Several posts ago, I discussed an article on the ‘shifting sands’ of contract provider/pharma relationships, and how smart providers were responding to pharma’s needs, rather than establishing fixed models of business.
I wanted to expand on that a bit, since it recently came up in a discussion with a major pharma company exec who was just a wee bit exasperated at being told precisely how a relationship would be structured by what amounted to a secondary supplier.
Business & Relationship Models As far as relationship models are concerned, at Neuland we’re very flexible, because the best model to apply depends on the project or product type.
For example, with life cycle extension of APIs, we find a conventional business model is favored in which contract pharma clients prefer to outsource the products to meet their quality and regulatory requirements while sourcing at a competitive price. This kind of business model is exclusive in nature, and historically offered a guaranteed volume uptake on an annual basis. Taking market dynamics in consideration, it’s clear that guaranteed annual volumes for procurement is a largely extinct model.
In fact, many of the models we encounter these days are geared more and more towards encouraging a CMO to improve cost in order to compete against generic pressures. This is becoming increasingly common in situations where innovator firms rely heavily on CMOs such as Neuland for better delivery at the most competitive pricing under standard quality norms.
Here are five more observations on what we’re seeing impact the provider-sponsor (or innovator) relationships:
More Contract Pharma Sponsor Audits
One aspect of the relationship that has received some coverage is the increasing number of audits of CMO firms by the sponsor companies. While this may have its origins in the revised FDA standards assigning responsibility for manufacturing to the sponsor company, one particular positive consequence has been to help contract pharma providers improve their overall quality systems.
QbD Drawing More Attention
Quality by Design (QbD) is standardizing across the industry in the development phase to ensure that manufacturing is done to meet consistent quality in deliveries of drugs. With the adoption of QbD, the processes relating to yield, quality and impurity profiling are increasingly drawing more regulatory attention. This has led pharma sponsors & innovator companies to seek out relationships with firms that are ‘QbD-enabled,’ for lack of a better term, in order to best address the regulatory concerns raised by the growing complexity of today’s drug science.
Large Molecules Draw Innovation, Small Molecules Draw Competition
The innovator’s focus is – and has been, for some time – shifting towards large molecule development. In the interim, the small molecule space has become increasingly competitive. This is highlighted by the decreasing number of approvals for small molecules drugs over the last decade. The reduction in value for small molecules has led to market erosion, and is forcing CMOs to upgrade the technology platforms to remain competitive. It is also driving a restructuring of contract pharma-client relationships, with an emphasis on competitive processes & technologies. The innovators are stressing development in the areas of mAb and proteomics, as well as peptides
Old Drugs Seek New Life
Pharma companies are looking for new indications for old drugs. There is a trend in replacing some of the active side elements with isotopes to enhance efficacy. It is also opening up new avenues for contract manufacturing as CMOs begin to work on drug repurposing on behalf of clients.
The Growing Role of I.P. Intellectual property has always played a major role in the contract pharma-drug company relationship. The importance of I.P. (and rights ownership) is taking on an even larger role with the passage of time. This is due – in large part – to the increasing complexity of drugs and their respective processes, which has led to highly-specialized CROs/CMOs with the ability to produce critical I.P. Relationships are now often structured around the presumed I.P. innovations that will emerge, and in many cases both parties work jointly to generate new IP innovations.
Just as every contract manufacturing project differs in its details, so – too – do the relationships between providers and clients. It is important to view the entire scope of the project, taking into account the variables that will have a bearing on the contract research or manufacturing agreement. Flexibility in designing the client relationship to meet the needs of the drug firm is the key to building a successful long-term alliance.
The limits of describing the relationship between supplier and sponsor are perhaps best captured in the article by the popular contract manufacturer statement: “it depends.”
It’s a truism: many different factors affect and impact how the relationship will come to be defined.
The VP of Global Business Development for one firm explained it nicely in relation to their CDMO services:
“I think it’s important for our potential customers to keep in mind why they went to a CDMO in the first place. Was it speed or technical advancements or a specific delivery platform, for example. If they keep that in the forefront of their minds, they will find a partner that is a good fit.”
