It is apparent that COVID-19 has permanently changed the ways of business operations for many industries across the globe. In fact, it has subtly given a renewed purpose to industries to evolve and advance in terms of tech-enabled and automated workflows.
In the Life Sciences sector, too, this has been true in all the ways, right from manufacturing to the products’ market entry; stakeholders adopted the technological workflows like never before and made their successful attempts to bring out safe and effective medicinal products and medical devices. To ensure these attempts are compliant enough and safe for the end public, the global Health Authorities (HAs) have also initiated various programs to oversee the technological improvements in the industry.
In this article, we try reminiscing major steps taken by the global HAs that transformed the Regulatory landscape of the life sciences industry in 2021.
EMA has recently revised the guidance on the steps to be followed during remote pharmacovigilance (PV) inspections for Marketing Authorization Holders (MAH). The purpose of this document was to help MAHs outline the specificities of remote pharmacovigilance inspections by identifying the inspection requirements for Centrally Authorized Products (CAPs) and Nationally Authorized Products (NAPs).
The revised contents include the following:
- The word 'distant/virtual' pharmacovigilance (PV) inspections have been changed to 'remote' pharmacovigilance inspections.
- Clarifications on the technical requirements for remote access to electronic systems and to maintain communication.
- Further inputs on the documentation and preparation conduct.
ANVISA of Brazil received the approval to become a member of the Pharmaceutical Inspection Co-operation Scheme (PIC/s) in November 2020. Considering the pandemic situation, for the first time in PIC/s history, the assessment was completed in a written procedure as opposed to at a meeting. On January 01, 2021, the PIC/s committee welcomed ANVISA as their valuable 54th member.
Recently, the Director-General of NAFDAC announced the commencement of a sensitization campaign in Nigeria. Through this campaign, NAFDAC intends to inform, sensitize, and educate the Nigerian citizens about the dangers of intake and use of bogus medicinal products surfacing in the market. With clear, concise, informative, and educative directives, the campaign spurred awareness about various infractions affecting the Nigerian healthcare system.
Post the National Medical Products Association’s (NMPA) membership in the ICH (International Council for Harmonization of Pharmaceuticals for Human Use) in 2017; China has to conform to the international guidelines with regards to the technical documents.
Consequently, the NMPA launched eCTD submissions for the initial New Drug Application (NDA) and Biologics License Applications (BLAs) on September 29, 2021. This document was released by the State Drug Administration and came into effect on December 29, 2021. As per the new eCTD mandate, any applicant who chooses to make an eCTD submission must also submit a physical copy within five (05) working days of submitting the electronic version. Secondly, the content of the dossier should be the same for both the paper and the eCTD submissions, which are currently being allowed on a CD/DVD. Finally, any other submission types are out of the scope of the eCTD, and there are no plans to include them in the near future.
Understanding the scope of their collaboration, ICH and SNOMED, as a joint effort, have announced the release of new maps in the Regulatory and clinical spaces. Collaborative efforts under the project WEB-RADR 2 led to the release of two (02) important roadmaps (MedDRA to SNOMED CT and SNOMED CT to MedDRA), which have been structured around the repeatability of term usage and additional key pharmacovigilance MedDRA terms identified by the European Medical Agency (EMA). To promote drug safety, interoperability among the pharmacovigilance database (MedDRA) and electronic health records (SNOMED CT) helped in identifying the possible side-effects and activated adverse events reporting simultaneously. The data collected through such reports was useful for conducting epidemiological research in patient demography. Key elements associated with MedDRA adverse event reporting was used to associate adverse drug events while providing “aid in clinical decision making.”
The European Medicines Agency (EMA) evaluated the risk of nitrosamine creation or presence during the manufacture of human medicines and advised Marketing Authorization Holders (MAHs) on how to avoid the presence of nitrosamine impurities. The following is the procedure to follow to remain compliant with the adjustments.
Risk Evaluation - Manufacturers had to conduct a risk evaluation process to identify the active substances and the finished product to check the nitrosamine levels. If there are any instances of cross-contamination, the same had to be included in the outcome report. The deadlines for submissions at this stage were set for March 31, 2021, for chemical medicines and July 01, 2021, for biological drugs. Since the deadline has passed, MAHs must adhere to the new guidance without fail.
