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Drug Manufacturing: Implications of the U.S. – E.U. Mutual Recognition Agreement

In July, the United States and European Union finalized a Mutual Recognition Agreement (MRA) for drug manufacturing inspections. Both parties have now fully implemented the MRA for specific therapeutics in their respective countries and territories.

First things first, what – exactly – does the MRA do, and why was it conceived?

The MRA allows regulators from EU member states and the FDA to rely on each other’s good manufacturing practice (GMP) inspections. It recognizes that each other’s regulatory systems have comparable capabilities, procedures and controls necessary to perform GMP drug inspections.

Every year, EU national authorities and the U.S. FDA inspect drug manufacturing facilities in the E.U. and U.S. – and also around the world – to ensure that they are operating in compliance with good manufacturing practices (GMPs). The now-finalized MRA enables

U.S. and E.U. regulatory authorities to recognize one another’s inspections in U.S. and E.U. facilities – and it should have a positive effect on drug manufacturers.

Early Moves Towards an MRA

The stage was set for today’s agreement back in 1998 when the EU and the US first signed a broad MRA. The agreement included a Pharmaceutical Annex which laid out reliance on each other’s inspections. The Agreement, however, was never fully implemented – falling by the wayside due to a number of other factors (which are well-explored in this Institute for International Economics chapter on US-EU Mutual Recognition Agreements).

In 2014 the EMA, EC, various EU national regulators and the FDA launched talks in order to fully adopt the annex, while beginning efforts to assess each other’s regulatory systems. The discussions culminated in the 2017 revision of the annex – which went into effect in November of that year. It allowed the U.S. and European Union to recognize each other’s inspections of drug manufacturing facilities.

PharmaceuticalOnline covered the reemergence of the MRA back in 2017:

“The passage of the Food and Drug Safety and Innovation Act (FDASIA) in 2012 reignited the dream of mutual recognition because the statutory language explicitly authorizes the FDA to accept the findings of a foreign inspector when its drug inspectorate is “capable” of conducting inspections that are equivalent to U.S. standards. Following FDASIA, negotiations between the FDA and the EU began again in earnest. Those efforts led to the historic 2017 amended Sectoral Annex to the 1998 U.S.-EU MRA.

The 2017 agreement originally applied only to EU Member States the FDA had evaluated. During this transition phase (as the EMA refers to it), the various regulatory bodies “assess each other’s pharmaceutical legislation, guidance documents and regulatory systems as part of the agreement.”

In 2019, Slovakia became the last EU nation to win approval (following on the heels of Germany, in June). The finalization of the MRA in July of this year marked the full extension of the agreement to all 28 EU Member States (with some exceptions – explained later) and the formal end of the transition phase.

What are the Benefits of the MRA?
So what does it mean for regulatory agencies (FDA and various EU regulatory bodies), as well as drug manufacturing firms?

There are a number of implications, all of which are positive:

  • Pharma Company Benefit: Streamlined Regulatory Regimes & Fewer Inspections
    One key benefit of the MRA – and it benefits both manufacturers and relevant regulatory agencies – is a more efficient and consistent inspection regime. By eliminating the need for duplicate inspections, companies in the EU and US will see cost savings by reducing their overall number of visits by regulators.This is perhaps the best example to date of a ‘highest-denominator’ global regulatory standard, set by two of the largest healthcare markets in the world. As a manufacturer, meeting a unified standard will potentially streamline our regulatory work, reduce administrative tasks and avoid the challenges that can arise with conflicting or contrary standards.
  • Regulatory Agency Benefits: Prioritization & Proactive Risk Management
    S. & E.U. regulators will now rely on each other’s drug facility inspections in their own territories. Much as manufacturers will be able to free up resources no longer necessary for duplicative GMP inspections, the agreement will also free up regulatory agency resources.Additional resources gives the respective regulatory agencies the capability to expand & extend inspections to countries where drug substances and finished dosage manufacturing increasingly occur, such as China, India and elsewhere. This allows the EU and FDA to prioritize higher risk manufacturing operations. It also improves their ability “to identify and address potential problems at manufacturing sites before they become a public health risk.
  • Patient Benefits
    The ultimate goal of everything we do in the life sciences is to better human health. From the patient’s standpoint, freeing up resources and allowing regulatory agencies to more proactively manage risk can help avert drug shortages. Patient can also more confidently rely on the quality and safety of the drugs they need – regardless of where they were manufactured.

Not everything is covered by the MRA.Benefits of the US-EU EMA
There are some exceptions to the broader MRA. In general, human blood, plasma, tissues and organs as well as veterinary immunological drugs are not covered by the MRA, and the respective regulatory regimes will continue with their own inspections.

Other exceptions exist for specific European nations. In Slovakia, the MRA will only cover single product facilities, while in Malta certain drug types are excluded (e.g., high potency).

What does the future hold for the MRA?

Beyond routine facility inspections, the goal is to extend the MRA to add other products & inspections.   For example, MRA coverage may be extended to include:

  • Vaccines
  • Plasma-derived pharmaceuticals
  • Investigational products/clinical trial materials
  • Veterinary products (with a decision due on expanding the operational scope next month).

 [ read more > Neuland Labs regulatory capabilities and services ]

From the Neuland Reading Room

From the Neuland Labs Reading RoomI thought I’d share some good reads this month. Have you checked out these articles? What did you think?

