Technical Development Activities and Issues
I never varied from the managerial rule that the worst possible thing we could do would be to lie dead in the water with any problem. Solve it, solve it quickly, solve it right or wrong. If you solved it wrong, it would come back and slap you in the face and then you could solve it right. Lying dead in the water and doing nothing is a comfortable alternative because it is without immediate risk, but it is an absolutely fatal way to manage a business.
–Thomas Watson, Jr., former Chief Executive of IBM. From Fortune (August 31, 1987).
The greater the difficulty, the more glory in surmounting it.
–Epicurus
INTRODUCTION
Many people in technical development do not accept Watson’s view in relation to their problems. They attempt to logically and systematically solve problems correctly and appropriately, even if their approach takes more time than attempting a quick fix. This more deliberate approach is generally appropriate in the pharmaceutical industry.
This chapter identifies and briefly describes a small selection of the many issues and problems that occur during a drug’s technical development. Most of these could be (or are) the subject of an entire chapter or book. This chapter provides the reader with a flavor of the types of problems that frequently arise in the technical development of drugs. This category includes scaling up the synthesis of a drug substance (i.e., the active ingredient) from milligrams to tons, formulating the drug substance into a drug product (i.e., the finished drug tablet, capsule, or other dosage form) with up to approximately 30 different ingredients, and developing analyses to measure the drug substance and drug product in different biological fluids (e.g., blood, plasma, urine). Although Good Manufacturing Practices are not discussed in detail in this chapter, they affect almost all stages of a drug’s path through technical development. One of the major issues faced by technical development managers is identifying at what point Good Manufacturing Practices begin to influence technical activities in a drug’s development, and how to deal with it.
Most of this chapter discusses small-molecule drugs because the issues involved in the technical development of medical devices or biologicals are so different that an entirely different chapter would have to be written to discuss their technical issues, which are often far more complex. Nonetheless, many of the activities and principles discussed are similar for those areas as well.
General Activities of Technical Development Departments during Periods of Drug Discovery, Development, and Marketing
Drug Discovery
Technical development departments usually play a minor role in drug discovery, although they may carry out various activities to facilitate this effort. Activities focus on providing large amounts of relatively few compounds for preclinical safety evaluation (e.g., toxicology) or involve preparation of radioactive compounds for specialized studies (e.g., metabolism). Other activities during the discovery period include limited efforts to address specific or general questions in areas such as profiling drug-like properties for lead selection, formulation, stability, or assay development. Finally, patent activities may be handled within the technical development division. Table 107.1 summarizes these activities.
Drug Development
During the drug development period, most types of activities associated with technical development are conducted. Many of these are described in this chapter and include:
Scaling up the chemical synthesis of drug
Developing a suitable process for chemical scaleup
Developing a drug formulation
Developing the process for formulating the drug
Supplying compound and the dosage forms (e.g., tablet, capsule, solution) required for clinical, toxicology, and other trials
Table 107.1 Activities of technical development departments during the drug discovery perioda
1.
Synthesize larger quantities of selected compounds for research evaluations and for toxicological testing.
2.
Submit information to group submitting patents on all inventions and conduct work to protect them.
3.
Conduct limited formulation development.
4.
Synthesize radioactive compounds.
a This period ends when a candidate compound is chosen for development.
Developing methods to analyze the drug in biological samples (e.g., blood, urine)
Transferring the process to production for large-scale manufacture
Providing documentation of technical data for regulatory submission and manufacturing support
Other major activities depend on the organization of the particular company (e.g., obtaining drug names, patenting compounds, developing waste-handling methods). Almost all activities require regulatory submissions that describe the work in detail. Regulatory submissions are also required for various compendia (e.g., US Pharmacopeia). See Table 107.2.
Postapproval
The greatest amount of technical development work occurs after a drug is marketed. This primarily relates to both the large quality assurance efforts during manufacturing (see Chapter 108) and other support activities to solve problems and keep production on schedule (Table 107.3). Technical development is also an essential part of creating new drug formulations and line extensions during the marketing period, often termed life cycle management.
