Validation compendial testing

It has to be said, there are a remarkable mix of topics in this section, ranging through a complete discussion of biotechnology-derived articles (<1045> and <1047>), cell and gene therapy products (<1046>), and validation of compendial (test) methods (<1225>). Specific methods for detection and measurement of suspended particulate matter are discussed in <788>, and there are detailed instructions on how to measure weights, <41>, volume <31>, or temperature <21>. Every student and, indeed, their supervisors need to be aware of what is in this valuable section there is so much valuable information that the compilers cannot be praised enough. 

Validation studies to show that the new preservative does not interfere with application/compendial test. 

Regulatory methods can be compendial or non-compendial. Wherever possible, methodologies are to be employed which are documented, generally recognized as official pharmacopoeia or compendial. Compendial methods are considered valid however, suitability must be verified under actual conditions of use. Non-compendial methods require validation, and must be selected if a compendial method does not exist. A non-compendial method can be chosen over an existing compendial method, if it can be demonstrated to be superior to the compendial test. 

It is not required to have prior FDA approval to use an alternate method to a compendial test. According to 21 CFR 314.70, Supplements and Other Changes to an Approved Application, the addition or deletion of an alternate analytical method does not require prior approval and may be filed in the Annual Product Report. However, we would need to document the equivalency of the alternate method to the regulatory or compendial test method and the validation report must be available for an FDA investigator to inspect at our manufacturing site. Where the test method is particularly novel it may be advisable to include the test in an NDA supplement so the FDA can review the new method and your company can get prior FDA approval before the new test method is implemented. 

The second supplement to USP 24-NF 19 includes a chapter (<1208>) entitled, Sterility Testing—Validation of Isolator Systems. This new chapter provides guidance for the validation of isolator systems for use in sterility testing of compendial articles. 

For non-compendial procedures, the performance parameters that should be determined in validation studies include specificity/selectivity, linearity, accuracy, precision (repeatability and intermediate precision), detection limit (DL), quantitation limit (QL), range, ruggedness, and robustness [6]. Other method validation information, such as the stability of analytical sample preparations, degradation/ stress studies, legible reproductions of representative instrumental output, identification and characterization of possible impurities, should be included [7], The parameters that are required to be validated depend on the type of analyses, so therefore different test methods require different validation schemes. 

The USP Dissolution General Chapter < 711 > describes the basket (Apparatus 1) and paddle (Apparatus 2) in detail. There are certain variations in usage of the apparatus that occur in the industry and are allowed with proper validation. The literature contains a recommendation for a new USP general chapter for dissolution testing (6). In this article, guidance for method validation and selection of equipment is described. It may be a useful guide when showing equipment equivalence to compendial equipment. 

Agut et al. (2011) assessed the different technology transfer options and reported that within Sanofi-Aventis that option 1 (comparative testing) is the approach of choice for critical methodologies, i.e. assay, degradation products, and in some cases water content and dissolution. Option 2 (co-validation) is reserved for less-critical methodologies, i.e. residual solvents by gas chromatography (GC), water content, dissolution and particle size methods whereas, option 4 (transfer waiver) is restricted to pharmacopoeial compendial methods, i.e. appearance, pH, particulate matter, etc. 

Generally, GMP manufacturers use compendial methods from the US Pharmacopoeia, British Pharmacopoeia, or European Pharmacopoeia as much as possible for analyses and testing purposes, as these methods have been validated and accepted by regulatory authorities. However, manufacturers are... 

There are occasions where new analytical methods have to be developed specifically for testing raw materials, intermediates, and finished products that are not covered by compendial methods. In these situations, the analytical methods are required to undergo a validation process to ensure they are suitable. One or more of the following parameters as defined in Exhibit 9.10 must be validated for newly developed analytical methods ... 

The USP 24 General Notices state that alternative methods may be used to determine that products comply with the pharmacopoeial standards for the advantages in accuracy, sensitivity, precision, selectivity, adaptability to automation or computerized data reduction, or any other special circumstances. Such alternative or automated methods shall be validated However, when disputed, the compendial method is conclusive as it is the official or referee test. In addition, USP Chapter (61) Microbial Limit Tests states that automated methods may be substituted provided they are validated and give equivalent or better results, whereas USP Chapter (71) Sterility Tests states that alternative procedures may be employed to demonstrate that an article is sterile, provided the results obtained are at least of equivalent reliability. 