At Neuland, we’ve found similar rationales behind a customer’s driving motivation. It may be that timelines are the key driver. It might be regulatory track record, or experience with a given technology or capability. In some cases, the interpersonal relationship might be a key deciding factor.
And just as those drivers vary with each client, so too does each client’s conception of what the relationship should look like – and how it should function. The Pharmaceutical Manufacturing article stated:
Much has been written about the role of contract manufacturers evolving from an “extra set of hands” to a more high-level, strategic partnership. But is the term “strategic partnership” truly the best way to describe the contract organization/drug manufacturer relationship? Again, the answer is: it depends.
Karen Langhauser, author of the article, goes on to point out that the term ‘strategic partnership’ is widely – and perhaps erroneously – used in the bio/pharma outsourcing industry. This may just be linguistic nuance. Most CMOs, CROs or CDMOs would acknowledge that the relationship isn’t exactly a partnership in traditional terms of shared risk/reward, but rather a partnership in the sense of long-term collaboration to create a successful drug product.
Regardless, the point that effective contract firms adapt to the desires of the sponsor drug company are spot-on, and much of this comes down to culture.
One last point from the article dovetailed nicely with our approach here at Neuland: “Building a good outsourcing relationship is the responsibility of both parties, and the best relationships have these three things in common: communication, flexibility and planning.”
Rare (or orphan) diseases may sound like a small, low-prevalence problem – hence their labeling as ‘rare.’ But with 7,000+ rare diseases having already been identified, affecting more than 50 million people in the U.S. and Europe alone, the overall scope of the problem is anything but small. And the number of known conditions continues to grow.
If designated, orphan drugs are eligible for the following financial incentives:
Tax Credits – 50% of clinical trials costs
Waiver of marketing application user fees – over $2 million
7-year Marketing Exclusivity if first approved
In that earlier post, I discussed how little difference there is – for an API supplier and contract manufacturer – between orphan and non-orphan drug projects. (To summarize – there is very little daylight between them, save for the often-smaller manufacturing scales found with orphan drugs).
Neuland has a number of clients who focus in the rare disease space (though it isn’t one single space, but rather a wide range of indications – as mentioned above).
Advantages of Lower Volumes
From a drug manufacturing standpoint, there are advantages to working with lower volume products. Reaction volumes – and the volumes of reagents & chemicals – are smaller, avoiding the challenges of linearity during scale-up of reactions.
With smaller volumes typically comes fewer waste and chemical/reagent storage considerations. Smaller, fewer batches also tend to pose less equipment infrastructure challenges, and provide more latitude for reaction and processing times.
Timelines can also be condensed to some degree, since such projects are easier to slot into production in sub-commercial scale (e.g., pilot or kilo) cGMP facilities.
Less Focus on Lifecycle Management
One of the key differences distinguishing rare drug manufacturing from the wider drug industry is lifecycle management – or rather, the lack thereof. Because the number of batches is smaller and the volumes are lower, many aspects of drug lifecycle management either are not feasible or are far less important. As I mentioned above, this can have certain benefits – lower volumes of chemical effluent, reagents, etc. – which provide some flexibility in production.
Streamlining Manufacturing to Reduce COGS Drugs are expensive to develop, and those costs can be elevated when dealing with very small patient populations.
With orphan drugs, the focus shifts to maximizing efficiency up front. Enhanced route scouting and other techniques are leveraged to reduce the cost of goods (COGS). Unlike typical drugs which progress through numerous stages of development and lifecycle, the focus on reducing COGS starts at the earliest stages of development and remains a core focus throughout manufacturing.
FDA guidance has addressed this issue, as well:
“FDA recommends that sponsors consider the potential development of the manufacturing process in the entire drug development program early, including which nonclinical and clinical studies are intended to be conducted with each change in the manufacturing process, and whether bridging studies will be needed.” (Rare Diseases: Common Issues in Drug Development Guidance for Industry)
It’s true of any drug product: the earlier in development that process optimization occurs (reducing later-stage changes), the fewer follow-on studies will be needed – thus speeding time to market. With the higher cost pressures on orphan drugs (only partially offset by the market & exclusivity benefits of pursuing rare disease therapeutics), this takes on even greater importance.
