Technical
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.
Technical
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...
Technical
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...
Technical
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.1
  • 1Trinity Life Sciences. “Ninety Percent of Large Pharma Companies Initiated Artificial Intelligence/Machine Learning Projects In...
Technical
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...
Technical
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...
Technical
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....
Technical
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...
Technical
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...
Technical
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.1
  • 1Snee, R. D. “Crucial Considerations in Monitoring Process Performance and...
Technical
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...
Technical
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.
Technical
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...
Technical
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...
Technical
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...
Technical
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...
Technical
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.
Technical
Software as a medical device (SaMD) is software intended to be used for one or more medical purposes without being part of a medical device.1
  • 1International Medical Device Regulators Forum. “Software as a Medical Device (SaMD): Key Definitions.” 9 December 2013.
Technical
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...
Technical
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...
Technical
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,...
Technical
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...
Technical
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.1
  • 1US Food and Drug Administration....
Technical
Online water bioburden analyzers (OWBAs) are analytical instruments providing real-time or near real-time measurement of bioburden in purified water systems.1
  • 1Cundell, A., O. Gordon, N. Haycocks, et al. “Novel Concept for Online Water Bioburden Analysis: Key Considerations, Applications, and Business Benefits for Microbiological Risk Reduction. American Pharmaceutical Review 16,...
Technical
The process life-cycle model, as discussed in the US FDA guidance on process validation, is a significant change in how we view validation.1
  • 1US Food and Drug Administration. “Guidance for Industry. Process Validation: General Principles and Practices.” January 2011.
Technical
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.
Technical
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...
Technical
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...
Technical
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.
Technical
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...
Technical
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.
Technical
Continued process verification (CPV) as defined in the US FDA process validation guideline1 helps bring quality management and compliance in the pharmaceutical industry to the next level, but it has been challenging to...
  • 1US Food and Drug Administration. “Guidance for Industry. Process Validation: General Principles and Practices.” 2011. https://www.fda.gov/media/71021/download
Technical
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...
Technical
Regulatory authorities have approved the use of recombinant monoclonal antibodies (mAbs) to treat infectious diseases1  and chronic conditions such as cancer2
  • 1Sparrow, E., M. Friede, M. Sheikh, and S. Torvaldsen. “Therapeutic Antibodies for Infectious Diseases.” Bulletin of the World Health Organization 95, no. 3 (2017):235–237. doi:10.2471/BLT.16.178061
  • 2
Technical
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.
Technical
The Advanced Digital Design of Pharmaceutical Therapeutics (ADDoPT) project1 is a recently completed UK-based design manufacture and supply chain research collaboration. This collaboration catalyzed work to define a system for top-down,...
  • 1“ADDoPT—Advanced Digital Design Transforming Pharmaceutical Development and Manufacture.” Accessed 1 September 2019. https://www.addopt.org
Technical
According to US Pharmacopeia (USP) Chapter <790>, “all parenteral products should be essentially free from any visible particles.”1  This is the first and foremost requirement stated in all pharmacopeia for any injectable product. However, yielding absolutely particle-free...
  • 1United States Pharmacopeia. USP Chapter <790>: Visible Particulates in Injections.
Technical
The internet has led to an increase in e-commerce of prescription and over-the-counter (OTC) medicinal products; one in four adults has purchased medicines online.1
  • 1Orizio, G., A. Merla, P. J. Schulz, and U. Gelatti. “Quality of Online Pharmacies and Websites Selling Prescription Drugs: A Systematic Review.” Journal of Medical Internet Research 13, no. 3 (September 2011): e74....
Technical
Cleanrooms and laboratories can save a significant amount of energy by reducing airflow of air handling units (AHUs) after closing hours. Although challenging, airflow reduction is a successful energy reduction measure and has been implemented within the energy reduction program of Janssen Vaccines & Prevention B.V. in Leiden, the Netherlands.
Technical
Newer container closure integrity (CCI) test methods are more accurate and reliable than longtime industry standards. Transitioning to include deterministic testing alongside probabilistic methods may seem daunting at first, but it is in the industry’s best interest.
