One of the key regulatory problems that are hindering the acceptance of AI in Bio-Pharma is the apocalyptic prediction about Human jobs being traded by machine intelligence and the other Key Problem is the siloed regulatory infrastructure. Although the technological advancements in the field of healthcare have grown heavily, the regulatory ecosystem has bungled to keep up.

One more aspect is that AI, particularly neural nets, is a Pandora box; while we can program it, we really don’t know how it rests with the existing technologies within the Organization. That creates the dilemma of explicability. More than the regulatory Reluctance Forebear AI, regulatory authorities are trying to keep pace.

Another core regulatory challenge is in administrating data accessibility in a way that is lean, balanced for benefits between the data-sources and data-users, and assures confidentiality and prevention of misuse.

How to Regulate AI in Bio-Pharma

• "Display of orthodox AI solutions with regulatory frameworks absorbs new standards to be developed that align with and Support existing regulatory structure while keeping pace with sprouting technologies."
• Collaborating Machine intelligence & humans in the loop compliment strengths to achieve a common goal, solve problems, gain insights, and create value.

Pivoting Ahead:

Leading organizations are taking a new tack, and are at a crossroads with respect to AI strategy despite the apocalyptic prediction about Human jobs being traded by machine intelligence,many life sciences companies are behind the maturity curve in the adoption of automation.

By understanding these considerations, Bio-Pharmaceutical Organizations can pursue Automation opportunities more assertively and potentially trounce the risks of falling behind competitors in technology adoption.

Drug labelling has changed over time because of evolving regulations and has increased in content and length, with a standard format to guide the safe and effective use of the drug. Product labels (drug or devices) contain comprehensive information enriched with product details, such as disease indications, target populations, drug-drug interactions, and ADRs. The labels and labelling documents prepared by manufacturers and approved by the Health Authorities, in its final form, reflect the collective input from regulators, drug manufacturers, and scientific experts. Drug-labelling data is an important resource for diverse applications, including support for policy development.

The global labelling management process continues to be a burden on the life sciences industry and is multiplying at a pace that is already becoming increasingly difficult to manage. Firms’ R&D ambitions are growing, businesses are expanding into multiple markets, and regulators are steadily strengthening safety requirements to protect patients and public health. The pharmaceutical industry operates on a global scale, and regulatory compliance across multiple geographies is fundamental to ensuring that the supply chain remains safe and secure.

As part of the dossier registration, all manufacturers must submit labelling support documents (USPI, SmPC, PIL, IFU, etc.) to HAs to grant marketing approval. Each time the benefit and risk profile or safety factors change, or as regional or local regulatory agencies update their standards, international biopharmaceutical firms must react swiftly with accurate, compliant labelling for all affected markets. This is a real-time and hectic process for multinational companies as there are major content interdependencies. Moreover, managing the local label changes (CCDS vs USPI, SmPC & other local labels) with company core safety information i.e. how a change anywhere along the safety-regulatory-manufacturing-supply chain continuum will affect all label content, from the global core datasheet, to patient-facing product information in each marketed country.

Though the manufacturers shall update and distribute the final updated labels where the products are being marketed. Where submissions are bundled and/or split at the country level to comply with local regulations or company’s internal needs and strategies, there are further considerations as companies try to maintain trace ability especially as changes trickle down to dependent countries. The traditional way of managing all of this has been via a combination of specific systems and manual processes. Typically, tracking of label status and changes are done in Excel spreadsheets internally, and content has been updated on a country-by-country basis using dedicated, often standalone labelling tools.

Triggers for labelling changes can occur at different points during product life cycle. Changes to the benefit/risk profile of a drug that require revised labelling requirements from the company's global core data sheet or local regulatory changes to specific countries can drive the need for a two-way amendment in the supply chain.. As a result, central labelling teams have not found it easy to build up a clear, accurate, and comprehensive picture of all labelling activities. Nor are they able to manage these systematically, end to end, irrespective of where the trigger for a change to the content might come from. In other words, it is difficult for them to efficiently map country/label interdependencies so that changes can be rolled out promptly and reliably wherever the new requirements apply.

In addition to the risk of non-compliance, all of this adds up to a laborious and cost-laden workload for life sciences organisations, as they try to keep track of the latest implemented labels in all of their markets and roll out each new set of changes, as applicable, within the required timeframe. To keep up with the ever-changing emerging safety regulations, companies must upgrade their approach to labelling management with some urgency now.

A modern label management system manages the entire label lifecycle, offers complete transparency throughout the label production process, and facilitates quality control procedures during its distribution. The best modern label management systems now allow business users to design, review, track, and control label data from a document management system. This increases traceability and eliminates scope for errors in the labelling documents for compliance procedures.

Many bio-pharma companies are now looking to ensure compliance, minimize the need for relabeling, and reduce the number of label templates, and transition from paper-based catalogues to digital document management systems. It makes sense to ensure labelling technology is a priority so it can address inconsistencies in processes, mitigate human errors. Timely tracking thus improves business agility for companies to produce compliant, high-quality labels in a cost and time-efficient manner.