Developing cost control measures during process development is a particular expertise of ours at Neuland, specifically enhanced route scouting & optimization. We’ve applied it towards orphan projects in a number of specialties, including neurological, cardiovascular and respiratory indications.
Neuland has recently welcomed the addition of a new, dedicated Process Engineering Lab to its R&D Center. The lab opened in March, and supports operations and safety studies via a Quality by Design (QbD) approach.
Three Keys to QbD Success
The success of a QbD approach hinges on three fundamental elements. First, the target product profile must be clearly understood. This involves the second key element, determining the critical quality attributes (CQAs) that must be within a certain range limit or distribution according to the ICH guideline governing the product.
The third and final phase of QbD centers on the process needed to deliver the product. In this phase, risk assessments are used to gauge the impact of the raw material attributes and process parameters on the CQAs. Based on this, a design space is developed, and a control strategy is conceived and implemented.
The product lifecycle is then actively managed, with continual improvements made along the way, as shown in the flow chart below:
Taking Advantage of the Latest Equipment
In addition to a full range of state-of-the-art instrumentation and systems, the Process Engineering Lab features several innovative devices essential to the work it performs. An HEL reaction calorimeter and TSu (thermal screening unit) increases safety while enabling risk analysis and evaluation.
The reaction calorimeter is a stirred and controlled reactor that measures the rate of heat release as the reaction is conducted under controlled conditions. The TSu uses only approximately 0.5 to 5g of a sample, and provides clear data concerning hazards, including pressure. Specifically, the TSu indicates the thermal stability of chemicals, the safe process/handling temperature, and any potential temperature/pressure rise following exotherm.
The HEL automated parallel reactors in the lab allow one chemist to perform multiple experiments, in parallel. Benefiting from precise stirring and temperature control, each experiment can be conducted at a separate temperature from -60 to 225C, and stirred separately, with different sized containers and different applications.
In addition, Design of Experiments software and Design Space methodology are used to create an optimal design.
The Process Engineering Lab will enable Neuland to continue meeting regulatory requirements, and providing quality products using cost-effective procedures. Through a scientific, risk-based approach, the work achieved in the Process Engineering Lab yields greater insight into active drug substance manufacturing process. The result includes improved scale-up efficiency and speed, and faster time to market.
The 2016 Barcelona CPhI show (CPhI Worldwide) was an excellent opportunity for Neuland to set in place some strengthened internal sales team processes. These processes allowed us to better capture and understand the concerns, issues and challenges of both our customers and attendees in general. A bit more about what seems to be on everyone’s mind in the industry a little later…
But first, back to Barcelona. It’s a remarkable city – cosmopolitan and modern, yet bursting with history. It served as an excellent backdrop for the conference. Barcelona has historically been a key trading connection between Europe, Africa and the East – so it was the perfect venue to discuss the increasingly global pharma API industry.
Neuland held nearly 150 meetings over the course of the three-day show – keeping the booth’s 5 meeting rooms in constant use.
Pradeep Jain, Neuland’s Head of Manufacturing Operations, was one of the team who also had the opportunity to attend technical seminars and other exhibitions to gain knowledge about the latest advances in containment systems, and clean room & micronization technologies. (Pradeep’s personal show highlight actually happened away from the conference: visiting the stadium of FC Barcelona – a mecca for football – where diehard fans purchase samples of the stadium’s grass field.)
Neuland’s CPhI Mixer Held Atop Roman Ruins
Neuland held its VIP event at the History Museum in the medieval quarter of Barcelona. In our internal Company newsletter – Neuworld – Pradeep Jain described the setting:
The museum event organized by Neuland was held in the Casa Padellàs – a 15th century Gothic palace that in 1931 was transported stone by stone from its original location on the Carrer dels Mercaders to the Plaça del Rei. The palace has a typical Catalan Gothic architecture, with a small inner courtyard and external staircase. During the excavation work necessary to build the new foundations for the palace, remains of the old Roman city were uncovered. To better preserve these remains it was decided to move Barcelona’s city museum to this site, which opened in 1973.
