Initiating change in drug development and manufacture

With R&D and production costs spiralling and the growing regulatory requirements biting into the profit margins of drug sales, the industry needs radical change to manufacturing models, argues Ed Price, President, PCI Synthesis

Edward S Price, founding member of the New England CRO/CMO Council and President of PCI Synthesis

Bringing a prescription drug to market now takes more than US$2.5bn and 10 years, according to a study published last year by the Tufts Center for the Study of Drug Development. The costs jumped by 145% compared with a similar study carried out by Tufts in 2003. That kind of staggering increase is not sustainable; drug development must change.

The Tufts study cited factors including increased clinical trial complexity, greater focus on targeting chronic and degenerative diseases, and changes in protocol design to include the gathering of health technology assessment information and testing on comparator drugs to accommodate payer demands for comparative effectiveness data.

However, the study overlooked three other significant factors: rising regulatory burdens; a batch manufacturing process that has not changed in more than a generation; and a changing R&D process that relies on developing trust more than ever before. These factors affect branded and generic drugs alike and understanding their impact can help when addressing them.

Systems and equipment used to prevent contamination, mix-ups and errors that may have been ‘state-of-the-art’ 10 years ago may be less than adequate by today’s standards

Manufacturers have to comply with an increasing number of regulations – adding to the industry’s already significant burden. One of the challenges of increasingly stringent rules is that systems and equipment used to prevent contamination, mix-ups and errors that may have been ‘state-of-the-art’ 10 years ago may be less than adequate or considered obsolete by today’s standards. Unfortunately, the number and complexity of those regulations are not going to decrease in the near future.

Therefore, manufacturers need to evaluate whether current processes can be streamlined and updated. A thorough audit can help identify whether a step is being carried out to meet current standards or simply because ‘that’s the way it has always been done’.

Manufacturers should look at the lifecycle of their equipment and determine whether it is time to purchase new systems. Simply buying recent models may not be enough – it may require a totally new approach. For example, consider whether new technology can automate the capture of information or make the information more accurate and faster to compile.

It might not need a redesign of all processes from the ground up. For example, many organisations have replaced paper files with iPads that automatically prompt users for the required information and won’t let them click forward if the information does not meet the appropriate formats. That information is also searchable and can be stored in the cloud, which is more secure than paper files that can get misfiled.

When looking at how to develop future-proof processes, be sure to pay attention to guidance from the US Food & Drug Administration (FDA) about what issues it considers to be ‘important’.

Batch manufacturing

At the AAPS Annual Meeting in 2011, Dr Janet Woodcock, Director of the FDA’s Center for Drug Evaluation and Research (CDER), identified an overlooked problem plaguing life sciences. Despite billions of dollars invested in state-of-the-art labs, equipment and training, the industry has not seen an expected growth in innovation. In fact, a case could be made that the opposite has occurred, given the exponential increase in the costs and time to get a drug approved. Dr Woodcock observed: ‘Manufacturing experts from the 1950s would easily recognise the pharmaceutical manufacturing processes of today.’

The reason for this is that life sciences continue to rely on batch-based processing, even as other industries have switched to continuous manufacturing, which is more efficient, faster and cleaner. Embracing processes like Quality by Design (QbD) is good but, while based on batch processing, QbD does not do enough to move things forward.

Manufacturers need to evaluate whether current processes can be streamlined and updated

It is time for life sciences to consider continuous manufacturing as a spur to innovation. Continuous manufacturing requires a radical rethink of manufacturing that may lead to new, more efficient and cost-effective drug development: for example, developing a single production line that can process all the ingredients from raw materials through to finished dosage. That alone represents a significant change in production logistics.

Already being successfully tested to a GMP standard at the Novartis-MIT Center, continuous manufacturing also requires more automation throughout the production line. The single production line and automation provide two benefits: first, automation should improve quality and reduce variation and other costly production errors and delays; and second, FDA inspections should be faster and easier as the FDA has to inspect only one location and one production line rather than multiple locations for each supplier.

Downsides currently include: substantial costs – easily in the millions of dollars – to design, develop and test the production line; there also may be less flexibility to change the line to accommodate a new drug, if a company needed additional short-term capacity. For example, because a continuous production line is designed specifically to process one specific drug, it may not be possible, in a shortage, easily to switch processing to another drug that requires a different process.

