Clinical trials process validation

It is clear that the quality assurance organization plays a central role in coordinating facilitating, and documenting the formal investigation of an OOS result, whether the affected batch is utilized prior to approval (i.e., clinical trials, process validation) or postapproval as marketed product. 

The FDA may also want to audit R D to gain assurance that the product development has been done satisfactorily. In particular, the FDA may wish to see data that support the manufacturing process and controls from preformulation, product/process optimisation, clinical trials process validation and stability studies. 

Prior to phase I clinical trials, process steps and assays that relate to safety should be validated. For example, sterility assays and sterilization processes must be validated. Cell lines should be qualified prior to any clinical trials, including testing for adventitious agents and identifying and quantifying indigenous virus. Virus clearance steps should be validated, and removal of any potentially toxic or otherwise harmful agents should be validated [41,42],... 

Validation of a biomarker begins with the description of the pathogenesis of a disease and culminates when it is determined that the biomarker is applicable to clinical trials. This validation process follows a stepwise process depending on the stage of drug development. 

Validation of clinical trial formulations Validation of in vitro tests on solid dosage forms Experimental strategy for validation of industrial processes Optimization of industrial processes by evolutionary operation (EVOP)... 

Before a clinical trial starts, the use of technical aids such as IVRT, remote data entry and electronic diaries has to be considered. In Section 7.5.3.3, mention will be made of the use of electronic tracking system that provide status and monitoring reports. All these systems utilise computer systems that must be validated. Double and McKendry described computer validation as the process which documents that a computer system reproducibly performs the functions it was designed to do. The document Guidance for Industry - Computerised Systems used in Clinical Trials published by the FDA in 1999 gives clear recommendations of what is required (also see Section 7.5.4.1). 

St John s Wort (Hypericum perforatum, S JW) has been on the herbal pharmacopeia for many years. It is a traditional remedy for depression which has been validated in recent randomized clinical trials. Like many herbal preparations levels of active constituents vary from one preparation to another. As a consequence of its validation as an active preparation it has been widely promoted. Recently it has been shown to interact with a variety of other substances probably through the process of drug interaction. 

A clinical trial is an experiment and not only do we have to ensure that the clinical elements fit with the objectives of the trial, we also have to design the trial in a tight scientific way to make sure that it is capable of providing valid answers to the key questions in an unbiased, precise and structured way. This is where the statistics comes in and statistical thinking is a vital element of the design process for every clinical trial. 

The basic structure of the ICH GMP guideline for API production is shown in Table 15. It consists of 19 chapters, which cover the requirements for quahty management, personnel, premises, equipment, documentation, materials, production and process controls, packaging and labeling, storage and distribution, laboratory controls, validation, change control, complaints, recalls, contract services, cooperators, APIs manufactured by cell culture/fermentation, and APIs used in clinical trials [52]. 

The key elements of an inspection are to ensure that the facility is capable of fulfilling the application commitments to manufacture, process, control, package, and label a drug product following GMP the adequacy and accuracy of analytical methods submitted, to ensure that these methods are proper for the testing proposed correlation between the manufacturing process for clinical trial material, bioavailability study material, and stability studies and submitted process that the scientific data support full-scale production procedures and controls that only factual data have been submitted and that the protocols are in place to validate the manufacturing process. 

There is clearly much to do to validate a biotechnology process. Obviously not all of it can be accomplished prior to entering clinical trials. As a process is designed, documentation should be sufficient so that the rationale for the devel-... 

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