Publications

Batch Selection • Best Practices • Best Practices • Equipment • Methods • Parameters • Protocols • Sample Control • Storage • Study Design • Study Types

Abstract Background: Although a highly common practice in hospital care, tablet splitting can cause dose variation and reduce drug stability, both of which impair drug therapy. Objective: To determine the overall prevalence of tablet splitting in hospital care as evidence supporting the rational prescription of split tablets in hospitals. Methods: Data collected from inpatients’ prescriptions were analyzed using descriptive statistics and used to calculate the overall prevalence of tablet splitting and the percentage of split tablets that had at least one lower-strength tablet available on the market. The associations between the overall prevalence and gender, age, and hospital unit of patients were also assessed. The results of laboratory tests, performed with a commercial splitter, allowed the calculation of the mass loss, mass variation, and friability of the split tablets. Results: The overall prevalence of tablet splitting was 4.5%, and 78.5% of tablets prescribed to be split had at least one lower-strength tablet on the market. The prevalence of tablet splitting was significantly associated with the patient’s age and hospital unit. Laboratory tests revealed mean values of mass loss and variation of 8.7% (SD 1.8) and 11.7% (SD 2.3), respectively, both of which were significantly affected by the presence of coating and scoreline. Data from laboratory tests indicated that the quality of 12 of the 14 tablets deviated in at least one parameter examined. Conclusions: The high percentage of unnecessary tablet splitting suggests that more regular, rational updates of the hospital’s list of standard medicines are needed. Also, inappropriate splitting behavior suggests the need to develop tablets with functional scores.

Chain of Custody • Storage • Transit

Introduction: IMPs (Investigational Medicinal Products) are not mentioned in current GDP guidance e.g. the EU GDP guidance or USP 1079 in the USA, but GMP and GCP regulations and principles request the same or even higher level of traceability and quality for IMP distribution and storage than for commercial medicinal products. At each moment in the clinical trial, sponsor, monitor and investigator must know the location, status, distribution history and usage of each individual IMP package. The whole supply chain must be documented, and related documentation is part of clinical trial files.

Best Practices • Chain of Custody • Inventory • Packaging • Sample Control • Storage • Systems • Transit

Introduction: In the article, some of the general risks in relation to data security, cyberattacks, data privacy, signal disruption, and data integrity are considered, alongside the specific risks that come with the application of Wi-Fi. For the most part these risks can be mitigated, provided appropriate protocols are adhered to enabling the benefits of Wi-Fi to be realized. This is not an overly technical article in terms of explaining the intricacies of wireless technology; the attention is to outline the main challenges and concerns to draw out those issues pertinent to a wireless technology digital strategy for the pharmaceutical organization.

Audits • Change Control • Compliance • Data Integrity • Quality

Opening Sentences: This article will expand and cover in more details the topics discussed in the Voices of Validation podcast from January 2020 and will further discuss strategies about how to implement a risk-based data integrity and audit trail reviews process. WHY ARE WE HEARING MORE ABOUT AUDITS AND AUDIT TRAIL REVIEWS LATELY? There are three major factors impacting the amount of “noise” or attention during audits to audit trail reviews and data integrity.

Best Practices • Laboratory Issues • LIMS • Resources

As the world continues to adapt to offsite work, Remote Laboratory Solutions have become increasingly important in maintaining efficient and secure operations. These solutions provide a myriad of benefits for laboratories, including streamlined workflows and improved collaboration among team members.

This blog post delves into various aspects of Remote Laboratory Solutions such as cloud-based LIMS systems that enable complete sample tracking and data management in virtual environments. It also explores mobile LIMS applications that enhance communication between field teams and remote workers by automating manual tasks.

Furthermore, this post discusses how recruiting remote staff can grant access to a larger pool of qualified candidates while reducing overhead costs. This aids in multi-location laboratory collaboration, allowing for better resource allocation based on specific site strengths and increased resilience against disruptions affecting one location.

Last but not least, ensuring data security in remote work environments is crucial for protecting sensitive information from unauthorized access and maintaining compliance with industry regulations. Finally, fostering a strong remote team atmosphere through regular virtual meetings and open communication channels is essential for success in today's digital landscape.

