Synthetic route selection is a crucial element in API manufacturing. While the requirements of the synthetic process of a drug will naturally evolve during its life cycle, scouting alternate routes early in process development offers you many benefits. Alternate routes have the potential to help you:
At Neuland Labs, our expertise is often called on to provide custom synthesis and route scouting, and we’ve found that demand for these services has continued to grow as more companies realize the cost, efficiency and safety benefits of process optimization. In this post, we’ll share some of the top things to consider when devising new routes.
Essential Drivers of API Route Scouting
When developing a new synthetic API route, you should look for a route that:
While meeting the three criteria above would yield the most benefit, focusing on even one or two of these criteria can provide significant process improvements. For niche products, most companies seek to reduce cost by 2-5% through alternate routes; for generics, much greater savings are sought.
In addition to cost, other factors to consider are batch sizes, throughput of the product, lead time and reducing batch cycle. Shortening the route is frequently a goal, as this one change can singlehandedly decrease cost, time, waste and regulatory constraints.
Ask the Right Questions to Improve Alternate Routes
Keys to Getting Route Scouting Right
As you consider your options, keep these final points in mind for greatest success:
By guiding your research with these tips, you should be able to create a new synthetic route that meets your expectations and is sustainable across the drug lifecycle.
Data integrity is a key factor for ensuring end products in the pharmaceutical industry meet all quality guidelines. It provides assurance that accuracy and consistency have been maintained throughout the drug life cycle.
Neuland’s Ashok Gawate, DQA & Regulatory Affairs General Manager, recently wrote a guide to promoting successful data integrity practices.
With attention to data growing, data validation plays a key role in maintaining an organization’s credibility in the pharma industry.
No Small Data Errors
There is no such thing as a small data error: one tiny mistake can call into question the validity of all your data.
A Contract Manufacturer’s Quality systems must have adequate controls to protect the validity of data and procedures for discovering, and more importantly, preventing problems even before they occur. Routine data audits are an effective method of weeding out errors, and a robust training program can decrease the number of innocent mistakes.
Data Integrity Issues
Data integrity problems go far beyond deliberate falsification of data. Untrained employees, disorganized systems and lack of oversight generate more errors and can be more difficult to spot than intentional acts of deception.
While the commitment to data integrity may come from the top, it’s the people in the trenches who are best able to spot and prevent mistakes – if they know where to look.
Data integrity falters when institutions prioritize financial success over product quality. This ultimately trickles down to unrealistic cost controls forcing inadequate investment in staffing, employee training and development, facilities, equipment, systems and controls. Also, leaders who are disinterested in two-way communication or team engagement may indirectly fuel an environment where employees are not empowered to do the right thing.
Preventing Data Integrity Issues
Lack of upper management focus thus results in lack of innovation and continuous improvement, which is integral for data integrity and security. To prevent data integrity issues, drug manufacturers need an atmosphere that fosters the sense that each employee has a responsibility towards data integrity.
A first step is to provide a way for employees to communicate data integrity concerns to managers who have the authority to address problems. Providing a pathway for data integrity concerns to be brought to management’s attention promptly can avoid having these issues discovered during FDA inspections.
A successful data integrity practice in an organization starts from the way training is imparted to the employees. Take a look at your training program and ask these questions:
Adjustments in the way employees are recruited, trained and assessed can yield positive results.
Common Sources of Data Problems
Let’s take a look at some common sources of data problems.
Batch Records Violations are one of the primary sources of data integrity issues. Here are some steps you can take to weed them out:
Weak documentation control opens windows of opportunity for data abuse. To close those windows, avoid:
Computer system controls can also impact data integrity. Good general data management controls should provide clear expectations of how data will be generated, reported, reviewed and maintained, including how access to computer systems for generating and modifying data will be limited to authorized personnel, and how data will be protected from tampering.
Pharma contract manufacturing companies should create SOPs that address system change control. These SOPs would govern how data integrity would be maintained during data backup, retention and recovery when changes are made to the computer system.
Electronic Document Control
If you are using electronic systems for data collection, analysis and/or storage, here are a few rules to follow:
Data Integrity in Laboratory Testing
Data integrity is essential in laboratory testing. You need to make sure that all procedures are clearly spelled out and understood. Check what notebook to use for data recording, which analytical method to use, how to cross reference data in other sources – all these need to be taken into consideration.
Investigations of lab nonconformities can also be problematic. You need to know that those conducting the investigation have really gotten to the heart of the problem, starting with the initial analysis of results and reviewing all investigation documentation and steps taken during the investigation.
