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Streamlining Postapproval Submissions Using ICH Q12 & SCDM
Jackie Gavin, PharmD
Jessica Lo Surdo, PhD
Nina S. Cauchon, PhD
Tabetha Bonacci, PhD
Michael Abernathy
Postapproval change management of pharmaceuticals is an essential part of life-cycle management but is associated with regulatory challenges. Incorporating concepts and tools from the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q12 guideline, combined with structured content and data management (SCDM) and a cloud-based data exchange platform, could provide synergistic benefits that will enable efficient supply maintenance of life-saving therapies worldwide.
Following approval of an initial marketing application, postapproval changes are needed to ensure adequate supply, mitigate supply risk, expand patient market access, optimize manufacturing processes, improve analytical methods, and comply with new regulatory expectations. Regulatory submission and evaluation of chemistry, manufacturing, and controls (CMC) data may be required for changes that have a higher risk to impact product quality. Such changes can include increasing batch sizes, adding manufacturing facilities, creating new product presentations, and updating analytical methods. Prior to implementation of a change, manufacturers conduct risk assessments and generate data to confirm there would be no adverse impact to product quality through shelf-life as a result of the change.1 ,2
Health authorities have specific regulations and guidelines that govern reporting requirements necessary to implement postapproval variations; however, regulatory submissions for a given change can vary based on differing regional requirements as specified by the health authority conducting the review. For changes requiring approval before implementation, once the necessary information has been submitted across regions, each health authority must review the data package and documentation based on local requirements.
The timing and data requirements vary depending on the reporting category, submission, and legal obligations in each individual jurisdiction. For products with a large global footprint, the time required from submission to global approval and implementation of a single change can take years while the change obtains approval across all the relevant regulatory agencies. The resulting complexity requires manufacturers to tightly control and manage supply chain activities for commercial products globally to maintain compliance. 1 ,2 Depending on the nature of the change, manufacturers may be required to maintain both the pre-and post-change equipment, processes, or methods until all approvals are received.
In an attempt to address these challenges, in 2019 the ICH endorsed ICH Q12, Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management (and Annexes). This guideline was developed and designed to provide a flexible framework to facilitate postapproval CMC change management, and outlines a risk-based, structured, and harmonized approach.3 ,4
The current lack of global harmonization for CMC content across regions requires the burdensome task of creating multiple submissions to fulfill varying regulatory requirements across different markets. Typically, CMC information needed to support a postapproval submission is accessed and transcribed manually from raw data systems (e.g., laboratory notebooks, batch records, and technical reports) to submission documents (e.g., Common Technical Document [CTD] sections). This information package is then submitted in electronic PDF format that health authorities must manually "unpack" or deconstruct in order to perform their assessments. These efforts consume substantial time and resources for both sponsors and health authorities, which may result in redundancies and the need for multiple data integrity checks. The use of SCDM can potentially help alleviate the burden of submission authoring by shifting the focus from document management to data management, including how information is stored, analyzed, authored, and reviewed.2 ,5
This article will examine the current global regulatory submission workflow for postapproval CMC changes and will propose principles to streamline regulatory submission authoring through the utilization of ICH Q12 concepts, in combination with SCDM. It will also discuss several challenges associated with full implementation of the ICH Q12 regulatory tools, including established conditions (ECs), postapproval change management protocols (PACMPs), and product lifecycle management (PLCM) documents. Other challenges addressed in this article include the varying interpretation and lack of standardization that must still be overcome to achieve true global harmonization. This review also considers the next steps toward achieving simultaneous global regulatory submissions and utilizing cloud-based technology to facilitate data exchange between sponsor and regulator.6
ICH Q12 Global Implementation: Status and Challenges
The ICH Q12 guideline provides a framework to facilitate post-approval CMC changes more predictably and efficiently through a unified risk-based approach that will benefit patients, the industry, and regulatory authorities.3 ,4 Full implementation of ICH Q12 tools across all jurisdictions may be delayed until the necessary legislative changes are made.7 ,8 ,10 ICH Q12 introduces the concept of established conditions (ECs), which provides a clear understanding between the manufacturer and health authorities regarding critical manufacturing, quality, and analytical elements that require regulatory actions.
In May 2021, the US Food and Drug Administration (FDA) published a draft industry guidance, ICH Q12: Implementation Considerations for FDA-Regulated Products. This guidance complements ICH Q12 guidelines by clarifying how the ICH Q12 tools and enablers can be implemented within the US regulatory framework, and reflects critical lessons learned from the 2019 FDA Pilot Program on Established Conditions. 9 ,10
The European Medicines Agency (EMA) issued its implementation guidance in March 2020.10 It emphasizes that one must always default to the requirements laid down in the current European Union (EU) variations of regulation and associated guidelines.6 Currently, the EU legal framework does not recognize the product life-cycle management (PLCM) document, which contains ECs and proposed reporting categories but does recognize PACMPs. The European Commission, together with the EMA and the National Competent Authorities, will continue to work on fully implementing the ICH Q12 guideline within the existing EU legal framework7 ,11 , 12
In Japan, the Pharmaceuticals and Medical Devices Agency (PMDA) introduced minor change notifications to the regulatory framework. However, there was no harmonization of post-approval change reporting categories across the ICH regions at the time. The application form, unique to Japan, can be the basis for using ECs to determine filing strategies for postapproval changes. Due to this unique approach, standardized global implementation of ICH Q12 has been challenging.13 In an effort to achieve global standardization, the PMDA released a notification in March 2021 that confirms the incorporation of PACMPs into the regulatory framework, and full implementation was expected soon at the time of this writing (late 2021).14
At ICH Day during DIA China 2021, industry and regulatory experts agreed that real experiences from well-established regulatory systems would help China implement ICH Q12 from policy and technical perspectives. At the regulatory level, the National Medical Products Administration (NMPA) Drug Administration Law (DAL), Drug Registration Regulation (DRR), and Provisions for Post-Approval Changes have provided support for the transformation and implementation of ICH Q12 in China. The FDA has also offered both early dialogue and training to share knowledge and experience with the industry, providing an excellent example for other regulators to follow. Based on these examples, the industry in China will look to NMPA to help guide and create similar tools for effective implementation.15
In July 2021, Health Canada (HC) released an updated draft guidance for its Post-Notice of Compliance (NOC) Changes and solicited public comments. The draft presents new guidance on what information should be submitted to HC to set ECs and proposed reporting categories, and requirements for PACMPs.16 As part of HC's implementation of ICH's Q12 guideline, HC announced a pilot program that is specifically seeking applications and supplemental applications for biologics and pharmaceuticals that will use ECs and PACMPs.17 HC is expected to have full implementation of ICH Q12 by late 2022.18
It is anticipated that even after full implementation of ICH Q12 in each region, varied health authority interpretations of the regulatory tools could lead to divergence in the approved ECs across jurisdictions, as different ECs and proposed reporting categories might be approved. Disagreement on ECs and their reporting categories could result in extended negotiations, potentially delaying review times.19 ICH has developed additional training materials for ICH Q12 to benefit both the industry and regulators. In the future, more guidance and experiences gained through participation in pilot programs, such as the FDA EC pilot, may be necessary to clarify some of the ambiguity in identifying ECs.17 Recent engagements between industry leads and health authorities have highlighted the value of using a standardized approach for the regulatory tools in ICH Q12.10 However, the long-term expectation is that the use of ICH Q12 and ECs will decrease the need for postapproval filings and regulatory agency interactions.20 ,21
1 a b Hoath, C., L. Chang, K. Ramalingam Iyer, J. Kutza, S. Murray, H. Smith, and R. Payne. "Postapproval Changes for Biopharmaceutical Drug-Substance and Drug-Product Manufacture: Regulatory Complexity and Impact." BioProcess International 14 (2016): 38–43. https://bioprocessintl.com/business/regulatory-affairs/postapproval-changes-biopharmaceutical-drug-substance-drug-product-manufacture-regulatory-complexity-impact/
2 a b c Algorri, M., N. S. Cauchon, and M. J. Abernathy. "Transitioning Chemistry, Manufacturing, and Controls Content With a Structured Data Management Solution: Streamlining Regulatory Submissions." Journal of Pharmaceutical Sciences 109 (2020):1427–1438.
3 a b International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. "ICH Harmonised Guideline Q12: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management." Published November 2019. https://database.ich.org/sites/default/files/Q12_Guideline_Step4_2019_1119.pdf
4 a b International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. "ICH Harmonised Guideline Q12 Annexes: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management." Published November 2019. https://database.ich.org/sites/default/files/Q12_Annexes_Step4_2019_1119.pdf
5Ahluwalia, K., M. J. Abernathy, J. Beierle, N. S. Cauchon, D. Cronin, S. Gaiki, A. Lennard, P. Mady, M. McGorry, K. Sugrue-Richards, and G. Xue. "The Future of CMC Regulatory Submissions: Streamlining Activities Using Structured Content and Data Management." Journal of Pharmaceutical Sciences (2021). doi:10.1016/j.xphs.2021.09.046
6 a b Accumulus Synergy. (2020). Accumulus Synergy White Paper. https://www.accumulus.org/wp-content/uploads/2021/06/Accumulus_Synergy_White_Paper.pdf
7 a b EMA/CHMP/ICH. "Note on EU Implementation of ICH Q12." (2020). https://www.ema.europa.eu/en/documents/other/note-eu-implementation-ich-q12-guideline-technical-regulatory-considerations-pharmaceutical-product_en.pdf
8International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. "Final Business Plan Q12: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management." Published July 2014. https://database.ich.org/sites/default/files/Q12%20Buisness%20Plan.pdf
10 a b c d Lo Surdo, J., N. S. Cauchon, C. Langer, S. Ramdas, and E. Zavialov. "A Vision for ICH Q12: Current Experience, Future Perspectives." Pharmaceutical Engineering 41, no. 5 (2021). https://ispe.org/pharmaceutical-engineering/september-october-2021/vision-ich-q12-current-experience-future
9US Food and Drug Administration. "Draft Guidance for Industry. ICH Q12: Implementation Considerations for FDA-Regulated Products Guidance for Industry." May 2021. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/ich-q12-implementation-considerations-fda-regulated-products
11European Medicines Agency. Committee for Medicinal Products for Human Use. "ICH Guidelines Q12 on Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management: Step 5." Published March 2020. https://www.ema.europa.eu/en/documents/scientific-guideline/ich-guideline-q12-technical-regulatory-considerations-pharmaceutical-product-lifecycle-management_en.pdf
12European Medicines Agency. Committee for Medicinal Products for Human Use. "ICH Guideline Q12 on Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management—Annexes: Step 5." Published March 2020. https://www.ema.europa.eu/en/documents/scientific-guideline/ich-guideline-q12-technical-regulatory-considerations-pharmaceutical-product-lifecycle-management_en-0.pdf
13Edwards, J., J. Kutza, M. Frazier, I. Markovic, E. Lacana, D. Macheras, and K. Wolfram. "Change Happens: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management." BioProcess International 15 (September 2017):24–47. https://bioprocessintl.com/wp-content/uploads/2017/09/BPI-15-8-CMCForum.pdf
14Pharmaceutical Safety and Environmental Health Bureau. Pharmaceutical Evaluation Division. "Handling Applications for Confirmation of Post-Approval Changes for Medicinal Products, etc." Published 23 March 2021. PSEHB/PED Notification No. 0616/14.
15Zhang, F. "Implementation of ICH Q12 for Post-Approval CMC Changes in China." Meeting Highlights: DIA China 2021. Accessed 7 September 2021. https://globalforum.diaglobal.org/issue/august-2021/implementation-of-ich-q12-for-post-approval-cmc-changes-in-china/
16Health Canada. "Post-Notice of Compliance (NOC) Changes: Quality Document–Guidance for Human Pharmaceuticals Draft Guidance." (2021). Accessed 11 November 2021. https://www.canada.ca/en/health-canada/programs/release-draft-revised-guidance-documents-post-notice-compliance-changes-quality.html
17 a b Health Canada. "Notice: Update on Health Canada's Implementation of ICH's Q12 Guideline and Pilot Programs." (2021). Accessed 11 November 2021. https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/applications-submissions/guidance-documents/international-conference-harmonisation/quality/notice-update-implementation-q12-guideline-pilot-programs.html
18Hamel, H. "Health Canada Implementation of ICH Q12: CMC Changes." CASSS CMC Strategy Forum. December 2020.
19Cauchon, N. S. and J. Beierle. "Leveraging Innovation to Streamline Chemistry, Manufacturing and Controls (CMC) Content and Data in Regulatory Submissions." ISPE India Best Practices Webinars. October 2020.
20Zavialov, E., A. V. Thomas, S. Ramdas, T. Ocheltree, and C. Langer. "ICH Q12: A Transformational Product Life-Cycle Management Guideline." Pharmaceutical Engineering 40, no. 3 (2020). https://ispe.org/pharmaceutical-engineering/may-june-2020/ich-q12-transformational-product-life-cycle-management
21Chang, A. "Progress on the Global Adoption and Implementation of ICH Q12." 2021 ISPE Annual Meeting & Expo. October 2021.
Implications for Existing Processes
Delays in global approvals experienced due to lengthy CMC postapproval regulatory processes can be traced to two factors: challenges with dossier preparation and challenges with data. These challenges exist because of outdated regulatory systems and the inability to leverage state-of-the-art technology for exchange of information such as data and narratives. Collectively, challenges such as the spread of data across multiple document sections, regional differences, staggered filing timelines across markets, and the immense volume of data locked in PDF format contribute to the high burden and redundancies in postapproval regulatory submissions. The accumulation of these redundancies contributes to delays in implementation of necessary post-approval CMC changes and discourages innovation.
The current CMC authoring process for a regulatory dossier requires writing, reviewing, verifying, and approving multiple sections and subsections within Modules 1, 2, and 3 (Figures 1 and 2). This information is often spread across separate documents within a section of the module and must be manually entered, often in multiple places, before reverifying data and reapproving. This arduous compilation process limits the ability to compare data collected for different products and submissions. In addition, if the information provided by the sponsor requires updates or is sent to different regulators, it must be manually updated and reverified in each document in which it appears, as information is not conveniently linked across documents to enable real-time editing (Figure 1). As a result, multiple regional variants of each document must be maintained and robust tracking efforts are required to ensure that each health authority receives accurate and updated information.2
It is similarly challenging for health authorities to provide consistent product feedback, as accessing sources, documenting prior decision-making, and review documents may also require manual work. Thus, the current submission and review process must transition from managing documents to managing data to address these challenges, remove unnecessary labor and repetition, and create more time for scientific rationale and risk-benefit analysis.5
Numerous steps are involved in the authoring process, with the integration of ECs into the process. The postapproval change authoring process involves many stages of writing, review, and verification for large amounts of data. SCDM implementation can potentially assist with streamlining the development and verification of data necessary for these regulatory submissions.
SCDM provides the framework for authoring human- and machine-readable content by enabling an enhanced review, organization, and standardization of electronic narrative and data, allowing uniformity of approved information across documents.5 Data automation with SCDM can potentially reduce errors and increase the accuracy of data across submissions. SCDM systems could improve the efficiency and quality of regulatory documents by establishing a standardized authoring process, mitigating risks, and decreasing time to implementation. Once the SCDM system is capable of this level of real-time data automation, the flow of existing data to finalized documents that are ready for health authority review can be established. Ideally, data and information from multiple regions could be submitted simultaneously, available for all regulatory bodies to access and review as required, thereby allowing regulators to communicate with each other and see previous questions and decisions of other regulatory bodies.
Substantial resources are required to develop and implement these advanced SCDM solutions, which has been a barrier to becoming the industry standard. SCDM could be especially useful for CMC data as it allows for creating, capturing, and reusing component information as product development progresses. Coupling the integration of ECs with the design and implementation of SCDM may increase postapproval process efficiency and enable some authoring automation. It would also ensure the ECs—which can be captured in multiple different CTD sections including Module 3 sections, Module 2 sections, and the PLCM document—are aligned. 2 ,3
SCDM systems could improve the efficiency and quality of regulatory documents by establishing a standardized authoring process, mitigating risks, and decreasing time to implementation.
Case Study 1: Potency Assay Change
Assessing potency of a drug product is a critical quality attribute of biological therapeutics.22 Frequently, potency assays for biologics are in vitro cell-based and have complicated mechanisms of action intended to parallel that expected in vivo. Though powerful tools, cell-based bioassays can be challenging and may require remediation to increase robustness and operational need (e.g., risk mitigation of critical reagents/instruments). It is a complex task to implement a modification to a potency assay across different regions as prior regulatory approval would typically be required.