What Were Attendees at CPhI Talking About?
Many of the questions we encounter as an API manufacturer were fairly conventional, and recur at every show. Among them:
Topics related to classes of compounds Neuland works with (e.g., amino acids, nucleosides, steroids, heterocyclics, quinolones, FMOC building blocks)
Project management-related topics: timelines, cost, IP, regulatory track record
Capabilities-related topics: route scouting & development, micronization, manufacturing scales (e.g., lab, pilot, kilo, production), process optimization, etc.
Aside from these customary questions, regulatory and supply chain queries seemed to grow as topics of discussion at this year’s show. These are two issues to which we happen to have an unrelenting commitment (and we’ve written about them frequently).
It’s fair to say that both of these issues are on everyone’s mind. There is a perception that the global economy is threatened by the possible rise of trade barriers. Combined with recent FDA guidance on Quality Agreements referencing the legal responsibilities of suppliers & pharma companies regarding cGMP manufacturing, both regulatory & supply chain issues should be expected to be a principal concern. (And truly, when hasn’t regulatory been a top issue for pharma, anyway?)
All in all, it was a successful show in a great city, and it was wonderful to catch-up with our customers and engage with those in our industry.
CPhI North America 2017
In you are in Philadelphia (or headed there) for the 2017 CPhI North America show, be sure to stop by the Neuland booth (#2059) and learn more about our API, Peptide and Contract Manufacturing services.
I read an article at PharmTech at the tail end of 2016 that I thought was quite interesting, and it reflects Neuland’s position on regulatory agencies & issues. The article – Nurturing the Relationship Between Industry and Regulators – emphasized the need for the pharma industry to partner with regulatory agencies to provide safe and effective therapeutics.
In the PharmTech article, author Susan Haigney, points out:
“It’s a partnership that can sometimes be contentious but is, ultimately, beneficial to all.”
To me, the relationship between regulators and the life sciences industry is (or, at least, should be) fairly straightforward: regulators hold us – as an industry – to uniform and consistent standards…and that’s a plus for us. And we – the industry – have the ability to deliver the tools and know-how to help regulators in their efforts.
The life sciences industry also has an obligation to inform regulatory agencies when we think they are off-base. Analytical standards are an excellent example in which industry often provides information, data and feedback about the widespread use of newer technologies that have come to replace older, potentially less accurate standards.
The article references this, as well: “international standard-setting organizations emphasize the importance of industry input. USP encourages pharma companies to participate in the development of public standards.”
The Industry-Regulatory Relationship: ‘It’s Complicated.’
The piece at Pharmtech also brought to mind an editorial I’d seen at DDNews on the 21st Century Cures Act, pointing to the at-times conflicting relationship industry and regulators tend to have:
“As chief editor of this magazine, I have an emotional and intellectual relationship with the FDA that would, were it a Facebook status, be ‘it’s complicated.’
On the one hand, the part of me that deals with pharma and biotech business issues knows that it would be nice to trim the costs of clinical trials and other aspects of the approval process. Unlike most of the American population, I know that high drug prices are often at least as much due to the economic necessity of recouping R&D costs as they are to do with greed.
On the other hand, I also deal with the academic and clinical researcher side of the news and a lot of the people on that side (and me, too) would like to see rigorous scientific study of potential drugs. I was happy in the early talk of 21st Century Cures to hear about working in “real world” results as part of the review/approval process and possibly streamlining some FDA processes.”
Finding Common Ground: Collaborating to Improve Patient Health
Back to the PharmTech article for a moment – it pointed out some key areas (beyond standards development) in which collaborative (or at least non-combative!) efforts can make some inroads towards improving patient health in ways that benefit industry participants, as well.
