The Importance of Fundamental Data Gathering and Planning for Solid Oral Drug Product Manufacturing

Solid oral drug products are one of the oldest of all manufactured dosage forms (1). Today, the development of an appropriate formulation of drug and excipients and of an effective manufacturing process to create a tablet or capsule is slowly transforming from a practice of applied art to one of applied science. The US Food and Drug Administration supports this change by expecting sponsors of new drug applications to understand, describe, and control materials and processes as well as the risks associated with drug product manufacturing (2). These steps will ensure the consistent production of products that meet their specifications and remain safe and effective during their shelf life.

Because of FDA's expectations, pharmaceutical companaies are making greater efforts to study the chemical and physical properties of drug substances and to learn how to manipulate the interactions between active and inactive ingredients and the apparatus used in the manufacturing process stream to produce the highest quality oral dosage forms.

This article identifies physical and chemical data about active pharmaceutical ingredient (APIs) and inactive ingredients (excipients) needed to develop a stable, proper strength, solid oral drug product. It also identifies ancillary information needed from biologists and pharmacologists for designing a drug delivery system, and information needed from marketing specialists to ensure a visually and culturally acceptable product design. This article emphasizes the need for early and ongoing planning to ensure that all the information is collected and used effectively to meet development, registration, launch, and marketing requirements.

This information gathering and planning is the first unit operation in a successful new product manufacturing process, without which many of the other unit operations (e.g., mixing, milling, granulation, compaction, analytical release, and stability testing) may fail.

Planning for effective solid drug product manufacturing

Project management for product development and execution begins with a detailed plan. This plan should remain fluid throughout a product's life cycle, however, because the planning and execution of each step will improve as new information becomes available.

Because each development project is different, it is impossible to provide an exhaustive list of information and data that must be assembled. This article describes only categories of information and relates them to their subsequent use in developing a formulation and manufacturing process. These categories of information include:

• the physical and chemical data for the API and excipients;

• the physical and chemical compatibility data for API–excipient interactions (both positive and negative);

• the interactions between these materials affected by the manufacturing equipment and operating parameters;

• the availability of equivalent manufacturing equipment and options for scaling-up to market scale;

• the facility-specific concerns related to working with a given API, including worker safety and environmental protection;

• the metabolic requirements and limitations of end users (including absorption, distribution, metabolism, and excretion);

• cultural and market considerations, including costs;

• regulatory considerations for registering the new product in each regulatory region.

Each category is discussed further to show the extensive interactions necessary for operating personnel to use the data effectively. Effectiveness in this case means the ability to develop a formulation and associated manufacturing process that will produce a solid dosage product that consistently and profitably achieves the following:

• it meets its specifications and acceptance criteria through the lot shelf life;

• it can deliver the drug in the desired manner throughout the lot shelf life;

• it is accepted readily in the market (by consumers).

Requisite information and data for API and excipients

Successful formulation design starts with the collection of adequate preformulation information. Preformulation information denotes the complete set of physical and chemical data about the API and each excipient that may be incorporated into the drug product.

API characteristics. The following summarizes key API characteristics and how those characteristics can influence the formulation and manufacturing process.

Crystal form and habit. Crystal form and crystal habit may affect an API's stability, dissolution rate, flow, and ability to mix with excipients. API materials may have more than one crystal form as well as a noncrystalline amorphous form. Each form, or polymorph, has its own inherent stability profile, dissolution rate in aqueous media, and mechanical properties. The amorphous form has the lowest melting point and usually the fastest dissolution rate. It is most likely to react or degrade. The most stable crystal form usually will have the highest melting point and the slowest dissolution rate. All forms, however, reach the same equilibrium-intrinsic solubility.

Mechanical properties such as the ability to flow, ability to mix, particle strength, and cohesiveness often vary among the polymorphs. Mechanical properties also can be influenced by the crystal shape, or habit. One polymorph may have different habits. Cohesiveness, the surface free energy effect that results in particles aggregation, also may be different for various polymorphs and habits. The more cohesive the material, the more difficult it is to mix that material with other materials. Similarly, cohesiveness between the API and an excipient or among excipients may hinder the successful blending process.