Pharma companies, especially those operating from a particular geographical source, will need to rearrange and upgrade their existing labelling processes and compliance structures to conform to the constantly evolving regulatory guidelines. Since details vary from region to region, companies must facilitate tracking units across the supply chain.

LABELai: A Complete Labelling Solution

Automation reduces human intervention and ensures the development of high-quality deliverables that significantly reduce overall operational costs and improve the time-to-market across regions. Some organizations have developed and streamlined the labelling process to minimize the errors, but they often lack the automation required to build a robust and error-free process.

LABELai uses advanced technology to offer end-to-end product labelling by leveraging artificial intelligence (AI) for 90% of the activities. LABELai has been developed with the intention of meeting regulatory requirements in labelling documents, as well as clients’ prospects during the product life cycle management. Our Labelling tool can do the effective process (tracking) for multiple versions of the same document. LABELai has a provision to track the status of labelling documents from production to final distribution and its life cycle management. By using the LABELai tool you can know the label status at any time during drafting, review, approval, and distribution. Corresponding changes to labels along with justifications for changes can also be tracked using this system.

It's a known fact that the Pandemic Effect of Covid-19 apart from creating the hurdles in Clinical Research has also fetched a possibility to many of the new innovations. Supply Chain Management is one of the majorly effected streams due to pandemic which lead to low stock of the API to pursue the Manufacturing of the IMP for clinical trials.

It's time to invest additional efforts on strategy development for managing the clinical supply activities in more efficient way. The scope of the supply chain management can be made efficient by creating solutions to the current and anticipated challenges.

As industry is also focused more on ‘Direct-to-Patient’ model, Drug Supply Chain Management has a primary role in this.

Few areas of focus for DSCM include:

• Quality: Quality is of course one of the first and foremost key point that needs to be focused. In DtP the concept basically relies on providing the Right Quantity of Supplies to a Right Subject at the Right Time in Right Condition. This shall enable the progress of the study more effectively. Even though it’s not easy to perform these type of tasks during a pandemic, but can be handled efficiently using newer technologies.
• Cost Effectiveness: The cost and the liability of the labor, logistics, and energy shall increase globally due to the current constraints. Even though the budget of the running project is approved upfront,to run the operations effectively with quality, within the set budget, proper cost control plans should be executed through constant monitoring of the logistics and wastage
• Risk Management: To meet the needs of the subject according to the protocolcriteria proper Risk Management Plans shall be implemented. Whereas for DtP in clinical research, shipping of supplies direct to subjects involves several risks right from shipping to storage to compliance and accountability. Each of these steps need to assessed with proper risk minimization or mitigations plans
• Qualified Resources: DSCM need to focus more on the qualification and training of the staff as DtP is not a simple logistic task. Manpower should be qualified, trained and accountable. They shall be trained and educated more on their responsibilities and action plans to be performed in DtP scenario. While supplying Direct to Patients, teams should develop interaction with the subjects in confirming their demographics, addresses and maintain a good relationship. Should also be trained to collect any return samples left at the subject in order to meet the accountability of the supplies.
• Delay in Delivery: In clinical research the delay in the Treatment Assignment leads to several consequences. Teams should be more cautious in planning the activities related to supplies by anticipating the unforeseen risks that shall lead to delay in supply delivery.
• Adaptation to Needs: It is not easy to adapt to changes but sometimes we cannot abandon the clinical or patent requirements if we need to stand in the race of the research. It is now mandatory to take up the challenge of delivering the supplies direct to patients to withstand the need of the hour.

DSCM should use an effective IRT system that can handle most of these activities to help save time. IRT can help in managing the risks by leveraging automation, supply options, timely alerts and maintain regulatory compliance

The complexity surrounding labeling often leads to errors, product mix-ups, and even misbranding. Labeling being an integral part of the quality management system, such errors often lead to product recalls which might have a negative impact on both the image and the finance of the company. The best way out of this might be through digitization and automation. Moreover, as the current scenario asks for remote working, this turns out to be the new normal.

Labeling Content Challenges

Latest studies have shown that labeling content accounts for almost 33% of the product recalls. Some of the challenges are:

• Delays in safety changes submission
• Delay in availability and updates of label superseded version and patient information
• Updating delays in national labels from core data sheet
• Issues with review and approval of Label change request
• Failure to timely update safety information and comments from Health Authorities
• Challenges with local and global RA teams’ priority issues

Labeling Automation and Digitization Tool

Content Management & Lifecycle Automation

Manual labeling and comparison of documents is a laborious task and due to the number of documents, the chances of error are quite high. Hence, automation will not only assist you in reducing errors but also is beneficial in managing the content and updating them within a given time frame.

Managing CCDS

Company Core Data Sheets (CCDS) need to be reviewed, edited and updated with time and this process generally needs to be automatic as the data becomes innumerable at the regional level. Automation tools help you in the version management to ensure regular updates.

Compliance

Choose a tool that has in-built local and foreign country regulations. This will allow you to have a comparison of the labels and understand the violations so that there is no need of any future manual reconciliation.

Generating Reports

Report generation helps in global marketing and a tool can easily support you in generating labeling change reports related to administration, safety, compliance, version, and HA updates.

