development and manufacturing of biotherapeutics

Developing your idea into a sterile IMP in a seamless process

Fraunhofer ITEM has more than 25 years of experience in bioprocess development and in GMP manufacturing of biopharmaceutical active ingredients (APIs) and investigational medicinal products (IMPs) for clinical trials. A multidisciplinary team of biologists, chemists, pharmacists, engineers and technicians assists leads you on your way from the idea for a new biotherapeutic via the development of a production cell line to the manufacturing and release of an IMP. Depending on your requirements, our services can cover either the complete process or only individual phases.

As a Fraunhofer ITEM client, you will benefit from competences and expertise accumulated over years in a broad range of projects on biotherapeutics – from recombinant proteins and glycoproteins to complex multimolecular structures such as viruses and cells.
We provide you with the API and IMP and will guide you through the regulatory requirements to an approved IMP dossier for your drug candidate.
We aid you on your way from the idea for a new biotherapeutic via development of a production cell line to GMP manufacturing of the IMP released for use in clinical trials.

Our services and expertise

Please contact us in order to come up with a joint solution for how we can meet your individual needs

Development of mammalian and microbial production cell lines

GMP manufacture of master and working cell banks

Development of robust upstream and downstream sequences with subsequent upscaling

GMP manufacturing of investigational APIs

Quality control testing of biopharmaceutical APIs and IMPs

Aseptic filling and release of liquid dosage forms of IMPs

Fraunhofer ITEM is embedded in a sustainable network of trusted partnerships, both internal and with external agency-approved service providers. Fraunhofer ITEM stands for professional access to state-of-the-art technologies that you need for your candidate biotherapeutics.

Fraunhofer ITEM is in close contact with the regulatory agencies from the very beginning of your project. We assist you in consulting and scientific advice meetings with the competent authorities such as Paul-Ehrlich-Institute (PEI) and the German Federal Institute for Drugs and Medical Devices (BfArM).

Preclinical development as well as clinical trials can be performed in other Fraunhofer ITEM departments, which are embedded in the same quality network. We can offer streamlined and sustainable project approaches.

A clean-room facility for aseptic fill and finish of vials and ampoules has been operational since 2015, enabling production of ready-to-use sterile IMPs and other small batches of up to 3000 dosage forms.

Biopharmaceutical consultancy

Selection of mammalian or microbial expression systems suitable for production of the desired molecule
Outline of appropriate cloning strategies
Assurance of technical and regulatory requirements for the production cell line/cell substrate
Scheme for master, working, and post production cell bank characterization
Evaluation and qualification of analytical service laboratories for cell bank and drug substance/drug product characterization
Development of cultivation and purification strategies
Identification and assessment of critical product and process attributes
ICH-associated/-compliant stability studies for biopharmaceutical drug substances and investigational medicinal products (IMP)
Design of protocols for transfer of processes and analytical procedures from and/or to third parties (CMOs, contract laboratories)
Due diligences of CMOs and contract laboratories
Strategy development, document preparation, and client support in preparation of and during scientific meetings/scientific advice with regulatory agencies
Preparation of CMC sections of IMPDs/medical writing

Roadmap for GMP manufacturing of investigational biopharmaceuticals

Roadmap GMP manufacturing of investigational biopharmaceuticals — © Fraunhofer ITEM
Roadmap for GMP manufacturing of investigational biopharmaceuticals

Investigational medicinal products (IMPs) are manufactured in compliance with European drug regulations and with the quality requirements laid down in the Good Manufacturing Practice (GMP) guidelines of the European Union.

Whenever the drug substance, that is, the pharmacologically active component of an IMP, is a complex biomolecule (a protein, glycoprotein, or nucleic acid), GMP quality requirements have to be considered already when initiating development of the manufacturing process for the drug substance.

Bioprocess development and GMP manufacture are a sequence of steps that has to comply with distinct quality attributes.

Explanations

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Step 1

1 Cell line development

The history of the established cell line has to be traceable: the host cell line, the laboratory where the host cell line was once isolated, or the culture collection where it was originated. Full documentation of passages, media, and media components, preferably with material certificates, is necessary. The sources of recombinant genes, expression systems, and cloning are well documented. Recombinant cell clones generated in the laboratory are screened for suitability (expression level, expression stability, and required posttranslational modifications).

