Complex Aseptic Manufacturing Outsourcing

Tips and tactics for optimizing your CMO partnership

By Carlos R. Fernandez and Douglas A. Jonas

Aseptic manufacturing processes are highly complex and require significant front-end investment in terms of technical expertise, capital equipment, facilities, process technology and quality control. The technology and equipment needed for aseptic processing carries both a hefty price tag and significant depreciation risk. Market uncertainty makes it difficult to accurately predict commercial volume, adding greater risk to the equation.

All photos courtesy of Pfizer CentreSource (PCS)

Against this backdrop, capital investment in aseptic manufacturing is increasingly perceived as a high-risk gamble that fewer and fewer pharmaceutical companies are willing to take.

The practice of outsourcing complex aseptic manufacturing, however, is growing. Market data suggests that outsourcing aseptic manufacturing processes is increasingly seen as an efficient, effective and value-added alternative to in-house production, and points toward this trend continuing. According to market intelligence firm PharmSource, the market for contract manufacturing of bulk and dosage form prescription drugs, estimated at $30 billion today, is expected to grow to $35.6 billion by 2012.

The best way for a sponsor to realize that added value is by tailoring its contract manufacturing organization (CMO) selection to result in a complementary and mutually beneficial CMO partnership. A true CMO partner leverages capabilities, optimizes process efficiency and assures successful delivery on your project requirements and provides the assurance of secure commercial product supply.

The decision process for selecting a CMO to manufacture your important product has never been more critical. Your selection criteria are equally critical, and must encompass the entire CMO value proposition, including delivery, quality and cost.

Delivery

The global economic downturn and recent global supply chain events highlight the importance of consistently excellent supply performance and the financial security and stability of well-managed, diversified organizations. The decision to trust a CMO for delivery of your important product, according to your timeline, will eventually be of extreme importance from your customers’ perspective as well as your own. You expect the product you want, when you want it, and your CMO must deliver every time. The CMO should be able to demonstrate the capacity and robust business systems — e.g., raw material supply, production planning, etc. — to provide reliable supply for the customer, both in terms of quantity of material and timing of deliveries.Does the supplier have the available capacity for your aseptic manufacturing requirements for the foreseeable future? Are its planning, execution, logistics, and customer service performance, infrastructure and procedures adequate to guarantee your supply requirements on a regional, national, or global basis?

Quality

Pharmaceutical manufacturers are under constant pressure to deliver quality and maintain compliance. International compliance standards, however, are continually evolving, as are industry trends in technology and supply chains. In this environment, a manufacturing organization benefits from critical mass in terms of its ability to stay on top of evolving standards, harmonizing global guidance such as ICH Q8-Q9-Q10, and regulatory submission requirements across all global markets.

Pressing down on the plastic activator of Pfizer’s Act-O-Vial system to displace the center stopper forces the diluent into the lower compartment – a convenient delivery option for otherwise unstable injectable formulations.

Cost

Product cost is an essential element of the total value proposition that a potential CMO must provide; business forces increasingly drive significant pressure on product costs and pricing, even for the highest margin blockbuster pharmaceutical product. Front-end project costs, enabling capital equipment costs, and unit manufacturing costs must all be considered. While cost is obviously important, it must be weighted within the context of the CMO’s overall value proposition.Costs should be competitive enough to complement all value proposition elements, including quality and delivery. The lowest-cost CMO is no bargain when product quality and/or supply are unreliable.

Choosing the “wrong” CMO can carry a hefty price tag in financial terms as well as lost or missed market opportunities. These missed market opportunities can arise from your CMO failing to live up to expectations in one or more elements of the overall value proposition, whether it be missing supply commitments, higher-than-expected cost, poor product quality, or regulatory compliance problems. Base your evaluation of potential aseptic processing partners on several factors, including: development and commercial-scale capabilities, end-to-end technology transfer project management, technical horsepower for process transfer, optimization and validation, demonstrated quality performance; competitive costs, and dedicated technical and customer service teams.

While size and reputation help a CMO supply the value outlined above, agility is equally important. After all, if the CMO can’t tailor its capabilities to your needs, all its technology and expertise are valueless for your purposes. Consider the total value proposition that your CMO candidate is offering from short-term development and tech transfer competency and agility, through to long-term commercial performance with secure and cost-effective supply of your important product.

The CMO selection process is the first step toward building a relationship with a true outsourcing partner that knows and understands your complex aseptic manufacturing challenges and is as invested in a successful outcome as you are, both now and as your organization’s needs evolve.The considerations that follow can help clarify your CMO selection criteria and evaluation process, and help you better inform your decision.