Guidance can be found regarding the validation of chemical methods applicable to mierobial testing. Examples inelude the USP Chapter (1225) Validation of Compendial Methods, and a recent publieation by the International Conference on Harmonization (ICH) Validation of Analytical Methods. These publications provide specific instruction regarding the demonstration of new ehemical analytical methods and then-equivalence to existing methods. 

USP 24 Testing Chapters (51) Antimicrobial Effectiveness Testing, (61) Microbial Limit Tests and (71) Sterility Tests, United States Pharmacopeial Convention, Inc., Rockville, MD, 2000. USP 24 Informational Chapters (1116) Microbiological Evaluation of Clean Rooms and other Controlled Environments, (1111) Microbiological Attributes of Pharmaceutical Articles, (1151) Pharmaceutical Dosage Forms, (1225) Validation of Compendial Methods, and (1231) Water for Pharmaceutical Purposes, United States Pharmacopeial Convention, Inc., Rockville, MD, 2000. 

Compendial assay procedures vary from highly exacting analytical determinations to subjective evaluation of attributes. Considering this variety of assays, it is only logical that different test methods require different validation schemes. Only the most common categories of assays for which validation data should be required are covered. These categories are as follows (see also Table 1) ... 

Each product is tested for interaction absorbance at 630 nm (the same wavelength used for green dye determination). If product interferes with the detection of green dye at 630 nm, the limit for green dye absorption may be adjusted to compensate for this interference. Acceptance criteria for green dye ingress are that the absorbance of the sample is less than or equal to zero or NMT 0.002 in absorbance difference between the negative control sample and the test sample. The acceptance specification was set at two times the sensitivity of the method per USP <1225> Validation of Compendial Methods. ... 

References of Relevant Information List the internal and external instrument validation guidance documents, compendial reference methods, qualification testing, and related SOPs for validation. 

Rotational Speed. The rotational speed of a basket or paddle is an important consideration in the development and validation of the dissolution test. A speed of 100 rpm is commonly used with the basket apparatus and a speed of 50 rpm is used with paddles. In method validation, one needs to ensure that slight variations in rotational speed will not affect the outcome of the dissolution test. The compendial limit for variations in rotational speed is 4%, but a wider variation (e.g., 10%) may be considered in testing the robustness of the method. 

We focus on the requirements for registration in Japan. Thus, we provide information that considers the peculiarities of the requirements for the JP heavy metals test at the method development process. The compendial descriptions and relevant ICH guidelines in relation to this chapter are listed in the reference section. The principles for the validation requirements discussed in this chapter can be applied to heavy metal testing in general. 

Optical rotation has the dual advantages of historical use and widespread recognition in the compendia. For an enantiopure material, it defines its configuration when used in conjunction with other valid chemical tests. However, optical rotation has been used ineffectively when the primary analytical goal is the determination of stereochemical purity. The limits selected for the specification seem to be unrelated to the purity required by other methods. For example, the compendial monograph for naproxen requires that the drug substance meet a specification of "between -f-63.0 and -1-68.5"" in a chloroform solution. Based on the published specific rotation, this corresponds to a stereochemical purity of 95.5 to 103.7%, compared to the assay limits of 98.5 to 100,5%, determined by titration with sodium hydroxide (5). 

Analytical method validation should track closely to the stages of development of the method itself However, it is not realistic to expect complete and thorough validation of the method until its development cycle is complete. An exception to this would be a situation where an accepted compendial method is applied to clinical material (such as a dissolution test or release testing of a compendial component). In these cases, companies must be prepared to demonstrate that consistent acceptable results can be obtained when using the compendial method in the company s laboratory (also known as methods verification). The obvious... 

The USP standards do not mandate that certain tests be performed on given products. In fact, testing procedures and quality limits are determined and provided to the pharmacopoeia by manufacturers. Compendial requirements simply specify the tests that a pharmacopeial article must pass if it were subjected to the regimen specified in the USP. To that end, any validated procedure or sampling system can be adequate for the assurance of quality. Manufacturers can choose to strive for quality far above that dictated in the USP. The USP requirements should be viewed simply as the quality criteria that any manufacturer should be able to reasonably guarantee. 

The other validation test that is used to approve containers for use with sensitive preparations is the moisture permeability test. This evaluation is notably more complex in that it sets permeation limits based both on the type of container and the classification of the material being stored within. In general, these tests measure the performance of the packaging system but offer no design guidance. For compendial applications, permeability testing of plastics are described in the USP general chapters (661) and (671) for all types of containers. 

All equipment, processes, and quality assurance test procedures must be validated (or verified if using a compendial method) prior to the start of Process Validation. 

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