This article presents experiences from seven recent accelerated development program case studies. These experiences provide insights that could help companies progressing through accelerated development programs for products meeting unmet medical needs or significant therapeutic needs, such as those with anticipated Breakthrough Therapy (United States) or PRIME (European Union) designation.
This article examines the regulatory landscape governing artificial intelligence (AI) in quality-critical systems and distinguishes between algorithms, AI, and a nuanced middle category called smart systems. It explains how organizations can responsibly embrace advanced programmatic solutions while preserving the integrity of validated test methods and safeguarding patient safety.
Shelf temperature mapping is a critical component of lyophilizer qualification. The previous articles in this series explored the methods used to record the shelf surface temperatures (Part I) and designing an appropriate study (Part II). Interpreting a shelf temperature mapping study’s result is as critical to assessing uniformity as the temperature measurement, the study design, and the...
The promise of single-use technologies (SUTs) in biopharmaceutical manufacturing is as compelling as it is contradictory. Noted for accelerating process development, enhancing sterility, and enabling unprecedented manufacturing agility, SUTs have also introduced a less visible but mounting challenge: the steady accumulation of complex plastic waste.
Bulk powders inherently exhibit unpredictable flow in feeders, dosing machines, and packed machines under gravity's pull. Meanwhile, particle engineering co-processed excipients can be more versatile and economical compared to conventional ingredients in the continuous manufacturing of drug products.
Since the US Food and Drug Administration (FDA) introduced the requirement for secure, computer-generated, time-stamped audit trails in 21 CFR Part 11, audit trail functionality has been recognized as a critical component of data integrity.
The COVID-19 pandemic revealed how unprepared the vaccine industry was for such a global health emergency, but also how the industry rose to meet this challenge. The first efficient COVID-19 vaccines approved were based on a new class of vaccines using messenger ribonucleic acid (mRNA) technology.
As facilities become more complex and equipment requirements more demanding, engineers face increasing challenges in ensuring optimal airflow patterns. Fortunately, advanced digital tools such as computational fluid dynamics (CFD) and building information modeling (BIM) are revolutionizing the way cleanrooms are engineered.
Qualification of equipment used in the manufacturing of pharmaceutical products is a critical step in ensuring the production of a product that consistently meets all critical quality attributes. The US Food and Drug Administration (FDA) has stated a shelf temperature mapping, or a shelf temperature uniformity study is an expected step in the qualification of lyophilizers (freeze dryers).
A single global digital chemistry, manufacturing, and controls (CMC) dossier is rapidly transitioning from a bold vision to a practical reality. However, realizing the full potential of these innovations requires significant coordination to harmonize and align across initiatives.
Batch uniformity and consistent critical quality attributes are vital to lyophilization as a process for product preservation. To achieve these goals adequate process control and reproducibility must be ensured.
To accelerate the adoption of innovation in the global administration of the pharmaceutical industry, regulatory authorities and industry trade organizations must expand their scope and pursue a collaborative approach to recognition and reliance to streamline processes, enhance product quality, and improve patient access to medicines.
Oligonucleotide therapies hold great promise for treating a wide range of diseases, including the undruggable, but their journey from lab to patient hinges on fundamental manufacturing challenges that the industry is racing to solve.
Visual inspection is nothing new to professionals who make, prescribe, prepare, and/or administer pharmaceutical parenteral products to patients of all backgrounds, especially those who may have immunity concerns. The pharmaceutical industry has tried to ensure that companies enact the best quality standards that are consistent with Current Good Manufacturing Practices (CGMPs) to prevent an...
Technology is advancing at an extraordinary rate. Industries are benefiting from automation and AI. As technological developments continue to reform the way industries run, the integration of AI and machine learning technologies in the life sciences industry is redefining the traditional approach to commissioning, qualification, and validation (CQV) in pharmaceutical manufacturing.