In this case study, a company is interested in optimizing a potency assay for a therapeutic monoclonal antibody approved in 50 countries to decrease the rate of invalid test results. As part of the change management process, personnel must manually find, view, and interpret the older data sets to establish a frame of reference for completing method validation exercises and compare the initial and optimized assays. Following data collection, the authoring and submission process begins as described in Figure 2, which could take a minimum of three months to complete. Testing with both potency assay methods, pre- and post-change, is necessary to gain approval from health authorities, resulting in two sets of data to be collected and submitted to each health authority.
As the product has an extensive global footprint, full approval for the change across all jurisdictions could take as long as five to six years. During this time, duplicate testing with both potency assay methods would be necessary, resulting in a significant cost burden to the sponsor. Incorporating ECs into this case study, when agreed upon with the regulator, can potentially lower the reporting category of the change, thereby reducing the timeline for approval (Figure 3). The use of a PACMP may be another option where similar timelines may be achieved. As a result, in this example, the applicant might implement the new potency assay method after 30 days for the US (CBE-30) and report the change to global health authorities afterwards in a more structured timeframe. Providing data in a usable SCDM format through a cloud-based ecosystem would have the potential to enhance data analysis, further improve global filing and review efficiencies, and shorten the overall time to global approval.
2 a b
22International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. "ICH Harmonised Tripartite Guideline; Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products Q6B." Published 10 March 1999. https://database.ich.org/sites/default/files/Q6B%20Guideline.pdf
The first row of the timeline (white) displays the approach taken without incorporating ECs or SCDM. The second row (blue) demonstrates how the use of ECs can lower the reporting category. The third row (green) demonstrates the shortened time to global approval that can be achieved by incorporating both ECs and SCDM.
Additional efficiencies and further reduction in time to global approval are possible by leveraging a cloud-based filing and review platform (fourth row, yellow).10 For example, two large data sets could be automatically imported into regulatory documents without manually transcribing and locking data in PDF format. The use of ECs can streamline the postapproval process by potentially reducing the reporting category of the change, while SCDM may increase the efficiency and automation of document generation for submission to multiple countries. The use of both ECs and SCDM could thus shorten the timeline for global change approval and implementation.
Case Study 2: Alternate Sterile Filter to Address Shortage
Filter shortages across the industry due to the COVID-19 pandemic are driving the need to rapidly qualify new filters from alternate vendors. All filters used in the manufacture of a product must be characterized by the pharmaceutical quality system (PQS). The characterization data need to demonstrate that the filters are equivalent, with no impact to bacterial retention, product binding, or the extractables/leachable risk profile.
According to existing guidance, prior approval is required to implement an alternate filter in most markets. Due to varying regulations and long approval timelines, global implementation of an alternate filter may lead to delays in implementation, and potentially lead to drug shortages.
Due to the nature of the change and potential impact to product quality, and per a sponsor's internal PQS, process validation data are required to support a filter change. In this case study, the sponsor submits a PACMP to a health authority. The PACMP contains small-scale characterization data for the alternate filter, with a commitment to provide at-scale data in subsequent annual reports. The filter validation acceptance criteria are ECs in the previously approved PLCM.
In this scenario, if the sponsor has an approved global PLCM document describing the ECs with a reduced reporting category, the time required to implement the alternate filter can be reduced. Identical submissions are created with the same viral filter load in-process controls (IPCs) and submitted to all regions with a reduced filing category and overall implementation timeline. However, information requests from various health authorities invariably lead to additional country-specific variants containing different acceptable ranges for viral filter load IPC, thus creating multiple variants of Module 3 sections and PLCM documents.
The use of SCDM in this case study could allow data from previous filter characterization studies, including cleaning validation, viral clearance, and extractables/leachables to be better tracked to improve efficiency of the authoring process. Filing preparation would be simplified, as data would not have to be manually transcribed and verified, saving on submission authoring time. When information requests from various health authorities are received, filing automation would allow efficient updates to Module 2, Module 3, and the PLCM document. Thus, use of ECs together with incorporation of SCDM concepts would shorten the timeline for change implementation, thus de-risking potential impact on patient supply.
Case Study 3: Trypsin Reagent Replacement for Peptide Map Method
Routine method revisions enhance method performance and mitigate critical reagent supply. In this theoretical case study, the sponsor must replace the trypsin reagent used in the peptide map method due to a raw material shortage. The sponsor is required to evaluate an alternate manufacturer for trypsin and to characterize the new trypsin (from the same source),23 which is then qualified, confirmed equivalent to the previous trypsin, and deemed acceptable for use. Execution of the peptide map method does not change in response to the new trypsin that is filed globally; however, some regions may require prior approval to implement this change. The sponsor incurs unnecessary expenditures by making this change because they must run peptide map testing twice, using both the old and the new trypsin, until global implementation of the change can be achieved. The sponsor also runs the risk of running out of stock of the currently approved trypsin, potentially leading to a supply risk in countries where the change has not been approved.
Using ICH Q12 principles, the peptide map method would be filed with an accompanying PLCM document in which any low-risk change to raw materials in a method is defined as an EC with a "notification low" reporting category, meaning the change would not require approval or notification prior to implementation. The required qualification data justifies the lower reporting category. With prior regulator agreement, this method reagent change can then be implemented as a notification low/annual reportable change with reduced reporting categories worldwide. The sponsor can implement the new trypsin immediately in drug substance/drug product (DS/DP) release testing with one peptide map method, eliminating costs associated with redundant testing. The old method can be replaced immediately, and duplicate testing would not be required.
However, the sponsor is still required to author the submission and submit the data for the peptide map raw material change to each region. As described earlier, creation of individual submissions for each region, including country-specific variants, is a resource-intensive process. The overall time required to author and submit the trypsin reagent change could be reduced by leveraging both ICH Q12 tools as well as SCDM and authoring automation.
23International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. "Concept Paper M4Q(R2) Common Technical Document on Quality Guideline." Published 15 November 2021. https://database.ich.org/sites/default/files/ICH_M4Q-R2_ConceptPaper_Endorsed_2021_1115.pdf
Use of ICH Q12 methodology would lower the reporting requirements, allowing for quicker implementation of the change. SCDM would decrease resources and time needed to manually transcribe and verify data in a CTD section. SCDM would also allow for rapid exchange of additional data if health authority reviewers needed it to support review.
During the COVID-19 pandemic, it has become apparent that the pharmaceutical industry can rapidly adapt in response to public health emergencies. The fragile nature of the pharmaceutical supply chain became apparent, demonstrating the need for manufacturing flexibility for existing products. The rapid transition between clinical studies to emergency use authorization, and then to the world's first fully approved vaccine in under two years, highlights the potential of biopharmaceutical companies and health authorities. On the basis of medical need, science-driven risk, and the need for manufacturing flexibility and efficiency, similar acceleration of regulatory approvals could potentially be achieved for any life-saving medication. The technology now exists for information and data exchange within the postapproval space to match the speed of product drug development and innovation.
To meet the challenges in the existing CMC regulatory landscape, standardization and harmonization of ICH Q12 regulatory tools across different regions (including non-ICH regions) would be needed. In addition, significant regulatory reform, and modernization, including digitalization and digitization, would be necessary to achieve a single standardized global submission. At the FDA, the Technology Modernization Action Plan (TMAP) and the Data Modernization Action Plan (DMAP) aim to modernize its digital infrastructure.24 The FDA has recently announced the reorganization of the agency's information technology (IT), data management, and cybersecurity functions into the new Office of Digital Transformation (ODT). The ODT allows more effective data management to streamline operations by reducing duplicative processes and implementing technological efficiencies.25
The flowchart in Figure 4 shows the overlap and proposed workflow after both the sponsor and the health authority implement ECs; SCDM; identified and mapped data parameters based upon FDA PQ/CMC (pharmaceutical quality/chemistry, manufacturing, and control) information; and universal standards, such as International Organization for Standardization (ISO) Identification of Medicinal Products (IDMP) and Health Level 7 (HL7) standards.
With the implementation of ECs and SCDM, sponsors could standardize and simplify their internal documentation while maintaining alignment with the externally standardized regulatory requirements. In that case, data and information can be further coded and standardized into an online, cloud-based data exchange platform that can facilitate automatic updates.26 ,27 ,28
The FDA's Center for Biologics Evaluation and Research (CBER)/Center for Drug Evaluation and Research (CDER) Data Standards Plan is an ongoing project that aims to map PQ/CMC data elements, standardizing application content to facilitate efficient risk-based reviews by linking data and common categories and elements across various application types. A secondary goal of this project is to provide recommendations for standardization of the categories and elements necessary for application review. Where corresponding data elements exist, the identified PQ/CMC data parameters overlap and, in some instances, directly align with the substance and product identifiers described by the ISO IDMP standards (Figure 4). After the identification and standardized mapping of these data parameters, they are submitted to the ICH CTD.24 ,29 The longer term goals of this project are to increasingly replace dossiers with structured content and data supporting dossier variations with more efficient online database updates.28
The need for a more templated and structured approach to the sections within Module 3 is clear. Revision of ICH M4Q has commenced with endorsement of the concept paper in November 2021, to be followed by an ICH topic proposal on structured product quality submissions.23 Both ECs and SCDM facilitate standardized language across regions, and this language can align with mapped data parameters using PQ/CMC, ISO IDMP, and HL7 standards and Fast Healthcare Interoperability Resources (FHIR) artifacts. The collaboration between these tools can allow sponsors to store structured information to potentially be used as a single global submission that is consistent, reproducible, and easily accessible by health authorities across different regions.24 ,29 ,30
To achieve the goal of a single global submission, up-to-date information must be exchanged seamlessly between sponsors and regulators. Accumulus Synergy, a nonprofit sponsored by leading biopharmaceutical companies, is developing a cloud-based platform intended to facilitate real-time data exchange and review in a worldwide setting. The platform under development proposes locked and shared spaces in the cloud, allowing both sponsors and regulators to work and communicate with each other across portals and protected by firewalls. Sponsors could use SCDM systems to automate the compilation of data and electronic narrative and push this information to the Accumulus cloud to facilitate efficient data exchange, collaboration, and parallel reviews, thus improving the submission and review process.
In addition to ease of access and exchange of information, reviewing regulatory submissions in parallel can reduce the total time to approval for a drug product in multiple regions. Providing a platform by which data can be exchanged in usable format enables more efficient filing processing and improved assessment capabilities. Once the principles of data exchange automation are established, they can be extended to clinical, preclinical, and summary data.6
There is a perception that once a product is commercialized, or a marketing application is approved, that the work associated with product filings is complete. On the contrary, the work is essentially only beginning from a CMC perspective because the product is optimized multiple times and in many areas over the lifetime of its commercial viability. Several challenges burden the current global regulatory submission workflow for postapproval CMC changes. There is a need for efficiency and consistency within the postapproval regulatory space to reduce the high costs, complicated surveillance of updated regulatory requirements, and management of the large volumes of data that accompany CMC changes.
The use of regulatory tools, namely ECs as described in the ICH Q12 guideline, provides a unified and flexible approach in reporting postapproval changes to health authorities, and an avenue for more efficient change implementation. Combining ECs with an SCDM system may enable automated authoring of human- and machine-readable content supporting an enhanced review, structured organization, and standardization of documents submitted to health authorities in line with the PCLM. With the varying interpretation of the ICH Q12 guideline by sponsors and health authorities, efforts must be made to enhance standardization and harmonization. As a complement to the initiatives taken by the FDA, SCDM could be an efficient solution to address challenges in the current CMC regulatory submission and review process. Combining the benefits of ICH Q12 and SCDM with a cloud-based filing and review ecosystem could propel the pharmaceutical industry digitally forward to deliver therapies more effectively and efficiently to patients around the world in a timelier manner. These concepts and platforms can subsequently be leveraged to expand beyond CMC data and attain a single global regulatory submission for new drug applications including non-clinical, clinical, and safety modules.
Reader note: This article was initially submitted to Pharmaceutical Engineering® during December 2021/January 2022.
24 a b c US Food and Drug Administration. Center for Biologics Evaluation and Research. Center for Drug Evaluation and Research. "Data Standards Strategy FY2018-FY2022." Published January 2018. https://www.fda.gov/media/110928/download
25US Food and Drug Administration News Release. "FDA Advances Data, IT Modernization Efforts with New Office of Digital Transformation." Published 15 September 2021. https://www.fda.gov/news-events/press-announcements/fda-advances-data-it-modernization-efforts-new-office-digital-transformation?utm_medium=email&utm_source=govdelivery
26Tschorn, U. "HL7–Health Level Seven." (2015). Accessed 14 September 2021. https://www.idmp1.com/wiki/hl7
27Tschorn, U. "IDMP Definition of Identification of Medicinal Products." (2015). Accessed 14 September 2021. https://www.idmp1.com/wiki/idmp-definition/
28 a b Tschorn, U. "How FDA Intends to Introduce IDMP Through the Backdoor." (2017). Accessed 14 September 2021.https://www.idmp1.com/how-fda-intends-to-introduce-idmp-through-the-backdoor/
29 a b Federal Register. US Food and Drug Administration. "Pharmaceutical Quality/Chemistry Manufacturing and Controls (PQ/CMC) Data Elements and Terminologies." Published July 2017. https://www.govinfo.gov/content/pkg/FR-2017-07-11/pdf/2017-14456.pdf
30US Food and Drug Administration. "Data Standards Program Action Plan." Published August 2021. https://www.fda.gov/media/151833/download
The authors acknowledge Rita Algorri and Andrew Lennard for providing comments on the manuscript.
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Post-Doctoral Regulatory Affairs Fellow
Jackie Gavin, PharmD, completed her Doctor of Pharmacy at the University of Texas at Austin College of Pharmacy. She was accepted into the Rutgers Pharmaceutical...
Regulatory Affairs Senior Manager
Jessica Lo Surdo, PhD, is a Regulatory Affairs Senior Manager at Amgen, Inc., focusing on CMC strategies for global clinical trial applications and postapproval variations...
Director Regulatory Affairs - CMC
Nina S. Cauchon, Ph.D. is Director Regulatory Affairs CMC at Amgen Inc in Thousand Oaks, CA, and leads RA-CMC Advocacy and External Engagement. She has...
Director in Regulatory Affairs-CMC
Tabetha M. Bonacci, PhD, is a Director in Regulatory Affairs-CMC at Amgen, Inc. She co-leads the Lifecycle Management group overseeing regulatory strategy and submissions for...
Executive Director, Leads
Michael J. Abernathy, Executive Director, leads Amgen's Global RA CMC function and is accountable for more than 65 staff globally and a product portfolio of...
Using Technology for Continuous Process Verification 4.0
In this article, potential Pharma 4.0™ technological solutions that can enhance continuous process verification (CPV) 4.0 are discussed. The necessary paradigm shift will allow companies to predict deviations more accurately, perform root cause analysis (RCA), ensure data integrity and GxP compliance, and ultimately be more competitive in a highly regulated industry.
What You Need to Know About GAMP® 5 Guide, 2nd Edition
ISPE's GAMP® 5: A Risk-Based Approach to Compliant GxP Computerized Systems (Second Edition) (GAMP® 5 Guide, 2nd Edition) maintains the principles and framework of the first edition and updates their application in the modern world, including the increased importance of service providers, evolving approaches to software development, and expanded use of software tools and...
The Road to Explainable AI in GXP-Regulated Areas
Recent advances in artificial intelligence (AI) have led to its widespread industrial adoption, with machine learning (ML) algorithms demonstrating advances in performance in a wide range of tasks. However, this comes with an ever-increasing complexity of the algorithms used, rendering such systems more difficult to explain.1
1Samek, W., and K. R. Müller. "Towards Explainable...


