Manufacturing clinical trials process validation

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. 

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. 

Quality assurance must approve each batch to be marketed by the unit, manufactured by the unit for use in clinical trials, submitted to regulatory agencies in support of registrations, or used to support validation of a process. 

The emphasis in the IND for phase 1 studies is on the identification and control of the new drug substance. As clinical development progresses, additional information should be submitted for new processes and larger-scale manufacturing procedures used to produce materials for the phase 2 and phase 3 clinical trials. Information for phase 1 studies may be submitted in a summary report with brief descriptions. The summaries are expanded and data are added as development and clinical trials progress. For example, established specifications and method validation need not be submitted for phase 1, but a detailed listing of all tests with a complete description of the corresponding procedures with validation information is expected by phase 3. 

In general, it is the final formulation that is used in Phase III clinical trials. If the materials are manufactured on the pilot scale, then results of the process study, of the kind described in chapter 5 and in sections IV and VI of this chapter, could be used to validate this programme, assuming the same equipment is used for the process study and for clinical trials manufacturing. 

Apart from the capital cost, other issues must be considered. cGMP requires the industry to follow strict guidelines as laid out by the relevant regulatory authorities (87). Broadly this may be classified into two categories (a) properly designed, installed, and commissioned equipment and (b) a reliable and consistent process. Validation is crucial for both process and equipment and must be successfully completed and demonstrated prior to the manufacture of any drug for clinical trial or for sale. The robustness of the process can be... 

In a perfect world—one with unlimited resources—all validation is performed prospectively three trials are performed and the results are reviewed and approved before commercial use of the process or system. In actuality, there are numerous instances in which concurrent approaches must be adopted, including preparation of clinical supplies, manufacture of orphan and expensive drugs, manufacture of low-volume products, and minor process changes to established products. For reliable processes, there is actually little difference between prospective and concurrent approaches. The results of the validation exercise, whether available from three batches produced over a longer period of time or closely spaced, should be the same if the underlying process is in a state of control (recalling that validation is merely a means of keeping score). 

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