1989 to Present: PharmTech Highlights 30 Years of Bio/Pharma
PharmTech tackles 30 years of the pharma & biopharmaceutical industries – from the launch of ICH, the Maastricht Treaty and the European Medicines Agency (EMA), to unrestrained M&A, specialty pharma and the impending Brexit. There’s nothing like a nice trip down memory lane! Read it at PharmTech >

M&A – Will 2019 Set New Records?
Speaking of the M&A boom – it continues unabated. In What’s Behind all the M&A Deals in Pharma?,’s senior editor Meagan Parrish shares how 2019 is on track to be a record-setting year for mergers…the result of only two mega-deals (BMS’s purchase of Celgene and AbbVie’s acquisition of Allergan). More >

Sartan Impurity Testing
A few months ago, we published an analysis of the Valsartan contamination by Ashok Gawate – Neuland’s General Manager of Developmental Quality Assurance & Regulatory Affairs (How the Valsartan Contamination Happened: Its Context & Implications). NDMA and NDEA contaminants continue to worry regulatory bodies, and an article at shares how the Swiss Agency for Therapeutic Products is revising testing protocols >

Brexit & Supply Chains ponders the implications of no-deal Brexit on life science supply chains: “Companies risk either using up too many resources in contingency planning or end up not putting  enough aside and struggle to cope should the worst-case scenario unfold. In short, Brexit presents companies with challenges unlike any other they have encountered.” Read it here >

Chinese APIs Earn Trump Admin Ire
On the topic of drug supply chains & trade conflicts – APIs sourced in China are raising the ire of the U.S., with the Trump administration seeing “the increasing use of Chinese-made active ingredients in drugs taken by U.S. troops and civilians as a national security risk.”

Blockchain graphicIs Blockchain the Answer for Pharma Supply Chain Woes?
As the pharma industry seeks tools to maintain parity with counterfeiters, much has been said about the potential of blockchain. While still in its infancy – and with many obstacles to overcome – is it a viable solution? Here’s an article at PackagingEurope discussing its potential role in helping to secure drug supply chains >

Agile Pharma
In a recent post on project management, we discussed how we leverage both the Waterfall and Agile management approaches – depending on the project. With a focus on minimizing waste and time, Neil Osmond shares his guide to implementing Agile in pharma.

Yet More on Brexit
Hope about the abundance of outstanding trade deals the UK was going to sign post-Brexit has given way to the hard slog of actually doing it. In an article in PharmaTimes, Ana Nichols discusses the yet-to-be-completed trade deals the UK will need to negotiate and conclude to keep their pharma industry on track.



On SABAM, Cyanide and Safety

Levetiracetam, an epilepsy medication used for partial onset, myoclonic or tonic-clonic seizures, was first approved for medical use in the United States in 1999...Levetiracetam, an epilepsy medication used for partial onset, myoclonic or tonic-clonic seizures, was first approved for medical use in the United States in 1999. As a drug, it boasts excellent safety & therapeutic indices and high compatibility with other anti-epileptics.

Levetiracetam is now available as a generic. The global market is closing on 2,500 metric tons, and continues to experience a combined annual growth rate (CAGR) of 8-10%.

Backward Integrating SABAM
From an API manufacturer’s standpoint, intermediate costs are increasingly defining drug manufacturing market dynamics. Companies with API manufacturing capabilities, capacity & know-how are in a position to control pricing dynamics. This is the case with Levetiracetam’s intermediate, SABAM.

It’s a drug that has experienced a number of global shortages in recent years, in a number of different formats (both injectable and oral dosages).

The precursor chemicals for SABAM manufacturing are widely available around the world at affordable prices, without supply bottlenecks. In spite of this easy access to starting materials, SABAM can be tricky to manufacture – increasing its price.

Neuland manufactures about 6-8% of the world’s supply of Levetiracetam. With multiple customers, it’s one of our core products – which led to the decision to backward integrate SABAM manufacturing. Our goal is to reduce Neuland’s reliance of external suppliers and secure our supply chain to avoid disruptions. It also ensures our customers aren’t exposed to constantly-shifting market pricing and availability.

Since SABAM is the critical raw material for Levetiracetam, the production cost depends largely on the cost of SABAM. In fact, nearly 50-60% of the cost of the entire API is for SABAM.

To bring manufacturing in-house, our team performed extensive development work. In our R&D Centre, we identified and compared various routes and processes. Once a preferred route along with an economical & safe process was chosen, SABAM underwent the same tech transfer and validation processes we use for external clients.

Challenges of Manufacturing SABAM
Now, there are some challenges to manufacturing SABAM. This key intermediate of Levetiracetam is (S)-2-amino-butanamide hydrochloride (SABAM). For a cost-effective, bulk manufacturing process, we determined – after exploring all other commercial manufacturing options – that it was necessary to use the ‘cyanide route.’

The cyanide route is referred to as Strecker synthesis, and is described as a method of synthesizing amino acids by reacting an aldehyde with ammonium chloride in the presence of potassium cyanide. Given the volumes of SABAM needed, this route requires handling hazardous materials in bulk quantities.

The cyanide route is optimal, as the necessary raw materials for SABAM are abundant, available, and easy to access. In fact, one of the key synthesis chemicals is available in abundance, as a commodity chemical. This ensures stable availability, and removes dependency on other markets and external suppliers.

Implementing a Safe & Effective Bulk SABAM Process
Bulk SABAM production faces one particularly large challenge: hazardous materials handling. Due to the bulk volumes of dangerous chemicals required during manufacture (including cyanide, ammonia and other potentially hazardous materials), comprehensive controls were needed to ensure the health & safety of our team, and prevent potential environmental issues.

First and foremost, we needed to be certain we had technology in place to detect trace amounts of the hazardous chemicals in solid, liquid and the gaseous form at parts per million (ppm) levels. This informed our use of detectors, devices, and new air handling mechanisms. We planned and deployed specifically-designed control measures, coupled with continuous 24X7 monitoring.

More Opportunities for Levetiracetam
The decision to manufacture the drug’s key intermediate in-house has already attracted additional new customers for Levetiracetam. One Japanese customer, in particular, cited supply chain worries and our backward integration as decisive in their choice of Neuland as a partner. As supply chain concerns have grown in recent years, pharma companies are relying on diversified supply as a key risk management technique.

Are you interested in learning more about SABAM? Contact us today!

