INTRODUCTION

Several attributes of the pilot plant allow it to serve as a vital function in achieving the
key strategic objectives of:
Formulation and process development.
Clinical supply manufacture.
Technology evaluation, scale-up, and transfer.
These attributes include:
1) A current good manufacturing practices (cGMPs) environment;
2) A flexible highly trained staff;
3) Equipment to support multiple dosage form development; and
4) Equipment at multiple scales based on similar operating principles to those in
production.
These key attributes help define current trends in pilot plant operation. Most of the
development and clinical manufacturing activities should be condensed and performed
under cGMPs. The application of cGMPs early in the development process is mandated
by the current regulatory environment, while at the same time market competition is
demanding shorter development times. These aspects, and the often limited availability of
drug substance, result in the necessity to obtain as much development information as
possible from each and every batch manufactured in the pilot plant. Even batches targeted
solely for clinical supplies often incorporate some aspect of experimental design, process
optimization, or scale-up in an effort to maximize the information obtained during new
product development. In order to improve efficiencies within the pilot plant, many firms
are abandoning the practice of having separate clinical supplies manufacturing staff and
formulation process development staff in favor of a more flexible, responsive group
capable of supporting product development from beginning to end. The staff must be
trained in formulation development, process development, scale-up, technology transfer,
cGMP compliance, and clinical supplies manufacturing. In order to maximize
development efficiency, it is crucial to incorporate clinical supplies manufacture, process
development, scale-up, and technology transfer activities within the same departmental
organization. To this end, a matrix-management approach is often utilized for project
teams responsible for product development activities. Although the pilot plant must
simulate the manufacturing environment in which the new product will ultimately be
produced, there are many differences in operation because of the specific objectives of the
two types of facilities. The pilot plant facilitates product development activities, whereas
the manufacturing plant routinely fabricates products for the marketplace. The pilot plant
must be flexible in operation in order to accommodate the very nature of product
development, which is often at odds with the routine required in a true
manufacturing facility. Recognizing and managing the difference in objectives between
the pilot plant and production facility form the basis for success in pilot plant operation.
This chapter highlights the unique operational aspects of the pilot plant environment.
VALIDATION
Most basic validation activities within the cGMP pilot plant are identical to those
expected in practice in a manufacturing facility.[15] A validation master plan should be
developed that addresses the design specifications and qualification, installation
qualification (IQ), operational qualification (OQ), and performance qualification (PQ) of

all major utility systems, process equipment, and computer control systems. Installation
and commissioning data should be retained as part of an engineering documentation
package. A workable change control system should be established.
Process areas should meet or exceed current Food and Drug Administration (FDA)
standards. A fully validated pilot plant ensures compliance with cGMPs, but more
importantly, guarantees data integrity during product development.
Data generated during this period in the pilot plant are typically used to set product
specifications and in-process controls, as well as process variable control limits.
Validation of the utilities and equipment in the pilot plant ensures that the facility
adequately simulates the manufacturing environment. This is especially true for
automated equipment and equipment requiring validation of computer control systems.[6]
The information collected during product development in a validated facility
provides the appropriate database for subsequent scale-up and technology transfer
to the manufacturing site.
There are several areas within the pilot plant environment that routinely differ with
respect to validation when compared to a production facility; these include manufacturing
process validation, cleaning validation, and revalidation activities.
Manufacturing processes within the pilot plant environment are often not repeated. A
process may be implemented only once before a change in scale, equipment, or process
variable is implemented. The usual manufacturing scenario of performing process
validation on three or more identical sequential batches is often not relevant in the pilot
plant environment. In order to ensure that each batch is acceptable, especially with
respect to clinical use, it is important to collect sufficient in-process data to guarantee the
quality of the batch.[7]
Data can be generated during the actual experimental development work showing that the
process achieves what it purports to do, or extensive samples can be collected from each
batch as manufactured. A combination of experimental data and batch manufacturing data
may also serve to prove process integrity.
Specifications should be set with respect to critical product characteristics, such as
content uniformity and potency. The lack of a sufficient database and minimal experience
with a process early in development often require that the specifications be set at the
widest limits allowed by current regulatory guidelines, e.g., USP specifications.
As experience with the product grows, and assuming the database supports it,
specifications may become tighter as technology transfer proceeds.
Cleaning validation is different in the pilot plant environment than in manufacturing.[8
10] Again, the lack of process repetition often creates the need to verify that equipment is
clean before and/or after the manufacture of batches used in clinical studies on a per batch
basis. This can be accomplished by swab testing critical product contact surfaces
before and/or after equipment use to ensure that residual drug is absent or at an
acceptably low level. Cleaning techniques for new chemical entities (NCEs) must be
verified on materials of construction or based on solubility before new compounds enter
the pilot plant environment. This information, combined with a routine cleaning
procedure, i.e., standard operating procedure (SOP), for a particular piece of equipment,
may serve as an acceptable alternative to swabbing after every batch.
Finally, utility and equipment revalidation or validation review may be structured
differently than techniques typically used in the manufacturing environment. Unlike the
production facility, the pilot plant may not use every piece of equipment or system on a
routine basis. In fact, some equipment may remain idle for significant periods of time.
Revalidation may need to be scheduled based on hours in use rather than a program