Formatting, Reviewing and Publishing

Modern tools can ensure comparison of documents of various formats. Moreover, a tool reviews any document 75% faster than in manual QC. All HAs have a different labeling format and to maintain that manually is difficult. If you can take the help of a tool with all such inbuilt data then it can make the task easier. The labels get published through automation in the desired format leaving a lesser scope for formatting issues.

Digitization and automation can give you the much needed results and let you move ahead towards an error free labeling and thereby preventing the repeated recalls and ensuring a proper approval.

Drug Accountability of the Investigation Medication begins from the selection of location for its storage. Issues with drug accountability are major and the majority of warning letters from regulators are a result of this. Major delays are faced by sites for non-conformity and it often leads to non-acceptance of trial data. Drug accountability is of utmost importance and it is the clinical investigator who remains responsible for the entire process taking place at the clinical site. If the supplies are controlled substances then more attention shall be needed from the Investigator in terms of its storage and disposition. IRT systems allow in streamlining such processes by keeping a single source of data and hence the process of Drug Accountability tracking becomes easier.

Paper-based Drug Accountability Challenges

It is the complexity surrounding the paper-based systems that makes them more prone to errors. Drug accountability shall be maintained at sponsor level and site level. The Investigational medication documented as shipped should reconcile with the documentation of used and unused. The Drug Accountability at site begins once an investigational drug reaches the site. Records need to be maintained and staffs need to confirm that the contents that have been shipped match its previous record. The authorized person needs to put his signature with date after thorough verification. Once these have been completed, the investigational drug needs to be stored securely maintaining the standards specified in the protocol. Entire details need to be updated in the drug accountability log and with the commencement of trials; drug dispensing records are to be updated in writing in multiple documents. Site shall maintain all the data of the drugs right from drug dispensing to final disposition. Paper-based drug accountability never ends with the end of study, discrepancies in accountability logs need to be resolved, and its copies are to be returned with the original shipment records. The sponsor should receive the reconciled log along with the returned investigational drugs. Any discrepancy in drug accountability not only violates the regulations but also points the integrity of the study and public health.

Mitigating Challenges through IRT

Utilizing electronic medium for data collection and tracking helps in mitigating the challenges associated with data accountability. When data associated with a trial gets centralized, then the visibility gets doubly enhanced and a single accountable system improves the process of reporting. This entire method eases regulatory compliance achievement process and accountability audit issues get resolved immediately. As the use of the IRT system increases the pace, end-of-study documents are prepared in no time using the single system as the source.

mIRT has a special feature to track Drug Accountability where the reconciliation of the supplies that are used, lost, damaged and returned shall be captured which enables the system to calculate the compliance of the drug automatically.

Future of Drug Accountability

With the current advancements, as the world is moving ahead and accepting technology, there is an increased level of visibility in the supply chain for both the regulators and sponsors.

Labeling process prominence has increased over the years and manufacturers are trying to manage product labeling & artwork at the same time while maintaining end-to-end life cycle changes of product labeling. In the current scenario, labeling can be in various forms, both physical and digital as well. Controlling the labeling content becomes difficult as it comes from diverse sources and all these content changes during the product lifecycle process is a daunting task for labeling teams. Labeling Automation can help ease these challenges.

Automation & AI

Artificial Intelligence is involved in various domains like education, retail marketing & healthcare sector, etc. To that, data labeling is a vital aspect in the healthcare domain (Pharmaceutical industry) with its keen specifications predefined by the health regulatory authorities (HRA). Systems need to understand what is shown on the display part such as images, symbols, written text & among many other things. Medical labeling is an imperative or integral stage of data preprocessing in supervised learning (machine learning) process. Historical data with predefined target attributes (values) is used for this process model.

Data Organization and Structure

Organizations look forward to collaboration so that all the data is available at the source thus enabling them to keep a check on the labeling content. To ensure this control, e-labeling has already entered the market and with time it is taking up much of the space in the life science industry.

Labeling data service comprises many different tasks. This includes adding electronic markings on image files, text files, categorizing texts, etc. As mentioned above, adding markings on images or text is an important part of data labeling service. Data coding is the key aspect in the Automation process and certain modules or templates to be designed and populate internally. All the labeling functional aspects will be identified, captured and coded in way of business rules (predefined data integrity) to the system. Each data element will give the system a better understanding and execution of the outcome for defined processes. This allows the algorithm to recognize different shapes in various positions and also possible to tag or map the data element. The algorithms can only function properly if there is some sort of human intervention then the system machines can produce human-like results

Data Digitization

The digital revolution is inevitable. It is already happening. Soon it will ease the burden of brand attraction and information which is at the moment moving swiftly onto packages. Converters will become the dominant producer of paper-based information. In simple terms, consumers will get product information online by scanning the RF tag or barcode with their Smartphone. This is already happening, so it is safe to conclude that the future is here. Fortunately, things can only get better and easier for the consumer. It can be combined with packaging and can be used by marketers to encourage potential buyers to purchase the product

Data Capturing & NLP Technology

Some specifications regarding labeling activity are the key thing in the machine learning process. For example, some of the label content may require to represent and executing in a particular native language or coming from a specific region. In other cases, a more detailed description of the individual field is necessary on how and what content to be present. In this process for each assigned task user-based credentials are given as needed by the customer for the required job. Understanding all text would be difficult in the machine learning process. Natural language or Natural language process (NLP) is unlike constructed or formal language and can therefore not easily be parsed by machines.