Unique API Particle Size Projects On the Rise

Why is there a growing preoccupation with particle size?
It’s because particle size can alter the efficacy (e.g., bioavailability) and safety profile (e.g., toxicity) of a compound.

Complex particle sizing is a growing trend, and expertise in particle reduction techniques for intermediates is evolving into a niche capability in its own right. It has taken on even more importance in recent years as the number of insoluble compounds with low bioavailability grows. Complex particle sizing is a growing trend, and expertise in particle reduction techniques for intermediates is evolving into a niche capability in its own right. It has taken on even more importance in recent years as the number of insoluble compounds with low bioavailability grows. And with dosages becoming smaller, tight control over particle size is even more critical.

According to PharmTech (Particle Size Reduction for Investigational New Drugs):

“More than 90% of small-molecule NCEs designed to be taken orally display solubility issues. Poor solubility makes absorption of the drug from the gastrointestinal tract into the bloodstream a challenge, and the resulting low bioavailability may require enabling technologies to achieve a therapeutic effect.

Most APIs in current development fall into DCS quadrant II (see chart, left), in that they have poor solubility but adequate permeability.”

Particle Size Distribution, or PSD, requirements are critical, since the smaller the particle size, the greater the efficacy (as there is a larger surface area – which translates to higher bioavailability). But if the particle size is too small, it could lead to toxicity. So the right balance has to be found.

The distribution of the particle sizes in a sample is a physical parameter, and is typically achieved using techniques such as controlled crystallization, post-drying micronization (e.g. jet milling) and wet milling.

How Many Requirement Tiers Are There?
Many projects involve products with a single tier of PSD requirements, for example, d90 < 10 microns (90% of the particles are 10 microns or less). As with any pharma project, challenges can arise even during single tier requirement products.

Projects become more challenging with two-tier requirements, in which materials are required to meet two distinct specifications. As the specifications move to three tiers, the difficulties become even more magnified. Controlling the particle sizes – for example, matching between the various tiers of d50/d90 – can require a combination of different particle reduction and particle sizing techniques.

Complex Particle Size Distribution Projects
In response to the growing need for tight control over particle size, Neuland launched a dedicated particle size engineering lab containing facilities for both dry and wet milling, and micronization. Some projects requiring a specific particle size and distribution have been completed which necessitated the use of all three size reduction methods. We’ve also adopted the latest particle size engineering technologies, including implementing inline and online particle size meters as well as the latest crystallization techniques.

We’ve conducted particle size engineering studies using micronization for products such as Indacaterol maleate (less than 5 microns) and Ticagrelor (less than 10 microns). In another project, data generated on experiments with the compound Levetiracetam were used to optimize process conditions to meet the PSD requirement prior to kg scale production.

The Four-Tier Specification – QbD & Labwork
Neuland recently worked on a project where the Particle Size Distributions (PSD) requirements were quite unique.

The product consisted of a 4-tier PSD specification. The API required a specific percentage mix of particle sizes to meet the customer’s formulation needs. The project also called for careful attention to the physical powder properties, to avoid negatively impacting processing & bulk powder handling.

When scaling a project from the bench to commercial bulk API quantities, knowledge of size reduction techniques and their impact on characteristics (e.g., flowability & hardness) is vital to successful process development.

This 4-tier project required a great deal of lab work. Using a QbD (Quality by Design) approach to process development, the team in Neuland’s Process Engineering (PE) Lab developed an efficient, effective and safe process to achieve the necessary complex specs.

QbD provides an effective framework under which processes can be modified to account for variations in the properties of the API. The project leveraged a number of QbD elements – process control, continuous improvementDesign of Experiments (DoE) and Design Space – to ensure a viable & scalable process emerged.

Neuland made key decisions during the process development project to achieve the customer’s unique specifications.

Instead of using a multi-milling technology, we chose a jet-stream milling technique. Jet mills grind materials using a jet of air or gas to impact particles into each other. Multimills operate differently, relying on beaters with different rotating edges to granulate and screen particles.

Neuland designed and created a special sieve to meet all four of the size specifications. (The actual process by which we arrived at the right sieve is confidential, but it was a critical aspect in driving development and commercialization forward.)

Particles in All Shapes & Sizes
From novel drug delivery techniques (e.g., inhalables) to the efficacy and safety of intermediates, particle size now plays a prominent role in pharma drug development & scale-up. The data generated by particle size distribution studies and experiments has expanded upstream – away from typical dosage form considerations – and is now used by the pharma industry earlier in the drug design process.

Are you ready to talk about your molecules? Contact us today.


Successful Pharmaceutical Project Management

In the pharmaceutical industry, projects now commonly span numerous stakeholders across multiple geographies.Think about your last project.

How many individuals and departments participated? How many locations around the world did it involve? How smoothly did the project progress?

Could you have improved outcomes?

Pharma Projects Are Growing Increasingly Complex
In the pharmaceutical industry, projects now commonly span numerous stakeholders across multiple geographies. The challenges involved with complex project management can materialize at virtually any stage: scope management, project planning, stakeholder & team management, regulatory strategy development, or budgeting & timeline development.

Pharmaceutical API Project Management
In recent years – as constantly-changing business dynamics have combined with more complex project environments – a firm grasp of project management has become more important.

Project management in the pharmaceutical and biopharmaceutical industries is slightly unique when compared to other sectors, such as infrastructure or IT. Though the formal adoption and use of project management is a bit less mature compared to the IT sector, the challenges confronting pharma are more or less the same – and sometimes far more complex – than non-life science-related spaces.

Project management is the heart and soul of virtually every undertaking in our industry. It has become the driving force of any project to track, monitor and deliver projects within the expected timelines & budget specified. Given the risky nature of scientific research, project management is closely aligned with risk management.

Waterfall and Agile Project Management Approaches
In the lexicon of project management, there are two approaches to managing pharmaceutical research or manufacturing projects. One is the Waterfall approach, and the other is Agile management.

