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The Impact of Impurities on the Pharmaceutical Industry

The Impact of Impurities on the Pharmaceutical Industry

A significant paradigm shift is underway in the regulatory environment for impurities in pharmaceutical products. Recent incidents involving genotoxic impurities (GTIs) are driving tighter restrictions and guidelines, as well as more stringent process standards.

As we’ve discussed in previous posts, the discovery of contamination in generic valsartan – despite the scrupulous care of the manufacturer – was a frightening wake-up call that highlighted significant risks to the industry. The impurity had gone undetected for years, demonstrating the need to not only assure the quality of pharmaceutical ingredients, but also the safety of chemical synthesis processes.

This was just one of several recent incidents involving GTIs. Similar cases included the discovery of ethyl mesylate contamination at a Roche plant in Switzerland and EE impurities in the manufacture of Terbinafine. The incidents and others underscored the need for the industry to reevaluate long-standing best practices and safety procedures.

Understanding Drug Impurities
The ICH broadly classifies impurities in one of three groups:

  1. Organic impurities: starting materials, process-related, intermediates, degradation products and formulation-related impurities
  2. Inorganic impurities: salts, catalysts, ligands, and heavy metals or other residual metals like Pd, Pt, Ni, Cu, Fe.
  3. Residual solvents: organic and inorganic liquids used during production.

According to the International Council for Harmonization (ICH), “(G)enotoxic impurities can be broadly defined as impurities that have been demonstrated to cause deleterious changes in the genetic material regardless of the mechanism.” The negative impacts of GTIs may include:

  • Mutagenesis: the formation of mutations
  • Carcinogenesis: the formation of cancers
  • Teratogenesis: damage to the DNA.

Regulators are Cracking Down
In the past, it was sufficient simply to characterize the final product and any associated impurities. In the wake of these incidents, however, regulatory agencies have made significant moves to reduce toxicity risks. Here are just a few of the changes we’ve seen in recent years:

  • The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guideline M7 requires all impurities that have been identified to be considered for their mutagenic potential.
  • Effective January 2018, Chapter <231> of the United States Pharmacopeia’s (USP) National Formulary (NF) was replaced by Chapters <232> and <233>. These changes eliminated the traditional “Heavy Metals Test,” which had been an industry standard for more than a century. The new regulations made significant changes to toxicity limits and to the standards for analytical procedures. Notably, toxic substances like lead, mercury, arsenic, and cadmium; as well as metals like platinum, palladium, ruthenium, rhodium, and rubidium; must now be tested and controlled for — even if they are not used in any process.
  • In addition, exhaustive GTI assessments and control strategies must now be demonstrated for all products and processes.

Analytical Challenges
These evolving standards have required API manufacturers to adopt more expensive and cumbersome development and validation strategies.

Why? Because unlike typical contaminants, which can be present in 1000, 100, or 10 parts per million (ppm), new toxicity limitations mandate the detection of impurities as low as 1 ppm.

Requiring this level of accuracy knocks a lot of standard lab equipment out of the process. Depending on the nature and quantity of the impurity under investigation, one or more advanced, specialized, and costly techniques may be required, from liquid chromatography–mass spectrometry (LC–MS) to gas chromatography–mass spectrometry (GC–MS) or inductively coupled plasma mass spectrometry (ICP–MS).

Manufacturing Process Challenges
Evolving standards also present new hurdles and concerns at every stage of the manufacturing process. These include:

  • Identification of potential impurities throughout the entire route of synthesis, possible byproducts, degradations, etc.
  • Redesigning the route of synthesis to eliminate possible GTIs, or to reduce their levels within the scope of the regulatory landscape to acceptable levels of safety and cost.
  • Synthesis of all potential impurities and GTIs, their characterization, spiking, and purge studies.
  • Development and validation of suitable analytical methods.
  • (Q)SAR (quantitative structure–activity relationship) models, in vitro — and sometimes in vivo — evaluation if required to avoid ambiguity.
  • Deployment of additional resources, time, cost and effort.
  • Possible delays in regulatory approval.

