R&D in GMP environment

It includes development of analytical methods, degradation studies, identification of unknown impurities, extractables & leachable. The Qualification of methods is described here. 

Development of analytical methods

The method development process is based on a planned approach, with the first phase consisting of specification of the project goals, literature search, scientific evaluation of known data, preparation of the experimental plan and collecting all required materials. The experiments are carried out in a systematic way in order to provide a robust analytical method and to get an extensive support for the whole life cycle of the developed method.

Pre-validation experiments, including testing of the key validation parameters (precision, accuracy…), are designed and carried out in order to determine the method performance parameters, to reveal possible weak points of the method and to assure smooth progression of the subsequent validation. 

Degradation studies

Forced degradation studies (FDS) play an important role in evaluation of stability-indicating ability of analytical methods, investigation of degradation pathways of active substances or assessment of sensitivity of chemical substances to different conditions. In FDS, the investigated substance undergoes degradation by various physicochemical processes (influence of heat, light, humidity, oxidation, presence of acidic/ basic environment etc.) in order to degrade a pre-defined fraction of the substance.

Depending on the FDS aim, an experimental plan is prepared, defining the employed degradation conditions and analytical methods used for subsequent analysis of the degraded samples. Then a series of FDS experiments is performed according to the plan and the obtained samples are analyzed.

The results of the FDS study are summarized in the report.

Identification of unknown impurities

R&D in Eurofins BioPharma Product Testing Czech Republic s.r.o. provides services associated with the identification of unknown impurities in pharmaceutical materials. The project typically requires employment of several analytical techniques. The selection depends on the complexity of the project and the chemical structure of the parent molecule.

Using knowledge on the studied active substance, investigation of degradation pathways using forced degradation approach is performed, in order to reveal conditions promoting the occurrence of the unknown impurity and to determine optimal degradation procedures for preparation of enriched material used for isolation of the unknown impurity by semi-preparative separation.

The determination of structure of the unknown impurity is based on results of multiple analytical techniques – mass spectrometry, NMR, UV-VIS, chromatographic behavior etc. The obtained data are combined in order to get an unambiguous assignment of the structure of the unknown impurity.

We are also able to provide the reference standard material of the impurity by preparing sufficient amount of the impurity substance with subsequent full characterization of the material to determine identity and purity of the prepared reference standard.

The very first service product of Eurofins BioPharma Product Testing Czech Republic s.r.o. – “Deep-inside Internal cross-reactions studies” happening in pharmaceuticals and final dosage forms including elucidation of mechanism of molecular changes, identification of unknown impurities and even the preparation of corresponding reference standard with MS/MS and NMR identification.

Extractables & leachable

Extractables

Chemical compounds that migrate from any product-contact material (including elastomeric, plastic, glass, stainless steel, or coating components) when exposed to an appropriate solvent under exaggerated conditions of time and temperature.

Leachables

Chemical compounds, typically a subset of extractables that migrate into a drug formulation from any product contact material (including elastomeric, plastic, glass, stainless steel, or coating components as a result of direct contact under normal process conditions or accelerated storage conditions. These are likely to be found in the final drug product.

Product Contact

Product contact is defined as contact with any liquid that has the potential to be included in a final product. This absolutely includes all liquid contact for starting materials and process intermediates. It also may include materials that contact gases or solids, depending on the chemical interactions involved. However, it is important to note that not all materials need to be in direct contact with a drug product to be of concern. Some extractables and leachables may migrate through a direct-contact layer. (An example would be a bag with multiple layers that contain differing materials. Extractables and leachables from the outer layers may migrate into a pharmaceutical formulation. Similarly, adhesives and inks from labels may migrate through the layers of a bag.)

Extractables and Leachables Studies

The goal of an extractable study is to identify as many compounds as possible that have the potential to become leachables. A positive outcome is one where the list of extractables from a material is sizable. Although it is not expected that many of those extractables will actually leach into the drug product at detectable levels, a materials extractables profile provides critical information in pursuit of a comprehensive leachables test. However, it is important to note that not all leachables may be found during the extractables survey (see Figure 1). For instance, drug formulation components or buffers may interact with a polymer or its additives to form a new “leachable” contaminant that was not previously identified during extractables analysis.

Numerous analytical techniques are used for E&L studies because no single analytical technique can detect them all. The techniques typically used in Eurofins BioPharma Product Testing Czech Republic s.r.o.:

• Gas Chromatography Mass Spectrometry (GC-MS)
• Liquid Chromatography Mass Spectrometry (LC-MS)
• High-performance Liquid Chromatography (HPLC)
• pH
• Conductivity
• Total Organic Carbon (TOC)
• Atomic Absorption Spectroscopy (AAS)
• Ion Chromatography (IC)