Depth of Aseptic Manufacturing Expertise

Component prep for primary packaging components: Consider the CMO’s capabilities for sterilization of primary components, including vials and closures. On-site capabilities for closure washing and sterilization, for example, provide greater assurance of supply and quality. Ask for demonstration that the firm uses well-characterized and validated processes for sterilization of primary components.

Bulk formulation capabilities: The CMO must have processes designed to prevent cross-contamination as well as to handle correct, accurate material additions. It will also be beneficial to your project if the firm’s capabilities include a wide range of bulk lot sizes available to enable scale-up commensurate with the growth of your product’s commercial volume.

Aseptic filling capabilities: Your CMO candidate must be able to handle all presentations desired for your product: vials, plastets, dual-chamber vials, ampoules, pre-filled syringes and blow/fill/seal containers. The supplier should be able to demonstrate that it maintains a robust media fill program to inspire confidence in sterility assurance.

An operator in Pfizer’s sterile manufacturing facility in Kalamazoo, MI, working on a restricted access barrier filling line.

Cleaning validation: Does the CMO have a robust cleaning validation program and the capability to develop a cleaning method for your important product or implement existing cleaning methods provided by the customer? This is essential for a CMO with manufacturing facilities designed to fill multiple products through a common filling line.

Lyophilization capability, capacity and technical expertise: Robust lyophilization cycle development is a scientific discipline that brings true value to your product in terms of product cost savings through optimal cycle design, high product quality and acceptable appearance. Ask your CMO candidates about their capabilities and expertise in this important area.

Finished goods packaging capacity and capabilities: Consider the fact that a CMO with integrated, same-site primary and secondary packaging capabilities can add incremental value to your project. With fewer inventories to manage between manufacturing and packaging operations, you’ll save time and money, simplify your supply chain, and reduce opportunities for quality issues. Select a CMO that has a full set of secondary packaging capabilities, including product labeling, packaging in single or multiple-vial cartons, kitting, cartoning and so on.

On-site analytical and quality control laboratories: Robust analytical method development, transfer and validation are capabilities often overlooked in the process of choosing a CMO. The firm must be able to handle a wide variety of capabilities and have sufficient analytical capacity to turn around results, enabling consistently excellent supply performance of your important product.

Enabling resources on-site: Engineering, microbiology, quality operations, regulatory, maintenance, release testing laboratories, warehouse/logistics, procurement, IT/automa-tion, packaging design and development for primary and secondary packaging, artwork management: a viable CMO candidate must demonstrate the resources and scope to respond expertly and efficiently to your evolving processing and other needs.

Product manufacturing support: The right CMO to handle your important product will have a well-qualified, diverse staff to provide technical support for its manufacturing operations. Specifically, look for depth of knowledge and experience in chemistry, engineering, pharmacy and statistics.

Recent experience with product introductions and transfers: Ask your CMO partner to demonstrate its recent experience specific to bringing products to market. Capabilities and expertise with both large- and small-molecule, as well as biotech molecules, may not be critical to your immediate processing needs, but will enable you to respond quickly and efficiently to the changing needs of your organization.

Process development technologies available on-site: As mentioned above, lyophilization cycle development, among other activities, can generate true value for your project.

Look for technical development capabilities such as freeze-dry microscopy, differential scanning calorimetry (DSC), and pilot-scale containment, aseptic filling and lyophilization capabilities.

Microbiological laboratories: Does the firm have full capability to develop and validate all microbiological methods, including sterility, endotoxins, microbial limits, bioburden, and antibiotic potency? Does the CMO perform its own sterility and endotoxin testing on-site?

Scope of available aseptic manufacturing technologies and dosage forms: Injectable dosage forms are highly challenging, including sterile solutions, suspensions or lyophilized drug products, filled into vials, ampoules, blow/fill/seal containers, or pre-filled syringes. Potent products, including cytotoxic solutions, require extremely complex equipment and enormous expertise in containment and handling. Although you may initially select a CMO on the basis of a particular project, it is wise to consider both your immediate and your potential future needs. Your product may benefit from extension to alternative dosage forms or presentations, (such as a line extension, for example) as it approaches loss-of-exclusivity.

Once you have established a successful and productive working relationship with a value-added CMO partner, working with that same CMO as your needs evolve can extend that value (by shaving months off project timelines, for example). Trimming project timelines translates to cost savings, either through commercial opportunities or direct project costs.Consider only those CMO candidates with the range of advanced capabilities and flexibility to efficiently and effectively transform all your aseptic manufacturing projects into finished products, regardless of batch size, process complexity, or package presentation.

