The past few years have seen major changes to the ways in which drug companies and their regulators go about ensuring the safety and efficacy of drugs. The response to COVID-19 accelerated trends that were already defining an era of significant change.
As scientific knowledge continues to advance, both in the fields of human biology and complex synthetic chemistry, most companies are either in the process of transitioning to digital data collection and retrieval or have already completed it. Manufacturing and Quality processes are also being streamlined and automated wherever possible.
Modernization is affecting everything from analytical instrumentation and process monitoring to risk management practices.
This work is enabling new levels of end-to-end visibility, helping to advance the goal of quality-focused cultures throughout the drug manufacturing industry. This is particularly important as globalized supply chains continue to expand, despite ongoing trade and supply chain uncertainties.
All of these factors have contributed to the increasing complexity of compliance as well as the importance of compliance. As a result, regulatory and quality excellence matters more than ever before.
Process validation has evolved significantly since it was first proposed by FDA officials as a one-time event to improve pharmaceutical quality in the 1970s. No longer merely a one-time “box-checking” exercise, it’s now an ongoing legal requirement in the drug industry, designed to build quality into every step of the process.
Good manufacturing practices (GMPs) for finished pharmaceuticals require drugmakers to determine that manufacturing processes can consistently meet finished product quality requirements, including those characteristics impacting the quality, purity and potency of a compound. This means your CMO must understand:
As the FDA makes clear in its Guideline on Process Validation: General Principles and Practices, this typically involves teams with “expertise from a variety of disciplines (e.g., process engineering, industrial pharmacy, analytical chemistry, microbiology, statistics, manufacturing, and quality assurance).”
Process validation is broken down into stages, as follows:
To keep pace with both technological advances and evolving regulations, Neuland complies with stringent international standards. In 2022, we continued to invest heavily in quality. Policy implementation is prompt and at times ahead of legislation thanks to focused monitoring of possible trends in regulations and standards.
Key initiatives of fiscal year 2022 have included:
Want to explore Neuland’s commitment to a quality culture? Learn about:
Digital transformation went from a popular corporate buzz phrase to an essential survival tool with the outbreak of the COVID-19 pandemic. Industries ranging from banking and restaurants to travel and manufacturing had to re-invent their business models literally overnight.
Although the acceleration of digital adoption changed many industries for good, few saw as significant an evolution as the bio/pharmaceutical industry.
As a result, IT has not only gained center stage; it has become a significant business enabler and differentiator. The early needs of social distancing, remote work and even (for a time) off-site regulatory inspections have given way to a new era of collaboration, diversity and flexible production — all of which is occurring at a faster pace than ever before.
Although these changes continue to open exciting new doors for the industry — including more advanced applications for artificial intelligence (AI), analytics tools, long-distance training and the promise of precision medicine — they’ve also brought new needs and challenges, both for pharma companies and their clients.
Going forward, contract manufacturers and other pharma stakeholders will need to satisfy two critical demands when it comes to IT:
Here’s a quick overview of key best practices that can help make these goals a reality, enabling contract manufacturers to better serve their customers while ensuring their peace of mind.
Before embarking on major IT investments, it’s important to have a clear vision of the capabilities and safeguards you will need to ensure smooth operations, data security and compliance. This was the process we pursued at Neuland, setting the following goals prior to our most recent round of upgrades:
Significant investments in IT are imperative for any pharma company that wants to compete in today’s rapidly evolving marketplace. A robust IT framework enables effective and seamless workflows – not only at individual sites, but offices, remote workplaces and operations worldwide. IT modernization also delivers benefits by making pharma organizations more cohesive and closely connected.
The pandemic has also forced a rethink of technology practices. One method of reducing disease transmission and limiting sterility issues was mandating the use of facial recognition, along with a temperature control system. After determining that this was the safest and fastest method of security, such systems were implemented across all Neuland locations.