Particle-size reduction and distribution. Particle-size distribution usually results from the way the API is precipitated from solution in the final synthetic step. The particle-size distribution may be monodisperse, which is desirable, or polydisperse, which is undesirable.

Particle-size reduction can be accomplished by using a hammer mill or a similar mill, but this process may only break up the larger crystal aggregates without significantly changing the distribution of smaller particle sizes. On the other hand, air jet mills, which impinge two streams of particles at a right angle to each other in high-velocity air streams, reduce particle size and the resultant particle-size distribution significantly. This technique, or the use of a ball mill, also can deliver microsized particles. Milling provides energy to the crystals, however, and may cause local melting of the crystals if their melting point is sufficiently low. If melting occurs, there is no guarantee that the original polymorph and habit will be regained upon resolidification, or even that a crystalline form will result.

Particle size and dissolution rate. The dissolution rate of any material increases as particle size decreases because smaller particles have a greater surface area for wetting by the dissolution solvent. Because the most common solvent in pharmaceutical processing is water, much of the preformulation evaluation should be performed in aqueous media to study what may happen to the API during wet granulation or to the drug product in a human or animal biological system.

Particle shape. Uniform mixing of materials occurs when the materials have similar particle-size distributions and particle shapes that are conducive to mixing. Spherical particles mix best, but few materials are spherical. Particles with jagged edges mix least well. Plate and fiber shapes also do not mix well because they tend to clump.

Particle size, shape, and surface energy are important factors for both the API and excipients because they affect unit operations such as blending, powder flow into and out of hoppers and storage bins, and granulation.

Moisture content. The moisture content of the API can affect the cohesiveness of particles through hydrogen bonding or by changing surface-energy effects. Water also can act as a plasticizing agent and can lower the glass-transition temperature of amorphous polymorphs, thus allowing a rubbery state to exist at a lower temperatures. Water also can take up intra- and intergranular pore space of the material. The former effect is easy to imagine by visualizing the particle pores as capillaries and picturing water flowing into those pores by capillary action. Water can fill intergranular pore space by acting as an interparticle bridge through hydrogen bonding or through surface adsorption mechanisms in which water acts like a glue between the particles.

Some materials are so hygroscopic that they will adsorb water until they deliquesce, or begin to dissolve. Knowledge of moisture adsorption is important because adsorbed water can cause incorrect weighing of API when adding it to a batch or during quality control. Some materials are labile and degrade in the presence of moisture. If water reacts with the API, then the API–water reaction will continue to a greater extent as the amount of water increases.

Adsorbed water also can act locally as a solvent and provide the opportunity for the API to react with other agents that may dissolve out of the excipients in a granulation or blended powder mass. Any free, unbound water in the mass can migrate throughout the material mass and act as a reagent, a solvent, or both. One familiar example of this is the strong odor of free salicyclic acid that develops from aspirin tablets stored, even in a closed bottle, in a humid area such as in a bathroom medicine cabinet. In time, one may even observe crystalline needles growing out of these tablets as the physical and chemical degradation continues. Such examples demonstrate the importance of correctly evaluating stability effects to draft the correct storage statement for the finished dosage form in its protective container–closure system.

During manufacturing operations, these characteristics of water can be advantageous. For example, static charge can build on the surface of powders as a result of milling or blending, thereby causing particles to jump away from each other by means of charge repulsion. For some materials, this effect can be reduced by adding a small amount of water.

Water's ability to act as a bridge between particles can improve the compression capabilities of powder masses. The degree of water bridging can affect the tensile strength, measured by the hardness, of the finished dosage form. Too much or too little residual water for bridging in the finished form may result in a weaker, softer tablet.

Thus, for each formulation, chemists must assess the effect of water on the chemical stability of the API, on the chemical and physical stability and workability of the powder blend or granulation mass, and on the tensile strength of the finished solid dosage form.

