In brief
Sterile medicinal products are mainly preparations for injection and infusion. They must not contain any viable microorganisms. Because the sterility test on the finished product is only the last of a whole series of controls and cannot demonstrate sterility on its own, sterility must be assured by the manufacturing process itself. This makes sterile manufacturing one of the most demanding areas of pharmaceutical production, with cleanrooms, specialised equipment and continuous monitoring of the environment and personnel.
In contract manufacturing, a contract manufacturer, often referred to as a CMO or CDMO, takes over manufacturing for the owner of the product. This ranges from compounding the solution through sterile filtration, filling and, where needed, freeze-drying to the inspection of the finished containers. Both parties set out in a written contract who takes on which obligations. The contract giver remains responsible for controlling the outsourced manufacturing.
When you need this
Most companies that have sterile products manufactured by others have no filling of their own, or none for the format in question. An in-house aseptic facility is expensive to build, laborious to qualify and can only be operated with experienced staff, which rarely pays off for a single product or small quantities. Contract manufacturing is therefore typical for biotech companies in clinical development that need investigational medicinal products, for companies that market an authorised product without their own sterile manufacturing, and for manufacturers whose own capacity or technology is not sufficient for a new format, for example when a product is to move from a vial to a prefilled syringe.
The path through development also often leads to a contract manufacturer. Small batches for early trials are sometimes made at a site that is not designed for later commercial supply, so that at some point a move to a manufacturer with a larger line becomes necessary. This move is a project in its own right and should be planned early.
Legal basis and rules
Anyone in Germany who manufactures medicinal products commercially or professionally needs a manufacturing authorisation under Section 13 AMG. Under Section 16 AMG it is granted for a specific site and for specific medicinal products and dosage forms, so it matters that it covers exactly what the contract manufacturer is to do for you. The site is also subject to the AMWHV, which refers to the EU GMP Guide for the interpretation of Good Manufacturing Practice.
The core of the revised Annex 1 is the Contamination Control Strategy (CCS). In it, every manufacturer must set out how it prevents contamination by microorganisms, endotoxins and pyrogens as well as particles across all stages, from facility design through personnel, material flow, cleaning and monitoring to release. The strategy is based on the principles of quality risk management and is reviewed on an ongoing basis and at fixed intervals. Changes to the systems must be assessed for their impact on the CCS before and after implementation.
Terminal sterilisation and aseptic manufacturing
Annex 1 distinguishes two routes to sterility. In terminal sterilisation, the product is sterilised in its sealed container, for example with steam. In aseptic manufacturing, the solution, container and closure are sterilised separately and brought together under aseptic conditions. Where possible, the finished product should be terminally sterilised, because this provides greater assurance than sterile filtration and aseptic filling. The EMA guideline on sterilisation therefore calls terminal sterilisation the method of choice. Many biotechnologically manufactured products, such as proteins and antibodies, do not tolerate heat sterilisation and are manufactured aseptically.
Cleanroom grades and barrier technology
Cleanrooms are classified into Grades A to D. Grade A is where the critical steps take place in which the product or sterile surfaces are exposed, such as filling and closing in aseptic manufacturing. The background environment depends on the technology. A Restricted Access Barrier System (RABS) for aseptic manufacturing must be located in a room of at least Grade B. An isolator may stand in a lower grade: for open isolators generally at least Grade C, for closed isolators at least Grade D, justified by a risk assessment in the CCS. Annex 1 names RABS and isolators as means of minimising contamination from direct human interventions in the critical zone. Grades C and D are used for less critical steps such as preparing solutions before filtration.
Process simulation and other tests
Every aseptic process must be supported by an aseptic process simulation (media fill). Instead of the product, a growth medium is filled under conditions that are as realistic as possible, including the interventions that occur in routine operation. The containers are then incubated and examined for growth. The target is zero growth. A single contaminated unit means the simulation is considered failed and triggers an investigation of the cause. For initial validation, Annex 1 requires at least three consecutive successful simulations, after which they are generally repeated twice a year for each aseptic process, filling line and shift.
Other important points are integrity testing of sterilising filters, testing container closure integrity with validated methods and the individual inspection of every filled container of parenteral products for extraneous particles and other defects.
How the collaboration works
The collaboration itself is governed by Chapter 7 of the EU GMP Guide. Before outsourcing an activity, the contract giver must assess whether the contract acceptor is legally authorised, suitable and competent to carry it out, and must then monitor its performance on an ongoing basis. The path from the first conversation to routine supply usually looks like this:
How much effort the technology transfer involves depends heavily on the product’s stage of development and on how well the process is already described by the contract giver.
What to look for when selecting a manufacturer
The following questions help you make providers comparable and follow up specifically during the audit.
Frequently asked questions
Who is responsible for the product towards the authority? +
Is an isolator always better than a RABS? +
Does Annex 1 also apply to investigational medicinal products? +
How long does a technology transfer take? +
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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- EU-Kommission (EudraLex) · vol4-chap7_2012-06_en_0.pdf
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- EMA · ich-q9-quality-risk-management-scientific-guideline
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- EMA · concept-paper-revision-part-iv-gmp-specific-atmp-guidelines…
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- EU-Kommission (EudraLex) · 2015-10_annex15_0.pdf