Compendial test, development

For example, finished-product release specifications such as content uniformity are rarely correlated to clinical evidence rather, they are set according to compendial test standards. Furthermore, the functional relationship between in-process material characteristics and finished-product quality is seldom known at a high level hence, the assigned in-process specifications for some operations may over- or underestimate the true level of process capability. As the level of process understanding in the pharmaceutical industry increases, development of science- and evidence-based in-process and release specifications will improve the reliability of Cpk as a tool for process characterization. 

Near-infrared spectroscopy was proposed as an alternative to several compendial test methods. As an example, ampicillin trihydrate was used to demonstrate that in total, eight quality criteria could be checked and its conformity index calculated.Additional che-mometrics for quality control were developed by the same group. Their strategy was used to distinguish differences in mean particle size of various lactose samples and to study the effectiveness of a blending process for homogenous mixture preparation. 

There is much debate about these particular tests and their appropriateness. However, the concept of the use of aerodynamic particle size testing as a compendial test is now well established. Both impactor testing and impingers testing have a role in the development of MDIs, because they are useful tools in studying aerosol clouds and can provide information that leads to formulation optimization (at least in terms of respirable dose). It should be emphasized that these data should not be taken in isolation, and other appropriate particle-sizing techniques should also be used. A more complete discussion of this topic can be found in Chapter 11. 

One of the greatest tasks in providing compendial standards is to obtain, adapt, or develop test methods for determining compliance with the standards. Such methods must be capable of routine use in many laboratories by different personnel and equipment. There is a vast difference between a method that can be used in one laboratory by speciaHsts and one that can be used in many laboratories by generaHsts to determine whether chemicals pass or fail the estabHshed specifications. Additionally, the deterrninations must be reHable, because the results obtained may determine whether a product is safe or legal. 

C. J. Milano and L. Bailey. Evaluation of current compendial physiochemical test procedures for pharmaceutical elastomeric closures and development of an improved HPLC procedure. J. Parenter. Sci. Technol., 53, 202 (1999). 

Various dissolution test systems have been developed and several of them now enjoy compendial status in pharmacopeias, for example the reciprocating cylinder (United States Pharmacopeia Apparatus 3), the flow-through apparatus [European Pharmacopoeia (Pharm. Eur.) 2.9.3], or the apparatus for transdermal delivery systems, such as the paddle over disc. Hydrodynamic properties of these and other apparatus have been described only sparingly. The paucity of quantitative data related to hydrodynamics of pharmacopeial dissolution testers is lamentable, since well-controllable hydrodynamics are essential to both biopharmaceutical simulations and quality control. Here, we focus the discussion on the paddle and the basket apparatus, since these are the most important and widely used for oral solid dosage forms. A brief treatise on the hydrodynamics of the flow-through apparatus completes this section. 

For the dissolution test to be used as an effective drug product characterization and quality control tool, the method must be developed with the various end uses in mind. In some cases, the method used in the early phase of product and formulation development could be different from the final test procedure utilized for control of the product quality. Methods used for formulation screening or BA and/or bioequivalency evaluations may simply be impractical for a quality control environment. It is essential that with the accumulation of experience, the early method be critically re-evaluated and potentially simplified, giving preference to compendial apparatus and media. Hence, the final dissolution method submitted for product registration may not necessarily closely imitate the in vivo environment but should still test the key performance indicators of the formulation. 

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 ... 

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. 

If the development formulation were considered a pilot batch, then increasing batch size from 10 kg to 1100 kg using equipment of the same design and operating principles (see later) would be considered a Level 2 change. Additional tests recommended include stability (three months accelerated stability and longterm stability data on one batch) and multipoint dissolution profile comparison in the application or compendial medium (Case B). 

USP Apparatus 1 (rotating basket) and 2 (paddle) are the first choices when developing a dissolution method for solid oral dosage forms. Even though the compendial equipment may not be suitable for all low-dose drug products, a brief discussion of these apparatuses is necessary in order to understand the basic operation of dissolution testing. 

Numerous specifications and control measures are employed to determine final product quality, the first of which is ensuring adequate quality of excipients and active ingredients. Excipient testing ensures compliance with compendial specifications, as well as specifications determined during development of the fill material and/ or shell formulation. Among these are limiting values for trace impurities, especially peroxides, aldehydes, some metals, and ionic salts. 

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... 

Compendial approaches are developed to protect the public and guide pharmaceutical manufacturers, prescribers, and dispensers. It is in the best interest of all stakeholders that quality pharmaceuticals be available for immediate patient use. In fact, it is imperative at all stages of drug distribution that the quality be maintained, both from the perspective of patient safety and from the standpoint of customer satisfaction and product liability. For these reasons, pharmacopeial standards throughout the world articulate accepted testing protocols and minimum quality standards to ensure that manufacturers have the tools they need to guarantee the quality of the available drug supply. 

Tremendous changes in the selection of compendial methods have occurred in recent decades. Classic physical and chemical measurements had long been established as objective criteria for quality assurance and for compliance testing, but these had significant limitations for dosage forms, both as assays and as limit tests. As recent decades have witnessed a torrent of instrumental developments, it should be no surprise that the compendia have experienced a resultant flood of applications that use those instrumental methods popular in the industry. The previous limiting factors, the availability of instruments their and reliability... 

Characterization in the solid-state and compendial methods has been discussed already. Quantitative tests to characterize drug substance and drug product composition require that significant consideration be given to method development. Methods such as thin layer chromatography, gas chromatography, HPLC, supercritical fluid chromatography, and capillary electrophoresis... 

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