Batch documentation and execution

Batch record documentation preparation. Manufacturing documentation is a basic requirement for all phases of clinical development. 21 CFR Parts 211.186 and 211.188 describe master production and batch production records, respectively (7). The stated purpose of the master production record is to "assure uniformity from batch to batch." Although the record assurance is important for a commercial validated manufacturing process, it does not necessarily apply to clinical-development batches. Material properties, manufacturing scale, and quality target product profile frequently change from batch to batch. Therefore, batch production records are the appropriate documentation for clinical trial supplies. Batch production records for Phase 1 materials should minimally include:

• Name, strength, and description of the dosage form
• A complete list of active and inactive ingredients, including weight or measure per dosage unit and total weight or measure per unit
• Theoretical batch size (number of units)
• Manufacturing and control instructions.

These minimum requirements are consistent with the FDA Guidance for Industry: cGMP for Early Phase Investigational Drugs, which requires a record of manufacturing that details the materials, equipment, procedures used and any problems encountered during manufacturing (2). The records should allow for the replication of the process. On this basis, there is flexibility in the manner for which documentation of batch activities can occur, provided that the documentation allows for the post execution review by the quality unit and for the retention of these records.

Room clearance. 21 CFR Part 211.130 requires inspection of packaging and labeling facilities immediately before use to ensure that all drug products from previous operations have been removed. This inspection should be documented and can be performed by any qualified individual.

Although line clearance for bulk manufacture is not specifically mentioned in the CFR, it is expected that a room clearance be performed. At a minimum, this clearance should be performed prior to the initiation of a new batch (i.e., prior to batch materials entering a processing room).

Hold time. During the early stages of development, final dosage form release testing confirms product quality and support establishment of hold times later in the clinical development. There is no requirement to establish hold times for work in process in early development. Specific formulation and stability experience, which is usually limited at this stage of development, should be leveraged to assess any substantial variations from expected batch processing times. The data gathered from these batches and subsequent development can be used to help establish hold times for future batches. (Exceptions to this approach may include solution or suspension preparations used in solid dosage form manufacturing, where procedures typically govern allowable hold times to ensure the absence of microbial contamination in the final product.)

Change control. Changes to raw materials, processes, and products during early development are inevitable. It is not required that these changes be controlled by a central system but rather may be appropriately documented in technical reports and manufacturing batch records. Any changes in manufacturing process from a previous batch should be captured as part of the batch record documentation and communicated to affected areas. The rationale for these changes should also be documented as this serves as a source for development history reports and for updating regulatory filings. The authors recommend that those changes that could affect a regulatory filing be captured in a formal system.

Process changes. Process parameters should be recorded but do not need to be predetermined because processes may not be fixed or established in early development. Given the limited API availability in early development, a clinical batch is often the first time a product is manufactured at a particular scale or using a particular process train. Therefore, process changes should be expected. Process trains and operating parameters must be documented in the batch record but changes should not trigger an exception report or CAPA. Changes should be documented as an operational note or modification to the batch record in real time. Such changes driven by technical observations should not require prior approval by the Quality unit, but should have the appropriate scientific justification (via formulator/scientist) or the appropriate flexibility built into the batch record to allow for the changes. This documentation should be available for Quality review prior to product disposition.

Calculation of yield. Actual yields should be calculated for major processing steps to further process understanding and enable optimization of processes. Expected yield tolerances are not always applicable to early development manufacture. At this stage of early development, when formulation and process knowledge is extremely limited, there may be no technical basis for setting yield tolerances and, therefore, this yield may not be an indicator of the quality of the final product.

In-process controls and R&D sampling. In-process tests and controls should follow basic requirements of GMPS to document consistency of the batch. For capsule products, these requirements may include capsule weights and physical inspection. For tablet products, compression force or tablet hardness and weights should be monitored together with appearance. R&D sampling, defined as samples taken for purposes of furthering process understanding but not utilized for batch disposition decisions, is a normal part of all phases of clinical manufacturing. In early development manufacturing, a sampling plan is required for in-process control tests, but not for R&D samples. However, for the purpose of material accountability, R&D sampling should be documented as part of batch execution. For these samples, testing results may be managed separately, and are not required to be included in regulatory documentation.