To progress compounds from candidacy to IND rapidly, manufacturers can adopt a strategy that involves front-loading as many studies as possible to reduce the number of potential problems, finding the best solid form for manufacture through a polymorph study or screen, developing a manufacturing process and formulation that preserves this form, and adopting process analytical technology and quality-by-design principles.
Although pharmaceutical research and development spending continues to increase dramatically from year to year, the number of new chemical entities (NCEs) reaching the market has remained relatively flat (1). This lack of growth reflects the portfolio maturity of many of the top pharmaceutical companies and potential revenue loss of drugs coming off patent. Moreover, the cost of moving a compound through the drug development process continues to increase (estimates are between US$150 and 750 million), and generic competition continues to grow as does the molecular complexity of drug molecules. These facts and others necessitate a more effective and efficient approach to drug development. As Pfizer's CEO Hank McKinnell succinctly stated, "Improving the new-product failure rate is really the ultimate answer to cost. We fail about 98% of the time. Somewhat amazingly, if we manage to fail 96% of the time, we would double our productivity."
Figure 1: The five stages of science-based product management.
Approximately 80% of all marketed drug products and more than 95% of the top-selling drug products are solid oral dosage forms. For the aforementioned reasons, strategies to reduce time to market by increasing efficiency and speeding the development of solid oral dosage forms while expanding their revenue lifecycles are important. This review discusses methods to simultaneously reduce time to Phase I clinical trials and to reduce failure rate in progressing compounds from candidacy to Phase I, with a focus on issues relative to the solid-state properties of an active pharmaceutical ingredient (API).
There are many difficulties in rapidly progressing NCEs from candidacy to Phase I. These include overcoming solubility problems, finding the best solid form for manufacture, developing an appropriate toxicological formulation, developing an appropriate Phase I formulation, manufacturing an API, and manufacturing clinical supplies. Recently, Bristol-Myers Squibb reported an 80% success rate in progressing its NCEs from selection to initial trial in human (Phase I) (2). Yet, other firms have reported much lower success rates. This review outlines a strategy based on API properties to achieve a high success rate of more than 75% of NCEs progressing to trial in humans.
Step 1: Selecting the optimal API
The first step involves identifying as many of the relevant solid forms or polymorphs as possible. For purposes of this review, the US Food and Drug Administration definition of polymorphs is used. Polymorphism is the occurrence of different crystalline forms of the same drug substance, including solvation or hydration products (also known as pseudopolymorphs) and amorphous forms. Solid forms or polymorphs are identified using a polymorph study or screen. This screen should be fast, not consume much compound, and should involve a range of conditions. It should not be solely based on crystallizations from solvents because solvent-based crystallizations explore crystals resulting from nuclei that exist in a liquid (or diluted) environment. Solvent-based crystallizations do not produce solids resulting from nuclei formed in the solid or liquid state in the absence of solvent. This importance of solventless crystallizations is supported by the extensive work of Kuhnert-Brandstatter and Yu and by recent studies of the ROY (ROY stands for red, orange, yellow), which are three of the color polymorphs of 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile) system by Yu (3). Yu's group recently discovered two new polymorphs of ROY, a well-studied pharmaceutical compound, after extensive solution-based screening work had been conducted. Yu stated:
"Solution crystallization is the method of choice today for polymorph screening. YT04 (one of the new polymorphs), however, had escaped years of solution crystallization in several laboratories and was discovered through melt crystallization and solid-state conversion. In fact, none of the last three polymorphs of ROY were found through solution crystallization. This experience underscores the importance of alternative approaches to polymorph screening."
Clearly, it is important to accurately perform a broad-based polymorph screen to prevent delays or failures owing to the appearance of a new polymorph during clinical-supply manufacturing.
The main goal of the initial polymorph screen is to find the most thermodynamically stable solid form. Scientists typically prefer to use the most stable form for Phase I clinical trials as well as subsequent development activities. If the compound progresses beyond early trials, then a second round of more extensive polymorph screening is recommended, particularly as the synthetic pathway matures, to check the first screen and to help ensure that polymorphs that could cause failures during later trials or launch do not appear. In addition, salt screening or cocrystal screening may be performed to alter the properties of the current solid, if necessary.
The intrinsic solubility of the compound in gastric fluid and relevant solvents is determined at this stage. The permeability also is estimated. If the solubility is too low, then salt screening and/or cocrystal screening is initiated immediately to find a more suitable form. It is not efficient to progress a highly insoluble compound beyond this first step because its solubility will likely cause failure as a result of poor bioavailability.
At the end of this first step, a crystallization method to recycle all available API into the desired crystal form is developed and implemented. The API prepared in this step should be used for stability studies, methods development work, studies of drug–excipient interactions, determination of mechanical properties, and preliminary process selection and formulation development.