designed for periodic review. It should be pointed out that some equipment or systems
might need more frequent revalidation activities because of lack of use.
No matter what basis is chosen, it is imperative that a formal revalidation program be
established in the pilot plant environment.
TRAINING
The development of a training program for pilot plant staff is complicated by the inherent
diversity of operations and personnel. Unlike the production facility, which is highly
specialized and subject to infrequent operation changes, the pilot plant must be prepared
to make a variety of dosage forms in response to a wide range of product development
programs. The diversity of pilot plant operations, equipment, and personnel requires a
flexible entry, reinforcement, and remedial training program. An extensive tracking
system and flexible scheduling system are also required. Most importantly, the training
program must be developed to meet the changing priorities of the product development
cycle while maintaining cGMP compliance in the manufacture of clinical supplies.
Training within the pilot plant can be broken down into four major areas:
1. Compliance with quality standards, such as cGMPs.
2. Safety and environmental responsibilities.
3. Compliance with SOPs.
4. Technical skills and knowledge.
The order in which these objectives are presented is referred to as the top-down
approach to training. It has been used successfully in the pharmaceutical industry. [11] A
systematic approach to develop a cGMP training program should include formal training
plans, written training manuals, effective training methods, assignment of responsibilities,
written documentation and periodic review, and written certification of instructors.[12] A
dynamic training process is extremely important. Initial training must be reinforced with
current, up-to-date programs that address changes in job requirements, performance
expectations, and
technology.
Pilot Plant Staff
The staff operating the pilot plant is often diverse in educational background, work
experience, and function. The multidisciplines can be divided into the broad categories of
scientific groups, support groups, and contractors. The last two groups can be further
subdivided into technical and non-technical personnel. Regardless of the category, a basic
training program should be defined for each. Access to specific areas of the pilot plant
may be based on the level of training applied to a particular category of staff, e.g., sterile
environment.
Training for the scientific group, which includes formulation and process development
scientists, represents the majority of the training requirements. Personnel with diverse
educational backgrounds may be challenged to operate in different areas of the pilot plant
on a multitude of equipment in different dosage form areas. The mindset of the scientist is
experimentation. The evaluation of formulations and processes is the focus of their work.
It is extremely important that training be well defined to attain an adequate level of
competency, and that all required training be completed prior to initiation of any pilot
plant activity.
This ensures the safety of personnel and equipment throughout the process and guarantees
the manufacture of a quality product.
Cross-training scientific staff in the use of many types of pilot plant equipment is vital to
carrying out efficient product development programs, but creates significant difficulties

with respect to training. Reinforcement training becomes paramount in order to maintain

the level of competency necessary to ensure proper operation of equipment and
compliance with procedures. A well-trained individual who regularly performs an
operation obtains the type of reinforcement necessary to successfully and correctly
complete a task. For this reason, it may be necessary to devote highly trained scientific
staff to operations in specific areas of the pilot plant, e.g., the sterile process areas.
Other scientific staff with less expertise in a particular operational area can assist in
development activities based on a lower level of basic training, but maybe relegated to
less technical operations compared to those with routine experience. It may sometimes be
necessary to assign experts in a defined operational area of the pilot plant based on the
development activities required. On-the-job training with an experienced guide or
expert is a simple and effective approach to entry and reinforcement training. Training
provided by the equipment manufacturer can be useful in the completion of entry-level
training and development of reinforcement training programs for the scientific and
support staff. The technical support groups must also be appropriately trained. They may
represent equipment and facility engineering, maintenance, and calibration groups, as
well as quality groups, i.e., QA/QC.
Although their educational backgrounds may be very diverse, the focus of these groups is
confined to pilot plant operation rather than the experimental techniques of the scientific
staff. The greatest challenge with respect to training equipment engineering, maintenance,
and calibration groups is to impart knowledge of how their responsibilities and actions in
the pilot
plant affect the ultimate quality of the products manufactured for clinical use. The quality
groups typically have a good grasp on cGMPs and how their activities within the pilot
plant can affect product quality. Training of quality groups is often very specific with
respect to their responsibilities, but it is important that they also receive appropriate basic
training in GMPs.[11]
The non-technical support groups represent individuals responsible for cleaning and
sanitation. Training requirements are usually limited to access specific areas of the pilot
plant.
The importance of training temporary and contract labor should not be overlooked. The
time period and frequency with which the contractor or temporary employee will operate
within the facility and the required level of access should be used to define requirements.
Training Program
A pilot plant training program has several key aspects that may require a different
approach compared to programs typically utilized in a production environment. These
include identification of educational and instructional training programs and development
of training manuals, individualized training syllabuses, and documentation and tracking
system. Educational and instructional training programs should be defined for the facility
based on the scope of operation of each functional area. For both educational and
instructional training, manuals should be developed. The instructional training manuals
can be divided into entry, reinforcement, and remedial training. Entry-level training is
targeted for a new or prospective employee and should provide assurance that a certain
skill level has been attained. Reinforcement level training is intended for an employee
who has already been trained in a certain area. This training is intended to reinforce skills
already acquired and to prevent performance problems. Remedial training is intended to
correct identified skill deficiencies. The training required for equipment may range from

