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This comprehensive resource covers product change evaluation, postmarket surveillance, audit/inspection compliance, and various other laws and regulations pertaining to maintaining a product on the market.
Hear from leaders around the globe as they share insights about their experiences and lessons learned throughout their certification journey.
Andrada Armasu, MPharm, RAC
Feature Articles | 07 December 2021 | Citation
Herbal medicinal products
HMPs are subject to the same pharmaceutical quality requirements (chemistry, manufacturing, and controls) as the other medicinal products.
The quality and the manufacturing process are secured by adherence to the guidelines for good agricultural and collection practices and good manufacturing practices. The following should be described in the initial application: Characteristics of the raw herbal materials, plant parts used, compliance with the European or national pharmacopoeia, extraction methods, tests to control for stability of the raw materials and methods to control the concentration of active constituents, and the absence of impurities.
In addition, the following should be described for the finished product: Components of the medicinal product control for consistency of the final product, validation of analytical procedures, and stability controls. For the complete list of requirements, Directive 2003/63/EC and other EMA guidelines for the production of HMPs should be consulted.3-5
Many herbal products on the market have not been thoroughly tested for their pharmacology and toxicology, so pharmacovigilance has paramount importance in detecting unwanted reactions.29
Herbal medicinal products
As with all medicinal products that have been placed on the market, HMPs are required to comply with the European regulations concerning continuous monitoring and pharmacovigilance, to assure that aspects impacting the safety profile are detected and assessed and necessary measures are taken.
A range of methods are used for postmarket monitoring of drug safety. The existing system was developed with conventional medicines in mind; adapting these methods to monitoring the safety of herbal medicines presents additional challenges because of their unique characteristics and the ways in which these are regulated, used and perceived.2
Spontaneous reporting is currently the main method of detecting signals of safety concerns associated with herbal medicines.2 Adverse drug reaction (ADR) reports are collated into repositories, the largest being the WHO Collaborating Centre for Monitoring Drug Safety (Uppsala Monitoring Centre, UMC), which gathers information from more than 100 countries. Statistical methods are then used to identify disproportionate reporting rates which can lead to a safety signal.29 In the EU, EudraVigilance is the platform used to manage information on safety reports. Collected data are being published in the European database of suspected adverse drug reaction reports.30
Under-reporting is a known problem with spontaneous reporting systems. It occurs for a range of reasons, such as lack of association between the herb and the adverse event, lack of awareness that herbal ADRs should be reported, and ADRs being managed by the patient alone.2,29
Another well-established method for monitoring safety is prescription event monitoring, however, this is of limited use for herbal medicines, given that are rarely prescribed. Pharmacoepidemiological methods, such as case-control and cohort studies, can be used to test hypotheses developed after signals are detected, but these methods have been underused for herbal medicines.29
As part of the pharmacovigilance obligations, manufacturers are required to submit to competent authorities periodic safety update reports (PSURs) for every authorized product. This contains an update of the product’s worldwide safety experience and critical analysis of the benefit-risk balance. For low-risk or old products, including well-established use medicines and THMPs, PSURs are not routinely required.31,32 For such products, PSURs must be submitted only on request or where there is a condition in the marketing authorization – for example, for Hypericum perforatum L., herba (every 5 years), senna glycosides standardized 60% (every 10 years), diosmin (every 13 years), silibinin, dry extract from Milk Thistle fruit (silymarin; every 13 years), and caffeine (every 28 years).33,34 The marketing authorization holders of medicinal products exempted from submitting PSURs should use alternative mechanisms to communicate relevant new safety information to regulatory authorities.35
Manufacturers are required to monitor the safety profile of medical devices, including herbal-based products, through implementation of a PMS plan. As part of the PMS system, postmarket clinical follow-up (PMCF) data is required for high-risk devices to confirm safety and performance, where long-term performance and safety information is unknown or where CE marking was based on equivalence. PMCF can be omitted for devices where long-term influence data is available. Data from PMCF will also be used to update the clinical evaluation report (CER) and the summary of safety and clinical performance (SSCP), where applicable.16,36
Main PMCF findings must also be included in the periodic safety update report, which is mandatory for Class IIa, IIb and III devices. For Class IIa medical devices, the PSUR is updated every 2 years, and annually for Class IIb and III devices.8,17 For Class I devices, manufacturers prepare a PMS report.21
To fulfill the vigilance or materiovigilance obligations, the manufacturer must report to national competent authorities any serious incidents related to the use their medical devices. If a field safety corrective action, including a recall, is deemed necessary, then the manufacturer must also issue a field safety notice and send copies to the competent authorities and to affected costumers.8
Competent authorities, on their end, should take all necessary steps to ensure information concerning serious incidents is centrally recorded and evaluated. This coordination is facilitated by a central database, Eudamed, through which authorities and European Commission exchange vigilance and other legal information.8,37
Moreover, manufacturers should have suitable systems in place and proactively scrutinize trends in complaints and incidents occurring with their devices.8
There is no centralized EU system for monitoring food safety‒related issues for food supplements. Monitoring is carried out just at the member state level (e.g., in France) on a voluntary basis and to varying extent.12
In the context of the EU legislation in place, when risks to public health are detected in the food chain, the RASFF (the Rapid Alert System for Food and Feed) is a key tool for ensuring the flow of information to enable swift reaction, including recalling products from the market. The European Commission notes that, because there is low number of reported incidents involving food supplements containing plant substances and a limited recourse to the RASFF for products containing plant substances, this could suggest an overall effectiveness of the current general regulatory framework.25
By way of example, in 2014, there were 208 RASFF notifications in the EU on food supplements (it should be noted this product category also includes dietetic and fortified foods). Of those notifications, 158 concerned the inclusion of unauthorized ingredients in food supplements. In addition, 89 of the 208 RASFF notifications (43%), the food supplements had been manufactured in another member state or were imported through another member state. Incidents were generally found to concern noncompliant products manufactured in third countries, marketed through specific channels, such as online purchases.25
Tags: efiicacy, EU, herbal medicinal product, HMP, PMS, postmarket surveillance, quality, safety