Process considerations
API development. Current literature about the API and about its possible future developments should be kept in one place. Challenges to overcome at this stage include:

• patent infringement;
• inconsistent raw material quality and supply;
• hazardous or nonregulated raw materials;
• costly raw materials;
• unsafe or environmentally hazardous reactions;
• low yields;
• difficult-to-achieve levels of purity (e.g., for enantiomers);
• scale-up;
• difficult-to-handle processes;
• polymorphism-related issues;
• stability of intermediates or products.

R&D chemists must devise a route that can address as many of these challenges as possible.

Cost. Raw materials, packaging materials, processes, and labor are major cost factors. R&D chemists can help reduce process expenses by:

• suggesting cheaper alternative reagents or synthetic routes;
• reducing raw material consumption (e.g., by conducting process-optimization studies);
• shortening process time cycles;
• recycling materials when possible.

Environmental friendliness. Today, R&D chemists are expected to use environmentally benign (i.e., green) chemistry. Ideally, high-yielding processes should be developed so that by-products are not pollutants or are treatable to eliminate pollution. Further processing of the spent materials should be attempted to recover the unreacted materials, by-products, and solvents. For example, a recovered solvent can be treated so that it can again match the desired quality specifications and thus be recycled in the same process step. Gaseous products should be scrubbed effectively. The final spent materials from the scrubber and the other processes should be assessed for their load on the environment and be handled appropriately, causing no environmental damage.

Solvent selection. The International Conference on Harmonization (ICH) guidelines have classified solvents on the basis of their risk to human health (1). Class 1 solvents should not be used during the manufacture of APIs. Such solvents include:

• benzene (carcinogenic);
• carbon tetrachloride (a toxic and an environmental hazard);
• 1,2-dichloroethane (toxic);
• 1,1-dichloroethane (toxic);
• 1,1,1-trichloroethane (an environmental hazard).

Class 2 solvents should be limited because of their inherent toxicity. These compounds include:

• toluene;
• hexane;
• methanol;
• dichloromethane;
• chloroform;
• acetonitrile.

Solvents in Class 3 may be regarded as less toxic and of lower risk to human health. These include:

• acetone;
• ethanol;
• ethyl acetate;
• ethyl ether;
• 1-butanol;
• acetic acid.

Process adaptability. R&D chemists should modify their techniques to fit manufacturing environments. For example, to isolate a product, R&D chemists should avoid evaporating the solvents to dryness because it is difficult to follow such procedures in the plant. Instead, a suitable technique such as crystallization or precipitation should be developed because, in such cases, the product can be isolated by centrifugation or filtration in the plant. Similarly, the purification of a product should be achieved by means of crystallization or selective precipitation because other typical laboratory techniques such as column chromatography have operational limitations at the plant scale.

Methods of handling viscous materials in a plant also must be taken into account because the large surface area of plant equipment and piping can pose problems during material transfer. Solutions to these problems include performing one-pot reactions using a suitable solvent to transfer such materials. In addition, reactions involving low temperatures or high pressures could be difficult to handle in the plant, and an alternative route should be considered.

Safety precautions. Material safety. At the time of route finalization, R&D chemists should collect all raw material safety information—typically,material safety data sheets (MSDS). The storing and handling risks of these materials should be assessed, and appropriate measures should be taken to minimize them.

Process safety. During process development, significant consideration should be given to the safety of the chemistry being developed. The majority of industrially useful reactions are exothermic, thereby suggesting the need for risk assessment. Figure 1 shows the reaction enthalpies of two common reactions, indicating the high degree of process hazard associated with them .

The magnitude of overall heat release can be influenced by the kind of solvents used, concentration, other simultaneous processes taking place, and so on. Together, these factors may have enormous destructive power if they are not controlled properly. Therefore, all chemical processes that may be performed in a pilot plant should be subjected to a safety evaluation.

Initially, the thermal stability of the compounds (e.g., raw materials and intermediates) should be screened using differential scanning calorimetry to detect endothermic or exothermic behavior. Then, these results can be used to determine whether more careful and tedious measurements are required.

In some scale-up cases, an exothermic reaction can lead to thermal runaway, which begins when the heat produced by the reaction exceeds the heat removed. The rate of heat production may increase exponentially. Once control of a reaction is lost, the reaction vessel may be at risk of overpressurization caused by violent boiling or rapid gas generation.

Elevated temperatures may initiate secondary, more hazardous runaway or decomposition. Such a reaction hazard should be assessed in a laboratory using methods such as thermal gravimetric analysis (measuring the thermal stability of the reactants or products) and adiabatic calorimetry (measuring the decomposition
and release of gases). A process should not be performed in the pilot plant before
such safety assessment. Other process hazards such as dust explosion during milling
or storage may also be assessed at an early stage, depending upon the potential of
such risks.