The next decade will demand bigger changes in process systems and expected greatly reduced materials used in packaging and goals of 80− 90% recovery.

Digitization and automation will enable comprehensive recovery and re-use of packaging materials. So the big question is how ready your teams and your company are for these changes. Take small steps with the phased approach supported by the right technology/tool and start applying to different labeling processes without boiling the ocean or waiting for a big silver bullet to rescue.

What is Data Integrity?

Integrity of data is ensured only when initial remains valid throughout the product life cycle. If the accuracy comes under question at any point in time then data integrity would collapse. ALCOA system is the best method of defining and measuring data integrity. It can be broadly expressed as:

Technology Driven Automation

Attributable: A single person to be held responsible and accountable from the beginning to the completion of a particular task.

Legible: The data gathered should be clear and simplified so that it is easy to read and conceive and can be preserved for future usages.

Contemporaneous: The data created and the activity conducted need to be running simultaneously i.e., in real-time.

Original: The data should be authentic and its validity to be maintained throughout the product life cycle.

Accurate: Resemblance of the task and data is necessary to prove accuracy.

IRT’s Impact on Data Integrity

a. Managing of Blinds Interactive Response Technology (IRT) helps in systematically maintaining data blind. All the data starting with assignment of treatment and continuing towards ultimate data analysis can be easily viewed in the audit trail timeline. Unblinding of data is generally the outcome when there is no or a poor IRT system in effect. Finally, it is the responsibility of all the stakeholders to pay special attention while the blind is being enforced so that it can be maintained all through.

b. Streamlining Audit Trail Data of Audit Trail are extremely significant as later inspections related to pharmacokinetic studies; randomization or a double-blind could be benefitted from it. The final data can be reviewed by comparing the source data with the end data. It is enough to reveal whether the subjects received opposite treatment meaning active drugs and not a placebo or they received mixed treatment where they were given both active drug and placebo or the drugs were given under wrong dietary conditions like dosage to be given in fasting were given after feeding and vice versa. IRT system makes it easier to trace all these details through the audit trail so that issues can be handled on time rather than discovering them during an inspection.

It is data integrity that the entire industry is concerned about and IRT systems will ensure it only if it is properly verified. So, for vendors it is of utmost importance to verify the IRT not only for vendor qualification but also during the implementation of protocol change or any such other changes. This will ensure that the data that you retrieve is completely integrated.

Current situation has led the world to remain secluded and engage more into remote activities. In such situations, like most other industries, healthcare industry too has been forced to think out of the box. Areas that have been mostly impacted are those where congregation and engagement of multiple people was necessary. One such section in healthcare is that of clinical trials. Data sharing, analysis and accumulation remains to be a major and most significant part while conducting a clinical trial. Now it is for us to find out how technology is driving the change.

Remote Monitoring

To conduct the ongoing clinical trials remotely, monitoring and management of data and document is necessary. There is no fixed method that can be implemented and hence files are generally shared in the form of email, fax or such other cloud-based tools. This leads to compliance risk issues if not kept under proper surveillance. Such file sharing systems are generally used as they are low in cost but they fail to be compliant with the authority regulations. Moreover, fax and mailing services require huge manual work and provide greater scope of error in updating the retrieved data. In areas of clinical trial such minute errors too can have severe impacts.

Technology Driven Automation

Automation is of great help in current situation as it allows collaboration and a seamless exchange and upgradation of data. Access to Electronic Medical Record (EMR) tends to be of great help in addition to SaaS based tools. These being cloud based, perform the tasks automatically and hence there is less of manual task and lesser scope for errors. This advanced technology comes with a central repository for the storage of bulk data which gets analysed regularly and in real time, thereby easing out much of the task.

Technological transformations especially in the field of clinical trials have already started. Automation has provided greater control, access to vast data, accountability, lesser compliance risks and scope for continuous communication. This allows in performing remote clinical trials with added visibility and helps more people to come forward and adopt the change.

Companies who did large implementations (like RIM, EDMS, Change Management, ERP, others) have all noticed their costs and timelines doubled than what is budgeted initially.

These large systems that BioPharma implemented have helped them streamline business functions and track data. However many of these systems still require significant manual processing. PwC's 2017 effectiveness benchmark report found that users spend half their time focused on mundane, repetitive tasks of gathering data from various systems. This led to many of the systems reaching the point of diminishing returns.

