Professional Documents
Culture Documents
Material Proses Flow
Material Proses Flow
com/production-activities-and-issues/
This chapter is focused on small-molecule drug production, and only a few comments are made about biotech
production of biologics due to its complexities and differences from small-molecule production. Production issues that
are relevant for many pharmaceutical companies are discussed. As with the marketing and finance chapters, the
issues covered represent a select sample intended to provide a general overview, and the issues are grouped into
broad categories.
PRODUCTION PROJECTS
● New products
● Transferring products from another plant or manufacturer
● Modifying products under change control
● Providing contract manufacturing for other companies
● Making engineering or equipment modifications
● Adding new technologies
● Expansion of existing facilities
New Products
A project team is assembled in production to launch a new drug, with representatives from all relevant production
groups. This team functions analogously to that in research and development (R and D), although it clearly has
different goals. The product may be for either prescription or over-the-counter (OTC) use. The team and also a
variety of other issues are described later in the chapter.
2. Transfer or obtain (e.g., lease, purchase) the equipment and install or modify utility services as nee
8. Coordinate initial production schedules, export or import licenses, and other documentation need
12. Conduct preapproval inspection of the manufacturing site and validation records.
Some of the issues that determine when a process is ready to be transferred to production include (a) determining if
the process is robust, (b) ensuring that all of the important manufacturing factors and possibilities have been
considered and worked out or at least evaluated, and (c) evaluating if the batch-to-batch variation is acceptable in
terms of specifications that must be met. It is desirable to increase the drug’s yield to a substantial degree before
manufacturing begins. Most of the work on each of these issues is usually completed prior to transferring the process
to production.
In most situations when a technical development department turns over a process to production, that process is well
defined and has been tested on a full-scale production basis. Personnel from both technical development and
production groups will have tried the manufacturing as an “EX” (experimental) batch using the actual equipment that
will eventually be used. During the later stages of technical development’s experimentation, the staff often “borrow”
production equipment to test one or more methods to learn which is best.
Producing an Intermediate
This is a project to start the manufacture of an intermediate substance that previously was made outside the
company. This project also involves some or all of the nontransfer items listed in Table 108.1.
Contract Manufacture
This is a project to manufacture a product for another company. This is done under contract, usually to utilize unused
plant capacity, although many companies do this type of contract work as their only business. Another reason this
work is done is when it is required as a quid pro quo for something the other company is doing for yours.
There is no actual product manufactured with this type of project whenever a new technology is introduced into
production. Yet, the introduction of many new technologies qualifies and must be dealt with as a production project.
Expansion of Facilities
Some companies would not consider the expansion of facilities with modifications to equipment as a project in the
same sense as those where a product is manufactured. Nonetheless, focusing attention on an important building
change by making it a project helps ensure the involvement and cooperation of all departments affected. Moreover, it
places the activity in a system where appropriate reporting and reviews can be conducted.
Table 108.2 Production and other groups that are often on a production project tea
1. Operations planning
3. Package engineering
5. Engineering
7. Industrial engineering
19. Purchasing
23. QA
a
Not all of these groups are likely to be represented on any one project team.
WHAT IS PRODUCED?
Some of the differences between producing foods and drugs are fascinating. For example, some processed foods use
clean rooms to prevent contamination by people while processing and packaging foods. Those foods that are not
sterilized are then typically refrigerated or frozen. People rarely become ill from food that is nonsterile, but recent
concerns of foods from outside the United States or Europe has highlighted the potential problem. The stomach and
intestines contain numerous bacteria that are not harmful to us, and some produce vitamins that are even essential
for our good health.
Nonsterile drugs, such as tablets and syrups, are handled basically the same way as foods, but drugs that are
injected, inhaled, or used in the eyes must be sterile. Sterile products must meet requirements for sterility and
pyrogens (i.e., bacterial endotoxin that will create a fever in a patient if injected).
