Stability batches

Finally, the registration stability batches were manufactured within a 6-month time period of transfer initiation. During the entire transfer process the marketed product had to have uninterrupted commercial supply, with minimal impact on the regulatory file (Anon, 2012). The product was subsequently manufactured at the production facility for a further 6-years, with good operating metrics (>95% on-time-in-full metrics). 

The equipment sterilization charts are included in the batch production record. The equipment sterilization charts for stability batch are produced in support of this submission. These sterilization charts shall be reviewed by Quality Assurance for adherence to the sterilization cycles specified in the batch records. 

All colony-forming units (CPUs) are enumerated if present. Isolates recovered in the level I and level II areas are identified as to genus and species. The summary of airborne microorganisms is monitored during the manufacturing of (product name) stability batch. 

Container-closure integrity of (product name) USP was performed on the stability batches produced in support of this submission per standard test method no. (specify number), Container/Closure Integrity Testing with Analysis via UV Spectrophotometry, included as (provide reference attachment number). The testing of the (product name) USP vials was performed under static conditions. Vials were immersed in a dye bath. The product in the vials was then tested for the presence of dye. The container/closure integrity testing yielded acceptable results. The final report for the container/ closure integrity test for (product name) is included in (provide reference attachment number). 

Examine other stability batches of the same product or that containg the same materials for similar behavior. 

The clinical batch record should be reviewed for GMP compliance and documentation requirements. The biobatch and stability batch records should be reviewed for equivalence to the information included in the NDA/ANDA submission. Process controls, specifications, bioequivalence data, and other information supported with foreign data should be submitted with a certified translation of that data. 

Regarding laboratory controls, a review of laboratory notebooks and chromatograms should be done to check the reliability and authenticity of the supporting data in the methods development and testing of the clinical, bio, and stability batches. Reference standards used should be certified as standards. The FDA expects that, for bulk substances, the suitability of reference standards should be more extensive than that of bulk drug substance specifications. A comparison of analytical methods and specifications for lots of drug substance used in clinical batches and biobatches should be performed to see if any deletions or revisions to any specifications occurred. 

Identify Critical Process and Packaging Parameters Pilot Scale Stability Batch Manufacture... 

Where long term data are not amenable to statistical analysis, but relevant supporting data are provided, the proposed shelf life can be up to one-and-a-half times, but should not be more than 6 months beyond, the period covered by long term data. Relevant supporting data include satisfactory long term data from development batches that are (/) made with a closely related formulation to, ( /) manufactured on a smaller scale than, or (/7/) packaged in a container closure system similar to, that of the primary stability batches. 

Process Development for Manufacturing and Quality Control—Engineering and manufacturing design activities to establish a company s capacity to produce a product in large volume and development of procedures to ensure chemical stability, batch-to-batch uniformity, and overall product quality. 

A useful approach to process optimisation is to identify all the critical process parameters that could potentially affect product quality or performance and prepare a Process Optimisation Protocol. Typically, data used to identify critical process parameters will be derived from laboratory or pilot-scale batches, and do not need to be confirmed on full-scale batches unless the control of the particular parameter can only be evaluated on a production scale. There is good incentive to use the production facilities at the earliest opportunity, drug availability permitting, to iron out any transfer difficulties. Manufacture of the stability batches to support Phase III studies, and also the Phase III clinical batches, at the final commercial site should minimise any questions from the FDA during PAI about possible differences between R D and Production process used. 

It is in the interest of pharmaceutical companies to be in a state of readiness for a PAI. Staff should be aware of all procedures, policies and regulations and have current training records. A good documentation storage and retrieval system is essential to be able to locate and retrieve records and reports efficiently. It is now considered essential to have prepared a Development Report for the FDA to aid the PAI. The purpose of the report is to summarise all the product development and to demonstrate the equivalence of the manufacturing process and controls used for the pivotal clinical and stability batches and the commercial product. The typical contents of the Development Report requested by the FDA are as follows ... 

Initial production batches for first launch supplies—additional stability work on first three production batches, using ICH storage conditions to verify shelf life if formal stability batches were not representative of final production scale. 

In principle, primary stability batches should be made at the intended commercial site. If the primary stability batches are not made at the intended commercial site,... 

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. 

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. 

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. 

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