Priorities for Technical Development Departments
The major internal company customers of technical development services are (a) production, (b) project team, (c) marketing, (d) clinical research, (e) preclinical research, (f) licensing, (g) regulatory, (h) contract manufacturing, (i) foreign subsidiaries, and (j) international partners.
Each of these groups may view technical development departments as primarily existing for their benefit. However, the major priorities of technical development staff are to (a) develop a viable process for the production of drug substance and formulated product, (b) provide drug supplies to the clinic, (c) support regulatory submissions, (d) support production (primarily after launch), and (e) provide quality assurance on all processes according to Good Manufacturing Practices. Supporting the commercial enterprise is done by troubleshooting problems that develop, providing assistance in certain areas of manufacturing (e.g., extremely small-scale or complex processes), and conducting validation protocols of production’s activities.
Table 107.2 Selected roles of technical development departments during Phases 1 to 3a | ||||||||||||||||||||||||||||
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Table 107.3 Activities of technical development departments after a drug is marketed | ||||||||||||||
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CHEMICAL ISSUES
Primary Functions
There is a twofold mission of the chemical development group inside a pharmaceutical company. Their first function is to develop a process to manufacture the compound or biological initially for clinical trials and, at a later stage, for the manufacturing group. There is a series of necessary steps to scale a synthesis from laboratory quantity to production quantity, and each of these may require significant time and resources to complete. Biologicals are made via totally different methods that may involve fermentation, cell synthesis, extraction from natural products or plants, or other methods. The process developed for synthesis or biological production should be safe, reproducible, cost effective, and environmentally sound.
The second function of the chemical/biological group is to provide chemical compound (i.e., drug substance) of appropriate purity and quality for both clinical and preclinical trials. Synthesis of drug product for preclinical trials is primarily used for toxicology tests.
Basic Dilemma
These two functions of a chemical development group create a basic dilemma. If a chemical group spends most of its time and resources improving the process of synthesizing the active compound or working on scaleup methods, then they may not be providing adequate supplies of the drug for clinical and toxicological testing. When they spend most of their efforts developing a process, the compound may be terminated, and all of the process development and scaleup work will have been for naught. If the group eschews the process development and, instead, devotes itself to providing compound, then the need for more and more compound (Table 107.4) will outstrip the group’s ability to provide it on schedule. The group may not have researched the scaleup adequately so that they cannot simply convert to a larger scale synthesis. Furthermore, the new process is likely to produce compound with a new impurity profile, which may lead to regulatory (toxicology) questions. Thus, the chemical group risks being the rate-limiting factor in the drug’s development.
The best solution to this dilemma is to spend most of the group’s efforts on providing compound early in the project’s life
and to spend more time on process development as the compound enters Phase 3. Of course, the strategy chosen must depend to some degree on regulatory and business pressures. Regulatory authorities are tending to request more process development and validation of the process at an earlier stage of development.
and to spend more time on process development as the compound enters Phase 3. Of course, the strategy chosen must depend to some degree on regulatory and business pressures. Regulatory authorities are tending to request more process development and validation of the process at an earlier stage of development.
Table 107.4 Typical scale factors for chemical syntheses | ||||||||||||||||||
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Issues Relating to Scaleup of the Chemical Synthesis
One goal of chemical development is to minimize the number of separate chemical steps required in a drug’s synthesis. Advantages of fewer chemical reactions are both practical and economical. This goal may be addressed by (a) exploring alternative synthetic routes early in the development process, (b) purchasing raw materials that are closer to the final synthetic step or that allow the chemists to reach the final step more easily, or (c) contracting the manufacture of dangerous, toxic, or highly specialized steps to other companies.
It is rarely possible to go directly from a laboratory scale of synthesizing milligrams or grams to a manufacturing scale where hundreds of kilograms or even metric tons of a chemical may be required. Scaleup often requires chemists and chemical engineers who were not involved in the original laboratory syntheses. Large glassware containers are used to make greater amounts of a drug. Still larger nonglassware reactors are used at the pilot plant scale. This is a stage between laboratory scale and manufacturing scale. Monitoring and testing systems must be developed to evaluate the performance and ruggedness of the various chemical stages. This must be done during the chemical operations and after each step in the synthesis to assure that quality, purity, and yield are maintained. One objective of this process is to fully automate these operations. The number of separate scaleup stages a drug goes through should be minimized.