Early Successes with New Solutions
API manufacturers and their partners are working hard to meet these new challenges. In one recent case, a Neuland client’s final API process involved the neutralization of salt with a sodium hydroxide solution. In a related substances test, high performance liquid chromatography (HPLC) detected an unknown impurity at a level of 0.14%.

To identify the impurity, we used LC–MS. The mass didn’t match any possible structure we could think of that was present in the starting materials, reagents, intermediates or their possible successive structures.

Subsequently, this impurity was isolated with preparative HPLC. Our investigation of the structure deduced from the isolated material found that it was formed with dichloromethane and acetone in the presence of a strong base. The isolated impurity was spiked with original material to re-confirm it by HPLC, then characterized by nuclear magnetic resonance (NMR) and mass spectrometry. Our hypothesis was further confirmed by lab experimentation.

In another recent case, an unknown impurity — which hadn’t been noticed during the entire development cycle — was detected during process validation. LC–MS analysis revealed an ester hydrolysed product.

Further investigation found that an accidental ammonia leak had occurred during unloading in an adjacent block. The impurity was duplicated in the lab by simulating similar conditions and confirmed by generating structural data and a spiking study.

The Way Forward
Ensuring safe and compliant products and processes will require the industry to take a number of new steps and precautions. We recommend the following practices to minimize your risk:

  • Avoid genotoxic reagents or their possible generation by design.
  • Allocate the best possible scientists and provide adequate resources for the detection of GTIs. Create a stand-alone cell for this activity.
  • Identify all potential structural alerts from the review of systems (ROS) and design a control strategy. Be aware that even this may not ensure “query free” approvals.
  • If possible, implement the highest possible levels of impurity control at an intermediate stage, rather that at the API/NCE stage.
  • Generate in vitro/in vivo safety data wherever it is difficult to control GTIs or where limits are on the borderline.

Genotoxic Impurities – Raising the Stakes for APIs
The need for greater attention to GTIs has raised the stakes for the entire API community. We’ve already seen multiple cases where impurities have required products to be withdrawn from the market — sometimes in lots or batches, and sometimes forever.

Even when GTIs can be eliminated by adapting a process, manufacturers may need to make considerable unplanned investments and endure time-consuming requalification before a product can be returned to market. Moreover, failure to detect, investigate, and provide corrective and preventive actions for GTIs also increases the risk of critical regulatory attention, such as the FDA’s 483 observations.

As a result, we’re already seeing major investments and manpower deployments in this area, and we anticipate many more. Tightening regulations mean big business for instrumentation companies, especially the makers of LC–MS and ICP–MS equipment. They’re also creating business opportunities for organizations capable of creating new standards and processes for detecting impurities in manufacturing and production.


Maintaining Quality and Supply During COVID-19

The need for API manufacturers to establish strong quality systems and plan for business continuity has never been greater than it is today. And you can probably guess the reason why.  Following on the heels of SARS, Ebola, swine flu and other emerging pathogen threats we’ve seen in recent years, COVID-19 represents the bullet we didn’t dodge. The need for API manufacturers to establish strong quality systems and plan for business continuity has never been greater than it is today. And you can probably guess the reason why.

Following on the heels of SARS, Ebola, swine flu and other emerging pathogen threats we’ve seen in recent years, COVID-19 represents the bullet we didn’t dodge. It’s a global crisis that has been decades in the making.

Experts have been pointing to the warning signs for years: climate change, urbanization, increased population density in proximity to farm or forest animals, the spread of microbes accelerated by war, the global economy, international air travel, and more.

In addition, institutions like the World Health Organization (WHO), World Bank, and the Global Preparedness Monitoring Board have been issuing warnings about the risks of pandemics for decades. The Worldwide Threat Assessment published each year by the US intelligence community has been highlighting the vulnerability of the United States — and the world — to a potential pandemic since 2017.