Questions you need to ask include:
In addition to reviewing documentation, observing the lab itself can help you spot data integrity issues. Take a walk through, considering these factors:
The Pharma Manufacturing Area
To maintain data integrity in pharmaceutical manufacturing areas, check if:
Another useful technique is to interview employees regarding their areas of responsibility. Ask where their instructions/SOPs are found and how problems are addressed.
Managing Turnover – in Both Equipment & People – to Ensure Data Integrity
Staff turnover can be an issue for some companies, as it is rare these days for people to stay with the same company for decades. This means the hiring and training of new employees is more frequent, leaving opportunities for inexperience or insufficient training to cause data integrity problems.
Likewise, equipment must be maintained and periodically replaced with newer machinery; both instances offer opportunities for data integrity failures to occur. If implementation of a new piece of equipment isn’t done properly, for instance, that can cause data issues.
Addressing these issues is critical to the process of maintaining data integrity. Utilizing best practices – in conjunction with top-down support – can serve to improve both compliance and operational efficiency.
In both the generic and innovator pharmaceutical API production sectors, time-to-market is a critical factor.
How critical? A one-day delay in reaching the market could mean the loss of $1 million.
Because of this, from a risk-analysis standpoint time- or speed-to-market may be the decisive factor when it comes to pursuing a product or candidate. And it continues to become even more important as the costs for drug development have soared.
Beyond just cost, time to market is also an issue of global dimension. Earlier this year, China began considering measures to shorten time to market for approved imported drugs in an effort to ease a shortage of such medicines.
As noted at American Pharmaceutical Review:
“Speed — specifically, speed-to-market — has been and remains the key to success. In order to achieve fastest time-to-market, one must have reliable access to cGMP process capacity, when and where it is needed. A product’s success depends on a rapid transition to market, which is why achieving full-scale production in less time has many benefits, such as extended patent protection for approved drugs. Likewise, penetrating new markets before the competition can produce a profound and lasting advantage. Manufacturing capability, once perceived as a time-consuming obstacle to initial market penetration, now determines success more than ever before.”
Controlling the Risk of Market Entry Delays
Fortunately, there are steps drug manufacturers typically take to help reduce the risk of market entry delays. While the risk cannot be completely eliminated, the use of certain Best Practices can decrease their likelihood.
“Briefly, in making a Paragraph IV Certification, the generic drug maker says the patent is at least one of the following: (1) invalid; (2) not infringed; or (3) unenforceable. That’s the Reader’s Digest version on the requirements for a Paragraph IV Certification; after that, the story gets much more complicated and adversarial.”
It’s fair to say that Paragraph IV certifications offer opportunity, but also some risks. As Guttag mentions, it is – in fact – a complex issue, and pharma companies risk losing the first-to-file advantages of Paragraph IV if clinical and manufacturing timelines are not met.
With rising drug development and commercialization costs, the smallest delays in getting to market can have large financial repercussions. Companies need to adopt strategies that minimize and control the risks to enhance speed-to-market.
This month, I managed to catch up on some of the industry articles I’ve been waiting to read which were relevant to APIs and pharma manufacturing generally. Here are a few you might find interesting:
What Does the Future Hold for the API Industry?
Patricia Van Arnum at DCAT tackled APIs and what the market holds in a DCAT Value Chain Insights piece:
The market for active pharmaceutical ingredients (APIs) is approximately $140 billion and is projected to reach nearly $190 billion by 2020. Read it at DCAT.
Growing Focus on Raw Materials Compliance
Mark Hoffman’s piece at PharmaManufacturing.com (Critical Success Factors in Raw Material Storage & Conveyance) took a look at the growing importance of raw material supply chain compliance:
“Increasingly, this environment also has become integral to the rigorous regulatory requirements for tracking and tracing products throughout the supply chain.”
We touched on this in our last post – accurate, comprehensive documentation is a must!
There were many interesting pieces in PharmTech’s 40th Anniversary section (you can see their complete coverage here: PharmTech Reflects on Four Decades of Bio/Pharma Innovation), but I’ll share a few that caught my eye:
Perspective: Big Pharma No Longer the Center of Innovation
Chris Moreton takes a look at the shifting role of Big Pharma over the years, and the positive effects of drug regulations.
Perspective: Drug Costs and Pharma’s Future
AAPS President Binodh Desilva discusses how drug costs, biosimilars, and cloud-based technologies will impact the pharma industry, and what the future holds for the American Association of Pharmaceutical Scientists (AAPS).
Process Validation Evolution: The Lifecycle Approach
Paul Pluta shares the history behind the FDA’s process validation guidance, discusses its evolution and the lifecycle approach.
Braille and Not-So-Common Drug Packaging Standards
Lastly – though unrelated to Neuland or APIs, I thought this piece on the use of Braille to label drugs for visually impaired patients in Pharmaceutical Processing magazine was interesting. There has been a shift towards common and comparable cross-border regulatory requirements for years, but there are still differences between the various rules & regulations. This article points out the different requirements for Braille between Europe and the U.S.