reading the SOP and completing an evaluation form, e.g., test, for simple equipment to
more extensive supervised and documented practical experience with a qualified trainer.
Pilot plant educational courses are usually tailored
to a general audience since they impact all personnel. Instructional courses, however, may
be very technical and assume a certain level of competency. In all cases, the evaluations
developed as part of the training manual should effectively assess the students level of
competency. Any deficiencies identified in the assessment should be immediately
corrected with additional training. New technologies, frequently encountered during the
development process, affect pilot plant training programs. New technologies pose a
special problem because training must be conducted by a qualified individual. Some new
technologies can be studied at the equipment suppliers facility and subsequent initial
training can occur in the pilot plant with a representative of the equipment manufacturer
as trainer. For technologies invented in the development group, it is recommended that
the inventor become the initial trainer.
The diversity of pilot plant operations to be performed and the variety of personnel
involved require an individualized training syllabus for each employee. The top-down
approach mentioned previously works well in this regard. The focus is again to complete
the higher education courses before proceeding to the instructional or area-specific
procedures.
Access to and operation within the pilot plant areas can be controlled by successful
completion of basic requirements defined for each functional area. A simple way to
identify and document each individuals training requirements is a checklist of courses
and procedural training required based on the pilot plant area and function within the
area. The employee reviews the
checklist with management and identifies the training required to work on a particular
project within the pilot plant. The result is a documented individualized training syllabus.
Once defined, the syllabus can be used to train personnel to meet the resource needs for
the project.
All training must be documented and a tracking system established by using the
individualized syllabus to identify initial and reinforcement training requirements.
The syllabus can also be used for entry into a database or one of the commercially
available computer tracking systems.
A master schedule of courses should be developed for distribution to the pilot plant staff.
Scheduling of courses can be very resource demanding, depending on the types of
courses. Resources can be optimized with the help of videos, computer-based training
(CBT), and well-designed self-study courses. However, the benefits of group on-thejob training are important in reinforcing the learning gained by self-study courses.[13]
Training Media
Self-study programs have been used to successfully meet the challenge of training a
diverse pilot plant staff. The computer industry has made significant strides in learning
retention with the aid of visualization technologies based on increased information
storage capabilities on compact discs.[14] The techniques include interactive CBTs and
interactive audio and video compact discs (CD-I).[15] The former is enhanced by
interactive courseware, which stimulates interest and documents completion of the course
work. Distribution of multimedia over local and wide area networks (LANS and WANS)
offers additional flexibility in that the operator can access the training program from work
and operational areas.
The advantages of these types of technology to pilot plant staff include:

1. Immediate availability of material for entry or

2. reinforcement training from various work locations
3. Immediate retrieval of specified information
4. Visual representation of procedures and operations
5. Consistency of instruction
6. Personalized learning rate
7. Practice by performing simulated operations
8. A more conducive environment for cross-training.
Although some of these advantages are limited by current technologies, more
sophisticated training media based on enhanced visualization systems will be available in
the future.
ENGINEERING, MAINTENANCE, AND CALIBRATION SUPPORT
As pilot plant facilities and operations become more complex and technically diverse, the
need for support groups, such as engineering, maintenance, and calibration, becomes
critical to perform planned activities in a cGMP-compliant manner.
Engineering

1.
2.
3.
4.
5.
6.
7.

Engineering and architectural support is obviously required during the design,

construction, commissioning, and validation of the pilot plant facility. However, some
larger facilities may require dedicated engineering support staff for the coordination,
scheduling, and direction of ongoing operations. The primary objective of the engineering
staff is to provide timely support and direction in facility and equipment requirements
necessary to ensure the efficient implementation of drug development projects.
Support provided by the engineering staff may include:
Equipment acquisition, installation, and repair
Engineering documentation and control for new systems and equipment.
Management of the facility to ensure that critical systems, e.g., environmental controls,
utilities, etc., are operational for compliance with cGMPs
Coordinating and scheduling equipment set-up and related activities for development
projects
Ensuring a controlled inventory of critical spare parts, e.g., tablet tooling
Budgeting for equipment, technology upgrades, and operating supplies
Directing housekeeping activities.
Engineering support staff also plays a pivotal role in pilot plant operation by contributing
to the selection and evaluation of new process and material-handling equipment,
recommending containment techniques to minimize exposure to potent drugs, and
providing support for new technologies which may be critical in the development of an
NCE. Equipment evaluation, procurement, installation, and qualification can be enhanced
by the formation of project teams, which include engineering and scientific staff, as well
as members from purchasing, validation, calibration, maintenance, safety, environmental,
quality assurance (QA), and other necessary functions. A written procedure outlining the
roles and responsibilities of members of the team can be critical to the successful
implementation of a new facility and process technologies necessary for product
development.
For large facilities, internally developed or commercially available computer software has
been found useful for the engineering support staff in scheduling process equipment and
space for development, maintenance, calibration, and validation activities.a