The integration of artificial intelligence (AI) and machine learning (ML) into bioprocess development represents a rapid shift in the way discovery, development, optimization, and production of biological products are approached.
The intersection of AI and drug development has ushered in a transformative era, revolutionizing the way researchers approach biomarker/target identification, drug/target interactions, and drug-like molecule design. AI in the life sciences seeks to unravel intricate biological phenomena through systematic assimilation, analysis, and interpretation of expansive and diverse datasets.
At first glance, ready-to-use (RTU) primary packaging material (tub systems) give production lines more flexibility and reduce container preparation complexity for aseptic fill/finish operations. However, the aseptic introduction of RTU tub systems requires a thoroughly designed transfer process to avoid contamination of the sterile RTU items and the aseptic core.
Many organizations are on the right path to sustainability, but more can still be done— especially for setting and meeting net-zero targets. Although a commitment to net-zero operations is important for all industries, it’s particularly necessary for the pharmaceutical industry, with its high energy consumption, high water demands, and the use of solvents for manufacturing.
The decision to pursue net-zero facility design in manufacturing is complicated. There are significant challenges related to initial project costs, physical space constraints, and project site considerations—but also substantive benefits from operational savings, environmental impact, building brand trust, and working toward a more sustainable future.
Single-use products used in the production of biologics provide flexibility that was unimaginable a few years ago. The implementation of single-use technology (SUT) in manufacturing operations has accelerated due to reduced risk, flexible process equipment adjustments, and lower capital cost. The widespread use of this technology has raised questions about its impact on the environment due to...
Traditionally, a regulated company is accountable for all aspects of their infrastructure qualification and application validation. With the introduction of public cloud service providers (CSPs), part of that technical responsibility has shifted to a cloud supplier, making supplier assessment and supplier management more important than ever—even though the regulated company is still...
The pharmaceutical landscape is rapidly evolving, and cell and gene therapies (C>) are at the forefront of this transformation. These therapies are revolutionizing how we approach patient care, particularly in the realm of personalized medicine. However, this innovation has also introduced challenges, especially when establishing new manufacturing facilities.
Computer software assurance (CSA) has been discussed widely in industry over the past five years. While the principles are well understood and welcomed, until now some of the practical detail on how exactly to implement CSA into an organization has been missing.
Drug delivery devices have become an essential component for many modern medical therapies, and it’s vital that they function as intended. However, the reality of marketed products shows that this is not always achieved because drug-device combination products are becoming increasingly complex, with an increasing number of potential failure modes. Significant challenges for engineers include...
Cell and gene therapy (C>) products address various diseases at the cellular or genetic level, offer innovative treatment approaches, and represent a significant advancement in the field of medicine. However, developers of C> products face unique challenges due to their complexity, such as establishing assays that show a clear link between potency, mechanism of action (MoA), and...
In 2011, the US Food and Drug Administration (FDA) introduced the revised “Guidance for Industry: Process Validation: General Principles and Practices.”
Welds used in biopharmaceutical manufacturing must meet critical criteria to maintain a defined level of purity and bioburden control. One highly debated area of concern is the level of discoloration allowable on the product contact surfaces in the welded condition and secondary finishing methods. This article addresses the studies commissioned by the American Society for Mechanical Engineers...
On 25 August 2023, the long-awaited revision to Annex 1 became effective, introducing significant regulatory changes, including the requirement of a documented contamination control strategy (CCS). During a workshop at the 2023 ISPE Annual Meeting & Expo, 11 teams of attendees were presented with a risk-based methodology to develop and evaluate CCS elements focused on extrinsic...
Artificial intelligence (AI) is used by pharmaceutical and biotech companies, providing support from drug discovery through manufacturing. The nature of AI and concerns of bias, privacy, transparency, and security in a regulated industry necessitate a governance framework to ensure concerns are controlled using “guardrails.” These guardrails ensure the quality, privacy, and security of data...
