USP Quality Control Spring 2021 PDF

PHA 339 Alekha K. Dash, Ph.D. 1 Ø Understand the Quality assurance aspects of pharmaceutical compounding (USP 1163) Ø Understand different steps of Analytical Instruments Qualification (USP 1058) Ø Understand the Validation Process: Accuracy, Specificity, Precision, Detection limits, Quantification...

PHA 339 Alekha K. Dash, Ph.D. 1 Ø Understand the Quality assurance aspects of pharmaceutical compounding (USP 1163) Ø Understand different steps of Analytical Instruments Qualification (USP 1058) Ø Understand the Validation Process: Accuracy, Specificity, Precision, Detection limits, Quantification limits, Linearity and Range, Robustness (USP 1225) 2 Ø Components: (1) training; (2) standard operating procedures (SOPs); (3) documentation; (4) verification; (5) testing; (6)cleaning, disinfecting, and safety; (7) containers, packaging, repackaging, labeling, and storage; (8) outsourcing, if used; and (9) responsible personnel 3 Ø Personnel involved in nonsterile or sterile compounding require additional, specific training and periodic retraining beyond the training needed for routine dispensing duties. Ø SOPs for pharmaceutical compounding are documents that describe how to perform routine and expected tasks in the compounding environment, including but not limited to procedures involving: ü ü ü ü ü ü ü ü Beyond-Use dating Chemical and physical stability Cleaning and disinfecting Component quality evaluation Compounding methods Dispensing Documentation Environmental quality and ………….. 4 Ø The purpose of documentation is to provide a record of all aspects of compounding operations and procedures that are described in 795 (Non-Sterile) and 797 (Sterile). Ø Beyond-use dating and sterility studies should be documented by reference to at least one of the following: ü ü ü ü Stability studies published in peer-reviewed literature, In-house or laboratory conducted stability and/or sterility studies, National compendia, or An extrapolation of above based on professional judgment. 5 Ø Verification involves authoritatively signed assurance and documentation that a process, procedure, or piece of equipment is functioning properly and producing the expected results. Ø Verification of a compounding procedure involves ü checking to ensure the calculations, ü weighing and measuring, ü order of mixing, and ü compounding techniques and equipment were appropriate and accurately performed. Ø The quality of ingredients should be verified upon receipt (e.g., Certificate of Analysis, manufacturer's label on commercial products, etc.). 6 Ø A quality assurance program for compounded preparations should include testing during the compounding process and of the finished compounded preparations. Ø Acceptance criteria shall be determined prior to testing. Ø Compounders should conduct visual inspections and know: (1) the importance of testing in the overall quality program in the compounding facility, (2) when to test, (3) what to test, (4) what appropriate method(s) and equipment to use, (5) how to interpret the results, (6) the limits of the test, and (7) specific actions required when a preparation does not meet specifications. 7 Table: U.S. Pharmacopeia Chapters for Selected Quality Testing Methods and Procedures Required: Powders, Capsules, Tablets, Solutions, Suspensions, Emulsions, Semi-Solids 8 Table: U.S. Pharmacopeia Chapters for Selected Quality Testing Methods and Procedures 9 Ø Sampling Requirements: Before collecting samples for testing, compounding professionals should consider the following factors: üQuantity of preparation being compounded, üfor a specific prescription versus in anticipation of prescriptions routinely received üNumber of samples needed üDestructive or nondestructive testing üAppropriate methods of obtaining representative samples üPhysical state of the samples (solid, liquid, or gas) üType of container required for collection and storage 10 Ø Physical and Chemical testing Ø Microbiological testing for pharmacy compounding includes ü ü ü ü Sterility Endotoxin Preservative effectiveness testing Microbial limit testing 11 Ø 6.Cleaning, disinfecting, and safety: Applies to both equipment and facilities. Ø 7. Containers, packaging, repackaging, labeling, and storage: Glass, Plastic, Closures for Injections, Good Packaging Practices, Good Repackaging Practices, Good Storage and Shipping Practices, Injections, Pharmaceutical Dosage Forms etc. Ø 8. Outsourcing: Documentation on file for all BUDs. Ø 9. Responsible personnel: Responsible personnel in the quality assurance program are essential in assuring the safety, identity, strength, quality, and purity of compounded drug preparations. 