Publications

Data Integrity • Quality

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Authorities • Guidances • Pharmacopoeia • Regulations • Regulatory

This is an overview of the global stability regulatory landscape with special attention to ICH.

Compliance • Quality • Regulatory • Submissions

Abtract: Many European Union (EU) countries have legalized or decriminalized the medical use of cannabis to some degree. The advent of broad acceptance of medical cannabis as public opinion shifts in the EU is driving the need for the cannabis industry to implement strict regulatory controls on the production of cannabis products. There is therefore a shift to implementation of GMP (Good Manufacturing Practices) in the cannabis space, most notably in Canada, where medical cannabis production has been legal since 2001 but regulated to a lesser extent than the GMP standard. Due to the lack of regulatory harmonization in the US, this shift to GMP standards for production is expected to impact the US market when medical cannabis laws become regulated federally. The interfaces of medical cannabis markets at the regulatory level is the subject of this article, as well as how GMP is being implemented in cannabis firms. The desire for global trade in cannabis will drive the regulatory compliance alignment to GMP in the future.

Best Practices • Equipment • Methods • Protocols • Study Design • Testing

Abstract: The characterization of protein aggregation and gelation using various methods, including scanning and transmission electron microscopy, small angle X-ray scattering, static light scattering, dynamic light scattering. infrared spectroscopy, Raman spectroscopy, rheology, and size exclusion chromatography (coupled with on-line laser light scattering, refractive index, and ultraviolet absorbance detection), are described in terms of theory and applications.

Best Practices • Protocols • Study Design • Study Types

Opening Paragraphs: Routine stability testing provides cosmetic manufacturers with critical data about their products’ safety and shelf life and can help you align your products with the FDA’s cosmetic stability testing guidelines. Although the US food and Drug Administration (FDA) does not yet require cosmetic manufacturers to conduct stability testing on products before commercially marketing them, we consider it a good manufacturing practice.

The information gained from stability testing can be useful to companies both externally and internally, creating successful ANDAs (abbreviated new drug applications) and informing product development, material procurement/management, and lifecycle management. This page provides an overview of the basics manufacturers should consider when developing a stability testing protocol for cosmetic products.

Pharmacopoeia • Regulatory

Seven key recommendations found in USP 1079 around ensuring your pharmaceutical storage units are always storing drugs safely within the manufacturer’s recommended temperature range

Best Practices • Equipment • Laboratory Issues • Methods • Testing

This book features contributions from labs around to globe to ensure thorough coverage of a wide variety of successful stability programs. It also contains key implementation advice from the experts and provides the kind of practical details necessary for lab implementation.

Authorities • Guidances • Regulations • Regulatory

Abstract: Brazil, the largest country in South America, has become the second largest pharmaceutical market in the emerging world. The Brazillian Health Surveillance Agency (Agencia Nacional de Vigilancia Sanitaria - ANVISA) was created in 1999 with the primary goal to protect and promote public health surveillance over products and services in Brazil. The governing body and structure of this new regulatory agency will be the aims of this paper, where the authors hope to share their understanding on the regulatory processes and its significant importance of this agency.

Audits • Best Practices • Compliance • Investigations • Laboratory Issues • Quality • Testing

Abstract: Despite the guidance that is in place, many regulatory cite poor OOS investigations and these features high up on lists of inspectorate findings. Failure to conduct detailed OOS investigations or not producing OOS investigations of sufficient quality regularly features among the top five inspection findings from European Union regulatory agencies and also from the U.S. Food and Drug Administration. This paper takes a look at how OOS are conducted and presents different ways through which OOS investigations can be improved. While the OOS concept discussed is generally more applicable to analytical data than microbiological data, there are aspects in this paper that will be of interest to all laboratory disciplines working in a regulated GMP environment. The paper provides some best practice tips and short case study.