API–excipient interactions. Interactions between APIs and excipients can be positive or negative. An example of a negative interaction is the degradation of the API when mixed with the excipients. Sometimes, such interactions require water as a mediator (i.e., a solvent) and other times they occur in the completely dry state. In some cases, API degradation can result from an excipient impurity such as a metal contaminant that may initiate API oxidation through a catalytic mechanism. In other cases, excipients may provide proton or hydroxyl ions that can, in the presence of free water in the mixture, initiate specific acid- or base-catalyzed degradation, respectively. Excipients that provide Brönsted acid or base moieties can initiate general acid- or base-catalyzed degradation. In such cases, available free water probably acts as a solvent.

API–excipient compatibility studies can be performed with minimal amounts of materials. Usually, small amounts of each material are weighed into a glass vial, in a ratio representative of the expected ratio in the formulation. The vials can be sealed as is or with additional water, either in an air environment or oxygen-free (nitrogen head space) environment, and stored in the presence or absence of ambient light, at various temperatures. Very complex factorial or partial factorial design experiments can be set up to determine important binary and multiple component interaction factors. This information helps determine which excipients should be avoided and whether there may be any concerns for oxidation or light instability in the formulation. Controls consisting of the API alone in the various conditions also should be run to determine whether the API is susceptible alone or must have the mediating excipient or water additives for instability.

Bioavailability. The API's solubility and stability in aqueous media as a function of pH, temperature, ionic strength, and buffer species must be determined in the physiologic range of pH 1–7.5. Once administered to the patient, the dosage form enters an aqueous medium in the pH range 1–3 in the stomach, interacting with bile acid surfactants and the pepsin enzyme, then enters a different aqueous milieu in the small intestine, which has a pH range of ~4–7. Once the API has crossed the intestinal membrane and enters the blood stream, it encounters an aqueous medium with a pH of ~7.4. A properly formulated and manufactured solid oral product must disintegrate in the stomach or intestine, dissolve in the stomach or intestine, migrate through the small intestine into the blood stream, and preferably be stable and pass completely into the blood stream without too much metabolic loss in the process. Many API materials are ionizable acids or bases, and therefore their solubility is dependent on the pH of their environment. If the API also experiences specific acid- or base-catalyzed degradation near body temperature (37.5 °C) or experiences salting-out effects with ionic species, then a dosage form other than a solid oral product may be indicated.

Passive or active transport. Transport across the intestinal wall can occur by a simple diffusion mechanism (passive diffusion) or by a facilitated mechanism (active transport). This topic will not be discussed further here except to note that the passive–diffusion potential for API materials traditionally has been estimated by measuring the partition coefficients in octanol–aqueous buffer and similar oil–water systems as a part of the preformulation protocol. Contemporary evaluation uses CACO-2 cells and Franz diffusion apparatus or a 96-well plate to evaluate the potential for active transport and passive diffusion in simulated live conditions (3).

Analytical method development. Much preformulation work depends on having a well-characterized and validated analytical method to measure the intact API and its degradants. Therefore, the development and validation of the analytical methods must be planned and executed very early in development. Of course, all analytical methods, including spectroscopic, chromatographic, or wet-chemistry methods, also must be sufficiently validated and use calibrated apparatus and reagents to provide scientifically correct data.

Most critical experiments can be conducted using only gram quantities of materials in a 3–6 month period. The data must be collected according to a systematic approach designed to show the probable manufacturability of a solid oral dosage form containing the API. Planning that overlooks or underestimates the importance of collecting a full battery of preformulation data often results in failed development, at worst, and much lost time collecting the data after some preliminary formulation deficiencies are noted, at best. The expenditure of approximately six person-months to gather the data before starting the formulation design will more than pay for itself in the faster delivery of an acceptable finished solid oral dosage form. In addition, negative aspects such as solubility or pH-related stability limitations for the API or API–excipient incompatibilities will be discovered quickly to improve the likelihood of successful product development.

