Moving From Cleanroom to Isolation Technology for ATMPs
Technical
Moving From Cleanroom to Isolation Technology for ATMPs
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...
Figure 1: General workfl ow for the application of model-assisted DoE (mDoE).
Technical
Mathematical Models in Experimental Design and Scale-up
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...
Figure 3: Example of spray coverage image and clean in place (CIP) execution image used as supporting evidence.
Technical
Accelerating Biopharmaceutical Virtual FATs in a Pandemic
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...
Article
Technical
Lessons Learned in Global CQV
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...
Figure 1: Points to consider when designing the media fill study.
Technical
Validation of Aseptic Processes Using Media Fill
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...
Figure 1: Potency assay blind control Xbar-S chart.
Technical
Risk-Based Continued Test-Method Performance Verification System
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...
Figure 3: AUC used as the metric evaluator for models 1 to 5 (2020 data) and model 1 (2018 data, bottom right).
Technical
Case Study: Water for Injection Plant AI-based Maintenance
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...
Figure 4
Technical
Safeguarding Vial Container Closure Integrity: A Systematic Approach
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...
Figure 1: Seasonal comfort (temperature and RH). ©ASHRAE, www.ashrae.org. Used with permission from 2017 ANSI/ASHRAE Standard 55 [4].
Technical
Temperature & Humidity Requirements in Pharmaceutical Facilities
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,...
Figure 1: A HEPA fi lter without a di user (left) and a HEPA fi lter with a di user (swirl di user; right).
Technical
Pharmaceutical Cleanroom Design & ISO 14644-16
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...
Article
Technical
Effect of Gum on in Vitro Dissolution of Powder for Oral Suspension
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...
Medical Device UDI Components Management in the European Union
Technical
Medical Device UDI Components Management in the European Union
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...
Figure 1: Software in healthcare.
Technical
Software as a Medical Device Fundamentals
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.International Medical Device Regulators Forum. “Software as a Medical Device (SaMD): Key Definitions.” 9 December 2013....
Master soil (Browne soil) applied to laboratory glassware.
Technical
Master Soil Selection for Cleaning Validation of Parts Washers
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...
Figure 1: Simplified CIP skid system.
Technical
Analyzing System Performance through Process Instrumentation Data
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...
Figure 1: Macro operation flowchart.
Technical
Automating MACO Calculations in Cleaning Validation
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...
Powder behavior is the result of a complex network of interactions between particle properties and system variables.
Technical
Material Properties Databases to Advance Pharmaceutical Processing
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...
Figure 1: Example of fishbone analysis as a tool for risk identification.
Technical
Quality Risk Management to Address Product Impurities
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...
Figure 1: Example of OWBA installation in a WFI system.
Technical
GMP Implementation of Online Water Bioburden Analyzers
Online water bioburden analyzers (OWBAs) are analytical instruments providing real-time or near real-time measurement of bioburden in purified water systems.Cundell, A., O. Gordon, N. Haycocks, et al. “Novel Concept for Online Water Bioburden Analysis: Key Considerations, Applications, and Business...
Figure 1: Traditional cleaning validation approach emphasizes validating the cleaning process.
Technical
Cleaning Validation Program Maintenance in a Process Life-Cycle Model
The process life-cycle model, as discussed in the US FDA guidance on process validation, is a significant change in how we view validation.US Food and Drug Administration. “Guidance for Industry. Process Validation: General Principles and Practices.” January 2011....
Figure 1: Illustration of sedimentation control in enclosed geometries using air-fi lled hydrophobic microcavities.
Technical
Passive Sedimentation Control in Containers Using Marangoni Forces
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...
Article
Technical
Justifying Investment in Manufacturing Execution Systems
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...
Self-Calibrating Thermometers for Use in Medical Autoclaves
Technical
Self-Calibrating Thermometers for Use in Medical Autoclaves
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...
Using CFD Multiphase Modeling to Predict Bioreactor Performance
Technical
Using CFD Multiphase Modeling to Predict Bioreactor Performance
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...