Meeting the Challenges of the “New Normal”
When we’re finally able to see COVID-19 in our rearview mirror, there will be plenty of finger-pointing, for good and ill. In the meantime, the world is adapting to this new reality.

From our standpoint as an API manufacturer for the pharma industry, the changes have occurred in rapid-fire. Supply chain hiccups, followed by curtailed regulatory activities, followed by a further increase in trade nationalism around the globe, combined with the search across drug portfolios for anything that might offer hope in the fight against SARS-CoV-2 — all of these challenges arose over a short six months.

To their credit, the pharmaceutical and biopharma industries have risen to the challenge, despite having fewer staff and resources to work with during the crisis.

As travel restrictions and social distancing needs took hold, regulators have taken a hands-off approach, cancelling the usual inspections in order to protect the health and safety of both inspectors and pharma workers. In response, companies are stepping up to maintain quality control and worker safety. A variety of digital tools have been implemented quickly, including virtual audits and inspections.

The API manufacturing industry was also fortunate to have strong health and sanitation practices already in place when the pandemic broke out. These have since been bolstered by new practices, including daily employee health screenings, increased sanitation and hygiene requirements, limiting unnecessary visitors, requiring masks and other PPE equipment. Social distancing is enforced throughout the industry and remote work encouraged when possible. Many companies turned to the World Health Organization, US Centers for Disease Control and Prevention, and other health institutions worldwide for guidance, and some added additional safeguards of their own.

Securing Supply Chains
A key priority for maintaining quality is keeping global supply chains running smoothly. Manufacturers stay in constant contact with suppliers, replacing face-to-face communication with video meetings and other digital technologies. Many also moved quickly to diversify and strengthen supply chains in order to minimize potential disruptions.

India, which manufactures about a third of all medications and 70 to 80 percent of generics, is a case in point. The country could potentially face supply shortages and price increases in the event of an extended shutdown. According to a report by HDFC Securities, however, there is limited immediate risk. Most companies are maintaining an inventory of 3–4 months and are closely monitoring the situation.

For the longer term, India’s government announced new incentives in July to boost domestic manufacturing of active pharmaceutical ingredients (API) and key starting materials (KSM). According to Fitch Ratings, this initiative could improve backward integration over the next few years and curtail supply-chain disruption risk for Indian drug makers.

What the Future Holds
In the years to come, we will undoubtedly see focus on more robust preparedness. Supply chains, in particular, are already becoming more diverse in an effort to minimize reliance on a single source of raw materials. Companies willing to take these precautions now are likely to realize dividends quickly in the event of a future health crisis, geopolitical tensions, or other disruptions.

One of the outcomes of the COVID-19 crisis has been an accelerated adoption of new tools by the pharma industry. One of the outcomes of the COVID-19 crisis has been an accelerated adoption of new tools by the pharma industry.

The sudden need for collaboration and information sharing platforms materialized to make use of the newest technologies – allowing companies to maintain quality, make and track orders, and get support quickly from suppliers, despite social distancing and travel restrictions.

These (and other) technologies will continue to enhance the speed and efficiency of the industry long after the pandemic era has ended.


The Need for Speed: Drug Development, Trials & Regulatory Pathways Accelerate in the Wake of COVID-19

For drug makers, speed has always mattered. Every day a drug is delayed on the path to market costs pharma companies millions of dollars. Delays can also lead to the loss of exclusivity, or the need for contentious reverse payment settlements.

A 2017 report found that “the clinical development duration of a trial was a key factor in driving up its cost, and found that each additional month in a Phase III trial added a median expense of $671,000.”

From discovery to market, a drug typically travels a 10+ year path – at a cost of about U.S. $2.6 billion. That cost, however, is highly dependent on the length of clinical development. Some drug companies are reported to perform better than others, with those better-performers bringing a drug to market for approximately $2 billion while many other companies report a $5-8 billion price tag.

