Using QbD and a DoE approach, API manufacturers and CDMOs can reduce unanticipated challenges by developing deep process knowledge at lab scale – which aids in transfer to scale-up.
That isn’t just a random statement: QbD can radically transform the scale up process, and help companies avoid unforeseen complications.
Increased Regulatory Scrutiny and the Rise of QbD
Regulatory agencies are emphasizing the need for a more thorough understanding of products and processes prior to validating. This has led to widespread adoption of QbD (Quality by Design) approaches, which emphasize thorough process knowledge to avoid poorly-scaled processes.
QbD approaches typically use a Process Validation Lifecycle Approach, which is a holistic approach to development which supports and leverages:
Use of modeling tools
Use of prior knowledge
Control strategy implementation
Proactive process monitoring, including PAT for trending, continuous verification and continuous proactive improvement.
Scale-up, which we previously discussed, is a critical link in this lifecycle. Without enough data, it can also be a ‘what if’ exercise. Bottom line: insufficient process knowledge can result in poorly scaled processes. This typically translates into more Out Of Specs (OOS), reduced process reliability, as well as higher production costs and a lower profit margin due to increased reprocessing.
With development and transfer to scale-up, the challenges which arise tend to be in a number of different categories: safety, environmental, health, quality and economics.
QbD Enables Robust Technology Development & Transfer to Manufacturing
With cause & effect analysis of Critical Process Parameters (CPP) on Critical Quality Attributes (CQA), QbD also aids in robust technology development & transfer at manufacturing plants. In order for QbD to aid in scale-up, an appropriate control strategy needs to be in place to ensure a focus on critical points.
Engineering API Scale-Up
The involvement of engineers in the laboratory during development and optimization of a process is the key to trouble-free scale up and technology transfer. The extent to which engineers need to address scale up of operations depends very strongly on the interaction between the chemist and the engineer, and the stage at which engineering became involved in the process.
While chemists tend to focus on process optimization, engineers focus on the scale- and hardware-dependent parameters, taking plant conditions under consideration. It is this dual approach that enables a ‘Right at First Time’ technology transfer. This can be achieved by adopting:
A scientific statistical approach (QbD-DOE, ICH Q8),
Simulation scale-up techniques (Dynochem / Visimix) for scale dependent parameters
Lab validation of process in conditions simulating the plant
The use of Quality Risk Assessment (ICH Q9) to evaluate each unit process and operations
Development and manufacturing (ICH Q10, 11) of robust/safe processes
Achieving successful technology transfer requires a robust manufacturing process, which – under QbD – is a collaborative effort, comprising Research and Development, Manufacturing Technical Operations, Quality and more.
The benefits of a QbD approach to scale-up are numerous:
Better manufacturing efficiencies
Enhanced process control
Higher design space, resulting in global regulatory flexibility
Fewer Deviations and a scientific rational for strong CAPA
QbD is an effective framework for bringing together a collaborative and inclusive team comprised of both chemists & engineers to ensure a successful API scale-up.
While linear drug scale-up sounds great on paper, the reality is usually much different. In fact, scaling up an API can be challenging even under the best circumstances.
In fact, most scale-up challenges arise from the non-linear nature of shifting from the bench to the manufacturing plant. Not only do chemical reactions function differently at larger scales, but the environmental health & safety (EHS) issues can be enormous. (How enormous? Well, just how do you safely store – and eventually dispose of – millions of gallons of potentially highly-toxic chemicals each day?)
Here are 5 Common Challenges in API Scale-up our scientists frequently confront:
Reactions In Unit Processes, reactions may poorly impact product selectivity during scale up if they are not properly understood at the lab scale. This can result in an increase in impurities – impacting both yield and quality.A thorough working knowledge of the chemical reactions includes the effects of scale-dependent factors (such as mixing, mass transfer and heat transfer). Using simulation software (for example, Dynochem or Visimix), the effects of mass, heat transfer and mixing changes can be predicted at larger scales.
Design of Experiment (DoE) should be followed at lab scale to develop a robust process, including the time, temperature and mixing scale criticalities. This exercise will provide adequate Design Space for variability, and avoid surprises during scale up & technology transfer.The lab process validation & qualification to be done in the manufacturing plant should mimic the conditions at the lab scale. For example, switching to cylindrical reactors during manufacturing may mean the slower addition of reagents, a slower rate of heat increase and decrease and more.
Safety Data Generation Runaway reactions are a challenge during scale-up. Generating safety data at lab scale can potentially help in designing the hardware for pilot or commercial scale batches – leading to inherently safer process technology.This typically involves Reactions hazards and Thermal hazards studies. These are performed using Reactor calorimeters, Thermal Screening units (TSu), or Rapid Screening Devices(RSD) to monitor:
reaction initiation temp
adiabatic temp rise
gas evolution rate.