The Waterfall approach remains the pharma industry’s primary approach to product development. The name describes the methodology...

The Waterfall Development Approach
The Waterfall approach remains the pharma industry’s primary approach to product development. The name describes the methodology – phases flow downward, like a waterfall. As a methodology, it is quite appropriate to the drug industry since requirements are often static, and well-understood from the start.

In the Waterfall approach, projects consist of a series of steps or phases which must be performed sequentially. The next phase begins when the preceding phase is completed and verified. Common phases performed in order include:

  • Requirements
  • Design
  • Implementation
  • Verification

Agile development takes a more flexible approach. Instead of delineating all of the requirements upfront (which may not be known), Agile defines each project as a set of tasksThe Agile Development Approach
Agile development takes a more flexible approach. Instead of delineating all of the requirements upfront (which may not be known), Agile defines each project as a set of tasks – many of which can be completed concurrently, rather than sequentially. Agile relies less on pre-planning, and more on flexibility and human interaction. Created in 2001, it was intended to streamline software development processes by de-emphasizing inefficient practices such as heavy documentation, excessive meetings, and rigid adherence to process.

In the June 2019 issue of PharmaVoice Denise Myshko discussed the rise of Agile management in the pharma space (The Agile R&D Organization), writing:

“Agile project management, first introduced in 2001, started out as a method used in software development that challenged the traditional, linear development model. The same benefits realized by the software industry, experts say, can be realized in pharmaceutical R&D.”

But – while it can help shorten drug development cycles – pharma does have some concerns with Agile. The de-emphasis on processes and tools seems to run counter to the highly-regulated nature of drug development – though it has also been pointed out that the reliance on human interactions instead “makes a robust process even stronger.”

The Right Pharma API Project Management Approach: What’s the Verdict?
Circumstances often dictate necessity. Different project management methodologies will appeal to different project types, timelines and other factors. Agile management in pharma – while lacking some of the robust documentation and other processes common to the industry – is growing in response to the need for more responsive approaches to address project uncertainties and the quest for shorter development cycles.

Neuland & the Balanced Matrix Approach
Hanover Research’s Best Practices for Matrix Organizational Structures (2013) describes balanced (or partial) matrix structures as:

“…considerably varied in form and might refer to a “temporary interdisciplinary task force for a specific purpose or a semi‐team structure developed in only part of the organization around certain functions or projects that need a high level of communication or coordination.”

At Neuland, we’ve adopted a balanced matrix design for project management, ensuring that technical leaders serve as the Project Managers (PMs). The balanced matrix gives Neuland the flexibility to create interdisciplinary, cross-functional teams, the need for which is dictated by the specifics of each project.

Although we follow the ‘Waterfall’ model (in which project planning, timelines and schedules are determined initially), we also utilize an ‘agile’ project methodology when appropriate. This allows us the flexibility to respond to issues as they arise during a project.

These two different approaches are not incongruous, and the end outcome remains the same regardless of approach: a safe and efficacious therapeutic. One method allows us to thoroughly plan out our static projects (ones with low likelihood of scope changes). The other method, well-suited to some of our earlier-stage projects, gives us (and the customer) the flexibility to adapt to changing or unpredictable circumstances, as well as tight deadlines.

Project Management Tools
To monitor and track the progress of our projects, Neuland uses the project management tool Concerto (which utilizes MS Project for the initial project planning). All project activities are sequenced or planned in parallel, depending on their dependencies. At the outset of every project, the following steps typically occur:

  • Project kickoff and charter development.
  • Project planning workshop, where timelines are discussed, debated, negotiated and finalized to fit the customer’s due date.
  • Task & task manager determination.

Our Project Management Office
Neuland’s Project Management Office (PMO) is made up of two groups: our project proposal team and our Project Coordinators (PCs).

Among their tasks, PCs manage project scope changes. The flexibility to manage project modifications is a necessity – especially in R&D and early phase projects. Projects shift over time and the earlier the project stage, the more likely it will see changes, additions or diversions over time.

You might be thinking since scope changes can and do happen, how are they typically handled at Neuland?

Below is our process for altering projects and communicating with customers:

  1. Project managers and coordinators along with the business development manager are the gatekeepers of scope changes. They communicate with both the customer and the business development manager if any work requested by the customer is outside the existing project scope.
  2. The scope change and its impact on the initial project timelines – and also the impact on the project cost – is evaluated and communicated to the customer for approval.
  3. After the customer indicates acceptance of the scope change, and the project owner and the Head of R&D approve the changes, the due dates are changed in the Concerto project management system.

Do you have an upcoming project? Contact us to find out how we can help ensure your project’s success.

Solving the Insoluble

Soluble drug APIs are now the exception, not the rule.

The overall complexity of molecules, along with their increasingly hydrophobic character, has led to increased obstacles that must be overcome during process development. It’s a challenge that continues through to formulation development and beyond.An article at PharmTech by Felicity Thomas (Looking Beyond the Solubility Horizon) caught my eye recently as it discussed a pharma (and biopharma) industry trend that’s on the rise. Insoluble drug compounds now comprise nearly three-quarters of all new NCEs – potentially compromising bioavailability…and thus their value as therapeutics.

Fact is, very few of our customers are able to dismiss solubility concerns outright. While solubility challenges seem to exist on something of a spectrum – with some drug solubility issues much easier to resolve than others – nearly everyone sees concerns arise during development.

Why the upsurge? According to the article, it “is a trend that is anticipated to continue to grow as a result of the industry drive toward development of more molecularly complex chemical entities.”

Our team concurs: the overall complexity of molecules, along with their increasingly hydrophobic character, has led to increased obstacles that must be overcome during process development. It’s a challenge that continues through to formulation development and beyond.

‘Making the Insoluble Soluble’
The PharmTech article shares some of the physical techniques used to overcome insolubility – namely, particle size reduction – when chemical synthesis techniques or the use of specific excipients is not practical or effective.