Subiaco Restoration ( Subi Rest ) has built a solid reputation as one of WA's foremost suppliers and manufacturers of high quality products and architectural building materials including timber, joining, decking,flooring, fireplaces, hardware and lighting.
Gro Agencies proudly offer one of the best selection centres in Perth, where you can completely fit out your house with the finest in European product from toilets to accessories to the kitchen sink.
Founded on the principles of design, quality and customer service, Phoenix has been producing innovative tapware, showers and bathroom accessories since 1989.


Masters Degree is a Post Graduate Degree in any discipline, be it Science, Arts and Humanities or Commerce. The duration of a Masters Degree program ranges between 2 – 6 years in the different countries. Generally one is eligible to enrol into a Masters Degree on the completion of the Bachelors degree that is also known as Graduate programs in many countries. Universities of the world award a Masters Degree to the students on the completion of the duration and on the success of the exams concerning the same.
Masters Degree is called by different names and abbreviations in the different countries of the world. In several countries a Masters degree is also called as a 'Magister Degree' especially in the countries that uses Latin. A Magister Degree in Science is abbreviated to SM (Scientiee Magister) and that in the realm of arts is called as AM (Artium Magister). In other countries especially in the commonwealth nations and Europe a Masters Degree in Science is abbreviated to M Sc and that of the Arts is known as M A (Master of Arts) and that of commerce is abbreviated to M Com (Master of Commerce).
Masters Degree in Europe: The Bologna process, a standardized process is followed in Europe that mentions categorically that a 3 year bachelor degree is followed by a 2 year Master Degree or Diploma before a student can enrol himself/ herself for a doctoral degree. Popular Universities in Europe offering Masters Degree are: Oxford University, University of Cambridge and University of Dublin.
Masters Degree in America: In America too a student is eligible to enrol himself in to a Master degree program on the completion of his / her Bachelors Degree. Some of the reputed universities offering Masters Degree program are: University of Phoenix, American InterContinental University, Boston University and Harvard University.


