Manufacturing of Medicinal Products

To be eligible to act as a Qualified Person, the individual must have:

• A university degree in one of the following fields:
  • Pharmacy
  • Human medicine / veterinary medicine
  • Chemistry or Biology (scientific disciplines)
  • Pharmaceutical chemistry and technology
  • A relevant technical field
  • Or an equivalent qualification obtained abroad.
• Relevant work experience in a GMP-certified pharmaceutical company within the last five years. The specific experience requirements vary based on the product type:

1. For Active Substances and Medical Gases

The Qualified Person must have:

• At least 1 year of work experience in quality assurance, including the application of Good Manufacturing Practice (GMP), in a company holding a manufacturing authorization.

2. For Medicinal Products, Intermediates, and Clinical Trial Medicines

The Qualified Person must have:

• A university degree as described above, and
• The following GMP-related experience, depending on the degree:
  • Pharmacy graduates: at least 1 year.
  • Graduates in medicine, chemistry, or biology: at least 2 years.
  • For veterinary medicinal products: practical experience at least 2 years; experience required may be reduced by one year where a university course lasts for at least five years and by a year and a half where the university course lasts for at least six years.

This experience must cover:

• Qualitative analysis of medicinal products.
• Quantitative analysis of active substances.
• Quality assurance, including implementation of GMP.

Alternatively, a person from another European Economic Area (EEA) country can act as a Qualified Person in Estonia if they are legally qualified to do so in their home country.

Special Cases

• For companies only involved in re-labelling, re-packaging, or physical import from outside the EEA, a minimum of 1 year of relevant experience is required, regardless of academic background.
• If a person has only worked in re-packaging, re-labelling, or import, they cannot act as a Qualified Person in companies that engage in other types of manufacturing activities.
• For companies only involved in manufacture of veterinary medicinal products, relevant work experience in a GMP-certified pharmaceutical company is not restricted to within the last five years.
• For companies manufacturing sterile medicinal products, the Qualified Person must have:
  • At least 1 year of experience in the production of sterile forms in a licensed GMP-compliant facility,
    or
  • Have completed specialized training in sterile manufacturing.

Important notes

• The Qualified Person's qualifications and experience must match the scope of manufacturing activities carried out by the company.
• The State Agency of Medicines verifies compliance with these requirements before authorizing the Qualified Person.
• Qualified Persons play a key role in maintaining product quality, patient safety, and regulatory compliance.

• You can find all legal persons holding an activity license for manufacture of medicinal products in Estonia in the National Registry of Activity Licenses: Activity license search.
• Manufacturing authorizations are typically issued without an expiration date and follow the standard format established by the European Union. The authorization specifies the activities the manufactures is permitted to carry out. The responsible person(s) is/are listed on the authorization and must personally fulfil their duties and be available at all times.
• Additionally, information about license holders and Good Manufacturing Practice (GMP) certificates, as well as their contact details, are available both in the EudraGMDP database Eudra GMP - Public Layout and the Estonian State Agency of Medicines' activity license register.
• Manufactures must comply with Good Manufacturing Practice (EU GMP) guidelines, as well as EU and national legislation.
• The State Agency of Medicines inspects manufactures to ensure compliance with EU GMP and relevant legislation, both before granting manufacturing authorization and routinely thereafter.
• The GMP certificate is generally for three years.
• Medicinal products can be produced and released to the market only by a company which has both manufacturing authorization and GMP certificate.
• Once authorized, manufactures must submit an application for amendments to their activity license to the State Agency of Medicines at least 30 days before the changes take effect. It should also be noted that all license changes are assessed during a Commission that meets once a month, the assessment of the submitted change may take up to 60 days.

• An initial GMP inspection is conducted as part of a new activity license application for a manufacturing or import.
• Routine GMP inspections carried out regularly after an authorization has been granted to ensure ongoing compliance with EU GMP requirements.
• Non-routine inspections may occur when a company applies for changes to its manufacturing activities or facilities.
• For-cause (targeted) inspections performed in response to specific concerns, such as suspected non-compliance or risks to public health. These inspections may be unannounced.
• Follow-up inspections are conducted to verify compliance and corrective actions in the wake of previous inspections.
• Inspections are usually scheduled in advance, and companies are notified several weeks before the inspection takes place. However, unannounced inspections may be conducted where necessary, especially in the case of for-cause inspections.

In general, a manufacturer will be notified 4-6 weeks in advance of a planned inspection. In relation to for-cause or triggered inspections, a shorter notice period may be given. The notification will outline the legal basis for the inspection, what will be reviewed as part of the inspection (the scope), names of the inspectors and the planned number of inspection days. The notification will include an initial list of pre-inspection requests for information and documentation which must be provided to the State Agency of Medicines in advance.

This may include (non-exhaustive list):

• Current Site Master File (SMF).
• Details of any significant changes to premises and equipment, key personnel and manufacturing processes in the period since the last inspection.
• List of SOP-s.
• List of medicinal products manufactured.
• List of complaints, recalls and/or rejected batches.
• List of deviations and quality or laboratory investigations, including OOS and OOT.

This information will be reviewed by the State Agency of Medicines and used to develop an inspection plan 1-2 weeks in advance of the inspection. The lead inspector will typically provide the inspection plan to the site, including the holder of the manufacturing authorization, prior to the start of the inspection.

The length of a GMP inspection and the number of inspectors involved depend on how complex the manufacturing operations are at the site. Typically, inspections last 2 to 5 days and take place on-site at the facility chosen for inspection. When appropriate, some inspections may also be carried out remotely.

During the inspection, activities will vary based on the type and scope of the inspection. Usually, the process includes:

• An opening meeting to introduce the inspection purpose, plan and participating inspectors.
• A thorough review of documents.
• A tour of the production site, including manufacturing areas and facilities.
• Meetings with key personnel.
• And a closing meeting where initial findings are shared.

Common areas reviewed during manufacturing site inspections include:

• Production areas.
• Facilities and equipment, including computerized systems.
• Management and storage of starting materials, printed packaging materials and drug product.
• Laboratory premises, procedures, and test results.
• Pharmaceutical quality system documents and records.
• Controls to prevent contamination and mix-ups.
• Personnel qualifications and training.
• Outsourced activities.

This non-exhaustive overview helps you understand what GMP inspections involve and how they ensure the quality and safety of medicinal products.

After the inspection, a written report outlining the topics and records reviewed for compliance during the inspection will be issued. The report will include a list of findings of non-compliance (known as deficiencies), which are classified into three categories: critical, major and other. The site will be requested to provide a response to the findings, including a proposal for corrective and preventative actions (CAPA) for each deficiency. The State Agency of Medicines will review the response.

A GMP certificate is issued after each GMP inspection. It is issued on the EMA's EudraGMDP  database within 90 days of the last day of the inspection usually when the responses to the inspection report are judged to be acceptable.

GMP certificates issued as part of a compliance management case will include the following statement on the certificate in public view:

GMP certificate issued with administrative action(s) described within the procedure for compliance management in the Compilation of Union Procedures'.

The authenticity of GMP certificates should be verified on the EudraGMDP database Eudra GMP - Public Layout. Please be advised the State Agency of Medicines does not extend the duration of GMP certificates. The presence of the current certificate on the EudraGMDP database is indicative that it remains valid.

Where a manufacturing site does not meet the minimum standards of EU GMP, the company may be informed that a statement of non-compliance will be issued on the EudraGMDP database.