Step 2: Producing the correct solid form
In step 2, the development scientist works closely with the API synthesis group to help ensure that the correct solid form is produced. Care is taken to achieve the proper impurity profile and chemical properties. In this regard, early specifications are established for purity, presence of important impurities, chiral purity, water content, solvent content, and so forth. In favorable cases in which a highly crystalline material is the solid form of choice, the crystalline nature of this form can ensure that the API specifications are met. In favorable cases, on-line process analytical technology (PAT) tools should be used to monitor the polymorph and particle size during crystallization and processing of the API. These studies are quite important because they can lay the groundwork for the development of the API design space and on-line methods for monitoring the process through scale-up. Furthermore, these studies can help elucidate the process critical control points for manufacture. Most development scientists believe that process critical control points are preserved throughout scale-up.
Concurrent with these studies, initial analytical methods are being developed for the API. These methods include determining impurities and an identity-type method for the solid form. The identity-type method typically will be X-ray powder diffraction or solid-state nuclear magnetic resonance (SSNMR) and will verify the presence of the correct solid form.
By defining the solid form, it is easier to develop a toxicological formulation. In most cases, a toxicologist will prefer a solution formulation, and in other cases a suspension is preferred. In either case, using the most stable polymorph provides a defined material to work with. This avoids various toxicological formulations with different concentrations because of different solubilities of the solid forms used.
Once the solid form is defined, its particle-size range is addressed. Particle size can affect dissolution rate, bioavailability, and manufacturability. For this reason, a preliminary particle-size specification is set. In most cases this specification is based on the particle sizes of the early lots because materials tend to crystallize in an intrinsic particle-size range for a given set of crystallization conditions. The desired particle-size distribution should be communicated to the API group from the formulation and process design groups so that, to the extent possible, milling during finishing is minimized.
Stability is tested on the defined solid form and particle size. This test usually is conducted at 40 °C and 75% relative humidity and at 80 °C. Drug–excipient interactions also are tested under stress conditions. Having a well-defined polymorph and particle size facilitates a realistic assessment of the stability and any potential stability problems. Nonetheless, it is critical to have intimate contact between the API and excipients to have a meaningful excipient interaction screen.
Step 3: Developing a noninteracting clinical trial formulation and a manufacturing process
For clinical trials supplies, the identified polymorph in an appropriate particle-size range is incorporated into a noninteracting formulation. A noninteracting formulation is one that does not alter the polymorph or API particle size. By using a noninteracting formulation, the release rate (i.e., the dissolution rate) is made dependent on the API polymorph and its particle size. The optimization of the polymorph and particle size are carried out earlier and on small amounts of material. Using this strategy, the critical steps in the process are pushed earlier, thereby providing more time for optimization and increasing the chance of success.
A typical noninteracting blend–fill formulation may contain the API, filler such as calcium phosphate, a flow aid such as talc, a disintegrant, and a lubricant. A noninteracting formulation based on roller compaction or wet granulation contains an API, filler such as microcrystaline cellulose, a binder, a disintegrant, a flow aid such as talc, and a lubricant. In some cases, it would be advantageous to avoid wet granulation or other formulation strategies that may alter the API crystals. In some cases, it may be easiest to use capsules at this stage to avoid the complications associated with compression processes.
At this step, a manufacturing process for the noninteracting formulation also is identified. Typically, this will be either a blend–fill capsule process or roller compaction. Whatever the manufacturing process, the polymorph and particle size of the API should be preserved. The excipients and process used should not recrystallize the API or cause it to transform.
Two other critical parameters of the API related to the manufacturing process are blendability and flowability. Scientists should pay particular attention to these parameters during early formulation development. It is possible to carry out small-scale blendability studies, especially if mapping or light-induced fluorescence methods are used.
PAT methods are used to monitor the manufacturing process. In this way, early information on the design space of the process is obtained. This information is invaluable in determining future manufacturing processes.
Step 4: Analysis of the formulation
Step 4 involves confirming the nature of the noninteracting formulation. Several powerful analytical techniques are available for this early analytical study. SSNMR is a particularly useful method because it can distinguish polymorphs. Carbon-13 SSNMR is a spectral technique that probes the environment of the carbon atoms in the sample. If various polymorphs are present, then various SSNMR spectra will be displayed (see Figure 2).
Figure 2: The carbon-13 cross polarization with magnetic angle spinning spectra of two polymorphs of the analgesic flufenamic acid.