Virtual desktop infrastructure (VDI) was also established for up to 90% of the organization to improve hybrid working and security. This enabled critical data to be stored safely in one central location while also enabling users to have convenient remote access.
Identifying a “single source of truth” (SSOT) can significantly improve management of master data. It’s the core process we use at Neuland to manage, centralize, and organize master data according to the business rules of the sales, marketing and the operational strategies of our company.
Better data quality delivers significant benefits in the form of improved business processes and greater efficiency, coupled with the elimination of manual processes — and the opportunities for human error that accompany them. All of these initiatives can reduce the workload on your team, which is a significant benefit as qualified talent becomes increasingly more difficult to find and retain. The adoption of robotic process automation (RPA) is also revolutionizing business operations by increasing productivity, enhancing accuracy and optimizing the use of resources in addition to the automation of the human process, response, and triggers.
At Neuland we’re also working on further improving resource management – including new strategies for planning, scheduling, and allocating resources to the right project at the right time to maximize customer profitability. The company recently undertook IFC automation to improve its governance process and implemented contract workforce management for all locations to efficiently manage the attendance and payroll of contractors.
Data protection and confidentiality are critical to any organization that works with innovator companies, especially in the pharmaceutical space. Regular vulnerability assessment and penetration testing (VAPT) should be conducted for any business unit operating critical devices. This ensures the resilience of IT infrastructure while enabling identification of possible routes attackers could use to break into the company network. In addition, security information and event management (SIEM) provides advanced threat detection so they can be addressed.
As remote collaboration, big data, and other information-rich needs continue to expand, it’s difficult to imagine how any pharma company can have too much bandwidth. We recently doubled ours across all global locations. Other effective initiatives include the implementation of network monitoring tools, centralized cloud-based WiFi infrastructure, and using applications such as Barracuda to provide email, spam and phishing filters.
Pharmaceutical process chemistry has come a long way since wholesale merchants began the commercial marketing of drugs in the 19th century. In fact, process chemistry has driven many of the key milestones in drug development over the last 100+ years.
Hydrogenation is an excellent example of a proven chemistry technique that is vital to modern drug discovery and development.
Chiral chemistry. Hydrogenation drives the field of chiral API synthesis.
Hydrogenation for API Synthesis
Hydrogenation refers to a chemical process in which molecular hydrogen (H2) is reacted with another compound, typically in the presence of a catalyst such as palladium or nickel. Catalytic asymmetric hydrogenation gives rise to a diverse array of chiral molecules useful for producing APIs.
The process involves the reduction of unsaturated compounds, often alkenes, to introduce one or two chiral centers. In turn, chirality plays a critical role in shaping a drug’s pharmacology by refining its target selectivity.
More than half of drugs on the market contain one or more chiral centers to ensure better binding affinity and stereoselectivity. However, achieving ideal compound chirality can be challenging.
Hydrogenation is a practical and convenient technique that is well-established in pharmaceutical process development. Its popularity and broad use are attributable to several key factors, including:
3-Step Guide to Scaling Up Hydrogenation Processes
There’s no denying the appeal of hydrogenation from both an economical and environmental perspective, but – and ultimately this is one of the most important questions in drug commercialization – is it scalable? There are a number of scales between bench and multi-ton bulk manufacturing. Translating processes across those scales is rarely linear – or straightforward.
Hydrogenation is quite scalable, but success hinges on 3 things:
Command of these 3 essential concepts will streamline the step up to large-scale production from laboratory/pilot plant hydrogenation. In addition, it will prevent surprises once hydrogenation in the plant commences.
Contact us today and learn how Neuland can help advance your chiral chemistry project.
Curious about Hydrogenation at Neuland?
Neuland’s investment in state-of-the-art hydrogenation capabilities has delivered key successes to our clients – from enhanced product development capabilities and improved operational efficiency to expedited time-to-market and more flexible manufacturing arrangements.
