Medicinal products for human use - Swedish Medical Products Agency

Chemical medicinal products

Even though medicinal products are based on originally natural products, today they are often produced synthetically and can be described most simply as chemical substances.

Non-clinical testing

A medicinal product that is to be evaluated in humans in a clinical trial must first be tested in non-clinical experiments regarding its effect (pharmacology) and safety (safety pharmacology and toxicology).

Pharmacological studies

In pharmacological experiments scientists study the functional mechanism and effect in suitable in vitro and/or in vivo models. These studies provide the foundation for the pharmacological rationale.

Safety studies

The purpose of safety studies is to characterize any toxic effects the medicinal product might have in terms of target organs, dosage addiction, and reversibility. What non-clinical safety studies are to be carried out depends on where the medicinal product is in its clinical development program. The scope and type of trials are described in various scientific guidelines. In the development of a medicinal product, safety studies must satisfy the quality system known as Good Laboratory Practice, GLP.

Who may carry out GLP studies?

Non-clinical safety studies in the development of a medicinal product must be performed observing Good Laboratory Practice, GLP, in laboratories that have been inspected by the GLP authority.

Guidelines, etc.

More detailed information about what non-clinical studies should be carried out prior to clinical medicinal product trials is available from:

Non-clinical safety studies for the conduct of human clinical studies and marketing authorization for pharmaceuticals (Doc. Ref. CPMP/ICH/286/95)

As a complement to this guideline, there is a ‘Question & Answer’ document:

ICH guideline M3 (R2)- questions and answers (Doc. Ref. CHMP/ICH/507008/2011)

For clinical trials of anticancer pharmaceuticals for treating patients with advanced cancer and limited treatment alternatives, see the guideline:

Non-clinical evaluation for anticancer pharmaceuticals (Doc. Ref. CHMP/ICH/646107/2008)

Information about how various non-clinical studies are to be performed is available in separate guidelines on the European Medicines Agency (EMA) website under Non-clinical guidelines and Multidisciplinary.

Production of an investigational medicinal product

Pharmaceutical quality comprises how a medicinal product is constructed from the synthesis of its active substance, the formulation of the intended form of preparation, and through the manufacture of the finished product.
An application also documents what the medicinal product contains, how the active substance, the auxiliary compounds included, and the finished medicinal product are monitored, and how long the useful life of the medicinal product is.

Documentation of the product

Pharmaceutical quality must be documented by describing how the medicinal product is produced and what controls are carried out during and after its manufacture. The complete composition of the medicinal product must be stated, with reference given to a pharmacopoeial monograph or own specification of each ingredient. Information about the useful life of the substance and the product must also be included.

Read about the European Pharmacopeia at EDQM

Permission for production

A production permit is required for the manufacture of an investigational medicinal product (IMP).

Inspection

Guideline

Information about what pharmaceutical quality documentation must be included in the application for an investigational medicinal product in clinical trials can be found in:

Guideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials

Clinical trials of medicinal products

A clinical trial of a medicinal product is a study that aims to discover or verify the clinical, pharmacological, or pharmacodynamic effects of a pharmaceutical that is administered to humans. The goal of the trial may also be to identify any side effects and to study the absorption, distribution, metabolism, or secretion of a medicinal product for the purpose of guaranteeing its safety and effect.

EU regulations for clinical trials on medicinal products

Application is done via a form that is used in all EU Member States. The trial requires an advance permit from the Medical Products Agency.

Read about clinical trials for medicinal products (in Swedish)

The trial must also be approved by the Regional Ethical Review Board.

the Regional Ethical Review Board

Regulations and permits for clinical trials

Regulations for the implementation of clinical trials for medicinal products were put in place to ensure that the trials are safe for participating subjects and to generate high-quality data. A summary of regulations in Sweden and an account of the national agreements regarding Good Clinical Practice, ICH-GCP, which apply both in the EU and in several countries in other parts of the world, can be found via the link below.

Clinical trial of medicinal product or not?

Guidance regarding whether a study is a clinical trial of a medicinal product or not can be found in the latest version of Questions & Answers, Eudralex Volume 10, chapter V.

Questions & Answers, Eudralex 10

The end of Questions & Answers, Eudralex 10 provides an account of the EU-wide principles that the Medical Products Agency uses to determine whether or not a clinical study is a clinical trial of a medicinal product requiring a permit.

