Wholesale distribution of medicines within the EU/EEA - questions and answers

Do the guidelines on good distribution practice of medicinal products for human use (the GDP guidelines) also apply to veterinary medicines?

No. In Denmark, wholesale distribution of veterinary medicines must take place according to the guidelines COMMISSION IMPLEMENTING REGULATION (EU) 2021/1248 of 29 July 2021.

This question and answers will primarily concern wholesale distribution of medicines for humane use.

Do the GDP guidelines also apply to medicinal products without marketing authorisation, including medicinal products for clinical trials and for compassionate use?

Yes. Medicinal products without marketing authorisation are not exempted from the executive order on good distribution practice. In Denmark, wholesale distribution of medicinal products for clinical trials and for compassionate use must also take place according to the guidelines on good distribution practice of medicinal products for human use, see section 13 of the Danish GDP order.

What should appear from an organisation chart as a minimum?

The responsible manager and the responsible person should be indicated in the organisation chart. Other key persons within GDP should also be indicated.

Should the responsible person hold a degree in pharmacy?

No. It is not a requirement that the responsible person holds a degree in pharmacy in Denmark. The responsible person should have the appropriate competence for carrying out the tasks of the job. The responsible person must acquire the necessary competence, for example via courses, seminars, meetings and the like. The responsible person is expected to keep updated on the latest legislation in the area.

Are there any requirements as to the responsible person's nationality?

No, but it is a condition that the responsible person can read and understand the Danish legislation and is able to keep updated on the activities in the area. It is not a requirement that the responsible person resides in Denmark. However, the person must be at the company regularly and to an adequate extent with due consideration to the company's activities.

Can there be more than one responsible person?

No, the company can only have one responsible person. The responsible person can delegate assignments to others, but not the responsibility. 

What should be described in the quality system as a minimum?

The quality system must as a minimum encompass the following:

• Organisation chart (GDP guideline 1.2)
• Job descriptions for GDP key positions (as a minimum for the responsible manager and the responsible person)
• Procedure for the control of documentation (GDP guidelines 1.2 and 4.1)
• Procedure for the control and review of outsourced activities (GDP guideline 1.3)
• Procedure for management review and monitoring (GDP guideline 1.4)
• Procedure for the training of employees (GDP guideline 2.4)
• Procedure for the qualification of suppliers and customers (GDP guidelines 5.2 and 5.3)
• Procedure for complaints and recalls (GDP guidelines, chapter 6)
• Procedure for self-inspections (GDP guidelines, chapter 8)
• Procedure for deviations, corrective and preventive actions (CAPA) (GDP guidelines 1.2 and 8.2)
• Procedure for risk assessment (GDP guidelines 1.1 and 1.5)

In addition, companies with storage and transportation of medicinal products must as a minimum have the following (GDP guidelines, chapters 5 and 9):

• Procedure for storage, including receipt, storage and distribution of medicinal products
• Procedure for temperature measurement etc.
• Procedure for cleaning, including service agreement with external cleaning company, if any
• Procedure for the calibration of equipment
• Procedure for returned medicinal products, falsified medicinal products and destruction
• Procedure for transportation, including control of temperature excursion, operation, maintenance, cleaning and safety precautions of vehicles
• Service agreement with pest control company

Moreover, the company should consider any quality risks and the need for a change control system, relevance for hygiene procedure, qualification and validation of equipment and description of IT systems. If these activities are considered to be relevant, procedures must be established for the activities in question.

In connection with transportation, a risk assessment of the delivery routes should be made and if non-dedicated vehicles are used, procedures should be in place to ensure that the quality of the medicinal products will not be compromised. Procedures for emergency deliveries should also be considered.

Please note that the above list is not exhaustive, but for guidance only. The scope of a quality system should always match the scope of the company's activities, its size and complexity. Consequently, an evaluation of the company's need for procedures should always be made on the basis of the rules of the executive order on distribution of medicinal products and the GDP guidelines. Handling of medicinal products requiring special conditions should also be taken into account.

The procedures and organisation chart must be dated and signed by the responsible person, and version control by adding a number should be applied. The responsible person may delegate the duty to sign for certain procedures to other people, where appropriate. The delegation must appear from the procedure for the control of documentation. Job descriptions must be dated and signed by the responsible manager and the respective employees. There are no requirements as to how the above procedures are structured (whether one or more procedures are merged) as long as the issues are comprised by the quality system.