An interesting study published in Cancer Med in 2018 (The importance of greater speed in drug development for advanced malignancies) shed light on this very issue.

“It takes on average 6–12 years to develop new anticancer drugs from discovery to approval…For every year by which time to drug approval could have been shortened, there would have been a median number of life‐years potentially saved of 79,920 worldwide per drug. Median number of life‐years lost between time of drug discovery and approval was 1,020,900 per example. If we were able to use available opportunities to decrease the time required to take a drug from discovery to approval to 5 years, the median number of life‐years saved per example would have been 523,890 worldwide.”

Maximizing Speed Through Industry Technologies
Some of the most important industry technologies have focused on maximizing speed and productivity, though virtually all have only led to incremental improvements. Our ability to rapidly discover new therapeutic molecules via high-throughput screening, our ability to manufacture those molecules efficiently via route scouting & optimization, or our ability to recruit and manage massive clinical trials are all examples.

This is tempered by the fact that both drug compounds and the protocols for their clinical trials are growing more complex. Clinical trials have become more difficult to perform, tend to run longer and demand more robust domain expertise.

Speed and the Public Eye
To the average layperson, the ‘speed’ of the drug industry has always seemed unhurried and sluggish. The industry doesn’t appear to move quickly…or sometimes at all. When we read of a new discovery that promises a cure for a debilitating disease, excitement builds. The process of translating a discovery published in a peer-reviewed journal to a finished, approved and marketed drug, however, stretches years…and in some cases even decades – if it can be translated into a finished therapeutic at all. When a drug finally reaches the market, it isn’t uncommon for people to wonder: “Wait, didn’t we cure that years ago?”

That gap between scientific discovery and marketed treatments has always existed, and it is the very reason the drug industry has focused so keenly on shortening that gap. Health conditions rarely wait for the science to catch up, and time is money, after all. The faster a product can be brought successfully to market, the better it is for patients, for medical practitioners and for the scientific and drug development communities.

COVID-19 has – without a doubt – changed everything. While people anxiously awaiting a vaccine may protest the delays in vaccine (or treatment) development, the science is moving at near-lightning speed these days.COVID-19 has – without a doubt – changed everything. While people anxiously awaiting a vaccine may protest the delays in vaccine (or treatment) development, the science is moving at near-lightning speed these days.

The Impact of 2020
Dr. Hank Fuchs, President of Worldwide R&D at BioMarin Pharmaceuticals, has discussed how game-changing therapeutics can experience accelerated and condensed development: “We work with devastating pediatric diseases for which there are no current therapies. That puts a lot of spring in everything and can really catalyze a program.”

While the compound Dr. Fuchs mentioned targets a rare disease (which enjoys accelerated FDA timelines), COVID-19 is anything but rare. With tens of millions of cases worldwide – and a death toll (as of this writing) approaching 10 million, treatments and vaccines for COVID-19 are forging a new path.

The Year 2020 will likely be remembered (among many, many other things) as the year when the global pharma industry teamed with governments, health regulators, research organizations and NGOs to expedite the funding, development, testing and commercial manufacturing of therapeutics and vaccines targeting a single disease.

The effort is truly something we’ve never seen before. Consider:

  • The WHO reports there are 536 clinical studies to develop post-infection therapies for COVID‑19 infections.
  • The FDA reports there are 570+ drug development programs in the planning phase, and 270+ clinical trials have already been reviewed (as of July 31, 2020).
  • The last several years have seen a number of initiatives created in order to stimulate vaccine and antiviral drug development. These include the E.U.’s Innovative Medicines Initiative, the and the U.S.’s Critical Path Initiative, in addition to the new Breakthrough Therapy designation. These are proving essential to accelerating the path for COVID-19 treatments and vaccines.
  • An unprecedented amount of supercomputing and Cloud computing power has been focused on COVID-19 drug discovery, tapping the capabilities of IBM, HP, Amazon, Microsoft, and Google.

