The continued growth in the development of cell and gene therapies (CGTs) has led to an exponential increase in the workload of the organisations involved. As ClinicalTrials.gov. indicates, there will be more than 1,000 ongoing clinical trials for CGTs registered in 20221. The US Food and Drug Administration (FDA) expects that they will receive more than 200 investigational new drugs (INDs) per year, building on the more than 800 active cell therapy or directly administered gene therapy INDs currently submitted to the FDA2. The diverse and complex nature of CGTs can often make regulatory affairs matters more intricate than traditional pharmaceutical products.
To meet the demand for advanced medicines, the FDA announced in the Federal Register that the Office of Tissue and Advanced Therapies (OTAT) in the Center for Biologics Research and Evaluation (CBER) has been changed to the Office of Therapeutic Products (OTP) and upgraded to a “Super Office” that should significantly improve the efficiency of the workflow for reviewing regulatory submissions. This will include therapeutic tissue-engineered products, human cell and tissue products and combination products, as well as gene therapies that result in persistent cellular modifications.
This initiative has also received significant financial support from the US Congress. More products will be able to be reviewed and supported by the knowledge of more scientific experts, which should help companies to launch their products in a timely manner. Advanced medicines such as CGTs are often intended to meet unmet medical needs and the steps taken by the FDA are a positive move to ensure patients receive life-changing treatments.
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The manufacturing of medicinal products for the EU market frequently occurs outside the EU zone and this presents logistics and regulatory considerations for the product owner. All stages of manufacturing medicinal products in third countries should be carried out in accordance with EU Good Manufacturing Practice (GMP) guidelines if the products are destined for the EU market. It is imperative to ensure that products are consistently manufactured and controlled according to quality standards.
This article outlines key considerations when importing medicinal products from outside the EU.
Manufacturer/Importer Authorisation (MIA)
To import products into the EU, wholesale distributors receiving medicinal products from third countries must hold a Manufacturer/Importer Authorisation (MIA) for the site where QP certification and physical importation occur. MIA is also required if the location where batch certification is performed is different from the location where the imported product is physically received.
Importers are required to adhere to GMP standards as MIA holders, which include setting up a pharmaceutical quality system, having sufficient personnel and workspace for the relevant activities, planning appropriately for the handling of complaints and recalls, and putting protocols in place to manage their supply chains.
Following Chapter 7 of the EU GMP guidelines, a written agreement should be signed between the premises engaged in manufacturing and importation activities and the Marketing Authorisation Holder (MAH), and should set out the respective responsibilities of the MAH, the importer, the QP certification site and the third country manufacturer.
Qualified Person (QP) Certification and Quality Control Testing of Imported Medicinal Products
Imported medicinal products must be physically imported and cleared through the customs territory of an EU country and then stored under quarantine upon receipt until released for QP certification. It is a legal requirement that the QP certify the batch to ensure that all medicinal products imported from third countries are manufactured under the EU GMP standards and that products will be tested when imported into the EU unless there is a Mutual Recognition Agreement (MRA) or Agreement on Conformity Assessment and Acceptance of Industrial Products (ACAA).
Full batch documentation must be provided to the MIA holder responsible for the QP certification of the batch to ensure continued product quality. (see Annex 21 of the EU GMP guidelines for details)
Relevant ordering and delivery documentation should be included in batch documentation, such as the details of transportation (e.g., temperature monitoring records).
If batches have been subdivided and individual quantities imported separately, documentation confirming quantity reconciliation should be provided at the QP certification site.
Details of the on-going stability programme, such as protocols, results and reports, should also be available for inspection at the QP certification site, as required in Chapter 6 of the EU GMP guidelines.
All documentation must be kept in compliance with the standards of Chapter 4 of the EU GMP Guidelines. Additionally, the certifying QP oversees making sure that reference and retention samples were obtained in compliance with relevant GMP for Investigational Medicinal Products (IMPs) guidelines as well as the criteria in Annex 19 of the EU GMP guidelines. Furthermore, all batches of medicinal products where a MRA is not present must undergo quality control testing in an EU based laboratory (e.g., a contract laboratory) to help ensure the quality and safety of the products entering the destination country.