Maintenance
A maintenance program is necessary within the pilot plant to meet the requirements of
cGMPs and to ensure data integrity and equipment reliability during the development
process. The maintenance program must be documented and written procedures
established.
All maintenance activities on critical systems and equipment must be documented,
approved, and archived for retrieval during FDA inspections. Changes not considered
routine must be documented and approved through an established control procedure. It is
important to document critical changes to computer systems or code necessary for
maintenance activities.
Although the basis for a pilot plant maintenance program is similar to that of a production
facility, there are several differences worth mentioning. The pilot plant maintenance
program may be more diverse with respect to systems and equipment because of the
nature of product development. Furthermore, equipment utilization within the pilot plant
may be less routine than in the manufacturing environment, requiring a different approach
to preventative maintenance.
A preventative maintenance program based on hours of utilization may be warranted for
some equipment in the pilot plant rather than the typical scheduled approach, e.g., annual,
semiannual, etc. Another approach is to routinely review the utilization of equipment in
the pilot plant and reestablish the preventative maintenance program based on historical
data. This requires close interaction between engineering support and maintenance staff.
The results are
significant improvements in resource utilization and efficiency during preventative
maintenance activities.
It is critical that the maintenance staff operating within the pilot plant be responsive, well
trained, and has expert knowledge of equipment and systems in the facility. Staff
members should be keenly aware of how changes to critical systems and equipment can
affect product quality. An effective written procedure is recommended for communicating
critical variances identified during routine and non-routine maintenance activities.
Changes and variances must be communicated in a rapid manner to the engineering
support staff and ultimately to the scientists in order to ensure the integrity of ongoing
development work. Quality staff should be rapidly notified if clinical batches are affected
in any way so that appropriate actions can be implemented. A computer-based system for
facility management, control, and data archiving is useful for identifying critical systems
that may require maintenance, as well as trending alarms and environmental data for
routine review.[16]b
Vibration analysis systems have been found useful in predicting maintenance and repair
needs of motors and other systems.[17]
Calibration
Routine calibration of critical instruments on systems and equipment is required for
compliance with cGMPs, as well as for maintaining the integrity of data generated during
the development process. The pilot plant environment is often more complex with respect
to instrumentation than that found in manufacturing. A preponderance of data is often
collected through extensive instrumentation during product and process development in
order to determine critical and noncritical process variables and control levels. Once this
information has been collected and analyzed in the pilot plant, only process variables

deemed critical and their related instrumentation may be transferred to the manufacturing
environment. For these reasons, pilot plant calibration staff must be well trained and have
expertise in a wide range of instrument technologies.
As with maintenance personnel, they must be fully aware of the effect of calibrationrelated activities on product quality, and variances should be relayed to appropriate
engineering, scientific, and quality staff via written procedures. Because of the extensive
instrumentation
on equipment and systems, it is important that engineering, calibration, maintenance, and
scientific staff determine those that are critical to product quality. Critical instruments
should be routinely calibrated and identified as such to the user. Non-critical instruments
may be used to collect additional data. They are often calibrated separately as part of the
routine preventative maintenance program.
MATERIAL CONTROL, INVENTORY, AND DISPENSING
Material flow and control in the pilot plant require
flexibility, precision, and broad scope. There are major
differences between production and pilot plant facilities
with regard to these activities. For example, longrange
planning for the manufacture of development
and clinical batches is often limited, inventory is highly
varied and often not used repetitively as a result of
the experimental nature of development activities,
and material use and quality status must be considered
as dispensing is planned. Conventional paper tracking
systems can be used and are highly effective in many
manufacturing and pilot facilities, but it is desirable to
implement a more flexible and efficient computerized
system in the development-oriented environment of
the pilot plant. The system should distinguish between
various function-based user groups. Membership in a
particular group determines what system capabilities
are available to the user. The detailed description that
follows addresses how experimental and clinical supply
requirements can be controlled andseparated within the
pilot plant, allowing maximum flexibility of activities.
Inventory
Inventory can be maintained in a validated computerbased
inventoryorderingdispensing system. Inventory
may consist of stock articles, which are kept on
hand for general use, and specialty articles, which are
ordered for a particular purpose. The former should
be automatically tested for approval, whereas the latter
can be received into inventory as either clinical or
experimental material. Clinical materials must be fully
tested and formally approved prior to use. Experimental
items are available for non-clinical work only.
This approach allows tracking of all lots received,
while minimizing resource requirements in the QA
and quality control (QC) areas.

Articles must be identified in the inventory database

with a unique code before they can be received into the
pilot plant.[18] Upon receipt, the materials should be
checked, verified, and labeled with inventory and quarantine
labels. A receipt report is electronically received
by the QA group, which initiates appropriate sampling.
The sampled material, which to this point is kept in a
secure holding area, is moved to a warehouse upon
release by QA.[19] Any change of location is recorded
in the computer system.
Quantity, status, and location of inventory should
be ascertained using a statistically based method,
which can separate the inventory according to the frequency
ofusage. Articles with high activity are sampled
at a higher rate. Inventory accuracy, in terms of quantity,
must be maintained within predetermined levels,
for example, between 95% and 105% of the actual level,
or an investigation will be required to identify the
cause of the discrepancy.[20] This approach differs from
the cycle count methodology typically employed in a
manufacturing operation.[21]
Inventory quantity, status, and location should be
tracked at the container level. The system should allow
users to review inventories on-line, or in printed form,
via a series of predefined queries and reports or via
flexible queries, which may be generated on an ad
hoc basis. Access to the system should be available
via any number of remote terminals.
Orders
All orders must be placed through the computer system.
A batch or general order can be placed for any
Pilot Plant Operation 2891
Pharmacopeial
Pilot
article defined in the inventory system directly from a
desktop computer. Placement of a batch order automatically
generates a batch number. General orders
are placed for all articles not used in a batch formulation.
The ordering mechanism should differentiate
between order types (experimental vs. clinical), which
will allow the system to check the intended use against
the material status. Should the material status not be
suitable for the intended use of the requested lot, e.g.,
quarantined or experimental material has been ordered
for clinical use, the user should be alerted immediately
to resolve the issue. A hold can be placed on the order,
pending attainment of the proper material status.
During this time, dispensing of the article in question
is blocked. The ordering procedure should be flexible to
the point that an individual placing an order may select