On positive side, the speed, scale and cost of automation are evolving better with help of robotic automation, natural language processing, machine learning systems that offer companies new opportunities to improve process performance and realize significant cost savings

For Regulatory processes, some of these technologies can be implemented in short sprints, focused on specific sub-processes, with manageable costs. This approach of "small & smart" automation leads to "fast" implementation of flexible and adaptable technologies that fill the gaps left by your current or legacy enterprise tools or document systems, thereby enabling much higher productivity for labeling teams

Small automation can improve the productivity of individual regulatory processes by 80 to 100 percent and overall labeling functions by 30 percent or more

Small automation does not replace large enterprise systems or your future big automation initiatives. These are easier to implement and much less expensive. They can be applied to individual processes or tasks without having to go through complex cross-functional discussions (negotiations) and coordination in large projects.

Traditionally, companies could not begin to capture gains from large IT implementations until they had standardized processes and databases that were accessible to a broad set of users, which could take years. In contrast, automation doesn't depend on standardization or centralization (unlike your large projects or systems) leading to higher flexibility and adaptability

Applying small automation is anew way of working, and company leaders will need to ensure that both they and their teams have right knowledge to be successful.

"small" automation can be applied to several processes like auto authoring, data with document merging, document publishing, submission readiness checks, translation automation, compliance checks, broad QC checks, and few more areas

Please reach out to us to discuss how we are helping customers achieve these automation goals using our patent-pending REGai which is a cloud based modular focused Regulatory platform that will work with your current systems / technology

The COVID-19 pandemic has taken a toll on the entire world affecting various sectors including the pharmaceutical industry. Unlike the other industries, the pharmaceutical industry has not come to a halt because of its need in such difficult times but some severe restrictions have been imposed. In the wake of this pandemic, some ongoing activities have been hampered and one such activity is the clinical trials that are already in process. As the borders of the countries have been sealed and opened from time to time and with the number of stakeholders associated in the process, maintaining the supplies has been difficult. This situation demands some strict measures that would help in easing out the ongoing clinical trial processes.

This situation has prevented most subjects from visiting the sites to collect the drug samples that lead to the dropout rate of subjects and has affected the recruitment rate as well. On the other hand, some have left the trials halfway. Moreover, the risk is higher when there is a need for multiple visits and financial prospects are affected when there is a stock overage. Taking these into consideration there aroused a scope for a special feature of IRT that is ‘Direct to Patients’ which has been discussed over years in the conferences. That if implemented in a situation like this, could give unthinkable results.

"Direct to Patient" (DtP) is the answer in which supplies can be directly sent to the subjects of clinical trials in a contactless manner. This would prevent them from coming to the sites, and at the same time would help in continuing the clinical trial in a smoothly manner and also there are chances to reduce the dropout rate in the studies as well. The implementation process of this feature might vary from country to country but once implemented, this can make the tracking and supply process easier.

IRT systems play a critical role in ensuring the right medication gets to the right patient at the right time. With the use of IRT it would be easier to track the shipments and arrange them on the basis of the kit status. Accompanying IRT with the digitalized supplies management systems would bring more sophisticated results in the implementation of this DtP which allows easy tracking of Supplies right from its package to the direct patients’ address to their acknowledgement of the supplies. The patient would be able to procure the kits and even return the unused or excess kits from their home on their next visit. Although IRT faces a number of challenges in the DtP supply process and these are related to cancellation of shipments, temperature adjustments necessary for the kits and even in the process of return and destruction of unused kits. Despite all these, IRT manages the entire procedure through the mitigation of these challenges.

The long term effects of COVID-19 might turn out to be severe and it might bring about many other changes in the pharmaceutical industry, clinical trial processes, and even in the management of supplies. Standing at this juncture, it is highly suggested that the implementation of such IRT systems with DtP enabled is prioritized. The individual technologies need to be re-evaluated to ensure that adopting this new design would be feasible. Now as the entire workforce is functioning remotely, adopting such advanced systems is a necessity to keep functioning amidst this situation.

FDA is committed to providing timely guidance to support response efforts to this pandemic situation of COVID-19. In this regard FDA has implemented few guidance documents immediately without prior public comment, because this is not feasible or appropriate at this pandemic time, but it remains subject to comment in accordance with the Agency's good guidance practices.
As recommended by FDA the devices submission would be required as per Quality System Regulation requirements (21 CFR Part 820 {21 CFR Subpart K - 820.120 Device labeling & 820.130 Device packaging Control}), Reports of Corrections and Removals requirements (21 CFR Part 806 {reporting information}), and Label to bear a unique device identifier (21 CFR Part 830 and 21 CFR 801.20) regulations as necessary.
The recommended guidance document contains proposed changes in both the device technical function and labeling context (including methods, standards, etc).

Below is one of the medical devices type as per new recommendations.

Modifications for Sterilizers, Disinfectant Devices, and Air Purifiers:

FDA has recommended standards (TABLE 1) and labeling modifications (TABLE 2) on sterilized or disinfected conditions to patients and healthcare providers for usage of sterilizers, disinfectant devices, and air purifiers during this public health emergency.