If this is unclear, the Medical Products Agency should be consulted, preferably by e-mail at registrator@mpa.se. Write “Clinical trial of medicinal product or not” in the subject field.

First-in-human clinical trials

For safety reasons, special requirements are in place for medicinal products that have not previously been administered to humans.

Guidelines for 'first-in-human clinical trials'

Guidelines for various therapy areas

The protocol of the trial of the medicinal product should follow the recommendations of the EMA (European Medicines Agency) for various therapy areas.

Guidelines for various therapy areas

Commercial production

All manufacture of medicinal products requires a production permit issued by the Medical Products Agency and must be done in compliance with Good Manufacturing Practice, GMP.

For production of medicinal substances (API) the Medical Products Agency grants permits following inspection.

To the application form for a production permit (in Swedish)

Medicinal products occur in various preparations with specific requirements. In EudraLex, Volume 4 (Good manufacturing practice (GMP) Guidelines), the basic chapters deal with quality assurance, which applies to the manufacture of medicinal products in general. Specific forms of preparation are treated in Annexes.

Eudralex Vol 4 GMP Guidelines

Approval of medicinal products

When a company wishes to place on the market a medicinal product it must be approved before sale, i.e. the company must apply for marketing authorisation of the medicinal product. There are different procedures to choose from for chemical pharmaceuticals: a centralised procedure, a mutual recognition procedure, and a decentralised procedure, as well as a national procedure.

Biological medicinal products

The way in which biological medicinal products are produced, controlled and administered make some particular precautions necessary. The production of biological medicinal products involves biological processes and materials, such as cultivation of cells or extraction of material from living organisms. These biological processes may display inherent variability, so that the range and nature of by-products are variable.

Control of biological medicinal products usually involves biological analytical techniques which have a greater variability than physico-chemical determinations. In-process controls therefore take on a great importance in the manufacture of biological medicinal products.

Some examples of biological medicinal products are: vaccines, blood/plasma derived products, antiserum, antibodies, enzymes, peptide hormones, advanced therapies.

Definition of biological medicinal products

Non-clinical testing

A medicinal product that is to be evaluated in humans in a clinical trial must first be tested in non-clinical experiments regarding its effect (pharmacology) and safety (safety pharmacology and toxicology).

Pharmacological studies

In pharmacological experiments scientists study the functional mechanism and effect in suitable in vitro and/or in vivo models. These studies provide the foundation for the pharmacological rationale.

Safety studies

The purpose of safety studies is to characterize any toxic effects the medicinal product might have in terms of target organs, dosage addiction, and reversibility. What non-clinical safety studies are to be carried out depends on where the medicinal product is in its clinical development program. The scope and type of trials are described in various scientific guidelines. In the development of a medicinal product, safety studies must satisfy the quality system known as Good Laboratory Practice, GLP.

Who may carry out GLP studies?

Non-clinical safety studies in the development of a medicinal product must be performed observing Good Laboratory Practice, GLP, in laboratories that have been inspected by the GLP authority.

Guidelines, etc.

More detailed information about what non-clinical studies should be carried out prior to clinical medicinal product trials is available from:

Preclinical safety evaluation of biotechnology-derived pharmaceuticals (Doc. Ref.CHMP/ICH/731268/1998)

Guidance regarding at what stage of clinical development various experiments must be performed is found in the guideline:

Non-clinical safety studies for the conduct of human clinical studies and marketing authorisation for pharmaceuticals (Doc. Ref. CPMP/ICH/286/95)

For clinical trials of anticancer pharmaceuticals for treating patients with advanced cancer and limited treatment alternatives, see the guideline:

Non-clinical evaluation for anticancer pharmaceuticals (Doc. Ref. CHMP/ICH/646107/2008)

Information about how various non-clinical studies are to be performed is available in separate guidelines on the European Medicines Agency (EMA) website under Non-Clinical guidelines and Multidisciplinary guidelines.

Production of an investigational medicinal product

Pharmaceutical quality comprises how a medicinal product is constructed through the synthesis of its active substance, the formulation of the intended form of preparation, and through the manufacture of the finished product. An application also documents what the medicinal product contains, how the active substance, the auxiliary compounds included, and the finished medicinal product are monitored, and how long the useful life of the medicinal product is.