Our hydrogenation capabilities span every step of the process and include the following:
cGMP Industrial Capacity
Neuland also offers substantial hydrogenation capabilities for R&D projects, allowing us to scale your process as needed from the bench through commercial production:
Sustainability has become a key trend in drug manufacturing. As we’ve previously discussed (here and here), this is being driven by environmental/good corporate stewardship efforts as well as various cost considerations. From greening supply chains to reductions in carbon emissions, pharmaceutical companies are increasingly taking steps to incorporate the principles of green chemistry into every aspect of their business.
With organizational spotlights focused on sustainable practices, Environment, Health, and Safety (EHS) departments are receiving a great deal of attention.
The Challenging Role of an EHS Department
Although ecological responsibility and sustainability are popular buzzwords today, EHS teams don’t have an easy job. Much of pharma’s success, in fact, rests on the EHS department. From a ‘green business’ perspective, the department is responsible for developing and implementing policies that encourage sustainable practices throughout an organization. They also monitor the progress of those efforts.
From a ‘green chemistry’ perspective, they work closely with process and product chemists to ensure the safety of manufacturing processes. Without a competent team, the safety of the workplace, the employees, and the environment is at risk.
Effective EHS policies keep operations running smoothly toward the goal of sustainability, ultimately creating a healthy balance between risk mitigation and adherence to sustainable green principles.
EHS and Continuous Improvement
Even as EHS teams achieve successes and make strides in supporting sustainability, they remain aware that their work isn’t once-and done. Rather, it is an ongoing process focused on continuous improvement. Key functions of EHS team members include evaluating processes and practices, focusing on employee education through green training and setting measurable goals for green actions.
EHS Focus on Employee Health
To prioritize occupational health, an EHS team should offer training that covers personal hygiene, health monitoring, first aid knowledge, and adherence to COVID protocols. These health-related issues recognize the importance of human workers and are indispensable to the protection of company manpower. Many pharmaceutical companies are still rebounding from the detrimental effects of COVID-19 on the workforce. Protective measures that preserve employee health are crucial.
Additional EHS training that focuses on other areas of concern – such as chemical safety and emergency procedure – are also vital. The success of the safety-based employee education is often evidenced by a reduction in the number of negative incidents and failed audits that occur.
Teams can monitor and facilitate company sustainability through:
Drug Manufacturing Sustainability Practices
The sustainability practices EHS teams employ are largely directed towards the reduction of waste output. Below are additional practices that EHS teams use to promote sustainability:
Despite the challenges associated with greener API manufacturing, some drug API manufacturers – including Neuland Labs – are leveraging better synthetic route design and sourcing alternate chemicals, reagents or precursors. The results can include less effluent and pollution, higher yields, shorter processing times, the use and storage of lower volumes of volatile chemicals, and the ability to downsize manufacturing infrastructure.
EHS, Sustainability & Neuland Labs
All of Neuland’s manufacturing units have adopted policies that protect the environment – including climate change and energy policies to reduce the company’s carbon footprint and Zero Waste Discharge policies to help minimize waste to landfills.
One key aspect of sustainable chemistry focuses on minimizing waste disposal via incineration. Working towards a goal of 0% incineration of waste, we send our spent solvent and other material waste to cement manufacturers, who use co-processing technology to convert this waste to an auxiliary fuel.
We achieved a recovery rate of 80-85% in FY 2021 using sophisticated solvent recovery systems. A wastewater treatment plant with higher capacity also came online, enabling the efficient management of additional load on the effluent system due to operational surges.
Some of the additional changes we’ve implemented are:
By assuming global good stewardship practices and incorporating EHS-focused actions, the pharmaceutical industry is well-positioned to optimize opportunities to protect the world’s citizens and ecological systems.
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Conjunctivitis (known as ‘pink eye’) is the infection or inflammation of the conjunctiva—the mucous membrane that covers the eye’s outer surface. In the United States, this uncomfortable ophthalmic condition affects an estimated 6 million people annually, accounting for one percent of all primary care visits.