Dialogue between production and technical development personnel should be established as early in a project’s life
as is convenient and practical. A committee (i.e., project) structure is often an appropriate mechanism to ensure that
relevant questions are both posed and answered satisfactorily. This allows production, at an early stage, to begin
monitoring a project’s progress, develop an awareness of potential future events, and consider various options for
facilities and equipment that may be used to make the drug.
● A new facility maybe built to focus primarily or exclusively on the new drug. However, this rarely occurs in practice
due to the significant resources needed and the potential impact if the product does not meet expectations.
However, an active pharmaceutical ingredient (API; i.e., the active substance that has a positive pharmaceutical
effect in patients) sometimes requires its own manufacturing facility, either due to safety or the complexity of the
process
● An existing facility may be “beefed-up” to handle the drug. This is usually more cost effective than the above
alternative.
● Several existing company manufacturing facilities may each handle different parts of the manufacturing. APIs are
typically made in a chemical (or biological) manufacturing site, whereas the filling and finishing normally are
separated from the synthetic production due to the higher level of cleanliness and different types of operations,
equipment, and levels of technical knowledge required by the operators.
● Part or all of the manufacturing may be contracted out to other companies. This is typical in the current
environment because many pharmaceutical companies have stated that manufacturing is no longer a core
competency. In addition, start-up companies must almost always depend on contractors to manufacture their
drugs because they do not have sufficient resources and expertise required to build and operate a manufacturing
plant.
HOW IS IT PRODUCED?
Tablets
After mixing the API and excipients, the formulated blend is then transferred to a granulator, which makes the mix
ready for compressing. The granulated product is normally stored while waiting for analytical results prior to
compressing the granulated product into tablets. Further processing may include adding a sugar coat or film coat
over the product. This coating enhances the product’s appearance and taste and, for some, helps with swallowing. It
may also be applied to delay absorption, either to create a sustained-release formulation or as an enteric coating to
allow the drug to pass through the stomach without dissolving. The product is tested and passed prior to moving to
the fill/finish shop floor.
Figure 108.2 Flow diagram of the bulk protein production of a biological. DNA, deoxyribonucleic acid. (Reprinted from Charlton W, Ing
clinical manufacturing. In: Agalloco JP, Carleton F, eds. Validation of pharmaceutical processes. 3rd ed. New York: Informa Healthca
Fill/Finish Operations
Operations are usually set up as continuous lines. Most fill lines include a bottle unscrambler, bottle filler, capper, cap
retorquer, cartner, and palletizer. These processes are briefly described.
● Bottle descrambler—This is a continuous motion machine that orients the bottle to an upright position and then
places the empty bottle on a continuous conveyor. The bottle then proceeds to the next machine.
● Bottle filler—This machine fills the product into a bottle. A method to ensure that each bottle has the correct count
(tablets) or weight (liquids) is included in this equipment. An alternative for tablets is filling into formed trays or
packets that are then sealed. An additional weighing check is often required within the line.
Figure 108.3 Flow diagram of the general fill and finish operations of a sterile and nonsterile product. (Reprinted from Charlton W
Validation of clinical manufacturing. In: Agalloco JP, Carleton F, eds. Validation of pharmaceutical processes. 3rd ed. New York: Infor
permission.)
● Bottle capper—A bottle capper accepts the bottle from the bottle filler and places caps onto the bottles, usually
after cotton and or a desiccant is placed in the bottle.
● Cap retorquer—This machine tightens the caps on the bottle one last time.
● Bottle labeler—The labeler prints a label and places it on the bottle. The drug product insert is either attached to
the bottle or added later into the product carton.
● Cartner—The cartner places the bottles and label inserts into cartons.
● Case palletizer—The case palletizer collates the boxes into rows, allowing a robotic arm to pick up the rows of
boxes and place them on a pallet.
Manufacture of Sterile Products
Depending on product stability in the container, two alternatives for processing exist:
● Aseptic filling—The ingredients, components, and process are sterilized, and the product is sterile filtered and
filled.
● Terminal sterilization—The product in the container closure is sterilized by a steam autoclave or radiation at the
end of the production.
The sterile product in its final dosage form must be pyrogen free, regardless of which method is used.