Best Practices • Parameters • Planning • Sample Control • Storage • Study Design

Abstract: This article describes how the increased use of energy-efficient solid-state light sources (e.g., light-emitting diode [LED]-based illumination) in hospitals, pharmacies, and at home can help alleviate concerns of photodegradation for pharmaceuticals. LED light sources, unlike fluorescent ones, do not have spurious spectral contributions <400 nm. Because photostability is primarily evaluated in the International Council of Harmonization Q1B tests with older fluorescent bulb standards (International Organization for Standardization 10977), the amount of photodegradation observed can over-predict what happens in reality, as products are increasingly being stored and used in environments fitted with LED bulbs. Because photodegradation is premised on light absorption by a compound of interest (or a photosensitizer), one can use the overlap between the spectral distribution of a light source and the absorption spectra of a given compound to estimate if photodegradation is a possibility. Based on the absorption spectra of a sample of 150 pharmaceutical compounds in development, only 15% would meet the required overlap to be a candidate to undergo direct photodegradation in the presence of LED lights, against a baseline of 55% of compounds that would, when considering regular fluorescent lights. Biological drug products such as peptides and monoclonal antibodies are also expected to benefit from the use of more efficient solid-state lighting.

Protocols • Quality • Study Design • Tools

Development and construction of validation protocols is a critical activity in the validation process. Writing protocols is a comprehensive activity that should involve the entire validation process. This discussion adds importance considerations for protocol writing.

Best Practices • Best Practices • Data Analysis • Determination • Life Cycle • Parameters • Protocols • Regulatory • Shelf-Life • Statistics • Study Design

Summary The shelf life for a combination product is determined from drug stability, device aging, and sterile barrier aging with the shortest estimate determining the overall shelf life. The shelf life of a product may vary between different countries/regions depending on regulatory requirements. Accelerated aging studies can be used for shelf life determination but must later be verified using data from the long-term storage conditions. Lastly, great attention should be paid in proper study design and early logistics as it is often unachievable to go back in time to fix a mistake or disagreement with agencies after several months or years have passed after a study has launched.

Determination • Shelf-Life

Combination products are therapeutic and diagnostic products that combine drugs, devices, and/or biological products. These products may include “single-entity” items such as monoclonal antibodies mixed with a therapeutic chemotherapy drug, devices impregnated or coated with drugs such as drug eluting stents, pacing lead with steroid-coated tip, catheter with antimicrobial coating, transdermal patch and or prefilled drug delivery systems such as insulin injectors. “Co-packaged” combination products are two or more separate classes of product contained in a single package or as a unit and finally “cross-labeled” combination products encompass individual products that are provided separately but are specifically labeled for use together.1 However, products intended to be used together may not strictly meet the regulatory definition of a combination product if, for example, a syringe is marketed for general delivery of unspecified drugs. Additionally, two or more of the same class of medical product (drug-drug, biological- biological, device-device) or a medical product combined with a non- medical product such as a dietary supplement does not constitute a combination product.

Parameters • Planning • Protocols • Study Design

Introduction: Stability is a critical quality attribute of pharmaceutical products and is a function of many factors, including the active drug substance itself, the excipients used within the formulation, the manufacturing process employed and the drug product’s container closure system. The purpose of stability testing is to provide evidence of how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity and exposure to light, and to establish a retest period for the drug substance or a shelf-life for the drug product, as well as recommended storage conditions.1 Stability studies are conducted throughout all phases of the drug product’s life cycle; the purpose, regulatory requirements and technical challenges for each study vary depending on the product type, the phase of the program and the intended markets.

Best Practices • Best Practices • Data Analysis • Protocols • Regulatory • Reports • Study Design • Study Types • Submissions

A published regulatory template sharing best practices for filing RBPS data would benefit the industry and regulatory reviewers by enabling a consistent presentation of predictive data and conclusions. Key Words: Model, Extension, Q1A

Batch Selection • Best Practices • Best Practices • Parameters • Planning • Protocols • Resources • Sample Control • Storage • Study Design • Study Types

ABSTRACT: The continued integrity of products in multi-dose containers after the first opening is an important quality issue. The purpose of in-use stability testing is to establish a period of time during which the product in multi-dose container can be used retaining quality within an accepted specification once the container is opened. KEYWORDS: Multi-dose, container, quality in-use, stability, testing

LIMS • Systems

Best Practices • Best Practices • Best Practices • Chambers • Education • Monitoring • Preventive Maintenance • Protocols • Quality • Sample Control • SOPS • Statistics • Storage • Study Design • Systems • Training

Course Description This course focuses on the Operations (excludes testing and data analysis) aspects of the Stability function as practiced by the pharmaceutical, biological and medical device industries. Establishing and maintaining strong stability operations programs will be covered, including: SOPs, training, protocols, life cycle stability strategies, storage conditions, chamber maintenance and monitoring, trending data and sample management.