A big piece of the growth trend, however, will be driven by high-potency APIs (a “staggering increase,” as the report puts it) and their increasing role in cancer therapeutics. The rise of peptide drugs also drew a mention, but came with some manufacturing and regulatory caveats:
“Popularity of peptide-based drugs and the patent expiry of blockbuster branded drugs in the near future is also expected to boost the growth of the market. Complex manufacturing guidelines and stringent regulatory processes will continue to pose challenges to widespread adoption of peptide-based drugs.”
This is Eroom’s law in practice. (Eroom’s law – Moore’s law spelled backwards – posits that pharmaceutical R&D costs go up while drug approvals fall.)
This is also something that has been mentioned elsewhere. In a January piece at PharmTech, the editors referenced the growing imbalance between investment in – and sales of – a new drug:
“Since 2015, the report states, the costs of launching a new drug have remained near where they were during the heyday of the blockbuster, at $1.539 billion, 30% above where they were six years ago. A three-fold improvement in productivity would be needed to restore balance the imbalance between investments and sales.”
Specialty APIs Driving Growth
Back to the API report: it rightfully, in my opinion, points out the nuance in the sector’s projected growth. Bottom line: As pressure mounts to streamline & increase the efficiency of traditional API production, especially in the generic space, newly-emerging compounds (e.g., peptides, HPAPIs) are beginning to shift the balance in the wider market – hence the still-quite-respectable projected growth rates.
Specialty API projects tend to be more complex, requiring extensive process discovery and development across multiple scales. With high-potency APIs, additional containment and infrastructure adds to the challenge, while peptides have their own complexities.
In response to the increasingly specialization-driven nature of the pharma manufacturing space, most manufacturers have evolved their own respective knowledge sets and expertise. In the case of Neuland, we bring mastery of complex chemistry to bear on small molecule drug manufacturing challenges, with an emphasis on regulatory excellence.
API Geographical Market Segmentation
In terms of the API Market report’s segmentation into North America, Europe and Rest of World (ROW), the breakdown seems broadly (and very generally) accurate. [Of course, we do take issue with ROW CMOs reportedly focusing on bulk manufacturing versus quality…the implication being that ‘bulk’ and ‘quality’ are somehow mutually exclusive. Neuland has been a bulk ROW manufacturer focused almost exclusively on the U.S., E.U. and Japanese markets for over 30 years with a spotless regulatory record. Our focus is on quality, high-purity and, yes, also bulk APIs that meet the most stringent global regulatory standards. It is just a long-time point of pride for us!]
A pharmaceutical manufacturer is only as good as its supply chain. Supply chain management and strategic sourcing are the key drivers which keep operations running smoothly.
Set the Right Inventory Targets
When planning for the coming quarter, you need to ensure capacities are fully met. Adequate inventory of required items and at right quantities ensures continuous production thereby exploiting capacities to the maximum.
An OTIF – or ‘On Time in Full’ – calculation with a target of 95% is measured against pre-agreed benchmark lead-times. Here at Neuland we treat all User Departments requesting consumables as internal customers. Against agreed timelines, timeliness of deliveries is measured based on which all OTIF calculations are recorded. To achieve a high OTIF score means to balance the cost of disservice with the cost of carrying more inventories.
Choose Pharma Supplier Sources with Care
It is critical to identify reliable sources that meet all aspects of your company’s requirements. When qualifying API supplier sources, consider among others:
route of synthesis
At each stage of the process, look for sources who meet your expectations for the supply of drug intermediates and key starting materials (KSM) for new products.
Line Up Multiple Sources
Once you’ve determined how to seek out and qualify your sources, you can use that same process to secure as many sources as possible for each KSM.
Remember, sources can suddenly be disqualified or lost without warning due to unforeseen issues—anything from pollution to business viability to regulatory issues or other problems which might prompt closures or supply chain constraints. While being caught in a single-source situation may be unavoidable (due to specific expertise or infrastructure), new alternate suppliers should be continuously sought and added to your source base. The more trusted sources you can enlist, the more your company’s reputation (or reliability) is potentially safeguarded.