a dispensing weight variance, e.g., _1%, identify a

specific lot and container, or allow the system to pick
the lot and container automatically based on first
in, first out (FIFO) criteria. The order may also be
employed to describe use, reference a notebook number,
or conduct other activities.
The dispensing of designated materials, typically
drug substances, should require specific authorization
before the order can be completed. Materials that
require this degree of control are identified during
the definition stage, prior to formal receipt into the
facility. An order submitted for dispensing can be
printed in the dispensing area for scheduling by dispensing
personnel. Receipt of the order, projected dispensing
date, and completion for dispensing can be
confirmed and communicated to the requester via
electronic mail.
Labeling
The system must provide the ability to print various
inventory, sample, and pre- and post-dispensing labels.
All labels should include a bar code and printed text
with the pertinent batch and/or lot information.
Labels must comply with GMPGLP (good laboratory
practices) requirements to meet the needs of
both laboratories and clinical manufacturing. Labels
should be available in multiple sizes to accommodate
laboratory sample containers as well as production
drums.
Future Systems
The electronic inventory, ordering, and dispensing
system is the first step in creating a computer-based
system to support the areas requiring GMP documentation,
and/or manually intensive operations,
which provide a disproportionatelysmall return on
the effort invested. Future improvements to the system
include:
1. An electronic interface between the user, the
inventory system, QA, and purchasing to support
a paperless purchase order.
2. Electronic logbooks.
3. Electronic batch records.
Implementation will improve efficiency as well as
quality compliance by consistent application of regulatory
guidelines. Ancillary benefits include the ability
to retrieve documentation quickly for an FDA inspection
and the development of accessible product histories,
which can be electronically passed to operations as
products move from development to commercial sites.
PROCESS AND MANUFACTURING
ACTIVITIES

Pilot plant processes and manufacturing activities

include formulation and process development studies,
clinical supply manufacture, and technology evaluation,
scale-up, and transfer. Packaging for stability
and clinical studies may also occur in the pilot plant,
but these activities are often performed in separate,
well-defined facilities. It is beyond the scope of this
article to discuss all of these areas in detail. Since pilot
plant construction is often driven by the strategic
necessities defined earlier, only these areas are addressed.
Formulation and Process Development
Scientific staff must be able to access the pilot plant
and operate in an experimental mode using procedures
and processes without compromising the cGMP integrity
of the facility.[22] Procedures should be flexible
enough to allow development batches to be manufactured
in a fashion considered efficient by the
development scientist. As previously discussed, it is
important to have a detailed material control,
inventory, and dispensing system in place to address
differences in materials for experimental and clinical
manufacturing. In-process and finished products
should be labeled and recognizable with respect to
experimental vs. clinical materials. For some early
development work or evaluation of new technologies,
equipment may be utilized before being fully validated.
Research notebooks, rather than formalized batch
records, are a necessity in the development environment.
Quality group involvement with the manufacture
of experimental batches may be limited. Typically,
procedures that address the operational aspects of the
facility are equivalent no matter what the manufacturing
2892 Pilot Plant Operation
Pharmacopeial
Pilot
activity. For example, equipment and room logs,
cleaning procedures, training in equipment operation
for safety purposes, and environmental monitoring
programs should be transparent with respect to manufacturing
activities.
Clinical Supplies
A key activity in a well-designed pilot plant is the
manufacture of clinical supplies. A pilot plant should
be flexible in design in order to accommodate a wide
range of dosage forms. Flexibility provides the following
advantages, which are directly applicable to clinical
supply and comparator (positive clinical control)
manufacture:
1. The optimum dosage form is chosen for development
based on physical, chemical, or biological

attributes of a new compound.

