Method validation products

Control All control points starting with the basic raw materials right through to the finished product must be identified. Descriptions of the specifications, test methods, reference standards, and methods validation data should be included. 

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). 

Today, when a pesticide with no detectable residues is registered for use, a Tolerance or maximum residue limit (MRL) is established at the lowest concentration level at which the method was validated. However, for risk assessment purposes it would be wrong to use this number in calculating the risk posed to humans by exposure to the pesticide from the consumption of the food product. This would be assuming that the amount of the pesticide present in all food products treated with the pesticide and for which no detectable residues were found is just less than the lowest level of method validation (LLMV). The assumption is wrong, but there is no better way of performing a risk assessment calculation unless the limit of detection (LOD) and limit of quantification (LOQ) of the method were clearly defined in a uniformly acceptable manner. 

Table 3 Comparison of US FDA, US EPA, and EU Committee for Veterinary Medicinal Products (CVMP) method validation requirements...

The QPP has three laboratories the Environmental Chemistry Laboratory (ECL) in Bay St. Louis, MS, and the Analytical Chemistry Laboratory (ACL) and the Microbiology Laboratory at the Environmental Science Center, both at Fort Meade, MD. The ECL is heavily involved with method validation efforts. The ACL evaluates enforcement analytical methods for product chemistry to ensure that the ingredient statements on the label are accurate and evaluates residue analytical methods for... 

In most pharmaceutical situations, however, there is often insufficient latitude in the formula or process to allow the necessary experimentation. The pharmaceutical industry is subject to regulatory constraints that make EVOP impossible to employ in validated production processes and, therefore, impractical and expensive to use. Moreover, EVOP is not a substitute for good laboratory-scale investigation and, because of the necessarily small changes utilized, is not particularly suitable to the laboratory. In pharmaceutical development, more efficient methods are desired. 

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. 

XRPD as a stability-indicating assay method When the phase identity, or degree of crystallinity (or lack thereof), of a drug substance is important to its performance in a drug product, XRPD can serve as a vital stability-indicating assay method. There is no doubt that XRPD can be validated to the status of any other stability-indicating assay, and that one can use the usual criteria of method validation to establish the performance parameters of the method. This aspect would... 

The method(s), supporting validation reports, related knowledge and target specifications are critical inputs into risk assessment process. A review is performed jointly by a transfer team from both sites. There is an assessment of complexity (simple vs. complex) and prior knowledge (similar methods/API/products already transferred vs. no experience), method robustness (low vs. high concern), which can affect quality post transfer (low vs. high risk). 

During phase III the analytical laboratory performs systematic methods validation and continues with product characterization. A suitable formulation or a formulation candidate is in place and testing for stability continues. Production evaluates the consistency of the manufacturing process, which should be at a scale capable of delivering commercial quantities. Advanced studies are continued or initiated to evaluate chronic toxicology and reproductive side effects in animal models. Parallel to phase III studies, preparations are made for the submission of the BLA. 

DQ is performed by the supplier of the equipment or system at the supplier s factory as part of the factory acceptance test (FAT). IQ (based on site acceptance test—SAT), OQ, and PQ are performed on-site at the GMP facility. For a GMP manufacturing facility, the validation activities include the facility design, FTVAC system, environment control, laboratory and production equipment, water system, gases and utilities, cleaning, and analytical methods. Validation protocols (IQ, QQ, and PQ) are prepared for each item, listing all critical steps and acceptance criteria. Deviations are reviewed and resolved before the validation activity proceeds to the next phase. 

Method validation is the process of proving that an analytical method is acceptable for its intended purpose. Many organizations provide a framework for performing such validations (ASTM, 2004). In general, methods for product specifications and regulatory submission must include studies on specificity, linearity, accuracy, precision, range, detection limit, and quantitation limit. 

Validation is the process of collecting documented evidence that the method performs according to the intended purpose. " The validation characteristics and the acceptance criteria to be applied in validation of HPLC methods for MAA/NDA filings and marketed products should comply with the international guidelines on method validation. Table 11 details validation activities to be conducted for type 1, type 2, and type 3 methods ... 

Once a method has been developed and validated, it should be transferred to each site that intends to use the method. A typical method transfer would take place between the research group that developed and validated the method and the QC group that will use the method to release the finished commercial product, although method transfer may occur at any point where knowledge moves from one group to another. As in the case of method validation, method transfer should be performed under the control of a protocol that details the steps required for the study. 

Eventually, even well-validated methods become dated and obsolete due to improvements in technology. When this occurs, development of a new method using the new technology should occur and start a new round of method-validation activities. Any change to the method should take into account the effect on the long-term data for the product. Comparison of the validation for the old and new procedures should verify that the change will provide some benefits before it is accepted. 

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. 

Quality control and assurance Final product must be made under current good manufacturing process (cGMP)— emphasis placed on the final bulk product The product is the manufacturing process —cGMPs from seed stock or first step onward evaluated with equal scrutiny Regulated under analytical procedures and method validation, chemistry, manufacturing and control (CMC) documentation... 

The validation master plan is a summary document stating the intention and the methods to be used to establish the adequacy of the performance of the equipment, systems, controls, or process to be validated. It is approved by the quality assurance, validation, production, and engineering groups. 

The method for sterility testing of (product name) USP is manufacturing site SOP and the microbiological sterility method validation summary report is provided in (provide reference attachment number). The USP bacteriostasis/fungistasis test was performed to validate the sterility test method... 

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. 

TABLE 4 Assay Method Validation in Early Phase for Drug Substance and Drug Product... 

An example of the minimum requirement for potency assay of the drug substance and drug product is tabulated in Table 4. Note that the postponement of intermediate precision is aligned with previous discussion that the use of early phase analytical method resides mainly in one laboratory and is used only by a very limited number of analysts. Each individual company s phased method validation procedures and processes will vary, but the overall philosophy is the same. The extent of and expectations from early phase method validation are lower than the requirements in the later stages of development. The validation exercise becomes larger and more detailed and collects a larger body of data to ensure that the method is robust and appropriate for use at the commercial site. 

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. 

The fit-for-purpose nature of chemical analysis tells us that there is an appropriate level of method validation. Too much and resources are squandered for no benefit too little and the product could be worthless. Modern... 

Analytical potency method development should be performed to the extent that it is sufficient for its intended purpose. It is important to understand and know the molecular structure of the analyte during the method development process, as this will facilitate the identification of potential degradation impurities. For example, an impurity of M + 16 in the mass spectrum of a sample may indicate the probability of a nitrogen oxide formation. Upon successful completion of method development, the potency method will then be validated to show proof that it is suitable for its intended purpose. Finally, the method validated will be transferred to the quality control laboratory in preparation for the launch of the drug substance or drug product. 

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

Instead of using spike samples (as in accuracy determination), drug product lots that are representative of the commercial products should be used for precision (repeatability, intermediate precision). This is to ensure that the commercial drug product is used in at least one part of the method validation and that the repeatability results are representative of those that can be expected in the future. 

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