Current Good Manufacturing Practices (cGMPs) are an essential aspect of compliance, and attention on them by regulators is growing.
In today’s global pharma industry, it’s common to have multiple investigators from around the world inspect your facilities. In recent years, manufacturing facility inspections have grown in frequency and are now performed on a routine basis to ensure compliance with appropriate standards & regulations.
Familiarity with Global Regulators
To date, Neuland has undergone 28 Regulatory inspections from 9 different regulatory agencies – stretching back to 1997. These included inspections by U.S. FDA, the European Medicine Agency, Japanese, Korean, German, Brazilian, Mexican, Australian and French regulators, as well as the EDQM (European Directorate for Quality of Medicines & Healthcare).
Typically, during an audit, companies will be asked to share a number of documents. This was true of Neuland’s most recent inspection by the U.S. FDA for which the FDA issued an Establishment Inspection Report (EIR) for FDA approval of Neuland’s facility.
Here’s just a sample of the documents or records we’ve been asked to provide regulators during FDA audits:
Intensifying Regulatory Scrutiny of Data.
An important part of every Regulatory inspection is a check of company quality records to assess whether the Company follows its own standard operating procedures (SOPs) and work instructions. In recent years, data integrity has become one of the most critical factors to ensuring GMP compliance in the pharma industry.
Regulatory bodies are digging deeper and deeper into data to ensure manufacturing and test information is accurate and consistent.
But here’s the good news: companies who treat every task, every batch and every day as if it were an audit have very little to prepare when it comes to an upcoming inspection.
Here are some of the key success factors we’ve found for regulatory inspections at Neuland:
Regulatory Success Roots in Team’s Dedication to Quality.
Neuland’s decades-long track record of regulatory success is due to continuously maintaining quality and excellence in our API development and manufacturing activities. That mindset owes itself to the Neuland team who constantly work to improve and grow – both as individuals and as a group – to ensure we maintain our focus on excellence.
Across all of our 2017 inspections and audits, I am thankful to each employee who worked hard – and who continues to work hard, every day – to keep Neuland’s facilities in compliance.
The healthcare industry is driven by scientific innovation, often in response to various public health crises. But while science & discovery often leap forward, the physical act of manufacturing a drug can lag behind.
A recent article at PharmTech (Breaking Through Obstacles to Improve Drug Manufacturing) bemoans the barriers to continuous process improvement.
“We saw what the industry can do and what regulators can support when the Ebola virus struck, and vaccines, which usually take over a decade to develop and approve, were developed and released in months,” says Maik Jornitz, CEO of G-CON. “Why can’t we bring these approaches for the urgent to the normal, and create a more rapid approval approach?” he asks.
I made this point in a post on the Pharma Industry and Regulatory Agencies back in April – and it is still quite applicable. Fact is, technology is shifting faster than industry can keep up – let alone the regulators. And even with the best of intentions, the regulations themselves often arrive only after they are long overdue.
Because of the nature of our work and the fact that lives depend on us getting it right – both in terms of safety and efficacy – caution is, of course, absolutely critical.
There are times, though, when it feels like we’re talking about finally adopting flip phones as the world contemplates the eighth generation of smart phones.
In the 30+ years we’ve spent developing APIs for drug companies, we’ve seen the pharma industry become globalized to a degree never even imagined. Our products alone end up in drugs spanning the globe – more than 85 countries at last count.
But, in light of the fractured regulatory standards worldwide, this globalization hasn’t streamlined manufacturing. Quite the opposite, in fact – as captured by this sentence in the PharmTech article: “One year, he says, Sanofi produced 83 batches of one of its vaccines according to 55 different configurations/variations, depending on the region involved.”
A More Agile Pharma Industry?
So what’s the answer? Pharma and its regulators need to become more agile – and as the article points out, it isn’t impossible, and it must be a collaborative effort between industry and regulators.
The FDA describes continuous improvement as “an essential element in a modern quality system and it aims at improving efficiency by optimizing a process and eliminating wasted efforts in production.” The challenge is getting the various parties on board with the overarching goal of modernization – refocusing from a mindset of ‘best historically-proven practices’ to ‘best available practices.’
The FDA is moving in this direction. Objectively, the FDA and other leading regulatory agencies have been enthusiastic supporters of improving pharma manufacturing processes. This has led to the widespread adoption of QbD, PAT and other innovative methodologies to enhance process control and quality.
The FDA is also evaluating how to best address changes to manufacturing processes post drug approval – reducing the need for multiple review cycles or CMC supplements. Again, this comes down to a collaborative effort: companies will need to be able to provide sufficient assurances that they understand how the changes they make will be controlled, and what the potential risk factors will be for both drug quality and efficacy.