TABLE 1: Modifications/applied standards for Sterilizers, Disinfectant devices, and Air purifiers

Device Type	Product Code	Device Classification	FDA-Recommended standards for Sterilized or Disinfected Devices on Indication or functionality
I. Sterilizers
Endodontic dry heat sterilizer	KOK	III	• Steam Sterilizers o ANSI/AAMI ST8:2013 Hospital Steam Sterilizers o ANSI/AAMI ST55:2016 Table-Top Steam Sterilizers o ANSI/AAMI ST79:2019 Comprehensive Guide to Steam Sterilization and Sterility Assurance in Health Care Facilities. • Dry Heat Sterilizers o AAMI ST50:2004 (R2018) Dry Heat (Heated Air) Sterilizers o ANSI/AAMI ST40:2004m (R2018) Table-Top Dry Heat (Heated Air) Sterilization and Sterility Assurance in Health Care Facilities • Ethylene Oxide Sterilizers o ANSI/AAMI ST24:1999 (R2018) Automatic, General Purpose Ethylene Oxide Sterilizers and Ethylene Oxide Sterilant Sources Intended for Use in Health Care Facilities, 3ed. o ANSI/AAMI ST41:2008 (R2018) Ethylene Oxide Sterilization in Health Care Facilities: Safety and Effectiveness • Other Sterilizers o ANSI/AAMI/ISO 14937 Sterilization of Health Care Products — General Requirements for Characterization of a Sterilizing Agent and the Development, Validation and Routine Control of a Sterilization Process for Medical Devices • Chemical Indicators o ANSI/AAMI/ISO 11140 – 1 Sterilization of Health Care Products—Chemical Indicators—Part 1: General Requirements • Sterile Packaging o ANSI/AAMI/ISO 11607-1 Packaging for Terminally Sterilized Medical Devices – Part 1: Requirements for Materials, Sterile Barrier Systems and Packaging Systems o ANSI/AAMI/ISO 11607-2 Packaging for Terminally Sterilized Medical Devices • Rigid Sterilization Containers o ANSI/AAMI/ISO ST77:2013 Containment Devices for Reusable Medical Device Sterilization • Biological Indicators o ANSI/AAMI/ISO 11138 Sterilization of Health Care Products—Biological Indicators Series o ANSI/AAMI/ISO 14161 Sterilization of Health Care Products — Biological Indicators — Guidance for the Selection, Use and Interpretation of Results
II. Disinfectant Devices
1. Chemical/Physical Disinfectant Devices
Cleaning accessories for endoscope	FEB	II	• AAMI ST58:2013 (R2018) Chemical Sterilization and High-Level Disinfection in Health Care Facilities • Association of Official Analytical Chemists (AOAC) 6.3.05:2013 Official Method 966.04 Sporicidal Activity of Disinfectants • AOAC 6.3.06:2012 Official Method 965.12 Tuberculocidal Activity of Disinfectants • AOAC 6.3.02:2006 Official Method 955.17 Fungicidal activity of Disinfectants Using Trichophyton Menta grophytes • AOAC 6.2.01:2013 Official Method 955.14, Testing Disinfectants Against Salmonella Choleraesuis, Use-Dilution Method • AOAC 6.2.04:2013 Official Method 955.15, Testing Disinfectants Against Staphylococcus Aureus, Use-Dilution Method • AOAC 6.2.06:2013 Official Method 964.02, Testing Disinfectants Against Pseudomonas Aeruginosa, Use-Dilution Method
Medical devices sterilant	MED	II
Medical devices disinfectors	MEC	II (exempt from premarket review unless indicated for high level disinfection or for use on endoscopes and accessories)
Medical devices cleaners	MDZ	II
High level disinfection reprocessing instrument for ultrasonic transducers, mist	OUJ	II
High level disinfection reprocessing instrument for ultrasonic transducers, liquid	PSW	II
II. Ultraviolet (UV) Disinfecting Devices
UV radiation chamber disinfection devices,	OSZ	II
III. Air Purifiers	For the purposes of this guidance, FDA recommends that manufacturers of air purifiers evaluate or perform the following:
Medical recirculation air cleaner	FRF	II	• Demonstration of a 4 log reduction (through a combination of capture or destruction) of claimed particulates. • If intended for use against bacteria, effectiveness against representative gram positive and gram negative species. • If intended for use related to SARS-CoV-2, effectiveness against a representative virus • If the device generates ozone, the maximum acceptable level of ozone per 21 CFR 801.415. If intended for use in areas that have a sterile field or controlled air flow, a risk assessment to address turbulent air flow and/or potential site contamination.
Medical UV air purifier	FRA	II

Table 2: Labeling Modifications for Sterilizers, Disinfectant Devices, and Air Purifiers:

FDA RECOMMENDED LABELING MODIFICATIONS	LABELING IMPACT (Yes/No)IFU	Art Work
1. A clear description of the available data on the device’s new indications or functions related to SARS-CoV-2 or co-existing conditions, such as: a) Device performance; and b) Potential risks (e.g., risk of UV exposure)	Yes	Yes (indication statement)
2. -A clear distinction delineating FDA-cleared or FDA-approved indications from those that are not FDA-clared or FDA-approved. In addition, FDA recommends the labeling include a general statement about changes that have not been cleared by FDA.	Yes	Yes
3. For all disinfectant devices, a clear statement of the level of disinfection.	Yes	Yes
a) A caution that UV disinfection will reduce the number of pathogens on the device, but it will not eliminate them completely.	Yes	No
b) A statement that the device is an adjunct to currently existing reprocessing practices and not a replacement or modification to such practices.	Yes	No
c) A statement regarding the time, distance, and maximum area over which the device has been evaluated for effectiveness.	Yes	No
d) An appropriate UV hazard warning label.	Yes	Yes
e) Identification of the expected UV lamp operational life and instructions for procedures on replacement of the UV lamp when needed.	Yes	No
f) Procedures to follow if the UV lamp malfunctions or fails.	Yes	No
g) Description of the preparation of equipment or the room for disinfection	Yes	No
h) A statement that the equipment intended to be disinfected is UV compatible.	Yes	No
i) Identification of the UV dose.	Yes	No