2. Different dosage forms can be developed in
response to different patient demographics.
3. Comparator dosage forms can be developed
which are different than forms routinely manufactured.
Efficient clinical supply manufacturing requires a
wide range of equipment sizes, preferably of identical
Fig. 1 Sterile dosage form processing equipment useful for clinical supply manufacture in
the pilot plant. (A) Vial and ampule
washer (Metromatic. Oyster Bay, NY). (B) Steam sterilizer (Amsco Finn-Aqua, Apex,
NC). (C) Vial filler (TL Systems Corp.,
Minneapolis). (D)Lyophilizer (Edwards High Vacuum International, Tonawanda, NY).
(E) Vial capper (The West Co., Phoenixville,
PA).
Pilot Plant Operation 2893
Pharmacopeial
Pilot
design, to handle requirements based on bulk drug
supply. Clinical supply needs can quickly move from
a few hundred dosage units in Phase III studies to
millions of dosage units for Phase IIIIV studies. The
ability to rapidly scale processes is directly linked to
the availability of similar, if not identical, equipment at
the large scale. As clinical supply needs continue to grow,
production of a few large batches compared to several
smaller batches results in a substantial savings in time
and resources for processing, testing, and documentation.
The generic regulatory requirement that biobatches
of solid, oral dosage forms one-tenth of the planned
commercial batch size, or at least a minimum of
100,000 dosage units, highlights the advantage of producing
large batches of clinical supplies in the pilot plant.
The quickest route of entry into a clinical trial is
often through the use of a sterile parenteral dosage
form. An ampule may be desirable early in development
because only one material has to be considered for
product compatibility, allowing rapid development and
entry into clinical studies. The sterile process areas
within a pilot plant should be operated with the same
degree of control as those found in a routine manufacturing
facility. Because of the unique environment,
training required, and specialized operating procedures,
sterile process areas within the pilot plant should
strictly adhere to defined regulatory requirements and
be operated under cGMPs.[23] The microbiological
integrity of the area must be maintained by regular
cleaning and sanitation. The sanitation program may
revolve around the utilization of the area. Periods
of heavy use may require more frequent sanitation.
Ultimately, the environmental monitoring program

determines the frequency required.

Because the scientific staff may utilize the sterile process
area on an infrequent basis, training is critical.[24]
Fig. 2 Encapsulation equipment useful for clinical supply manufacture in the pilot plant.
(A) Manual encapsulation equipment
(Dott. Bonapace & C., Milano, Italy). (B) Semiautomated encapsulation equipment
(Elanco Qualicaps, Indianapolis). (C) Automated
encapsulation equipment (MG America, Inc., Fairfield, NJ).
2894 Pilot Plant Operation
Pharmacopeial
Pilot
Staff expecting to work in the area should be thoroughly
trained and participate in regularly scheduled
bacteriagrowthmedia fills. Since batch sizes may be
smaller than those typically found in production, the
number of units filled during bacteriagrowthmedia
simulations may be based on the actual scale and process
time of the product manufactured in the pilot plant
environment. It is recommended that at least 3000 units
be filled to meet current regulatory guidelines if the
scale of equipment warrants.[23]
A range of process equipment should be available
for the manufacture of sterile clinical supplies:
1. Glass and stopper washing and siliconization
equipment.
2. Dry heat and steam sterilizers.
3. Ampule and vial fillers.
4. Freeze dryers.
5. Capping equipment.
The process equipment should cover a wide range of
sizes, units, volumes, and operating conditions, e.g.,
speeds, for maximum flexibility in relationship to batch
size and sterile dosage form requirements. Examples of
pilot plant equipment utilized for the manufacture of
sterile products are shown in Fig. 1.
As in a routine production facility, programs for
environmental monitoring of viable and non-viable
particulates, bioburden, and pyrogen loads of incoming
materials should be established. Prewashed and sterilized
components may be useful in improving operating
efficiency.
The ability to manufacture a wide range of solid and
non-sterile liquid dosage forms within the pilot plant is
required for efficient clinical supply development.
Areas within the pilot plant dedicated to non-sterile
manufacturing should be of flexible design. Operation
in these areas should meet the same standards of
cGMP required in a routine manufacturing facility.
Flexibility in equipment size is required to meet
demands based on drug availability. Since many clinical

supplies are double-blinded with the help of encapsulation

technology, equipment should be capable of
filling and overfilling powders, granules, beads, and
tablets into hard gelatin capsules. Fig. 2 shows typical
encapsulation equipment for the manufacture of clinical
supplies.
Aerosol and semisolid dosage forms may be
required in some clinical trials. Aerosol manufacturing
needs semiautomatic and automatic equipment (Fig. 3)
with the capability to produce from 100 to 10,000 units
in order to meet clinical supply demands.
All of the above mentioned dosage forms may be
utilized in clinical trials as the developed product or
as a clinical comparator. Clinical comparators
(positive clinical controls) are an outgrowth of the
regulatory environment in which Phase III clinical
studies must include the comparison of the generally
recognized therapeutic treatment with the NCE being
developed and a placebo. To avoid bias in the clinical
program, the comparator and placebo products are
blinded, that is, manufactured in such a way that they
are virtually indistinguishable from each other. For
products that differ in dosage form, a double-dummy
design is often employed. For example, if an NCE is
being developed as a tablet and the desired comparator
is marketed as a metered-dose inhaler (MDI), identical
placebos of each product would be produced. The
patient in the clinic would receive an active MDI along
with placebo tablets or vice versa. The blinding of comparator
agents often mimics the development program
for an NCE, but with greatly reduced timing. The
blinding process typically requires limited preformulation
studies, formulation studies, process development
and optimization, scale-up and regulatory documentation.
Depending on the process, in vivo bioequivalence
studies may also be required to ensure that blinding
Fig. 3 Aerosol filling equipment useful for clinical supply
manufacture in the pilot plant. (A) Manual filling equipment.
(B) Automated rotary filling equipment (both D. H. Industries
Limited, Barking Essex, UK).
Pilot Plant Operation 2895
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Pilot
does not alter drug availability. Fig. 4 gives the details
of the activities involved with the development of
blinded clinical comparators. Blinding techniques for
common dosage forms are shown in Table 1.
A matrix team approach has been utilized successfully
by the authors to optimize the interfacing between
development groups, support groups, and customers