Techniques for improving drug solubilityChemical modifications during the development & scaling of an API can seem straightforward (replacing or changing the concentration of an ingredient, or buffer & pH changes). Unfortunately, even the smallest changes can have significant repercussions in terms of pharmacodynamics and pharmacokinetics – rendering it often a less-than-ideal technique.

The preferred technique today for APIs is to physically modify the molecule – typically through milling (particle reduction). There are a number of different milling techniques, and each one has advantages and disadvantages. Much, of course, depending on the nature of the compound, its sensitivity to various forces (e.g., sheer or heat), and how successful a basic technique such as crystallization may be.

This topic was also discussed in a recent article at Drug Development & Delivery (Improving Bioavailability & Solubility: Chemical & Physical Modification vs. Formulation Development):

“Functional lipids are a versatile tool for formulators and offer delivery strategies like self-emulsifying drug delivery systems (SEDDS) and lipid nanoparticles (LNPs). Nanoemulsions (SEDDS, SMEDDS, SNEDDS) were developed to provide improved bioavailability, reproducibility, and enhanced API permeation.”

One conclusion of the article – “While physical and formulation strategies can individually increase bioavailability of molecules, a combinatorial approach may be the best” – perhaps best captures the increased complexity this issue poses to industry, and the need for increasingly complex – and multifaceted – solutions.

Neuland is no stranger to solubility challenges. Our NCE customers are seeing this issue emerge much more frequently than in decades past given the types of molecules we are developing. For this reason, we launched our PEL, or Process Engineering Lab (here’s a post on our PEL’s success stories with particle reduction). The PEL is well-suited to tackling particle engineering studies to resolve drug intermediate solubility issues.

And while we have had success via route selection or process modifications, we often find one of the various types of milling (e.g., jet milling or multi-milling) is a good option to optimize API solubility.

The advent of so many different techniques to address solubility, however, can make a combinatorial – and cross-functional (chemical, physical, formulation and/or delivery) – approach ideal. Dr. Bowers in the Drug Development & Delivery article sums it up best:

“While physical and formulation strategies can individually increase bioavailability of molecules, a combinatorial approach may be the best. A SEDDS formulation that solubilizes a salified API created with a lipophilic salt is a perfect example. This combinatorial approach has demonstrated better drug loading and pharmacokinetic profiles then SEDDS alone. In the end, there is no wrong answer if the desired therapeutic response is delivered,” Dr. Bowers says.

Does your company have questions about API development & solubility?
We’re here to help! Contact Us Today >

How Pharma Controls Generic & NCE Manufacturing Costs by Backward Integrating APIs Ingredients

In the U.S., drug pricing pressures are mounting, and the profusion of lower-priced generics exacerbates the situationThe pharma industry is facing some outsized business challenges at present – from burgeoning trade wars to downward-pricing pressures and increased regulatory scrutiny.

More than one conversation our team members have had recently has turned to cost controls, with an emphasis on supply chain security. The tit-for-tat tariff increases between the U.S. and China have left some C-level execs shaking their heads…and pondering the impacts given that only finished pharmaceuticals are exempt – and not chemicals or APIs.

In the U.S., drug pricing pressures are mounting, and the profusion of lower-priced generics exacerbates the situation. In the generic space itself, only one lucky winner gets the Paragraph IV benefit – even if only for 180 days. For everyone else, cost controls – whether in manufacturing, distribution, or some other part of the ingredient-to-customer chain – are the primary option for maintaining a competitive advantage.

The Attraction of Backward Integration in Pharma Supply Chains
These days, ‘stable and predictable’ and ‘pharma manufacturing’ are becoming almost diametrically-opposed concepts. Companies reliant on API manufacturers in China received a rude awakening in recent years, when multiple plants faced government action over environmental and safety violations. (And ongoing tariff uncertainty has done nothing to placate concerns.)

This has led companies who want to secure their supply chains to place much more emphasis on backward integration. There are several ways in which a pharma company could seek to backward integrate. In the classical sense of the term, they could acquire their suppliers, which – while vastly more expensive and not feasible for most companies – does constitute true backward integration.

Pharma firms often secure supply chains by backward integrating ingredient supply. More typically, however, pharma firms secure supply chains by backward integrating ingredient supply. Rather than purchase a facility outright, both small pharma and large MNCs are looking for suppliers who can alleviate their concerns – without creating other, unpredictable complications such as ‘supplier-turns-direct competitor.’ (See #3 in our list of key supplier traits for securing the API supply chain, below.)

One key benefit of backward integration is that it helps bring down costs by increasing bargaining power when negotiating prices.

But how can companies address these various supply chain impediments? What should they be looking for in their drug ingredient supply chain?

Securing the Pharma API Supply Chain: 4 Key Supplier Traits
There are three key elements to securing an API supply chain, each of which leads to further strengthening of the supply.

  1. Choose a Supplier with In-House API Synthesis
    Why look for in-house synthesis capabilities? Security and stability of API supply. In-house synthesis helps reduce dependence on other, often foreign, chemical manufacturers for the API manufacturer’s supply…and thus yours.

    In the contract pharma business, this typically means the process for the raw material will be developed by supplier and then validated in-house. This reduces risk by ensuring greater control over the process, and eliminates the need for multiple raw ingredient sources – a practice which can lead to product variance/consistency and quality issues.

    Greater control means greater predictability. With manufacturing performed in-house at Neuland, for example, we exert greater process control to ensure production, compliance and quality targets are all consistent & predictable.

  1. Multiple sites for manufacture, to offset risk
    The API manufacturer should have internal supply chain risk mitigation capabilities. In the event of a natural (or compliance) disaster, they will ideally have in place alternate sites or facilities capable of providing seamless supply, at the capacities and frequencies you require. In some cases, an API supplier may be willing to develop the process on your behalf and outsource the manufacturing to further secure the supply chain (Neuland will do this in some circumstances).

