Quality by design compliant analytical method validation

in Analytical Chemistry (2012), 84

The concept of quality by design (QbD) has recently been adopted for the development of pharmaceutical processes to ensure a predefined product quality. Focus on applying the QbD concept to analytical ... [more ▼]

The concept of quality by design (QbD) has recently been adopted for the development of pharmaceutical processes to ensure a predefined product quality. Focus on applying the QbD concept to analytical methods has increased as it is fully integrated within pharmaceutical processes and especially in the process control strategy. In addition, there is the need to switch from the traditional checklist implementation of method validation requirements to a method validation approach that should provide a high level of assurance of method reliability in order to adequately measure the Critical Quality Attributes (CQAs) of the drug product. The intended purpose of analytical methods is directly related to the final decision that will be made with the results generated by these methods under study. The final aim for quantitative impurity assays is to correctly declare a substance or a product as compliant with respect to the corresponding product specifications. For content assays, the aim is similar: making the correct decision about product compliance with respect to their specification limits. It is for these reasons that the fitness of these methods should be defined, as they are key elements of the Analytical Target Profile (ATP). Therefore, validation criteria, corresponding acceptance limits and method validation decision approaches should be settled in accordance with the final use of these analytical procedures. This work proposes a general methodology to achieve this in order to align method validation within the QbD framework and philosophy. β-expectation tolerance intervals are implemented to decide about the validity of analytical methods. The proposed methodology is also applied to the validation of analytical procedures dedicated to the quantification of impurities or active product ingredients (API) in drug substances or drug products and its applicability is illustrated with two case studies. [less ▲]

Silicone-based drug reservoirs manufacturing process - Critical quality attributes evaluation using NIR and Raman spectroscopy

Poster (2011, October)

NEW TRENDS IN VALIDATION OF ANALYTICAL METHODS

Conference (2011, September 08)

Analytical method validation is a mandatory step to evaluate the ability of developed methods to provide accurate results for their routine application in order to trust the critical decisions that will ... [more ▼]

Analytical method validation is a mandatory step to evaluate the ability of developed methods to provide accurate results for their routine application in order to trust the critical decisions that will be made with them. Even if several guidelines exist to help perform analytical method validations (ICH Q2R1 [1], USP <1225> [2], …) there is still the need to clarify the meaning and interpretation of analytical method validation criteria and methodology. Indeed, actually method validation is mostly realised as the traditional check list implementation of e.g. the ICH Q2R1 or USP <1225> method validation requirements. However, within the trend of Quality by Design [3], there is the need to switch from this traditional vision to an analytical method validation really adding value and providing a high level of assurance of analytical methods results reliability. Yet, different interpretations can be made of the validation guidelines as well as for the definitions of the validation criteria. This will lead to diverse experimental designs implemented to try fulfilling these criteria. Finally, different decision methodologies can also be interpreted from these guidelines. Therefore, the risk that a validated analytical method may be unfit for its future purpose will depend on a personal interpretation of these guidelines. The objective of this presentation is thus to show that analytical method validation should be planned and performed by first starting with the end in mind: what is the objective of the analytical methods under study? In such a way analytical method validation is coherent with the actual Quality by Design regulatory expectations. The risk of having validated an analytical method unfit for its purpose is strongly reduced as well as the risk of generating Out of Specification (OOS) results due to an unfit method. References [1] International Conference on Harmonisation (ICH) of Technical Requirements for registration of Pharmaceuticals for Human Use, Topic Q2 (R1): Validation of Analytical Procedures: Text and Methodology, Geneva, 2005. [2] USP 33 NF 28 S1, U.S. Pharmacopeia, 2007. USP–NF General Chapter <1225>. [3] International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use, Topic Q8(R2): Pharmaceutical development, Geneva, 2009. [less ▲]

BUILDING THE QUALITY INTO THE POLYMERIC SOLID DOSAGE FORM MANUFACTURING LINE - CRITICAL QUALITY ATTRIBUTES EVALUATION WITH NIR AND RAMAN PAT TOOLS

Poster (2011, September)

Development and validation of a UHPLC-UV method for the detection and quantification of erectile dysfunction drugs and some of their analogues found in counterfeit medicines.

Poster (2011, June 20)

La spectroscopie vibrationnelle, outil indispensable pour l'industrie pharmaceutique ?

Scientific conference (2011, June)

Comment adéquatement déclarer valide ou non valide une méthode analytique ?

Conference (2011, April 04)

Vu le rôle central que jouent les méthodes d’analyse dans l’ensemble des activités tant de l’industrie (bio)pharmaceutique, agro-alimentaire, chimique ou dans l’environnement, il est essentiel de les ... [more ▼]

Vu le rôle central que jouent les méthodes d’analyse dans l’ensemble des activités tant de l’industrie (bio)pharmaceutique, agro-alimentaire, chimique ou dans l’environnement, il est essentiel de les valider. Les critères de validation ne sont pas une finalité et il est nécessaire de rappeler l’objectif d’une méthode analytique et de sa validation afin de planifier adéquatement cette étape de validation. Par ailleurs, les approches de décision habituelles qui se basent seulement sur des estimateurs ponctuelles ne répondent pas à l’objectif de la validation. Une stratégie alternative pour décider de la validité des méthodes est proposée utilisant les intervalles de tolérance : "ß-expectation tolerance interval". [less ▲]

Performance of three HIV-1 DNA real-time PCRs for early diagnosis in infants and adults

Poster (2011, March)

Background Early pediatric HIV-1 diagnosis is a challenge in resource limited countries to identify HIV-infected newborns to provide early ART treatment. HIV DNA PCR testing is an accurate method for ... [more ▼]