If a company has outsourced activities, a contract must be made between the parties. Outsourced activities must comply with the requirements of section 35 of the Danish GDP order. For more information, see chapter 7 of the GDP guidelines.

Records should be kept for the following, if relevant:

• Cleaning
• Equipment repair, maintenance and calibration operations
• Destroyed medicinal products
• Actual location of medicinal products (storage records)
• Complaints
• Returns and recalls
• Falsified medicinal products, including suspected falsified medicinal products
• Self-inspections
• Temperature monitoring

What should appear from a contract?

If a company outsources activities, there must be a contract between the contract giver and the contract acceptor. This contract must meet the requirements of section 35 of the Danish GDP order.

It must be clearly specified which companies have entered into the contract. The contract must be signed by both parties.

The contract must include the following:

• a detailed description of the division of responsibilities and tasks
• an indication that the contract acceptor is obliged to comply with the good distribution practice (GDP)
• a specification that the contract acceptor should only pass work to a third party subject to written approval from the contract giver

If the contract acceptor is located in another EU/EEA country and holds authorisation issued in accordance with the legislation of another EU/EEA country, the contract must reflect any additional requirements laid down in section 35 of the Danish GDP order.

The contract must describe the division of responsibilities and tasks in such detail that there will be no doubt about the division of responsibilities and tasks. A matrix may be used for this purpose (table of the division of responsibilities and tasks). In this way, the contract giver ensures that the contract acceptor will perform the agreed work.

The Danish Medicines Agency will carry out inspections and randomly control that the contracts meet the requirements. Consequently, the company is expected to show where in the contract the above requirements are included during an inspection.

How often must companies audit their contract acceptors?

The GDP executive order and guidelines require companies to audit their contract acceptors before commencement of the outsourced activities and regularly thereafter. The frequency of audits of contract acceptors must be determined on the basis of a documented risk assessment. However, the Danish Medicines Agency will expect contract acceptors to be audited at least every three years. The Danish Medicines Agency will randomly review the risk assessment at inspections. In the case of new contract acceptors, the Danish Medicines Agency will expect the first audit after commencement of the outsourced activities to take place within the first year.

What is expected in the use of external auditors for audits of contract acceptors?

It is possible to use an external auditor for audits of contract acceptors, in which case the Danish Medicines Agency will expect the following:

• The responsible person of the contract giver must document having reviewed the audit report to ensure the report adequately covers the activities to be outsourced, including any special requirements applicable to, for example, receipt and delivery.

   

• The contract giver must ensure that the external auditor is independent of the contract acceptor and has no conflicts of interest, including financial interests or other significant relationship, with the audited contract acceptor.

   

• The contract giver must document that the external auditor has the relevant skills and experience in auditing.

What are the expectations of the Danish Medicines Agency to the performance of the management review and monitoring?

The management review and monitoring are new in relation to the previous GDP guidelines. A procedure for management review and monitoring must be available (GDP guideline 1.4). The management review should be performed in light of the company's level of activity, size and complexity.

For more information on management review and monitoring, see Guidelines on Good Distribution Practice of medicinal products for human use, chapter 1.4

Who is responsible for ensuring that the transport of medicinal products takes place in compliance with the GDP rules?

It must be agreed by way of a contract between the supplier and recipient who is responsible for the transport and thereby also responsible for compliance with the GDP rules during transport. The GDP guidelines stipulate that it is the responsibility of the supplying wholesale distributor to transport the medicinal products in compliance with good distribution practice (GDP). In practice, the Danish Medicines Agency will accept an agreement between the supplier and recipient for the receiving wholesale distributor to be responsible for transportation.

What does GDP responsibility during the transport of medicinal products imply?

GDP responsibility for medicinal products during transport implies having to protect the medicinal products against breakage, adulteration and theft, and to ensure that temperature conditions are maintained within acceptable limits during transport. Documentation thereof must at all times be held available and kept at the GDP company (supplying or receiving wholesale distributor) responsible for the transport. The GDP company responsible for transport must ensure that its own transports and/or carriers used comply with this.

Are carriers required to hold a wholesale distribution authorisation for medicinal products?

A carrier whose only activity with medicinal products is transport is not required to hold a wholesale distribution authorisation for medicinal products (WDA/section 39 authorisation). A wholesale distribution authorisation is also not required in cases where medicinal products are not transported directly from A to B, but, for example, held at a transportation centre for a shorter period of time (e.g. over the weekend). In connection with the transport, reloading is permitted, but any form of unpacking or repackaging is not.