The expectations for room differential pressures to maintain air quality in pharmaceutical facility design are consistent and well defined from a regulatory perspective. However, there is no common approach to the design, monitoring, or alarming of area differential pressures. This article explores differential pressure concerns in aseptic manufacturing, or cleanroom classes B, C, and D.
As the pharma industry moves to an ambitious Validation 4.0 paradigm, computerized systems play a pivotal role in enabling the rapid transition. Innovation and agility in computerized system validation (CSV) received a strong push in the second half of 2022 with the publication of the FDA draft guidance on “Computer Software Assurance for Production and Quality System Software”
The validation of media and buffer mixing is a continuing area of resource constraint in the pharmaceutical industry. These validations require materials, validation associates’ time, and the use of equipment and processing areas. This article proposes a risk-based life cycle for minimizing mixing validation resource inputs, with the objective of optimizing validation efforts through the use...
In 2022, the US Food and Drug Administration (FDA) issued their draft guidance “Computer Software Assurance for Production and Quality System Software”
Pharmaceutical manufacturing facilities produce a variety of products, including highly potent products that require safety measures to prevent adverse health effects on patients and operators. To ensure safety, these facilities use containment equipment to minimize the risk of contamination. This article presents criteria for selecting containment equipment, considering both...
Pharmaceutical critical utilities are typically built of 316L stainless steel; nevertheless, surface degradation has been reported due to the occurrence of different phenomena. This article aims to explain how field electrochemical techniques using a portable tool can be an effective method for surface inspection, qualification, and monitoring. The surface finish assessment considered...
The world is beginning to grasp the huge challenge of achieving net-zero carbon emissions, or carbon neutrality, by 2050. Many countries have committed to achieving this ambitious goal. As a major global industry, the pharmaceutical sector has a significant role to play. For thermal energy–intensive industries, such as pharmaceutical manufacturing, the long-term future options to maintain...
The biotechnology and pharmaceutical sectors have pledged to reduce greenhouse gas (GHG) emissions as the climate concerns of consumers, investors, and regulators continue to grow. In seeking to benefit from this demand for sustainability and the potential for cost-saving opportunities, life science product manufacturers have started to evaluate the climate impact of their own labs and...
Calibration plays a critical role in ensuring a measurement instrument’s accuracy—especially if the instrument has a direct impact on product quality and patient safety. However, the calibration process is a complex system, and the traditional analytical approach for planning this process is often not sufficient to improve service performance. Using a digital simulation model as a...
Cell therapies have been used to treat thousands of patients worldwide ever since the CAR T cell medication Kymriah was the first cell therapy approved by the FDA in 2017. Yet significant manufacturing challenges continue to hamper patient access to life-saving cell therapies, particularly the high cost of these treatments. Kymriah can cost as much as $475,000 per dose and an allogeneic...
Process capability is a fundamental concept for manufacturers. Pharmaceutical, biopharmaceutical, and medical device manufacturers leverage capability analysis along with other statistical quality control (SQC) techniques to enable timely supply of quality medicine to patients.
To improve the energy efficiency of cleanrooms, the Roche Global Engineering and Oceanside facilities and Engineering team collaborated to implement a risk-based approach to achieve lower air changes during operation without adversely impacting the facility, equipment, or reliability, while meeting environmental requirements.
ChatGPT and other large language models are positioned to change the world. They can also shift acceptance and prevalence of machine learning solutions in regulated industries in general. However, their arrival requires reconsiderations on risks, quality assurance, and validation from a GxP perspective.
In the context of data integrity, data flows are essential. The FDA, PIC/S, and WHO have all emphasized the importance and benefits of data flows in their guidance on data integrity. The key to data integrity compliance is a well-functioning data governance system
We will show how continuous, real-time capturing of data with immediate data analysis by an ML algorithm can improve control over a critical quality attribute. The ML-analyzed data provides the evidence for validation of the change by demonstrating more control over the process along with a decrease in process risks.