The number of separate scaleup stages necessary in a pilot plant depends on the drug and problems encountered. One of the many reasons why problems arise is that numerous aspects of scaleup cannot be directly extrapolated from one size of a chemical vessel to a larger size. For example, (a) the temperature gradients may vary more in a larger vessel, (b) there are mechanical differences in stirring (e.g., shear forces), (c) a loss of visual observation occurs because the metal reactors used are opaque, (d) the changing surface-to-volume ratio that occurs is critical to heat transfer, and (e) the mechanical handling operations generally take longer on a larger scale. All of these factors may contribute to the variable performance of the process. These factors and others can markedly affect the chemical reaction and results obtained. The general quantities used for various functions are summarized in Table 107.5.
Process Development
The chemical development staff must balance priorities and available resources to successfully complete process development and provide project support work. Chemical development specialists modify or develop new synthetic routes for ultimate use in production. Their goal may be to improve bulk drug yields or purity, decrease costs, or eliminate manufacturing hazards and toxic byproducts. At the same time, an adequate supply of drug substance must be generated to continue the various development activities (e.g., toxicology, clinical trials) on the project. Resource issues typically involve shortages in (a) personnel assigned to the work, (b) available starting materials, (c) available equipment, or (d) time to explore fully new chemical technologies. This is sometimes the central dilemma in a compound’s development.
Table 107.5 Typical quantities of a compound required by various groups for conducting development activities | ||||||||||||||||||||||||||||
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Safety of the Process
Safety is a critically important factor to consider in improving the process of synthesis and scaleup. Some of the primary factors to consider in this regard are as follows:
Temperature changes occur more slowly in large-scale reactions.
Thermodynamics must ascertain whether the reaction is safe and will not “run away” (i.e., autocatalysis).
Increasing the temperature of a reaction by 10°C may double its rate of reaction. This may cause unwanted byproducts, reduce yield, influence product uniformity, and affect equipment functioning.
Heat must be removed from the reacting ingredients rapidly at precisely the right time to stop the process at the desired juncture.
Reproducibility of the Process
The underlying principle in scaleup is that a reaction at one size of a vessel may behave differently at a larger scale. As an example, consider the following. A six-inch-diameter stirrer in a small flask has its tip moving at 4.5 feet per second. The propeller-driven agitator in a 200-gallon reactor with a diameter of 30 inches has its tip moving at 13 feet per second. The tip could beat the crystals of the reaction into small particles and change the product’s uniformity, yield, purity, shape, density, and consistency.
Cost Effectiveness of the Process
The cost of synthesizing a compound is based on (a) material costs, (b) labor costs, (c) overhead costs, and (d) yield. Overhead refers, in part, to the specific equipment used and how long it is used, as well as to other plant operations.
Some routes of synthesis are more cost effective than others. The major factors include the costs of starting materials, number of steps involved, batch processing parameters, and cost of environmental cleanup. If starting materials are impure or unavailable, it may be necessary to synthesize them or to find other suppliers.
Environmental Cleanup of the Process
Waste materials are recycled if possible and cost effective. More regulations are being passed that require companies to control emissions of reactors, evaluate all waste streams, and perform environmental assessments. Incinerators sometimes have scrubbers in them to clear materials burned. If possible, expensive and volatile solvents are recovered. Table 107.6 lists the sections of an environmental impact analysis that must be included in a New Drug Application (NDA). Costs for environmental cleanup are rising rapidly.
Synopsis of the Process
Modern chemical reactors are like giant thermos containers (i.e., metal containers, usually stainless steel, around a glass-lined interior). Fluids flow between these two layers to heat or cool the contents. Heat is generally applied with steam, and cooling is done by refrigerated glycol or running water.