Step 2

2 Manufacturing of the master cell bank

A master cell bank (MCB) consisting of 200-300 vials is manufactured from a suitable cell clone and is tested for purity, identity, amount of viable cells, and suitability. GMP-compliant storage of the MCB is performed at low temperatures, that is, in the gas phase of liquid nitrogen or in an ultra-deep freezer at < -150 °C.

A scalable laboratory cultivation process is subsequently developed. Set points, proven acceptable ranges, and edges of failure of individual process parameters have to be established. The composition of the growth medium is optimized with respect to cell and process requirements.

Step 3

3 Manufacturing of the working cell bank

One vial of the MCB is expanded in growth medium and aliquoted as working cell bank (WCB) into > 300 vials, which are then cryoconserved in a GMP process comparable to that of the MCB. Like the MCB, the WCB is tested and characterized with regard to purity, identity, content, and viability. For animal cells, special emphasis is placed on virus safety testing.

Step 4

4 Cultivation scale-up

The cultivation regime is scaled up to technical (i.e. manufacturing) scale. Process parameters and target substance quality are monitored and controlled.

Step 5

5 Purification sequence scale-up

Based on the two intermediates, a) cell mass or b) cell-free supernatant (depending on where the cell deposits the target substance), a purification scheme consisting of a sequence of chromatography and filtration units is established. Set points, proven acceptable ranges, and edges of failure for the parameters of each unit operation are established with respect to target substance integrity, step yield, and purity. In the purification sequence for target substances generated from animal cell cultures, steps for virus removal (inactivation, nanofiltration) are implemented. The purification sequence is scaled up to technical and manufacturing scale.

Analytical procedures and in-process controls

For all stages of process development, analytical procedures suitable for characterizing the product with regard to identity, activity, content, and impurities are established. Analytical procedures used for the testing of incoming starting materials, release of target substance, and critical steps within the manufacturing sequence have to be validated for their purpose and in compliance with the requirements of the ICH Q2 guideline.

Verification of cleaning procedures

Cleaning procedures for all multi-use equipment components that are in direct contact with the target substance are verified for cleaning success on the basis of visual inspections, target substance carryover, and total organic carbon. Acceptance criteria for equipment cleaning procedures are established with risk-based approaches.

Stability assessment

Stability data for almost all unit operations in the purification sequence are recorded. Potential holding points for intermediates in the process sequence and storage conditions for intermediates are identified. Stability data for the purified bulk drug substance are generated in compliance with the requirements of the ICH Q5C/Q1A guidelines for standard and challenged storage conditions. Expiry and retesting dates are derived.

Step 6 - 10

6 - 10 Process documentation

The results of cell line development, process development, analytical development, and stability data are documented and condensed in development reports. Critical parameters for process and equipment are addressed in a preliminary risk-based validation master plan. A master batch production record and a master batch analysis record addressing all aspects of process and target substance quality (identity, purity, activity, and content) are prepared.

Manageability of the master batch production record and the batch analysis record is verified by execution of a minimum of one technical batch in the GMP facility. Target substance material (purified bulk) from the technical batch may be used in preclinical research and serve as reference standard.

Step 11

11 Manufacturing license

An application for a manufacturing license according to §13 of the German Drug Act is filed with the local drug authorities. In direct consultation with the German Federal Institute for Drugs and Medical Devices (BfArM) or the Paul Ehrlich Institute (PEI), the local drug authorities will decide about the manufacturing license within 100 days. The decision about the manufacturing license is based on process documentation quality, inspection of the manufacturing facility, qualification of the operating personnel, and the quality assurance system in place to guarantee compliance with local applicable GMP regulations.

Step 12

12 GMP manufacture of clinical-grade target substance

Once the manufacturing license has been issued, one or several GMP batches of the target substance are manufactured, analytically tested, and released.

Contact

Many years of experience are an asset which our Division of Pharmaceutical Biotechnology uses for consultancy services on a wide variety of biopharmaceutical drug candidates over their entire development life cycle, from the initial idea to first-in-man trials.

Contact Press / Media

Christian Heine

Project Manager - Pharmaceutical Biotechnology

Phone +49 531 6181-6406

Send email
christian.heine@item.fraunhofer.de

GMP manufacturing of biopharmaceuticals for clinical trials