Here you will find answers to the following questions:
- What is the development report?
- What does the development report contain?
- When must a development report be compiled?
- What is a biobatch?
The development report is a document that systematically and comprehensively presents the development history of a medicinal product, and which explains the deliberate, organised process in the development of a medicinal product to any external observer (for example the regulatory authorities or inspectors). Nowadays, it is no longer acceptable that medicinal products are developed purely intuitively or by chance and have optimal characteristics at the first attempt. Instead, a logical chain of experiments, investigations, and optimisations must be demonstrated that provides a traceable thread through the sometimes labyrinthine paths of development. It must also be made plausible why, for example, the formulation or manufacturing procedure of the commercial product is comparable with the formulation and manufacturing procedure of the clinical samples.
Although the development report under this name is currently not a legal requirement in the EU or in the US, the authorities expect that "a formalised system exists for collecting the information obtained during development". Independently of the regulatory requirement, with the involvement of industry associations and organisations, it has become standard procedure to summarise this information in a development report shortly before marketing authorisation (see figure 16.F-1).
Figure 16.F-1 Development report
Typical content of a development report
- Development of the formulation
- Results of the compatibility tests
- Rationale for the selection of components in formulations
- Necessity of the use of stabilising agents such as antioxidants, complex formers, preservatives
- Rationale of the selection of the clinical test formulation/commercial formulation
- Development of packaging
- Influence of light, oxygen, and humidity
- Rationale for the selection of packaging for the clinical test formulation/commercial formulation
- Development of the manufacturing process
- Development of the product specifications and release parameters
- Rationale for the limits of the definitive specifications
- Development of the specifications for active pharmaceutical ingredients, excipients and packaging materials
- Determination of stability, transport and storage conditions in a particular type of packaging (for clinical samples and commercial products)
- Influence of temperature and variations in temperature
- If applicable, in-use (microbiological) stability (for determining the consumption period after packaging is opened first time)
The development report must contain a list of all the clinical batches used for clinical trials together with a comment on their comparability in terms of formulation, process, specifications, etc. The "history of specifications" must list and justify all changes to the specifications.
It is important to highlight the pivotal studies and the investigational drugs used in these studies. It must also be scientifically justified and proven with data to what extent these clinical samples can be compared with the commercial product, and therefore the extent to which the clinical results are transferable.
If the clinical investigations were performed using a different galenical formulation (for example, capsules) to that intended for the commercial product (for example, tablets), a bioequivalence test is required. In this clinical study, the bioavailability of the commercial formulation is compared directly with the bioavailability of the clinical samples. Particular emphasis is attributed to the quality of the planned commercial product. The batch used for the bioequivalence test is known as the biobatch, and must fulfill certain requirements: The biobatch must be manufactured using the production equipment and, for solid oral forms, must have a minimum batch size of 100,000 tablets or capsules, or 1/10 of the production batch size.
If the commercial product has the same galenic form as the clinical samples, this clinical batch is known as the biobatch, with which the most important clinical study for this product was performed (for example, absolute bioavailability or dose-effectiveness study).
The composition, manufacturing process, analysis data, and stability results of the biobatch are usually in particular demand by the authorities and must therefore be described and commented in detail in the development report.
Although there is no regulatory obligation to compile a development report, the FDA at least still has an idea of what the content of a development report should cover (see figure 16.F-2).
Figure 16.F-2 Content of an FDA development report
Content of a development report (FDA)
- Active pharmaceutical ingredient
- Synthesis and supplier
- Physicochemical properties
- Storage and safety issues
- Development of the galenic form
- Compatibility tests between drug substance and excipients
- Formulation development and optimisation
- Selection of the final market form and packaging
- Process optimisation
- Definitive formulation and manufacturing equipment
- Master production record incl. in-process controls, limits, and data
- Control of the final product incl. data
In addition, for sterile products:
- Physical factors: absence of particles, etc.
- Filter compatibility and filter integrity test
- Sensitivity to oxygen
- Sensitivity to temperature
- Container - closure system
- Microbiological data and if applicable, antimicrobial preservative effectiveness test
The development report systematically summarises the development history of a medicinal product. It is designed to describe all development activities and provide evidence that the quality of the future commercial product is the same as the quality of the investigational medicinal products tested in the clinical trials.