Technical
Despite introducing modern analytical technology to assess blend uniformity, many companies are still using traditional blend sampling thieves and wet chemistry to assess blend homogeneity. The use of statistically based sampling plans allows variance component analysis to be conducted on both blend and dosage unit data. This article shows how various combinations of blend and dosage unit...
Technical
The unavailability of a backup pharmaceutical water system has been a severe limitation for pharmaceutical manufacturers. Until recently, qualification concepts that adhered to current Good Manufacturing Practice (GMP) guidelines hindered the rapid setup of a water system. A new, tailor-made qualification concept for mobile water treatment has been developed to align with guidance from various...
Technical
As the global population demands faster and more affordable drugs, biopharmaceutical companies are continually trying to find ways to produce their drug products more economically and efficiently. Today, the competition and need for drugs are greater than ever before. Companies have been considering operational alternatives to reduce production costs and increase manufacturing rates.1
Technical
Sampling is the selection of a representative portion of the population to make inferences about the entire population. In pharmaceutical manufacturing, samples are drawn from different stages of the process for both controlling process parameters and assessing drug product quality. In the case of a traditional batch process, a fixed amount of material is processed and the batch quality is...
Technical
High-pressure liquid chromatography employing the multicolumn countercurrent solvent gradient purification (MCSGP) process principle has been developed as a novel purification technology for peptides produced by chemical synthesis. MCSGP offers a step change in efficiency compared to batch high-performance liquid chromatography (HPLC) processing. With MCSGP, two identical reverse-phase (RP)...
Technical
It is a common practice in the pharmaceutical and biopharmaceutical industries to execute a factory acceptance test (FAT) for equipment involved with various drug manufacturing processes. The FAT is a project milestone in purchasing good manufacturing practice–compliant equipment.
Technical
In recent years, the concept of quality in the pharmaceutical industry has evolved from the idea of testing the quality to designing the quality. The fundamental idea is very simple; it is necessary to understand the material and process variables that determine the final product’s quality from the beginning of product development. Such an approach permits an in-depth understanding of the...
Technical
This article discusses how blockchain technology may disrupt the way we collect and manage data within regulated processes. The first section is a nontechnical summary of blockchain’s features, including a description of what it is (and what it is not). This sets the context for the next section, in which we discuss several blockchain use cases currently being piloted by life sciences...
Technical
Although other industry publications have explored the effect of surface finish on biofilm formation, background data indicating that imperfections exceeding the American Society of Mechanical Engineers (ASME) Bioprocessing Equipment (BPE) standard are detrimental to chemical cleaning performance are lacking.1
  • 1Arnold, J. W., and O. Suzuki. “E ects of Corrosive Treatment on...
Technical
Although it includes some background material, this article is based predominantly on a series of interviews with SMEs at Eli Lilly, Janssen, Hovione, C-SOPS, and Patheon from October to December 2017. The comments and observations that follow are theirs.
Technical
The amount of data collected in a typical pharmaceutical manufacturing operation is staggering, yet research shows that much of this information is rarely used for anything more than compliance. New technologies such as big data, artificial intelligence, machine learning, and deep learning permit unprecedented analysis of realtime data and can even predict trends in processes and operations....
Technical
This article illustrates the importance of experimental conditions to evaluate analytical methods. Italicized text is used throughout the article to emphasize key points and illustrate formula variables. 
Technical
Recent cyberattacks like WannaCry and Petya have affected GxP computerized systems, prompting questions on how to address risk from cyberspace using traditional computerized systems validation according to GAMP® 5. This article explores life cycle management of GxP computerized systems and associated cybersecurity risks that can affect patient safety.
Technical
Double-wall containment: an answer to unsafe piping systems While most in the pharmaceutical industry understand the need for double-wall containment piping systems, our field observations indicate that many companies do not. We frequently see pipes that should be (but are not) double-wall containment systems. This article presents an overview of the topic, so that readers who...
Technical
Change often takes years longer in the pharmaceutical industry than in others. Why can we not challenge that paradigm? The auto industry, for example, successfully forced changes to its supplier base within a couple of years. By benchmarking other industries that have dealt with similar problems, we can learn from their experiences.
