT development and manufacturing that is most related to the therapeutic product’s mechanism of action (MoA). However, developing and validating appropriate potency assays that reflect the MoA acceptable to regulators is a process fraught with challenges.

Chain of Custody • Sample Control • Storage • Transit

Introduction: Much of the discussion in the cell therapy industry today focuses on the complexity of manufacturing and the unique characteristics of each dose. However, the ultimate success of a cell therapy clinical trial rests on the ability to deliver a viable, potent product to the patient. Ensuring this living drug is delivered to the right patient at the right time, location, and temperature is essential to patient safety and product effectiveness. Having a sound logistics strategy is critical to achieving this goal.

Best Practices • Equipment • Methods • Testing

Using a toolbox of Waters LC systems, chemistries, and software, an innovative pharmaceutical services provider solves customer's challenges with method development and validation.

Packaging • Storage • Transit

A gene therapy’s path from the research lab to the clinic and ultimately the market requires manufacturing processes that will meet regulatory requirements and the logistics to get therapies to clinical trial sites. Having Chemistry, Manufacturing and Controls (CMC) in place early can help avoid issues during regulatory reviews. Understanding packaging design and storage requirements as well as having a distribution plan are also critical to successful trials.

Best Practices • Equipment • Methods • Testing

The USP Water Activity was published as a general chapter in May-2021. As water activity increases, more loosely bound water is available to accelerate undesirable chemical, physical and microbiological reactions than can cause stability failures. Measuring the change in the equilibrium relative humidity of tablets and capsules inside the blister packs and bottles will provide the information required to understand long term stability.

This webinar includes: - How does relative humidity and water activity change inside the primary packaging over time? - How does water activity correlate to microbial growth, degradation and dissolution failures? - What information does water activity provide that Karl Fischer cannot provide?

Best Practices • Methods • Packaging • Primary • Regulatory • Submissions

This article discusses how expert detection of impurities can improve product safety and regulatory success with the following topics covered: -Safety first: Extracting value from packaging components -Gathering the suspects: Designing a targeted analysis -Drilling down: A peek into the E&L toolbox -Integrating capabilities: Building product safety into process design

Closure Integrity • Equipment • Methods • Packaging • Testing

Certain sterile pharmaceutical products require deep cold storage, either at -80°C or even cryogenic temperatures (down to -196°C). Live viral vaccines, gene therapies, or products that contain active cells (cell therapies) often need deep cold storage to maintain stability and/or activity. Studies have shown that deep cold storage temperatures can introduce risk to the container closure integrity (CCI) of vial-rubber stopper combinations traditionally used to fill sterile pharmaceutical products. This eBook describes the risk of CCI issues during deep cold storage and transport, and a framework to minimize this risk including case study examples.

What you will learn: - Effects of deep cold storage at -80°C on the CCI of sterile vials - Holistic approach to ensure CCI of products needing deep cold storage - Seal quality testing; test method development for vials

Best Practices • Extension • Packaging • Primary • Shelf-Life • Sterile

Summary Section from The Article: While single-use technology has been widely accepted in the field of medicine and in many areas of biopharmaceutical manufacturing, adoption for BDS packaging has lagged. This is largely due to difficulties in finding materials that do not leach chemicals into valuable drug product and can withstand the temperatures at which drugs are frozen. At the same time and largely because the materials had not been identified, scalable processes for packaging, freezing, storing, and handling single-use containers had not been developed.

The proven benefits of single-use packaging have driven research and development in BDS packaging, and suitable options are already being tested. Manufacturers can now seriously consider single-use bags as a viable and cost-effective option for bulk drug storage at every step of drug development and manufacturing. New systems can now package drugs at any scale, from a few liters during R&D to hundreds of liters during high-volume manufacturing. Innovative packaging materials are now available that will not contaminate sensitive biopharmaceuticals or become brittle at temperatures below -80°C. Additionally, multi-functional systems have been developed to quickly and safely freeze, thaw, store, and transport large-volume single-use bags.

The success of biopharmaceutical manufacturers relies on hitting performance targets at high yields. To reach these targets, new materials and process advancements can reduce both capital and operating expense, as well as the complexity of bulk drug packaging. Sourcing from suppliers with raw materials expertise and a solid understanding of the process requirements is paramount.