It usually starts with inflammation, burning, and itchy eyes. It may present as a cold, or upper respiratory infection. Vision blurring and tearing are also common symptoms.
There are several varieties of conjunctivitis, including viral, bacterial, and allergic. While viral conjunctivitis constitutes about 80% of infectious cases and bacterial conjunctivitis accounts for up to 75% of pediatric conjunctivitis diagnoses, allergic conjunctivitis is the most prevalent form of the condition. In the U.S. alone, the allergic condition affects 15 to 40 percent of the population, presenting most frequently in spring and summer when seasonal allergens peak.
However, only a fraction of sufferers seek medical care. Consequently, the condition is frequently underdiagnosed and undertreated, and the actual number of allergic pink eye sufferers could be much higher.
With the incidence of allergic ocular disease continuing to climb, a direct link to a single, sole contributor has not yet been established. But experts believe multiple factors – pollution, genetics, household pets – may contribute to the increasing prevalence.
Treatment of Allergic Conjunctivitis with Antihistamines
Among pharmacological treatments, antihistamines have been shown to successfully treat flair-ups as well as chronic symptoms. Histamine blockers effectively address the inflammatory response that is secondary to the allergic occurrence.
In the past, oral antihistamines were the drugs of choice for allergic conjunctivitis because of their effectiveness in controlling allergic symptoms. However, concerns over negative side effects have made the first-generation drugs less preferable when compared to topical antihistamine applications, such as Alcaftadine. The second-generation agents offer faster relief, greater efficacy, and fewer side effects.
What Is Alcaftadine?
Chemically, Alcaftadine is identified as 6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-b]benzazepine-3-carboxaldehyde and is classified as an H1 histamine receptor antagonist.
The medication is applied as a .25 percent ophthalmic solution that is dropped directly into the eye once daily to help stop ocular irritation.
Alcaftadine was first approved by the FDA in 2010 under Allergan’s tradename ‘Lastacaft.’ Within 2 years, sales exceeded those of Elesta, another prescription ophthalmic antihistamine. A number of studies have shown (here and here, for example) that Alcaftadine may offer greater symptom relief than other second-generation antihistamines.
Challenges of Alcaftadine Manufacturing
Multiple challenges are associated with the traditional method of synthesizing Alcaftadine. Among them:
The impact of these various challenges can be dramatic, from raising manufacturing and process safety costs to lengthening synthesis cycles.
Neuland scientists have developed a novel route of synthesis (ROS) to address each of the areas of concern identified above.
The new methodology eliminates the time-consuming chromatographic purification step—utilizing two oxidation reactions instead. Toluene, rather than benzene, is used as a solvent.
With our approach, the overall product yield increases from 6.7% in the traditional process to 20% while eliminating the use of platinum.
To ensure that the Alcaftadine API meets International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) purity standards, we identify and remove any impurities that were created during the synthesis.
The Search for a Technique to Remove Diol Impurity
A key challenge during process development was removal of the diol impurity and unreacted Stage-III from the reaction mixture. The original method was recrystallization, but yields were low and other solvents aside from acetone resulted in a sticky reaction mixture.
We worked through a number of methods, including purification via column chromatography using silica gel (neutralized with triethyl amine) and complete oxidation of the crude reaction mass.
Ultimately, these experiments led our team to a process using two oxidation reactions instead of column chromatography – with ~20% overall yield from Stage-III, versus the product patent yield of ~6.7%.
Neuland’s Cost Effective & Ready-to-Scale Double Oxidation Process
Neuland’s technique uses manganese dioxide (MnO2) in an effective yet simple double-oxidation process. To perform the synthesis, we partially oxidate hydroxymethylated crude mass using a relatively small amount of MnO2. This oxidation eliminates the diol impurity and facilitates the alcohol crude crystallization.
