Clinical Batch release

The real-time in situ measurement does not allow for sample reanalysis. If an error occurs, no retained sample exists for retesting. This is an acceptable risk during non-GMP formulation support activities. If an error occurs, we only lose efficiency, since the test may have to be repeated. For a GMP analysis, such as a clinical batch release, the analytical failure could bring into question the quality of the clinical material, and could delay a pivotal clinical study. 

FIGURE 2 Comparison of in vitro release profiles of phase II and phase III clinical batches of 90-day norethisterone microspheres. 

Dissolution tests are used nowadays in the pharmaceutical industry in a wide variety of applications to help identify which formulations will produce the best results in the clinic, to release products to the market, to verify batch-to-batch reproducibility, and to help identify whether changes made to formulations or their manufacturing procedure after marketing approval are likely to affect the performance in the clinic. Further, dissolution tests can sometimes be implemented to help determine whether a generic version of the medicine can be approved or not. 

The history of analytical methods used to control the product is prepared The analytical development department prepares a chronological history of the various analytical methods used during the product development. This includes justifications for any changes made in the methods during the development process and a comparison of the methods used to release clinical batch vis-a-vis the commercial batches. 

The development of in-process and final product release specifications is an activity that must rely on experience with the production of the clinical batch. Ideally, trial batches made using the equipment and materials identical to those used for the clinical batches should be tested beforehand by QC. The specification for the vector preparation is dependent on what is regulatorily acceptable (i.e., passing a sterility test) and what the process is capable of producing. For Phase 1 clinical materials, it may be necessary to rely on data generated in the research laboratory using different equipment to establish an expected or needed specification. 

During clinical phases of a development project, there will be few batches that will need a clinical release status, so they can be utilized in clinical trials in humans. For a clinical release, all test methods need to be written by an analytical chemist and approved by a quality assurance group. All test methods that are utilized to test a clinical batch needs method validation as described in Chapter 9. Everything at this stage is performed by following cGMPs. 

We recognize the expanding role of the Internet in electronic recordkeeping in the context of part 11. Vital records, such as clinical data reports or batch release approvals, can be transmitted from source to destination computing systems by way of the Internet ... 

Within the analytical research and development (R D) unit, specifications and methods for clinical trial materials are approved and results from shortterm stability evaluations are reported. Method validation is completed for critical validation parameters for those methods used in release and stability testing of the clinical materials. Impurities and degradation products are tabulated for the toxicology and clinical batches to assure the safety of the materials for human use. 

The target product quality profile (TPQP) provides quantitative descriptions of clinical safety and efficacy that can be utilized to design and optimize a drug product. Because it describes aspects of clinical safety, the TPQP should comprise quantitative targets for attributes that are related to product performance. Examples include stability requirements and release profiles as these attributes are specifically related to the product s performance. It must be noted that the TPQP is not a specification because it may include analyses that are not required for batch release. Effectively, the TPQP serves as the interface between the prod-uct/process and the patient, where performance characteristics of the product relevant to the clinical performance are quantified. Providing the link between the clinical performance and the process is essential in the QbD paradigm because pharmaceutical quality is defined such that risk to the consumer is minimized and the product performance is commensurate with the label. 

In vitro release profiles on phase II and phase III clinical supplies prepared more than 2 years apart are shown in Fig. 2. SeveT al thousand doses were prepared for the phase III trial initiated in 1988. Figure 3 shows the reproducibility of six individual batches of microspheres produced by the solvent evaporation method. Other studies have been reported with similar processes (47). 

The product specification should include a measure of uniformity of content and a dissolution test following the release of the active ingredient until steady state is achieved (or justifying shorter periods of testing). Where possible, the dissolution specification (often expressed as quantity of active ingredient released per unit area of surface per unit time) should be related to the results obtained from batches found to be acceptable in clinical studies. In these tests six units should be tested for dissolution characteristics and the mean value stated with a measure of variability. 

Prior to formulating a drug substance into a dosage form, the desired product type must be detemined for planning the product formulation activities. Then, various initial formulations are developed and then evaluated for selected parameters, such as drug-release profile, bioavailability, clinical effectiveness, and for any scale-up problems. The best formulation is selected and becomes the master formula. Each batch of the product subsequently prepared must meet the specifications established in this master formula. 

Dissolution kinetics was studied under sink conditions by placing one implant in varying volumes (usually 100 ml) of phosphate buffer pH 7.4, while agitating in a horizontally shaking water bath (50 1 rev/min) at 37 1°C. Samples were withdrawn at varying time intervals for a duration of 21 days (an estimate of the expected duration of clinical use) and the amount of tobramycin sulphate released was determined spectrophotometrically. Equal volumes of fresh medium were added to replace aliquots removed for assay and the amount of drug release was corrected for dilution. Triplicate measurements were performed for each batch of implants prepared. 

Limits of acceptance should relate to the release limits (where applicable), to be derived from consideration of all the available stability information. The shelf life specification could allow acceptable and justifiable derivations from the release specification based on the stability evaluation and the changes observed on storage. It will need to include specific upper limits for degradation products, the justification for which should be influenced by the levels observed in material used in pre-clinical studies and clinical trials. The justification for the limits proposed for certain other tests such as particle size and/or dissolution rate will require reference to the results observed for batch(es) used in bioavailability and/or clinical studies. Any differences between the release and shelf life specifications for antimicrobial preservatives should be supported by preservative efficacy testing. 

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