Documentation of the product

Pharmaceutical quality must be documented by describing how the medicinal product is produced and what controls are carried out during and after its manufacture. The complete composition of the medicinal product must be stated, with reference given to a pharmacopoeial monograph or own specification of each ingredient. Information about the useful life of the substance and the product must also be included.

Read about the European Pharmacopeia at EDQM

Permission for production

A production permit is required for the manufacture of an investigational medicinal product (IMP).

Inspection

Guideline

Information about what pharmaceutical quality documentation must be included in the application for an investigational medicinal product in clinical trials can be found in:

Guideline on the requirements for quality documentation concerning biological investigational medicinal products in clinical trials

Clinical trials of medicinal products

A clinical trial of a medicinal product is a study that aims to discover or verify the clinical, pharmacological, or pharmacodynamic effects of a pharmaceutical that is administered to humans. The goal of the trial may also be to identify any side effects and to study the absorption, distribution, metabolism, or secretion of a medicinal product for the purpose of guaranteeing its safety and effect.

EU regulations for clinical trials on medicinal products

Application is done via a form that is used in all EU Member States. The trial requires an advance permit from the Medical Products Agency.

Read about clinical trials for medicinal products (in Swedish)

The trial must also be approved by the Regional Ethical Review Board.

the Regional Ethical Review Board

Regulations and permits for clinical trials

Regulations for the implementation of clinical trials for medicinal products were put in place to ensure that the trials are safe for participating subjects and to generate high-quality data. A summary of regulations in Sweden and an account of the national agreements regarding Good Clinical Practice, ICH-GCP, which apply both in the EU and in several countries in other parts of the world, can be found via the link below.

Clinical trial of medicinal product or not?

Guidance regarding whether a study is a clinical trial of a medicinal product or not can be found in the latest version of Questions & Answers, Eudralex Volume 10, chapter V.

Questions & Answers, Eudralex 10

The end of Questions & Answers, Eudralex 10 provides an account of the EU-wide principles that the Medical Products Agency uses to determine whether or not a clinical study is a clinical trial of a medicinal product requiring a permit.

If this is unclear, the Medical Products Agency should be consulted, preferably by e-mail at registrator@mpa.se. Write “Clinical trial of medicinal product or not” in the subject field.

First-in-human clinical trials

For safety reasons, special requirements are in place for medicinal products that have not previously been administered to humans.

Guidelines for 'first-in-human clinical trials'

Guidelines for various therapy areas

The protocol of the trial of the medicinal product should follow the recommendations of the EMA (European Medicines Agency) for various therapy areas.

Guidelines for various therapy areas

Commercial production

All manufacture of medicinal products requires a production permit issued by the Medical Products Agency and must be done in compliance with Good Manufacturing Practice, GMP.

For production of medicinal substances (API) the Medical Products Agency grants permits following inspection.

To the application form for a production permit (in Swedish)

Medicinal products occur in various preparations with specific requirements. In EudraLex, Volume 4 (Good manufacturing practice (GMP) Guidelines), the basic chapters deal with quality assurance, which applies to the manufacture of medicinal products in general. Specific forms of preparation are treated in Annexes.

Eudralex Vol 4 GMP Guidelines

Approval of biological medicinal products

When a company wishes to place on the market a medicinal product it must be approved before sale, i.e. the company must apply for marketing authorisation of the medicinal product. Most biological medicinal products require a centralised authorisation procedure, which is managed by the European Medicines Agency (EMA). For some biological medicinal products it is possible to choose other procedures, a mutual recognition procedure, and a decentralised procedure, as well as a national procedure.

Read more aboout the different procedures in the European system:

Authorisation procedures in the European system

Read about national authorisation procedures in Sweden

Radioactive medicinal products

By radioactive medicinal products is meant pharmaceuticals that emit ionizing radiation. Closed radiation sources are not counted as radioactive medicinal products. All medical activity with ionizing radiation requires an approved application from the Swedish Radiation Safety Authority. Beyond this, a permit and approval may be required from the Medical Products Agency and the Regional Ethical Review Board.

For more information see the ‘Chemical substances’ tab in this guide.

Read about radioactive medicinal products (in Swedish)

Swedish Radiation Safety Authority

Regional Ethical Review Board

Advanced therapy medicinal products

Medicinal products for advanced therapy (ATMP) comprise gene therapy, somatic cell therapy, or tissue technology products that are medicinal products according to regulations established in Regulation (EC) No 1394/20. The Committee for Advanced Therapies (CAT) is the committee at the European Medicines Agency that is responsible for assessing the quality, safety and efficacy of advanced therapy medicinal products (ATMPs) and following scientific developments in the field.