The QP will certify the batch upon approval of the batch testing results listed below: (see Annex 16 of the EU GMP guidelines for details)
Quantitative and qualitative analysis of active ingredients and related medicine components. All the other tests or checks necessary to ensure the quality of medicinal products is in accordance with the requirements of the MA.
Importer of Record (IoR)
During importation, an Importer of Record (IOR) in the destination country is required, as they are responsible for ensuring that the medical devices/goods are imported in accordance with the laws and regulations of the importing country. The following documents are example requirements:
Product Classification – details of the category and value of the imports.
Import and Export licenses – permission to import products.
Fees/Taxes/Duties – documents when paying related fees, taxes or duties.
In addition, the IOR also needs a valid Value Added Tax (VAT) number and a valid EU Economic Operator Registration and Identification (EORI) number, which can be applied to the local tax authorities (usually the EU country where the imported products will arrive) as an identification number for all customs procedures when exchanging information with the EU customs authorities.
Contact us today for further information on importation of medicinal products into the EU. HiTech Health holds Manufacturer’s/Importer’s Authorisations (MIAs) for the importation and QP certification of both Commercial and Clinical products within the EU. By partnering with us and working with our experienced cross-functional team under our already approved MIAs, you reduce personnel and regulatory cost, thereby making considerable financial and time savings in getting your product to the clinic or market. HiTech Health have a team of Qualified Persons (QPs) and Responsible Persons (RPs) available to support your product portfolio.
HiTech Health is delighted to be selected as the ‘Spotlight’ company by the Pharmaceutical Manufacturing Technology Center (PMTC). Read the article in the PMTC Monthly Spotlight.
HiTech Health is a full-service Contract Development and Manufacturing Organisation (CDMO) in the cell and gene therapy space. We have added GMP Clean Rooms to our state-of-the-art laboratories in Galway, allowing for the manufacture of clinical materials. This adds significantly to existing capabilities which includes process, analytical development and supporting services.
Please email info@hitech-health.com to request further information on the range of services HiTech Health can provide.
Ensuring product quality and integrity is maintained throughout the end-to-end supply chain of medicinal products is imperative. The system for managing quality should encompass the organisational structure, procedures, processes and resources, as well as activities necessary to ensure confidence that the product delivered maintains its quality and integrity and remains within the legal supply chain during storage and transportation. This means that the legal owner of the product must have full oversight and traceability of the product at all times during distribution, ensuring that falsified and counterfeit medicines do not enter the product supply network. Below are three key points to consider when seeking to comply with Good Distribution Practice (GDP).
Are GDP Self-Inspections being performed?
Performing self-inspections to ensure your company is maintaining compliance with the latest GDP requirements can be beneficial. Self-inspections can support identifying gaps and areas that are higher risk in your supply chain. An internal team assigned with the task of performing GDP self-inspections can:
Critically review processes and procedures to check that the company is conducting supply chain activities in a GDP-compliant manner
Review CAPAs and ensure that they are implemented and closed
Examine records and agreements as well as procedures to ensure there are no deficiencies
Regular self-inspections can help foster a company culture of continuous improvement and compliance.
Does your company perform Bona Fide Checks on Customers and Suppliers?
Bona fide checks, in simple terms, provide evidence that someone is who they say they are, or has the authority and experience they claim to have. Performing bona fide checks is an activity that can often be overlooked in the pharmaceutical industry but is essential for maintaining GDP compliance. Regulatory deficiencies may include:
No bona fide checks carried out at all
No verification that customers or suppliers are authorised to perform the operations that they are performing
The address of the customer or supplier has not been verified, or the wrong address is provided
Licences of the customers or suppliers not requested and reviewed. For example, a wholesaling partner who does not provide a copy of a Wholesale Distribution Authorisation (WDA) licence in the EU
Ensuring your company has a well defined procedure for performing bona fide checks and appropriately qualifying customers and suppliers can help ensure GDP compliance.
Are company employees being effectively trained on GDP?
Personnel involved in the supply chain activities of medicinal products are required to receive training on GDP and how it pertains to the duties they perform. Deficiencies that may be observed during a regulatory audit include:
Personnel conducting duties prior to being trained on the relevant procedures, guidelines, and legislation of GDP
When a Responsible Person (RP) has been assigned, a role profile (job description) did not include all the required responsibilities as per Chapter 2 of the EU guidelines
No evidence of maintaining competence through regular training/refresher training
There was no company requirement for an assessment of the effectiveness of training to be conducted or it was not conducted adequately
Developing a training programme that is based around the guidelines and legislation will support safeguarding end users against potential hazards in the supply chain.
