DEVELOPING THE PRELIMINARY SCOPE

A preliminary scope of the new process should be developed in parallel with process chemistry and engineering development and early piloting for the new API. The scope should include a definition of the process, preliminary process flow diagrams (PFDs) and piping and instrumentation diagrams (P&IDs), equipment specifications and requirements (vessel types and sizes), preliminary facility fit, permitting requirements (local building and environmental), and any regulatory (cGMP) requirements. The producer’s process-engineering group will have to determine the best process fit to ensure speed to mar-ket, cost-effective manufacturing, compliance with safety and environmental requirements, and GMP compliance.

An analysis of alternatives is desirable once enough pro-cess definition is developed. Propro-cess siting and development decisions should be based on scientific, business, and regula-tory analysis. Questions the producer should consider in the preliminary scoping exercise include:

Should the facility be multiuse (Fig. 1) (campaigning) or dedicated?

Can the API be manufactured in an existing facility (retrofit) or will it require a new facility?

Will the new=retrofitted facility be cGMP compliant?

What are the safety and environmental concerns of the new compound?

Utilities:

– What is the status of process water and building utility systems?

– Do existing assets have the utility capacity(s) for expansion?

Schedule and cost: What is the best approach to sup-port a product launch?

A. Campaign vs. Dedicated

Many of the newer compounds developed for market are of a higher potency, reducing the need for large (greater than 1 million kilograms annually) volumes of the API. A dedicated process may be the easiest approach to design and construct, but may not be the most cost effective or strategic. A dedi-cated process is ideal for a one-product organization or high-volume product. It may be easier to manage, with unchanging processing parameters. Varying market product demand can impact usage of the facility and the cost of operations.

A campaign style facility will allow the manufac-turer to better utilize assets, integrating different product Figure 1 Typical vertical processing facility designed for batch production with barrier separation between processing steps.

manufacturing using similar equipment configurations. The producer has different options available for product volumes and production time. The campaigning facility will have differ-ent processing capabilities (Fig. 2) through various manifolds or hard piped equipment configurations (equipment trains). These configurations can be manipulated for different processes. This provides the manufacturer with the flexibility to vary produc-tion sequencing to produce several products vs. one.

Good manufacturing practice (GMP) considerations must be reviewed carefully with a multiuse facility. Good manufac-turing practices controls are applied with the use of API starting materials. The controls increase as process proceeds to final isolation and purification. The producer will

Figure 2 Typical specific ventilation system designed to protect operators during the care of vessels with cytotopic-high potency compounds.

be required to ensure GMP integrity for the new or renovated facility. Some of the considerations include proper product isolation (barrier separation), cleaning systems for multiproduct equipment (CIP—clean in place) and pharmaceutical grade water systems (for isolation and purification).

B. New vs. Retrofit

The API manufacturer will be required to decide whether a new facility will be required or an existing facility can be retrofitted. Questions that the manufacturer should ask include:

What existing assets are available in the manufac-turer’s portfolio?

Can these assets be modified to process the new product?

What are the costs associated with the renovations?

How do they compare to a new facility(s)?

What renovations are required to qualify the process or facility?

A careful cGMP review will be necessary as part of ana-lyzing an existing facility for a new product fit. The current guide for GMP guidance for API facilities is the International Conference on Harmonization (ICH) of Technical Require-ments for Registration of Pharmaceuticals for Human Use guide Q7A—referred to as ICH Q7A (1).

Facilities currently manufacturing fine chemicals may not meet the standards outlined in ICH Q7A and not hold up under the scrutiny of a regulatory inspection. Major renovations may be required retrofitting an existing facility(s) to assure GMP compliance. The manufacturer can be required to install new systems such as CIP and pharmaceutical grade process water. In product isolation=purification and finishing facilities, the manufacturer will have to insure product separation in multiproduct suites, through physical barriers such as walls, and also through differential room pressuriza-tion with minimum room air exchanges.

Understanding the requirements of a GMP facility is critical to developing an accurate cost and schedule model for the new product. A process fit that appears simple for a fine chemical could require substantial renovations for an API.

C. Equipment and Facility GMP Compliance

Good manufacturing practice regulations affect the architec-tural and building engineering components of the building along with equipment and systems. The building must be cap-able of providing items such as adequate lighting, proper waste water management, validated process water, product separation areas (warehousing), and heating ventilation air conditioning (HVAC) and room separations for final step (iso-lation=purification) processing. The facility should have the appearance of a pharmaceutical facility. The processing areas should be clean and free of debris. ‘‘Cleanability’’ is critical for all processing equipment involved in ‘‘critical step’’ and post-critical step manufacturing.

D. Safety and Environmental Concerns

Many of the new APIs are designed with a higher potency (cytotoxic) than previous generations. The stronger potencies require the designer to integrate materials handling and HVAC systems that protect the operators from exposure to the product. Specific ventilation systems are incorporated to protect personnel while charging and operating vessels (Fig. 2). The facilities are designed to contain all materials within the confines of the facility. Similar to sterile processing, there will be air locks separating the different rooms (Fig. 3).

High potency facilities will normally have separate com-partments for gowning=dressing and entering, proces-sing=manufacturing, and decontamination=degowning. The HVAC system will be dedicated for the facility. Wastewater will be discharged to a holding tank for testing prior to dispo-sal. The concept for the facility is total containment.

Process wastes will be managed similar to any organic fine chemical operation. The producer must separate and contain all waste materials not suitable for wastewater treatment.

IV. UTILITIES AND BUILDING SYSTEMS