Hospital Exemption

The Hospital Exemption is outlined in article 28 of the European Regulation 1394/2007. Article 28 specifies that an ATMP only qualifies for a Hospital Exemption if all of the following criteria are met:

Preparation on a non-routine basis
Preparation according to specific quality standards (equivalent to those for ATMPs with a centralized marketing authorization)
Use within the same Member State
Use in a hospital
Use under the exclusive responsibility of a medical practitioner
Comply with an individual medical prescription for a custom-made product for an individual patient.

Regulation (EC) No 1394/2007

Manufacturers need to apply for a manufacturing licence for “hospital exemption products”. Provisions from the Medical Products Agency sets up the specific requirements for the “hospital exemption products”.

Is the product an ATMP?

Thus far only a few medicinal products have been classified or approved as pharmaceuticals for advanced therapy (so-called Advanced Therapy Medicinal Product, ATMP). Questions regarding whether a certain gene therapy, cell therapy, or tissue technology therapy is a pharmaceutical may be directed to the Medical Products Agency expert group for AT by sending a mail to registrator@mpa.se. Write “Advanced therapy” in the subject field.

Questions may also be put to the European Medicines Agency (EMA) by mail to advancedtherapies@ema.europa.eu.

Approval of ATMPs

Advanced therapy medicinal products must be approved via the central procedure in the EU. The European Medicines Agency (EMA) is responsible for investigation of applications for approval together with national experts. The final decision is made by the European Commission.

Read about regulation for advanced therapy at EMA

Herbal medicinal products

Herbal medicinal products are pharmaceuticals whose active ingredients consist exclusively of herbal materials or herbal preparations. Herbal materials and preparations are defined in the Directive on Medicinal Products for Human Use (2001/83/EC)

Documentation of effect and safety

The scope of effect and safety documentation (non-clinical and clinical documentation) required for herbal medicinal products varies depending on the section of the law covering the application

Complete application

Herbal medicinal products may be approved via a complete application (product-specific effect and safety data) in the same way as conventional medicinal products.

Well-established medicinal use

Herbal medicinal products may be approved via a bibliographical application* in the same way as conventional medicinal products.

(* Data on effects and safety have been published in the scientific literature)

Community herbal monographs

Monographs of herbal substances may facilitate an application for registration for sale.

Traditional herbal medicinal products

Herbal medicinal products that have long been in use and that lack any possibility of being approved regarding effect and safety documentation may be registered as traditional herbal medicinal products via a simplified procedure under certain conditions.

Community herbal monographs

Monographs of herbal substances may facilitate an application for registration for sale.

European Commission's register

For herbal material/preparations that are included in the Commission’s register, traditional use is regarded as having been established, and reference to the register may replace parts of effect and safety documentation.

Quality and manufacture of the product

All manufacture of medicinal products requires a production permit from the Medical Products Agency and must be done in compliance with Good Manufacturing Practice (GMP).

To the application form for a production permit (in Swedish)

Herbal substance/Raw material

All production (e.g. cultivation and collection) must be done in compliance with GACP (Good Agricultural and Collection Practices).

Read more about quality documentation

Active substance

Part II of EU GMP lays down the requirements for production of active substances.

Read more about quality documentation

Finished product

In EU GMP the basic chapters deal with quality assurance, which applies to the manufacture of medicinal products in general. Specific forms of preparation are treated in annexes.

Read more about quality documentation

Quality documentation

The part of application documents that describes production and various controls of raw materials and the finished product is called quality documentation. The same requirements apply to herbal medicinal products as to conventional medicinal products.

Read more about quality documentation

Approval/Registration

Herbal medicinal products must be approved by the Medical Products Agency before sale in Sweden. Traditional herbal medicinal products must be registered by the Medical Products Agency before sale in Sweden. In practice there is no difference in the procedure for approving or registering a medicinal product.

Procedures

The procedures for approval or registration of an herbal medicinal product are the same as for conventional medicinal products, with certain exceptions.

National procedure

An application in the national procedure applies only to the Member State to which the application is submitted. Following approval, registration applies only to the Member State in question.