There are several suggestions, recommendations from different health authorities for sponsors to handle clinical trial aspects during this very challenging time of COVID. Most of them recommended not starting any new studies for time being. For the ongoing studies, below is the compilation from their documents pertaining to Clinical monitoring of ongoing studies:

MHRA

Remote monitoring for trials

We support remote monitoring where appropriate but consider the following:

• Direct access to patients EHR (Electronic Health Record) away from the site creates issues around confidentiality. Consider where this access takes place, for example will CRAs (Clinical Research Associates) be accessing records in an open plan office, public space or other location where others who are not authorised could view sensitive information
• Trial participants will need to consent to any identifiers leaving the site and be assured that their confidentiality will be protected
• It is likely that there will be increased pressures on clinical staff during this period, so it is important to make sure that extra burdens are not placed on investigators around scanning and uploading many documents.
• The use of alternative means of oversight such as teleconferences/videoconferences is encouraged Replacing in-person visits with phone calls

Using phone calls instead of protocol-directed in-person study visits is acceptable where possible. This will not constitute a serious breach of the protocol. A substantial amendment to update the protocol will not be required. We would however expect that any protocol deviations are well documented internally.

EU

Changes to monitoring

Certain sponsor oversight responsibilities, such as monitoring and quality assurance activities need to be re-assessed and temporary, alternative proportionate mechanisms of oversight may be required. The extent of on-site monitoring, if it remains feasible, should take into account national and local restrictions, the urgency (e.g. source data verification can often be postponed) and the availability of site staff, and should only be performed as agreed with investigator sites. The burden of the introduction of any alternative measures for the site staff and facilities should also be considered in order to strike an acceptable balance between appropriate oversight and the capacity of and possibilities at the site.

Possible temporary, alternative measures could include:

• Cancelling of on-site monitoring visits and extending of the period between monitoring visit
• Implementing phone and video visits (without unnecessarily increased burden to the investigator site and taking into account trial participant integrity)
• Adapting the on-site monitoring plan when it is impossible to follow, supplementing it with (additional/increased) centralised monitoring and central review of data if possible and meaningful.

Results of adjusted monitoring/review measures should be reported to the sponsor in monitoring reports and in the clinical study report.

It is essential that robust follow-up measures are planned and ready to be implemented when the situation is normalised. This should likely include increased on-site monitoring for a period that is sufficient to ensure that the impact of the reduced monitoring could be rectified and problems resolved or properly documented for reporting in the clinical study report.

So-called remote source data verification (e.g. providing sponsor with copies of medical records or remote access to electronic medical records) is currently not allowed in most member states as it might infringe trial participants’ rights. In addition, provision of redacted/ de-identified pdfs files will not be acceptable as it puts disproportionate burden on site staff.

Nevertheless, since the corona virus emergency situation and containment measures are likely to last for a prolonged period, several NCAs have started to look into possible, temporary solutions related to remote access and conditions for such, providing that methods can be used that restricts access to trial participant records, in line with the principles of necessity and proportionality. This should however also be clarified with other relevant authorities in this area (such as, without limitation, Ethics Committees and data protection agencies) and is consequently not allowed unless a member state has given specific guidance allowing this.

FDA

Since trial participants may not be able to come to the investigational site for protocol-specified visits, sponsors should evaluate whether alternative methods for safety assessments (e.g., phone contact, virtual visit, alternative location for assessment, including local labs or imaging centers) could be implemented when necessary and feasible, and would be sufficient to assure the safety of trial participants. Sponsors should determine if in-person visits are necessary to fully assure the safety of trial participants (for example to carry out procedures necessary to assess safety or the safe use of the investigational product appropriately); in making the decision to continue use or administration of the investigational product, the sponsor should consider whether the safety of trial participants can be assured with the implementation of the altered monitoring approach.

If planned on-site monitoring visits are no longer possible, sponsors should consider optimizing use of central and remote monitoring programs to maintain oversight of clinical sites.

TGA

Site monitoring visits

• Remote monitoring visits are encouraged as the first option in all cases and sponsors and institutions should ensure that these are facilitated, taking into account the need to avoid undue burden on hospital or institutional resources. These arrangements must adhere to patient confidentiality protocols already in place. Remote source data verification may be done electronically as long as appropriate security arrangements either are or can be put in place.