12 Ø Four critical components involved in the generation of reliable and consistent data. 13 Ø Analytical Validation instrument instrument data. Ø System suitability tests verify that the system will perform in accordance with the criteria set forth in the procedure. Ø Quality Control Check Samples: Tests on instruments standardized using reference materials and/or calibration standards. Some analyses also require the inclusion of quality control check samples to provide an in-process or ongoing assurance of the test's suitable performance. ü AIQ and AMV contribute to the quality of analysis before analysts conduct the tests. System suitability tests and quality control checks help ensure the quality of analytical results immediately before or during sample analysis. ü Instrument Qualification (AIQ) and Analytical Method (AMV): They are the collection of documented evidence that an performs suitably for its intended purpose. Use of a qualified in analysis contributes to confidence in the validity of generated 14 Ø Instrument qualification is not a single continuous process, but instead results from several discrete activities. These activities can be grouped into four phases: design qualification (DQ), installation qualification (IQ), operational qualification (OQ), and performance qualification (PQ). 15 Ø Validation of an analytical procedure is the process by which it is established, by laboratory studies, that the performance characteristics of the procedure meet the requirements for the intended analytical applications. 16 Ø The accuracy of an analytical procedure is the closeness of test results obtained by that procedure to the true value. Ø The accuracy of an analytical procedure should be established across its range. Ø Determination: Determined by application of the analytical procedure to an analyte of known purity (e.g., a Reference Standard) or by comparison of the results of the procedure with those of a second, well-characterized procedure, the accuracy of which has been stated or defined. 17 Ø The precision of an analytical procedure is the degree of agreement among individual test results when the procedure is applied repeatedly to multiple samplings of a homogeneous sample. Ø Expressed as the standard deviation or relative standard deviation (coefficient of variation) of a series of measurements. Ø Determination: Assaying a sufficient number of aliquots of a homogeneous sample to be able to calculate statistically valid estimates of standard deviation or relative standard deviation (coefficient of variation). 18 Ø Ability to assess the analyte in the presence of components that may be expected to be present, such as impurities, degradation products, and matrix components. Ø Identification Tests: Ensure the identity of the analyte. ü Determination: the ability to select between compounds of closely related structure that are likely to be present should be demonstrated Ø Purity Tests: Accurate estimation of the content of impurities of an analyte (e.g., related substances test, heavy metals limit, organic volatile impurities). ü Determination: Spiking the drug substance or product with appropriate levels of impurities and demonstrating that these impurities are determined with appropriate accuracy and precision. Ø Assays: Accurate estimation of the content or potency of the analyte in a sample. ü Determination: Spiking the drug substance or product with appropriate levels of impurities or excipients and demonstrating that the assay result is unaffected by the presence of these extraneous materials. 19 Ø It is the lowest amount of analyte in a sample that can be detected, but not necessarily quantitated, under the stated experimental conditions. Ø The detection limit is usually expressed as the concentration of analyte (e.g., percentage, parts per billion) in the sample. üDetermination: Analysis of samples with known concentrations of analyte and by establishing the minimum level at which the analyte can be reliably detected. 20 Ø It is the lowest amount of analyte in a sample that can be determined with acceptable precision and accuracy under the stated experimental conditions. Ø Quantitative assays for low levels of compounds in sample matrices, such as impurities in bulk drug substances and degradation products in finished pharmaceuticals. Ø The quantitation limit is expressed as the concentration of analyte (e.g., percentage, parts per billion) in the sample. üDetermination: Analysis of samples with known concentrations of analyte and by establishing the minimum level at which the analyte can be determined with acceptable accuracy and precision. 21 Ø The linearity of an analytical procedure is its ability to elicit test results that are directly, or by a well-defined mathematical transformation, proportional to the concentration of analyte in samples within a given range. Example: Relationship of concentration and assay measurement. Ø Linear (Log, Square root, reciprocal etc.) or Non-linear model Ø The range of an analytical procedure is the interval between the upper and lower levels of analyte (including these levels) that have been demonstrated to be determined with a suitable level of precision, accuracy, and linearity using the procedure as written. Ø The range is normally expressed in the same units as test results (e.g., percent, parts per million) obtained by the analytical procedure. 