One of the most significant challenges facing today’s parenteral drug manufacturer is how best to evaluate and implement advanced aseptic technologies to maintain a robust regulatory compliance profile while optimizing cost of goods sold.

The past 15 – 20 years has seen the introduction and maturation of a number of “new” technologies that offer tangible benefits and quality improvements for aseptic pharmaceutical fill/finish, such as barrier isolators, 100% checkweigh, single-use disposable fluid path technologies, etc. Many of these technologies have matured to the point where the question is no longer whether these technologies are ready for prime time; their use in dozens or hundreds of commercial facilities is proof positive.

The question now is more pointed – “Is your company ready for these technologies?”

Discussion

There exist today clear regulatory expectations that firms employ continuous improvement (CI) models in order to maintain their facilities in a state of robust CGMP compliance. One of the first items on many auditors list is a review of a company’s CAPA program, which is ostensibly designed to identify root causes of problems and implement corrective measures to prevent recurrence. Associated metrics, such as the number of open CAPA’s, time required to implement corrective actions, etc. provides excellent insight into the quality of a firm’s QA systems.

CAPA associated corrective measures can generally be classified as either administrative or engineering controls. Administrative controls involve modifying or creating additional SOP’s or work instructions to provide redundant checks that the manufacturing process is being executed properly. Engineering controls, on the other hand, design the process equipment and facility itself to ensure proper execution of the manufacturing process. Obviously, the latter process is more robust, and results in a higher quality product.

In most cases, firms have no choice but to implement administrative controls. Especially for existing production facilities, a number of factors contribute to their inability to implement the more robust engineering controls. These factors may include, but are not limited to: 

• Requirement to maintain production
• Restrictions on capital expenditures (lack of available funds, or unwillingness to prioritize funding) 
• Regulatory Concerns (we don’t want to open the filing)
• Validation Concerns (It’s already validated” inertia, or the additional time required to validate a new system) 

To their advantage, administrative controls are generally much faster to implement than engineering controls, and have only an incremental impact on Cost of Goods Sold (COGS). However, implementing successive administrative controls can be a slippery slope, since these additional encumbrances invariably increase cost, difficulty of execution, and overall complexity of operations, and thereby erode the production capacity of the facility. Eventually, the lack of substantive capital improvements results in a facility that represents a significant regulatory liability to the firm.

Therefore, the question of how and when to implement new technologies to maintain continuous GMP compliance is of critical importance in our industry.

As an engineering consulting firm, IPS-Integrated Project Services executes dozens of concept design/feasibility studies for clients each year. Many of these projects include a technology assessment phase, wherein the client asks us to assess and cost alternative technologies as part of our scope of services. At least in theory, this will allow the client to select the optimal technology on a case-by-case basis, or to decide if the “time is right” for them to adopt a new technology.

Unfortunately, this approach often fails. Concept/feasibility studies are typically executed in a 6-8 week timeframe. For those of you that are unfamiliar with the engineering process, this means that at most 2 weeks are available for process definition and technology selection, so that remaining disciplines (architectural, MEP, fire safety, etc.) can produce their design deliverables, which are required for the key end result, i.e. an estimated project cost. The 2-week interval is simply insufficient time for most companies to reach an informed decision about these complex issues, especially if the decision will impact multiple facilities within their network.

Another misconception is that technical selection can be sorted out during the Basis of Design (BOD) phase, which typically follows the Concept/Feasibility Report. Unfortunately, this approach also usually fails, due in part to the compressed timeframe for the BOD. Since the entire BOD activity is typically 8-12 weeks total, only 2-4 additional weeks are available for process definition and technology selection. Furthermore, there is often reluctance on the part of project sponsors to change the selected technologies from those that were reviewed and presented to upper management via a concept report. These issues generally conspire to prevent post-Concept Report technology changes.

Another misconception is that technology selection (e.g. isolator vs. RABS, etc.) should be, or can be, performed on a case by case basis. We seldom see companies switch from one technology to another on a project-by-project basis, e.g. Project A = Isolator, whereas Project B = RABS. Instead, we see clients who have made the decision to go with a particular technology, and implement that technology across their manufacturing networks over time. This again points to a need for a different technology selection paradigm. 

Solution

Evaluation & Selection

Companies must develop and manage an ongoing technology assessment and selection process, to evaluate and establish corporate “standards” for these technologies. These standards can then be applied to future projects, thus providing a sound basis for technology selection from the very beginning for all projects.