Best Practices • Best Practices • Extension • Methods • Parameters • Protocols • Shelf-Life • Study Design • Testing

Abstract: Adeno-associated virus (AAV) has become an emerging tool for human gene therapies. Currently, AAV gene therapies are subjected to multiple freeze–thaw cycles during manufacturing, storage, transportation, and administration. While studies have shown that multiple freeze–thaw cycles led to a decrease in transduction efficiency, the AAV degradation mechanism during freeze–thaw is not well understood. Here, we have characterized the impact of freeze–thaw on AAV8 by employing a variety of assays, which revealed significant increases in the amount of free single–stranded DNA (ssDNA) in AAV8 formulations after multiple freeze–thaw cycles. Subsequent analysis using Next Generation Sequencing (NGS) revealed that the ssDNA primarily consisted of genome DNA, indicating that the increased ssDNA leaked out from AAV8. Experiments performed using different serotypes of AAV confirmed the pervasiveness of such behavior amongst AAVs. In addition, formulation screening studies were performed to understand the impact on genome DNA leakage from AAV. The formulation screening results showed that the addition of 10% sucrose and 0.1% poloxamer 188 to Dulbecco’s phosphate-buffered saline (DPBS) reduced the leakage of ssDNA in AAV samples after freeze–thaw cycles compared to the base formulation of DPBS alone. These findings shed new light on the degradation mechanism of AAVs and stabilization of the AAV–based gene therapies.

Transit

Advances in regenerative medicine manufacturing continue to be a priority for achieving the full commercial potential of important breakthrough therapies. Equally important will be the establishment of distribution chains that support the transport of live cells and engineered tissues and organs resulting from these advanced biomanufacturing processes. The importance of a well-managed distribution chain for products requiring specialized handling procedures was highlighted during the COVID-19 pandemic and serves as a reminder of the critical role of logistics and distribution in the success of breakthrough therapies. This perspective article will provide insight into current practices and future considerations for creating global distribution chains that facilitate the successful deployment of regenerative medicine therapies to the vast number of patients that would benefit from them worldwide.

Equipment • Methods • Testing

Introduction: Liquid-chromatography-mass spectrometry (LC-MS) is a critical methodology for accurately characterizing the wide-ranging variability of biologics. This knowledge can be transformed into single multiplexed assays for monitoring attributes across development, manufacturing, and release. LC-MS-based peptide multi-attribute method (MAM) workflows, like those offered by the Waters BioAccord LC-MS System, have been gaining interest across development and commercialization organizations to accomplish this.

Sample Control • Transit

With any new high-tech industry that’s growing very rapidly, standards often lag, and this has been the case for the manufacture and distribution of cell and gene therapies. The industry determined that the establishment of new standards for the transportation of these advanced therapies has become a necessity since these products are considerably more sensitive to their environment during transit than more conventional therapies. For traditional biologics and small molecule products, there is a significant allowance for time out of environment (TOE), but in the cell and gene therapy space, the TOE tolerance is essentially zero. As such, the existing paradigms used for pharmaceutical distribution are not appropriate, and it was necessary to redevelop methodologies from a distribution standpoint that would eliminate those allowances for TOE and similar criteria and be significantly more rigorous.

Equipment • Laboratory Issues • Methods • Testing

Introduction: Regulators require pharmaceutical products that are injected into the human body (which are by inference sterile products) to be free of visible particulates (1). This is because the presence of visible particulates in injectable products may affect patient safety. There are various controls that need to be built into the manufacturing process to minimize the possibility of particle and particulate formation. These controls will begin with product development and proceed to manufacturing controls. In terms of ‘testing,’ this is based on visual inspection techniques, conducted as part of batch release and for stability samples (and retained samples in the event of a customer complaint). Any identified particulates need to be identified, investigated, and corrected. Following this, a preventative action should be put in place to prevent recurrence.

Audits • Compliance • Investigations • Quality

Introduction: Recently the U.S. Food and Drug Administration (FDA) issued a warning letter dated January 7, 2022, due to inadequate investigations into out-of-specification (OOS) test results.

In May and June 2021, the FDA inspected the drug manufacturing facility Professional Disposables International, Inc, located in Orangeburg, New York. During that inspection, the FDA investigators observed specific GMP violations.

Data Integrity • Quality

Summary Section of the Article: The data integrity strategy's foundation originates in the GDPs that can be found in the GMPs. The expectations and supporting controls listed in Table 1 are performed throughout the data retention period and are the essential elements of data integrity applicable to paper records. The requirements for record integrity do not differ depending on the data format; paper and electronic-based systems. Both systems are subject to the exact requirements. The e-records data integrity controls listed in this article summarize the same listed control applicable to paper records.

Audits • Quality

Abstract: - The FDA conducts Pre-approval Inspections to assure that a manufacturing site named in a drug application can manufacture the product and that the data submitted in the application is complete and accurate. - The PAI has three stated objectives: 1) Readiness for Commercial Manufacturing; 2) Conformance to Application, and 3) Data Integrity Audit - A Mock PAI planned and executed by a knowledgeable and experienced auditing professional is a critically important assurance activity. Following this assessment, any findings that require attention should be remediated through a diligent remediation project. - As part of any preparation plan, companies should designate a readiness team, identify and work with subject matter experts who will be involved, and ready their facility to receive regulators. Key Words: Mock, Objective, Integrity

Change Control • Investigations • Quality • Tools

INTRODUCTION In terms of how human error can be defined, then one potentially useful definition of human errors is as “any member of a set of human actions that exceed some limit of acceptability, i.e., an out-of-tolerance action, where the limits of tolerable performance are defined by the system”. In other words, an outcome that was not intended or desired. At first glance the cause of a human error may seem straightforward, all too often followed by the hasty conclusion that training or retraining can fix the issue. However, ‘human error’ is very rarely the root cause and instead a more detailed and iterative human error root cause analysis investigation will more often reveals a deeper issue at the heart of the matter and allows for an appropriate preventative action to be set.