Audits • Quality • Resources

Course Description: A significant number of 483’s and Warning Letters related to the stability function is proof that not all companies have an adequate program in place. Since regulatory requirements and guidance’s provide only a general picture of expectations for stability programs, much interpretation is left up to individual companies. A better understanding of regulatory expectations and careful preparation is warranted to avoid joining those organizations receiving stability citations.

This 90-minute, accredited ON DEMAND online training will cover all aspects of preparing for and conducting/hosting an audit of the medical product stability function.

Best Practices • Protocols • Study Design

Abstract: Proteins are increasingly used in basic and applied biomedical research. Many proteins, however, are only marginally stable and can be expressed in limited amounts, thus hampering research and applications. Research has revealed the thermodynamic, cellular, and evolutionary principles and mechanisms that underlie marginal stability. With this growing understanding, computational stability design methods have advanced over the past two decades starting from methods that selectively addressed only some aspects of marginal stability. Current methods are more general and, by combining phylogenetic analysis with atomistic design, have shown drastic improvements in solubility, thermal stability, and aggregation resistance while maintaining the protein's primary molecular activity. Stability design is opening the way to rational engineering of improved enzymes, therapeutics, and vaccines and to the application of protein design methodology to large proteins and molecular activities that have proven challenging in the past.

Data Analysis • Determination • Education • Regulatory • Resources • Shelf-Life • Statistics • Submissions

Book Summary: Accelerated Predictive Stability (APS): Fundamentals and Pharmaceutical Industry Practices provides coverage of both the fundamental principles and pharmaceutical industry applications of the APS approach. Fundamental chapters explain the scientific basis of the APS approach, while case study chapters from many innovative pharmaceutical companies provide a thorough overview of the current status of APS applications in the pharmaceutical industry. In addition, up-to-date experiences in utilizing APS data for regulatory submissions in many regions and countries highlight the potential of APS in support of registration stability testing for certain regulatory submissions. This book provides high level strategies for the successful implementation of APS in a pharmaceutical company. It offers scientists and regulators a comprehensive resource on how the pharmaceutical industry can enhance their understanding of a product’s stability and predict drug expiry more accurately and quickly.

Best Practices • Best Practices • Laboratory Issues • Sample Control • Specifications • Storage

Abstract: Background: The stability limit of an analyte in a biological sample can be defined as the time required until a measured property acquires a bias higher than a defined specification. Many studies assessing stability and presenting recommendations of stability limits are available, but differences among them are frequent. The aim of this study was to classify and to grade a set of bibliographic studies on the stability of five common blood measurands and subsequently generate a consensus stability function.

Methods: First, a bibliographic search was made for stability studies for five analytes in blood: alanine aminotransferase (ALT), glucose, phosphorus, potassium and prostate specific antigen (PSA). The quality of every study was evaluated using an in-house grading tool. Second, the different conditions of stability were uniformly defined and the percent deviation (PD%) over time for each analyte and condition were scattered while unifying studies with similar conditions.

Results: From the 37 articles considered as valid, up to 130 experiments were evaluated and 629 PD% data were included (106 for ALT, 180 for glucose, 113 for phosphorus, 145 for potassium and 85 for PSA). Consensus stability equations were established for glucose, potassium, phosphorus and PSA, but not for ALT.

Conclusions: Time is the main variable affecting stability in medical laboratory samples. Bibliographic studies differ in recommendations of stability limits mainly because of different specifications for maximum allowable error. Definition of a consensus stability function in specific conditions can help laboratories define stability limits using their own quality specifications.

Compliance • Investigations • Quality • SOPS • Tools

Abstract: Deviations occur across the pharmaceutical and device industries nearly every day. Companies have spent hundreds of hours and thousands of dollars to investigate deviations, identify their causes and implement corrective actions to prevent their recurrence. Yet with all of the investment we continue to frustrate both our personnel and our management as the same problems continue to recur.

FDA and other regulators routinely request to see lists of deviations, non-conformances, CAPAs, complaints, and out of specification investigations during inspections. For nearly 20 years, failure in these systems has been in the top 5 of all observations issued. So what are we doing wrong? This article attempts to explore the issues and provide some possible solutions and paths forward to eliminate the problems routinely documented as deviations within our manufacturing and testing environments. Although the examples focus on U.S. FDA, the problems and solutions are applicable worldwide.