Table 108.3 Different standards for number of allowable particles in air in clean and sterile en
International US Federal European Maximum a number of particles 0.5 Maximum a number of particles
standard (ISO) Std 209E standard Annex µm and larger per ft2 (in operation) 0.5 µm and larger per m3
1
a There are 35.32 cubic feet to a cubic meter. Many more changes of air per hour occur in higher class rooms o
● Washing and sterilization in a dry heat tunnel where glass components such as vials, syringes, and bottles are
cleaned and sterilized by heat, normally in excess of 300°C
● Processing of stoppers and other “rubber”-type components—Washing, sterilizing, depyrogenating, and sometimes
siliconization are used to enhance component handling.
● Steam autoclaves are used for sterilization of product contact parts (e.g., stoppers) and product flow parts (e.g.,
sterile filters, piping, valves, and filling machine parts). Most terminal sterilization is done in steam autoclaves, but
gamma radiation is another good method of terminal sterilization.
● Other types of sterilization technologies may be used (e.g., hydrogen peroxide, chlorine dioxide, ethylene oxide,
and electron beam radiation).
● Freeze drying—This is the process of removing water from a liquid product by sublimation to form a dried cake
product that enhances stability. Product can be reconstituted by injecting sterile water.
● Sterile filtration—Process of filtering a product through a 0.2-µm or smaller filter into a sterilized receiving vessel.
The filtration process effectively removes the bacteria. Pyrogens or endotoxin must be controlled by cleaning the
equipment and assuring that all drugs and chemicals are pyrogen free.
Sterile Filling Lines
The evolution of sterile filling has changed significantly since the 1980s. Prior to 1990, most filling lines were not
continuous and were located within an “aseptic processing room” with HEPA filters directly over each piece of
equipment, but few rules of cleanliness were defined, and few rules controlled the separation of the production from
the operators. Today, the sterile operator must have a defined and controlled separation or contact from the product.
The filling lines currently used in the industry have been focused on two methods for containment and control:
● Restricted access barrier systems—A restricted access barrier systems filling line and associated transfers must be
placed in a Grade A [International Organization for Standardization (ISO) 5] environment. The advantage of this
approach is reduced cost and versatility of the production line.
● Isolators require Grade C (ISO 8)—This is a more intense system that meets a higher standard than the restricted
access barrier systems. The advantage of this approach is added assurance of control and sterility because the
entire chamber is cleaned and sterilized. Another significant advantage is that employees are working in a Grade C
environment. The disadvantages are that the set up for multiple products is more difficult and time consuming
when using different components and the costs are greater.
A continuous line normally consists of washer, dry heat tunnel, sterile filler with pre- and postfilling check weighing,
stoppering with verification of stopper placement, and sealing separated from the filler due to particle generation
while sealing. The filler, stoppering, freeze drying (i.e., if included), and capping operations are under
unidirectional HEPA-filtered air. Product flow to a freeze dryer requires unidirectional HEPA-filtered air (Grade
A; ISO 5). Airflow pattern at the location where the product enters the freeze dryer should consider potential issues
of operator handling.
Definition
The International Conference on Harmonisation defines GMP as: a standard for the performance and recording of all
activities associated with manufacturing, processing, packing, labeling, holding, and distributing drugs or devices
intended for human use or to support human use. These regulations are further elucidated by guidelines and
common practice that are regulatorily accepted with respect to the types of documentation (including archives)
required for demonstrating the identity, strength, quality, and purity of the drug substance and drug product, plus a
detailed description of the methods used in synthesis, sampling, testing, approval or nonapproval of batches and lots,
labeling, quarantine, stability tests, release, and destruction of returned product or materials that were not
approved. GMP refer to the drug substance, drug product, equipment used, methods to evaluate all procedures, and
the buildings used in all production activities (e.g., cleanliness, access, security, lighting). Personnel are included
under GMP in terms of their training, supervision, and safety.