(medical or marketing groups) when preparing to

manufacture new clinical supplies or comparators.
This ensures that the finished products meet the customers
needs. Fig. 5 is aprocess map showing key matrix
groups and activities typically involved with supplying
clinical dosage forms. The breadth and scope of
clinical supplies manufacturing, packaging, and shipping
activities can become remarkably complex as
illustrated by the following detailed description of a
single block activity taken from Fig. 5 (preparation
for manufacturing and packaging):
_ Finalization of dosage formulas
_ Development, validation, and transfer of analytical
methods
_ Final product specifications
_ Schedule of manufacturing
_ Secrecy agreements and statement of work and service
contracts for contractors
_ In-process tests and specifications
_ Cleaning of manufacturing facility
_ Cleaning of equipment
_ Swabbing of equipment for residuals
_ Testing of equipment by microbiological means
_ Testing of facility by microbiological means
_ Sampling requirements
_ Swab results
_ GMP validation audit (contractor)
_ Productitem code identification
_ Raw materials order
_ Certificates of analysis (COAs) for raw materials
_ Raw materials receiving and sampling
_ Testing of raw materials and recommendation for
release
_ Raw materials release
_ Packaging materials order
_ COAs for packaging components
_ Release of packaging components.
Once a specific clinical product or comparator is
developed, it may become more efficient and cost effective
to manufacture and stock bulk supplies from the
pilot plant when it is known that they will be routinely
used in future clinical studies.
Technology Evaluation, Scale-Up,
and Transfers
The pilot plant and its staff play a critical role in technology
evaluation, scale-up, and transfer activities of
new products. These activities begin early in the development
cycle and include technical aspects of process
development and scale-up, organization and responsibilities
of technology-transfer teams, documentation

of the transfer process, and often preparation for an

FDA pre-approval inspection (PAI). A properly
designed and operated pilot plant can enhance the collection
of scientific data necessary to support internal
transfer activities, as well as regulatory submissions
and FDA PAIs.[25]
Comparator Need
Identified
Limited
Preformulation
Studies
Excipient
Compatability
Short Term
Stability
Overencapsulation
Optimization
Bioavailability
Excipient
Effects
Testing of Innovator
Product
Blending
Properties
Process
Validation
Tableting or
Encapsulation
Properties Solubility Data
for Cleaning
Methods
Process
Development/
Optimization
Formulation
Studies
Process
Scale-up
CMC Section
for IND
Amendment
Fig. 4 Typical activities in the development of blinded clinical comparators.
2896 Pilot Plant Operation
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Following are four key technical aspects that must
be addressed during scale-up in the pilot plant:
1. Identification and control of critical component
and formulation variables early in development.
2. Pilot plant equipment that simulates as closely

as possible equipment used at the manufacturing

site.
3. Identification of critical process parameters and
operating ranges with pilot plant equipment
through the use of engineering and regression
models, i.e., statistically designed experiments.
4. Collection of product and process data to
adequately characterize each unit operation.
The facility design plays a critical role in addressing
each of these technical aspects. However, scientific and
pilot plant staff involved in manufacturing operations
within the pilot facility also play a key role in ensuring
the smooth and timely transfer of process technology
to the manufacturing site.
In the past, the transfer of formulation and manufacturing
technology was sometimes discretely passed
from development staff to manufacturing staff with
little interaction or foresight. Nowadays, however, it
is commonly recognized that interaction of these
groups at an early development stage is critical in
obtaining an efficient and successful transfer. Scientific
and pilot plant staff play a key role in demonstrating
new product manufacturing techniques to production
personnel in the pilot plant environment. A teamoriented
approach to the manufacture of pilot or
large-scale batches in the pilot plant will allow key
production site personnel to view and comment on
the process and make specific recommendations for
improvement based on knowledge of the manufacturing
site. An example of the matrix team approach to
the transfer of manufacturing technology, key development,
and production milestones, and the activities
related to these milestones, is presented in Fig. 6.
Interactions between pilot plant staff that begin during
product development and carry through production
start-up ensure a smooth transition of the product to
the marketplace.[26]
Precise documentation of manufacturing trials at
both the pilot plant and the production facility, with
Table 1 Blinding techniques for common clinical dosage forms manufactured in the pilot
plant
Techniques Purpose
Solidsa
Overencapsulation of intact tablet or capsule and filler Stability testing and comparative
dissolution
Film coating to obscure logos and proprietary color Stability testing and comparative
dissolution
Milling of dosage form and recompression on standard tooling Stability testing and
bioequivalency test