text:
Leadership ›
James Versalovic, MD, PhD
Baylor Partnership
Legendary Care
Community Benefit Efforts
Pathologist-in-Chief
Dr. Versalovic serves as Pathologist-In-Chief at Texas Children's Hospital and Director of Texas Children's Microbiome Center. He is the Milton J. Finegold Professor and Vice Chair of Pathology & Immunology at Baylor College of Medicine. He also is Professor of Molecular and Human Genetics, Molecular Virology & Microbiology, and Pediatrics, and Co-Director of the Medical Scientist (MD/PhD) Training Program at Baylor College of Medicine.
Dr. James Versalovic received his M.D. with Honors at Baylor College of Medicine (BCM) in 1995 and his Ph.D. in Cellular and Molecular Biology at BCM in 1994. He pursued clinical pathology/medical microbiology residency training at the Massachusetts General Hospital and Harvard Medical School. He also completed a postdoctoral research fellowship in the Division of Comparative Medicine at the Massachusetts Institute of Technology (MIT). Dr. Versalovic joined the medical staff as a clinical pathologist at the Massachusetts General Hospital and served as Assistant Professor of Pathology at Harvard Medical School. He is board-certified in clinical pathology, molecular genetic pathology, and molecular diagnostics.
Dr. Versalovic directs the delivery of diagnostic services and laboratory medicine at Texas Children's by serving as Director of Laboratories, for the medical center campus. Dr. Versalovic's main clinical interests are medical microbiology, molecular diagnostics of infectious diseases, microbiome science applies to pediatric gastroenterology, genomic and metagenomic medicine, and molecular pathology. Dr. Versalovic has created the first microbiome center based in a children's hospital and the first therapeutic microbiology fellowship program in the country. He has helped create the new field of metagenomic medicine by exploring ways that metagenomics and microbial manipulation can be used to diagnose and treat human diseases. He served as Editor-in-Chief of the Manual of Clinical Microbiology, the "bible" of laboratory-based diagnosis of human infections.
As Principal Investigator since 1999, Dr. Versalovic's primary research areas include gastrointestinal microbiology, the human gastrointestinal microbiome and mechanisms of signaling between the microbiome and human cells. With a focus on the gastrointestinal microbiome, beneficial microbes and chronic disease, Dr. Versalovic's research team has studied mouse models and human subjects/patients to understand basic concepts of microbiome science, human microbiology, and how the microbiome impacts human development and children's health. Dr. Versalovic is advancing metagenomic medicine and its applications in chronic gastrointestinal disorders such as pediatric irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). His research program has been supported by the U.S. National Institutes of Health, Department of Defense, and Crohn's and Colitis Foundation of America. Dr. Versalovic has authored more than 135 primary manuscripts, more than 30 book chapters, and 2 patents.
Dr. Versalovic has received several notable awards including the Lansky Award as a national leader in pathology under the age of 45 from the College of American Pathologists Foundation. He also received the BioGaia Ivan Casas Probiotics Research Award (2007) and the BCM Graduate School of Biomedical Sciences Distinguished Alumnus Award (2010).

