Process Selection and Control

Process Selection and Control

The production of sterile products is profoundly impacted both by formulation and the selection of primary packaging components. Design parameters for a facility and selection of appropriate manufacturing technologies for the product require that the formulation process and packaging components be chosen and evaluated in advance.

  1. Formulation and Compounding
  2. Primary Packaging
  3. Process Objectives

Formulation and Compounding
The vast majority of parenteral formulations are solutions requiring a variety of tankage, piping, and ancillary equipment for liquid mixing (or powder blending), filtration, transfer, and related activities. Suspensions, ointments, and other similar products, including the preparation of the solutions for lyophilized products, can be manufactured in the same or very similar equipment. The scale of manufacturing can vary substantially, with the largest batches being well in excess of 5000 L (typically for large-volume parenteral production), down to less than 50 mL for radiopharmaceuticals or biologicals customized for a particular patient.
The majority of this equipment is composed of 300 series austenitic stainless steel, with tantalum or glass-lined vessels employed for the preparation of formulations sensitive to iron and other metal ions. The vessels can be equipped with external jackets for heating and/or cooling and various types of agitators, depending upon the mixing requirements of the individual formulation. In many facilities, a variety of tank sizes are available for use. Larger facilities may have high-capacity tanks permanently installed and permanently connected to process utilities. Smaller vessels are generally mobile and positioned in individual processing booths or rooms as needed.

After sterilizing filtration (or sterilization by heat or other means), comparably sized vessels are sometimes utilized to contain the product prior to and during the filling process. These holding vessels are often steam sterilized along with the connecting piping prior to use. There are a number of firms that fill directly from the compounding vessel using in-line filtration eliminating the intermediate vessel. When this approach is used, a small moist – heat-sterilized surge tank or reservoir tank may be required, particularly with modern time–pressure filling systems. This practice may reduce initial facility and equipment costs but places additional constraints on operational flexibility. The use of disposable equipment for compounding and holding sterile formulations is coming into greater use. This eliminates the cleaning of vessels prior to reuse, but confirmation of material compatibility is required.
Disposable equipment is often used with products manufactured in small to moderate volumes, and while reducing initial equipment expenses disposable equipment also results in contaminated waste, which cannot be recycled or reused and must be treated appropriately.

Aseptic compounding as required for suspensions and other formulations in which open-vessel processes are required mandate an ISO 5 environment providing ideally > 400 air changes/hour in which these steps can be performed with minimal opportunity for adventitious contamination. This could be accomplished using a protective curtain and a unidirectional flow hood (UFH) or other more evolved
designs such as a restricted access barrier (RABs) system or an isolator (technologies that provide a higher level of employee separation from the area in which materials are handled can get by with lower air exchange rates). All activities requiring the opening of processing lines such as sampling or filter integrity testing should be performed using similar protective measures. The preparation of sterile suspensions requires a facility/equipment design capable of the safe addition of sterile solids to a liquid vehicle and is conventionally performed using a specifically designed processing area to minimize contamination potential. Comparable and greater complexity
is generally required for creams, ointments, emulsions, and the increasingly common liposome formulations.

Some sterile powder formulations (these are predominantly, but not exclusively, antibiotics) may require sampling, mixing, milling, and subdivision activities similar to those found in oral powder manufacturing. The facilities and equipment utilized for these products is substantially different from that used for liquids, and the production area bears little resemblance to that utilized for liquids. These materials are received sterile and must be processed through sterilized equipment specifically intended for powder handling in a fully aseptic environment with ISO 5 protection overall open container activities.

Primary Packaging

The primary package for parenteral formulations provides protection to the sterile materials throughout the shelf life. The components of the primary package are every bit as important to contamination control and hence safety of the finished product as the formulation itself, and their preparation must be given a comparable level of consideration. The most commonly used container is glass; vials are still the
most common, although increasingly prefilled syringes are chosen. Glass ampoules are still seen. However, although convenient from a manufacturing perspective, the difficulty involved in opening ampoules while at the same time avoiding problems with glass particulate or microbial contamination has reduced their popularity. The use of plastic containers (as vials, ampoules, or syringes) is increasingly common given their reduced weight and resistance to breakage. Blow-fill seals (BFS) and form-fill seals (FFS) are utilized for the filling of numerous ophthalmic and other noninjectable formulations in predominantly low-density polyethylene (LDPE) containers. With the exception of ampoules and BFS/FFS, an elastomeric closure system is also necessary to seal the containers. Some delivery systems (i.e., prefilled syringes, multi-chamber vials, and others may require more than one elastomeric component to operate properly. In the case of vials, an aluminum crimp is applied to secure the closure of the vial. Prefilled syringes may require the preparation and assembly of additional components such as needles, needle guards, stoppers, dia phragmites, or plungers, depending on the specifics of the design. Lyophilization is required to ensure the stability of some formulations and requires the use of closures that allow venting of the container during the freeze-drying process. Full seating of the closure is accomplished within the lyophilizer using moving shelves to seat the closure. 

Glass is ordinarily washed prior to sterilization/depyrogenation to reduce contamination with foreign material prior to filling. In aseptic fill processes, the glass is then depyrogenated using dry heat. This can be accomplished using either a continuous ous tunnel (common for larger volumes and high-speed lines) or a dry heat oven (predominantly for small batches). The depyrogenation process serves to sterilize
the glass at the same time, and thus the glass components must be protected post-processing. This is generally accomplished by short-term storage in an ISO 5 environment often accompanied by covering within a lidded tray. There are suppliers that offer depyrogenated glass vials and partially assembled syringes in sealed packages for filling at a customer’s site. In this instance, the supplier assumes responsibility for the preparation, depyrogenation, and aseptic packaging. Glass ampoules are available pre-sealed and depyrogenated; the end-user has merely to open, fi ll, and reseal the syringe under appropriate conditions.

Plastic components (whether container or closure) can be sterilized using steam, ethylene oxide, hydrogen peroxide, or ionizing radiation. The γ irradiation is accomplished off-site by a subcontractor with appropriate expertise as these methods are considered the province of specialists because of the extreme health hazards directly related to the sterilization method. Electron beam sterilization may also be done
by a contractor, although compact lower energy electron beam systems have been introduced that allow sterilization in-house. Steam sterilization is ordinarily performed in-house, though many common components are becoming available pre-sterilized by the supplier. Preparation steps prior to sterilization vary with the component and the methods used to produce the component. Rubber components
are washed to reduce particles, while this is less common with plastic materials.

Syringes vary substantially in design details and can be aseptically assembled from individual components. However, increasingly, these are supplied as pre-sterilized partial assemblies in sealed containers.
The BFS and FFS are unique systems in that the final container is formed as a sterile container just prior to the aseptic filling step. The BFS requires careful control over the endotoxin content of the LDPE (and other polymeric materials) beads used to create the containers as well as the melting conditions utilized to form them.

The FFS utilizes in-line sterilization/drying of the film prior to the shaping of the containers.

Process Objectives

The production of parenteral products requires near-absolute control over the microorganisms. Endotoxin contamination is a serious health concern, particularly among neonates and infants, and also requires a high level of control and validation. Additionally, the control of foreign matter, including particles and fibers of various types, is also vitally important to end-user safety. Assuring appropriate control over these potential contaminants requires careful attention to several factors: facility design, equipment selection, sterilization procedures, cleaning regimens, management of personnel, and the process details associated with compounding, filling, and sealing
of product containers. Each of these will be discussed in detail.