Compliance analytical documentation

This chapter highlights the important aspects of the analytical transfer process as they relate to compliance, analytical data, and documentation. Other chapters in this text should be consulted for elaboration on the various important facets of technical transfer, including method development, method validation, documentation, and stability. 

Figure 1. A declaration of conformity according to EN 45014 should be shipped with analytical instruments that show evidence of compliance to documented manufacturing specifications (from reference 9)...

This chapter highlights the important aspects of the analytical transfer processes as they relate to process, compliance, analytical data, and documentation. Types of method transfers and the timeline of transfer activities are discussed. The risk assessment prior to initiation of transfer activities is also described. The chapter describes content and utility of the transfer protocol and final report, as well as documents that govern analytical method transfers (i.e., SOPs and master plan). The importance of selecting appropriate method transfer acceptance criteria and use of statistical methods to evaluate results are described. The significance of the inclusion of an adequate level of detail in the methods, protocol(s), and other documents cannot be overly stressed. Last of all, the process for transfer of technical ownership of the analytical methods is discussed. Other chapters in this text should be consulted for elaboration on the various important facets of technical transfer, including method development, method validation, documentation, and stability. 

ISO, IUPAC and AOAC INTERNATIONAL have co-operated to produce agreed protocols on the Design, Conduct and Interpretation of Collaborative Studies 14 and on the Proficiency Testing of [Chemical] Analytical Laboratories .11 The Working Group that produced these protocols has prepared a further protocol on the internal quality control of data produced in analytical laboratories. The document was finalised in 1994 and published in 1995 as the Harmonised Guidelines For Internal Quality Control In Analytical Chemistry Laboratories .12 The use of the procedures outlined in the Protocol should aid compliance with the accreditation requirements specified above. 

QA requires the efficient analysis of many samples to support routine production release and stability programs. Methods are typically established in the analytical development group. Efficiency and convenience issues, including the speed of media preparation and the relative convenience of data handling and documentation, are important here. While compliance is important in all aspects of the pharmaceutical industry, QA functions must approach compliance perfection. Depending upon the facility, the automated apparatus may be tailored to specific methods with fixed configurations. Dissolution methods may be routine enough that a custom system, optimized for productivity, may be justified. Compliance of USP and use of industry standard apparatus is important to maintain compatibility with other company laboratories or in the case contract laboratory services are required. 

It is ultimately the sponsor s responsibility to ensure that cGCP is followed in its clinical trials, even though some of the work is contracted out to CROs and other service providers. With regard to analytical laboratories, GCP guidances require that all laboratories have full documentation, data-audit trails, standard procedures, trained staff, archives of samples and data, and routine quality assurance inspections (Prokscha, 2007). If multiple laboratories were to be used, the sponsor would need assurance that GCP requirements were met for every one. In contrast, if a central laboratory is used and all samples are shipped to it, the sponsor only needs to check GCP compliance at that laboratory. 

It is generally recognized and accepted that analytical methods must be suitable for the intended use. Furthermore, EU Directives 85/591/EEC, 89/397/EEC and 93/99/ EEC state that analytical procedures for compliance testing with food laws are to be carried out on the basis of validated methods. Method validation is known as the process used to confirm that a procedure is fit for a particular analytical purpose. This process, an essential part of analytical quality assurance, can be described as the set of tests used to establish and document performance characteristics of a method. The performance characteristics of a method are experimentally derived values for the fundamental parameters of importance in assessing the suitability of the method (Horwitz 1988, 1995 Thompson and Wood 1993, 1995 Eurachem 1996 FAO 1998 US EPA 1995 US FDA 1993a). These parameters include ... 

Examples of product quality GxP data include study data (e.g., stability trial data, clinical trial data, patient and animal records/results), regulatory submissions (e.g., stability data, development summary reports), analytical production data (e.g., analytical methods, quality reference data), and compliance management (e.g., indexes to archived documents/records). 

A requirement, in line with Regulation (EC) No 1935/2004, concerning a declaration of compliance and the availability of appropriate documentation, has been confirmed in the draft regulation. It means that for any active and intelligent material a statement shall be provided that certifies that the material is safe to be used in contact with food under specified conditions of contact. To support such a statement the certifier shall have documentation that can prove the validity of the certificated. These documents shall be available to relevant authorities for inspection. In many cases this will include analytical data on, e.g., migration, total release, and effectivity of the active and intelligent of active components. 

Method validation is a process by which documented evidence is prepared and provided to show that the method meets the intended need. Highly regulated pharmaceutical analytical laboratories perform method validation and generate data on the following parameters, to comply with the compliance requirements of government agencies such FDA, EPA and/or to provide data for compendial agencies like USP, BP, etc. 

The manufacturing department ships the product in accordance with manufacturing guidelines, based on the receipt of valid purchase orders. The product documentation includes a Declaration of System Validation with statements from Hewlett-Packard that the software was developed and tested according to the Hewlett-Packard Analytical Software Life Cycle, a process that has been certified for ISO 9001 quality standard and for the information technology quality system (ITQS) compliance and that has been inspected by representatives from both computer validation companies and the pharmaceutical industry. 

In addition to the mass spectral aspects of these assays, which are outlined below, there may also be extensive requirements to be met by the analyst with respect to compliance with good laboratory practice, which governs the operations of analytical laboratories and includes sampling regimes, assay validation procedures (e.g., limits of detection, limits of quantification, accuracy, reproducibility, and ruggedness), and laboratory accreditation (e.g., staff training, laboratory equipment, documentation, quality assurance, and quality control).142-145... 

Compliance members, with the help of analytical members of the preapproval audit inspection team, audit the following product-specific documents ... 

Typical analytical compliance documents are discussed in the following sections. 

The primary focus of this section will be on the criteria that apply to most analytical methods and that must be adequately estimated and documented for ensuring compliance with regulations. Criteria that entail significant statistical considerations will be discussed in this chapter. 

Each quality attribute required of the API must have a sound and proven test procedure. In regulatory compliance terms, this means the test must be validated that is, to have documented proof that it performs reliably, is indicative of the attribute under question, and is not biased by interfering components. There are eight specific components of a validated test, and for an excellent treatise on this, the reader is referred to the current USP or the ICH guidance on analytical test validation. Most regulatory authorities require a test for all significant API quality attributes on each lot produced. In nearly all cases, the pharmaceutical manufacturer requires a certificate of analysis (C of A( documenting the results obtained on each lot, as well as a statement from the quality office that the batch met its established quality criteria. 

The USP methods contained in the monographs are considered validated. The USP states ... users of analytical methods described in USP-NF are not required to validate the accuracy and reliability of these methods but merely verify their suitability for use. Recognizing the legal status of the USP and NF standards, it is essential, therefore, that proposals of new or revised compendial analytical procedures are supported by sufficient laboratory data to document their validity. The Code of Federal Regulations also recognizes that USP methods are validated. The section on laboratory records [8] states Laboratory records shall include completed data derived from all tests necessary to assure compliance with established specifications and standards,... and further states if the method employed is in the current revision of the United States Pharmacopeia [or] National Formulary... and the referenced method is not modified, a statement indicating the method and reference will suffice [8]. 

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