redpajama_set_name: RedPajamaCommonCrawl


The Louvre (Paris, France), The Prado Museum in Madrid (Madrid, Spain), The Art Institute of Chicago (Chicago, USA), The Orsay Museum (Paris, France), Metropolitan Museum of Art (New York, USA) | 17 Most Interesting Museums In The World According to Seasoned Travelers!
Try to unravel the smile of "Mona Lisa" through the lens of the smartphone - a sacred duty of every Paris visitor. To do this, have a look at the most popular art museum in the world. However, before a meeting with the paintings of Leonardo da Vinci, you will take a picture near a glass pyramid, a main entrance to the Louvre.
Along with vibrant artwork belonging to the masters of the Flemish, English, German and French schools, a museum, of course, keeps a rich collection of paintings by Spanish artists. Fans of El Greco, Velázquez and Goya will be delighted.
Museum is also a supreme art institution, where such creators as Walt Disney have been educated. Of course, among of the many exhibits there are a lot of American artworks.
The museum collection is housed in a former train station. In addition to the rich set of works of the Impressionists and post-Impressionists, here visitors can enjoy wonderful views of the Seine in Paris.
In the "Big Apple" there is no place for an apple to fall, and additionally there are millions of visitors are running from one sights of the city to the other in order to review it speedy. However, it won't work with the Metropolitan Museum: even a cursory acquaintance with the part of the exhibits will take many hours.
Next: Top 9 Terrible Numbers From Around the World!


text:
/* DO NOT EDIT! GENERATED AUTOMATICALLY! */

#line 1 "html-styled-ostream.oo.h"
/* Output stream for CSS styled text, producing HTML output.
   Copyright (C) 2006 Free Software Foundation, Inc.
   Written by Bruno Haible <bruno@clisp.org>, 2006.

   This program is free software: you can redistribute it and/or modify
   it under the terms of the GNU General Public License as published by
   the Free Software Foundation; either version 3 of the License, or
   (at your option) any later version.

   This program is distributed in the hope that it will be useful,
   but WITHOUT ANY WARRANTY; without even the implied warranty of
   MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE.  See the
   GNU General Public License for more details.

   You should have received a copy of the GNU General Public License
   along with this program.  If not, see <http://www.gnu.org/licenses/>.  */

#ifndef _HTML_STYLED_OSTREAM_H
#define _HTML_STYLED_OSTREAM_H

#include "styled-ostream.h"

#line 28 "html-styled-ostream.h"
struct html_styled_ostream_representation;
/* html_styled_ostream_t is defined as a pointer to struct html_styled_ostream_representation.
   In C++ mode, we use a smart pointer class.
   In C mode, we have no other choice than a typedef to the root class type.  */
#if IS_CPLUSPLUS
struct html_styled_ostream_t
{
private:
  struct html_styled_ostream_representation *_pointer;
public:
  html_styled_ostream_t () : _pointer (NULL) {}
  html_styled_ostream_t (struct html_styled_ostream_representation *pointer) : _pointer (pointer) {}
  struct html_styled_ostream_representation * operator -> () { return _pointer; }
  operator struct html_styled_ostream_representation * () { return _pointer; }
  operator struct any_ostream_representation * () { return (struct any_ostream_representation *) _pointer; }
  operator struct styled_ostream_representation * () { return (struct styled_ostream_representation *) _pointer; }
  operator void * () { return _pointer; }
  bool operator == (const void *p) { return _pointer == p; }
  bool operator != (const void *p) { return _pointer != p; }
  operator ostream_t () { return (ostream_t) (struct any_ostream_representation *) _pointer; }
  explicit html_styled_ostream_t (ostream_t x) : _pointer ((struct html_styled_ostream_representation *) (void *) x) {}
  operator styled_ostream_t () { return (styled_ostream_t) (struct styled_ostream_representation *) _pointer; }
  explicit html_styled_ostream_t (styled_ostream_t x) : _pointer ((struct html_styled_ostream_representation *) (void *) x) {}
};
#else
typedef styled_ostream_t html_styled_ostream_t;
#endif