Selecting and implementing new technologies impacts many disciplines within an organization; adequate resources within each discipline are required for proper evaluation.

For example, a request we often receive for aseptic fill-finish facilities is to incorporate single-use fluid path technology, either on the formulation/bulk holding side or on the filling equipment fluid path side. There are an increasing number of suitable alternatives available; however, selecting amongst the various vendors and technologies requires a significant amount of time and corporate resources. Required owner side activities include, but are not limited to:

• Selection of bag film material(s) & suppliers
• QA audits of potential suppliers
• Establishing specifications for single-use systems and components 
• Establishing supply chain strategy (multiple manufacturing sites, multiple vendors, etc.)
• Determining “target products” for transfer into single-use systems (existing portfolio)
• Establishing test protocols for extractables and leachables, as well as stability testing
• Executing preliminary testing on target products

It’s easy to see that even this partial list of activities cannot be completed in anywhere near a 2-week timeframe. As a result, we are unable to proceed forward on a firm basis during conceptual design. The best we can do is to select a design basis technology and vendor, and incorporate this in the facility design. However, the chances of eventual realization of the selected technology are low, since the decision is not made by or for the client stakeholders. Corporate politics play an important role here as well; if the decision is not supported within the organization, then chances of implementation are virtually nil.

As an alternative, companies need a funded, ongoing technical evaluation and selection process that allows them to develop an overarching technology strategy. This process is necessarily multi-disciplinary and high level; without the support of upper management, efforts to implement these technologies will likely be unsuccessful. The objective of this process is to identify “best available technologies” from a corporate perspective, and to gather information as required for financial evaluation of these alternatives. Certainly, some of the evaluated technologies will prove to be “too new” or “not a good fit”. This information is nonetheless valuable during the Conceptual Design phase, since resources are not misdirected to evaluate these technologies.

Another key deliverable from the technology assessment process is financial justification for these technologies. Often we see clients that do not understand capital costs for various technologies. As a result, these technologies are often de-scoped during the “Value Engineering” phase of the project. Having an accurate understanding of these costs, as well as broad organizational support for the expenditures, ensures their inclusion in the project design basis.

Metrics for Evaluation

As noted above, a key objective of the technical selection process should be to optimize Cost of Goods Sold (COGS). For many companies, this “optimization” is synonymous with incessant downward pressure on COGS.

However, the relentless focus on lower lowering COGS fails to take into account the quality/cost ratio of the resultant drug product(s). Manufacturing resources are directed to lower quality/lower COGS facilities, as witnessed by several decades of manufacturing outsourcing. Recent quality issues at a number of such facilities have been a significant contributor to the current drug shortage crisis.

This “COGS” only approach generally precludes introduction/adoption of advanced technologies, due to the increased capital costs for these systems in conjunction with the extended timeframes that may be required for implementation. This in turn ensures the eventual obsolescence of these facilities, which is accompanied by a continually eroding compliance profile for these facilities and the company in general.

As an alternative, companies can develop metrics that combine COGS analysis with a “Facility Grade” evaluation. The “Facility Grade” in this case is recommended as a surrogate for product quality, since overall product quality is difficult to measure prospectively. However, a “Facility Grade” can be assigned prospectively, based on technology selection, engineering controls, personnel, materials and equipment flows, etc.

Use of an objective tool of this nature allows companies to accurately assess their risk tolerance and establish COGS/“Facility Grade” ratios. By comparing different facilities in network, companies can establish benchmarks for these ratios, which in turn can provide the financial justification for the implementation of various technologies.

Conclusion

In conclusion, the need for a different model to assess, justify and implement new technology in the aseptic fill/finish industry is clear. Lack of continuous improvement in facilities results in their obsolescence and associated regulatory compliance issues. This has been a major contributing factor in the current drug shortage issue.

As an alternative, firms are urged to adopt a long-term, strategic, and funded technology assessment program. Such a program necessarily requires support from upper management; said support needs to take the form of adequate funding and headcount allocation, as opposed to “philosophical support” for unfunded initiatives.

During the upcoming IPS Technologies Tours, you’ll no doubt see a number of exciting new technologies that may be a great fit for your manufacturing facilities. This would be a great time to begin considering how to lay the groundwork for these in your company.

This article originally appeared as a supplement to the 2016 IPS Technologies Tours at INTERPHEX.