Materials and vendors. It is important to conduct vendor audits and approval to ensure consistent quality and supply of raw materials, packaging materials, and other process components such as filtration media, gaskets, and O rings that might contact raw materials, process fluids, intermediates, or the API. Vendors should be selected according to criteria such as their market recognition, record, ability to supply consistent quality materials in time, and customer orientation.

Certificates of analysis (CoA) and MSDS of the materials should be obtained from vendors. Such information is useful while designing the specifications of raw materials and packaging materials and for obtaining recommended storage conditions.

Developing the specifications
In-house specifications can be developed on the basis of the results of user trials and the CoA of a vendor’s samples.

Process scale-up issues. It is important for R&D chemists to identify potential plant issues and to attempt to address these concerns suitably at the R&D stage. Laboratory studies such as those described below can help address many issues a priori to avoid surprises that might occur in the plant scale-up batches.

Simulating the R&D plant environment. Once the route is finalized, the plant environment in R&D should be simulated as far as possible by:

• using reaction vessels of similar type and shape (e.g., material of construction, vessel shape, stirrer type, number of baffles, and diameter:length ratio of the vessel);
• using the same charging sequence of the raw materials;
• using similar mixing pattern and stirring parameters that are achievable in plant vessels (e.g., similar tip speed or power requirement per unit volume of the reaction mass that can be maintained in R&D);
• developing suitable in-process sampling procedures that are feasible in the “controlled” environment of a good manufacturing practice plant;
• using similar filtration cloth or medium;
• using a similar type of dryer and drying parameters.

Such simulation experiments can help achieve better reproducibility at that plant scale because the possible deviations can be minimized.

Determining the scale-up factor. Many scale-up operations require more time than laboratory-scale experiments because the volume of materials is larger. R&D chemists should take into account the scale to which the process can be operated in the plant
and the required time cycles for such process steps. They should deliberately increase the process time cycles in a laboratory experiment to match the plant time cycles for similar operations. Process steps that may be considered for such studies include:

• adding reactants;
• mixing;
• filtration;
• centrifugation;
• drying;
• maintaining temperature.

The effect of such an increased cycle time on product quality and yield should be assessed. Thus, a scale-up factor at which the process can be operated without affecting the quality and yield can be determined prospectively.

Critical process parameters. While performing laboratory experiments, R&D chemists can test the limits of some operating conditions such as time, temperature, and pH or the quality parameter of key raw materials such as water content and impurity level. The effect of such challenges on product quality and/or yield should be assessed. If a parameter adversely affects either product quality or yield, it should be identified as a critical process parameter and be documented during the development stage.When scaling up, it is necessary to control such parameters strictly to ensure consistent product quality and yield.

Critical observations. During R&D experiments, it is important to record observations such as any signs of exothermic or endothermic activity during reaction, frothing, fuming, sublimation, pressure development, change in color, and change in phase. Similarly, observations related to reaction rate (e.g., vigorous or mild), filtration rate, flow characteristics of fluids, nature of the product (e.g., sticky, fluffy, amorphous, crystalline, semisolid) should be noted so that appropriate measures can be taken in the plant during scale-up.

Chemical compatibility studies. Certain process chemicals such as process fluids and intermediates may react chemically with manufacturing items such as process equipment, piping, flexible hoses, and filters while in direct contact with them, thereby leading to serious contamination and impurity issues.

R&D chemists should consider all process chemicals involved in API synthesis and obtain the data on their compatibility with various materials of construction of all processing items that may be involved during various operations  (3). In
the absence of such data, in-house data should be generated by simulating the exact contact conditions in a laboratory experiment, and the observations should be recorded.

For example, to determine the compatibility of a filter cloth with a process fluid, a sample piece of the filter cloth can be kept in contact with the process fluid for a specified time, temperature, or pressure in a laboratory, and the effect of such fluid on the weight, size, shape, color, elasticity, texture, and so forth of the sample cloth can be recorded. Such observations can help determine the suitability of using various processing items in the plant. During the purchase of such plant items, vendors
should supply material of construction certificates and chemical compatibility information.

Cleaning procedures. To develop prospective cleaning methods for plant equipment, suitable cleaning procedures for similar laboratory apparatus should be established. In a typical cleaning procedure, a similar flow pattern of cleaning solvents to that in plant equipment should be followed. Cleaning solvents such as acetone, methanol, and water should be selected on the basis of the solubility of the particular product that is to be washed from the empty apparatus. The visual observations regarding the effectiveness of cleaning and the analytical results of the rinse samples may facilitate the development of a prospective cleaning method for plant equipment during scale-up.

Stability data. Short-term stability data of the critical raw materials and intermediates should be generated in R&D under conditions similar to those in the plant. On the basis of these data, packaging and storage conditions for critical raw materials and intermediates can be established.