Computational fluid dynamics (CFD) can reduce or eliminate the uncertainty associated with a cleanroom facility as the planned design can be simulated to predict performance to a high degree of accuracy. This article discusses the use of CFD for the purpose of predicting and optimizing the performance of a cleanroom facility in terms of steady-state airborne particulate levels and for...
Pandemic-related supply chain shortages have placed constraints on the supply of essential filters and chromatography resins. An agile regulatory pathway to implement alternative filters and resins into manufacturing is necessary to ensure the continued supply of approved biologics. To allow this in the US and potentially globally, the regulatory strategy proposed in this article is to provide...
Topical drug products and cosmetics are often manufactured in the same facility under a unified quality standard that supports the topical drug products’ performance and label claims. Cleaning is an important component of a manufacturing process, and the process life-cycle approach should be followed for cleaning validation.
Before the COVID-19 pandemic, it was unthinkable for a system integrator to suggest remotely conducting an acceptance test for an automation project. This article shows how automation engineers and client validation personnel were successful in navigating COVID-19 restrictions and overcoming previously held preconceptions about remote testing to meet end-user and regulatory requirements....
This artificial intelligence (AI) retrofit project was a unique approach to implementing AI technology in a pharmaceutical environment within three months. This project tackles a commonly known industry challenge by integrating AI into an existing automatic visual inspection (AVI) machine. The proof of value allowed us to benchmark added value through AI compared with state-of-the-art...
Three case studies on Validation 4.0 demonstrate how quality by design (QbD) principles, when applied with digitization, can verify processes in scale-up and technology transfer, and why blend and content uniformity matter for tablet integrity.
Chlorine dioxide has been shown effective in decontaminating various types of chambers and volumes such as rooms, isolators, processing tanks, and entire facilities, but its use to decontaminate compressed gas piping systems has not been documented. This article discusses using dry gaseous chlorine dioxide (ClO2) to decontaminate an oxygen (O2) feed piping system in a...
Steam is the most powerful and effective thermal energy transfer fluid, and its use continues to grow in process industries around the world. However, there is very little written about the commissioning and qualification of pharmaceutical pure steam systems in GMP regulations or regulatory guidance. This article provides the background and science behind the steam quality tests and proposes a...
Artificial intelligence (AI) has the potential to benefit the pharmaceutical industry and its GxP-regulated areas. Several pharmaceutical companies are currently running digital pilots; 90% of large pharmaceutical companies have initiated AI projects.
Advanced therapy medicinal products (ATMPs) pose specific manufacturing challenges beyond those typically addressed by pharmaceutical chemistry. Often in current ATMP applications, a change in approach is introduced at some point in the development process out of convenience or necessity, which then results in a change in technology. This article analyzes the possibility of transferring a cell...
The implementation of a mammalian cell-based biopharmaceutical manufacturing process demands robust methods for knowledge handling, from early-stage development and technology transfer to production scale. Mathematical process modeling can summarize this knowledge as the relationships of critical quality attributes to critical process parameters using mathematical equations and sound...
Heightened awareness, due to the pandemic, of the need for domestic manufacturing capacity has rejuvenated the biopharmaceutical manufacturing industry and resulted in new commissioning projects. However, cross-country/continental travel restrictions and social distancing–based work protocols during the first two years of the pandemic necessitated adopting unique commissioning approaches....
Global commissioning, qualification, and validation (CQV) project delivery has in recent years been required to push the boundaries on delivery methodologies and techniques to ensure sufficient production capacity is available to meet ever-expanding patient needs. This article focuses on lessons captured in the execution and resource management of large-scale global CQV projects in an...
Aseptic process simulation (APS) is essential for validation of an aseptic manufacturing process and is required by regulators to demonstrate the aseptic capability of such processes. A successful program of APS and aseptic manufacturing requires significant operator training, skills, and supervision; thorough maintenance; effective cleaning and disinfection; significant oversight of every...
