Production Activities and Issues
We can no longer live with commonly accepted levels of mistakes, defects, material not suited to the job, people on the job that do not know what the job is and are afraid to ask, handling damage, failure of management to understand their job, antiquated methods of training on the job, inadequate and ineffective supervision. Acceptance of defective materials, poor workmanship, and inattentive and sullen service as a way of life in America is a roadblock to better quality and productivity. We have learned to live in a world of mistakes and defective products as if they were necessary to life. It is time to adopt a new religion in America.
–W. Edwards Deming. From Quality, Productivity, and Competitive Position.
Production is not the application of tools to materials, but logic to work.
–Peter E Drucker, American educator.
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
Types of Projects in Production
Projects typically found in production include:
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.
Transferring a Manufacturing Process from Technical Development to a Production Group
This project is to transfer manufacturing from one group to another. It is quite different than the previous project and involves some or all of the activities listed in Table 108.1. The sense of urgency with which the manufacturing process is transferred from technical development to production varies greatly from drug to drug, whether the process is transferred from technical development in R and D or another group. If the sense of urgency is high, there may be insufficient time to develop a robust process (i.e., one that is reliable and reproducible and insensitive to minor changes in conditions and where all the relevant parameters have been optimized).
Table 108.1 Selected production activities to support various projects | ||||||||||||||||||||||||
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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.
Modification of a Product Using a Different Raw Material or Component
These types of changes are normally handled under what is called change control or “Corrective and Preventative Action.” The change in specification may have significant impact on the efficacy or even safety of the product. Included in this project group are changes in suppliers and processes that are not indicated in the Drug Master File (DMF).
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.
Engineering or Equipment Modifications
The amount of work required to change a room’s design, a formulation process, or equipment varies greatly and often requires a full team in production to plan, coordinate, and conduct necessary activities. The vast number of pipes, wires, tubes, and other infrastructure that has to be moved or altered while production continues to run smoothly often makes these projects highly complex for the engineering and planning staff.
Introduction of New Technologies
New technologies are often considered under the Food and Drug Administration (FDA) initiative called Process Analytical Technologies, which is seen as providing additional production assurance that the product is produced as it was intended. Some examples are continuous weighing of all products produced and 100% verification of the head space of vials after filling to ensure that only inert gas is present (if high levels of oxygen are found, the vial would be rejected). Both of these examples assure that a better product reaches the customer, but addition of the testing equipment to the production line could have a negative impact. For example, if the production line that the testing equipment was installed on was in the aseptic (i.e., sterile) area, then either the setup or location of the equipment could adversely impact the sterility of the product due to airflows or people handling equipment during the setup. Validation of new technologies verifies that the equipment did what it intended to do and has had no impact on the product during processing.
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.
Project Team Members
The individuals on a production project team are as variable in function and responsibility as those on R and D project teams. Typically, members come from the departments listed in Table 108.2. Although the specific project determines the makeup of a project team, every team should include a production and quality assurance (QA) representative. Other departments to consider for membership are: automation, engineering, validation, technical development, technical support, maintenance, logistics, instrumentation (metrology), safety, packaging engineering, and quality control (QC). Ad hoc or full members may be invited from R and D and marketing.
Table 108.2 Production and other groups that are often on a production project teama | ||||||||||||||||||||||||||||||||||||||||||||||||||||
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Enhancing Coordination among Production, Research and Development, and Marketing Teams Working on the Same Project
In some cases, there are separate project teams for the same investigational (or marketed) drug within production, R and D, marketing, and possibly other functional areas. In any of these situations, the relevant marketing, production, or R and D project leader should be a member or at least receive all correspondence from each of the other project teams. The two or more project leaders (or project managers) may, at some stages during the drug’s development and marketing, find it worthwhile to periodically meet as a small group. Another possibility is to call a combined meeting of representatives or all members of both project teams.
WHAT IS PRODUCED?
Differences between Producing Drugs, Foods, and Other Materials
The major difference between producing drugs and other materials is that government regulations are more extensive and the standards are higher for producing drugs. Most of the relevant manufacturing regulations for both prescription and OTC drugs are referred to as Good Manufacturing Practices (GMP).
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).
When Does Production Become Involved with Investigational Drugs?
There appears to be a trend at many pharmaceutical companies for production personnel to become involved with investigational drugs at an earlier point in the development process than they did approximately 20 years ago. Traditionally, this involvement was sometime during Phase 3, but it is now generally during Phase 2 or even occasionally during Phase 1. When a number of formulations are being considered for development, it is important to consider production’s ability to manufacture each of the possible formulations. There may be significant differences in the investment in equipment required, the degree of risk involved, the amount of hazardous waste products produced, the labor required, and other important factors associated with their production.