Most manufacturers should develop a strategic plan to help them move towards automation over the next five to 10 years. The plan should evaluate the equipment, personnel and training needed before making the leap to continuous manufacturing. Manufacturers should make sure they understand the potential benefits, e.g. an increasingly automated production line, which should also help capture and report information required by the FDA, streamlining the often arduous process. While the costs of transforming batch-process manufacturing to continuous manufacturing will be steep, the cost of not making the change may put manufacturers out of business.

Trust and outsourced R&D

It may take a decade before continuous manufacturing gains widespread acceptance among life sciences companies. In the meantime, R&D is continuing on the path to more outsourcing, which can lower development costs by not supporting standalone resources, capital investments or keeping staff on as full-time when they’re only needed for project work.

But even as the workplace has changed to accommodate remote access, telecommuting and communications via email and text, one of the key ingredients for a successful project is something pretty simple: it takes trust.

Trust is the key ingredient for a successful outsourcer-client relationship

Trust is the key ingredient for a successful outsourcer-client relationship. And both the client and the CMO have to find a way to trust each other. This is especially true when dealing with virtual biotechs that have a concept and funding but usually only a handful of employees (and often have business experience but not lab experience). Clients need to see the value a CMO brings in terms of experience, the right technologies and understanding and compliance with constantly changing FDA regulations; at the same time, CMOs need to make sure they understand the client, its business model and vision.

In fact, while prospective clients may tell you they need the same thing, it is important for CMOs to understand their potential clients’ goals because a client’s business model and real goals can vary significantly, including:

  • Those that are looking to show proof of concept to get more funding – this includes virtual organisations with little funding such as those in Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) programmes who will use this work to get fully funded but have a tight budget with no room for development.
  • ‘Just get me to IND (Investigational New Drug)’ – these firms have either series A private funding or first venture tranche, and are looking to sell assets at the next inflection point, and want to do the bare minimum as the need is for speed.
  • Later stage firms – these are venture-backed and pre-IPO, and are looking to invest in R&D and expect to commercialise the drug. If they are post-IPO, they may be looking to sell the company or partner with a big pharma company. They are often willing to invest in R&D but need lots of help.

There are plenty of great clients out there; great in many different ways. But just as important, CMOs must be able to understand the range of difficult clients, which seem to follow four distinct types:

  • The Bully
    • Usually in larger organisations
    • Knows the industry well
    • Not strong technically but has credentials
    • Very political – will never compliment and will always find fault.

When dealing with bullies, CMOs need to get the upper level management intervention needed to clear the air and re-set expectations.

  • The Business Manager
    • Usually in start-ups or small companies
    • Non-technical
    • Does not understand investment and its advantages
    • Has a commodity mindset
    • Will never trust you
    • Always looking for the CMO to take risk and wants to cut corners.

The project manager or business leader needs to intervene and explain company policies to a business manager client.

  • Mr Indecision
    • Usually in larger organisations
    • Knows the industry well
    • Strong technically
    • Very risk averse.

The CMO’s upper management or business leader should reach out to upper management on the other side to help focus and get Mr Indecision to make decisions. Without intervention, indecision can eat up time and budget.

  • The Micromanaging CEO
    • Start-ups or small companies
    • Micromanages his own technical staff
    • Makes unilateral decisions, usually cost-based
    • Does not understand investment and its advantages.

To deal with micromanagers, especially at the top of a client organisation, the CEO/COO needs to conduct a peer-level intervention with the client’s CEO.

Without trust on both sides, the end result of most projects is the same: lost money on both sides, missed timelines, and a bad experience

Without trust on both sides, the end result of most projects is the same: lost money on both sides, missed timelines, and a bad experience. For the CMO, it means less efficiency, which raises other costs and potentially has an impact on other business.

Overall, it is important to understand each client’s business model – and make sure the teams involved know it as well. CMOs need to over-communicate, adjust or manage expectations, deliver bad news quickly and admit mistakes – while offering up solutions to address any problems or concerns.

All three issues – regulatory burden, batch processing and lack of trust during R&D can have a significant and negative impact on the amount of time and money required to successfully bring a drug to market. With the right mindset and preparation, CMOs and clients can find ways to streamline processes, work effectively, and find ways to at least meet timelines and keep within budgets.