Considerations for manufacturing equipment and scale-up

Developing a formulation and its manufacturing process should follow from the preformulation studies. A formulation chemist can use preformulation data to develop a powder mass granulation that has the correct density, porosity, and flow properties, and API concentration, and the desired powder blend uniformity. Then, appropriate machine conditions can be developed for compacting the powder mass into a tablet or filling it into a capsule shell.

Granulation for volumetric dispensing. All manufacturing operations depend on volumetric dispensing. Capsule shells and tablet dies are filled volumetrically by the machinery to provide the correct amount of granulation mass containing the correct amount of API for each capsule or tablet. Therefore, the goal of bringing together the API and excipients in a formulation is to achieve a powder mass with the necessary density (mass per unit volume). This may be achieved through wet granulation, in which the materials are brought together into uniform aggregates using a solvent or by compaction (known as slugging or dry compression).

The resultant granulation ideally should contain uniformly sized granules, each of which is made up of a uniform amount of each excipient and API. Achieving the correct density of the granules to allow for consistency in volumetric dispensing is achieved by aggregating the particles and eliminating void space. Granule aggregation results from a combination of particle attractions. These attractions include energetic interactions such as Van der Waals forces and hydrogen bonding and mechanical connections formed by liquid or solid bridging among particles. Formulation considerations include finding the correct binding excipient and solvent, if necessary, to blend the API with the diluent and/or bulking agent.

The need for various excipients. Selecting excipients is a delicate balancing act for the formulation chemist. The more potent (measured as pharmacologic effect per unit of API) an API is, the less API is needed per unit of product. Tablet and capsule units must be of a certain minimal size, however, to be handled easily by patients. In addition, most API materials do not have the correct flow and compaction characteristics to allow them to be made directly into solid products.

Therefore, some inert excipient material must be added to the mass of API to provide sufficient bulk to yield an acceptable final size of the finished dosage form. These materials are referred to as diluents or bulking agents. These excipients and the API are incorporated into the granulation mass with excipients called binders. Glidants are additional agents that improve flow by eliminating friction between the particles and the surfaces of bins, chutes, and die tables, for example, or by filling in the surface texture of granules to provide a smoother surface. Lubricants also can be added to help remove compacted tablets from die cavities, to help fill the compacted plug of granules into a capsule shell, and to facilitate the movement of the granulation mass in manufacturing machinery.

Early development and scale-up. Formulation development begins at the bench level with gram quantities of materials and simple hand-operated equipment. Experimental formulations are tested by manufacturing finished product with larger amounts of materials (partial kilo quantities) with developmental-scale automated machinery. The formulation and process steps are scaled up to clinical production equipment at the 20–100 kg scale. Finally, when the likelihood of product development success is high (during Phase III clinical trials), the formulation is scaled to the final commercial scale of 100–1000 kg.

Planning for this progression of scale change should occur from the beginning. This planning should take into account what equipment will be available to manufacture the commercial product. Then, the formulation and process development chemists should ensure that similar equipment will be used during the development phases so that scale-up to commercial-size equipment will be possible.

Similarly, excipients that are readily available and already used by the commercial operation should be chosen when possible. Establishing the specifications, test procedures, acceptance criteria, supply chain, and supplier qualification for an excipient that is not used by the organization can add significant time and cost to the project. If an uncommon excipient is necessary to ensure manufacturing capability and product performance, then the cost is worthwhile. If the choice of an exotic excipient or apparatus is based on the personal whim of a formulation or process chemist, however, then the cost is not worth bearing unless such new excipients or technology will be used frequently in the future and will provide significant time or economic gains in later projects.

Communication between formulation, process, and analytical development personnel with production and quality control personnel is essential from the very beginning of the project to ensure continuity from development to successful market supply. Collaborating on matters such as selecting materials for function and cost, designing the process equipment stream for availability and utility, planning validation steps, and using new materials and technologies during the developmental and commercial steps is necessary for success. This statement applies to formulation and process development as well as to development of the analytical and control methods.