Good data are a characteristic of good science. Quality data are arguably more important today than ever before and are considered by many to be a corporate asset because they are used to develop products and processes, control our manufacturing processes, and improve products and processes when needed.
This article presents the results of applying artificial intelligence (AI), such as machine learning algorithms, to identifying and predicting anomalies for corrective maintenance in a water for injection (WFI) processing plant. The aim is to avoid the yearly stoppage of the water for injection plant for preventive maintenance activities, common in the industry, and use a more scientific...
Use of software as a service (SaaS) applications within the life sciences industry is growing. This article reviews the issues and challenges faced by SaaS providers and identifies the qualities of successful providers for this highly regulated industry.
Viral inactivation (VI) is a critical step in ensuring the safety of monoclonal antibody (mAb), Fc fusion, and recombinant protein therapeutics and it is typically an important component of an overall virus control strategy for downstream biotherapeutic production processes. Considerations for successful implementation of an inline VI process are discussed in this article.
Any systematic pharmaceutical engineering approach for ensuring vial container closure system (CCS) performance must include choosing qualified container closure system components, the proper pharmaceutical process setup, and applicable testing methods. Container closure integrity (CCI) is an essential part of container closure system performance. A holistic strategy is needed to qualify...
![Figure 1: Seasonal comfort (temperature and RH). ©ASHRAE, www.ashrae.org. Used with permission from 2017 ANSI/ASHRAE Standard 55 [4].](https://ispewebassets.org/files/styles/teaser_image/public/2021-08/0921_PE_SO_TechHaycock_01.jpg?itok=mJiPGN_X)
Defining room temperature and humidity limits is a frequent topic of debate when designing and operating pharmaceutical and biotechnology facilities. What are appropriate alarm limits and acceptable durations for an alarm condition? Understanding the source of temperature and humidity requirements, and strategies for setting limits, can ensure both compliance and optimum use of energy. This...
Cleanrooms and controlled contamination environments are increasingly being used across many industrial sectors, including the pharmaceutical industry. An important issue is the operating cost associated with cleanroom energy consumption and, consequently, the identification of applicable energy containment measures. This article reviews pharmaceutical cleanroom calculations for...
Powder for oral suspension (PfOS) bioavailability is mostly on the basis of drug absorption from the gastrointestinal tract. PfOS formulation pH, viscosity, vehicle buffer capacity, drug particle size distribution, density, and viscosity are often critical for absorption. Therefore, careful design and selection of excipients—including suspending agents—are necessary during PfOS formulation...
Since 2019, the ISPE France Affiliate’s Unique Device Identification (UDI) Medical Device Work Group has been producing tools to help project stakeholders within the EU or overseas understand and comply with EU regulations of UDIs in medical devices. Some of those tools are highlighted in the article.
One of the goals of the cleaning validation design phase is to define critical process parameters (inputs) and acceptance criteria (outputs) of the cleaning process. This article explores the selection of a master soil as part of the cleaning validation design phase for automated parts washers. The selection and qualification of a master soil through laboratory testing and during factory...
What if the reliability of a system could be improved by accessing the standard data provided with modern process instrumentation? These data, accessed from existing instrumentation, can be used to analyze the fitness of processes, equipment, and instruments; better understand processes; support discrepancy investigations; and provide a data-driven basis for the timing of maintenance and...
For a multiproduct facility where equipment is shared, there is always a risk from cross-contamination. The correct calculation of the cleaning validation limits from maximum allowable carryover (MACO) of a marker compound to the next product is vital for the integrity and success of the cleaning validation program. However, the process yielding those limits often involves cumbersome,...
Pharmaceutical manufacturers rely heavily on powder processes, the majority of which are designed and operated on the basis of empirical correlations between material properties and performance. The development of material properties databases for pharmaceutical excipients and active pharmaceutical ingredients (APIs) has the potential to enhance such correlations and, more generally, to...
