Pharmaceutical methods, validation

Research reports—Research reports such as stability reports, method validation and transfer reports, and pharmaceutical development reports are key documents used for NDA/MAA filings. These documents are strictly version controlled. 

A pharmacopoeial reference substance is intended for the determination of the main component of a substance or for the active ingredient of a pharmaceutical formulation which is usually present at a high proportion of the total. The reference substance is to be used as a primary standard in a specific method validated as prescribed in the ICH Guideline Validation of Analytical Procedure Methodology" (Technical Guide for the Elaboration of Monographs 1996 ICH Guideline 1997). the reproducibility of which is known. This is taken into account when the limits of acceptance (tolerance) for the substance or product are fixed (Daas and Miller 1997,1998). 

C. C. Chan and E. Jensen, Overview of pharmaceutical product development and its associated quality system, in Analytical Method Validation and Instrument Performance Verification (eds. C. C. Chan, H. Lam, Y. C. Lee and X.-U. Zhang), Wiley-Interscience, Hoboken, NJ, 2004, pp. 1-10. 

Ermer, J., Miller, J. H. McB. Method validation in pharmaceutical analysis. Wiley VCH Verlag GmbH, KGaA, Weinheim, 2005. 

Rozet, E., Ceccato, A., Hubert, C., Ziemons, E., Oprean, R., Rudaz, S., Boulanger, B., Hubert, P. Analysis of recent pharmaceutical regulatory documents on analytical method validation. J. Chromatogr. A., 1158, 2007, 111-125. 

Why do we have to worry about method validation in the first place The most compelling reason is that the law requires it. Title 21, Part 211 of the Code of Federal Regulations on Current Good Manufacturing Practice for Finished Pharmaceuticals states ... 

In addition to online resources, other texts and references have discussed the process of validation for methods used in the pharmaceutical industry in relation to the regulatory guidance documents. These guides include discussions on method development in relation to method validation, the validation of non-chromatographic methods and stability indicating methods. 

HPLC is the leading Analytical procedure used for the verification of pharmaceutical cleaning validation programs. HPLC provides a linear, sensitive method for quantitating low levels of residues making the chromatographic finish the most reliable part of the cleaning verification. 

Sanger-van de Griend, C. E., Wahlstrom, H., Groningsson, K., and Widahl-Nasman, M. (1997). A chiral capillary electrophoresis method for ropivacaine hydrochloride in pharmaceutical formulations validation and comparison with chiral liquid chromatography. /. Pharm. Biomed. Anal. 15(8), 1051-1061. 

In biomedical and pharmaceutical analysis, and particularly in the pharmaceutical industry, much attention is paid to the quality of the obtained analytical results because of the strict regulations set by regulatory bodies. Proper method validation demonstrates the fit of an analytical method for a given purpose. In this context, robustness testing has become increasingly important. 

Pluym et al. compared the use of CE to that of HPLC in chemical and pharmaceutical quality control. They stated that CE could be considered as a complementary technique to HPLC because of its large separation capacity, its simplicity, and its economical benefits. Jimidar et al. decided that CE offers high separation efficiency and can be applied as an adjunct in HPLC method validation. Mol et al. evaluated the use of micellar electrokinetic chromatography (MEKC) coupled with electrospray ionization mass spectrometry (ESI—MS) in impurity profiling of drugs, which resulted in efficient separations. 

T.R.M. De Beer, W.R.G. Baeyens, A. Venneire, D. Broes, J.R Remon, and C. Vervaet, Raman spectroscopic method for the determination of medroxyprogesterone acetate in a pharmaceutical suspension Validation of quantifying abilities, uncertainty assessment and comparison with the high performance liquid chromatography reference method. Anal. Chim. Acta, 589, 192-199 (2007). 

Once an application has been accepted for evaluation, the Pharmaceutical Chemistry Evaluation Section, Toxicology Section and Clinical Evaluation Units evaluate the Module 3, 4 and 5 data, respectively. For applications relating to products of biological origin, a second copy of the Module 3 data is also evaluated by the TGA Laboratories (TGAL) Branch, which evaluates aspects such as laboratory methodology, method validation and shelf-life. 

The CISs are rapidly becoming more popular and reliable as their field of application broadens. This is mainly due to the production of surface images by multipoint scanning and mapping. Hyperspectral imaging has proven its potential for qualitative analysis of pharmaceutical products and can be used when spatial information becomes relevant for an analytical application. Even if online applications and regulatory method validation require further development, the power of CIS in quality control and PAT needs no further demonstration, whatever the wavelength domain or method of spectra collection. 

According to the ICH guidance, the objective of method validation is to demonstrate that analytical procedures are suitable for their intended purpose. Therefore the method s purpose should be linked to the clinical studies and the pharmaceutical purpose of the product being studied. 

Analytical methods validation is one of the most regulated validation processes in the pharmaceutical industry. Analytical validations are required to demonstrate that the methods employed are the most indicated for each product and that the results obtained are reliably correct. All methods employed in raw and finished product materials analysis are required to be validated. 

Chung Chow Chan, Azopharma Contract Pharmaceutical Services, Miramar, Florida, Analytical Method Validation Principles and Practices... 

METHOD VALIDATION FOR HPLC ANALYSIS OF RELATED SUBSTANCES IN PHARMACEUTICAL DRUG PRODUCTS... 

During the 1990 Washington Conference on Analytical Methods Validation Bioavailability, Bioequivalence and Pharmacokinetic Studies [1], parameters that should be used for method validation were defined. The final report of this conference is considered the most comprehensive document on the validation of bioanalytical methods. Many multinational pharmaceutical companies and contract research organizations contributed to its final draft. This scientific meeting was sponsored by the American Association of Pharmaceutical Scientists (AAPS), the Association of Official Analytical Chemists (AOAC), and the U.S. Food and Drug Administration (FDA). The conference report has been used as a reference by bioanalytical laboratories and regulatory agencies worldwide. 

Some industries that are highly regulated, such as the pharmaceutical sector, have placed great emphasis on method validation in, for example, HPLC. However, until recently, there has been little direct requirement for assuring that the analytical instruments are working properly. 

Method validation is the process of proving that an analytical method is acceptable for its intended purpose.3 In pharmaceutical chemistry, method validation requirements for regulatory submission include studies of method specificity, linearity, accuracy, precision, range, limit of detection, limit of quantitation, and robustness. 

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