22 Ø Linearity should be established across the range of the analytical procedure. It should be established initially by visual examination of a plot of signals as a function of analyte concentration of content. Ø If there appears to be a linear relationship, test results should be established by appropriate statistical methods (e.g., by calculation of a regression line by the method of least squares). Ø Data from the regression line itself may be helpful to provide mathematical estimates of the degree of linearity. The correlation coefficient, y-intercept, slope of the regression line, and residual sum of squares should be submitted. Ø The range of the procedure is validated by verifying that the analytical procedure provides acceptable precision, accuracy, and linearity when applied to samples containing analyte at the extremes of the range as well as within the range. 23 Ø ICH recommends that, for the establishment of linearity, a minimum of five concentrations normally be used. It is also recommended that the following minimum specified ranges should be considered: ØAssay of a Drug Substance (or a finished product): from 80% to 120% of the test concentration. ØDetermination of an Impurity: from 50% to 120% of the acceptance criterion. ØFor Content Uniformity: a minimum of 70% to 130% of the test concentration, unless a wider or more appropriate range based on the nature of the dosage form (e.g., metered-dose inhalers) is justified. ØFor Dissolution Testing: ±20% over the specified range (e.g., if the acceptance criteria for a controlled-release product cover a region from 30%, after 1 hour, and up to 90%, after 24 hours, the validated range would be 10% to 110% of the label claim). 24 Ø The robustness of an analytical procedure is a measure of its capacity to remain unaffected by small but deliberate variations in procedural parameters listed in the procedure documentation and provides an indication of its suitability during normal usage. 25 Ø Category I: Analytical procedures for quantitation of major components of bulk drug substances or active ingredients (including preservatives) in finished pharmaceutical products. Ø Category II: Analytical procedures for determination of impurities in bulk drug substances or degradation compounds in finished pharmaceutical products. These procedures include quantitative assays and limit tests. Ø Category III: Analytical procedures for determination of performance characteristics (e.g., dissolution, drug release, etc.). Ø Category IV: Identification tests. 26 27 Ø Ø Ø Ø Ø Ø Ø Average Mean, Median, Mode Range % Errors Variance Standard Deviation Relative Standard deviations….. 28 If an assay method reports 495 mg of ampicillin in a 500 mg capsule of ampicillin, the measurement accuracy will be X? If the assay is repeated 5 times for the same sample of ampicillin capsule and each time the result is 495 mg of ampicillin, what will be the precision? } Accuracy is 99% [(495/500) x 100], i.e., a 1% error. } Precision of the experimental method is 100%. As, precision indicates the repeatability of an experimental method. 29 Ø USP 1163 Ø USP 1058 Ø USP 1225 30 31 Curcumin showed maximum absorbance at a wavelength of 425 nm and that for resveratrol was 305 1 Absorbance Ø 1.2 0.8 0.6 0.4 0.2 nm. Ø 0 200 developed. equations 400 500 600 Wavelength (nm) Based on standard curve equations, simultaneous 300 Resveratrol were Curcumin Figure 23: UV spectral scans of curcumin and resveratrol. 32 1.2 Ø Gelucire 1 Absorbance 50/13 and HPβCD did not show any interference at the wavelengths selected for the analysis of curcumin and resveratrol 0.8 0.6 0.4 0.2 0 200 250 300 350 400 450 500 550 Wavelength (nm) Resveratrol Curcumin Gelucire 50/13 Gelucire 50/13-HPβCD Figure 24: UV spectral scans of curcumin, resveratrol, Gelucire 50/13 and Gelucire 50/13- HPβCD. 33 Table. 5: Accuracy for curcumin and resveratrol Drug Concentration (μg/mL) % Accuracy N=3 % RSD N=3 Curcumin 30 91.84 1.12 15 93.20 0.55 7.5 94.17 0.80 30 101.67 1.43 15 103.28 0.65 7.5 107.1 1.18 Resveratrol 34 Table. 3: Intraday and Interday Precision for curcumin Concentration (μg/mL) Intraday (% RSD) N=4 Interday (% RSD) N=4 1.875 1.39 6.17 3.75 1.84 5.51 7.5 0.66 4.73 15 1.44 4.63 30 2.23 2.18 35 Table. 4: Intraday and Interday Precision for resveratrol Concentration (μg/mL) Intraday (% RSD) N=4 Interday (% RSD) N=4 1.875 2.26 9.32 3.75 0.94 9.12 7.5 0.91 7.39 15 0.65 6.45 30 0.53 5.65 36 (a) 3.000 2.500 Absorbance 2.500 Absorbance (c) y = 0.0824x + 0.0083 R² = 0.9996 2.000 1.500 1.000 0.500 0.000 0 20 30 1.500 1.000 0.500 0.000 40 Concentration (μg/mL) (b) 0 0.010 0.600 y = 0.0091x + 0.012 R² = 0.999 0.500 0.400 0.300 0.200 0.100 10 20 30 40 Concentration (μg/mL) (d) Absorbance Absorbance 10 y = 0.0703x + 0.0203 R² = 0.9995 2.000 y = 5E-06x + 0.0002 R² = 0.0757 0.005 0.000 0 20 40 60 Concentration (μg/mL) 80 0.000 0 20 40 60 80 Concentration (μg/mL) Figure 25: Standard curves of (a) curcumin at 425 nm; (b) curcumin at 305 nm; (c) resveratrol at 305 nm and (d) resveratrol at 425 nm 37 38