Considerations for worker safety and environmental protection

Industry has come to recognize the importance of understanding and controlling the effect of toxicologic factors of APIs on the personnel working with them, on the facilities in which they are used, and on the environment. Advances in analytical capabilities provide the means to assess carry-over of the API from the intended batch and the areas in which the batch is manufactured to other areas of the facilities and even areas outside the facilities. In addition, the industry now works more frequently with highly potent APIs, thus increasing the level of concern for both operators and facilities.

Current good manufacturing practice regulations require processing controls that prevent cross contamination between product lots (4). The Occupational Safety and Health Administration regulations also require that workers and facilities are managed in ways that avoid the possibility for inadvertent dosing of any material to workers (5). Compliance with these requirements, however, must be planned for during the development of a new product, particularly if the new API is potent (i.e., a small amount of material causes a large pharmacologic effect that is reversible) or potent and hazardous (i.e., a small amount of material causes a large pharmacologic effect that is not reversible and may cause permanent damage to cells, organs, or metabolic systems).

The challenges of controlling the creation of dust, developing strategies for managing and controlling the movement of API dust, and removing residues from equipment and operating areas increase with scale. What can be managed easily in the laboratory with gram quantities of API, for example by using a glove box or laminar flow hood, may not be achievable at the 100-kg manufacturing scale (6). It may be relatively easy to build or buy containment equipment for developmental-scale equipment, but not very easy, and much more expensive, to specify and install similar performance equipment for commercial-scale equipment (7, 8). A strategic approach must be developed to ensure containment (9).

Planning for product development must take these worker and environmental safety concerns into account from the beginning. This is the only way the organization can develop and implement appropriate levels of control in the best time frame and at the lowest cost throughout the development process. These controls must be established for manufacturing at both developmental and commercial scales.

Use of pharmacokinetic data

Two important aspects of API performance that a formulation chemist must understand are what dosage strength is required to produce the effective therapeutic blood level and in which region of the intestine absorption occurs.

If the dose required is high, the formulation chemist may have difficulty developing a formulation and process that incorporate sufficient API in a single dosage unit. This is particularly true for capsules that have a limited volume to contain relatively loose powder. In such cases, the formulation chemist must make a convincing argument to medical and marketing personnel for dosing as a multiple of the unit dosage form. The planning must also include sufficient storage capacity for the API because a large volume will be used in each batch of product.

On the other hand, when the API is so potent that only a very small dose is required, it may be difficult to achieve the desired API content uniformity in each dosage unit. And, the dosage unit may be very small.

When designing the dosage unit size, several factors must be considered. First, the unit must not be so small that it cannot be handled easily by elderly patients. Second, high-speed commercial packaging equipment must be able to accommodate the size and shape. It would not be wise to develop a size or shape that would require purchasing significant additional tooling for counting or packaging the final product. Because each unit operation has a set of costs, the development team must take into account each operation carefully.

When an API is absorbed preferentially in a certain region (i.e., an absorption window) of the intestine, the formulation chemist must develop a formulation that is most soluble in that region of the intestine. This can be achieved by choosing tablet film coating materials that only dissolve at the desired pH and therefore will protect the tablet from disintegrating and dissolving until it reaches the absorption window (i.e., an enteric coating). For capsule development, the same approach can be used by making granulation pellets that are coated with such a material before encapsulation. In this way, the capsule shell will disintegrate and dissolve as usual, but, the pellets will travel intact to the appropriate region of the intestine before disintegrating and dissolving.

Market image and cultural impact of the finished product

The market image of a finished dosage form is important for product recognition. This image includes shape and size, color, and branding on the product, produced by embossing (i.e., pressing letters, numbers, or a logo onto the tablet) or by imprinting with ink. In addition, some markets will not accept certain excipient materials, so such materials must be excluded from the list of possibilities for product development. For example, such restrictions include alcohol and porcine-derived excipients for products distributed in the Middle East.