Best Practices • Data Analysis • Regulatory • Statistical • Statistics • Submissions • Systems

Abstract: Risk-Based Predictive Stability (RBPS) tools, such as the Accelerated Stability Assessment Program (ASAP) and other models, are used routinely within pharmaceutical development to quickly assess stability characteristics, especially to understand mechanisms of degradation. These modeling tools provide stability insights within weeks that could take months or years to understand using long-term stability conditions only. Despite their usefulness, the knowledge gained through these tools are not as broadly used to support regulatory filing strategies. This paper aims to communicate how industry has used RBPS data to support regulatory submissions and discuss the regulatory feedback that was received.

Sample Control • Study Design • Testing

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly contagious virus that can transmit through respiratory droplets, aerosols, or contacts. Frequent touching of contaminated surfaces in public areas is therefore a potential route of SARS-CoV-2 transmission. The inanimate surfaces have often been described as a source of nosocomial infections. However, summaries on the transmissibility of coronaviruses from contaminated surfaces to induce the coronavirus disease 2019 are rare at present. This review aims to summarize data on the persistence of different coronaviruses on inanimate surfaces. The literature was systematically searched on Medline without language restrictions. All reports with experimental evidence on the duration persistence of coronaviruses on any type of surface were included. Most viruses from the respiratory tract, such as coronaviruses, influenza, SARS-CoV, or rhinovirus, can persist on surfaces for a few days. Persistence time on inanimate surfaces varied from minutes to up to one month, depending on the environmental conditions. SARS-CoV-2 can be sustained in air in closed unventilated buses for at least 30 min without losing infectivity. The most common coronaviruses may well survive or persist on surfaces for up to one month. Viruses in respiratory or fecal specimens can maintain infectivity for quite a long time at room temperature. Absorbent materials like cotton are safer than unabsorbent materials for protection from virus infection. The risk of transmission via touching contaminated paper is low. Preventive strategies such as washing hands and wearing masks are critical to the control of coronavirus disease 2019.

Compliance • Guidances • Quality • Tools

In this video, Stacey Bruzzese welcomes back Ivan Soto, Director Manufacturing Validation Emergent BioSolutions. Stacey and Ivan talk about the current challenges with the implementation of quality metrics for validation.

Guidances • Regulations • Regulatory

Introductory Paragraph: Pursuant to the Charter of the Chinese Pharmacopoeia Commission and the compilation procedures of the Pharmacopoeia of the People's Republic of China (hereinafter referred to as ChP), on April 9, the 11th Conference of the Chinese Pharmacopoeia Commission (ChPC) Executive Committee was held in Beijing for a briefing on ChPC's compilation of the ChP 2020 Edition, as well as the deliberation and approval of its draft. Jiao Hong, NMPA Commissioner and Chairperson of the 11th ChPC, and Zeng Yixin, ChPC Deputy Chairman and Vice-minister of the National Health Commission attended the Conference and delivered speeches. Chen Shifei, NMPA Deputy Commissioner and ChPC Deputy Chairman, chaired the Conference. Lan Fen, Secretary General of ChPC, briefed to all executive committees on the compilation of the ChP 2020 Edition.

Compliance • Quality • Regulations • Regulatory

Portion from Opening Paragraph: Information concerning any incident that causes the drug product or its labeling to be mistaken for, or applied to, another article. Information concerning any bacteriological contamination, or any significant chemical, physical, or other change or deterioration in the distributed drug product, or any failure of one or more distributed batches of the drug product to meet the specification established for it in the application. The term “bacteriological” used in 21 CFR 314.81(b)(1)(ii) has been interpreted by the FDA to mean “microbiological” and encompasses any kind...

Investigations • Quality

Corrective and preventive action (CAPA) issues continue to be one of the top Form 483 observational findings by the FDA. Many times, CAPAs fail due to the structure and flow of the process and not necessarily the efforts of those managing the CAPAs. Frequently, organizations do not fully document the CAPA phases and confuse verification of implementation and verification of effectiveness activities. (For an introduction to the CAPA phases, read my previous article “The 10 Phases Of An Effective CAPA.”) This article will look at using the SMART (specific, measurable, achievable, relevant, and time-bound) methodology for use in developing a CAPA verification of effectiveness plan

Guidances • Regulations • Regulatory

Introductory Paragraph: ANVISA published the Resolution RDC 318/2019, which details about the criteria for carrying out stability studies of active pharmaceutical ingredients (IFAs), and of new, innovative, generic, similar, streamlined, specific drugs, with simplified notification, herbal and radiopharmaceuticals.