This article looks at a process of defining human error and provides some guidance on constructing a checklist for getting to the root of the error. In following this method, there are very few cases of actual human error; instead, there is typically a fault with a system, procedure, knowledge, or with the environment within which the error occurred.

Audits • Compliance • Investigations • Quality

Introduction: This article looks at some of the reasons for, and patterns behind, laboratory errors. The article represents a brief look into the subject area, drawing on some of the issues that the author is aware of. Generally, laboratory errors should not be categorized as "human error" since these are not the problem but generally a symptom of a system or facility or operation. By delving deeper into the nature of the event (using techniques to get to the real cause of the problem) more meaningful CAPAs can be developed, CAPAs with a stronger chance of remedying the problems first time. Hence an important focus is to seek a significant reduction of repeat observations. This should lead to improved laboratory efficiency supported by right first-time testing and control.

Audits • Compliance • Investigations • Quality

INTRODUCTION It is well established that regulators do not like the root causes of deviations to conclude ‘human error’ and for the resultant corrective or preventative action (CAPA) to recommend additional training. Instead, regulators expect organizations to go deeper and to unpick the underlying reasons as to why a person made an error and, from this, error risk reduction actions can be initiated. Probing the cause of human error can be achieved through an interactive process, such as by asking ‘why’ multiple times until the answer emerges (this parallels the 5-whys technique or the repetitive questioning of a recalcitrant child).

In a paper published in the Journal of Validation Technology (“Error Risk Reduction: Concept and Case Study”) this author presented risk reduction processes centered on two case studies. The paper demonstrated why simply resorting to ‘human error’ as the root cause of an incident is often inaccurate and generally prejudicial; it also hides too much about how a system functions or malfunctions and hence prevents an appropriate preventative action from being formulated. As an adjunct to this, this article looks more closely at why human error may occur.

This article is part one of a three-part IVT series: Managing workplace error #1: Unpicking patterns of human error. Managing workplace error #2: Getting to the heart of the matter through human error checklists. Managing workplace error #3: Dissecting reasons and causes of laboratory error.

These articles are designed to help organizations to beyond the simplification of a cause as ‘human error’ and to reveal the deeper systematic underpinnings that cause things to go wrong.

Sample Control • Storage • Transit

Introduction: For effective delivery of many cell therapies, a cryogenic cold chain is essential. However, cryopreservation can damage biologics if optimal cooling, storage, and thawing strategies are not used. While the traditional cooling agent for controlled-rate freezing in clean room settings is liquid nitrogen, there are challenges to meet cGMP guidelines by using liquid nitrogen in medicinal product manufacturing. To address these challenges, Cytiva’s range of VIA Freeze™ systems deliver liquid nitrogen-free controlled cooling for optimized, compliant cell cryopreservation.

Best Practices • Chambers • Sample Control • Storage

Introduction: The potential of cell therapies has been recognized for some time, but commercialization is a relatively recent endeavor. Cryopreservation is a crucial part of the manufacturing process, because it allows cell therapies to be efficiently stored and transported; however, it is only beneficial if cell viability is maintained. Here, we speak with Asymptote (now part of Cytiva) CEO John Morris, who has been freezing cells for over 40 years, to delve into the good, the bad, and the icy aspects of cryopreservation.

Sample Control • Storage

Summary: This webinar presents the underpinning mechanisms driving freeze thaw applications and their implications across varied drug product containment configurations and volumes. The links between controlled freezing rates, container design, and cellular outcomes are explored by science-based research approaches taken on by industry collaborators. The outputs will support the future development of cell therapy cryopreservation configurations and options proven through a science-based approach to supplier-side process development and driven by technologies and best practices present in the cell and gene industry.

Storage • Transit

Introduction: Cell therapies are changing the landscape of clinical care, and their temperature-related vulnerability has made continuous cold chain management even more critical in the delivery of treatments to patients.

Cold chain management comprises three key phases: cooling, storage, and thawing. Thawing errors for a potentially lifesaving therapy could compromise treatment efficacy and may have significant impact on patients, costs, and a product developer’s reputation.

Best Practices • Best Practices • Determination • Extrapolation • Guidances • Life Cycle • Parameters • Regulations • Regulatory • Sample Control • Shelf-Life • Study Design • Study Types

Abstract: This article introduces the concept, significance, and applicability of in-use stability testing for drug products. The article references relevant domestic and foreign guidelines for drug stability studies and discusses methods for evaluating the in-use stability of drug products based on the kinetic model of drug degradation.