Coloring agents. Coloring agents are specially controlled for food, drugs, and cosmetics because many are derived from natural products and have pharmacologic effects of their own (10). In addition, the rules governing coloring agents, just like all quality standards, are different in various regulatory regions, and these rules may affect the supply chain, analytical control, and regulatory registration.

From a manufacturing perspective, coloring agents may be problematic because they can be highly reactive with the API. Also, it is difficult to ensure uniform distribution of these agents—whether soluble (often called dyes) or insoluble (often called lakes)—in a granulation mass. This difficulty is similar to the challenge of ensuring uniform distribution of potent API materials: Only a small amount of coloring agent is necessary, and it is difficult to distribute that small amount uniformly throughout the powder mass. These materials also may adsorb strongly onto metal surfaces of manufacturing equipment, thereby leading to additional cleaning clearance and validation exercises.

Embossing. Embossing tablets requires special tooling. The design blueprints for such tooling must be controlled in a manner similar to the way master documents for all other labeling operations are controlled. In addition, because of the difference in pressure applied to the granulation by the different regions of an embossing tool, tablet compaction characteristics for this tooling may be different from those for similar tools that provide a nonembossed tablet surface. This must be taken into account during development because non-embossed tablets will most likely be used in the clinical trials and in the stability evaluations performed during the development period.

Printing. Printing on tablets or capsules also requires special equipment, careful selection of the appropriate pharmaceutical-grade ink, and careful formulation development and tablet compaction to provide the appropriate surface for accepting the ink. The formulator must assess whether specific stability studies must be performed before submitting the registration documents to ensure that the ink does not result in API instability.

Summary

Formulation, process, and analytical development scientists must consider many technical, pharmacological, organizational, market requirement, and regulatory factors to develop an appropriate solid oral drug product for today's market. Good scientific and technical knowledge, forethought, input from other sectors of the organization, proper planning, and coordinated execution can provide the bases for success.

Charles F. Carney is a senior affiliate consultant at Seraphim Life Sciences Consulting LLC, 25 Head of Meadow Road, Newtown, CT 06470, tel. 203.426.1860, ccarney@seraphimlifesciences.com

References

1. M. Çelik and C. Ruegger, "An Overview of Tableting Technology Part I: Tablet Presses and Instrumentation," in Tableting and Granulation Yearbook, supplement to Pharm. Technol. 20–39 (1996).

2. US Food and Drug Administration, "Pharmaceutical CGMPs for the Twenty-First Century: A Risk Based Approach" (FDA, Rockville, MD, 2004), www.fda.gov/cder/gmp2004/GMP_finalreport2004.htm.

3. Millipore Corporation, "Drug Transport Assay Using the 96-Well MultiScreen Caco-2 Filter Plate on the Tecan Genesis 150 Workstation," www.millipore.com/publications.nsf/docs/tn1156en00 (accessed Nov. 4, 2005).

4. Code of Federal Regulations, Title 21, Food and Drugs (General Services Administration, Washington, DC, April 1973), Parts 210 and 211.

5. Refer to regulations of the US Department of Labor, Occupational Safety & Health Administration (www.osha.gov) and relevant state regulations.

6. D. Liberman et al., "Barrier Isolation Technology: A Safe and Effective Solution for Providing Pharmaceutical Development Facilities," Pharm. Eng. 21 (4), 20–30 (2001).

7. K. Chiarello, "Pharma Industry Drives Innovation in Barrier/Isolation Design," Pharm. Technol. 28 (3), 44–54 (2004).

8. G. Herreman, "Current Technology for Contained Manufacturing," Pharm. Technol. 27 (10), 132–146 (2003).

9. S. Kaplan, "Containment: Reducing Operator Exposure," Pharm. Eng. 20 (2), 66–70 (2000).

10. Code of Federal Regulations, Title 21, Food and Drugs, (General Services Administration, Washington, DC, April 1973), Parts 70–82.