API Manufacturing

NPI-0052 is currently manufactured under cGMP through a robust saline fermentation process by S. tropica strain NPS21184. It was quite an effort to find the proper contract manufacturing organisations (CMOs) that would accept and adapt our saline fermentation process, developed in laboratory fermenters, to their industrial-scale production fermenters and also have the proper containment facility to handle the downstream processing (DSP) of the highly potent NPI-0052. 

Despite our development of protocols to minimise the corrosive effect of saline media on laboratory stainless steel fermenters and processing equipment on a relatively small scale, saline fermentation was not a common, acceptable practice in a large scale production process and the corrosiveness of saline media on seed and production fermenters and processing equipment remained the major concern of many CMOs. Nonetheless, we identified several CMOs that accepted our manufacturing proposal and selected two for the large-scale production of NPI-0052. 

The final process fermentation development standardised parameters such as temperature exposure, operating parameters, cleaning and passivation to overcome the corrosive effect of saline fermentation and was performed in 500-1500 L industrial-scale stainless steel fermenters. This, together with careful design of the timing and method for introducing the resin to the production fermenter, resulted in production titres of 250-300 mg/L in 500-1500 L industrial fermenters. 

This highly purified substance may contain up to 3% of a diastereomeric impurity. By using an evaporative crystallisation process that exploits subtle solubility differences between the parent compound and the diastereomer, this impurity level is reduced to 1 % and the API is isolated as a white crystalline solid. The final pharmaceutical grade cGMP drug substance is obtained in 98% purity with overall 50% recovery from the crude extract. 

Based on the potency of NPI-0052, the production titre is adequate for both clinical development and commercial production. To our knowledge, this represents the first manufacture of clinical trial materials by saline fermentation. 

---

This recommendation is applicable for most conditions encountered in the use of this type mast. There will be exceptions where location clearance, ground conditions, or other unusual circumstances require special considerations. Figure 4-5 shows a recommended guying pattern that may be used under general conditions in the absence of an authorized API manufacturer s recommendations. Guy lines should be maintained in good condition, free from rust, corrosion, frays, and kinks. Old sand line is not recommended for guy lines. 

Type of manufacturing Application of ICH GMP guide to indicated steps (shown in grey) of API manufacturing ... 

Figure 11.1 Applicability of GMP requirements to API manufacture (from ICH Q7 guideline).

Figure 11.5 Headings of ICH CMP guideline for Active Pharmaceutical Ingredients (API) manufacture.

Specific Guidance for APis Manufactured by Cell Culture/Fermentation... 

As discussed in Sections 14.2 and 14.3, a critical difference between batch and continuous processes lies in equipment utilization. The complexity (or simplicity) of synthesis and isolation is a critical factor in determining whether a whole process is viable for switching from B2C. Given that it takes an average of eight synthetic steps to produce an API from raw materials [51], it is clear that the average API manufacturing process is probably too complex in its current form. Reduction in the number of process steps for a continuous process will, to a first approximation, reduce the plant costs pro rata. 

The pharmaceutical industry produces between 25 and 100 kg or more of waste for every kilogram of active pharmaceutical ingredient (API) manufactured.1 According to a leading practitioner of the industry, the potential waste coproduced with APIs is in the range of 500 million to 2 billion kg per year. Even at a nominal disposal cost of 1 per kg, the potential savings just in waste avoidance is significant faced to the pharmaceutical industry annual sales (almost 500 billion in 2003). 2... 

Specific Guidance for APIs Manufactured by Cell Culture/ Fermentation General... 

In API manufacture, whether via chemical synthesis, rDNA technology, or extraction from natural products, there are significant changes (physical and chemical) from the starting materials to the API. In the formulation process, however, the quality and specifications of the API are retained. The addition of excipients to produce the drug product in a finished dosage form does not present physical or chemical changes to the API. 

The finished product is centrifuged and purified via a number of processes, including filtration, fractional distillation, condensation, crystallization, and chromatographic separation techniques. The purified API is tested and then it is ready to be formulated into the finished dosage form, as discussed in Section 10.6. Exhibit 10.5 illustrates some of the typical reagents for API manufacture and Exhibit 10.6 presents selected chemical reactions as examples of the... 

Exhibit 10.6 Selected Chemical Reactions as Examples for API Manufacture... 

Given the large capital investment required for specialist equipment, the fermentation needs to display considerable production cost benefits over the chemical process to be considered seriously as a route to API manufacture. 

The manufacturing of the API is in principle a synthesis of fine chemicals with high quality requirements for the final product and a tight external regulatory framework. In API manufacturing, the process steps, physical and chemical characteristics of the sample and equipment are very similar to the chemical industries ... 

Unlike most of the rest of the chemical industry, continuous processing is a relatively new concept in API manufacture. It is therefore necessary to understand where the industry has come from in terms of manufacturing methods before considering the factors necessary for change. 

DMFs are generic dossiers filed with the FDA in order to allow the API to appear in marketed drugs. Thus an API manufacturer files just one application for a product, which can then be used to support approval of any generic based on that API. 

The same concentration of 3 and 4 in toluene yielded similar results to those obtained for DMF solutions (Table 2). Therefore, this study illustrates two important concepts (1) whether in polar or nonpolar solvent Deloxan THP II and MP are capable of removing Pd and (2) regardless of oxidation state of Pd, even if Pd(0) and Pd(II) species are present in the same process solution, Deloxan THP II and MP are effective at removing Pd to levels well within the regulation limits for API manufacture. 

Agents, brokers, traders, distributors, repackers, and relabelers Specific guidance for APIs manufactured by cell culture/fermentation APIs for use in clinical trials Glossary... 

The basic structure of the ICH GMP guideline for API production is shown in Table 15. It consists of 19 chapters, which cover the requirements for quahty management, personnel, premises, equipment, documentation, materials, production and process controls, packaging and labeling, storage and distribution, laboratory controls, validation, change control, complaints, recalls, contract services, cooperators, APIs manufactured by cell culture/fermentation, and APIs used in clinical trials [52]. 

Creen Chemistry Considerations in Peptide-like API Manufacture 1181... 

In the following section, taking diabetic drug candidates 1 and 2 [8, 9] as case studies (Figure 9.3), the purification and chirality control issues of peptide-hke API manufacturing are considered from a Green Chemistry perspective. 

---