Subsequently, we perform a secondary oxidation by adding additional MnO2 to produce Alcaftadine. This approach to Alcaftadine synthesis prioritizes quality, while delivering significant improvements in process efficiency, speed and commercial sustainability. Neuland has successfully completed three process validation batches, has filed a US DMF (No. 28277). This novel technique has received patent approval in India and is patent pending in the U.S.
Read the peer-reviewed Asian Journal of Chemistry article here > Investigation of Alcaftadine using a Double Oxidation Process by Eliminating Column Chromatography.
Do you have a complex pharmaceutical chemistry challenge you need to solve? Neuland can help! Contact us today to discuss your next API project or to learn more about Neuland’s novel Alcaftadine process.
Green chemistry principles first emerged in the 1990s, and the pharmaceutical industry – especially larger, global organizations – began steadily incorporating its principles in subsequent years.
Here are some recent examples of how Big Pharma has embraced the opportunity of green chemistry:
Green Chemistry: Needs to be Made the Norm, Not the Exception
Green chemistry is no longer the sole preserve of Big Pharma MNCs. With global pollution levels rising at an alarming rate and worst-case climate scenarios playing out around the world, significant efforts are underway across the industry.
Much more remains to be done, however. Adopting green chemistry principles in pharmaceutical process design and development unfortunately still remains the exception rather than the rule – something which must be changed in order to fully transform the industry.
Conceptually, the aim is waste and hazard prevention, but green chemistry is more than just an environmentally responsible approach to chemical product applications and processes. It has become critically important to the corporate bottom line, as well – hence its increasing adoption.
To minimize pharma’s adverse ecological impact and eliminate or reduce the global production and use of harmful chemical contaminants, pharmaceutical industry leaders are concentrating their efforts on embracing green chemistry concepts.
Pharmaceutical chemists are aware of the correlation between an increase in the organic syntheses of life-changing pharma products and surges in hazardous waste generation. Generally, the response has been a growing focus on greener alternatives to current processes.
Assuming Ecological Stewardship
For Neuland, assuming ecological stewardship means we remain aware that the application of green principles must progress from the lab bench to commercial scales. As we have voiced during various presentations in the past, the research of greening methods in the drug industry must fundamentally include actual process research rather than only the exploration of process design changes.
Successfully putting green chemistry into practice at scale, however, demands a rethink of existing practices. Chief amongst them is ensuring consideration is given to research across the various stages in the manufacturing process. Rather than highlighting only downstream process changes, we’ve found it effective to also prioritize research into front-end processes to identify pathways which promote process efficiency.
Focusing on Green Concepts
Green chemistry includes 12 principles— all designed to facilitate safety and reduce waste. As Neuland embraces these greening concepts, we are directing particular focus toward areas that apply to active pharmaceutical ingredients, such as atom economy, zero liquid discharge and chemical safety.
As the pharmaceutical industry strives for sustainable development, Neuland continues to research and develop safer processes for products, focusing on reducing waste generation, and improving efficiencies. Not only will these strategies lessen pharma’s ecological footprint, but they can also realize significant cost savings in the long run by decreasing the need for waste disposal and reagent procurement.
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As a follow-up to our recent two-part series on Regulatory Starting Materials Sourcing & Supplier Management, we sat down with Senior Vice President of Supply Chain Management at Neuland Labs Dr. Sundar Narsimhan to get his take on finding and qualifying suppliers for regulatory starting materials (RSMs).
What was Dr. Sundar’s key takeaway? Invest the time necessary in supply chain management of RSMs upfront to minimize the likelihood of problems downstream – and across the drug lifecycle.
What tips and tricks can you share for identifying and qualifying a supplier of regulatory starting materials?
In my 15 years in the pharma industry, a sustained search of the supply base usually leads to the jackpot. Fine-tooth combing through high-quality databases like DWCP and Row2Technologies can unearth excellent sourcing options for any given API and its intermediates.
That being said, results can be hit or miss if NECs are involved, and commercial RSM options are limited. In that case, it may be up to the R&D team to develop a cost-effective manufacturing process for the starting material to facilitate commercial external manufacturing.