In this figure, the differences in peak positions provide a unique fingerprint that clearly distinguishes the two solid forms. Currently, SSNMR is even used for regulatory documentation, and the International Conference on Harmonization Q6A guidance specifically mentions SSNMR. SSNMR is nondestructive and is a bulk technique that measures the entire sample in the NMR probe. It also is relatively insensitive to particle size and shape. Carbon-13 SSNMR can routinely confirm the solid form present in drug products unless the drug loading is very small. Typically, the API carbon-13 SSNMR spectrum is used as the standard. A formulation that contains the same polymorph as the initial API will show SSNMR peaks at the same position as the API. Moreover, the use of calcium phosphate and talc as noninteracting excipients minimize interference in the carbon-13 SSNMR spectra. In cases in which fluorine is present in the API, fluorine-19 SSNMR can be used to detect less sample than is possible with carbon-13 SSNMR. Few, if any, excipients contain fluorine. SSNMR also can facilitate chemical identification or quantitative analysis of the amount of drug present.
X-ray powder diffraction is a powerful alternative to SSNMR spectroscopy. The powder diffraction pattern of a dosage form characterizes the unit cells of all components. In some cases, the form present in a drug product can be determined by comparing the X-ray diffraction pattern of the dosage form with that of the standard.
Microscopy with chemical imaging (especially Raman imaging) is another technique that can be used to confirm the presence of solid form in a formulation. In this case, a microscopic image is augmented with a chemical image, which is determined by taking the Raman spectrum of individual points in a tablet and comparing the spectra of those individual points with a library for identification. An image is then produced that provides a visual identification of the material present at any particular point.
Finally, a simple dissolution test is carried out on both the noninteracting formulation and the powdered-drug sample. This dissolution test is used to prove that the formulated product essentially has the same dissolution rate as the bulk drug. In other words, this test confirms the noninteracting nature of the formulation.
Step 5: Manufacturing clinical material
The final step involves manufacturing clinical supplies. The noninteracting formulation is manufactured using the new API lots. The nature of the drug in the formulation is verified using the SSNMR method developed. And the stability of the formulation is verified as the clinical trials are initiated.
An important advantage of the strategy outlined is that it allows a preliminary definition of the design space for manufacturing the API and a simplified formulation. The design space is the established range of process parameters that has been demonstrated to provide assurance of quality. With respect to manufacturing, this early work is only useful if the manufacturing process for subsequent phases is the same as that used for clinical trials. Even if the process is changed later, some information about the design space for manufacturing can be gained from this early work. Another advantage is that it is much easier to reproduce the manufacturing of a dosage form that is defined and much easier to identify problems if the dosage form is defined.
The timing of this strategy is critical. As discussed previously, this strategy begins late in the discovery process when an API is being defined. At this early stage, every effort should be made to find the most stable polymorph. This task is particularly advantageous because defining the polymorph at this stage will provide an understanding of the API's solubility. Once permeability is measured or estimated, it should be possible to provide a biopharmaceutical description of the material and, to some extent, predict its pharmacokinetics. It is also important to involve cross-functional groups in the proposed strategy including preformulation, formulation, and development scientists as well as legal teams. The silos many pharmaceutical companies develop often hinder productivity and efficiency at the early stage of drug development because these silos inhibit communication and can foster competition rather than teamwork.
The toxicological formulation also is defined as soon as possible after the solid form is selected. In this way, any problems with this formulation can be anticipated, thereby providing more time for finding solutions to these problems. Only small amounts of material are needed to test solubility or suspension properties in a range of vehicles.
The development of a simplified formulation begins as soon as sufficient material is available. Although more material is needed at this stage, it is still possible to carry out preliminary formulation experiments at the gram scale by hand mixing and analysis SSNMR. Failed API lots may not pass with respect to purity but may still be valuable with respect to their physical properties and be used to develop the formulations for Phase I clinical studies.
The overall timing of the various steps in a hypothetical development project is shown in Figure 3. It is important to realize that this figure is hypothetical and that each development project will vary. This timeline assumes that six months is required to synthesize API for clinical supplies. It is possible to start the trials after a one-month stability study and allow stability studies to continue. Thus the investigational new drug (IND) trial in this hypothetical case could start after nine months. If the synthesis of the API can be shortened, then formulation development and other studies of this formulation can be abbreviated. The goal is always to start clinical trials three months or less after clinical API is delivered. In favorable cases, it also should be possible to reduce the clinical trials manufacturing time to one month, thereby reducing the time to start clinical trials to two months after the API is delivered. Additional time gains can be achieved by starting clinical supplies manufacturing while the API is being released. Again, it is important to realize that this is a hypothetical timeline and firms will have various strategies to address many of these issues.
Figure 3: Hypothetical timeline for science-based product management.
Chemistry, manufacturing, and controls section of the IND
The strategy discussed previously also will facilitate the preparation of the chemistry, manufacturing, and controls (CMC) section of the IND submission. The primary purpose of this section is to ensure safety. By showing that the solid form used in a clinical trial is the same as that used in toxicological studies, regulatory authorities can be assured that everything has been done to ensure the product's safety. This strategy will assist the assessment of risk in that it will provide a well-defined drug product for testing.