The requirements applying to transportation are described in Guidelines on Good Distribution Practice of medicinal products for human use chapter 9.

Should a wholesale distributor audit the transportation provider?

It is the responsibility of the supplying wholesale distributor to ensure that the medicinal products are transported in compliance with the good distribution practice (GDP). This must be agreed in a contract between the wholesale distributor and the transportation provider. The wholesale distributor must assess whether the contract acceptor has the competence required to carry out the agreed work. This can be done by auditing the transportation provider. It is not a requirement that the wholesale distributor audits the transportation provider.

The requirements applying to transportation are described in Guidelines on Good Distribution Practice of medicinal products for human use chapter 9.

Can a manufacturer transport its medicinal products at temperatures outside the temperature conditions specified on the outer packaging?

In general, medicinal products should be transported under the temperature conditions specified on the outer packaging. If the original site of manufacture can provide stability data that the medicinal product, within a fixed time limit, can tolerate storage at higher or lower temperatures than the temperature conditions specified on the outer packaging of the product, it is acceptable that the transportation takes place at a higher or lower temperature. The original site of manufacture must be able to provide documentation that the transportation was acceptable. Only this documentation from the original site of manufacture can form the basis for the medicinal product being considered as a saleable product. This is only accepted for the transportation of the medicinal product handled by the original site of manufacturer. Transportation of the medicinal product between other wholesalers must take place at the temperature specified on the outer packaging.

Is ”type qualification” of equipment and ”worst case validation” of processes acceptable?

The company should identify which qualifications of key equipment and/or validation of central processes are required to ensure correct installation and operation (GDP guideline 3.3.2.). In general, the Danish Medicines Agency does not accept ”type qualification” or ”worst case validation”. If, in special circumstances, a company wishes to use ”type qualification” or ”worst case validation”, the company should make a risk assessment to evaluate whether this is acceptable. Documentation for the risk assessment must be provided.

Should the responsible person be continuously contactable?

According to section 33 of the GDP executive order, wholesale distributors are obliged to introduce an effective system for the processing of complaints, which makes it possible to initiate recall operations of medicinal products in the distribution network promptly and at any time.

We expect companies to be continuously contactable to be able to perform a recall, if required. It is not a requirement that the responsible person or the qualified person can be contacted directly. But it must be ensured that the responsible person is informed about any enquiries that are relevant to his responsibilities, and the company should have relevant procedures for how to handle such calls.

We also expect that contact details are made readily available to citizens as well as the Danish Medicines Agency. If the company can be contacted on a special phone number outside opening hours, we expect that a call to your main phone number will inform about the possibility to call the relevant phone number. Any unanswered calls should be returned as soon as possible.

Which medicinal products should be physically segregated (GDP guideline 3.2)?

The following medicinal products require physical segregation:

• Expired
• Medicinal products received from a third country but not intended for the Union market (introduced – free warehouses)
• Recalled and rejected
• Falsified
• Medicinal products for destruction

The following medicinal products require physical segregation, alternatively electronic segregation:

• Medicinal products pending a decision as to their disposition (e.g. medicinal products for which receipt control has not been performed)
• Medicinal products suspected of falsification
• Returned medicinal products

Which stock rotation principle should be used (FEFO/FIFO)?

The Danish Medicines Agency expects that stock rotation is managed by the company. Generally, the First Expiry, First Out principle (FEFO) is recommended. The First In, First Out principle (FIFO) is also accepted.

When should stock inventories be performed according to the Danish Medicines Agency?

Taking into account the national legislation for euphoriant substances, stock inventories should be performed for products containing euphoriant substances as a minimum every quarter, see section 20 of the executive order on euphoriant substances.

In addition, an accurate review of received, delivered and distributed veterinary medicinal products must be made every year and be compared to the stocks, see article 101 section 8 of COMMISSION IMPLEMENTING REGULATION (EU) 2021/1248 of 29 July 2021.

Stock inventories of other medicinal products may also be appropriate.

Can a self-inspection be replaced by an audit performed by another company?

No. A self-inspection must be conducted by the company. It is acceptable that an external expert is asked to conduct the self-inspection but the GDP responsible persons in the company are expected to participate actively. An audit performed by another company, for example a contract giver, cannot be used as a substitute for self-inspection. Under certain conditions it can be acceptable that companies that are part of global corporations can conduct self-inspection with the assistance of the global corporations audit team.