In your opinion, how crucial is supply chain management when applied to regulatory starting materials?
The criticality of supply chain management in the procurement of RSMs can’t be overstated. Lives are literally at stake, so the first objective of supply chain management is to ensure consistent application of cGMP practices.
As a professional in the pharmaceutical industry, the industry’s objectives of preventing deaths and illnesses while improving health have always been a point of pride, and I believe effective supply chain management is a huge part of that.
What’s the most important step in sourcing and supplier management?
Due diligence has always been an essential part of RSM procurement. If you’re looking to establish a long-term relationship with a supplier, you can’t afford to skimp on due diligence. Do due diligence on your due diligence, and you should be good to go with RSMs.
How do contract manufacturers like Neuland align their sourcing strategy with clients’ requirements?
Flexibility and proactiveness are the biggest secret ingredients. For instance, at Neuland, our global sourcing strategy means we have a wider reach when it comes to ensuring the desired regulatory status and cost competitiveness for each client. Our regulatory affairs and other teams have a wealth of experience with RSM sourcing, which provides greater confidence to clients seeking to mitigate business risks.
Any parting words of wisdom to pharmaceutical companies regarding supply chain management of RSMs?
Don’t overlook this critical upstream process because it can potentially impact downstream processes. That’s a key reason why you should always work with an API contract manufacturer that is familiar with RSMs, has well-established sourcing procedures and understands the chemistry. The benefits include better traceability from starting material to final drug substance, reduced time to commercial launch, lower development costs, improved supply chain security, and more.
In Part I of this two-part series, we explored sourcing and supplier management of Regulatory Starting Materials (RSMs), and how effective designation and justification of RSMs begins with supplier market analysis, feasibility studies, lab validation, and source differentiation.
These stages reduce the available supplier options. But there are additional steps to take on the path to a commercial launch. This brings us to Part II of our in-depth dissection of the selection process for RSMs.
The initial stages of sourcing and supply management of RSMs generate massive amounts of data. Therefore, API manufacturers have a significant amount of information at their disposal for shortlisting of sources. Due diligence then kicks in to ensure only verified data is used when further narrowing the shortlist. Performing due diligence is vital for critical starting materials to ensure accurate risk assessment.
The first step in data verification involves getting information directly from the supplier, in addition to information sourced from external sources. A tailored and detailed supplier questionnaire is typically sent out, and the collected information should match details from external sources.
The second step in this process involves a site visit by the due diligence team. This allows for more detailed verification of critical aspects, including capacities and infrastructure, health, safety, quality culture, and general compliance.
What the due diligence team finds on the ground should corroborate previously collected information. The assurance of contracting with the right supplier can only happen by conducting appropriate due diligence beforehand. The combined data is then condensed into a report. Ultimately, the final go or no-go decision rests with senior management.
At this stage, teams tasked with the selection of RSMs turn to audit plan implementation and plant validation. Audit plans and validation are necessary to support the final ‘Go’ or ‘No-Go’ decision. Both processes should be tailored to the particular chemical, precursor, or intermediate incorporated into the API manufacturing process.
Generally, an audit is based on key parameters such as material classification, risk level as identified during due diligence, assurance of supply at a commercial scale, and the acceptance criteria for regulatory approval.
The audit plan is a valuable quality assessment tool that ensures the procurement process is headed in the right direction in the final stages. It culminates in an audit report that will potentially drive the finalization of the quality assessment and signing of the quality agreement.
With plant validation, the central focus is procuring starting materials for the commercial phase. The validation process encompasses the production of 3-4 batches of the API to ensure process repeatability and establish if the yield, quality, and impurity profiles generated from prior lab experiments remain acceptable at the commercial scale.
Plant validation also includes the validation of equipment, labs, and processes as part of regulatory compliance for pharmaceutical manufacturing facilities. Doing this early can reduce time-to-market and increase budget optimization.