Compliance • Investigations • Quality • Tools

Abstract: Problem solving is critical to successfully maintaining and improving pharmaceutical and biotech processes. Processes are dynamic and as predicted by the 2ndlaw of thermodynamics will deteriorate over time if left alone. Federal Regulation Title 21 requires that an organization’s quality system include a process for Corrective and Preventive Action (CAPA). Central to an effective CAPA system is the identification of root causes of problems. Systematic approaches for problem solutions have been called for but few have appeared. Problem solutions tend to be handled individually. The frequent result is root causes are not identified and the problems reoccur. A systematic approach based on process and systems thinking and the DMAIC problem solving, and improvement framework is presented, discussed and illustrated. The focus is on getting to root cause and putting permanent fixes in place so that he problems do not occur again. The concepts and methods involved illustrated with pharmaceutical and biotech case studies and examples.

Best Practices • Best Practices • Data Analysis • Determination • Efficiencies • Statistical • Statistics • Study Types

Stability studies are a time consuming and resource intensive task in the development of new drugs. Therefore products are tested under accelerated conditions to increase the rate of chemical and/or physical degradation. Based on the Arrhenius equation the chemical degradation increases with the temperature and therefore it should be possible to project the degradation rate at low temperature from the data generated under accelerated or stressed conditions. However, the predictive power of those experiments is not always sufficient. On the one hand, long-term studies or real-time studies are still needed and experience shows often different results between accelerated and long-term conditions. On the other hand, it is not possible to increase the temperature unlimited to get meaningful results at high temperature. Baking a cake at 160°C for 30 minutes is not the same as baking a cake at 240°C for 1 minute. Key Words: Predictive, Arrhenius, ASAP

Best Practices • Methods • Testing • Types

Abstract: Microbial identification represents an important part of the microbiology function. This includes screening products for objectionable organisms, profiling the environmental microbiota, and investigating out-of-limits events with a view to assigning a probable point of origin. In deciding what and when (and subsequently to which level) to identify, and by the way of which methods, requires an identification strategy. This is a document each microbiology laboratory should develop. Many parts of pharmaceutical microbiology are outlined in compendia or in guidance documents issued by regulators; included within these are the importance of bioburden assessments of intermediate and finished products, and the need to monitor the environment using standard environmental monitoring methods. What is less clear is with microbial identification. For identification there are established and emerging methods, based around the microbial phenotype or genotype, yet the choice between systems is not straightforward and the selection depends, in part, on what needs to be identified. Deciding which types of samples to identify; which level of identification is appropriate (morphology, genus, or species); and what can be done with the collected information needs careful thought. A further decision point is whether the testing laboratory carries out the testing ‘in house’ or contracts out the function. This article addresses these points and provides a basis of the microbiologist in each pharmaceutical or healthcare organization to develop a microbial identification strategy.

Statistics

This article is the product of a collaborative effort between two of IVT Network's highly esteemed event speakers, addressing top issues frequently asked in the validation community.

Audits • Change Control • Data Integrity • Facilities • Guidances • LIMS • Quality • Systems

The author describes a brief history of where the impetus came for the focus on data integrity and then answers some commonly asked questions. Key Words: CFR, PICs, WHO, audit, FDA, EMA

Data Integrity • Guidances • Quality • Regulatory

This is an article found in the E-Book, "Ensuring Data Integrity for GXP Compliance" accessible through the link, below. The book provides multiple perspectives from experts in the industry, with solutions to common challenges. This compilation of previously published material on the IVT Network website is excellent for the beginner or the experienced professional working for data integrity compliance, with papers geared towards a general understanding, as well as papers dealing with more complex issues.

