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...

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.1

• 1Snee, R. D. “Crucial Considerations in Monitoring Process Performance and...

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...

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.

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...

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...

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...

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,...

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.

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.

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...

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

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.

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) 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

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.

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.

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.

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...

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...

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.

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...

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)...

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.

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...

This article presents an adaptation of clinical trial management to ICH E6 (R2). A case study assesses quality risks in a clinical data management system.

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...

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...

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.

Continuous biotech manufacturing has the potential to achieve greater product quality at lower cost and shorter time to market. Recent advances in fully integrated control systems and a dynamic market make it more relevant than ever.

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....

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. 

An overview of pass-through boxes as they relate to the life sciences industry, defining their purpose, applications, and available options.

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.

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...

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.

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...

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.

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...

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...

Biopharmaceutical products manufactured from mammalian or microbial cells are inherently at risk of contamination from two major types of entities.

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....

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.

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...

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.

Workflow-based technology in the clinical trial continuum encourages process optimization, helps break down silos, enhances performance quality, and has a measurable effect on the electronic trial master file.

Integrated VPHP systems offer a versatile, automated, sporicidal process for cleanroom suites, isolators, RABS, chambers, and pass-throughs. 

Free-surface electrospinning of microemulsions increases API solubility and may offer an alternative to batch powder processes.  

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...

As economic pressures and legislated environmental protection measures continue to increase, the pharmaceutical industry is moving to control cost, reduce energy use, and become a better steward of the environment.

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...

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...

The following is an example of an evaluation of room air change rates for potential reduction using QRM, providing more detail on engineering considerations.

Understanding the fundamental assumption of independence (and the violation thereof) enables an appropriate response to control chart trend rule violations and challenges us to think differently about special cause variation in control charts.

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."

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.

Guidance from ISPE's Investigational Medicinal Products Community of Practice

What is cleaning validation and where does it fall in the life cycle validation scheme? How can an automated washing system be validated? This article provides insights that may help answer these questions.

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...

This article was published in the March/April 2016 edition of Pharmaceutical Engineering® magazine. It is one of five articles nominated for the Roger F. Sherwood...

This article was published in the January/February 2016 edition of Pharmaceutical Engineering® Magazine. It is one of five articles nominated for the Roger F....

This article was published in the May/June 2016 edition of Pharmaceutical Engineering® magazine. It is one of five articles nominated for the

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. 

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.

This article compares the performance of two statistical approaches (tolerance interval and ASTM E2709/E2810) to assess dosage unit uniformity. The potential impact that the approaches can have on the USP <905> monograph is also discussed

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.

By the GAMP Cloud Computing Special Interest Group (SIG)

This article presents the key items that must be addressed to adopt an IaaS model within a regulated firm.

Written by the GAMP Cloud Computing Special Interest Group (SIG)

This article presents a strategy for providing guidance on the use of the cloud within the pharmaceutical industry.

This article presents how a good understanding of basic steam sterilization principles can help with avoiding most common mistakes made when using steam autoclaves.