Data is consistently generated at each stage of the procurement process. This presents an opportunity for continuous data analysis to better ensure compliance with regulatory standards. In other words, a systematic evaluation of collected data allows for the judicious selection of RSMs and increases the chances of regulatory acceptance.
For instance, if a synthetic route has been developed using the proposed RSM, data analysis shows if there are enough chemical steps from the final drug substance. Shorter synthetic routes are unpopular with regulators since they typically don’t leave enough time or space to effectively remove impurities and isolate APIs.
Once an analysis of the data shows the appropriate level of alignment required for commercial approval, it’s time for regulatory filing and review. Regulatory review of the proposed RSM generally depends on the location and the type of regulatory agency involved. So, knowing location-specific regulations and regulator protocols helps with accurate data analysis and anticipation of potential risks.
Data analysis and regulatory filing are better off performed before developing downstream processes, since failures in upstream processes could cause an expensive redo of downstream development work.
The sourcing and supply chain management of regulatory starting materials is a critical factor in the balancing act of meeting or exceeding regulatory requirements – while maximizing commercialization and de-risking supply. Investments made into the process allow stakeholders needs to be addressed and operational sustainability to be met.
Supply chain management is an essential chapter in the pharmaceutical manufacturing handbook. Managing regulatory starting materials (RSMs) seeks to maximize commercialization and sustainability while meeting and/or exceeding regulatory requirements.
Drugmakers must also ensure the final product conforms to the non-negotiable, pharmaceutical standards of excellence relating to quality, safety, and efficacy.
Admittedly, it’s a fine line between advancing the priorities of regulatory authorities and the interests of stakeholders.
This two-part blog series offers an exploration of the critical stages of sourcing and supplier management of regulatory starting materials.
Supply market analysis sets the stage for identifying and qualifying a supplier of RSMs. It develops an understanding of the essential factors of the market, and the information helps formulate the right sourcing strategy for future, large-scale procurement initiatives.
Because of this, supply market analysis should be considered obligatory before building new collaborations, especially if there’s a high degree of risk and/or value chain competitiveness. Generally, the rewards outweigh the resource investment for this analysis. Supply market analysis involves the following steps:
Basic manufacturer requirements of the soon-to-be-procured material should already be in place to ensure a narrower focus and efficient data gathering. The requisite details include product and material specifications, quantity, and regulatory classifications.
Supply market analysis should result in the beginnings of a viable supplier list. This, in turn, is a solid starting point for selecting suppliers and starting materials. Before manufacturing a new product, feasibility studies and lab validation are paramount.
Feasibility studies and laboratory validation are used to assess whether starting materials are suitable. Feasibility studies shed light on the costs, routes, purity levels, process criticalities and technology deployment for the possible routes.
Suitable samples must be procured, assessed, and used to define the preferred route of synthesis. These steps define the number of critical process stages, the ease or difficulty of impurity purging, and the overall risk from start to finish.
After performing multi-batch feasibility studies and finalizing experimental work and production trials, a comprehensive validation report is compiled and signed off on. The next step is selecting the right RSM for procurement.
There’s a crucial connectivity between selecting suitable regulatory starting materials, and feasibility studies and laboratory validation. Remember, the validation stage involves the analytical testing of procured samples ahead of commercial production.
This stage of starting material designation and justification should arrive at a finalized shortlist of at least three suppliers. Generally, source selection uses wide-ranging acceptance criteria that cover the following:
These are some of the basics of supply management. In Part II, we’ll cover the later stages of sourcing and supply management with regard to regulatory materials.
In 1905, George Santayana published his famous aphorism: “Those who cannot remember the past are condemned to repeat it.” More than 100 years later, this is could be an unofficial guiding principle of analytical drug chemistry. The entire point of analytical chemistry is to build on those discoveries which have come before.
Genotoxic impurities? We’ve established thresholds and control strategies. Nitrosamines? Drugmakers are now mindful of their presence.