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.
Balancing Production Effort with a Drug’s Value to a Company
Is it logical to believe that the effort expended on a drug’s production should relate to the amount of sales a product generates or is expected to generate? This question may be interpreted as either referring to each unit of drug made or to the total effort for the entire drug’s production. In fact, the number of units of a drug produced often does not correlate well with the drug’s sales. Some drugs have extremely low prices and a high number of units are sold, and the opposite situation also occurs. In addition, small-volume products (i.e., when few units are produced) may require a relatively large amount of plant capacity and resources to manufacture the product. This places pressure on those resources (i.e., equipment and labor) that are also needed to manufacture other products. Potential solutions to this problem include (a) having small-volume products synthesized and packaged by other manufacturers; (b) increasing the number of work shifts; (c) expanding plant capacity; and (d) selling, licensing, or dropping the product from the company’s product line.
The Number of Plants Needed to Produce a New Drug
A new drug may require equipment and processes at more than one plant for its production. This issue may be addressed in several ways:
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?
Types of Manufacturing Processes
Although the process for manufacturing all drugs differs, there are two basic types of manufacturing pharmaceuticals: small molecules and large molecules (e.g., usually proteins). A general schema for producing small molecules is shown in Fig. 108.1, and bulk protein production is shown in Fig. 108.2. Of course the production of even small molecules requires many steps in most situations. After the API is made, it is mixed with various excipients and compressed into tablets or formulated into other types of dosage forms; placed into bottles, vials, etc.; and packaged and labeled as shown in Fig. 108.3.
 Figure 108.1 Flow diagram of an overview of the chemical production of a hypothetical bulk drug API. These steps are often repeated with additional raw materials or intermediates. (Reprinted from Charlton W, Ingallinera T, Shive D. Validation of clinical manufacturing. In: Agalloco JP, Carleton F, eds. Validation of pharmaceutical processes. 3rd ed. New York: Informa Healthcare; 2007 with permission.) |
Manufacture of Tablets, Liquids, Ointments, and Creams
An API is the pharmaceutically active substance in a drug. If a solid is being produced, the API is combined with a few or many excipients to make the “drug product.” This section concerns nonsterile drugs where operations are by batch, using one or more APIs and other ingredients. These operations usually start with blending or mixing.
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.
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, Ingallinera T, Shive D. Validation of clinical manufacturing. In: Agalloco JP, Carleton F, eds. Validation of pharmaceutical processes. 3rd ed. New York: Informa Healthcare; 2007 with permission.) |
Ointments, Liquids, and Creams
Liquids are mixed and blended and then tested for uniformity and other characteristics. They are then ready to move to the fill/finish operations as soon as the bulk product is passed by inspection. Ointments, creams, and suspensions may require further processing to ensure the API is properly uniform within the batch. Suspensions may require continuous recirculation of the mixture while filling a vial or other container to ensure that settling does not affect the consistency of the batch.
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, Ingallinera T, Shive D. Validation of clinical manufacturing. In: Agalloco JP, Carleton F, eds. Validation of pharmaceutical processes. 3rd ed. New York: Informa Healthcare; 2007 with 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.
Types of Sterile Products
Liquids (solutions and suspensions) for eye and ear—Products usually have a closed dispensing method to minimize the exposure of the product to air and sometimes light. Some products are filled in a plastic form and are then sealed, while others are placed in glass vials with droppers or plastic drop dose bottles.
Liquid injectables—The product may be filled into ampoules, vials, form-fill seal, or syringes.
Powders—Filled into vials or depots. Depots are deposited into the body, often just under the skin for administration of a drug for a period of weeks or months.
Freeze-dried products—These are liquid products that are filled into a vial and then lyophilized (i.e., the solvent, usually water, is removed during this process to form a dried cake that enhances the products stability). This process is sometime used with dual-chamber syringes. The first chamber would have the freeze-dried cake, and the second would contain the solvent (e.g., water). When the syringe is activated, the water and cake will mix prior to being injected.
Ophthalmic ointments
Inhalants
Levels of Cleanliness: How Sterile Is Sterile?
People, components, drugs, and processes all must follow the strict rule of flow (both of air and people’s movement) where the flow is from lesser clean areas to progressively more clean areas. This principle and practice is required to properly manufacture a sterile drug product. This flow from one class of area or room to another relates to the different levels of clean rooms, as illustrated in Table 108.3.
