In brief
Under Section 4(19) of the German Medicines Act (AMG), active substances are substances that are used as pharmacologically active ingredients in the manufacture of medicinal products or that become such ingredients during manufacture. They are also referred to as API (active pharmaceutical ingredient) or drug substance. They are produced by chemical synthesis, by fermentation or cell culture, by extraction from plant or animal material, or by a combination of such processes.
In contract manufacturing of active substances, a specialised manufacturer takes over the synthesis or individual steps of it, purification, isolation and drying, and testing. The Good Manufacturing Practice requirements for active substances are set out in a separate part of the EU GMP Guide, which in substance is based on the international guideline ICH Q7.
When you need this
Most medicinal product manufacturers do not make their active substances themselves. Anyone developing a new molecule first needs small quantities for toxicology and early trials and later a manufacturer that can run the process at a larger scale. Generic manufacturers often source active substances from manufacturers that make them for several customers. Protection against supply shortages is another reason to qualify a second manufacturer.
Legal basis and rules
Whether an active substance manufacturer in Germany needs a manufacturing authorisation depends on the type of active substance. Section 13(1) AMG requires one for active substances of human, animal or microbial origin and for active substances produced by genetic engineering. Other active substances, mainly chemically synthesised ones, are not named in Section 13. They do, however, fall under the AMWHV, which covers all active substances intended for the manufacture of medicinal products, and sites that work with them are subject to the notification obligations under Section 67 AMG, insofar as the AMWHV governs their activity.
When GMP starts to apply
Part II does not apply to every step of active substance chemistry. The manufacturer must define and justify the point at which the manufacture of the active substance begins. For syntheses, this is the point at which the API starting material enters the process, that is a material incorporated as a significant structural fragment into the active substance. For fermentation, extraction or purification, this point is justified case by case. Table 1 of Part II shows for chemical synthesis, active substances of animal and plant origin, herbal extracts, biotechnological manufacture and classical fermentation at which step this usually is. From there on, the requirements of Part II apply, and they become stricter towards the later steps, up to purification and packaging. Physical processing such as granulation, milling or micronisation must be carried out at least in accordance with Part II. For sterile active substances, Part II applies only up to the point immediately before sterilisation, and the sterilisation itself and aseptic processing are governed by Annex 1.
Contract manufacturers under Part II
Section 16 of Part II requires contract manufacturers and contract laboratories to comply with Good Manufacturing Practice and to be evaluated by the contract giver for GMP compliance for the specific operations. A written contract sets out the GMP responsibilities of both parties and allows the contract giver to audit. Subcontracting to third parties is only permitted after prior evaluation and approval by the contract giver, and changes to the process, equipment, test methods or specifications must not be made without informing the contract giver and obtaining its approval.
Active substances from third countries
For imported active substances, Directive 2001/83/EC requires a written confirmation from the competent authority of the exporting country. It confirms that the GMP standards at the site are at least equivalent to those of the EU, that the site is subject to regular and also unannounced inspections, and that findings of non-compliance are reported to the EU without delay. German law calls this confirmation a certificate: Section 72a(1) AMG requires a certificate from the authority of the country of manufacture with the same content, so it is the same document. The confirmation is not required for countries that the Commission has placed on its list of equivalent systems. The list currently includes Australia, Brazil, Israel, Japan, Canada, Switzerland, Singapore, South Korea, Taiwan and the United States, Singapore since October 2026.
How the collaboration works
What to look for when selecting a manufacturer
Frequently asked questions
Does every active substance manufacturer need a manufacturing authorisation? +
Is the manufacturer’s certificate of analysis sufficient? +
Does Part II also apply to active substances in investigational medicinal products? +
Can the written confirmation be waived? +
Sources
Every statement in this text was checked against these primary sources (as of 10.11.2026). Laws, guidelines and authority websites, no advertising.
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