    At Neuland, we’re in a better position to backward integrate due to our acquisition of Unit III. This acquisition has ensured we have the commercial capacities needed to shift the manufacture of intermediates as needed.

  1. Choose a Supplier, Not a Competitor
    In what has become something of a rarity, API suppliers remain just that: API suppliers. These manufacturers avoid competing with customers. In a growing number of instances, API manufacturers have chosen to jump onto the generics bandwagon…competing against their customers. This has led to numerous situations in which today’s supplier is tomorrow’s generic competitor – which is clearly not the best long-term risk mitigation strategy. Find an API supplier who is (and intends to remain) a pure-play API provider who focuses on maximizing the value of your drug.

  2. Focus on Regulatory Track Records & Chemistry Expertise
    This is always worth mentioning: an API manufacturer’s regulatory experience & track record as well as their complex chemistry expertise should match your future development & commercial needs. Nothing negatively impacts supply chain security more than an ill-suited supplier incapable of delivering your drug intermediates. This often boils down to proven experience with specific chemical reactions and classes of molecules, as well as a track record of compliance with the relevant regulatory bodies.

Each of these four elements – in-house synthesis, multiple site security, a focus strictly on API supply and a supplier’s compliance track record & expertise – contributes to stronger API supply chains. As a whole, they provide a single- or multi-source backward integration API supply solution for pharma companies.

Does your business want to improve supply chains and drive profitability with stable, secure access to the highest-quality APIs? Learn more about Neuland’s supply chain-securing Pharma API Capabilities >

How the Valsartan Contamination Happened: Its Context & Implications

Last year’s valsartan contamination and recall brought some surprising chemical synthesis issues to light in the pharma industry. While the reactions used in generic valsartan production are known to be a source of certain impurities, they were below current disregard limits and didn’t raise any red flags. It was the impurities that no one thought to look for, however, which led to the recall.

Valsartan is an angiotensin receptor blocker, or ARB, used to treat high blood pressure & heart failure. Neuland Labs does not manufacture valsartan, but the chemical synthesis risk management takeaways from this series of events apply uniformly across the API industry.

Generic valartan: better yields, but hidden toxicity raises questions about process chemistry quality managementWhen Novartis’ patent for valsartan expired in 2011 in Europe and in September 2012 in the U.S., manufacturers of generic active pharmaceutical ingredients (API) raced to develop their own synthesis processes. A market that in 2010 was worth six billion USD was about to open its doors.

Judging from the patents filed around that time, Novartis/Ciba-Geigys original method for the tetrazole-forming step relied on the use of tributyltin azide. The yield of this step was 65%.

Generic Valsartan – Better Yields, But Hidden Toxicity?
With valsartan, higher synthesis yields were critical in order to achieve costs low enough to capture the business of pharma companies.

Various methods for forming 5-substituted tetrazole cycles on nitrile groups with sodium azide had been around for some time – relying on the use of metal catalysts, strong Lewis acids or tertiary amines.

In September 2010 Zhejiang Huahai patented a sodium azide-based synthesis method for valsartan, resulting in much improved yields approaching 90%. At the time the inventors boasted: “The method has the advantages that the operation is simple, the yield is high, the product purity is high, and the industrial production is easy.”

But sodium azide, it turned out, was a dangerous substance whose toxicity compares to that of potassium cyanide. It was fatal if swallowed, inhaled or put in contact with the skin. Since the new synthesis method required bringing a stoichiometric excess of sodium azide to the reaction, an unreacted residue of this highly toxic substance would remain in the product.

To deal with the toxicity of sodium azide, Zhejiang Huahai’s valsartan process chemists opted to add nitrous acid to the production broth as soon as an in-process control confirmed the complete formation of the tetrazole cycle. They did so in the form of sodium nitrite –  which in the acidic environment of the broth turned into nitrous acid. Nitrous acid was a known decontaminating agent of sodium azide. It caused the degradation of sodium azide to nitrogen gas, nitric oxide and sodium hydroxide. The toxicity issue was thus resolved.

NDMA: Toxicity Tragedy
Zhejiang Huahai patented this production method in 2014, but their valsartan process had been based on the use of sodium azide as far back as 2012. Tragically, Zhejiang Huahai’s chemists failed to realize that while eliminating the toxicity due to sodium azide, their process generated another toxic substance: N-nitrosodimethylamine (NDMA) – a probable carcinogen in humans.

The solvent of the tetrazole-forming step was dimethylformamide, whose industrial production process starts from dimethylamine. It is now suspected that the residue of dimethylamine in the solvent reacted with nitrous acid to generate NDMA.

The presence of this contaminant remained undetected until early June 2018, when the manufacturer was reviewing and optimizing its processes. It is important to underline that the levels of NDMA eventually identified in valsartan were well below 0.05% – the disregard limit of the European and American pharmacopoeias for the related substances of valsartan.

According to the European Medicines Agency (EMA), NDMA was found in Zhejiang Huahai’s valsartan, on average at 66.5 ppm, and at most at 120 ppm – enough to represent an unacceptable health hazard, but not enough to be distinguished from analytical noise during routine quality control of valsartan.

Besides, whereas HPLC was used for control of the related substances of valsartan, gas chromatography would be the preferred method for separating NDMA. In 2017 FDA investigators had reported occasional issues with the tests of impurities during inspections of Zhejiang Huahai, but those issues were not critical and concerned chromatography peaks above the disregard limit.

Since it was below the normal reporting level of impurities, the presence of NDMA had been missed for years, not due to any fault of the company’s quality control. Rather, it was missed as a consequence of the faulty assessment of the safety of the synthesis process.

The presence of the NDMA contamination implied that the company’s European pharmacopoeia (CEP) certificate of suitability for valsartan was wrong. The European Directorate for the Quality of Medicines (EDQM) thus suspended the validity of the certificate as soon as the contamination became known.