Technical
In-line concentration solves problems found in mAb production, including insufficient storage capacity and process tank volumes, extended processing times, and large hold-up loop volumes for ultrafiltration concentration. It optimizes the ion-exchange step following capture, reduces costs and processing times for virus filtration and polishing, and significantly improves the...
Technical
This article presents the work of the newly formed ISPE Holistic Production Control Strategy Working Group, which has identified and summarized the need for a redefined control strategy implementation methodology.
Technical
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. Terminal HEPA filters in HVAC applications serving Grade B, Grade C, Grade D, CNC, and unclassified areas are...
Technical
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...
Technical
India is a worldwide leader in drug manufacturing, producing 10% of global pharmaceuticals, with 2016–2017 exports valued at $16.4 billion.1
  • 1RxGPS: The Alliance for Global Pharmaceutical Serialization. "Implementing India's Drug Serialization and Traceability Requirements to Advance Patient Safety and Support Global Trade." White paper, May 2017....
Technical
ISPE's Process Capability team has developed an industry-specific maturity model that can help companies design a robust process-capability program and compare it to those of their peers. The model has been substantiated by surveying 15 companies.
Technical
Every business has legal, economical, and ethical objectives that range from mandatory safety to commercial goals to corporate citizenship. Businesses undertake a certain amount of risk to achieve these objectives. The balance between risk and reward is an ongoing challenge regardless of the activities involved. The bowtie technique can be used to visualize, assess, and manage...
Technical
Does electron-beam surface decontamination radiation damage COC syringes? Experimental investigations confirm that no measurable dose is delivered if irradiation parameters are selected correctly. Even a dose of a few kGy (equivalent to a few 0.1 Mrad) would not cause significant change.
Technical
The USP <905> UDU test, widely used for batch release since 2007, is no longer supported by FDA. We propose a two-sided tolerance interval method to alleviate this deficiency. The approach provides 50% confidence and 95% probability that future samples from the batch will conform to USP <905> criteria. In addition, this new statistical assessment provides the same practical...
Technical
We propose a method for demonstrating content uniformity in the context of variables sampling and relate this to the acceptance criteria and probability of passing the USP CU test. We demonstrate that a variable sampling plan with 99.4% coverage between 83.5% and 116.5% of label content is approximatively equivalent to (and even stricter than) the 95% probability of passing the USP...
Technical
Despite the advantages of ozone technology as a powerful commercially available oxidant and disinfectant, this technology has not been adopted broadly by the pharmaceutical industry. This article contains the rationale for applying ozone technology in a packaged system, which offers greater reliability and efficacy, using best practices that eliminate variables common in on-site integrated...
Technical
The following is an example of an evaluation of room air change rates for potential reduction using QRM, providing more detail on engineering considerations.
Technical
Much has been published on advantages of predictive maintenance, yet many do not realize that it is a tool to help achieve their facility's goals and objectives. If you need to convince management of the need for PredM, this article contains information that you can use as an "elevator speech."
Technical
This article presents current research on the problem of rouge in clean steam generators and their distribution systems, as well as possible deleterious effects on capital equipment and final drug products.
Technical
This paper was written by members of the BioPhorum Operations Group CPV and Informatics team and widely reviewed across the BPOG collaboration. As such, it represents the current consensus view of process verification subject matter experts in the biopharmaceutical industry, but does not represent the procedural details of any individual company. It is designed to be informative for industry...
Technical
This three-part paper focuses on the final results from the EU and China Patient Perceptions of Investigational Medicinal Products surveys and compares some of these results with the original "ISPE Project Concerning Patient Experience with Clinical Trial Materials" published in 2013. 
Technical
This article presents the standards and guidelines typically used by manufacturers to design and build GMP washers and sterilizers. It describes the characteristics that differentiate GMP from regular laboratory equipment.
Technical
This article discusses the impact on Chemistry, Manufacturing and Control (CMC) part of a development project when a project is assigned Breakthrough Therapy (BT) status as given in Food and Drug Administration Safety and Innovation Act (FDASIA)1 and FDA...
  • 1Food and Drug Administration Safety and Innovation Act (FDASIA), (Pub. L. 112-144), 9 July 2012, www.fda.gov.