According to the revised Manual of Policies and Procedures (MAPP) of the United States Food and Drug Administration (USFDA) dated July 27, 2021, new labeling rules were proposed under Section 505(j)(10) of the Federal Food, Drug, and Cosmetic Act (FD & C Act). This Section covers the FDA’s approval of an Abbreviated New Drug Application (ANDA) even after a few changes in the labeling for the Reference Listed Drug (RLD). When the FDA’s approvals of labeling changes for the RLD and the ANDA are scheduled simultaneously, the revised process needs to be followed.
The revised MAPP was sixteen (16) pages and has been effective from July 27, 2021. It administered Section 10609 of the Patient Protection and Affordable Care Act (PPACA), which was passed in 2010 and added to 505(j)(10) of the FD and C Act. The MAPP contained a detailed description of what needs to be done by the ANDA applicant when the changes in RLD’s labeling are not included in the proposed ANDA labeling.
Product-Specific-Guidance (PSG) documents lay down the United States Food and Drug Administration’s (USFDA) current thought process on the evidence and markers needed to prove and qualify a generic drug being therapeutically equivalent to a Reference Listed Drug (RLD).
On November 11, 2021, forty-eight (48) new drafts were added to the existing PSGs. Of these, twenty-one (21) are revised, and twenty-seven (27) are new PSGs. About nineteen hundred and forty-eight (1948) PSGs have been documented and released on this date, and they can be found here. Knowledge of these is mandatory for generics manufacturers to ensure compliant ANDA submissions.
In January 2021, the TGA had undertaken a post-market review of face masks included in the Australian Register of Therapeutic Goods (ARTG) and identified common areas of non-compliance against claimed standards in this review process. Based on the same, the TGA has devised guidance intending to assist manufacturers in choosing the appropriate standards and set expectations for performance testing of respirators, surgical respirators, and medical/surgical facemasks before inclusion in the ARTG. To assess the performance of medical devices, the manufacturers must take note of several elements when considering the application of testing methods and must adhere to the guidelines to avoid market-entry pitfalls.
In recent times, the use of Artificial Intelligence/Machine Learning (AI/ML) has caused a huge technological sweep in the medical devices and healthcare industries because of their ability to diagnose, manage, and treat a variety of medical conditions and enhance patient care. But there seem to be obstacles in implementing AI/ML in daily practices with respect to the transparency issues surrounding their software programs. Hence, it is crucial to regulate these technologies and to do so the Regulatory bodies are trying hard to govern the AI/ML implementation. Based on the same, in March 2021, the FDA had released a five-part action plan for its oversight of safe and patient-centric AI/ML-based SaMD. The Agency anticipates that this action plan will continue to evolve and provide additional clarity.
The integration of software with medical devices has rapidly increased and is driving incredible advancements in delivering healthcare solutions across various domains like diagnosis, disease prevention, and treatment of an injury or illness. However, the effect of software on the safety and performance of medical devices has been dubious, particularly when the device itself is a software alone product. Hence, the medical device software regulations are constantly revised to determine the consideration of Software as a Medical Device (SaMD). In April 2021, the advisory board of the European Commission, the Medical Device Coordination Group (MDCG) focused on improving the regulations of medical device software and published guidance describing the approach to be applied while determining whether a software is a medical device or not.
You might be aware, in the context of pending agreements between Switzerland and the EU, there are certain modifications/amendments made to the Medical Devices Ordinance (MedDO) and the Federal Council-approved supplementary provisions for implementing medical device regulations which have been in force since May 26, 2021. These provisions are designed to offset the negative consequences in the absence of an MRA (Mutual Recognition Agreement) update and to ensure a sufficient supply of medical devices in Switzerland. As the MedDO changes have come into force on May 26, 2021, medical device manufacturers willing to enter the Swiss market must understand the amendments and ensure to align with them in their processes for successful compliance.
The application of software technologies in varied healthcare management, including diagnosis or treatment of a disease, is accelerating at an unprecedented rate. Global medical device authorities are revamping their regulations and guidelines to address these booming device technologies. In January 2021, the TGA released the original draft on medical device software regulations, which was further revised in February 2021. On July 27, 2021, the TGA released a detailed flow chart addressing the common ambiguities that device manufacturers and Regulatory professionals may have about the medical device software classification.