Recently, recalls of angiotensin receptor antagonists, particularly valsartan, and warning alerts about N-nitrosodimethylamine (NDMA) impurities in drug substances such as ranitidine and metformin have demonstrated the urgent need for manufacturers and regulators to control impurities throughout the product life cycle to ensure patient safety.
Online water bioburden analyzers (OWBAs) are analytical instruments providing real-time or near real-time measurement of bioburden in purified water systems.
When fluid-filled containers are stored for long periods of time with negligible motion, sedimentation and gravitational settling of particles can occur. This article discusses a passive sedimentation control mechanism that is driven by Marangoni stress, which is induced in enclosed geometries when their walls are lined with gas-filled hydrophobic microcavities.
Executives at manufacturing companies of all sizes need to make decisions about where to invest to maintain and grow their businesses. Investments in manufacturing execution system (MES) applications may reduce costs and increase revenues, but they also might compete with other investment priorities, such as marketing campaigns and capital equipment upgrades. This article offers guidance for...
A temperature sensor in a medical autoclave is typically calibrated once a year. If the sensor proves to be inaccurate, all batches produced since the last calibration must be evaluated. Endress+Hauser has developed a self-calibrating sensor that automatically verifies its accuracy during each sterilization batch. This article describes a case study at the Merck Healthcare KGaA sterile...
Computational fluid dynamics (CFD) can reduce or eliminate the need to perform bioreactor scale-up studies because full-scale manufacturing bioreactors can be simulated to predict performance. This article discusses the use of computational fluid dynamics for that purpose, to predict the performance of a manufacturing-scale bioreactor under various operating conditions.
Process analytical technology (PAT) is perceived as the main enabler for a robust control strategy with continuous manufacturing (CM) because process analytical technology can aid in implementing continuous manufacturing throughout the entire life cycle. This article discusses quality and regulatory hurdles in the life cycle of a process analytical technology application—including model...
Historically, the pharmaceutical industry’s focus has been on the lyophilization process and equipment, but discussion about calibration of process monitoring and control instrumentation has been quite limited. Recently, focused attention has been given to control and monitoring instrumentation for lyophilization.
Continued process verification (CPV) as defined in the US FDA process validation guideline
The solubility behavior of drugs remains one of the most challenging aspects of formulation development and is a key determinant of a drug’s bioavailability. This article describes research aimed to improve solubility of a poorly water-soluble drug (ibuprofen) by preparing a porous solid dispersion using a flash evaporation technique.
Over the years, the roles and responsibilities of engineering and quality/validation personnel for commissioning and qualification (C&Q) activities have evolved. Now more than ever, commissioning and qualification approaches based on quality risk management (QRM) principles rely heavily on engineering and the application of Good Engineering Practice (GEP) to provide documentation for the...
Regulatory authorities have approved the use of recombinant monoclonal antibodies (mAbs) to treat infectious diseases
Manual decontamination procedures are laborious processes and can be costly, requiring significant time and resources to complete. Manual procedures also may need to be repeated if initial efforts do not fully kill pathogens. To reduce failures and potentially reduce cost, chlorine dioxide gas decontamination was investigated as an alternative solution.
The Advanced Digital Design of Pharmaceutical Therapeutics (ADDoPT) project
According to US Pharmacopeia (USP) Chapter <790>, “all parenteral products should be essentially free from any visible particles.”
This article shares a process used to evaluate terminal HEPA filter maintenance programs serving a parenteral manufacturing plant. The evaluation determines whether maintenance history data supports extending preventive maintenance frequency.
Analytical target profile criteria for judging the quality of results generated by analytical methods are framed in an optimization paradigm by illustrating the ATP criteria as a loss function. In the case where specifications are based on quality arguments and process capability, a probability-defined loss function is useful for providing a direct measurement of risk for making incorrect...