The EDQM assessors of valsartan’s CEP application dossier had failed to realize the risk, as had Zhejiang Huahai, the U.S. FDA and everyone else.

Sodium Nitrate – a Missed Red Flag
The risk of formation of carcinogenic nitrosamines from nitrites and secondary amines in acidic conditions has long been known to the food industry. It was not rocket science – yet it came as a surprise to the pharmaceutical industry.

The use of sodium nitrite in the valsartan processes of Zhejiang Huahai and other manufacturers should have been a red flag prompting an evaluation of any presence of secondary amines, but it did not. From this perspective, it would be a mistake to see Zhejiang Huahai as an exceptionally careless actor.

In fact, quite the contrary seems to be the case.

Better Synthesis Risk Management
This company actually managed the risk of genotoxic and mutagenic impurities better than the average manufacturer. For instance, in one of their products – dabigatran etexilate mesylate – Zhejiang Huahai had specified a tight ppm acceptance limit for control of the potential presence of ethyl mesylate.

Ethyl mesylate is a genotoxic substance known for having caused a carcinogenic contamination in Nelfinavir at a Swiss plant in 2007. Such careful controls are not commonly seen at mesylate substance manufacturing plants.

Zhejiang Huahai’s discovery of the presence of NDMA in valsartan in June 2018 was – of course – overdue, but anyone familiar with the API industry will recognize that it was beyond what the average generic API company would likely do.

How often do we see an elective ICH M7 compliance program at any API plant? Rather than any exceptional sin on the part of the manufacturer, the valsartan contamination event might reveal that the pharmaceutical industry – focused as it is on the quality of pharmaceutical ingredients – has not been paying enough attention to the safety of chemical synthesis processes.

As soon as the valsartan contamination became known, the manufacturer and regulatory authorities rushed to test NDMA in other company products. They were satisfied to detect no NDMA in those products.

Irbesartan, which is another tetrazole molecule, was one of those products. Like valsartan, Zhejiang Huahai synthesized it according to the sodium azide method. Unlike valsartan, though, no dimethylformamide was used, but triethylamine was – which implied the natural presence of a residue of diethylamine from the manufacturing process of triethylamine by alkylation of ammonia with ethanol.

Looking for the Right Impurities
Because sodium nitrite was used in this process, the potential contaminant that needed to be tested in irbesartan was not N-nitrosodimethylamine (NDMA), but Nnitrosodiethylamine (NDEA). Everyone was looking for the wrong impurity. Just like the valsartan process, the chemical synthesis process of irbesartan had not been carefully studied. The scope of investigation was extended to other valsartan manufacturers, as well.

On 16 July 2018, the European Medicines Agency wrote to a number of manufacturers of the substance to inquire about their production methods for a re-evaluation of risk of generation of NDMA. Obviously, the investigation will also need to be extended to candesartan cilexetil, irbesartan, losartan and olmesartanmedoxomil, as these substances contain 5-substituted tetrazole cycles that are formed through the same method based on sodium azide.

It seems we will have to look deeper and wider than just NDMA in valsartan.

A Proper Response to Drug Contamination
We can be confident the valsartan contamination incident will be corrected although some patients will suffer serious consequences. Zhejiang Huahai reacted to their discovery responsibly. They halted production, sealed the stocks at the warehouse, and promptly notified the authorities and customers. The synthesis process will undoubtedly be modified, and NDMA will be routinely evaluated in valsartan.

This event will eventually be brought under control. But we would do well to understand that the contamination of valsartan remained undetected for years because the industry’s approach to the quality control of pharmaceutical ingredients tends to focus on the generally-harmless related substances of synthesis.

The Future of API Quality Management
The troubling question is: How many NDMA, NDEA, ethyl mesilate and other highly toxic, low concentration, impurities might lie hidden in the hundreds of pharmaceutical ingredients made by thousands of manufacturers around the world?

Something needs to change in our quality management of pharmaceutical ingredients, not only to prevent similar contaminants in the future, but also to become aware of the ones which may be there – right now – in our medicines.

This article was first published in Neuland’s internal newsletter, Neuworld, by Ashok Gawate – Neuland’s General Manager of Developmental Quality Assurance & Regulatory Affairs.

Complex Synthesis in Action: Achieving a Commercial-Scale 16 AA Peptide

Peptide process development projects have increased in the last few years. Judging by our blog readership and social interactions, interest in peptide drugs is continuing to grow by leaps and bounds.Peptide process development projects have increased in the last few years. Judging by our blog readership and social interactions, interest in peptide drugs is continuing to grow by leaps and bounds.

We’ve seen questions focused on whether a given peptide can even be produced give way to questions focused on whether a peptide can be produced at X volume, for Y cost and at Z purity.

Peptides are a unique class of drugs nestled between small molecules and proteins. Between 1920 (the introduction of the world’s first peptide drug – insulin) and 2017, more than 60 peptides have been approved by the FDA.

Peptides are attractive as a drug class due to their high specificity and low toxicity, but certain properties have historically limited its utility (e.g., parenteral route of administration, proteolytic instability, etc.). These are among the limitations of peptides that are currently being overcome, and have been the focus on increased research and industry attention over the last decade or so.

We’ve written on a number of peptide topics over the years, and much of our focus has been on the various techniques used to synthesize the peptide APIliquid phase, solid or hybrid.

History of Peptide Synthesis
Peptide synthesis technique selection is extremely important. The very first liquid phase synthesis of a peptide hormone, Oxytocin, was reported in 1954 – an elegant synthesis for which Vincent du Vigneaud received the Nobel Prize.

In 1963, Robert Bruce Merrifield reported synthesis of a tetrapeptide (4 amino acids) using solid phase synthesis. While solid phase synthesis is convenient to perform, liquid phase synthesis is preferred for peptides which:

  • are typically less than 15 amino acids in length.
  • have commercial requirements of 100+ kilograms.
  • are price sensitive, and cost considerations are either very important or absolutely critical.

