The cost of designing and constructing a manufacturing facility to produce a bulk biological active ingredient for a biotechnology-derived pharmaceutical product is becoming increasingly expensive in today’s biotech industry. This initial capital expense, along with the annual costs required to operate such a facility in a validated state of control, are placing significant financial burdens on manufacturers. This high cost of manufacturing the bulk biological active ingredient for a biotech product is, in turn, increasing prices of such products that the public and insurance companies must shoulder. Why is the cost of manufacturing a bulk biological active ingredient for drug products higher today than in the past? Have the Current Good Manufacturing Practice (cGMP) regulations changed so much as to be creating added cost to the industry’s manufacturers? Or are manufacturing facilities being over designed in order to meet perceived cGMP requirements? Is it possible that the problem is simply due to the need to control contamination risks during the manufacturing of the bulk biological active ingredients that past drug manufacturers did not have to face?

The Cost of Product Control

The manufacturers of biotechnology-derived pharmaceuticals face the critical challenge of producing products free from the presence of foreign microbial and pyrogen contamination. Throughout the entire manufacturing processes that yield the final sterile product forms, it is equally important that the bulk biological active ingredients going into these products do not lose their intended effectiveness. If biological activity of the active ingredient is diminished in order to achieve a final product free of foreign microbial and pyrogen contamination, then the product will no longer be effective in treating the targeted indications.

With this challenge facing the manufacturer, a different manufacturing methodology for such biologically active materials must exist. Past acceptable methods employed for the manufacturing of bulk active chemical ingredients for drugs may no longer be appropriate for biologically active products. A tighter level of operational and facility control over the processes producing bulk biological active ingredients must be established during manufacturing in order to assure the absence of microbial and pyrogenic activity in the final product. This again, must be achieved without negatively impacting the active ingredient’s effectiveness in the final product.

This article will explore the basis for achieving this manufacturing control. Other questions pertaining to the concepts of sterile products and aseptic processing will be examined alongside the principles of clean manufacturing. How can such tight control be put in place for bulk biological active ingredients without creating such a financial burden that the final product would be rendered unaffordable to much of the patient population? Has the industry’s understanding or interpretation of Current Good Manufacturing Practice (cGMP) created an added layer of complexity and manufacturing cost that is not necessary? With such high costs associated with the production of the bulk biological active ingredients today, how can small biotechnology companies survive the financial drain on capital resources in order to get their initial products through clinical trials and launched commercially?

A Look Back

If we look back into the history of modern-day pharmaceutical manufacturing, it is reasonable to recognize the passing of the Federal Food, Drug and Cosmetic (FD&C) Act in 1938 as the beginning of this era. By the passing of this law, drug manufacturers were required to produce a final product form, unadulterated, and of a known strength, as previously purported. This included the manufacture of the active ingredient as well. A more standardized understanding of this requirement was better established within the industry by the finalization of 21 Code of Federal Regulations (CFR), Parts 210 & 211 in the latter part of the 1970’s.

For much of the 20th century, the majority of all pharmaceuticals consisted of chemical compounds isolated from natural sources, or compounds chemically synthesized and/or modified during manufacturing. A great deal of these products were manufactured on a large scale from predominantly solvent-based processes and marketed to a mass patient population. Therefore, the manufacturing operations producing the bulk active ingredients for these products was typical of many other non-pharmaceutical chemical processes at the time. Most manufacturing facilities of both types were very similar in design. Biologics on the other hand consisted primarily of vaccines and blood products and their derivatives. The manufacture of such biological products was not performed on the grand scale as their drug counterparts at that time. Because of this, microbial and pyrogen contamination prevention of these biologics was controllable for the most part on a smaller scale without a significant financial impact to the final product form.

As the 20th century neared its end, the application of biotechnology in the pharmaceutical industry had emerged on the scene. No longer would the family of biologically active pharmaceutical products be limited to the narrow list of products of years past, but rather a much more extensive list of products emerged rivaling that of current drug products. With the birth of such technology for developing new biologically active pharmaceutical products, the manufacturing of such products also began migrating to the same large scale of production as current drug products.

Rather than the production of the active ingredient resulting from a solvent-based process, new bulk biological active ingredients were produced in an aqueous medium. Large scale manufacturing can now no longer capitalize on the built-in natural contamination protection characteristics of chemical processes. The survival of foreign microbials and their toxic by products in the bulk active ingredient product stream was significantly reduced due to the harsh environments generated by the chemical reactions and solvents used in the past. New biotechnology-derived active ingredients are now typically protein and cellular based. These ingredients are intended to survive the entire manufacturing process without losing their biological activity, despite existing in a medium ideal for advantageous microbial contaminants to thrive. The manufacturers of these new forms of pharmaceuticals have quickly realized that past methodologies of manufacture will no longer suffice.

