Site-specific batches

Other factors, such as lack of experience at the new site in a particular dosage form or difference in the environmental conditions between the sites, can potentially affect the quality or stability of a drug product. Therefore, one site-specific batch may not be sufficient in these cases. More than one site-specific batch may be needed for a drug substance or product that is intrinsically unstable. 

Although one site-specific batch may be sufficient under certain situations, the data so generated, particularly if limited to accelerated studies, may not be amenable to statistical analysis for the establishment of a retest period or expiration dating period. Instead, the single site-specific batch may serve only to verify the stability profile of a drug substance or product that has been established based on primary stability batches at a pilot plant. 

Although pilot and commercial facilities may or may not be located on the same campus or within the same geographical area, they will generally employ similar processes and equipment of the same design and operating principles. If different processes or equipment are used, more site-specific batches or longer duration of data are recommended. If the pilot plant where the primary stability... 

For ANDAs, the primary batch or batches to support the application are usually manufactured in the production facility. If the primary stability batch or batches are not made at the intended commercial site, stability data should be generated on the drug product manufactured at that site, that is, site-specific batches, and the data should be included in the original submission to demonstrate that the product made at each site is equivalent. 

For complex dosage forms as described in the previous section, a reduced number of site-specific batches may be justified if accelerated and long-term data are available at the time of application submission on batches made at a different pilot or commercial site from the intended commercial facility. 

Most models only simulate the batch type of chemical systems, and lack the time and spatial information needed to address a site-specific problem, e.g., the arrival of a contaminant at a particular point in space. This type of model, however, can be useful in evaluating some laboratory experiments. 

A drug substance should be adequately characterized (i.e., results of chemical, physical, and, when applicable, biological testing). Material produced at different sites should be of comparable quality. In general, 3 to 6 months of stability data on one to three site-specific drug substance batches, depending on the availability of sufficient primary stability data from another site, should be provided at the time of application submission. 

In general, site-specific drug product batches should be made with identifiable site-specific drug substance batches both for original applications, wherever possible, and for postapproval stability commitment. 

If the pilot plant where the primary stability batches are made is located at the intended commercial site (i.e., on the same campus as the intended commercial facility), the site-specific stability recommendations are met and no additional data will be needed. A commitment should be made to place the first three production batches and annual batches thereafter on long-term stability studies. 

The participants were instructed to expose these racks in representative spent nuclear fuel assembly storage basins. They were also encouraged either to add coupons made of site specific alloys to these CRP racks or to fabricate similar racks with site specific alloy coupons. None of the participants added site specific alloy coupons to the racks of Batch I. China, however, prepared and exposed a separate rack with Chinese alloy coupons. This rack was exposed prior to the second RCM. The Chinese rack included coupons of the aluminium alloys 305 and LT24L and of SUS 304-8K the composition of these alloys is given in Table 4.2. A photograph of this rack is shown in Fig. 4.3. Table 4.3 shows the position of these alloy coupons in their additional rack. Brazil manufactured a separate rack (the IPEN rack) of coupons. This included a large number of coupons in different configurations, to allow evaluation of the effect of fuel... 

As it pertains to batch selection, site-specific stability has been the subject for discussion between FDA and industry. Site-specific means that stability batches are manufactured at the proposed manufacturing site. The site-specific stability is to assure that the batches used for expiration date determination will be representative of the batches made for commerce. Although site-specific stability testing has typically been implemented for years, it is not an absolute requirement from all authorities. It is recommended that the requirements for site-specific stability be determined for each country prior to initiation of the registration stability studies. 

A very versatile polymeric scaffold for site-specific double PPM is poly( 1 -aceto-l-pentalluorophenoxycarbonyl-2-vinylcyclopropane) [poly(APVCP)] (see Scheme 8) [139]. In this case, the two-step modification is performed in a sequential batch process. Following aminolysis by treatment with various primary amines, the ketone can be converted in the presence of hydrazide or hydroxylamine derivatives. Fmthermore, the ketone can be reduced to the secondary alcohol, which is subsequently converted into the ester or carbamate through the use of different acyl halides and isocyanates. 

Inspections should be carried out as study-specific inspections for critical phases of the study or as a batch of process inspections relating to critical tasks which are performed regularly and although may not be inspected for a specific study are inspected on a regular basis (e.g., once per month). The coordination of inspections is perhaps more difficult to predict than actually conducting the critical event. The use of local QA staff close to the sites where the field work is being conducted helps to reduce the travel time to the field sites and also the down time if the critical event cannot be made at the specified time. The use of computer planning tools to schedule fieldwork is very helpful, not only to the field staff but also to QA. 

Company E is a large chemical manufacturer with worldwide operations. CSB staff visited a mediumsized manufacturing site. Operations included storage and handling/processing of monomers, as well as extensive batch polymerization. The site uses standardized manufacturing methods and typically handles a specific set of chemicals. 

The use of spiked batches (with levels approaching the specification limit) is recommended for the transfer of impurity or related substances methodology. In parallel, the receiving site should also assess the LOD/LOQ (Limit of Detection/Limit of Quantitation) of the method for each of the specified impurities or related substances. This can help to identify whether specificity and sensitivity are issues at the receiving laboratory. 

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