Milling of dosage form and encapsulation of powder Stability testing and bioequivalency
test
Encapsulation of tablet granulation Stability testing and comparative dissolution
Sugar coating of tablets to obscure engravings Stability testing and comparative
dissolution
Liquidsb
Repackage product and produce matching placebo Stability testing
Obliterate all product labeling and packaging matching
placebo in identical container dosage system
Stability testing of placebo
Metered-Dose Inhalersc
Obliterate all product labeling and produce matching placebo
utilizing identical valve and canister, (utilize active product
actuators for active and placebo products)
Stability testing of placebo only
Powder (for reconstitution)d
Obliterate all labeling and product packaging for a
matching placebo powder
Stability testing for palcebo only
Repackage product into standard packaging and produce
packaging for a matching placebo powder
Stability testing for active placebo
aFor critical studies, bioequivalency testing should be considered in all cases. All
techniques typically require the development of a matching
placebo dosage form. Overencapsulation of a bead-filled capsule may necessitate a beadfilled placebo to match the rattling sound of the active
product.
bColor, clarity, viscosity, smell, taste, and identical packaging are critical blinding
parameters.
cCanister pressure, fill weight, actuation sound, and taste are critical blinding parameters.
dPowder color, texture, particle size, fill weight, smell, case of reconstitution,
reconstitution volume, viscosity, taste, color stability after reconstitution,
and physical stability of suspension are critical blinding parameters.
Pilot Plant Operation 2897
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Fig. 5 Process map depicting key functional areas and matrix-related activities involved
with supplying clinical dosage forms
from the pilot plant.
Fig. 6 The relationship of key groups, activities, and development milestones typically
experienced during the transfer of formulation
and process technology from the pilot plant to the production facility.
2898 Pilot Plant Operation
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comparison of the results, assists in the development of
a rationale relating biobatches and stability batches
manufactured at the pilot scale to full scale product
manufactured at the production site. Establishing the
link between pilot and production scale batches is

often critical in obtaining a successful FDA PAI.

QAQC
As the size and complexity of the pilot plant increases,
it may become necessary to have dedicated staff in the
QC and QA areas to ensure compliance with cGMP
and other regulatory requirements.
QA
The FDA promulgated that when the drug development
process reaches the stage where product is manufactured
for human use, compliance with cGMP is
required.[27] The facility should be validated with
respect to utilities, equipment, and procedures and
meet necessary regulatory requirements. Activities of
the pilot plant QA scientist may differ from those performed
at the production facility. The QA scientist
should establish the procedural systems required to
operate the pilot plant in a cGMP-compliant manner
during the drug development process, especially with
respect to clinical supply manufacturing. The QA
scientist responsible for pilot plant activities should
have a firm grasp on the breadth and scope of new product
development activities and how regulatory
requirements should be applied in the development
atmosphere of the pilot plant. It is recommended that
QA personnel be included as part of the team responsible
for new product development in order to maintain
an awareness of specific project activities in the
pilot plant and provide expertise when necessary.
Other QA activities similar to those in the production
environment include documentation control of the
production process and QC laboratory, raw material
control, in-process material control, addressing deviations,
overseeing production cleaning and processing,
assessing of product quality, and establishing training
programs for the pilot plant.[28] It is particularly
important for smooth operation of the pilot plant that
systems, procedures, and communication links be
established in all these areas and that pilot plant staff
be fully aware of and trained in each.
QC
The QC function responsible for activities in the pilot
plant may be structured somewhat differently than
that found in a production operation. Release testing
of finished products and materials may be undertaken
by the analytical chemistry group responsible for the
development of methods for an NCE. Release testing
of materials and products for clinical studies in which
methods have been formally developed may be undertaken
by a separate QC group. For larger, more complex
pilot plants, it becomes necessary to have a pilot

plant QC function dedicated to the facility and responsible

for physical, chemical, and microbiological testing
of finished clinical products, components, and raw
materials; physical, chemical and microbiological
environmental sampling, testing, and trending within
the pilot plant, e.g., water, compressed gases, air; and
testing for validation and revalidation programs. It
is also advantageous to have the QC team perform
in-process testing during development, scale-up, and
technology transfer activities. The QC personnel may
become involved with project teams responsible for
new product development and lend their expertise
when required.
CONCLUSIONS
The pilot plant is designed with basic strategic objectives
in mind. As the facility becomes larger and more
complex, organizational support is required from a
number of technical disciplines. Although many activities
are similar to those required in a production
facility, it is imperative to recognize that basic differences
exist between theresearch and development
(R&D) environment and the manufacturing environment.
Organization of personnel and definition of
activities revolve around the development of new
compounds and products rather than routine manufacturing.
Successful operation of the pilot plant
requires that these differences be taken into account,
structured, and managed toward efficient new product
development while meeting the rigorous scientific and
regulatory standards required for the pharmaceutical
industry.
ACKNOWLEDGMENTS
The second edition authors would like to sincerely
acknowledge the work of the first edition authors
Leonard A. Amico, Ralph B. Caricofe, James D.
English, Gary W. Goodson, Lawrence D. Lewis, and
Robert M. Franzand those who provided critical
reviews and helpful input for the first edition of this
chapterBob Copeland, Bill Stagner, Phil Keicher,
Ray Starrett, Mike Jozwiakowski, Linda Parks, Ken
Korndoerfer, June Mullaney, Dave Moyer, and Anh
Nguyen. Most of the first editions text is retained.
The basic goal in revising the first edition article
Pilot Plant Operation 2899
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was to add current references. This was easily done
with the excellent foundation and framework the first
edition authors provided.
Next, the authors would like to acknowledge Alan

F. Parr for reviewing the revised chapter.

Finally, the authors would like to acknowledge the
administrative help of Cindy Rozier in preparing this
revision.