Today’s Challenge

Although some slight changes have occurred to the cGMP regulations over the last decades, they for the most part, still exist as they were written back in the 1970’s (21 Code of Federal Regulations, Parts 210 & 211). The manufacturers of new biological products find themselves manufacturing large complex active molecules which are very susceptible to foreign microbial contamination and stable only within narrow environmental conditions. They seek to find effective methodologies and standards of manufacturing that will safely produce a sterile ingredient, while also not driving up operational costs to an all time industry high. What specifically should manufacturers do in order to establish the tight contamination control of their products fulfilling cGMP requirements as they understand the regulations?

Aseptic Processing of Sterile Products

Prior to the biotechnology age of pharmaceuticals, drug manufacturers established the means of producing sterile injectable forms of their final drug products effectively. Before reaching final formulation of both active and inactive ingredients, drug manufacturers would pursue various methods of sterilization of packaging components, product ingredients, and equipment in order to bring the sterile product together in its final form, all within a sterile environment. Such final steps of manufacturing were called “sterile finish fill,” carried out under aseptic processing, and allowed for the manufacture of a final sterile drug product form to be made from non-sterile components and materials.

Aseptic processing is today, as it was in the past, a highly critical manufacturing methodology necessary to assure the safety of the population using the product. Its critical nature is also regulated within the European Union of Member States by the European Commission’s adoption of Directive 91/356/EEC, which laid down the principles of Good Manufacturing Practice (GMP) for medical products for human use. Annex 1 of Volume 4 - Good Manufacturing Practices (1998 edition) is titled “Manufacture of Sterile Medicinal Products,” and describes the special requirements necessary for the aseptic processing of sterile products.

In the United States, a draft guidance document is currently under review, prepared by the Center for Drug Evaluation and Research (CDER), the Center for Biologic Evaluation and Research (CBER), and the Office of Regulatory Affairs (ORA); it is titled “Sterile Drug Products Produced by Aseptic Processing.” This document addresses the differences between the production of sterile drug products by aseptic processing and by terminal sterilization. Again, in order to assure sterility of drugs and address the complexities of aseptic processing of such products, it is necessary for regulatory authorities to have a clear requirement for the industry regarding standardized practices. Therefore, such documents are beneficial for both parties to assure safety to the public.

The Expanded Application of Aseptic Processing

Do these documents detailing the requirements of aseptic processing either in the form of guidance documents or actual cGMP regulations, apply to the manufacture of bulk biological active ingredients? Are the methods of aseptic processing as described in such cGMP regulations and guidelines to be fully followed for the large scale manufacture of modern day bulk biological active ingredients? In order to answer these questions, it is important to fully understand the principles upon which aseptic processing is based upon.

Aseptic processing is a means of handling components, materials, and equipment in such a manner that foreign microbials and endotoxins (a pyrogenic product of microbial physiology) that exceed pre-determined acceptable levels are not introduced to the product stream. On one hand, aseptic processing may assure a level of sterility of handled sterile components, materials, and equipment. On the other hand, it may assure an acceptable level of exposure to foreign microbials and endotoxins in handled non-sterile components, materials, and equipment. Aseptic processing does not mean sterile in all circumstances; it is a controlled state of microbial exposure to the product being produced at any step of that product’s overall manufacture.

In order for a manufacturer of a sterile drug product to incorporate aseptic processing into the overall manufacturing of the product, aseptic processing can be applied for the most part at the final finish fill steps. The necessity for incorporating aseptic processing at the levels of operational and facility control during the manufacturing of the bulk active chemical ingredient, is not typically necessary for the reason discussed earlier: the typical harshness of a chemical process. Therefore, the added manufacturing cost of such sterile drug products is minimized by limiting the application of aseptic processing to the final steps of the overall manufacturing operation. This form of aseptic processing would assure a level of sterility of handled sterile components, materials, and equipment during manufacture.

A producer of a sterile biotechnology-derived pharmaceutical products must not only incorporate aseptic processing during the final finish fill steps as the drug manufacturing counterparts do, but must also provide added levels of operational and facility control to the manufacturing of the bulk biological active ingredient. This produces an acceptable level of product stream exposure to foreign microbials and endotoxins in handled non-sterile components, materials, and equipment during manufacture, but can result in a tremendous additional manufacturing cost to the final sterile product form. How can such an impact be economically managed?