Aim High, with First Time Right Approach
With the goal of continuous improvement, employ a First Time Right (FTR) approach. The FTR thinking focuses on suppliers and helping them to avoid potential rejections – internally though, it aims to focus and attack wherever gaps exist in specifications, methods and analyses. Striking a balance between supplier focus and internal accountability, such an approach can extend to everything from alignment of test methods including HPLC/GC columns and release procedures to pre-shipment clearance of CoAs. It can also be used to verify the recentness of production batches with select Suppliers of your KSM and Intermediates, to confirm the quality of incoming materials is in line with expectations.
Ensure Regulatory Compliance of the Supplier Base
A compliance program designed for KSM and Intermediate Suppliers can keep your supplier base audit-ready. Such a program should emphasize traceability, and clearly demonstrate that all processes are performed in compliance with relevant regulatory standards and the quality agreements made with Suppliers.
To improve supplier performance on commercial and technical parameters, you can measure and score:
speed of supplier response
All of these can be measured on an objective pre-determined scale, plotting supply base performance on two different axes of a Supplier Performance Dashboard. From there, Supplier Improvement Actions can be devised with the goal of moving the suppliers from three different sub-optimal quadrants (Q1, Q2 and Q3) to a more desirable fourth quadrant (Q4) [see image, at right].
Buying competitiveness can be measured using relevant benchmarks. Via a transparent RFQ process, you can invite multiple quotes, and then fine-tune the results based on Commodity Price Trends.
Deliver On Time
A manual tracking program can be used to track outbound cargo from origin to destination, per delivery terms. The Outbound Delivery OTIF, which is an effectiveness metric, (at Neuland, the target is >=95%) should reflect successful delivery lead-times vis-à-vis pre-determined target lead-times taking into account mode of transport and destination. Good performance in OTIF is a key indicator (barometer) of an end-to-end supply chain that’s working effectively.
By effectively pursuing and gaining visibility of demand to plan inventory, choosing and guiding sources that meet your expectations for quality, and keeping everything on track with an OTIF that makes sense for your business, you can manage your supply chain and sources with greater efficiency – improving your bottom line and benefiting your customers.
For us at Neuland quality is an obsession, as the article points out. As global pharma suppliers, we don’t put much stock into the perception that Indian pharma – or Chinese pharma (or any other particular region, for that matter) – is necessarily weak or subpar. For us, it’s a supplier issue…not a geopolitical issue.
The Cost of Outsourcing
The decision to outsource in the pharma and biopharma business is driven by one factor, and one factor only: cost. Everything else – from facilities & infrastructure, to developing & implementing a quality-driven mindset, to the collective team experience of having worked with hundreds or thousands of diverse compounds – all of those things can be acquired, given enough resources. It often simply isn’t cost-effective to do so.
So the decision to outsource is virtually always cost-driven.
But choosing who – which contract pharma provider – to turn to is driven by all of those other things that I mentioned above:
Does the provider have sufficient facilities?
Do they have the technical processes needed?
Do they have deep working knowledge of my class or specific type of compound?
What are the timelines?
Floating above all of these questions aimed at finding the supplier who is a good fit is quality:
What is the supplier’s regulatory track record?
How robust are their quality systems?
What is their quality adherence mindset?
So yes – the supplier must be able to scale a product accordingly. They must have the infrastructure and skills needed in whatever niche space the sponsor occupies. But the number one most important factor, given the highly-regulated environment we operate in? Quality.
That’s been our experience as a global provider. Since 99% of our products are exported to the U.S., Europe and Japan, we’ve always been keenly aware of quality. Our earliest FDA inspection occurred in 1997 – one of the first in India. In the article, our head of manufacturing operations – Pradeep Kumar Jain – is quoted at referring to Neuland as “a non-compromising organization” when it comes to quality. That mentality – at the core of what we do – is a key reason we’ve never once received a critical observation from any regulatory or customer audit.
Pradeep also said “production done without GMP compliance and quality in mind does not have any value to Neuland Labs or our customers” – a great reflection of our absolute insistence on quality.