Compendial limits

Shelf life or compendial limits are intended to account for all impurities found from the starting materials to the degradation products. These limits determine the societal boundaries of safety and efficacy. 

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. 

Because the objective of this process is the preservation of the lyophilized material, the presence of collapsed material is suspect. Collapse may simply be considered a cosmetic defect. When the collapsed material exhibits an increased reconstitution time or poor solubility, the presence of collapse becomes more than just a cosmetic defect. If, however, the collapsed material retains a higher amount of residual water, where this water becomes involved in degradation of the product through hydrolysis, then there is a more serious concern. The presence of a significant amount of residual water may promote degradation of the product, such that the assay falls outside of the compendial limits. There would also be a concern for the toxicity or an influence on the therapeutic effectiveness of the product. Both potential results should be considered during product development. 

Pyrogenic contamination is detected using two tests. In the older method, rabbits are injected with product samples, and rectal temperature is measured. Compendial limits are established with respect to how much temperature increase is permitted before the product is judged to be free or contaminated with pyrogens. The newer method involves a relatively simple in vitro technique called the Limulus Amebocyte Lysate (LAL) test. It is based on the high senstivity of amebocytes of the horseshoe crab (Limulus) to the lipopolysaccharide component of endotoxins originating from Gramnegative bacteria. The LAL test is now the USP method of choice with endotoxin limits established for most SVIs. ... 

These methods of testing glass are basically similar to other compendial limits and other standards on glass such as those in International Organization for Standardization (ISO), German DIN (Deutsches Insti-tut fiir Normung), and the ASTM. The expected limit... 

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. 

In addition to the searchable library compilations, several compendial books on the electron ionization fragmentation behavior of compounds have been published [34-36]. They are dated, but nevertheless effectively capture the collective fragmentation information prior to their publication. All of these information sources discuss electron ionization spectra. El fragmentation rules, however, can be of limited assistance in interpreting soft ionization and MS-MS product ion spectra. 

In comparison to the approach of Ginski et al. [48], the Miyazaki s method appears to be more elaborate and complex and is thus coming closer to the in vivo situation. The device can simulate various effects of pH on dissolution and is, as an open system, closer to in vivo conditions compared to a closed one. However, it exhibits the drawback of not freely adjustable pH values acting on the drug. Low flow rate in the dissolution vessel may limit applications of complete dosage forms and allows predominantly only the use of granules, pellets, or grinded tablets. Furthermore, the application of compendial dissolution devices appears to be a more robust approach. 

These tests would include compendial tests for Microbial Limits, Sterility, Bacterial Endotoxins, and Antimicrobial Effectiveness. 

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. 

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. 

USP XXIV specifies the limits and method of testing for chemical and pyrogenic contaminants for various compendial classifications of water, such as purified water and water for injection. 

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. ... 

Excipients used in injectable formulations have to meet several stringent requirements. A positive identification test uniquely applicable to the excipients is required (e.g., infrared spectrophotometry and chromatography). It is important that manufacturers identify and set appropriate limits for impurities. These limits should be based upon appropriate toxicological data, or the limits described in national compendial requirements. Manufacturing processes should be adequately controlled so that the impurities do not exceed such established specifications. Solvents or catalysts used in the excipient production process should be removed to appropriate levels. If naturally derived, excipients should meet endotoxin levels and may require further testing for bovine spongiform encephalopathy (BSE) /... 

Unlike many dosage form specifications, the sterility specification is an absolute value. A product is either sterile or nonsterile. Historically, judgment of sterility has relied on an official compendial sterility test however, end-product sterility testing suffers from a myriad of limitations [1-4], The most obvious limitation is the nature of the sterility test. It is a destructive test thus, it depends on the statistical selection of a random sample of the whole lot. Uncertainty will always exist as to whether or not the sample unequivocally represents the whole. If it were known that one unit out of 1000 units was contaminated (i.e., contamination rate = 0.1%) and 20 units were randomly sampled out of those 1000 units, the probability of that one contaminated unit being included in those 20 samples is 0.02 [5], In other words, the chances are only 2% that the contaminated unit would be selected as part of the 20 representative samples of the whole 1000-unit lot. 

Each individual sample should meet compendial assay limits (e.g., 90.0-... 

The USP XX limits for the nitrogen content of melphalan are 8.90—9.45% [25]. Several compendial assays are based on the determination of the chlorine liberated by alkaline hydrolysis (see 5.4). 

Once a result that does not comply with either a regulatory or compendial specification (such as a regulatory limit) or an internal specification (e.g., in-process, alert, warning, or OOT limit) is discovered by the responsible analyst the following events should occur as rapidly as possible ... 

Compendial methods for drug substances generally do not require any additional validation however, drug products may require some limited validation to demonstrate that the drug matrix does not interfere with the compendial method. 

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). 

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. 

Various dry powder attributes are assessed at release and on stability. These include physical characteristics such as powder appearance, content uniformity, delivered dose uniformity, and particle size distribution. Chemical attributes that may be assessed include drug content, purity, and identity as well as the water content of a powder. Dry powders may also undergo microscopic evaluation for foreign particulate matter, unusual agglomeration, and particle size. Microbial limits also should be examined, including the total aerobic, yeast, and mold counts. The presence of specific pathogens should be ruled out. The dry powders also may be dissolved to test for pH level. In addition, certain compendial requirements for content and delivered-dose uniformity should also be measured. 

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. 

These tests include compendial tests for microbial limits, sterility, bacterial endotoxins, and antimicrobial effectiveness. 

Essential aspects of compendial standards are intrinsic in the history and composition of the Convention. USP standards are meant to describe an acceptable article from the point of view of the physician-pharmacist-patient interfaces and they are inherently time-of-use (that is, shelf life) requirements. Another outcome of this focus is that practical, medically significant aspects are dominant in assigning requirements and the limits therein. Compendial standards are always established from the viewpoints of the medical and pharmaceutical professions, which in the United States are represented by the USPC. 

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... 

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