Commitment batches

Commitment Batches — Production batches of a drug substance or drug product for which the stability studies are initiated or completed postapproval through a commitment made in the registration application. 

Formal Stability Studies — Long-term and accelerated (and intermediate) studies undertaken on primary or commitment batches according to a prescribed stability protocol to establish or confirm the retest period of a drug substance or the shelf life of a drug product. Impermeable Containers — Containers that provide a permanent barrier to the passage of gases or solvents (e.g., sealed aluminum tubes for semisolids, sealed glass ampoules for solutions). 

Where applicable, an appropriate statistical method should be employed to analyze the long-term primary stability data in an original application. The purpose of this analysis is to establish, with a high degree of confidence, a retest period or shelf life during which a quantitative attribute will remain within acceptance criteria for all future batches manufactured, packaged, and stored under similar circumstances. This same method could also be applied to commitment batches to verify or extend the originally approved retest period or shelf life. 

Q1A(R2) also indicates that the commitment batches must be placed on stability with the same protocol as submission batches. Therefore, if there is signiticant change on the accelerated conditions of the primary batches and samples of intermediate conditions must be tested, then samples of intermediate condition of three production batches must also be tested. 

Production Controls The nature of the produc tion control logic differs greatly between continuous and batch plants. A good example of produc tion control in a continuous process is refineiy optimization. From the assay of the incoming crude oil, the values of the various possible refined products, the contractual commitments to dehver certain products, the performance measures of the various units within a refinery, and the hke, it is possible to determine the mix of produc ts that optimizes the economic return from processing this crude. The solution of this problem involves many relationships and constraints and is solved with techniques such as linear programming. 

Protocols for these batches and a commitment to continue them along with a tentative expiry date should also be included. Approval of these protocols will allow extension of the expiry date without a special supplement as long as the data remain within specifications. These data will ultimately be reported to FDA as part of periodic reports following NDA approval. Protocols intended for use on commercial batches should also be submitted. 

Finally, the three-part commitment to mount studies for the first three production batches and a statistically determined number (at least one) each year,... 

After mixing, the propellant is transferred into a casting pot, a container in which it may be held and from which it may be cast. The long pot life of mixed PVC plastisol propellant permits it to be held almost indefinitely to meet the convenience of the production schedule. The long pot life also makes possible the full characterization of a batch of mixed propellant, by extensive tests on batch samples, before the batch is committed to further processing. 

Drug substances intended for storage below -20°C should be treated on a case-by-case basis. When available longterm stability data on primary batches do not cover the proposed retest period granted at the time of approval, a commitment should be made to continue the stability studies postapproval to firmly establish the retest period. 

Where the submission includes long-term stability data on three production batches covering the proposed retest period, a postapproval commitment is considered unnecessary. Otherwise, one of the following commitments should be made ... 

If the submission includes data from stability studies on at least three production batches, a commitment should be made to continue these studies through the proposed retest period. 

Identification of key batch records These documents are then compared with the commitments that are contained in the Regulatory Commitment Document (see above). Any discrepancies identified are resolved, and explanations are documented when appropriate. This is done by the product development group in collaboration with the quality control and regulatory affairs departments. 

A commitment should be included to conduct long-term stability studies through the expiration dating period, according to tlie approved protocol, on the first or first three (see text for details) production batches and to report the results in the annual reports. 

Unfortunately, there is still much confusion as to what process validation is and what constitutes process validation documentation. At the beginning of this introduction several different definitions for process validation were provided, which were taken from FDA guidelines and the CGMPs. Chapman calls process validation simply organized, documented common sense [6], Others have said that it is more than three good manufactured batches and should represent a lifetime commitment as long as the product is in production, which is pretty much analogous to the retrospective process validation concept. 

Include data from at least the last 20-30 manufactured batches for analysis. If the number of batches is less than 20, then include all manufactured batches and commit to obtain the required number for analysis. 

The scope section describes what the process validation protocol covers, the number of batches, and what it does not cover. In this part, usually packaging validation or mouthpiece testing is included or excluded. Any worst-case tests may be briefly described. Stability commitments and stability protocols should be mentioned. 

Commitment to place first production batch of production FT/RT studies using the approved protocol in the application. Submit data in annual reports. 

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