GLP procedures

If any study type can be considered to allow for the application of a highly standardised study plan, if this type is of short duration and so frequently conducted at a test facility, that the study personnel therefore can be expected to possess a high degree of routine in the conduct of this study type, then the GLP procedures may be alleviated to some degree, as it is provided in the Principles. 

For a wider acceptance, conformance to internationally accepted practices and standards is desired. These requirements are rigorous, entailing chitin and chitosan materials and their products to have been produced under some form of Good Manufacturing Practice (GMP) process and evaluated under Good Laboratory Practice (GLP) procedures. Featured next, by no means exhaustive, are four of the better known examples. Collectively, they demonstrate that chitin and chitosan biomedical products conforming to the present international regulatory requirements can be attained. 

In accordance to GCP, the sponsor should appoint clinical trial monitors. These act as the main communication interface between the sponsor and the trial site, and should regularly visit the site to oversee that the trials are being conducted and correctly documented in accordance with the protocol and GCP. Reports should be supplied to the sponsor after each visit. It is also good practice for the sponsor to establish an auditing system for independently verifying that the activities in relation to the collection and processing of data at the trial site, and at related laboratories or sponsor s facilities, are conducted in accordance with applicable protocols, procedures, regulations, GCP and GLP. 

Laboratory notebooks—It may be debatable to consider laboratory notebooks as text documents, but they should be mentioned here because of their importance in preclinical development. Laboratory notebooks are used to record experimental procedures, observations, raw data, and other important information. Although laboratory notebooks are rarely used for submission to regulatory agencies directly, they are available for inspection by the authorities in the Preapproval Inspection (PAI) and other GMP/GLP-related inspections. Currently, most of the major pharmaceutical companies still use paper-based laboratory notebooks. Electronic-based notebook systems are being developed and commercialized, which are discussed in Chapter 9. 

In the author s experience, field residue trials can be conducted in Latin America under complete compliance with all ERA guidelines and recommendations. More time does need to be spent in planning and preparation to ensure that the personnel involved in the testing have been trained in GLP and that this training, as well as the compliance of equipment, storage and archival sites, standard operating procedures (SOPs), and quality assurance (QA) audits, are properly documented. 

The GLP training should consist of two parts first, a classroom presentation of the materials described in Section 4 above, and second, a field training session where the principals of documentation of mixing, calibration, and applications can be demonstrated. Disposal, cleaning, and maintenance procedures should also be discussed and demonstrated. The classroom presentation should stress that the four key areas to successful implementation of GLPs are (1) Good Science, (2) Documentation,... 

Good Laboratory Practice (GLP) regulations and their impact on the small-scale processing procedures... 

An additional requirement not noted in Table 1 is compliance with GLP7 These practices establish a paper trail for all procedures involved in the determination of residues. With regard to immunoassays, GLPs require calibration of measurement devices such as adjustable pipettors and dedicated spectrophotometers. Computer software output, as noted above, must be verified prior to use. This process can be simplified by limiting the application of specialized software to the operation of an instrument and carrying out the residue calculations in a broadly available spreadsheet such as Excel. On a positive note, in recent years, the software accompanying most microtiter plate readers has become generally easier to use and usually incorporates internal spreadsheets that are compatible with external systems. 

Today, much more than just data are produced electronically. Many documents needed for studies that fall under the Good Laboratory Practice (GLP) standards regulations are being managed electronically. These records include not only data, such as chromatographic data from automated electronic capture systems and raw data collected in electronic field notebooks, but also other documents, such as methods, protocols, reports and standard operating procedures (SOPs). Frequently, these records are generated, distributed, reviewed, and archived electronically. 

GLP compliance for electronic records does not differ from GLP compliance for paper records. The increased access and distribution of records and documents enabled by electronic systems provide compliance challenges. There are many new questions to answer for example, what is the difference between electronic approvals and electronic signatures The solutions to these challenges lie in ensuring that system validation and management processes are in place, such as SOPs or procedures... 