• If remote monitoring visits are not feasible, then clinical research associates may continue to undertake on-site monitoring visits as long as they are not symptomatic, have not returned from overseas in the last 14 days or had contact with a known case of COVID-19, in accordance with the most current public health guidance and advice from jurisdictional health departments.

That’s 40 hours time saved per year. The more per day time saving, obviously means more time saved in addition.

Use this time that you’ll save for your strategic planning, process optimizations, improvement planning, or more coffee indulging breaks or relaxing yoga time

With saving time for labeling teams in mind, LABELai addresses content development or tracking challenges and processes in day-to-day labeling teams work. LABELai innovatively automates local content utilizing AI and NLP technologies augmented by built-in Regulatory requirements of several countries.

Benefits:

Higher Accuracy of local labeling content creation and maintenance

Less Oversight & time required form Head Quarters / central teams

Deep Cost savings

Finally, top-down label compliance achievement

In the process of implementation of QMS standard ISO 13485, many companies face common struggles; however their mistakes can be avoided when you look and analyze these things more closely. The more closer you look at the QMS requirements, you understand the more and can apply your own QMS processes in your organization according to these guidelines.

1. Treating the ISO 13485 Requirements as a "CHECKBOX" Activities

Business market is a series of interrelated processes and functions. Implementation should never be about checking a box; there are many chances to miss the potential benefits of the activities it actually involves.
Implementation of ISO 13485 should be a holistic approach, where the culture of "QUALITY" increases across the entire company by adopting quality-first mindset and doing a lot of value-add exercises and ensure these standards are met in all operations.

2. Limited CAPA Understanding ->Overload on CAPA ->Hide CAPAs ->cause Audit Failure

Due to company’s poor processes, CAPA can quickly be over loaded; unable to eliminate & prevent non-conformities which leads to overburdened with excess CAPA events. Generally as an initial step, auditors check the CAPA procedures to understand “how the root causes are identified& how efficient are the QMS processes”. The more you understand the CAPA, you can judge where CAPA required or not and can eliminate and prevent the cause(s).

3. Failure to Perform Internal Audits

If you don’t conduct internal audits, you’re missing out on the opportunity to stay at the pulse of what’s really happening and make improvements as you go. You are in a big trouble if do not conduct internal audits or follow checkbox activity in the internal audits. Ensure to perform frequent, effective and comprehensive internal audits to meet the compliance.

Other important avoidable mistakes from the medical device manufacturing companies:

• Ineffective Management Reviews
• Struggle with properly Handling Customer Feedback
• Failure to manage the Risk-Based Processes
• Common mistakes when implementing Documentation Control

Manufacturers can avoid common mistakes in implementing the ISO 13485 Quality Management System by dropping the checkbox activities and use a structured QMS to bring safe, effective medical devices to market. This is the overall essential purpose of the standard.

With EU MDR changing the plain field of med devices to a whole a new level, other countries are following similar path of increasing demands in product safety, traceability, performance areas.

Companies not organized on information management with a system will end up duplicating lot of activities leading to loss of productivity and increase risk of non-compliance.

There are 3 categories of Challenges grouped by:

Process Challenges:

Training must be required to simplify the complexity of multiple system & user interface. As a result, users work outside of the system using local file shares or email to collaborate. To check the work status and to create report most of the companies depends on separate reporting tool or manual spreadsheets.

System Challenges:

Medical device regulation is much versatile. Upgrading a system with updated integrations is challenging and expensive as well. Systems that lie behind corporate firewalls are difficult to outsource to business partners or service providers.

Compliance Challenges:

Users develop manual tracking spreadsheets when planning & tracking capabilities aren’t part of a content management system. Many times users share information and documents via email that cause inconsistent use of document template and it is much difficult to Re-import.

Importance of a RIM system

Medical device registrations differ from country to country, with the difference in FDA’s 510K (Class I and II devices) and Premarket Approval (Class III devices) processes from the EU's CE Marking process. The current regulatory environment in which the medical devices and diagnostics companies are competing is complex.

There is a higher demand for regulatory and compliance information required to support submissions 510 (k), PMA, De Novo and HDE.A cloud based RIM can effectively help management of product registration, commitments and regulatory submissions to medical device and diagnostics companies. This unified, single-source system provides a global user base with real-time information necessary to ensure the quality of the product and the registration.

Following capabilities should be present in an effective regulatory information management system

• Identifies device-specific global regulatory requirements.
• Assembles product information into country-specific TF template.
• Controls the dossier configurations for internal review and external review.
• Manages changes and revisions to TFs and product information.
• Generates compliant submission documents in various HA/NB formats.
• Tracks & retains submission status& manage commitments.
• Decreases effort and calendar time to replicate regulatory submission between products and regulatory agencies.
• Provides clear oversight of original and lifecycle submissions.

RIM in future:

With the versatile and novel reporting requirements set out by regulatory authorities, the plea to need Regulatory Information Management System (RIMS) is emerging brassier. The medical device market is progressively adopting regulations for UDI, eIFU, electronic submissions, others. Making these things happen without a proper RIM system is very challenging.

At the same time, Medical device companies themselves are now realizing the strategically important role that various forms of product data could play in the future; enhancing new productivity, efficiency and create competitive differentiation.