Proficiency at handling expensive, potent and sensitive drug substances and drug products

Consider a CMO with experience handling highly potent substances, cytotoxics, biotech molecules and controlled substances. Even if your current processing needs do not fall into one of these classes, the CMO’s demonstrated ability to handle these types of materials demonstrates that it can provide the well-developed, robust systems for operator protection, material inventory control, product quality assurance and prevention of cross-contamination that are needed to protect the integrity, identity and purity of your product.

Depth of Global Regulatory & Quality Expertise

The CMO should be a worldwide supplier, including the U.S., EU, Japan plus other important global markets. They should be able to demonstrate a depth of knowledge in global regulatory and quality standards and proven successful track record of strong performance in these areas. Compliance is critical, as both a license to operate and a prerequisite for reliable quality and consistent supply.

With the implementation of risk-based regulatory inspections, you can be sure that there is increased emphasis on aseptic drug product manufacturing. Your CMO should have a demonstrated strong record of regulatory inspection success, and a record of resolving regulatory issues promptly and transparently. A review of FDA audits and filings with non-U.S.-based regulatory agencies is vital, and it’s important to look at the candidate’s entire regulatory history, including workplace safety and environmental compliance. In the context of technical transfer project execution, a CMO’s strong working knowledge of regulatory submission practices will add significant value to your partnership. The firm should be able to demonstrate strong performance with FDA pre-approval inspections, and meet your internal standards for electronic transfer of FDA and other regulatory filing data.

At the bottom line, any organization, in any industry, is only as good as its trusted outsourcing partners, and this is especially true in today’s pharmaceutical industry. Quality assurance is critical, throughout the technical transfer process, at every step of the aseptic manufacturing process and across all manufacturing and business functions.

Commitment to Industry Best Practices

If your company’s corporate culture encourages keeping abreast of new and emerging industry standards and best practices and actively implements programs such as lean process design, Six Sigma and Process Analytical Technology, seek an outsourcing partner that is equally committed to excellence. Doing so will optimize product and project cost, result in improved process stability, efficiency and capability, and will also result in a robust collaborative partnership with you and your CMO speaking the same language as you engage projects and obstacles together.

Rapid and Flexible Process Technology Transfer

Aseptic manufacturing tech transfer demands exacting replication of established, validated and registered procedures and process operations. Can the CMO handle full scope of technology transfer? Look for demonstrated capabilities in analytical and microbiological method development, transfer and validation. Engage them in their experience with technical transfer project management, and with process optimization and validation for improvements in product cost and process robustness.

The CMO must have the technical resources in place to receive technology from a customer and implement successful scale-up and commercial supply in a timely manner. Evaluate their ability to demonstrate success in this key area. Technology transfer includes a number of challenging steps — transferring process knowledge, analytical methods, raw material specifications, equipment requirements, etc. — so look for a strong project technical team that can successfully implement every single step.

Along with manufacturing process transfer, your CMO partner should stand ready with full-service project management to manage artwork changes and set up packaging and logistics operations to assure continuity of supply of your important product to all markets you serve.

Does the CMO structure and scope of capabilities extend beyond aseptic manufacturing to support and complement your organization’s other manufacturing needs?

To best support your mutually beneficial partnership, the design of a CMO’s structure should leverage capabilities across the continuum of customer needs. Thus optimized, efficiencies can be achieved across, and beyond, the aseptic manufacturing function. The best CMO candidates will draw upon an advanced, truly global network of manufacturing infrastructure, proven technology and processes, and deep technical, regulatory, and customer support expertise to complement and extend your manufacturing and related business goals. Does the CMO have the financial resources and global infrastructure to serve your business’s immediate and long-term needs? Is manufacturing capacity relatively consistent, and is the CMO flexible enough to handle unexpected demand? And finally, in today’s global economy, does the CMO have the financial stability to ensure supply security and continuity for your important products?

How extensive is the CMO’s customer and technical support? Who will service your business?

Will you have a dedicated ‘go-to’ team of technical experts and customer support professionals to ensure that you get the technical, quality and regulatory support you need, when you need it? Don’t wait until something goes wrong to find out.

Complex aseptic manufacturing requires a commitment to excellence at each stage of the manufacturing and supply process, a substantial investment in highly specialized expertise and infrastructure, and a series of best practices across the broad spectrum of contract manufacturing support services. Definition and application of well-considered CMO selection criteria is essential to selecting a reputable, expert, experienced and truly global manufacturing partner with the agility to provide a comprehensive value proposition for your complex aseptic manufacturing needs.

Carlos R. Fernandez is director of marketing for Pfizer CentreSource (PCS), with responsibility for PCS’ third-party global contract manufacturing business.
Douglas A. Jonas is Competitiveness Project Manager in Drug Product Operations at Pfizer’s Kalamazoo, MI site.