The biggest challenge seems to be in harmonizing the view of process improvement globally. As the article notes, regulatory bodies tend to focus on the countries or regions for which they have responsibility, while pharma companies tend to consider a product’s markets.
If you have even a passing interest in drug manufacturing, this PharmTech article is worth a read: Breaking through obstacles to improve drug manufacturing.
Peptides are a complex drug class, and have historically proven challenging from a manufacturing standpoint. They are, however, experiencing a renaissance due to improvements in peptide synthesis, the development of high-throughput approaches and various innovations to overcome some of their traditional limitations, such as stability and half-life. These advances are expected to drive the peptide drug market to over $48 billion by 2025.
As we’ve discussed in earlier posts, there are three main strategies for synthesizing peptide active pharmaceutical ingredients (APIs):
The decision regarding which production technique to use is driven by three pivotal factors:
The latter two criteria go hand-in-hand: as a drug candidate progresses through development and clinical stages, the required volumes grow, as do batch sizes.
These three criteria – more than anything else – drive the peptide API synthesis strategy.
Shifting from Solid to Liquid Phase Synthesis
Transitioning from one synthesis to another often maximizes manufacturing efficiencies and minimizes unwanted substances in a peptide API. The progression from one synthesis strategy to another typically flows like this:
Peptide Synthesis Selection Criteria
Solid Phase: 25 Amino Acids & Up|
Conventional wisdom suggests using a solid phase approach for peptides containing greater than 25 amino acids, for commercial quantities in the 1-10 kg range. Solid phase peptide synthesis utilizes an excess of protected amino acids to ensure as close to a 100% complete reaction as possible.
When larger quantities are needed, this can add considerable cost to the synthesis. However, a significant benefit of solid phase synthesis is the relatively shorter cycle time when compared to liquid phase synthesis. A secondary benefit: liquid phase synthesis of peptides larger than 15 amino acids is labor intensive.
Liquid Phase: 15 and Fewer Amino Acids
While the traditional approach to building peptides – liquid-phase peptide synthesis – has largely been succeeded by solid-phase synthesis, it remains useful for large-scale production. In fact, it’s an ideal strategy for peptides containing less than 15 amino acids and when commercial requirements range from 10+ kilograms to tons.
Hybrid Synthesis: More Than 25 Amino Acids & Larger Commercial Quantities
Today, a hybrid peptide synthesis strategy is generally chosen for peptides that are greater than 25 amino acids in length, and commercial requirements range from 10 to 200 kilograms. According to a recent market report, hybrid synthesis is expected to be a key driver of growth in the peptide drug market.
One notable success from hybrid synthesis was the pioneering work on Fuzeon, an approved 36 amino acid therapeutic for HIV-1.
Liquid Phase & Hybrid Synthesis for Improved API Substance Profiles
Whenever possible, transitioning from solid phase synthesis to a hybrid – and ultimately liquid phase – methodology is recommended due to the successive improvements in purification. With each change in strategy – from solid to hybrid, and from hybrid to liquid – significant improvements in the substance profile are observed with APIs.
Peptide APIs produced with a solid phase approach contain inherent deletion- and insertion-related substances. These substances decrease progressively with the transition to hybrid or liquid phase techniques. As peptide production progresses across these 3 distinct methods, the intervening purification steps increase – leading to fewer unwanted substances in the APIs.
As an example, Neuland experienced substantive improvements when we successfully used a liquid phase segment condensation strategy for the cGMP manufacture of 35 kilograms of a decapeptide NCE.
Exceptions to the Peptide Synthesis Selection Method Rule
While amino acid chain length and the need for various bulk quantities would seem to point to one synthesis technique over another, exceptions exist. Certain complex peptides such as Linaclotide are most conveniently produced by solid phase synthesis. In the case of Linaclotide, for example, Neuland – and others – have successfully leveraged this approach using 2-chlorotrityl resin.
Leveraging New Discoveries to Improve Peptide Synthesis
At Neuland, we routinely employ all three methods for the cGMP manufacture of peptides – solid phase, a hybrid strategy and liquid phase. We’ve also developed and patented a preparative HPLC technology which yields 10-12X higher output compared to classical Prep RP-HPLC. Among the advantages of our patented process (and the reason many of our peptide customers find it appealing), our Prep RP-HPLC technique results in reduced purification & post purification cycle times.
Earlier this month we wrote a piece on the Five Challenges Scaling Up an Active Pharmaceutical Ingredient (API). In the post’s conclusion, we discussed the role of QbD in aiding in scale-up:
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:
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:
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:
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:
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.
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.
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.