Additionally, companies should consider what items are appropriate for the manufacture. For example, the use of a certified
laminar flow hood may be a better choice for manufacturing than a fume hood, because the former is designed to prevent contamination
of the product, protect the operator, and the laboratory environment. In addition, with the appropriate cleaning, a laminar
flow hood can more easily be used for multiple products. Small scale/manual equipment or procedures may be the best approach
because the space is likely to be limited. With a small batch size, the use of small scale or manual equipment/procedures
will minimize yield loss. Additional measures to be assessed include appropriate gowning and operator personal protection
devices, area and operator monitoring for potent or radiolabeled drug exposure, and so forth.
Documentation of the facility preparation, product manufacture, and the return of the facility to the previous state, if needed,
is recommended. This documentation should describe the rationale for the manufacture in the nondedicated area, risk assessment,
preparation of the area, cleaning procedures, and list of responsible persons. This documentation can reference existing procedures
or standard operating procedures (SOPs) along with documents associated with the meetings and preparation for the manufacture
of the batch. Batch records and cleaning records should be part of the documentation and should follow the company's data-retention
Preparation at the clinical site.
On-site preparation of formulations, sometimes referred to as "extemporaneous preparation" or "compounding," is not considered
manufacturing, but is an effective method to prepare early clinical supplies using the local laws governing the practice of
pharmacy. The processes used for on-site preparation can be as simple as preparing and diluting solutions or filling capsules
with API to more complicated processes such as blending and compression of tablets. An IQ working group addressing current
practices in extemporaneous preparation has conducted a survey to be communicated at a later date, which confirms that only
a few companies have adopted practices to take advantage of more advanced formulation approaches at the clinic site (8). This
is a missed opportunity, because on-site preparation of formulations has the potential to dramatically speed industry's ability
to answer critical questions related to pharmacokinetic parameters, absolute or relative bioavailability, feasibility of extended
release and bioavailability enhancement approaches for difficult to deliver molecules. Currently, each company must develop
its own best practices to assure product quality and patient safety; often, these practices are based on compendial or professional
association publications (9–11). The authors believe this topic warrants further discussion between the industry and regulatory
authorities to determine when dose preparation at the clinical site is appropriate and the level of quality controls required.
The results of such a discussion could help to increase the utilization of on-site preparation of clinical trial materials
to facilitate quick answers to critical questions in early drug development and ultimately bring the best possible products
to patients in the shortest time.
Most equipment used to manufacture early GMP drug product is be managed under a qualification, preventive maintenance, and
calibration program for the GMP facility. However, in early development, there may occasionally be a need to use equipment
that is not part of such a program. Rather than performing a comprehensive qualification for a piece of equipment not expected
to be frequently used, an organization may choose to qualify it for a single step or campaign. Documentation from an installation
qualification/operational qualification (IQ/OQ) and or performance verification at the proposed operating condition is sufficient.
For example, if solution preparation needs a mixer with a rotation speed of 75 rpm, then documentation in the batch record
using a calibrated tachometer to verify that the mixer was operating at 75 rpm will suffice.
The use of dedicated or disposable equipment or product contact parts may be preferable to following standard cleaning procedures
to ensure equipment is clean and acceptable for use. However, not all equipment or equipment parts are disposable or may have
a substantial cost that makes disposal prohibitive. In that case, the product contact parts could be dedicated to a specific
drug substance for use in drug product manufacture. Dedicating product contact parts to a compound may be costly and may be
avoided in some cases by carefully considering product changeover and effective cleaning methods when purchasing equipment.
Another item to consider with respect to equipment, is that the more complicated the equipment is to run or maintain, the
less desirable it might be for early GMP batches. In most cases, simple equipment is adequate and will uses less material
and consume less total time for preparation, operation, and cleaning activities.