Because the drug substance and drug product are well defined, the chemical composition section of the IND submission should be easier to prepare. The stability section of the drug substance summary also should be well defined and easy to prepare. It will be easier to meet the requirement of describing any differences between the drug product used for toxicology and that used for the IND trial.
As a project moves to the NDA or dossier stage, both the S and P sections of the common technical document (CTD) require detailed description of the drug substance and drug product. Section S.3 requires, among other things, physicochemical characterization of the polymorphs. Section S.4 requires justification of the acceptance criteria for polymorphs, if needed. Section P2 of the CTD Module 3 requires, among other things, a formulation development rationale. Section P5 requires the justification of the drug product specifications. Generating these sections are greatly facilitated by understanding the specific physicochemical and mechanical properties of the API and how they were used to select the logical processes and associated formulation.
The subsequent design space for process and formulation development and scale-up is based on the variables associated with the processes, the properties of the materials, and the desired endpoints for the particular unit operations. Both the process critical API and raw material parameters must be identified and understood to take advantage of a first-principles design space. The approach previously outlined, therefore, leads the process of designing a dosage form with desired critical performance attributes.
Revenue and intellectual property implications
While accelerating the solid-form development path, the posed strategy also generates significant intellectual property in the process. A precise understanding of the solid state and its genesis can ensure precise patents. Imminent patent expirations will expose approximately US$30 billion in blockbuster sales at risk (4). Unfortunately, the pipelines of new drugs are not full to replace this and other losses. One strategy we propose to extend the revenue streams of new drugs approaching market is to leverage the intellectual property generated early for broader patent protection as well as information for second and tertiary formulations. Although not always possible, new formulations (e.g., AstraZeneca's Nexium), combined products, novel delivery mechanisms, and so forth can significantly extend API lifecycles and should be addressed as soon as possible during development.
The approach previously described has major advantages: It provides the highest probability of reducing time to market, and it will increase the frequency of right-the-first-time manufacturing of clinical supplies. This latter point is particularly important. As Pisano has shown, preparing drug substance and drug product right the first time is the greatest single factor in reducing time to market (5). Another advantage is that this strategy will minimize delays associated with handing off the project to the various groups involved in the industrialization of the drug, including chemical development, chemical process, analytical, formulation development, manufacturing, and regulatory groups.
This approach also allows easy definition of the process critical control points. By defining these points and making preliminary measurements with on-line sensors, one can set the stage for a well-designed process that can be easily monitored by on-line sensors. In other words, this approach will allow the development of a PAT process inside a design space.
This strategy will provide well-characterized, highly controlled clinical trial supplies, which will minimize errors and avoid expensive mistakes during clinical trials and mitigating several risks, including:
This approach also will increase a firm's ability to handle more-difficult drugs. The approach enables rapid completion of simple development projects, which leaves more time for developing difficult drugs. In addition, as a firm becomes increasingly skilled in carrying out the steps in the strategy, it will develop more skill in each step, which also will lead to quickly finding solutions to difficult problems.
Defining a design space also helps minimize variability. Working within a design space is not a regulatory change, thus the defined design space will facilitate continuous improvement of the manufacturing process (6, 7).
It is highly likely that firms using this approach will be able to take more difficult drugs to clinical trial and ultimately to market. Moreover, it is easy to see how this strategy can be extended to Phase II and Phase II clinical supplies. With each subsequent phase, the importance of this general approach is magnified.
Stephen R. Byrn, PhD,* is a study director at SSCI, Inc., a Charles B. Jordan professor of medicinal chemistry, and head of the Department of Industrial and Physical Pharmacy at Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47906, tel. 765.714.2808, email@example.comKenneth Morris is a study director at SSCI, Inc., and professor of industrial pharmacy at Purdue University. Shawn Comella is vice-president for business development at SSCI, Inc.
*To whom all correspondence should be addressed.
1. Tufts Center for the Study of Drug Development, Approved NCE Database, http://csdd.tufts.edu.
2. The Pink Sheet (F-D-C Reports, Chevy Chase, MD, Nov. 29, 2004).
3. Yu et al., "New Polymorphs of ROY and a New Record for Coexisting Polymorphs of Solved Structures," J. Amer. Chem. Soc. (in press).
4. White and Kearney, Pharmaceutical R&D Statistical Sourcebook 2005–2006 (PAREXEL International Corp., Waltham, MA).
5. G. Pisano, The Development Factory (Harvard Business School Press, Cambridge, MA, 1994).
6. International Conference on Harmonization (ICH), Q8 Draft Guidance: Pharmaceutical Development (ICH, Geneva, Switzerland), www.fda.gov/cder.
7. ICH, M4 Guidance: The Common Technical Document (ICH, Geneva, Switzerland), www.fda.gov/cder.