Contact us today for further information on ensuring GDP compliance. HiTech Health have a team of Qualified Persons (QPs) and Responsible Persons (RPs) available to support your product portfolio.
EudraLex Directive 2013/C 343/01 Guidelines on Good Distribution Practice of Medicinal Products for Human Use
Health Products Regulatory Authority (HPRA) – Guide to Control and Monitoring of Storage and Transportation Temperature Conditions for Medicinal Products and Active Substances
HPRA GDP Information Day – May 2022 – http://www.hpra.ie/homepage/medicines/news-events/item?t=/gdp-and-gmp-conferences-registration-announcement&id=50581126-9782-6eee-9b55-ff00008c97d0
HiTech Health are delighted to have attended the 3rd Global Bioprocessing, Bioanalytics and ATMP Manufacturing Congress on 16th and 17th May. HiTech Health’s Quality and Compliance Lead Julie-Anne O’Neill and Manager of Cell and Gene Therapy Operations Aoife Duffy presented at this in-person event and shared experiences in navigating the quality, regulatory and manufacturing challenges of ATMPs.
On day 1, Julie-Anne talked about ATMP manufacturing and regulatory challenges from a QP’s perspective, including considerations for; materials and supplier control, manufacturing complexities, sterility assurance, release strategy and regulatory, training and personnel, traceability of ATMPs, stability; and concessionary release. ATMPs are complex products and risks may differ according to the type of product, nature or characteristics of the starting materials as well as the level of complexity of the manufacturing process. This presents a number of unique challenges to ATMP development and manufacturing that Julie-Anne talked about on the day.
It is important to have a QP experienced in ATMPs involved as early as possible in the development process to ensure quality and compliance standards are met. You can find out more about our QP services here.
On day 2, Aoife presented how to create and establish an ATMP infrastructure and what is needed to build a robust supply chain for cell and gene therapies. Aoife talked about key considerations for building the right capabilities and systems to ensure patients receive the vital therapies. During the presentation, Aoife announced that during the early stage of the Covid-19 pandemic, HiTech Health established a laboratory in County Galway, providing process and analytical development services. The company now has two R&D laboratories operating and offers a growing range of services in the ATMP space. The next expansion phase, adding GMP clean rooms, is almost completed and will include manufacturing services for clinical trial materials.
We would like to thank Global Engage for organising this exciting event as well as the attendees who engaged with this year’s Global Bioprocessing, Bioanalytics and ATMP Manufacturing Congress in Dublin.
On the 31st January 2022, The Clinical Trials Regulation ((Regulation (EU) No 536/2014)) became effective and replaced the previous Directive (EC) 2001/20/EC and corresponding national legislation. The Clinical Trials Regulation (CTR) coordinates the review and regulatory process for drug clinical trials across the EU. Prior to the implementation of the new CTR, clinical trial sponsors were required to submit clinical trial applications separately to national competent authorities and ethics committees in each country to gain regulatory approval to run a clinical trial.
The new CTR enables sponsors to submit a single application via an online platform known as the Clinical Trials Information System (CTIS) for approval to run a clinical trial in up to 30 EEA countries. The goal is to optimise the clinical trial process and make it more efficient to conduct pan-European trials. The regulation seeks to provide a single, unified portal and database for both trial sponsors and regulatory agencies in each member state. For sponsors, the portal will be the main platform to submit applications and notifications allowing regulators to conduct their assessments and supervise the trial. During a clinical trial, users of CTIS can collaborate with national regulators while recording the results. In addition to this, the CTIS enables the monitoring of results and assessing safety-related data in this single integrated online platform.
The CTR and CTIS aims include the implementation of clinical trial regulations, to improve the efficiency and transparency of drug clinical trials and ensure the highest safety standards for trial participants. Under the new CTR, clinical trial sponsors can use the Clinical Trials Information System (CTIS) from 31 January 2022, but are not obliged to use it immediately, in line with a three-year transition period. National regulators in the EU Member States and EEA countries will use CTIS from 31st January 2022. The Clinical Trials website can be visited here and the CTIS can be visited here where you can find out more information.
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