Crystallization Crystallization often causes problems if the Critical Process Parameters and their impacts on Critical Quality Attributes (CQA) have not been adequately studied.Crystallization can negatively impact solubility and dissolution rates. Changes in crystal habit (the external structure) or the crystal form (polymorphism – in which the internal arrangement of atoms is different) can have wider impacts on ease of filtration, washing and drying.
These changes, in turn, can impact the Particle Size Distribution and bulk density, porosity, surface area or polymorph-pseudo polymorph (solvates/hydrates) to ultimately affect the formulated product’s drug activity.Process Analytical Techniques (PAT) can be used during lab development to understand the impact of process parameters on physicochemical properties.
Drying Drying APIs at larger scales – much as with crystallization – can be complicated. It is common to use an NIR probe to perform an on-line moisture checks.Residual solvents are a frequently-encountered problem during drying, and they are mainly the result of the crystallization process.When crystallization solvent is trapped in the lattice, it is difficult to remove it to a level that meets solvent limits during drying. Crystallization process parameters should be studied at the lab scale, including the super saturation driving force and its impact of residual solvent.
Particle Size An APIs’ particle size has become increasingly important – down to the micron level. Equally as important, however, is the Particle Size Distribution (PSD) – essentially, how wide the range of particle sizes in a given sample. Common size reduction techniques to meet today’s small, tightly-banded distributions include multi-milling, micronization or other size reduction (or sometimes enlargement) techniques & systems.
Where particle size matters (and when doesn’t it?) Particle Engineering studies should be performed for both drying and crystallization using focused beam reflectance measurement (FBRM) and particle vision and measurement (PVM) probes to understand the impact of process parameters on target particle size and shape distribution.
Determining the proper parameters for API scale-up can be difficult. Using QbD and DoE approaches, API manufacturers and CDMOs can reduce unanticipated challenges by developing deep process knowledge at lab scale – which aids in transfer to scale-up.
As a pharmaceutical company, Neuland has always been committed to impacting life positively across the globe. Whether it is manufacturing products to improve health, or improving the life of its employees, the Company’s focus on ‘quality’ reigns supreme – and is reflected in our Corporate Social Responsibility activities as well.
The Company recently turned its attention to the issue of food waste and how we can help reduce it in order to contribute towards the global movement to eradicate hunger.
In R&D and each of Neuland’s other facilities, a set of Food Waste Awareness posters were recently displayed.
A ‘conversation-over-tea’ session was then conducted on 3rd July in our R&D center by Senior HR Manager, Mr. Shiva Kumar. During this interactive session which aimed to create awareness among Neulanders, participants discussed some of the facts and data about food waste, and shared their thoughts on the topic.
A Commitment to Good Corporate Stewardship
The result of Neuland’s collective effort was an astounding 75% reduction in food waste, beginning the very next day!
Thanks to everyone who came together to fight food-waste and contribute to ending hunger.
The changes we’ve witnessed in the fields of science and medicine over the last decade or two have been truly astonishing. When we stood at the beginning of the ‘omics revolution two short decades ago – long before the advent of Big Data or precision medicine – protease inhibitors and plasma TVs were just launching. It would have been nearly impossible to see what lay down the road 20- or even a scant 10 years ago.
Shrinking Planet, Increasing Opportunity
The typical business desktop computer in 1997 had significantly less computing power and storage space than an entry-level phone does today. And all of those technologies involved in developing a drug – chromatography, mass spec, imaging, data collection and analysis, and much more – have seen equal or even greater shifts.
Even within Neuland’s microcosm of the scientific world – advanced drug chemistry, peptides, contract pharm and APIs – the world has undergone massive shifts. Outsourcing, once an obscure option, has become the standard business model for research and drug manufacturing – thanks to rapid (and far-reaching) globalization. Supply chains have grown far more convoluted and complex, thanks to more efficient & faster manufacturing coupled with better infrastructure.
In the same timeframe, peptides shifted from a drug class of the past (insulin was discovered in 1922) to an up-and-coming drug class of the future.
APIs have also grown increasingly complex, with techniques unimaginable a handful of years ago now considered standard practice. Issues such as drug solubility, drug delivery, and the ability to process potent, very-low-volume compounds are seeing barriers drop rapidly (while new ones undoubtedly emerge).
Underlying all of this change has been technology. We’ve experienced this change as we do all changes: incrementally, and not as a single breakthrough. When taken in historical context, however, the two decade long change has been astounding in its breadth.
Drug APIs – More Complex, But Simpler to Make?
It’s hard to fathom what technology will look like or be capable of 20 years from now. What we know is that technology has allowed us to develop drugs that are far more complex than anything seen before. At the same time, however, technology has simplified things enormously.
That’s the key – we are able to perform much more complex tasks with greater simplicity and less effort or expense. Thus, tomorrow’s drug chemistry might very well make our current efforts look like the discovery of germs, or hygiene. These technology advances will have enabled medicine and science advances, further pushing out the boundaries of our knowledge.
