Products subject to medicinal product legislation need a marketing authorisation from TİTCK before they are placed on the market in Türkiye. The application is made with a dossier in Common Technical Document (CTD) format showing the quality, safety and efficacy of the product. Drug-device combinations whose principal action comes from the medicinal substance follow the same route; conformity of the device part with the MDR is demonstrated separately.
How is the dossier built?
The CTD has five modules: administrative and product information (Module 1), summaries (Module 2), quality data (Module 3), non-clinical studies (Module 4) and clinical studies (Module 5). Module 1 is country specific; in Türkiye the documents and product information required by TİTCK are collected there.
The part of the dossier that attracts the most questions is usually the quality section: specifications for the active substance and excipients, analytical method validations, stability studies and the description of the manufacturing site. That information has to match what happens on site exactly.
Preparing for GMP
Good Manufacturing Practice (GMP) is the set of rules that assures the product is manufactured to the same quality every time. In Türkiye GMP inspections are carried out by TİTCK, and the guideline applied is aligned with the EU GMP Guide (EudraLex Volume 4).
Preparation focuses on the quality manual and document control, personnel competence, facility and equipment qualification, process validation, deviation and change management, complaints and recalls, and internal audits. In drug-device combinations the medicinal and device files have to be consistent documents that reference each other.
What happens after authorisation?
An authorisation does not freeze the dossier. When the manufacturing site, the manufacturing process, a specification, an analytical method, the packaging or the product information changes, a variation application is made. Depending on the type of change, approval may be required or a notification may be enough; knowing that distinction in advance protects your production plan.
Continuing stability studies, pharmacovigilance obligations and staying ready for GMP inspections are also part of the post-authorisation period.
What it covers
- Compiling the marketing authorisation dossier (Modules 1–5) and gap analysis
- Post-authorisation variation applications
- GMP inspection readiness, mock inspection and closing of findings
- Setting up quality assurance and quality control processes
How do the two frameworks meet in drug-device combinations?
When a product contains both a medicinal substance and a device, the first question is where the principal action comes from. If it comes from the medicinal substance, the product as a whole falls under medicinal product legislation and reaches the market through a marketing authorisation. The device part does not disappear, though: MDR Article 117 amended the relevant annex of Directive 2001/83/EC so that a notified body opinion on the device part of an integral product is included in the authorisation dossier.
That opinion assesses whether the device part meets the general safety and performance requirements in MDR Annex I. In practice the two timetables have to run together: while the opinion is pending, the authorisation application does not move. Pre-filled syringes, inhalers and drug-eluting implants are typical examples.
If the principal action comes from the device, the route is reversed: the product is CE marked under the MDR and an opinion on the ancillary medicinal substance is obtained from a medicines authority.
Annex 1 and the contamination control strategy in sterile manufacturing
Annex 1 of the EU GMP Guide, which governs sterile manufacturing, came into operation on 25 August 2023. Arriving fifteen years after the previous version, the revision changed the approach fundamentally: beyond numerical limits, the text now asks for a written contamination control strategy covering the whole site. Sources of contamination, the controls applied, the monitoring programme and how they support each other are all shown in a single document.
The other prominent themes are barrier technologies (isolators and restricted access barrier systems), tying quality risk management to every decision as its justification, and building the gowning regime and environmental monitoring programme on a risk basis. When preparing for an inspection, that strategy is often the first document examined; the rest of the site is read through it.
How are variations classified?
Not every post-authorisation change follows the same route. Some proceed by notification, others wait for approval. Getting the classification right from the start is the cheapest way to protect your production plan: a misclassified change put into production without waiting for approval makes the conformity of the product arguable.
What works in practice is mapping the change control procedure onto the dossier. If it is written down which internal document corresponds to which module, then the day a specification changes on site you can see whether an application is needed.
How does inspection preparation run?
Once the inspection date is known, a timetable is built backwards. The typical steps: checking that the document set is current, closing open corrective actions and deviations, completing qualification and validation records, reviewing training records, and a mock inspection.
The value of a mock inspection is finding the observation before the inspector does. The most common gaps on site are records filled in retrospectively, equipment whose calibration has expired, and a drift between the written procedure and what people actually do. Fixing those takes weeks; it cannot be done on the day of the inspection.
Common problems
It is common for the quality section of the dossier (Module 3) not to match the real process on site. The analytical method, specification or supplier written in the dossier is expected to be seen exactly that way during a GMP inspection. For that reason the dossier and the GMP preparation should run on the same calendar.