/* Functions that invoke the methods.  */
extern        void html_styled_ostream_write_mem (html_styled_ostream_t first_arg, const void *data, size_t len);
extern         void html_styled_ostream_flush (html_styled_ostream_t first_arg);
extern         void html_styled_ostream_free (html_styled_ostream_t first_arg);
extern          void html_styled_ostream_begin_use_class (html_styled_ostream_t first_arg, const char *classname);
extern          void html_styled_ostream_end_use_class (html_styled_ostream_t first_arg, const char *classname);

/* Type representing an implementation of html_styled_ostream_t.  */
struct html_styled_ostream_implementation
{
  const typeinfo_t * const *superclasses;
  size_t superclasses_length;
  size_t instance_size;
#define THIS_ARG html_styled_ostream_t first_arg
#include "html_styled_ostream.vt.h"
#undef THIS_ARG
};

/* Public portion of the object pointed to by a html_styled_ostream_t.  */
struct html_styled_ostream_representation_header
{
  const struct html_styled_ostream_implementation *vtable;
};

#if HAVE_INLINE

/* Define the functions that invoke the methods as inline accesses to
   the html_styled_ostream_implementation.
   Use #define to avoid a warning because of extern vs. static.  */

# define html_styled_ostream_write_mem html_styled_ostream_write_mem_inline
static inline void
html_styled_ostream_write_mem (html_styled_ostream_t first_arg, const void *data, size_t len)
{
  const struct html_styled_ostream_implementation *vtable =
    ((struct html_styled_ostream_representation_header *) (struct html_styled_ostream_representation *) first_arg)->vtable;
  vtable->write_mem (first_arg,data,len);
}

# define html_styled_ostream_flush html_styled_ostream_flush_inline
static inline void
html_styled_ostream_flush (html_styled_ostream_t first_arg)
{
  const struct html_styled_ostream_implementation *vtable =
    ((struct html_styled_ostream_representation_header *) (struct html_styled_ostream_representation *) first_arg)->vtable;
  vtable->flush (first_arg);
}

# define html_styled_ostream_free html_styled_ostream_free_inline
static inline void
html_styled_ostream_free (html_styled_ostream_t first_arg)
{
  const struct html_styled_ostream_implementation *vtable =
    ((struct html_styled_ostream_representation_header *) (struct html_styled_ostream_representation *) first_arg)->vtable;
  vtable->free (first_arg);
}

# define html_styled_ostream_begin_use_class html_styled_ostream_begin_use_class_inline
static inline void
html_styled_ostream_begin_use_class (html_styled_ostream_t first_arg, const char *classname)
{
  const struct html_styled_ostream_implementation *vtable =
    ((struct html_styled_ostream_representation_header *) (struct html_styled_ostream_representation *) first_arg)->vtable;
  vtable->begin_use_class (first_arg,classname);
}

# define html_styled_ostream_end_use_class html_styled_ostream_end_use_class_inline
static inline void
html_styled_ostream_end_use_class (html_styled_ostream_t first_arg, const char *classname)
{
  const struct html_styled_ostream_implementation *vtable =
    ((struct html_styled_ostream_representation_header *) (struct html_styled_ostream_representation *) first_arg)->vtable;
  vtable->end_use_class (first_arg,classname);
}

#endif

extern const typeinfo_t html_styled_ostream_typeinfo;
#define html_styled_ostream_SUPERCLASSES &html_styled_ostream_typeinfo, styled_ostream_SUPERCLASSES
#define html_styled_ostream_SUPERCLASSES_LENGTH (1 + styled_ostream_SUPERCLASSES_LENGTH)

extern const struct html_styled_ostream_implementation html_styled_ostream_vtable;

#line 28 "html-styled-ostream.oo.h"

#ifdef __cplusplus
extern "C" {
#endif

/* Create an output stream that takes input in the UTF-8 encoding and
   writes it in HTML form on DESTINATION, styled with the file CSS_FILENAME.
   Note that the resulting stream must be closed before DESTINATION can be
   closed.  */
extern html_styled_ostream_t
       html_styled_ostream_create (ostream_t destination,
                                   const char *css_filename);

#ifdef __cplusplus
}
#endif

#endif /* _HTML_STYLED_OSTREAM_H */

redpajama_set_name: RedPajamaGithub


Our annual youth parking lot sale begins this Friday at 3pm and continues through Saturday! Items for donation can be dropped off this week at the church. Contact Cole before you head to the church or if you have large items that you need picked up ($20 fee) at lonniecolemcgee@gmail.com.
As part of intentional discipleship this fall, we are forming groups of 3 people to meet once a week for 90 minutes to share our lives together. If you have put a group together or would like to be a part of a triad, please contact Beth Price at beth@redemptionchurchkc.com.
Our annual church BBQ is Saturday, October 8th at 5:30pm! We provide the meats, beans, cole slaw, cheesy potatoes, 'smores and fun! Please bring your lawn chairs and a side dish to share. $5 per person or $15 per family max.
Our men's retreat will be at Shalom Retreat Center (12985 County Road #1095, Mound City, KS) from Friday Oct. 21st at 6pm thru noon Saturday. Dinner and breakfast provided. Bring: Sleeping Bag, Pillow, and Bible. $30 per personContact Josh Madden at jmadden@youthfront.com if you would like to register.
Elementary age childcare help needed on Monday evenings for ESL students! NO SPANISH NEEDED! Please email Mandy Hill at andy@redemptionchurchkc.com if you can help.
Great opportunity to make a difference in our neighborhood! Youth mentors needed at Ridgeview Elementary! Youth mentors have the opportunity to eat lunch, help with math & reading, and offer support to a specific student on a weekly basis. If you would like to become a "youth mentor" at Ridgeview Elementary school, contact Mandy Hill at mandy@redemptionchurchkc.com.


The title of this post may sound a bit strange for those who have not faced this problem but it may sound a Sweet Tune Music 🙂 to those who want to resolve this nasty error in their application.
If you fall into the latter category, you can directly jump to the Solution section though everybody is definitely welcomed to read the entire post.
An error which occurs when using Enterprise Library Data Access Block in instantiating a Database using factory approach.
You may have followed the msdn article to setup DataAccessBlock with the correct code and the configuration in your application but always resulting into the error when you try to instantiate a database object.
Typically, software solutions are multi-layered. One of them being a Data Access Layer, aka DAL, which interacts with the Data Store(s) and performs the CRUD operations on the data in the data store. In this layer, you can either opt for ADO.Net or Enterprise Library Data Access Block to connect to Data Store (database) besides other options.
Since, the post is talking about a specific error resulted in the EntLib, lets assume that we preferred to implement DAL using EntLib Data Access Block.
This error occurs on the below code statement, the very first statement to perform the CRUD operation into the DataStore.
Enterprise library consists of number of classes in different namespaces and assemblies.
The above code statement is present in the former assembly. After a series of function calls in the same assembly and the latter assembly, a function in the latter assembly tries to load the former assembly using the partial name.
This is what leads to the error if the Enterprise libraries assemblies are GACed and not copied locally into the application directory.
Assembly with a partial name won't be found in the GAC and then the search/probing of an assembly will continue to Local Application Directory or sub-directories with the same name or as per configuration.
Since assembly is not present anywhere else except GAC, assembly loading will fail and leading to this error.
You can see this in action by launching Fusion Log Viewer utility, which comes by default. Command is : "fuslogvw" in case yof could not locate the utility. Type the command in the Visual Studio Command Prompt.
You may need to customize the Log Viewer to log all binding to disks to view every log.
So, is there a solution or a workaround for the above problem?
Problem can be solved in many ways, you choose what suits you the best.
Thanks to Mr. Philippe for this 2nd solution posted @ CodePlex.
activation errordata access blockdatabaseEnterprise libraryentlib 5.0key ""
Each application has it's own configuration file, be it a windows based application or web based.
This application configuration file defines information which can be used by application to make decisions, to load some other information or may contain the custom configuration which can be empowered to do anything.
There can also be scenarios where an application may want to change\modify the existing setting in the application configuration file and those changes should not only take effect immediately but should also be persisted.
APIs are available which can load and modify the configuration despite reading.
Make use of Configuration class in System.Configuration namespace.
And, finally refresh the Configuration Section by calling RefreshSection() so that the next read from Config file happens by reading it from disk.