(Also linked Regulatory Information)

Investigations • Quality

Corrective and preventive action (CAPA) issues continue to be one of the top Form 483 observational findings by the FDA. Many times, CAPAs fail due to the structure and flow of the process and not necessarily the efforts of those managing the CAPAs. A poor paper-based CAPA process will not improve with an electronic-based CAPA system. Oftentimes, organizations do not fully document the CAPA phases and confuse verification of implementation and verification of implantation activities. This article will look at some of the regulations governing CAPAs and discuss the elements of 10 phases of a CAPA investigation that will help organizations ensure their CAPA processes are destined to succeed.

Audits • Data Integrity • Quality

This presentation gives some key insights into preparing for an audit, audit tactics and a look at actual findings from some recent (2019) FDA audits. It can be downloaded for a fee.

Best Practices • Chain of Custody • Sample Control • Storage • Transit

Abstract: An early-phase development shipping study was designed to interrogate the stability of liquid formulations under normal shipping conditions. Parcel shipments were made between Seattle, WA, and Indianapolis, IN, during 2018-2019. Each parcel contained a data recorder that tracked the shipment by GPS and measured shock and temperature. During the transport process, the parcels received up to 40 shock events with strengths ranging from 8 to 36G. After shipment, the formulations without polysorbate showed considerable increases in submicron and visible particles while little to no change occurred when polysorbate was present. Samples dropped repeatedly from a height of 18 inches to produce a shock of ∼25G caused visible particle formation with little increase in the subvisible particles, suggesting that other factors, such as vibration, in addition to the shock, were necessary to produce particle formation. These results provide a basis for further studies in the relationships between physical stability of mAbs and the challenges introduced by the shipment network, specifically shock and vibration. The findings indicate that the shock events as measured are repeatable and attributable to the layout of the sorting facility.

Data Analysis • Determination • Organizations • Shelf-Life • Statistics • Submissions

Summary Statement: • Some early adopters have been filing RBPS data for over a decade, and the regulatory acceptance has been high • More companies started to use RBPS and to file the data in submissions • Support pharmaceutical development (P.2) (Formulation, packaging, comparability after changes) : usually no queries • Support initial retest period/shelf life with RBPS only and a commitment for long term and accelerated stability • Acceptable by FDA and several other authorities • Often challenged by some countries, e.g., Germany and UK, but acceptable if standard stability data is provided during the review cycle • There has been a noticeable drop off in direct acceptance since 2017 in some EU countries, which seems align with the 2017 EMA “Guideline on the requirements for the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials” (EMA/CHMP/QWP/545525/2017) Key Words: Pharmsci, course, regulatory

Authorities • Guidances • Regulations • Regulatory • Submissions

Course Description: This 12-hour accredited training, will provide in-depth instruction on Chemistry, Manufacturing and Controls (CMC) requirements and review processes for clinical trial, registration and post approval drug applications in the US, Europe, and Japan.

Authorities • Regulations • Regulatory • Submissions

Course Description: This advanced, highly interactive course will take CMC submission training to the next level. This one-day workshop will allow participants to simulate steps involved in the creation of the CMC section (CTD Modules 2.3 and 3) of global marketing applications in a hands-on setting through guided role-playing and analysis of outcomes. The simulation will cover technical data collation, application of relevant regulatory guidelines, creation of a cohesive submission, and strategies during agency review. Case studies pertinent to NDAs/ANDAs/BLAs, MAAs and JNDAs will be used and include drug substance and oral and parenteral dosage forms. The simulation will conclude with an interactive discussion of the case studies in terms of best practices for critical thinking and informed decision-making to increase the chances of regulatory success.

Best Practices • Methods • Pharmacopoeia • Testing

Course Description: This 90-minute accredited training will discuss the requirements of current USP Bacterial Endotoxin Test (BET) European Pharmacopoeia (Chapter 2.6.14) and the Japanese Pharmacopoeia (General Tests, No. 4.01). It will address the different LAL testing methodologies and how to choose the best test method applicable to the product type. This seminar will outline the importance, regulatory and testing requirements of products for compliance by applying the sequential steps in testing the product to rule out the presence of endotoxins.