In July 2021, the Medical Device Coordination Group (MDCG) published a joint implementation and preparedness plan for the In Vitro Diagnostic medical devices Regulation 2017/745 (IVDR). The IVDR is expected to come into force later in May 2022. As the IVDR implementation sets specific challenges for the stakeholders, the European Commission (EC), and the Member States, the MDCG reviewed relevant inputs from all the stakeholders and established a joint implementation plan. The MDCG document highlighted the most critical aspects of the IVDR implementation process to assist the parties involved in focusing on their resources and acting in the most efficient way. As per the document, the actual implementation of the IVDR will require active involvement of all the stakeholders and will include some milestones as well.
The US FDA published a guidance document to help the industry and the Health Agency (HA) staff determine when software changes to a medical device require a manufacturer to submit and obtain FDA clearance of a new premarket notification (510(k)). This guidance intends to enhance the predictability, consistency, and transparency of the “when to submit” decision-making process by providing a least burdensome approach and describing the Regulatory framework, policies, and practices underlying such a decision specifically related to software changes.
In July 2021, Health Canada released guidance describing how the Agency inspected the licensed medical device establishments, the inspection process and explained how inspectors should assess the compliance with the Food and Drugs Act and Medical Device Regulations. One section of the guidance describes that the entities involved in manufacturing, promoting, or marketing the medical devices should achieve and sustain compliance with the appropriate requirements set forth under the Food and Drugs Act. The other section describes the factors to be considered by inspectors when assessing the compliance of a medical device establishment with the Regulatory requirements set forth by the Medical Devices Regulations.
Software and Artificial Intelligence (AI) play an important role in the medical device sector with a fast-developing and wide set of applications in the health care system. However, alongside the rapid developments, Regulatory Agencies are updating measures to further protect patient safety and ensure device efficiency. In September 2021, the MHRA developed an extensive work program that provides Regulatory changes across the software as a medical device lifecycle from qualification to classification to pre and post-market requirements. The changes provided in this program are expected to deliver a high degree of protection for patients and intend to ensure that the UK is the home of responsible innovation for medical device software.
Global Health Authorities’ Guiding Principles on GMLP for Medical Devices
Over the past few years, evolving technologies have led to exponential growth of Artificial Intelligence (AI) and Machine Learning (ML). While AI and ML create new opportunities for medical device organizations, the rapid adoption of AI and ML has several risks and complexities and hence requires stringent regulations. Accordingly, global Health Authorities (HAs) and policymakers keep track of the growing number of AI/ML developments to ensure the laws and regulations are relevant to the new challenges and inventions. To avoid Regulatory challenges and ensure smooth functioning of AI/ML while implementation, the HAs have devised several guidance documents. In October 2021, the USA, Canada, and the UK Health Authorities have jointly identified ten (10) guiding principles for the development of Good Machine Learning Practice (GMLP) for medical devices. These guiding principles assist in promoting safe, effective, and high-quality medical devices that use AI/ML.
Food & Food Supplements
On October 01, 2021, the UK passed a new labeling law, ‘Natasha’s Law,’ requiring all food retailers to display an entire list of ingredients and allergen labeling on each food item made on the premises and prepacked for direct sale. This law is named after Natasha Ednan-Laperouse, a teenager who died after eating a prepacked baguette containing sesame, which did not require allergen labeling at the time. After this event, the Government decided to implement severe laws that would protect the consumer from ingesting food with allergic ingredients.
This Law came into force in October 2021, giving businesses a transition period to prepare for the new rules. It is expected to bring more consistency in the labeling regulations of prepacked food products besides preventing end-users from consuming food that has allergic ingredients.
The Food Safety and Standards (Health Supplements, Nutraceuticals, Foods for Special Dietary Use, Food for Special Medical Purpose, Functional Food and Novel Food) Regulations 2016 was implemented on January 01, 2018. Recently, the FSSAI, with the previous approval of the Central Government, made the first amendment in the above regulations. These regulations cover eight (08) categories of functional foods - Health Supplements, Nutraceuticals, Food for Special Dietary Use, Food for Special Medical Purposes, Specialty Food Containing Plant or Botanicals, Foods Containing Probiotics, Foods Containing Prebiotics, and Novel Foods. All the Food Business Operators (FBOs) need to comply with these regulations’ provisions from April 01, 2022.