Dreamy Darkness - WiKirby: it's a wiki, about Kirby!
Dreamy Darkness is the second stage of Neo Greo in Kirby: Canvas Curse. Kirby travels through this area on his quest to defeat Drawcia. Dreamy Darkness is a collection of dark stages with a similar appearance to Ghost Grounds. This stage also joins Rift Ruin by having more than three areas. Dreamy Darkness contains three hidden medals for Medal Swap purchases, and courses in Rainbow Run offer six more medals.
Keeping consistency with the name, this stage is completely dark. Only Kirby, enemies, and some objects are visible. The layout of the stage is mostly horizontal, but walls and ledges only open in staggered spots. Most of the openings are near an array of spikes on the wall. When the lanterns are not lighting the area, the spiked patches of wall are likely to be hit, as they are invisible in the darkness. Open pits are another danger lurking in the dark. Waddle Dees, Bouncies, Shotzos, and a Needle-yielding enemy can be found in this area.
With the Needle Copy Ability and some backtracking the medal for this area can be found behind blocks that can only be broken with that ability. Several Point Stars can be acquired from the middle chambers and just before the exit door.
This area appears as the Time Trial mode of Rainbow Run.
The second area is one of the smallest. Kirby begins at the lowest section. The room is divided into several floors with different enemies on each level. To reach the door, Kirby merely needs to ascend through each floor. The floors are "one-way" as backtracking to lower levels is not possible. If the Needle copy ability has been retained from the previous area, a second medal can be acquired. Blocks specifically weak against the Needle ability are on the lowest level.
This area appears as the Line Trial challenge of Rainbow Run.
This treacherous area, though small drops Kirby through nests of Gordos, spiked surfaces, and contact activated fans. Point Stars are abundant, but can be hazardous to attempt obtaining.
Another very small and dangerous area. The walls and floors are lined with electrical blocks and the space between them is very narrow. Even the Waddle Dee in the area is damaged by the blocks. This area is also dark until activating one of the lanterns. The final medal for Dreamy Darkness also rests here beneath stone blocks destroyed by a Bomb Block.
This small area again places Kirby near the top, requiring him to descend to the exit door. The area has plenty of point stars, but is also full of Gordos and clear blocks. An Energy Drink can be found just before the exit door.
This page was last edited on 15 September 2017, at 17:58.


text:
Q: Is superposition of charge possible? Maybe majorana fermions could exist but is very different from both quasi particle pair and particle hole pair, it could have both positive and negative charge in superposition until it is being measured, is this possible?

A: States with different charges cannot be superposed, because they are in different superselection sectors. This is because charge is a globally conserved quantity.
Consider two states $| \psi_+ \rangle$ and $|\psi_-\rangle$, where the first has a charge of $+1$ and the second of $-1$. Charge conservation implies that
$$\langle \psi_+ |A|\psi_-\rangle = 0$$
for all observables $A$. This means that a system initially in state $| \psi_+ \rangle$ can never be prepared into a superposition of states with $|\psi_- \rangle $, so writing down a state that is a superposition of the two would be physically meaningless.

redpajama_set_name: RedPajamaStackExchange


text:
Home>news and events>news>cryo em seminar dr wayne hendrickson violin family professor of physiology and cellular biophysics columbia university
PHOTO CREDIT: KIRA KOOP
HENDRICKSON, WAYNE A., PH.D.
UNIVERSITY PROFESSOR AND THE VIOLIN FAMILY PROFESSOR OF PHYSIOLOGY AND CELLULAR BIOPHYSICS
Dr. Wayne Hendrickson, the Violin Family Professor of Physiology and Cellular Biophysics and Professor, Department of Biochemistry and Molecular Biophysics at Columbia University will deliver a seminar on technological advances in cryo EM, part of the Manitoba Group in Protein Structure and Function Cryo-Electron Microscopy Seminar Series.
Dr. Hendrickson has made numerous seminal contributions to structural biology research and is best known for developing multi-wavelength anomalous dispersion as a tool for solving the 'phase problem', which revolutionized protein X-ray crystallography in the late 1990s. His honors include the Gairdner International Award and the Aminoff Prize of the Royal Swedish Academy of Sciences. He is a fellow of the American Academy of Arts and Sciences and a member of the National Academy of Sciences.
Dr. Hendrickson and his colleagues have recently used cryo-electron microscopy to gain unprecedented views into the molecular basis for how the massive ryanodine receptor mediates calcium release into the cytosol of the cell, which is of central importance to many cellular functions, including muscle contraction.
Please join us on Wednesday Feb 7 to hear Dr. Hendrickson describe how incredible technological advances in cryo EM allowed he and his colleagues to achieve such detailed insight into this massive protein structure.
What: Dr. Wayne Hendrickson, University Professor and the Violin Family Professor of Physiology and Cellular Biophysics, Columbia University
Topic: Structural Basis for RyR1 Calcium Release Activity
When: Wednesday, February 7, 3:30 p.m.
Where: 205 Armes, University of Manitoba, Fort Garry campus
IMAGE SOURCE: NATURE (2015) 517(7532):44-9.
The Manitoba Protein Structure Group Cryo-Electron Microscopy Series:
JORG STETEFELD
Wednesday January 31, 3:30 PM, 205 Armes
Hybrid Method Approach in Structural Biology – Future perspectives of cryo-EM at the University of Manitoba
Dr. Jörg Stetefeld
Tier I CRC in Structural Biology and Biophysics, Professor of Chemistry, University of Manitoba
DR. ANDY HOENGER
Wednesday April 18th, 3:30 PM 205 Armes
Cryo-Electron Tomography from Organelles to Macromolecular Complexes
Professor, Department of Molecular, Cellular and Developmental Biology, University of Colorado at Boulder
Research at the University of Manitoba is partially supported by funding from the Government of Canada Research Support Fund.
biological sciences campus community graduate studies International max rady college of medicine microbiology Research Chemistry
Research Projects for: CHEM4710 "Project in Chemistry 2022/2023"
Meet Sabine Kuss, 2021 Rh Award Winner in the Applied Sciences Category
Elite researchers recognized with Rh Awards
Department Seminar: Thursday 21 April, 2022