Table 108.3 Different standards for number of allowable particles in air in clean and sterile environments | ||||||||||||||||||||||||||||||||||||||||||||||||
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Operations Supporting Manufacturing of Sterile Drugs
Sterile gowning—Rooms are designed to handle the environmental load of people entering and gowning with methods that assure the least contamination possible. All employees who are approved to enter the Grade A areas must go through training and testing that verify their capability to properly gown. Periodically, without notice and even after being approved, employees are tested as they enter, as they perform clean room responsibilities, and also as they leave to check whether they could have impacted the batch.
Water for injection—Water defined in the US Pharmacopeia (USP) and manufactured normally by distillation, but other methods are also available such as reverse osmosis and ultra filtration.
Pure steam system—Supplies process steam for sterilization of manufacturing equipment and processes.
High Efficiency Particulate Air Filter (HEPA) filtration of the room air supply—The efficiency of this air filter retains particles with a minimum size of 0.3 µm and has a particle retaining efficiency of 99.97%.
Production Processes
Significant attention to appropriate processing of all components used in manufacturing is necessary to ensure they are sterile and pyrogen free. A pyrogen is a substance that induces a febrile (fever) reaction in a patient. Types of component processing of equipment include:
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.
Inspection and Packaging of Sterile Products
Inspection for Particulates
All sterile injectables must be inspected for particulates. Methods of particulate inspection include manual human visual inspection, semi-automated inspection (machine presents the object or product to the inspector for inspection), and fully automated inspection (machine provides the inspection that meets or exceeds human eye capability). Usually, particulate inspection is done in a batch mode prior to final packaging.
Leak Detection for Glass Seal Integrity
High voltage and low current are effective to test for leaks from ampoules and vials with stoppers. Current flow across the vial is an indicator of a leak, and when found, the product is rejected. This technology needs access to the product to conduct the test
Determination of air flow when vacuum is applied to the container, which is in a sealed cupping device. There is no impact on the product.
Spark testing of freeze-dried products filled under full vacuum. This technology needs access to the product to run the test.
Vial head space gas analysis. This technology can determine leaks in a product that has been freeze dried and sealed with nitrogen in the head space. The testing, using laser technology, can check for oxygen and other gases in the vial head space without any impact on the product.
Packaging for sterile products after the inspection operation is very similar to the process for nonsterile products and requires labeling and then final packaging in single and multiple packages.
Good Manufacturing Practices
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.
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.
What Equipment Is Used to Produce Drugs?
Drugs may require new or highly specialized equipment for their manufacture. A decision has to be reached about whether to invest in new equipment. The pertinent issue is to determine which criteria to use when deciding about purchasing or leasing new equipment. It is often helpful if a standard approach has been developed that may be applied to a new situation so that a decision may be reached rapidly. The main alternative is to redefine the criteria and procedures to follow each time an important question arises. This would result in unnecessary delays and a great deal of frustration.
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.
Single versus Multiple Sourcing
When a compound enters the project system, it usually must be scaled up to provide supplies for tests throughout R and D. Where will this compound be made? Some of the possibilities are shown in Fig. 12.2. If a company has only a single site to manufacture all of its drugs and compounds, then the answer simply depends on whether it wishes to contract the work out or make it itself.
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.
Contracting Manufacture to Outside Groups
Companies that manufacture drugs periodically (as opposed to continually) usually have to decide whether to use contract manufacturers to make certain drugs. This question becomes particularly important when new techniques or equipment are required
to make a new drug and it is uncertain whether a company desires to bring that technology in-house. A company may have a tradition of manufacturing all of their own products, but it makes no sense to rigidly adhere to this principle when it is economically preferable to have other manufacturers make a new drug. However, a thorough evaluation must be undertaken to understand the actual benefits and negative aspects of manufacturing in-house versus outsourcing to a contract manufacturer.
to make a new drug and it is uncertain whether a company desires to bring that technology in-house. A company may have a tradition of manufacturing all of their own products, but it makes no sense to rigidly adhere to this principle when it is economically preferable to have other manufacturers make a new drug. However, a thorough evaluation must be undertaken to understand the actual benefits and negative aspects of manufacturing in-house versus outsourcing to a contract manufacturer.
Pros and Cons of Using a Contract Manufacturer
Some of the benefits of using a contract manufacturer are often as follows:
It is easy to define the cost of manufacturing.
The price is set by the contract, but be aware that there may be hidden costs.
It may serve as a backup for disaster planning.
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