Laboratory Issues • Methods • Testing

Summary: This article considers some of the sources of variation which affect the LAL test. These sources are important for the laboratory user to understand, especially for the design of the assay and with the investigation of test anomalies. The article also considers one key measure of variability: the coefficient of variation. This is an important check for the laboratory supervisor to include when reviewing test results. One final and important aspect of LAL test variation is analyst error. This will be assessed in a second article which will appear in a future issue of the PMF Newsletter.

Determination • Extrapolation • Planning • Regulations • Regulatory • Sample Control • Shelf-Life

The Joint Pharmaceutical Analysis Group (JPAG) held a stability meeting at the Royal Society of Chemistry’s headquarters in London earlier in 2019. Attended by 65 delegates, its focus was on developments in stability testing and evaluation. This article is a summary of the presentations made at the meeting.

Best Practices • Best Practices • Data Analysis • Determination • Shelf-Life • Statistical • Statistics

Conclusion Statement: • Two challenging situations for accelerated aging examined • Assigning a minimum shelf-life when nothing happens was developed using mostly a statistical argument • Now incorporated into ASAPprime® • Handling secondary degradation complex but possible with accelerated aging • Only critical to deconvolute two rate constants when activation parameters (Ea, B) differ significantly • With enough data, can accurately model behavior across storage condition Key Words: Conditions, Shelf, Confidence

Best Practices • Methods • Testing

No summary is available. The link provided is to a request form for archived presentations.

Best Practices • Data Analysis • Determination

Conclusion Statement: ✓ Kinetic modeling can be used also when the degradation is not linear ✓ Good predictions of behavior at different temperatures – Different degradation routes at different temperatures ✓ Valuable predictions to support product development and impact assessments (e.g. temperature excursions) ▪ Fits based purely on mathematics, not on understanding of reaction mechanism – Information on mechanism obtained from fits ▪ Confidence intervals can get very large for longer-term predictions; input variability critical for output Key Words: Case, Develop, Biologic

Best Practices • Best Practices • Parameters • Shelf-Life • Study Design • Study Types

No summary is available. The link provided is to a request form for archived presentations.

Determination • Extrapolation • Shelf-Life

Presentation Summary: -Can the shelf life of multicomponent drug products be predicted from API: excipient binary mixtures? -Data from real-world stability studies are encouraging…consistent with contact surface area model -Studies designed to more rigorously test the model are underway – Binary blends and multi-composite samples are being tested

Parameters • Study Design

No summary is available. The link provided is to a request form for archived presentations.

Best Practices • Methods • Testing • Types

Conclusion: IMC stability measurements of biopharmaceuticals •Can detect denaturation/aggregation kinetics at temperatures below the Tm •Gives accurate stability assessment in 3-5 days, compared to weeks for storage tests •Provides sensitivity to detect heat signal in small volume (100 mg/mL) •Provides adequate sample throughput (1-48 samples) to assess multiple buffers and excipient conditions simultaneously •Can identify mAbs and their formulations that have best long-term stability much quicker then conventional methods •Measures rates of aggregation and therefore have the potential to predict time of storage while SEC, AUC and DLS measure the existence of aggregates after storage, while IMC

Best Practices • Best Practices • Best Practices • Determination • Protocols • Regulatory • Study Design • Submissions

Conclusions: • Product knowledge underpins understanding of the stability-related risks associated with the product • Scientific rationale combined with product understanding has been used to leverage lean stability strategies throughout development • However, a unified regulatory position to science- and risk-based stability strategies does not exist at present, potentially leading to conservatism within drug companies • Although challenges remain both within companies and externally from regulators these case studies demonstrate that many scientifically sound lean strategies are acceptable from a regulatory perspective Key Words: Biologic, Bracket, Annual

Data Analysis • Determination • Shelf-Life • Statistical • Statistics

Conclusion Points: • Predictive physical stability modelling de-risked the late-stage development of a chemically stable BCS class II SDD • ASAPprime® successfully predicted rate of crystallization over 12 months in clinically relevant packaging • Predictive stability modelling can be applied to understanding the physical stability profile of chemically stable SDDs that have similar mechanisms of recrystallisation • Prone to initial phase separation, low miscibility, low MW, low Tg • Application of predictive stability approaches to physical stability broadens the opportunity to progress NCE’s with otherwise unfavorable pharmaceutical profiles Key words: Commercial, Manufacture, Model

Best Practices • Closure Integrity • Packaging

Topics Covered in Presentation: - What is Aclar? - Moisture Barrier Concept - Impact of Forming - Measurements vs MVTR Estimates. - Benefits & Values

Methods • Testing • Types

Determination • Shelf-Life

No summary is available. The link provided is to a request form for archived presentations.