In the 100+ years since Santayana’s saying, our scientific knowledge of impurities has changed as radically and as quickly as the instrumentation and technology used to study them.
But the subtext here is also strikingly clear: with each passing discovery, we gain a little bit more insight into how much we still don’t know.
What we do know guides modern pharmaceutical science. We know impurities can appear in drug products at all stages of manufacturing, and we know that they can impact the safety or efficacy of a compound.
We also understand the primary sources of concern for impurities:
[For a full exploration of each of these categories – and many more – read PharmTech’s excellent 3-part rundown on impurities. While a bit dated (2012), it’s an excellent overview.]
As the role played by analytical chemistry in drug development has grown, our working body of knowledge – impurity formation, genotoxins, route design and much more – has allowed us to proactively confront impurities in an effort to ensure drug safety.
At the same time, it’s recognized that it is practically impossible to completely remove impurities during manufacturing. For that reason, manufacturers must leverage a variety of different strategies for effective impurity detection, quantification and control. Comprehensive impurity profiles should be developed to understand:
In a 2020 article in the International Journal of Environmental research and Public Health (Chemical Impurities: An Epistemological Riddle with Serious Side Effects), the authors wrote: “Although impurities are considered a nuisance in chemical synthesis, they are generally of little concern as long as their identity is clear and their amounts are under control.”
Xpurities: Exploring Unknown Impurities
Impurity control is clearly essential, but what about the impurities we don’t yet know about – the ones yet to be identified and characterized? They are often referred to as unidentified impurities “that can be identified only with qualitative analytical values (e.g., peak area, retention time, etc.), for which structural information is not yet available.”
The authors of the article labelled these “Xpurities” to distinguish them from known, identified impurities. They were reported to be “surprisingly common and constitutes a major issue in pharmaceutical research and practice.”
A PharmTech article last Fall on unknown impurities discussed the various technologies currently in-use for impurity detection, as well as what’s on the radar. Current methods for small molecule impurities, based on an orthogonal approach, tend to rely on chromatography with UV-detection. Mass spectrometry (MS) is also a popular approach, but older mass specs (e.g., single-quadrupole MS) face challenges due to lower resolution.
Other methods to isolate and characterize impurities in pharmaceuticals, as described in the Journal of Advanced Pharmaceutical Technology & Research include:
“Capillary electrophoresis, electron paramagnetic resonance, gas–liquid chromatography, HPLC, solid-phase extraction, liquid–liquid extraction, UV spectrometry, infrared spectroscopy, supercritical fluid extraction, NMR and RAMAN spectroscopy.
Among all hyphenated techniques, the most exploited techniques for impurity profiling of drugs are LC-MS, LC-NMR, LC-NMR-MS, GC-MS, and LC-MS.”
The next generation gas chromatography-MS (GC-MS) and high-resolution MS (HRMS) are being developed to work in tandem with other technologies to detect and identify impurities in samples.
An article on USP’s Quality Matters blog discussed nitrosamine contaminants in drug products and how the initial 2018 valsartan problem grew in scope and continues to impact supply chains today.
“The complexity and global nature of the pharmaceutical supply chain demands greater diligence, transparency, and collaboration between manufacturers and regulatory agencies around the world to protect patient safety. Collaborative efforts between these and other stakeholders, along with effective tools to detect and control impurity levels, will help safeguard patients’ continued access to safe medicines that deliver the intended therapeutic benefit.”
Impurity detection and control is a dynamic practice, and it relies on process chemistry expertise, a best practices approach, and familiarity with the latest instrumentation, methods & capabilities.
The valsartan nitrosamine issue was a clearcut example of how we – as an industry – build upon new discoveries and understandings. Nitrosamines have been around for quite some time, but it was only more recently that it became an issue for the drug industry and regulators.
Check out our in-depth explainer on How the Valsartan Contamination Happened: Its Context & Implications, or our follow-up post tracking the regulatory changes in response to nitrosamine contaminants.