India has a rich tradition of sweets, snacks, and savories with a difference in taste, texture, and ingredients. Traditional milk-based sweets are mostly prepared from khoya, chhena, sugar, and other ingredients such as maida, flavors, and colors. In addition, there are sweets containing cereal, starch, or grain as the main ingredient. There are also sweet snacks coated with jaggery, sugar, honey, and other ingredients.
With no specific regulations in place, there are many challenges in the manufacturing and selling of sweets, snacks, and savory food. The packaging and labeling requirements are often neglected. As a result, small and medium food business operators are required to obtain a central license under the proprietary food products, which is costly and entails numerous compliance requirements. Hence, the FSSAI has come up with a new food category to imply standard procedures for the aforementioned food categories.
One of the amendments applied in the year 2020 for the labeling compliance of food and drinks is the update of the Nutritional Facts Panel by the United States Food and Drug Administration (US FDA). This amendment has been made by considering certain factors, most important of which was the ease for a consumer to choose better food and make informed food choices leading to a long and healthy life.
While existing manufacturers had time until July 2021 to comply with the updated regulations, the new manufacturers and distributors are already taking care of the label compliance in this regard. As per the US FDA, manufacturers with $10 million or more in annual sales were required to update their labels by January 01, 2020, and manufacturers with less than $10 million in annual food sales were required to update their labels by January 01, 2021.
January 01, 2021, was marked as the deadline for the United Kingdom (UK)-based food and beverages manufacturers to implement their product labeling changes. On November 05, 2020, the UK Department for Environment, Food & Rural Affairs (DEFRA) published an update related to the information to be mentioned on the label of food products that are intended for sale in the UK and the European Union (EU), particularly in Northern Ireland. According to the update, from January 01, 2021, manufacturers distributing pre-packaged food or caseins in Northern Ireland must include the address of a Northern Ireland or EU Food Business Operator (FBO) on the product label. Manufacturers can also mention the address of a Northern Ireland or an EU27-based importer.
The U.S. Environmental Protection Agency (EPA) revised the Lead and Copper Rule (LCR) to protect children and communities from the risks of lead exposure. EPA aims to get lead out of the drinking water and empower communities through the correct information.
Effective date: The final rule was going to be effective from December 16, 2021.
Postponed Effective Date: Previously, the effective date of the final rule was published on January 15, 2021, and then delayed in a rule published on March 12, 2021, in which it was postponed until December 16, 2021.
Compliance Date: The compliance date for the final rule is delayed until October 16, 2024.
Chemical regulations in South Korea are managed by various Ministries such as the Ministry of Environment, Ministry of Employment and Labor, Ministry of Health and Welfare, Ministry of Agriculture, etc., under numerous laws based on the uses and hazard properties of chemical substances. All the Authorities aim to protect human health and the environment from the toxicity of chemicals. The K-REACH amended Act was published in March 2018 and came into force on January 01, 2019. Any company with an intent to import or manufacture a new chemical substance or an existing chemical substance must register under K-REACH.
Based on the amended K-REACH, the deadline for the registration of new substances to manufacture or import the existing chemical substances greater than or equal to 1000 tonnes per year and CMR substances greater than or equal to 1 ton per year ended on December 31, 2021.
Following the Brexit on December 31, 2020, Great Britain is no longer a part of the EU scheme for regulating biocidal products. The existing EU Biocidal Products Regulation (EU BPR) has been transformed to the Great Britain Biocidal Product Regulation (GB BPR). However, most aspects of the EU BPR will continue in the same way under the GB BPR.
Here are a few deadlines that ended in the year 2021 for GB BPR:
Authorization Holder must be Established in
January 01, 2021
January 01, 2021
Poison Centres take the responsibility to collect relevant information about hazardous mixtures and provide medical advice during health emergencies. With various notification systems and information requirements across different countries in the EU, ANNEX VIII of the CLP Regulation was implemented. It aims to harmonize the hazardous information and the format that must be submitted to Poison Centres to improve emergency responses.
