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
- 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
- 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.
Batch documentation approvals.
Review and approval of executed batch records by the Quality unit is required per 21 CFR Part 211.192 (7). This review and approval is required for all stages of clinical manufacturing. Pre-approvals of batch records
should be governed by internal procedures as there is no requirement in CFR 21 that the Quality unit pre-approves the batch record (though this is highly recommended in order to minimize the chance
of errors). Indeed, Table I shows that pre-approval of batch records by the Quality Unit is practiced by all 10 companies that participated in the IQ
Consortium's drug-product manufacturing survey related to early development. Batch records must be retained for at least 1
year after the expiration of the batch according to CFR Part 211.180, but many companies keep their GMP records archived for
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).
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.)
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 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.