To satisfy government agencies, instruments need to be adequately tested, calibrated, and/or standardized according to documented procedures. Current GLP standards state that equipment used in the generation, measurement, or assessment of data and equipment used for facility environmental control must be of appropriate design and capacity to function according to the protocol and shall be suitably located for operation, inspection, cleaning, and maintenance. 

GLP regulations require QA personnel to inspect/audit each study conducted, but the extent to which QA personnel are involved in software development and the val-idation/verification process varies from company to company. In some companies, there is little or no QA involvement in these processes, whereas in others QA personnel are involved. QA personnel can provide assistance in the area of vendor audits for purchased software or can conduct inspections of in-house software development to ensure that internal procedures are being followed. QA personnel, who conduct in-process inspections and review the resulting data and validation report for accuracy, could provide inspection support during the validation and verification process. During system development and validation, properly trained QA personnel can provide the regulatory advice needed to ensure that the system will meet government standards. QA personnel become more familiar with the system(s) that will be used when they are involved early in the validation process. 

The responsibility of the QA unit should not be limited to in-process inspections and data and report audits. To be in full compliance with GLP, the QA unit should review all procedures for storing and archiving electronic as well as paper raw data. This review should include ensuring that back up and archiving procedures were performed as specified in the SOPs, that archiving was documented properly, and that long-term storage procedures were followed. 

Method validation, on the other hand, is normally considered part of the study in which the method will subsequently be used or consists of a separate defined study unto itself as such, it is normally required to be accomplished under GLP purview. There is, however, some confusion in some circles as to exactly what is meant by analytical method validation. Some chemists describe it as adaptation of one method from one type of matrix for use with another using basically the same or similar analytical approach. Others take a more strict interpretation and define validation as simply demonstration of the ability to achieve satisfactory results using a published procedure in one s own laboratory setting. Often, validation incorporates both interpretations. 

There must be systems in place to monitor the study while it is in progress and to check that all systems are working in accordance with GLP requirements, to record any problems identified and to ensure that remedial action is taken. The person responsible for these quality assurance procedures must be independent of the study being audited. In large organizations, there may be a separate Quality Assurance unit but this will not be practical in smaller organizations. 

The Study Director needs to have an understanding of the extent to which the computerized system impacts on the study results. The Quality Assurance team will also check that there are procedures in place to meet the GLP requirements for all stages of development, use and maintenance of the systems used. They will require read-only access to the system. 

A system for auditing and reviewing quality procedures is a specific requirement of ISO/IEC 17025, ISO 9001 and GLP. This is a critically important aspect of any quality management system so we will consider these activities in some detail. The first, and most important, thing to realize about Quality Audit and Management Review is that they are two completely different activities. This section deals with auditing while Section 9.5 deals with management review. 

The most common (off-line) sample preparation procedures after protein precipitation are solid phase extraction and liquid-liquid extraction. Multiple vendors and available chemistries utilize 96-well plates for solid phase extraction systems and liquid-liquid extraction procedures. Both extraction process can prepare samples for HPLC/MS/MS assay. Jemal et al.110 compared liquid-liquid extraction in a 96-well plate to semi-automated solid phase extraction in a 96-well plate for a carboxylic acid containing analyte in a human plasma matrix and reported that both clean-up procedures worked well. Yang et al.111 112 described two validated methods for compounds in plasma using semi-automated 96-well plate solid phase extraction procedures. Zimmer et al.113 compared solid phase extraction and liquid-liquid extraction to a turbulent flow chromatography clean-up for two test compounds in plasma all three clean-up approaches led to HPLC/MS/MS assays that met GLP requirements. 

This procedure allows one to identify the source of a problem if an assay shows poor process efficiency. The main disadvantage is the effort required that may be justified for a GLP validated assay but not for most discovery PK assays except as a tool for finding the source of a problem when an assay fails to work properly. 

To date, the Part II Programme has focused upon four major projects (1) The development and implementation of a set of Principles of Good Laboratory Practice (GLP s) (2) Resolution of issues concerning Confidentiality of Data (3) Development of a Glossary of Key Terms and (4) Development of guidelines and other procedures for the exchange of information (e.g., re test data, the export of hazardous chemicals, and the labelling of hazardous chemicals). 

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