@phdthesis{Zilker2019,
  author    = {Zilker, Markus},
  title     = {The stability of finished pharmaceutical products and drug substances beyond their labeled expiry dates},
  doi       = {10.25972/OPUS-18069},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-180695},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2019},
  abstract  = {Upon approval of a drug, the stability of the API and the FPP has to be studied intensively because it determines the shelf-life. If a drug is found to be stable, the expiry date is arbitrary set to five years at the maximum, if a drug tends to undergo degradation, the expiry date is set shorter. The drug product must comply with predefined specifications in accordance with the ICH guidelines Q6A and Q6B during its entire market life. The content of the active substance is required to be within a specification of 95-105\% of its labeled claim until expiry corresponding to the ICH guideline Q1A(R2). However, there is little or scattered literature information addressing the stability of drug products beyond their expiry dates. The objective of this thesis was to study and assess the long-term stability of a collection involving numerous pure drug substances and ampoules manufactured in the 20th century. The content and the impurity profile were examined by means of appropriate analytical methods, mainly using liquid chromatography. The results were compared to data being available in the literature. Assessing the stability regarding the dosage form and the affiliation of the drug class was conducted. The experimental studies comprise the examination of 50 drug substances manufactured 20-30 years ago and 14 long expired ampoules which were older than 40 years in the time of analysis, exceeding many times the maximum shelf life of five years. For investigation of the solid drug substances, pharmacopoeial methods were applied as far as possible. Indeed, results of the study showed that 44 tested substances still complied with the specification of the Ph. Eur. with regard to the content and impurity profile, even after more than two decades of storage. For analysis of the injection solutions, HPLC-UV and HPLC-ESI/MS techniques were applied, commonly based on liquid chromatography methods of the Ph. Eur. for determination of related substances. Each method was further validated for its application to ensure accurate API quantification corresponding to ICH Q2(R1). Quite a few ampoules were identified to show surprisingly high stability. In spite of their age of 53-72 years, APIs such as caffeine, etilefrine, synephrine, metamizole sodium, furosemide, and sodium salicylate complied with the specified content that is valid nowadays, respectively. Nevertheless, typical degradation reaction, e.g. hydrolysis, oxidation, or isomerization, was observed in all remaining ampoules. Various degrees of hydrolysis were revealed for scopolamine, procaine, and adenosine triphosphate, the contents were decreased to 71\%, 70\%, and 15\% of the declared concentrations, respectively. In the epinephrine and dipyridamole ampoules, oxidative degradation has been occurred, finding respective API contents of more or less 70\%. For dihydroergotamine, excessive decomposition by epimerization was observed, resulting in an API content of 21\% and degradation by isomerization was found in lobeline, still containing 64\% of the labeled claim. In conclusion, supported by the data of the present studies and the literature, defining and authorizing a longer shelf-life may be applicable to numerous pharmaceuticals which should be considered by pharmaceutical manufacturers and regulatory authorities, if justified based on stability studies. A general extension of the shelf-lives of drug products and the abolishment or extension of the maximum shelf-life limit of five years would prevent disposing of still potent medications and save a lot of money to the entire health care system.},
  subject      = {Stabilit{\"a}t},
  language  = {en}
}
@phdthesis{Wahl2016,
  author    = {Wahl, Oliver},
  title     = {Impurity Profiling of Challenging Active Pharmaceutical Ingredients without Chromophore},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-137205},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2016},
  abstract  = {The impurity profiling of pharmaceutical ingredients can oppose many challenges. The best part of active pharmaceutical ingredients (APIs) and the related substances are detectable by UV detection, a very common detection principle. However, if an API lacks a suitable chromophore other means of detection are necessary. The corona charged aerosol detector (CAD) is a detector capable of detecting substances independent of their chemical structure. This "universal" detector has only one limitation: The analyte has to have a sufficiently low vapor pressure. Another important challenge that comes often together with the lack of a chromophore concerns the separation. These substances (e.g. most amino acids and derivatives) often contain structures that make them difficult to retain on conventional reversed phase columns. Possible solutions to overcome these challenges, like the application of the CAD and the benefit of so-called mixed-mode stationary phases in impurity profiling for pharmacopoeial purposes were explored in this work. The related substances analyzed in this thesis comprise amino acids, inorganic ions, bisphosphonic acids, basic and acidic derivatives of amino acids (esters and amides). The successful development and validation of mixed-mode liquid chromatography methods with CAD detection for carbocisteine and ibandronate sodium might help to increase the acceptance of this versatile detector in the pharmaceutical industry and in official authorities dealing with the determination of related substances. The combination of UV and CAD detection proved very useful during the analysis of Bicisate. Most of the related substances and some unidentified impurities were detectable by CAD whereas a synthesis by-product, a semi-volatile ester, was only detectable in the UV trace. The simple combination covers all relevant impurities in a single analysis. Two truly orthogonal methods regarding separation and detection for the enantiomeric purity of magnesium-L-aspartate helped to find the reason for elevated D aspartic acid content in the drug substance. A very quick and sensitive indirect separation using the OPA derivatization with NAC was developed as a powerful screening tool, whereas the direct separation of D- and L-CBQCA-Asp derivatives confirmed the results. Both methods were optimized in order to do without substances mentioned on the REACH list, like sodium tetraborate which is very frequently applied in standard derivatization protocols and CE separations. The importance of orthogonal detection principles in the determination of related substances of amino acids was discussed in a review article dealing with the revision of amino acid monographs in the Ph. Eur..},
  subject      = {Chromatographie},
  language  = {en}
}