Should a supplier be audited?

It is not a requirement that a supplier must be audited, but a relevant qualification should be made. For more information, see GDP guideline 5.2.

Should cleaning companies and pest control companies be audited?

No. A service agreement must be made with such companies. These services are not covered by the GDP guidelines, chapter 7 – Outsourced activities.

Contract acceptors are considered as companies performing GDP tasks requiring a GDP authorisation (including purchase, sale, receipt, supply and storage).

Are there any requirements as to measuring the humidity of stocks of medicinal products?

The company should decide by way of a risk assessment whether the humidity should be measured. It should be considered whether the stored medicinal products should be protected against moisture and whether the humidity should be measured. When storing medicinal products in basements, the humidity should be known.

For how long should the records for destruction be kept?

Records of all destroyed medicinal products should be kept for the same period of time as any other documentation. They should be retained for a period of 5 years (section 31 of the Danish GDP order).

When is a GDP certificate issued?

Companies holding an authorisation for wholesale distribution will receive a GDP certificate when a satisfactory inspection has been made. GDP certificates are issued from 1 January 2013 and in the future.

A company, which is only authorised to manufacture and import medicinal products (GMP authorisation) and which can thereby wholesale distribute own released medicinal products, will only receive a GMP certificate.

If, in connection with an inspection, it is found that a company does not comply with the GDP, a non-compliance report will appear from EudraGMDP

How is temperature mapping made?

When new premises are to be used, temperature mapping must be made. The purpose of temperature mapping is to identify any critical areas of the premises and determine where temperature loggers should be placed to perform a representative continuous daily measurement of the premises (temperature monitoring). The final placement of the temperature loggers, and the reasoning for the chosen location, should be documented.

Temperature mapping should be made in the summer and in the winter to ensure a stable temperature under worst-case weather conditions. Measurements should also be made when the premises are empty and full.

How often should the validity of a supplier's and customer's authorisation be controlled?

On receipt and supply to other companies, the company must make sure that the company concerned has a valid authorisation. This should be controlled for each consignment. If the company trades with the same companies, periodic control of the authorisations can be made based on a risk assessment. The reasons for the periodic control interval should be given. This could form part of the qualification of the supplier or the customer (see GDP guidelines 5.2 and 5.3).

All Danish companies that hold a section 39 authorization can be found in the EudraGMDP database.

What should be stated in a control report?

The GDP executive order defines a control report as

”A certificate signed by the qualified person with the manufacturer, with the person responsible for the import or with the contract acceptor, stating that the medicinal product, including intermediate products and active substances, is manufactured in accordance with good manufacturing practice and meets the requirements forming the basis for the marketing authorisation.”

The qualified person (QP) with the manufacturer of a medicinal product must perform batch certification in accordance with the EU GMP Annex 16. According to Appendix II to Annex 16, the following statement must appear from the batch certificate:

"I hereby certify that all the manufacturing stages of this batch of finished product have been carried out in full compliance with the GMP requirements of the EU and [when within the EU] with the requirements of the Marketing Authorisation(s) of the destination country/countries."

If the batch certificate is issued in accordance with the EU GMP Annex 16, and the wording mentioned in Appendix II is applied, it will be accepted as a wording complying with the GDP executive order’s definition of a control report.

Are wholesale distributors allowed to buy medicines from a company outside the EU/EEA?

No. A wholesale distributor can only buy medicines from a company with a physical presence in the EU/EEA. This also applies if the medicinal products are physically located in the EU/EEA. Only companies holding a Manufacturing and Importation Authorisation in the EU/EEA, which comprises import, are allowed to buy medicines to the EU/EEA market from companies in third countries.

Are wholesale distributors allowed to store medicines owned by a company in a country outside the EU/EEA?

No. A wholesale distributor can only store medicines owned by companies in the EU/EEA. The reason is that a wholesale distributor can only store medicines released for the EU/EEA market. Medicines sold by a company from a third country must be released for the EU/EEA market after the ownership has been passed to the EU/EEA company. Consequently, the medicines are not released for the EU/EEA market until this last release has taken place.

A wholesale distributor in Denmark wants to be a contract acceptor responsible for receipt, storage facilities and distribution for a Swiss company – is that possible?

No. A pharmaceutical wholesaler can only handle medicinal products released for the EU/EEA. Thus, the medicinal products must be released for the EU and owned by a company in the EU/EEA before the wholesaler can distribute, receive and store the products.