Article 45 of the CLP Regulation describes the notification obligations for importers and downstream users who want to place hazardous chemical mixtures in the EU market. The first deadline ended on January 01, 2021, for mixtures classified as hazardous for consumer use and professional use products. Therefore, companies manufacturing these products must comply with the new harmonized Poison Centre Notification (PCN) format.
The CDCSO is responsible for regulating imported beauty and personal care products in India. Over the years, the DTAB had received several proposals and VIP references for an indication to classify products as per their vegetarian or non-vegetarian origin. After detailed deliberation, the Board had given an official notice concerning the indication. The notice specified that manufacturers may indicate red/brown or green dots on beauty care products to indicate their non-vegetarian or vegetarian nature, respectively. This labeling method is applicable for packaging tubes of toothpaste, shampoos, soaps, other cosmetics, and toiletries. The indication, however, would be voluntary for cosmetic manufacturers. This new indication will allow consumers to gain more information about product ingredients and make informed decisions as per their individual preferences.
Brexit had brought about significant changes in the EU and the UK in terms of regulations affiliated with cosmetics, pharmaceuticals, personal care products, and medical devices. The UK decided to leave the EU in 2016 and officially left the trading bloc on January 31, 2020. Both countries decided to keep a few things unaltered until December 31, 2020.
In 2021, some of the significant changes that took place in the UK cosmetic industry include the role of a Responsible Person (RP), Product Labeling- Responsible Person (RP), Product Labeling - Country of Origin, and Notification.
In Brazil, the Agencia Nacional de Vigilancia Sanitaria (ANVISA), i.e., the National Health Surveillance Agency, regulates the production, import, and trade of cosmetics products. To ensure consumer safety and well-being, the ANVISA introduced three (03) resolutions of the collegiate Board (RDCs). These resolutions, published in the official gazette on August 11, 2021, are applicable to cosmetics, perfumes, and personal care products. They are as follows:
This resolution includes elements of preservative action that are allowed in cosmetics, perfumes, and personal care products. It contains a list with a description of sixty (60) substances.
In this resolution, the identification of one thousand four hundred and four (1,404) banned substances that cannot be used in personal care products, cosmetics, and perfumes, are listed.
The third regulation, RDC 530/2021, contains a list of more than a hundred (100) elements that are not permitted in cosmetic products except under the conditions and restrictions established by the Agency. The same Act also contains a separate list of twenty-six (26) components of fragrances and aromas. These components must be indicated on the labeling of cosmetics, perfumes, and personal care items when their concentration exceeds 0.001% in non-rinse products and 0.01% in rinse-off products.
In December 2020, the European Commission published the Regulation (EU) 2020/2151, which set out harmonized marking requirements for single-use plastic products. Plastic and plastic products have been a constant threat to the marine environment and have far-reaching consequences on marine life. One such example is the Pacific Trash Vortex - a garbage patch of a gyre of marine debris particles in the central North Pacific Ocean. Considering such devastating effects on marine habitats, the updated regulation is a much-needed change that will help in reducing marine waste. The Regulation applied to all the EU Member States from July 03, 2021. It requires marking to be added as a sticker to all packaging of ‘Wet Wipes’ placed on the market before July 03, 2021.
In a nutshell, 2021 has been a great comeback and has been quite far-reaching in terms of developing stringent regulations. The developments made many manufacturers and stakeholders align with the regulations for the best of compliance and successful and quick market entry of the products.
As a pioneer in offering end-to-end Regulatory services, Freyr has offered customized assistance to many global customers in fulfilling their on-demand needs. In addition to expanding operations to new locations, Freyr has been with the industry to meet new age requirements and hence, has initiated service offerings like UKRP in-country representation and Swiss AR, along with a specialized focus on digital transformation and comprehensive software solutions. Freyr has given a facelift to technological services in the Regulatory arena with the introduction of Freyr Digital.
With a strong foothold in the industry and with advanced service offerings, Freyr is looking forward to stepping into 2022 to ensure that the world sees the best of compliant, safe, and effective medicinal products, devices, cosmetics, food and food supplements, and chemical products.