Quality & Regulatory Solutions for PAT in Continuous Manufacturing
Technical
Quality & Regulatory Solutions for PAT in Continuous Manufacturing
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...
Figure 1: Dry block instruments for calibration to 55°C (left) and 75°C
Technical
Lyophilizer Instrumentation Calibration: Principles & Practices
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...
Figure 1: Batch simulation using MVDA
Technical
Continued Process Verification in Stages 1–3
Continued process verification (CPV) as defined in the US FDA process validation guidelineUS Food and Drug Administration. “Guidance for Industry. Process Validation: General Principles and Practices.” 2011. https://www.fda.gov/media/71021/download helps bring quality management and compliance in...
Good Engineering Practice in Risk-Based Commissioning & Qualification diagram
Technical
Good Engineering Practice in Risk-Based Commissioning & Qualification
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...
Figure 4: SDS-PAGE under nonreduced conditions of the fi nal purified SP Sepharose Fast Flow.
Technical
Effects of Tank-Agitated Fermentation on Therapeutic mAb Quality
Regulatory authorities have approved the use of recombinant monoclonal antibodies (mAbs) to treat infectious diseasesSparrow, 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....
Chlorine dioxide gas sample readings (mg/L) charted over time
Technical
Chlorine Dioxide Gas Decontamination vs. Liquid Disinfection
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...
Generic information fl ow for digital design of manufacturing process
Technical
A Systems-Based Approach to Digital Design & Operation
The Advanced Digital Design of Pharmaceutical Therapeutics (ADDoPT) project“ADDoPT—Advanced Digital Design Transforming Pharmaceutical Development and Manufacture.” Accessed 1 September 2019. https://www.addopt.org is a recently completed UK-based design manufacture and supply chain research...
Article
Technical
Evaluation of Visual Inspection in Parenteral Products
According to US Pharmacopeia (USP) Chapter <790>, “all parenteral products should be essentially free from any visible particles.”United States Pharmacopeia. USP Chapter <790>: Visible Particulates in Injections. This is the first and foremost requirement stated in all pharmacopeia for...
Accreditation organizations’ systems to show online pharmacy legitimacy
Technical
Regulating Online Pharmacies & Medicinal Product E-Commerce
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.Orizio, G., A. Merla, P. J. Schulz, and U. Gelatti. “Quality of Online Pharmacies and Websites Selling Prescription Drugs: A Systematic...
Comparison of electricity consumption at the main distribution board
Technical
Airflow Reduction in Cleanrooms after Closing Hours
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...
Shifts in Container Closure Integrity Test Methods
Technical
Shifts in Container Closure Integrity Test Methods
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.
Interpretation of Variance Components for Blend and Content Uniformity
Technical
Interpretation of Variance Components for Blend and Content Uniformity
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...
Mobile water treatment in an ISO container
Technical
A New Qualification Approach for Mobile Purified Water Systems
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...
A Strategy for the Analysis of Dissolution Profiles
Technical
A Strategy for the Analysis of Dissolution Profiles
In this article, a new method for the analysis and comparison of dissolution profiles is proposed and illustrated with case studies. This useful strategy makes effective use of dissolution profile data by using all data in each profile to create two...
Article
Technical
Inline Dilution: An Agile Capability for Downstream Manufacturing
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...
Article
Technical
Sampling Considerations in Continuous Manufacturing
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...
Article
Technical
Purification Of Synthetic Peptides
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...
Automated Parts Washer Factory Acceptance
Technical
Automated Parts Washer Factory Acceptance Test
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.
Article
Technical
Quality By Redesign of a Legacy Product Case Study
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...
Article
Technical
Blockchain for Pharmaceutical Engineers
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,...
Article
Technical
Continuous Oral Solid Dosage in the Field - A Status Update
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.
Data
Technical
Getting Ready for Pharma 4.0™
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...
Experimental Conditions Define the ATP Inference Space - ISPE Pharmaceutical Engineering
Technical
Experimental Conditions Define the ATP Inference Space
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.
cyber security
Technical
Bringing Cybersecurity to GxP Systems
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...
underground system
Technical
Surrounding & Controlling Underground Leaks
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...
testing
Technical
Making CPV a Proactive Component of Process & Product Improvement
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,...
