Please note that updates to regulations may have been implemented since the publication of this article.
The 20th century was the century of many scientific discoveries in the field of medicine. Clinical trials play an important role not only in the research of new drugs but are also used in lifecycle management of drugs already existing on the market. Innovative medicines go through a long research and development process before being introduced to the market. The generic medicines are studied for a shorter time when bioequivalence and bioavailability studies are conducted to confirm equivalency with the originally patented medicine. Each manufactured drug intended for human use must be certified prior to its use in a clinical trial by a Qualified Person (QP). A QP ensures the compliance of each batch of Investigational Medicinal Products (IMP), manufactured in, or imported into the European Union, with current requirements. In this blog we explain the steps and the requirements for QP certification of an IMP.
Why Is A Qualified Person Required in Clinical Trial Process?
Each batch of manufactured / imported IMP must be certified, just like any batch of medicinal product intended for human use. Only a QP residing in EU territory is authorized to carry out batch certification of a manufactured / imported IMP. Each of the EU Member States has established specific domestic requirements that such a person must fulfil (e.g. education, experience, knowledge of the national language etc.).
Certification and Release of IMP
IMP remains under the control of the Sponsor of the clinical study until completion of a two-step procedure: certification by the QP, and release by the Sponsor for use in a clinical trial following fulfillment of the requirements of Article 9 (Commencement of a clinical trial) of Directive 2001/20/EC [repealed Jan 2022]; the so called “regulatory green light”. Once the two-step procedure has been cleared the IMP can be administered to the patients enrolled in the clinical study. ProPharma Group can help you get the MIA license your company needs to bring an IMP to market; alternatively you can make use of ProPharma Group’s own MIA license to have your IMP certified by one of the ProPharma Group’s experienced QPs.
Administration of IMP to patients should not occur until the QP has certified it in line with Article 62(1) of Regulation (EU) No 536/2014 that the requirements of Article 63(1) and (3) of Regulation (EU) No 536/2014 and those set out in Article 12 of the Commission Delegated Regulation (EU) No 2017/1569 are met.
Manufacturing and Import of IMP
Below are listed a few of the elements that should be considered during certification of IMP batches according to annex 13 of Eudralex Volume 4, prior to its administration to patients. The list presented below contains minimum elements to be taken under consideration by QP’s during certification of IMP and additional ones may be required depending on product specific aspects:
- Batch records, including control reports, in-process test reports and release reports demonstrating compliance with the product specification file, the order, protocol, and randomization code
- All deviations or planned changes. In the case of an unexpected deviation during manufacturing process or inspection in relation to the details included in authorization, the QP may consider confirmation of compliance or batch certification if:
- The requirements of registered specifications are met for Active Pharmaceutical Ingredient (API), excipients, packaging materials and finished product
- The deviation has been thoroughly investigated and the root cause remedied (a modification of the authorization may be necessary) and it has been confirmed that it has been included in the stability studies
- The impact of the deviation has been assessed in accordance with the principles of QRM using the correct approach (assessing the potential impact of the deviation on the quality, safety, and efficacy of the product and demonstrating that this impact is negligible)
- Production conditions
- The validation status of facilities, processes, and methods
- Examination of finished packs
- Where relevant, the results of any analyses or tests performed after importation
- Stability reports
- The source and verification of conditions of storage and shipment
- Audit reports concerning the quality system of the manufacturer
- Storage of retain and reference samples
- The documents certifying that the manufacturer is authorized to manufacture investigational medicinal products or comparators for export by the appropriate authorities in the country of export
- Where relevant, regulatory requirements for marketing authorization, GMP standards applicable and any official verification of GMP compliance
- All other factors of which the QP is aware that are relevant to the quality of the batch
And remember... where IMP is manufactured and packaged at different sites under the supervision of different Qualified Persons, the recommendations listed in Annex 16 of Eudralex Volume 4 should be followed as applicable. Any sharing of responsibilities amongst QPs must be defined in a document formally agreed by all parties.
Source of IMP - Supply Chain
Certification by a QP takes place in an European country, which means that the legal entity holding the MIA license and the QP, respectively, are registered and reside in an EU Member State. Multiple supply chain scenarios are possible, below some examples are listed.
- Product manufactured within EU but not subject to an EU marketing authorization; in other words, not intended for administration to patients in Europe, still require batch certification by a QP
- Product sourced from the open market and subject to an EU marketing authorization; in other words, intended for administration to patients in Europe, do require batch certification by a QP
- Product imported directly from a 3rd country and intended for administration to patients in Europe, do require batch certification by a QP
The European Union has signed mutual recognition agreements (MRAs) with third- country authorities concerning the conformity assessment of regulated products. MRAs allow EU authorities and their counterparts to rely on each other's GMP inspection system, share information on inspections and quality defects, waive batch testing of products on import into their territories. For e.g. with the USA, the transition phase for human medicines ended on 11 July 2019. As of 11 July 2019, QPs in the EU Member States do not need to test batch of human medicines covered by MRA, provided that they have verified that theses controls have been carried out in USA for products manufactured in and imported from the United States. Although some products are excluded from the MRA: human blood and plasma, human tissues and organs, veterinary immunological, advanced therapy medicinal products. Decisions are expected on expansion of the operational scope of the MRA to vaccines for human use and plasma-derived medicines (July 2022) and products intended for use in clinical trials (later stage).
Ensure Your IMP Gets to Market Quickly
The road to regulatory approval is long, and only 10% of Phase I studies will get there, as there are many obstacles and pitfalls. Not preparing properly for a Phase I study, can cause interruptions of the process which are costly delays. Lack of understanding of what is required in all the steps leading to approval, and their implications, will have organizations make costly mistakes.
This blog highlights how an understanding of the complex and various regulation across multiple European regulatory agencies can be quite a challenge. Our experts can support you in preparing for a successful EU batch release. ProPharma project management experts and QPs can help you every step of the way. With our expert guidance for your upcoming European batch release, you can focus on successfully finishing your study and bringing your product to the market.
For more information on our qualifications and capabilities, or for support in performing a clinical study in Europe, contact us today.