Best Practices • Closure Integrity • Methods • Packaging • Primary • Testing

Summary: This presentation shows some key factors involved in blister packaging as well as some services the author's company provides, such as BlisterPro XCEL®, a suite of services, moving from prediction to prototyping to assist on stability and packaging development. The main idea behind this set of services is to accurately select the packaging materials that pass stability and reduce the time to market.

Best Practices • Determination • Shelf-Life

No summary is available. The link provided is to a request form for archived presentations.

Audits • Best Practices • Laboratory Issues • Quality

Abstract: The concept of quality is central to the delivery of laboratory services and this is achieved through the incorporation of quality systems, quality control and quality assurance in all aspects of laboratory practice. Essential to all aspects of laboratory results is to ensure that they are accurate, reliable and delivered in a timely fashion. To ensure that these requirements are in place and that they are consistently being met, audits should be regularly undertaken. Quality audits play an essential role in the Quality Management System and these are typically a systematic examination of a system, discrete operate, product or process. In pharmaceuticals and healthcare, the analytical laboratory function plays an important role in testing products and samples against defined acceptance criteria and this information is used for release purposes. Such laboratories tend to be organized along specific disciplines (such as chemistry or microbiology) and fall within a generalized control laboratory (or quality control laboratory) unit. Audits of the laboratory will be performed at predefined time intervals, assessing whether the laboratory complies with the defined quality system processes and this can involve procedural or results-based assessment criteria. Such audits (sometimes called ‘assessments’) can be internal (from within the company) or external (such as conducted by customers or inspectors from regulator bodies or standards / certification agencies for accreditation purposes or where inspections are performed by regulatory agencies).

Best Practices • Data Analysis • Determination • Extrapolation • Shelf-Life • Statistics

Researchers have developed a model that describes how antibody solutions separate into different phases and could be used to anticipate the stability and shelf-life of drugs.

Best Practices • Chambers • Facilities • Monitoring • Planning • Qualification • Storage

Pharmaceutical, biological and medical device products require controlled environmental storage conditions. Degradation can occur when the storage environment of the product exceeds the range of safe conditions of the product. For example, some pharmaceutical materials need to be stored at ambient temperature to preserve the potency of the product. If the temperature of the storage environment goes outside that range, damage to the pharmaceutical material may occur. Thermal mapping of all storage areas is required to assess the environmental conditions stored pharmaceutical materials will be exposed to. This is especially true of warehouse storage due to large seasonal variations of environmental conditions.

Best Practices • Chain of Custody • Sample Control • Storage • Transit

Introduction: The maintenance of cold chain product integrity across the entire supply chain demands rigorous processes and cold chain expertise of the highest calibre—from packaging, handling, storage & distribution of temperature sensitive Investigational Medicinal Products (IMP), all the way to the investigator site. These eBooks outline industry trends and reviews how Fisher Clinical Services solutions are meeting the challenges of the cold chain distribution of clinical trial supplies all over the world.

Study Design

Study Design

Best Practices • Chambers • Excursions • Statistical • Study Design • Study Types • Systems

Problem Statement: - ASAPprime® models RH as a function of time in closed containers →determines impact on shelf-life.

-When the container is opened periodically and some dosages removed, does the final unit dose remain within specifications?

Methods • Regulatory • Specifications • Submissions • Testing

Summary: -The post changes of methods and specifications require thorough evaluation and fully control. -Evaluation and implementation of post approval changes needs to follow internal quality system. -Post approval changes may require regulatory agency’s approval. -During stability testing, thorough evaluation and appropriate process should be in place when test methods and specifications are changed and the updated methods/specifications are implemented.