Article
Technical
Evaluating In-line Volume Reduction During mAb Production
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...
A Holistic Approach to Production Control
Technical
A Holistic Approach to Production Control
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.
Article
Technical
Parenteral HEPA Filter PM Interval
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...
Article
Technical
Defining the Analytical Target Profile
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...
Article
Technical
Indian Serialization Mandate & The US Supply Chain
India is a worldwide leader in drug manufacturing, producing 10% of global pharmaceuticals, with 2016–2017 exports valued at $16.4 billion.RxGPS: The Alliance for Global Pharmaceutical Serialization. "Implementing India's Drug Serialization and Traceability Requirements to Advance Patient Safety...
Article
Technical
How Robust Is Your Process Capability Program?
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.
Article
Technical
Bowtie Analysis and Barrier-Based Risk Management
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...
Article
Technical
Effect of Low-Energy E-Beam Irradiation on Presterilized COC Packaging
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.
Article
Technical
Statistical Approach for CU Testing CPV Batches & Comparison with USP <905> UDU
The USP &lt;905&gt; 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...
Article
Technical
Manufacturing Excellence Utilizing a Life Cycle Approach
The emergence of “big data” has allowed pharmaceutical organizations to harness the vast amount of information they generate. By collecting equipment, facility, and manufacturing data (process parameters, calibration, qualification, environmental...
Article
Technical
A Variable Sampling & Acceptance Polygon Approach for Content Uniformity
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...
Article
Technical
Performance & Validation of Ozone Generation for Pharma Water Systems
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...
Article
Technical
Applying QRM to Air Change Reduction
The following is an example of an evaluation of room air change rates for potential reduction using QRM, providing more detail on engineering considerations.
Article
Technical
An Introduction to Predictive Maintenance
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."
Article
Technical
Extractables & Leachables: Not the Same
With the integration of single-use systems (SUS)* into downstream processing and thus closer to the final drug product, considerations of extractables and leachables (E&L) have become a critical issue within the industry. Lack of standardization,...
Article
Technical
Corrosion Investigation of Pharma Clean Steam Systems
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.
Article
Technical
EU Clinical Trials Regulation: The Application Process
One of the major changes introduced by the European Union (EU) regulation 536/2014 is an application procedure that will require sponsors to apply for authorization to conduct an interventional/low-intervention clinical trial (CT) via a new EU portal.3 ...
Article
Technical
Continued Process Verification (CPV) Signal Responses in Biopharma
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...
Article
Technical
Process & Product Contact Surfaces in Bioprocessing
As part of their quality risk management (QRM) programs, many biopharmaceutical manufacturers have made deliberate efforts to classify systems, equipment, and components by their potential to affect product quality. In assessing these risks, it is...
Article
Technical
History of Quality & the Evolution of the Modern Leader
The Food and Drug Administration (FDA) report “Pharmaceutical Quality for the 21st Century: A Risk-Based Approach”14 was an introduction to quality by design (QbD), the concept that quality should be built into a product. According to the FDA report...
Article
Technical
Quality Risk Management for Legacy Products in CMOs
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 Article of the Year Award, all which will be posted to iSpeak throughout the week of 5 December.
Article
Technical
Cleaning Buffer Preparation Tank Air-Liquid Interface Rings
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. Sherwood Article of the Year Award, all which will be posted to iSpeak throughout the week of 5 December.
Article
Technical
Balancing Pre and Post-Market Control of Health Supplements
Regulatory authorities (RAs) worldwide employ different terminologies to describe various medicinal and health products. According to the definition by the Association of Southeast Asian Nations (ASEAN), Health supplements (HS) are products used to...
Article
Technical
Patient Perceptions of IMPs Survey
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.
Non-GMP or GMP Washers and Sterilizers: How to Choose
Technical
Non-GMP or GMP Washers and Sterilizers: How to Choose
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.