After a chemical reaction is complete, it is often necessary to separate two immiscible layers where the less dense phase is on top of the denser phase. In a glass flask, it is easy to see the two layers and to separate them, whereas that is impossible in a stainless steel reactor. This problem is solved by removing the lower (i.e., heavier) fluid through a small glass opening through a spout until the other colored fluid is observed at the interface. If the two fluids are both uncolored or the same color, then a nonreactive dye could be added to color one of the phases and thereby facilitate the separation.
Table 107.6 Requirements of an environmental assessment in the United Statesa | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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The product is then isolated from solution with a solvent remover. The solvent can be evaporated away to crystallize the product from solution or spray dried to yield a crystalline product. The solid material is then isolated by filtration, centrifugation, or recrystallization and then washed a number of times, milled, and dried. A vacuum oven may be used with material on drying trays, or a tumble dryer may be used.
Development of Optically Pure Drugs
The issues and debate surrounding chirality (i.e., molecules with one or more asymmetric centers) and the development of optically pure drugs have become more intense in recent years. In the past, companies developed optically pure drugs (i.e., single enantiomers) when it was clear to them that racemates (i.e., a compound with an equal proportion of enantiomers) were less safe or less potent. New biotechnology methods have made the isolation and scaleup of optically pure enantiomers more practical. Some companies have exploited these technologies by patenting isomers of well-known drugs that were not patented by the originator. After a couple of examples of this occurrence, companies rapidly learned the necessity of patenting each of the enantiomers as well as the racemate of all of their new compounds.
The Food and Drug Administration (FDA) issued the “Policy Statement for the Development of New Stereoisomeric Drugs” in 1992 (FDA 1992). The document discusses three categories of compounds: (a) those where both enantiomers have similar desirable actions (e.g., ibuprofen), (b) those where one enantiomer is active and the other is inactive (e.g., propranolol), and (c) those where the enantiomers have different activities (e.g., sotalol). The policy statement advocates clinical evaluation of both enantiomers even if only one is chosen to be developed or if the racemate is developed. The major point is that a company must examine the issue scientifically during the early development period and reach a rational conclusion before Phase 2 trials are completed.
This policy is reasonable in that it does not consider all clinical drugs as a single group and also because it encourages development choices of enantiomers to be based on good science and logic. It rejects the claims of some scientists that all new drugs should be single enantiomers.
A single enantiomer should be developed if it is easy to synthesize and if it has improved clinical activities than the racemate. Other reasons to develop a single enantiomer are ease of development to obtain absorption, metabolism, excretion, or physiological advantages. Racemates should be developed if there is a rapid interconversion of enantiomers, if individual enantiomers are difficult to synthesize, or if the separate enantiomers have similar activity and safety profiles.
PHARMACEUTICAL ISSUES
The major functions conducted by a pharmaceutical development department are listed in Table 107.7.
Formulation—Creating Drugs from Chemicals
Master Formula
There is a big difference between an active pharmaceutical ingredient (referred to as API or drug substance) and a drug product. Most chemicals are a single pure compound or possibly a mixture of different compounds, whereas a drug product contains added materials called excipients. These materials are combined according to a precise formula, and each ingredient in that formula has a specific and necessary function. Some people refer to the drug formula as a recipe, but this is somewhat misleading because it implies a certain degree of imprecision and empiricism. Drug formulas specify ingredients up to four significant figures, and all changes in the formula for both marketed and investigational drugs must be approved both by the company’s strict internal standards and by relevant regulatory agencies.
Agents that should be added to the final drug formula must be determined. Choosing the most nearly optimal list and proportion of ingredients that together make up a drug product often takes substantial time and effort. For example, the company must determine the implications of adding each of these substances. Excipients must not react with the drug substance or affect its absorption into the body. A classic example of an adverse drug-excipient interaction is that amines are inactivated by lactose. Controlled-release and entericcoated formulations are two exceptions where excipients are specifically chosen to delay the drug’s absorption.
Table 107.7 Activities conducted by a pharmaceutical development department | ||||||||||||||||
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Importance of Creating the Optimal Formulation
There are many reasons why creating the optimal formulation is critical for any pharmaceutical company. These include the ability to:
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