Best Practices • Data Analysis • Expiry • Extrapolation • Statistics • Study Types

A survey on risk-based predictive stability tools reveals how pharma companies are leveraging advanced stability approaches throughout the drug development process. Key Words: Trend, Forecast, Statistics

Climate Zones • Parameters • Planning • Protocols • Regulatory • Sample Control • Storage • Study Design

Abstract A review of the methodology for determination of the storage conditions for stability testing according to Schumacher/Grimm is presented in this paper. The purpose is to provide scientific information useful for the definition of storage conditions for stability testing of pharmaceuticals suitable to the region where the product will be dispensed. Special attention is given to stability testing in the new markets located in developing countries with very hot and humid climates. Finally, storage conditions for stability testing in the Brazilian regions were derived and examined comparatively with the guidelines of the world health organization (WHO) and regulatory bodies. The storage conditions were derived from the calculated values of the mean kinetic temperature and the relative humidity (RH). These parameters were estimated from daily values of dry and dew point temperatures of all Brazilian capitals from 1998 to 2002; collected in the morning (9 a.m.), in the afternoon (3 p.m.), and at night (9 p.m.). The Brazilian Center of Weather Forecast and Climatic Studies of the National Institute of Spatial Research (CPTEC/INPE) kindly furnished these data. Significant differences of the mean kinetic temperature (MKT) and relative humidity (RH) for Brazilian regions were observed. These results indicate the existence of a high climatic diversity between the Brazilian regions, making challenging the definition of a single storage condition for the stability testing. Some regions present RH values higher than 80%, giving support to the concerns of the WHO, indicating the necessity of revision of existing guidelines for stability testing mainly for very hot and humid regions.

Best Practices • Planning • Protocols • Study Design

Introductory Paragraph: A drug stability program that is above reproach is critical to successfully navigating the complexities of drug development. A well-managed stability program with thoughtfully constructed protocols demonstrates your lab and quality systems are in control.

Data Integrity • Quality

This is an article found in the E-Book, "Ensuring Data Integrity for GXP Compliance" accessible through the link, below. The book provides multiple perspectives from experts in the industry, with solutions to common challenges. This compilation of previously published material on the IVT Network website is excellent for the beginner or the experienced professional working for data integrity compliance, with papers geared towards a general understanding, as well as papers dealing with more complex issues.

Guidances • Planning • Regulatory • Resources • Storage • Study Design

Abstract: The ICH Q1B guidance and additional clarifying manuscripts provide the essential information needed to conduct photostability testing for pharmaceutical drug products in the context of manufacturing, packaging, and storage. As the previous 2 papers in this series highlight for drug products administered by injection (part 1) and drug products administered via topical application (part 2), there remains a paucity of guidance and methodological approaches to conducting photostability testing to ensure effective product administration. Part 3 in the series is presented here to provide a similar approach and commentary for photostability testing for oral drug products. The approach taken, as was done previously, is to examine “worst case” photoexposure scenarios in combination with ICH-defined light sources to derive a set of practical experimental approaches to support the safe and effective administration of photosensitive oral drug products.

Determination • Extension • Extrapolation • Shelf-Life • Statistics

This book brings together relevant statistical methods for nonclinical research in pharma/biotech industries with a mission promoting nonclinical statistics as a single discipline as clinical biostatistics. It also serves as an excellent resource for academic researchers and graduate students who want to pursue their research in these areas.

Equipment • Methods • Pharmacopoeia • Testing

Instroduction: Water activity, or the relative humidity inside a package, is commonly measured by manufacturers in industries such as food and pharmaceuticals. The food industry has used water activity testing for more than two decades in development and quality control applications. The FDA and USDA consider water activity a key parameter to control mold, fungus and bacterial growth on packaged foods. Food producers also use water activity measurements in product development to understand how water migrates between the package and the product itself, and between the individual food components.

In the pharmaceutical industry, water activity is a critical quality attribute and a key factor to maintain stability over the shelf life. Since December, 2012, when the United States Pharmacopeia (USP) added a new chapter “Application of Water Activity Determination to Non-sterile Pharmaceutical Products” <1112&GT that defines aw testing for bacterial growth on solid dosage forms, measuring the water activity inside drug packaging is increasing.

Methods • Testing

Forced degradation is a degradation of new drug substance and drug product at conditions more severe than accelerated conditions. It is required to demonstrate specificity of stability indicating methods and also provides an insight into degradation pathways and degradation products of the drug substance and helps in elucidation of the structure of the degradation products. Forced degradation studies show the chemical behavior of the molecule which in turn helps in the development of formulation and package. In addition, the regulatory guidance is very general and does not explain about the performance of forced degradation studies. Thus, this review discusses the current trends in performance of forced degradation studies by providing a strategy for conducting studies on degradation mechanisms and also describes the analytical methods helpful for development of stability indicating method.