Science constantly amazes me, so it is likely that the future of medicine – while perhaps somewhat unknowable – will certainly change how we look at treating human health issues in another decade or two.
What has amazed you the most about science advances in the latest 10 or 20 years? Join the conversation on Facebook, Twitter or LinkedIn using the hashtag #AmazingScience.
IP has fostered a redefinition of strategy, a focus on constant innovation, and a complete restructuring & diversification of businesses. In that earlier post, we wrote that an essential aspect of newer strategies is to ignore the patent cliff and focus on filling product pipelines.
I.P. – The Power Behind Growth
While frequently an intangible asset, intellectual property has always been a powerful driver for company growth. And while this is true almost regardless of industry, virtually the entire drug sector revenue model is constructed around IP rights. In fact, IP is likely the single most important factor in securing capital and developing partnerships in the life sciences industry.
Pharma and biopharma firms leverage intellectual property rights (IPR) in a number of ways to maximize business value – from out-licensing to partnering to the outright sale of IP.
Neuland’s Track Record of IP Innovation
Located at our Bonthapally R&D Center, Neuland’s Intellectual Property Rights Group manages all of Neuland’s and its client’s IP-related matters.
Our IPR department performs a number of critical functions. One key task is to create and maintain our value proposition. The department also focuses on adding capabilities to APIs that differentiate them from competitor APIs.
In most cases, this entails supporting Neuland’s Research & Development teams by identifying whitespace in each portfolio API molecule and converting the whitespace into commercial advantage.
Neuland has a 30+ year track record of innovation. We have filed 172 patent applications around the world, including: the USA, Europe, China, Canada, Japan and India. We have been granted 48 patents, and we have an extensive portfolio of patent applications in different stages of examination. We have been the recipient of the Silver Award for Patents under the category of Bulk Drugs/API by PHARMEXCIL (Pharmaceuticals Export Promotion Council, 8th Edition of Patents Award, 2015-2016).
By using a unique client-focused approach to I.P., we remove IP as an issue between us and you, the client. We’ve found this fosters the scientific creativity needed to develop better, faster, safer, less-expensive drug manufacturing processes. Our clients benefit from Neuland’s expertise & innovation, and we benefit by building successful, long-term customer relationships.
An Active Intellectual Property Group
Our intellectual property team performs a whole host of other tasks aimed at strengthening Neuland’s competitive differentiators. Here are some of the other Neuland IPR Group responsibilities:
Monitoring and managing IP administration
Providing vital input for IP-driven product selection
Assisting and guiding scientists in designing potentially patentable inventions
Supporting the Business Development and Marketing teams with IP-related issues
Resolving all IP-related customer queries
Maintaining a strong and focused patent portfolio
Identifying Paragraph 4 (IV) & early launch opportunities
This year’s DCAT Week saw a new format and setting, while Neuland’s first AsiaTIDES show demonstrated the growing importance of peptides to the Japanese & Asian pharma industries. Here are brief recaps of these two global shows:
We have historically been a sponsor at DCAT Week, and this year was no exception. We did expand our sponsorship activities this year to include the DCAT mobile app. This proved an excellent choice, given that DCAT changed venues this year for the first time in its history. With events spread out across New York City, the app enabled participants to navigate different events & suites and schedule meetings, while also learning more about Neuland and its various contract pharma products & services.
This year’s DCAT show began on a Monday, as opposed to previous years in which it was a mid-week show. It was one of many changes – notably, the venue shift from the venerable Waldorf Astoria to the Hotel Continental Barclay. From our standpoint, it actually worked out for the better. There just generally seemed to be more cross-pollination of people from other hotels – leading to better attendance at various events – including our own.
AsiaTIDES AsiaTIDES – held earlier this year in Kyoto, Japan’s oldest city (and former capital city) – is a conference focused exclusively on peptides and oligonucleotides (hence the ‘tides’). The last ten years has seen growing research, deal-making and clinical activity in peptide and oligo therapeutic programs, and AsiaTIDES represents one of the key events focused on oligonucleotide and peptide research and commercialization.
At the show, our team did an excellent job promoting Neuland’s advanced capabilities in the peptide space. Neuland – with expertise in both solution phase and solid phase synthesis methodologies – offers a full range of peptide synthesis services. These include the production of peptides from milligrams to multi-kilogram scale by standard sequential chemical peptide syntheses and segment condensation strategies.
Among the services our team discussed with attendees were our proprietary Prep-HPLC technique to increase throughput during peptide purification 10-20 fold, our large-scale manufacturing capabilities for complex amino acids & Fmoc-building blocks, and our peptide regulatory support services.
It was a well-attended show, which speaks highly of the therapeutic potential for the growing ‘-tides industry.
Thanks to all of our team members who helped make both shows a success!
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.