Goals of Good Manufacturing Practices
Not only do GMP assure the many audiences about the quality and purity of drugs, devices, and other materials, but
they also are designed to prevent fraud and to produce a written record that may be referenced as required. The
scope of GMP is extensive and requires detailed standard operating procedures for each aspect of the manufacturing,
storage, handling, etc., covered by these regulations. Clinical trials are covered by GMP in that all products made are
covered by GMP as well as the return and destruction of all unused and partially used containers of drugs. A director
is responsible for the overall GMP in terms of the product, processes, and controls. All GMP data must be quality
assured by an audit, and the data must be archived per the company’s standard operating procedures.
Return on Investment
Return on investment is the primary criterion used to address the issue of obtaining new equipment. This is
determined using cost accounting procedures. The total cost for the purchase of new equipment plus drug
manufacture is determined and contrasted with the total cost either using existing equipment or following another
course. If the new equipment will lead to a savings over the current methods, then the time to reach a savings equal
to the equipment’s purchase and installation price is calculated. This is the payback time. If the payback time issue is
not relevant, then other factors must be considered (e.g., competition, time to install the equipment, production
downtime) in reaching a decision on whether to purchase the new equipment.
Utilizing Automation
Another aspect relating to new equipment is how a company should optimally use automation and remain current
with state-of-the-art technologies. These technologies include use of computer-controlled production, robotics, and
other equipment. These issues are a continual concern to companies because there are always new procedures and
equipment to evaluate and new drugs or line extensions to manufacture. In addition, the competition between
companies in many therapeutic areas and with generic drugs places a high premium on achieving greater cost
efficiencies in production.
WHERE IS IT PRODUCED?
Companies often make most of their drugs in more than one manufacturing plant, or at least they develop
contingency plans to make each drug at multiple plants. Companies must protect themselves against unknown
situations that could threaten, decrease, or eliminate a plant’s ability to make one or more drugs. One reasonable
approach to reduce threats and the dependency of a company on a single plant is to build, lease, or occupy a second
backup plant. Alternatively, a second manufacturing source could be approved to manufacture one or more drugs, if
necessary. This plant must be licensed by the FDA or other regulatory agency to manufacture drugs of interest to the
company and could also serve as a contract manufacturing facility for other companies if the plant has excess
capacity. The site, processes, equipment, and product must all be qualified/validated and ready for use to be an
effective backup. Any change to this state of readiness needs to be communicated. Change controls that affect your
product need to be reviewed and approved. Without good change control procedures, documentation, and
communication, it is possible that other contracts could affect your product. One example is cross-contamination from
another product’s residual in the environment or process. It is also recommended that all product contact parts be
purchased or at least owned by the contractee and identified for sole use in manufacturing your product.
For most multinational companies with more than a single possible manufacturing site, the issue of sourcing must be
addressed. Single sourcing of a drug is a realistic strategy to follow early in a drug’s development, but as the drug
approaches the market, this approach is often unrealistic.
Some of the concerns that limit a company’s ability to use a single source of a drug worldwide are as follows:
● Inability to use a common formulation. Having a single formulation worldwide is a goal that is often abridged
because of different regulations and marketing practices in various countries. While many different formulations
can theoretically be made in one factory, it is usually unfeasible because of the possibility of higher manufacturing
costs, limited capacity, limited human resources, transportation costs, and regulatory considerations.
● Need for a backup plant exists in case of a major problem such as fire, flood, prolonged strike, sabotage, and so
forth. A company’s income could be seriously affected if any of those situations occur and affect a major source of
company revenue. For investigational drugs, any of the problems mentioned could greatly delay development.
● There are differences in a company’s production plants, techniques, and equipment in different countries that limit
a company’s ability to use only a single plant.
● Policies of the company to protect itself in case of problems also play a role in influencing this issue.
Although a single standard is desirable for producing a drug anywhere in the world, there are constraints on a
company that may make this goal difficult to achieve. In general, a single sourcing of drug during preclinical and
early clinical development followed by multiple sourcing is a realistic strategy. A New Drug Application submission
requires identification of sources and presence of adequate stability data for a drug manufactured in each site. This is
likely to limit the number of manufacturing sites in an initial New Drug Application.