Basis for Compliance

Imposing aseptic processing principles during the bulk biological active ingredient’s manufacture must be driven separately from an effort to comply with cGMP regulations for sterile products because the methods described in the European Union’s GMP regulations, Annex 1, “Manufacturing of Sterile Medicinal Products,” and the various guidance documents developed in the United States and abroad, were developed for sterile finish fill operational steps for sterile products. Scaling up such methods referenced in these documents to a large enough scale to accommodate the level of manufacturing necessary for many of today’s bulk biological active ingredients is not a practical approach from an economical perspective. The operational costs of facility features, and added labor activities to support these methods of aseptic processing during large-scale bulk production can cripple some companies, especially small start-up ventures with limited resources.

21 CFR Section 211.42(c)(10) defines the requirements for aseptic processing as follows:

(i) Floors, walls, and ceilings of smooth, hard surfaces that are easily cleanable;

(ii) Temperature and humidity controls;

(iii) An air supply filtered through high-efficiency particulate air filters under positive pressure, regardless of whether flow is laminar or nonlaminar;

(iv) A system for monitoring environmental conditions;

(v) A system for cleaning and disinfecting the room and equipment used to produce aseptic conditions;

(vi) A system for maintaining any equipment used to control the aseptic conditions.

Nowhere do these U.S. cGMP regulations dictate the criteria defining “aseptic,” but rather only specify those general aspects of the aseptic condition which require control. Therefore, it is up to the manufacturer to determine what is appropriate for assuring that the bulk biological active ingredient will not contribute a level of contamination to the final sterile product form that would render it nonsterile and/or pyrogenic.

As stated above, aseptic processing is a means of handling components, materials, and equipment in such a manner that foreign microbials and pyrogens are not introduced exceeding pre-determined acceptable levels that subsequent manufacturing steps could not reliably remove. This acceptable level must be defined for the final bulk active biological ingredient and once this has been established, then the appropriate means of producing and controlling that aseptic condition during the manufacture of the bulk ingredient prior to these last steps can be developed. Such a manufacturing control rationale is therefore based on methods independent of those commonly used for sterile finish fill operations.

The Concept of Clean Manufacturing

Clean manufacturing differs from aseptic processing in that the methodologies of manufacturing control are based upon the specific process characteristics producing the bulk active product. Each ingredient will be manufactured to some extent by a unique process. What methods a manufacturer chooses to utilize in order to assure sterility in the final bulk active product cannot be determined by cGMP regulations or guidelines, but rather is the responsibility of the manufacturer to define and implement. The basis of compliance with cGMP is to establish a methodology of manufacturing control driven by specific process requirements and documenting evidence that demonstrates regular operational control of those acceptable levels of environmental exposure leading to the final bulk biological active ingredient. Once established, clean manufacturing becomes a principle which all manufacturers of biotechnology-derived products can rely on to assure safety of their sterile final products, while also minimizing the overall financial impact of the cost of manufacturing the product.

Control of Manufacturing Costs

Manufacturing facilities housing final sterile formulation and filling processing steps for parenteral products that are designed to accommodate the sterile control methodologies of aseptic processing cost on the order of $700 - $900 per square foot. While this cost per square foot represents a high dollar value, sterile formulation and filling facilities—being on the order of 15,000 to 25,000 sq ft— are typically not as large as bulk production facilities. Therefore, the overall cost of the facility is manageable. On the other hand, the design of large bulk production facilities that can accommodate the manufacture of today’s bulk biological active ingredients are commonly on the order of 80,000 to 200,000 sq ft. Therefore, if the same aseptic control methodologies are designed into these large facilities that are found in sterile filling facilities, total costs on the order of $60 million to $170 million can result. In some circumstances, several large production facilities are required in order to produce the final bulk sterile active ingredient due to the need for large-scale cell culture or fermentation manufacturing, along with downstream isolation and purification steps of the process. These multi-building facilities can cost up to $700 - $800 million to design and construct.

It is clear to see that the cost of such facilities designed to accommodate aseptic processing as found in the manufacture of sterile final product forms is exceptionally high. Such high initial capital expenditures and operating costs drives the price of the final sterile biologic product form significantly high. Therefore, in order to manage the production costs of new mass marketed biotechnology-derived products, manufacturers must establish control of their bulk operations based on the principle of “clean manufacturing,” rather than aseptic processing common to sterile manufacturing operations.