Background Early pediatric HIV-1 diagnosis is a challenge in resource limited countries to identify HIV-infected newborns to provide early ART treatment. HIV DNA PCR testing is an accurate method for diagnosis in newborns and could be valuable for monitoring HIV infection in adults. We have evaluated the analytical, clinical performances and genotype inclusivity of 3 real-time Taqman PCRs targeting the ltr, int and env genes. Material and methods Total DNA was extracted from whole blood and Dried Blood Spots (DBS) using the NucleoSpin Blood kit (Macherey Nagel) and the Chelex resin. DNA amplification was performed using the Qiagen Multiplex PCR kit and detected on a 7300 Real time PCR system (Applied Biosystems). Method validation was realized as required by ISO 15189 standard. The accuracy profile methodology was applied. HIV-1 DNA of ACH2 cells (0, 25, 50, 100, 1000 and 5000 copies/PCR) mixed in whole blood were measured in 4 different series (2 PCR kits and 2 operators) of 5 independent DNA extraction of each standard. Linear and quadratic weighted and non weighted regression models were tested. Trueness, precision, limit of quantifications of the method and accuracy of the results were obtained for each model and compared. 93 whole blood samples of ART treated-patients with undetectable or low viraemia of 16 B and 77 non-B subtypes were assessed. Clinical evaluation of the assay was performed on 26 whole blood samples and 238 DBS from infants of Guinea Conakry determined HIV+ using the rapid Bioline HIV test Results The calibration model providing the most accurate results was the linear regression with an r² equal to 0.92 for ltr, 0.88 for int and 0.95 for env. Trueness, precision and accuracy were highly acceptable for the 3 sets of primers/probe not exceeding -0.23 log(copies/PCR) for bias and 0.5 log(copies) for intermediate precision standard deviation, respectively. The estimated lower limit of quantification was 41, 475 and 25 copies/PCR for ltr, int and env respectively. The accuracy profile of each gene showed that each future measurement using this assay has 80% probability to be within a limit of 0.5 log (copies/PCR) around the reference or true value of copies of each gene. 52/93 whole blood samples of ART-treated patients had 3 positive genes (Ct<40 cycles), 38/93 had two positive genes and 4/93 had only one positive gene (ltr). Among these patients, 3 were assigned as long term progressors and one was a subtype C strain. Clinical evaluation of the assay identified 1 HIV-1 infected newborn and 3 adults (at least 2 positive genes) for which HIV-1 infection was confirmed either by serology or viral load techniques as well as 96 HIV-1 infected infants using DBS. Conclusions This assay is suitable for detection of proviral HIV-1 DNA in infants and adults on whole blood and DBS samples. Despite an estimated lower limit of quantification higher than ltr and env, the int PCR was required to achieve a good genotype inclusivity. The method was fully validated as required by ISO 15189 and showed to provide sufficiently reliable results. [less ▲]

Development and validation of a ultra-high-performance liquid chromatography-UV method for the detection and quantification of erectile dysfunction drugs and some of their analogues found in counterfeit medicines

in Journal of Chromatography. A (2011), 1218

Pharmaceutical counterfeiting is a permanently growing problem. Control laboratories are constantly analysing counterfeit medicines. In industrialised countries, one of the main counterfeited class of ... [more ▼]

Pharmaceutical counterfeiting is a permanently growing problem. Control laboratories are constantly analysing counterfeit medicines. In industrialised countries, one of the main counterfeited class of medicines are erectile dysfunction drugs. This paper describes the development and validation of a fast method to detect and quantify the three authorised phosphodiesterase type 5 inhibitors and five analogues. The method is based on the use of a sub-2 microns polar-embedded column with a gradient using acetonitrile as organic modifier and 10 mM ammonium formate buffer (pH 3.5) as aqueous component of the mobile phase. The separation was achieved in less than 4.5 min. The method has also been compared to the registered HPLC method for the assay of Viagra® which was considered as the reference method. The method is also compatible with on-line coupling mass spectrometry and will significantly reduce analysis times and solvent consumption. [less ▲]

Evaluating the reliability of analytical results using a probability criterion: a Bayesian perspective

in Analytica Chimica Acta (2011), 705

Methods validation is mandatory in order to assess the fitness of purpose of the developed analytical method. Of core importance at the end of the validation is the evaluation of the reliability of the ... [more ▼]

Methods validation is mandatory in order to assess the fitness of purpose of the developed analytical method. Of core importance at the end of the validation is the evaluation of the reliability of the individual results that will be generated during the routine application of the method. Regulatory guidelines provide a general framework to assess the validity of a method, but none address the issue of results reliability. In this study, a Bayesian approach is proposed to address this concern. Results reliability is defined here as “the probability of an analytical method to provide analytical results within predefined acceptance limits around their reference or conventional true concentration values over a defined concentration range and under given environmental and operating conditions.” By providing the minimum reliability probability needed for the subsequent routine application of the method, as well as specifications or acceptance limits , the proposed Bayesian approach provides the effective probability of obtaining reliable future analytical results over the whole concentration range investigated. This is summarized in a single graph: the reliability profile. This Bayesian reliability profile is also compared to two frequentist approaches, the first one derived from the work of Dewé et al. [Dewé W., Govaerts B., Boulanger B., Rozet E., Chiap P., Hubert Ph., Chemometr. Intell. Lab. Syst. 85 (2007) 262-268] and the second proposed by Govaerts et al. [B. Govaerts, W. Dewé, M. Maumy, B. Boulanger, Qual. Reliab. Engng. Int. 24 (2008) 667-680]. Furthermore, to illustrate the applicability of the Bayesian reliability profile, this approach is also applied here to a bioanalytical method dedicated to the determination of ketoglutaric acid (KG) and hydroxymethylfurfural (HMF) in human plasma by SPE-HPLC-UV. [less ▲]