Elemental impurities risk assessment can be a challenge for pharmaceutical companies.
As described in the next paragraph elemental impurities risk assessment is mandatory, since January 2023, for the most of the VMP on the market.
These risk assessment can be challenging for pharmaceutical companies for different reasons, for example:
- Old dossier with leak of information;
- Problem on obtaining information from supplier of API and excipients;
- Problem on obtaining information from supplier of container closure systems;
- Problem on obtaining information on manufacturing equipment;
- No experience inside the companies in Chemistry and Pharmaceutical Technologies.
For all the problems cited above, and others more specific, some companies are still conducting their risk assessment without being able to identify any potential elemental impurity. In all that case, it is important for the companies to act to guarantee the safety of its products and be compliant with the regulatory requirement.
The updated European Pharmacopoeia General Monograph 2619 is being used in January 2023 as a base for new regulations regarding the control of elemental impurities.
The European Medicines Agency (EMA) has revised the European Pharmacopoeia General Monograph 2619, which is an accepted standard for risk management in regards to the levels of elemental impurities. Since it came into effect in January 2018, manufacturers of products outside of the General Chapter 5.20 and in ICH Q3D, such as veterinary medicinal products, have not elaborated on the scientific principles on which risk assessment/risk management should be based.
Mandatory Risk Assessment
As a result, a decision tree has been created by the Committee for Veterinary Medicinal Products (CVMP) with the goal of allowing regulators to conduct a full risk assessment by January 2023, demonstrating compliance with European Pharmacopeia General Monograph 2619 as seen below.
For Marketing Authorization Applications is requested a full risk assessment demonstrating the compliance with European Pharmacopeia General Monograph 2619. For the existing Marketing Authorizations with or without intentionally added elemental impurities the risk assessment should have been done within January 2022 and January 2023.
For companies that are marketing authorization holder and not manufacturer performing a risk assessment is a challenge, as the know-how of the part 2 of their product dossier is managed by third parties.
In addition is know that, as reported in Reg.(EU) 2019/6 it is a responsibilities of the marketing authorisation holders to take account of scientific and technical progress and introduce any changes that may be required to enable the veterinary medicinal product to be manufactured and controlled by means of generally accepted scientific methods. So is mandatory to be compliant with the VICH guidance closing the identified discrepancies with the international scientific progress and last developments.
How we can identify the risk related to elemental impurities?
The first step of a risk assessment is every time the “risk identification”; in our case the risk to be identified is the potential presence of elemental impurities inside the veterinary medicinal products.
If for a new marketing authorization that should be easy, as the product is developed considering the risk of presence of EI since the beginning, for existing Marketing authorization identifying a potential presence of EI is more challenging.
There are currently three approaches to construct the risk assessment:
- The medicinal product approach
- The component approach
- The combination of the medicinal product and component approaches
For all the cited approach, the risk identification must consider all the possible sources of elemental impurities:
- Residual impurities resulting from elements intentionally added (e.g. catalysts) during the synthesis of the active substance, excipients or other medicinal product components. The risk assessment should address the potential for inclusion of elemental impurities in the medicinal product;
- Elemental impurities that are not intentionally added and are potentially present in the active substance, water or excipients used in the preparation of the medicinal product;
- Elemental impurities that are potentially introduced into the medicinal product components and/or the medicinal product itself from manufacturing equipment;
- Elemental impurities that have the potential to be leached into the medicinal product components and to the medicinal product itself from primary packaging.
Stakeholder involved in the Risk identification
Risk identification is the first phase of the assessment and probably the more challenging as many stakeholder are involved as source of data. The most important to be considered are:
- Regulatory department, managing the part 2 of VMP dossier;
- Quality Control laboratory
- Manufacturer of active substances and excipients;
- Distributor of active substances/excipient if they perform repackaging activities;
- Manufacturer of container closure system;
- Manufacturer of the VMP finished product;
- Supplier/manufacturer of the equipment involved in the manufacturing process.
The collection of information from all the stakeholder is the crucial part of the assessment. In order to evaluate the potential presence of EI in the VMP a structured approach with evidences is mandatory to demonstrate how the decisions are taken.
PQE Group can provide support to your business and ensure the full compliance with the guidelines on Elemental Impurities and help your organization to get the missing information to speed up the process and understand if actions are needed as risk minimization measures.
Our services portfolio guarantees a comprehensive solution to cover all of your needs by using our Glocal approach -- we work at a local level while maintaining a global mindset.
- Perform/write the EI risk assessment
- Support your QC for the EI testing of API, Exicipient and finished product
- Webinars and trainings to educate your workforce on the new concepts of the recent release
- Support for integrating new concepts and methodologies in your QMS
- Workshops, Assessments & Gap Analysis oriented to prepare for the update of the CVMP
- Writing of new procedures and/or updating existing ones
- Support for the application of new concepts to real (pilot) projects, systems, equipment and infrastructures
For more information read our previous article on the topic: https://blog.pqegroup.com/ra-phv/elemental-impurities-in-veterinary-medicinal-product
- European Medicines Agency REF: EMA/CVMP/QWP/631010/2017-REV2 - Committee for Medicinal Products for Veterinary Use (CVMP)
- ICH Harmonized Guideline: GUIDELINE FOR ELEMENTAL IMPURITIES Q3D (R2)
- European Pharmacopoeia General Monograph 2619