“Freezing” of specifications. As processes are fully developed and optimized, specifications of the in-process controls, intermediates, API, and the packaging materials can be “frozen.” That is, no change in the process should be allowed without change control assessment and approval.

Working standards. A working standard is a sample of highest purity that can be synthesized in R&D and purified to the maximum extent by repetitive crystallization or column chromatography. It then can be qualified by comparison with a suitable
reference standard such as a pharmacopeial reference standard. In the absence of such a reference standard, one should generate sufficient analytical data to support the structure of the working standard.

Stability. A representative sample of the R&D batch obtained by a “frozen” procedure should be kept for the stability studies. Therefore, early indications on the stability profile of future scale-up batches can be obtained, provided the same process is followed.

Other important challenges. In recent years, API process development has become more challenging because of the need for making APIs with a desired enantiomeric purity and a desired polymorphic form. The following examples justify the need for
the stringent regulatory requirements in these areas.

Enantioselective synthesis. More than half of the drugs used in clinical medicine are chiral compounds (4). Yet, the majority of these drugs are still prescribed as racemates. There is a need to make enantiomerically pure APIs when one enantiomer does not contribute to efficacy but may contribute to toxicity. Some interesting examples of isomers with various activities are shown in  (5).

The data  indicate a need for enantioselective synthesis in many racemic APIs. In such cases, one must validate the process carefully to ensure the formation of only the desired isomer. The other isomers should be considered impurities. In addition, it must be ensured that there is no chiral inversion during formulation, storage, or in the human body to avoid adverse side effects.

Synthesis of the desired polymorph. Polymorphism is the ability of a substance to exist in two or more crystalline phases that have different arrangements and/or conformations of molecules in a crystal lattice.Many APIs exist in several polymorphic forms with various properties such as crystallinity, bulk density, solubility, and bioavailability. Two interesting cases of product recalls that were a result of drug polymorphism follow (6).

Abbot Laboratories had to withdraw its HIV protease inhibitory drug Norvir (Ritonavir) from the market because an unwanted polymorph of the drug was produced (Form II) during shelf life. This form has a different dissolution rate to the known polymorph (Form I), thereby affecting the drug’s bioavailability.

Chloramphenicol-3-palmitate of Form B is a metastable form having eightfold higher bioavailability than the other polymorph, Form A, thereby creating a danger of fatal dosages when the unwanted polymorph is unwittingly administered as a result of alterations in process and storage conditions.

These examples demonstrate the need to identify all polymorphs of an API at the R&D stage. One can establish the polymorphs by determining physicochemical properties, by conducting thermodynamic stabilities, and by studying conditions of interconversions. Useful tools for such determinations include Fourier transform infrared spectroscopy, X-ray powder diffraction, and differential scanning calorimetry. The formation of a specific polymorph can depend on the type and composition of the solvents, temperature, synthetic route, storage conditions, and so forth. An interesting example of solvent composition giving various polymorphs is cholamide (7),which exhibits needle-like crystals (Form I) by recrystallization from a solution of 1:1 acetonitrile:water and platelet-like crystals (Form II) by recrystallization from a solution of 25:1 acetonitrile:water.

Once the desired polymorph has been identified, the process must be validated to obtain the desired polymorph consistently. Further, the stability protocol of the formulated drug must include some suitable tests to ensure that there is no change in the polymorphic form under these conditions.

Conclusion
The various process considerations described in this article can help chemists understand and adopt a systematic and prospective approach in research and development to have documented and controlled synthetic processes. This approach will help manufacturers meet product-quality objectives consistently and build a good basis for achieving the goals of prospective validation and scale-up activities.

References

1. Impurities: Guidelines for Residual Solvents, Q3C, recommended by ICH on July 17, 1997.
2. Process Chemistry in the Pharmaceutical Industry, K.G. Gadamasetti, Ed. (Marcell Dekker, Inc., New York, NY, 1999), p. 389.
3. Internet databases such as Cole-Palmer Chemical compatibility database, ARO chemical compatibility, eFunda O ring material compatibility with chemicals, Varidisk chemical compatibility information, Flowline Chemical compatibility database and DMRTM fluid compatibility table by Daemar Inc.
4. Physician’s Desk Reference (Thomson PDR,Montvale, NJ, 1997).
5. S. Ahuja, Chiral Separations: Applications and Technology (ACS Publications,Washington, DC, 1996), p. 4.
6. G. Chawla and A. Bansal, “Challenges in Polymorphism of Pharmaceuticals,” Scrip 5(1), 9 (Jan.–Mar. 2004).
7. N. Yoswathananont et al., “A Novel Three-Component Pseudo-Polymorphism in the Cholamide Inclusion Crystals Promoted by the Combination of Organic Guest and Water,” Chem. Lett. 12, 1234 (2002).
8.