text:
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> Anders Gustafsson
Chief Executive Officer, Zebra Technologies
Views expressed on author's social media accounts do not necessarily reflect those of Zebra Technologies.
Anders Gustafsson became chief executive officer and a director of Zebra Technologies on September 4, 2007. Prior to joining Zebra, Mr. Gustafsson served as CEO of Spirent Communications plc, a publicly traded telecommunications company. At Spirent, Mr. Gustafsson redirected that company's growth strategy, divested non-core operations, integrated historic acquisitions and streamlined the organization to realize significant cost savings. Prior to Spirent, he was senior executive vice president, global business operations, of Tellabs, Inc. While at Tellabs, Mr. Gustafsson also served as president, Tellabs International, as well as president, global sales, and vice president and general manager, Europe, Middle East and Africa.
Earlier in his career, he held executive positions with Motorola and Network Equipment Technologies. Mr. Gustafsson holds a master's degree in business administration from the Harvard Graduate School of Business and a master of science degree in electrical engineering from Chalmers University of Technology in Gothenburg, Sweden. He was a Fulbright Scholar and received numerous fellowships and scholarships for academic excellence.
Most Recent Posts by Anders Gustafsson
What I Have Learned About Leadership as CEO the Past 15 Years
by Anders Gustafsson
This Is What It Was Like Ringing the Bell
Winning in 2021: Meet Some of the Customers, Partners, and Employees Who are Delivering a Performance Edge and Changing How Business is Done.
2020 May Not Have Been the Year We All Hoped for, But We Still Accomplished Remarkable Feats, Proving Just How Resilient We Can Be
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This guest post is by Daria Marmaluk-Hajioannou. An award-winning children's performer, DARIA (Daria Marmaluk-Hajioannou) has seven cd's that have won national honors. She has the most awesome job of traveling the world to sing for kids and peace. Her website; located at dariamusic.com, was given a 2009 Parents Choice Award for its musical and cultural content.
My Dad was a tall, serious fellow. Despite that fact, he often walked to the breakfast table while singing this little ditty: "Good morning to you, Good morning to you, Good morning bright sunshine, oh how do you do?". He would say that he learned the song from his first grade teacher. Despite the fact that it had been decades since he sat at a tiny desk and used chalk on a blackboard, the song still brought back happy memories. And even though it has been years since he passed away, "Good morning bright sunshine" never fails to bring a smile to my face. Such is the power of song.
How do you get a guaranteed smile from a grandparent or senior citizen? Ask them about their favorite memories from the past. How do you make a child giggle and pay attention? Share a favorite song with them. If you put these two powerful activities together, you have an unbeatable combination. Sharing music between younger and older listeners is a way to actively engage hearts and minds and create new shared memories between the generations.
So what songs are best for making this kind of musical magic? The answer is simple. Ask the grandparents or seniors themselves. I know from my musical work with elderly and Alzheimer's patients that songs they treasure and recognize most generally come from childhood memories. Sure hits are songs that they heard in school, in their neighborhood, places of worship or during special holidays. How do you find out? Ask simple questions and listen for the answers. "Did you sing songs at school?" "Did anyone sing you a lullaby at night." "What was your favorite song when you were growing up". "Did you and your siblings sing songs on the playground or on your block?" What was your favorite song for Christmas, Hanukkah, Fourth of July (etc.)? You might be surprised and delighted at the answers as you discover what music carries the most meaning to people who are special to you.
When someone is a young child or an older person, it can seem like they have fewer choices of things to do and places to go than active adults. So time spent one-on-one with a special friend or playmate can be a really treasured experience. Whether you are listening to favorite songs together, making a musical craft or making a chore or activity more enjoyable with a song, music can benefit both older and younger listeners.
And some of the older songs have great stories or questions built into them. Do you remember the song "Playmate" (lyrics below)? It talks about rain barrels, apple trees, favorite dolls and cellar doors. "What is a rain barrel" "How can you slide down a cellar door?". These are great questions that help start conversations about what life was life when the older person was young. When I sing "Grand Old Flag" I often hear the best stories about summer picnics, 4th of July celebrations and ways that communities celebrated or honored veterans. By sharing stories and songs, music can create a meaningful way for childhoods to merge and create combined family history.
Of all the things that a grandparent or relative can give a child, one of the most important is their full attention and encouragement. If you ask a child what they might be singing in school or at home, they'll usually share a song or two with great pride and put on an impromptu concert for you. Grandparents can always share fingerplays or other simple action songs such as Kumbayah or John Jacob Jingleheimer Schmidt. If motor skills or dexterity is an issue, they can ask the child to "play teacher" and demonstrate such things as how the Itsy Bitsy Spider climbs up the waterspout. Although many things may be new, difficult and unapproachable to a child, the act of making music for and with a grandparent is a place they can truly shine. Encouraging a young child, listening to them and giving them undivided attention builds confidence, self-awareness and self-esteem – gifts that will remain in a child's life forever.
I often perform at religious organizations such as Jewish Community Centers and Catholic Nursing Homes. In this type of setting, it's wonderful to see how songs that celebrate faith can become very special to both older and younger listeners. Aside for their own power as statements of deeply held belief, it is encouraging and exciting for older listeners to feel they are passing along religious, spiritual or cultural values to ones that may be the tradition bearers into the next generation. Music that expresses faith is a wonderful way to encourage, comfort and renew older ears and to awaken and delight young ones.
Make Some Musical Crafts – Together!
Want to take musical fun a step farther? Make something musical together! My website has some easy activities that any child can make for or with their grandparent or older friend with "around the house" supplies. Make a recycled rattle, maracas from sets of old buttons, a box drum from an older cardboard box and much more. All of these create musical fun both during the making and the playing.
If you'd like to find out about some of the songs I sing at intergenerational and family concerts, check out my cd entitled Grandchildren's Delight. I recorded it after years of playing family concerts and having people say" "Oh I love that song", "I wish my grandchildren could hear these good old songs". In short, I let my audiences pick what went onto the album from their favorite songs such as "Oh Susannah", "Grand Old Flag", You Are My Sunshine", "This Little Light of Mine" and much more. I'm pleased to say that Grandchildren's Delight won a Parent's Choice award and was nominated for a Grammy as well! You can hear song snippets at the link below.
So how can music bring the generations together? There are so many different ways. Explore some of them and you will be weaving together the past with the present to create a beautiful, harmonious future for young and old alike!
Glad you enjoyed the post, Ralph.
What a great post here! I love the idea of sharing music to be able to connect with other people, especially with other generations. Although I don't know how to sing the song made by Daria, I'm very glad to read the lyrics.
Hi JoAnn! love your concept and idea. Music is the universal language of people and a lot people unites when it comes to music. Thanks for sharing this wonderful post to us and i'm looking forward to read from you!
Daria did a beautiful job writing this post, You are correct about her photos being beautiful. I hope other article on the site also meet your interests.
Music is good in our ears. Whatever genre it is, as long as we could relate to its meaning behind every beat of it, we just sing. Most of the time when one song is a big hit and it is played, every body would love to sing along and even dance. Music is one way of making the world united.
What do you a few songs you think work best for getting everyone singing?


Once the grapes are separated according to quality, the ones destined for Gran Reserva are fermented for 14 days at 26º C and completed a maceration of 14 days in total, with the must pumped over on a daily basis to facilitate the extraction of colour. The malolactic fermentation is carried out in spontaneous form, after which the wine passes directly to the barrel for ageing.
This Gran Reserva wine has been aged in 3-4 year old American and French oak barrels for 26 months. The wine is racked every eight months to remove impurities and clean the barrel. After ageing in the barrel, the wine is bottled and sealed with natural cork of premium quality in order to complete its bottle ageing. The bottles are stored for four years before their commercial release.
Colour: Dense centre with a clean, dark cherry tone and medium intensity. The edge shifts to a maroon color. Abundant tears.
Nose: Powerful and complex. Very ripe wild fruit, honey, liquorice and chocolate with notes of vanilla and pepper spices. The wood is well integrated.
Palate: Strong and intense. Liquorice and dark cherry, it shows good acidity on the attack with a pleasant, velvety feel. Balanced and meaty with a long, pleasant aftertaste.
Food matches: Rice and pasta dishes, fish in sauce, meat stews, roasted lamb, chicken and cured meats.


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A Raritan woman was leaving the Time to Eat Diner in Bridgewater, N.J. and fell on the steps that had formed ice while she was inside. She suffered spinal injuries, which required her to have two surgeries, leaving her disabled.
The woman was represented by Christopher G. Aiello and Evan M. Harris of Aiello, Harris, Marth, Tunnero & Schiffman, P.C. located in Watchung, N.J.
Mr. Aiello and Mr. Harris said their expert estimated that their client suffered $1.7 million in lost wages. The defense argued that their client held responsibility for the accident because she was wearing three-inch heels and that the ice formed too quickly for the diner to clear the steps.
Mr. Aiello and Mr. Harris settled the case in Somerset County for $1.3 million.
If you have a slip and fall accident injury in New Jersey, contact Aiello, Harris, Marth, Tunnero & Schiffman, P.C. today and we will be more than happy to answer your questions and address your concerns. Our personal injury lawyers keep flexible office hours, with weekend appointments available, and we can meet you in your home or hospital room if you cannot travel to our office. Call us today, or contact us online, we're standing by to assist you at (908) 561-5577.


Can Organic Farming Feed Africa?
David King, the British government's former chief scientist, caused a stir last month when he accused organic-farming activists of "keeping Africa poor." His argument was that Africa needs to significantly increase its food production and the only way to do that was to move toward technology-intensive, industrial-scale agriculture. Using small-scale organic agriculture, King said, would result only in "hundreds of people with little piles of their crops for sale"—hardly the most efficient way to go about feeding a continent.
It's a critique of organic farming that refuses to go away: Going organic results in lower per-acre yields, making it a fine choice for a handful of arugula-munching global elites, but not for poor countries, where starvation is a real concern. Yet the critique has little basis in fact. Switching to organic does result in lower per-acre yields when done in richer countries, but it can actually increase per-acre yields in the developing world. The reason is that organic agriculture is less-dependent on external inputs like fertilizer or other chemicals—inputs that can fluctuate wildly in price, especially in recent years, as fertilizer prices have soared. Farmers in poor countries who use green manure to add nitrogen to their soil are now faring better than their counterparts who depend on synthetic fertilizers.
So perhaps it shouldn't come as a surprise that the U.N. just released a report pointing toward organic agriculture as the path to food security in Africa. The study doesn't argue that getting rid of pesticides and fertilizers on the few African farms that can afford them will magically cause yields on those farms to rise. Rather, it suggests that the most cost-effective way to increase food production on under-producing farms is to teach those farmers how to use low-cost organic technologies. You might call it a strategy of farming smarter, not harder. It makes a lot of sense in a world of crazily fluctuating input and commodity prices, where a farmer's own expertise is the one input that's not going to become too expensive to afford.