Process Description and Challenges

Formulation involves the careful mixing of active and inactive ingredients
to meet a precisely-determined ratio of components. Because the final
products are typically delivered in very small doses, it is important to
ensure thorough mixing at the smallest of scales.

There are several process control challenges in this area. These include:

• Ensuring an exact ratio of components
• Ensuring mixing under optimal conditions, such as:
  • Temperature
  • pH
  • Agitation
• Carefully accounting for all active ingredients

The product may be stored or transported in portable tanks. These tanks
may require some instrumentation as well. Some companies have even
included dedicated logging devices on portable tanks to ensure a more
complete history of the tank's condition.

Hard-piped delivery systems may also be used.

Typical Instrumentation Requirements

Typical instrumentation requirements for formulation vary greatly
depending on the nature of the formula, but generally would include:

• Mass flow and/or weight measurements
• Fluid and tank temperatures
• Agitation speeds
• pH, concentration, or other quality instrumentation

Portable Tanks

Temperature instrumentation is almost always assumed to be in place for
portable tanks.

Pressure instrumentation may be used to track tank integrity. Portable
tanks are often pressurized to reduce the risk of contamination. They may
also be pressurized in order to dispense materials from the tank.

Control Strategies

The basic control strategies involve material additions, heating or cooling,
and agitation. Most often, formulation is a batch process, although there
may be some continuous ratio-controlled blending.

Communications

The formulation area may serve multiple parts of the bio-pharmaceutical
facility. Each specific batch must be prepared on schedule, and to specification.
Lot tracking information must be communicated to the receiving
department. All of this communication may occur manually, in paper
records, but it is becoming more common for the information to be stored
and transmitted electronically.

Sequences
Ingredient addition may involve a combination of manual and automated
steps. Many raw materials are provided in solid form. For smaller
systems, these are weighed out manually, and then added to water in a
formulation tank. Water may then be added automatically or manually.

Accurate delivery of water or other materials may require special control
techniques. One such technique is the use of "dribble flow" near the end
of water addition. Using this technique, the bulk of the ingredient (i.e.,
water) addition occurs with the control valve fully open. As the weight
approaches target, the inlet flow rate is reduced dramatically, allowing the
tank to fill accurately to the desired weight. The reduced flow rate may be
accomplished through the use of a smaller inlet valve in parallel with a
large inlet, or by throttling a control valve.

Agitation control brings additional challenges. Formulation requires good
steady mixing. However, many biological ingredients, especially those
that are protein-based, may foam if agitated excessively. Agitation
sequences may have specific start and stop triggers based on liquid level in
the tank relative to agitator blade height.

Delivery of product through hard-piped systems is often followed by a liquid
buffer "chaser," or an air purge, to ensure complete delivery of formulated
material to the use tank.

Control Loops

Temperature control is typically accomplished through jacketed tanks.
Keep in mind that dynamic response to heating and cooling may vary
dramatically, requiring different controller tuning.

Calculations

The control system may perform concentration-related calculations for
the formulated materials. It is absolutely critical to distinguish between
calculations based on weight and those based on volume. Process development
scientists can help to clarify the required calculation.

Tuneables

Tuneables for formulation may include:

• Agitator start/stop trigger heights and/or times
• Time to start temperature control
• Inlet flow rate and/or dribble rate
• Volume of buffer chase
• Duration of air purge