Pharmaceutical Manufacturing Handbook: Production and

assembly/technique) using a growth medium. Through this approach the operator
gradually acquires the necessary skills to be a fully qualifi ed member of the production
staff. Training/qualifi cation of personnel is an ongoing requirement and must
be repeated periodically to assure the skills are maintained. Continuing evaluation
of operator qualifi cation is accomplished using written examinations, practical challenges,
documented observation, and participation in process simulation trials.
There is general acknowledgment of the risk associated with heavy reliance on
personnel for aseptic processing. This has fostered much of the innovative designs
for aseptic fi lling such as RABS and isolators where personnel are largely removed
from the critical environment. The future will undoubtedly witness aseptic technologies
where human interaction with sterile materials has been eliminated.
2.1.11
ASEPTIC PROCESSING CONTROL AND EVALUATION 129
ASEPTIC PROCESSING CONTROL AND EVALUATION
The preparation of any pharmaceutical product requires controls over the production
operations to assure the end result is a product that meets the required quality
attributes. The methods utilized for this control are supported by formalized validation
studies in which proof of consistency is demonstrated by appropriately designed
experiments. The defi nition of appropriate operating parameters is the primary
objective of the development activities and is further confi rmed during scale - up to
commercial operations. The validation supports that the routine controls applied to
the process are appropriate to assure product quality [36] . This is typically accomplished
in formalized validation activities in which expanded sampling/testing of the
product materials is performed to substantiate their uniformity and suitability for
use [30] .
2.1.11.1 In - Process Testing
The sampling and testing of in - process materials during the course of the manufacturing
process can confi rm that essential conditions have been provided. This is
appropriate in preparation, compounding, and fi lling activities. Sampling in preparation
processes can confi rm the absence of particles, proper siliconization levels, and
cleanliness of equipment to assure that production items and equipment are suitable
for use. Samples for microbiological quality, must, as previously mentioned, always
be done by fully gowned staff under ISO 5 conditions using excellent aseptic techniques.
During compounding, in - process testing can confi rm proper pH, dissolution
of materials, bioburden, and potency prior to fi lling. Filling operations can be monitored
for fi ll volume (weight), headspace oxygen, and particles. These activities can
all be automated to reduce interventions. These are typical examples of in - process
controls utilized to assure acceptability of the process while it is underway. In the
event of an abnormal result, corrective measures could be applied before further
processing. The validation effort supports that these control measures are suffi cient
to assure product quality, when met during production operations. The sample
intervals, sizes, and locations for in - process testing are chosen to enhance the validation.
The tolerance limits are usually tightened relative to the release requirements
to further assure that no out - of - tolerance materials are produced.