Scale-up, confirmatory batch production, process optimization and analytical methods development are all milestones on the path a peptide therapeutic takes through clinical trials to market. Most of our peptide projects extend well beyond synthesis technique selection and development to encompass other key areas of peptide drug commercialization.

Scale-up, confirmatory batch production, process optimization and analytical methods development are all milestones on the path a peptide therapeutic takes through clinical trials to market. It is the collective advances in these related disciplines – better chromatographic resolutions, or our greater knowledgebase for methods creation and validation, for example – which have contributed to the resurgence of pharma peptides.

16 Amino Acids. 100 Kilograms. 98% Purity!
Our previous liquid phase synthesis of a decapeptide (10 amino acids) at 35 Kg scale involved 24 steps. At the time, we considered this a very significant peptide manufacturing milestone for Neuland.

Then one of our U.S.-based customers asked us to develop a liquid phase synthesis route for a cyclic sixteen amino acid peptide API which possessed multiple disulfide bonds.

They also wanted the peptide scalable to 100+ kilograms per year.

Peptide amino acidsFor this particular API, Neuland developed a liquid phase synthesis strategy using four protected segments, including:

  • a hexapeptide
  • a tripeptide
  • a pentapeptide
  • a dipeptide.

Overall, the final process involved 40 isolated stages. Each stage required evaluation of optimal reaction conditions. For each of the 40 steps, reaction parameters – including temperature, reactant molar ratios, and pH – were optimized.

Specific analytical methods were also developed, and critical process parameters and critical quality attributes were established for each stage.

To demonstrate scalability, Neuland prepared all the segments in several hundred grams quantities (with purity exceeding 95%).

Process consistency was established by conducting three lab verification batches for each of the stages. The yield for the verification batch of the lyophilized peptide API (post-preparative HPLC) was ~30% and the final API purity was 98+%, per the customer’s specification.

The Peptide Class is in Session
While this was just a single project at Neuland, it was an example of a successful – and quite complex – liquid phase synthesis scaled to commercial volumes.

From analytical and process instrumentation to novel peptide assembly methods, much has happened to pave the way for the peptide API industry to routinely discuss projects at 100+ kg/yr scales…at 98+% purities…across 40 manufacturing steps.

We’ve reached a juncture where complex peptide manufacturing techniques and instrumentation are starting to bend the cost- and scale curves, just as the science of peptides seems to be coming to fruition. This is building a more compelling revenue case for peptide therapeutics – something that has generally been out of reach.

The peptide class, it seems, is in session.

Alzheimer’s and Brain Awareness Month

Alzheimers factsJune is Alzheimer’s and Brain Awareness Month.

Alzheimer’s Disease (AD) is a heartbreaking and tragic condition affecting millions of families worldwide. This month, we highlight how health and pharma intersect.

Gender & Alzheimer’s Disease
Gender is a key risk factor for Alzheimer’s Disease…much more so for women than men.

From the Journal of Alzheimer’s Disease:

The incidence of the disease is higher in women than in men, and this cannot simply be attributed to the higher longevity of women versus men. Thus, there must be a specific pathogenic mechanism to explain the higher incidence of AD cases in women. In this regard, it is notable that mitochondria from young females are protected against amyloid-beta toxicity, generate less reactive oxygen species, and release less apoptogenic signals than those from males. However, all this advantage is lost in mitochondria from old females.”

How much more likely are women than men to suffer from AD? Cognitive Vitality, a program of the Alzheimer’s Drug Discovery Foundation, reported last summer that “more than 5.5 million Americans are living with Alzheimer’s disease, of whom two-thirds are women.”

Treating Alzheimer’s Disease
Worldwide, 50 million people suffer from Alzheimer’s and other forms of dementia. While there are currently no drugs which can cure Alzheimer’s outright, common drug interventions for AD can – in some patients – temporarily alleviate the symptoms or slow their progression.

Such drugs include cholinesterase inhibitors such as the Donepezil, which is approved to treat all stages of Alzheimer’s. Other cholinesterase inhibitors (Rivastigmine and Galantamine) are approved to treat mild to moderate AD.

The Alzheimer’s Association discusses another drug, Memantine (Namenda) – as well as a combination of memantine and Donepezil (Namzaric) as treatments which are approved by the FDA for moderate to severe Alzheimer’s.

There are also a number of drugs in various stages of development worldwide, including selective beta secretase inhibitors, immunotherapies, inhibitors targeting the accumulation of tau, anti-inflammatory combinatorials and more.

Neuland is a manufacturer of Donepezil – the generic API of Aricept (we produce both Donepezil base and Donepezil hydrochloride). Donepzeil was first approved in 1996, and is a reversible acetylcholinesterase inhibitor. As an enzyme blocker, controlled studies have shown modest benefits in cognition or behavior. While it does not cure Alzheimer’s disease, it may temporarily improve memory, awareness, and the ability to function.


Ending Alzheimer’s – #ENDALZ
While drugs such as Donepezil can provide modest temporary benefit, the focus this month is on ending Alzheimer’s entirely. Essential to this are ongoing efforts to build awareness – awareness of Alzheimer’s disease itself, its progression & stages and its signs & symptoms.

Preventing Alzheimer’s Disease: What You Need to Know
While scientists continue to look for a cure to Alzheimer’s, or at least a way to stop it’s progression more permanently, there are steps we can take to ensure our brains remain as healthy as possible. Check out these tips from Harvard Health on keeping your brain healthy.

Want More Alzheimer’s Resources?
The NIH’s National Institute on Aging is a good resource for general information on Alzheimer’s Disease, and CenterWatch has updated lists of dementia-related research and clinical trials. DDNews’ yearly neuroscience report is also worthwhile – here’s the April 2019 report.