Decentralised and Mutual recognition procedures

Decentralised procedure (DCP)
Mutual recognition procedure (MRP)

The decentralised procedure and the procedure for mutual recognition are applicable to herbal medicinal products and under certain conditions also to traditional plant-basedherbal medicinal products.

Fees

Fees are charged in accordance with the Ordinance on Fees for State Control of Medicinal Products (2010:1167) and are payable upon receipt of invoice from the Medical Product Agency.

Applications

Applications must be in CTD format (Common Technical Document).

Natural remedies

Natural remedies are medicinal products whose active ingredients are natural in origin and consist of animal parts, bacteria cultures, minerals, or salts. The active ingredients may not be overly processed, which means that e.g. purified substances or chemically modified ingredients cannot be included as natural medicinal products.

Documentation of effect and safety

Natural remedies must be intended for personal use, which means that they must be used for simple complaints that are temporary or mild in character. The indication must be based on a well-established domestic tradition in Sweden or countries similar to Sweden in terms of their use of medicinal products.

Quality and manufacture of the product

All manufacture of medicinal products requires a production permit from the Medical Products Agency and must be done in compliance with Good Manufacturing Practice (GMP).

To the application form for a production permit (in Swedish)

Active substance

Part II of EU GMP lays down the requirements for production of active substances.

Read more about quality documentation

Finished product

In EU GMP the basic chapters deal with quality assurance, which applies to the manufacture of medicinal products in general. Specific forms of preparation are treated in annexes.

Read more about quality documentation

Quality documentation

The part of application documents that describes production and various controls of raw materials and the finished product is called quality documentation. The same requirements apply to natural remedies as to conventional medicinal products.

Read more about quality documentation

Approval procedure

Natural remedies must be approved by the Medical Products Agency before sale in Sweden.

Applications

Applications must be in CTD format (Common Technical Document). The same application forms are to be used as for conventional medicinal products.

Fees

Fees are charged in accordance with the Ordinance on Fees for State Control of Medicinal Products (2010:1167) and are payable upon receipt of invoice from the Medical Product Agency.

National procedure

Only the national procedure is applicable to natural remedies.

Homeopathic medicinal products

Homeopathic medicinal products must be produced in accordance with established homeopathic methods and contain raw materials with documented homeopathic use. Registration in Sweden is done in accordance with articles 14 and 15 in the Directive on Medicinal Products for Human Use (2001/82/EC).

Regulations for homeopathic medicinal products

Safety documentation

The safety of homeopathic medicinal products must be demonstrated through reference to the scientific literature or product-specific data.

Effect documentation

There are no requirements to show via clinical studies or literature references that homeopathic medicinal products have an effect. Nor may any effect and/or indication be stated for a homeopathic medicinal product.

Quality and manufacture of the product

All manufacture of medicinal products requires a production permit from the Medical Products Agency and must be done in compliance with Good Manufacturing Practice (GMP).

To the application form for a production permit (in Swedish)

Raw materials and mother tincture preparations

Read more about quality requirements for raw materials and homeopathic mother tincture preparations in Medical Product Agency regulations and general advice about registering certain homeopathic products (LVFS 1997:9 consolidated version).

LVFS 1997:9 (consolidated version) in Swedish

Finished products

Read more about quality requirements for finished products in Medical Product Agency regulations and general advice about registering certain homeopathic products (LVFS 1997:9 consolidated version).

LVFS 1997:9 (consolidated version) in Swedish

Quality documentation

The part of application documents that describes production and various controls of raw materials and the finished product is called quality documentation. The same requirements apply to homeopathic medicinal products as to conventional medicinal products.

LVFS 1997:9 (consolidated version) in Swedish

Registration procedure

Homeopathic products must be registered with the Medical Products Agency before sale in Sweden.

Applications

Applications must be in the CTD-format (Common Technical Document)

Fees

Read more about application fees and annual fees for application and registration of homeopathic medicinal products

Procedures

Application to register a homeopathic medicinal product may involve national registration in Sweden or, under certain conditions, registration in several EU countries simultaneously.

National procedure

An application in the national procedure applies only to the Member State to which the application is submitted. Following approval, registration applies only to the Member State in question.

Decentralised and mutual recognition procedures

Decentralised procedure (DCP)
Mutual recognition procedure (MRP)

Under certain conditions, DCP and MRP are applicable to homeopathic medicinal products.

Regulatory advice