News | October 6, 1998

Technology Transfer–From Clinical Trial Supplies To Production

By Jay Hamilton, Coopers and Lybrand

The transfer of technology between R&D and manufacturing operations is critical to successful and timely product development in the pharmaceutical industry. By putting in place a new, process-oriented culture, companies can minimize the degree to which technical aspects of drug development impact the critical path. A proactive approach will also support successful results from pre-approval inspections.

If technology transfer is excluded from a company's efforts to re-engineer Development, then a sub-optimal result will be obtained and true speed to market is in danger of being compromised.

Project Organization

The concept of cross-functional project teams is well adopted in pharmaceutical development. The leading industry players work through teams planning development activities together, supported by modern information technology for data organization and shared learning.

However, even for high-performing development project teams, such areas as clinical trial supplies and technology transfer are often poorly understood, and managed only in a reactive manner. It is essential for fast and seamless development to integrate these processes into the project activities. A true project team approach has to be understood and become a vital part of the organization.

Clinical Supply Chain

Too often managed as a cottage industry and in a non-integrated way, this is now seen as a key area where modern logistics management principles are being applied. Key checkpoints in the clinical trial supply chain can be used to measure performance in terms of speed of delivery. Here is a listing of these checkpoints and how they are broken down into support activities:

  • Final step to release–active drug substance
  • Manufacturing lead time–formulated product
  • Manufacture formulated product
  • QA release formulated product
  • Clinical supplies packed and labeled
  • QA review and release of packed supplies
  • Supplies shipped from site
  • Supplies available at country/affiliate
  • Supplies available at clinic

Fast time to market re-engineering in R&D activities can be negated by avoidable delays in the supply of clinical trial supplies. For example, lead times from receipt of request to starting primary packaging may typically amount to a high proportion of the total process time. A large part of this time is made up of administrative and bureaucratic activities that do not add value. Benchmarking studies show wide improvement gaps between industry average or worst performance, compared to what is achievable as best practice performance for priority projects.

Best practice performance ensures that clinical trial supplies are never on the critical path. However, it is not sufficient to make, pack and label dosage forms well in advance to keep supplies off the critical path. Fast clinical development plans require some flexibility in the design of the next study as clinical results become available. Thus dosage form strengths and ship destinations are inherently subject to late changes, and clinical supplies manufacture and packaging operations have to build in flexibility as well as timely delivery.

Production Issues

Production Scaleup

Managing production scale-up and technology transfer is a difficult process. The first time a process is run on production scale, previously insignificant or unnoticed variables can contribute to batch failure. A combination of factors such as large scale, different equipment, new operators and new environmental conditions can lead to unexpected results. Finding the cause of poor performance can be a time-consuming process at a critical stage in the clinical and regulatory program.

When things do go wrong, production groups commonly complain that products are 'thrown over the wall' from R&D, and that the formulation groups do not consider the input of Production to the process as their customer. In addition, there may be a lack of standardization of equipment, excipient sourcing, and packs.

A common complaint from R&D is that Production is not interested in becoming involved in projects early enough, so that choices cannot be made to gear for production requirements.

For example, in tablet processing, wet granulation processes are simple and flexible in early formulation development, and wetting the drug substance or dissolving small quantities of highly potent drugs can be advantageous. However, production facilities are likely to prefer directly compressible formulations, which have fewer process steps and can save several millions of dollars per year in yield and resources. As development of a compound proceeds, and the drug dose and physical characteristics are better understood, the emphasis for formulation development shifts towards the needs of the Production customer.

Thus for fast development, it is essential to achieve early integration of R&D and Production efforts in planning for right-first-time process and knowledge transfer, and a straightforward and successful pre-approval inspection

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Investment Risk Management

Project development plans lead to clear go/no-go checkpoints based on safety and efficacy, after which decisions to make large capital investments for the production facility are made. The shorter the development time, the more the technology transfer lead time is compressed.

Fast time to market developers will find capital investment plans must be committed to earlier, and early capital investments need to be made before efficacy is proven. Organizations will need to evaluate and decide at which point it is necessary and desirable to commit money to large capital investments, to agree to contracted-out manufacture, or to source costly raw materials or intermediates without being certain that the product will reach the market.

Intersite Transfers

With so much plant rationalization and consolidation in progress, there is a need to define what is best practice in the management of site to site transfers. Elements of inter-site transfers to address include:

  • Management/technical boundaries of responsibility for the process
  • regulatory requirements
  • maintaining the supply chain continuum
  • skills requirements
  • cost reduction and fiscal issues

Regulatory Aspects

CMC Section

The CMC section of the regulatory dossier is the basis for the pre-approval and subsequent inspections. Therefore it is vital that this is optimized from the outset.

  • Being uncertain of information requirements and therefore generating too much data for CMC sections is common, and is a waste of precious time and resource.
  • The Regulatory Affairs function do not always ensure that the CMC groups are aware of current regulatory requirements. Very often we find that requirements are over-specified adding to the complexity of the CMC section.
  • CMC stability data should not be rate-limiting for submission.
  • Regulatory Affairs should not be treated as a document writing service–leading organizations are already exploiting IT for compiling CMC data in the generating departments quickly, in regulatory submission format.

Pre-Approval Inspection (PAI)

This is now an integral element of the approval process for FDA, and companies must gear up for success first time, every time. There should be no inspection-related delays to launch. Key points include:

  • Build in QA to the process–no surprises at the pre-inspection audit
  • validation/recording requirements clearly defined–no overkill in data generation
  • record keeping systems in place to cope with PAI questions when they arise
  • establish with the FDA how much validation batch stability data they want to see at the PAI
  • integrate learning from PAIs
  • no regulatory citations

Contractor Management

The use of external contractors is becoming a feature of pharmaceutical development. Whilst in many cases, external contractors are merely used to handle peaks in demand, companies are increasingly recognizing that non-core activities are most efficiently performed by specialist outside contractors. This means that the identification of outsourcing opportunities and the management of external partners are themselves becoming core skills in pharmaceutical development. However, whilst tasks can be delegated to contractors, the responsibility for them is retained in-house, and the loss of control of a key operation by outsourcing can introduce unacceptable risks to project timelines. Companies need to understand how to minimize risks and to achieve competitive advantage through the use of contractors.

Factors to consider:

  • measures of performance, time, quality and cost
  • payment terms
  • penalties
  • knowledge transfer
  • integrating the use of contractors into development planning
  • protection of intellectual property

Compressed Milestones

The clear need to get to market quickly to maintain competitive effectiveness is driving companies to adopt fast time to market initiatives. Leaner, more effective clinical programs and rapid data reporting are cutting clinical development times. These must be supported by a fast and reliable clinical supply chain.

Successful compression of clinical milestones will in turn concertina down the times available for preparation for launch activities. This is resulting in fundamental reconsideration of standard development triggers for primary and secondary technology transfer activities to define:

  • the final synthetic route
  • the final NDA formulation
  • agreement of country markets on the commercial image and pack
  • timing for availability of the first GMP batches.

Boundaries of responsibility between R&D and Production are less clearly marked as a shared responsibility approach is adopted. What is emerging is a seamless technology and knowledge interchange between Development and factory, rather than passing the product from one organization into another.

For more information: Jay Hamilton, Partner, Coopers and Lybrand, 145 King St. North, Toronto, Canada M5H IV8. Tel: 416-941-8319.