Obviously, the efforts to contain SARS-CoV-2 and ultimately eliminate COVID-19 as a health risk stretch well beyond these few bullets. It is an exciting and unparalleled concentration of resources – never before witnessed as an industry. It is a global effort that holds the hope that our lives can – hopefully sooner rather than later – return to some semblance of normal.


API Industry Faces Challenges and Opportunities

The global market for active pharmaceutical ingredients (APIs) is expected to grow at a 3–6% Compound Annual Growth Rate (CAGR) over the next five years, exceeding U.S. $1.5 trillion by 2023. While the overall outlook is upward, the industry as a whole is dealing with a complicated mix of trends — some beneficial, others potentially damaging.

On the plus side, many new drugs on the market enjoy better success rates than in the past. Many more are also on the way — the number of new products launching in the next five years is on the rise, with an average of 54 new active ingredients.

Pharma companies have a lot riding on these new drugs, however, because of significant losses of exclusivity that are already underway in developed markets. By 2033, 18 of the current top-20 branded drugs will face generic or biosimilar competition. The impact of these and related losses is expected to total around U.S. $121 billion between 2019 and 2023.

In addition, the COVID-19 pandemic has created unprecedented challenges, including supply chain disruptions, labor shortages, and calls to reduce dependence on offshore API manufacturing, notably in the United States but also in other countries, including India.

The Global Drug API Picture
The United States continues to lead the world, with moving annual total (MAT) sales of U.S. $476 billion and a market share of around 45%. China and Japan are the nearest contenders, capturing 8% and 7% of the market respectively. They are followed by Germany, France, Italy, the UK, Brazil, Spain and Canada – each with 2–4%.

The rest of the world makes up the remaining 20%, valued at U.S. $215 billion. See the charts below for additional details. (India currently ranks 13th worldwide.)

Global Pharma Market: US $1,130 Billion

Leading Therapies
At U.S. $49.52 billion, treatments for autoimmune diseases are the top sellers in today’s market, followed closely by oncology biologics ($46.47 billion) and medications for diabetes ($41.3 billion). Others in the top 10 include HIV antivirals, oncology, treatments for multiple sclerosis and epilepsy, anti-coagulants, anti-psychotics, and hepatitis antivirals.

Best-Selling Drugs
Humira (Adalimumab) is the top-selling drug globally, with worldwide sales valued at $24.77 billion — nearly 2-1/2 times that of its nearest rivals. The top 10 performers are shown below.

The Indian Pharma Market
The Indian API market has shown steady growth of 8.6% since 2016. This trend is expected to continue thanks to an increased focus on new markets in the global pharmaceutical industry, transitions to specialty segments, and strong domestic demand.

The COVID-19 outbreak has generated a great deal of attention to the percentage of APIs India currently imports from other countries, primarily China. Chinese imports have risen steadily in recent years, growing from 62% in 2012 to 68% in 2019 – largely due to the low-cost advantage enjoyed by Chinese manufacturers.

This high dependency on a single nation creates significant risks for India’s domestic pharmaceutical industry. Frequent supply disruptions from China are not just a concern for India, but for global pharma concerns as well. Recent events have also included unexpected price movements, genotoxic impurities, shutdowns of plants because of pollution, and other disruptions related to the outbreak of COVID-19.

Emerging Opportunities for India’s API Business
India has responded to these concerns in multiple ways that are creating new opportunities for API manufacturers based in the country. These began with increased U.S. FDA scrutiny to improve compliance in the detection of Nitrosamine impurities in Sartan APIs. The country is also moving to strengthen its API pipeline relative to China.

India already has the advantage of more U.S. FDA-approved plants than China. The domestic API industry benefits from a large talent pool with strong chemistry skills. Together, these and other factors enable India to offer a more nimble and stable source of API supply than Chinese rivals.

In addition, the Government of India recently announced two new schemes designed to help support domestic API manufacturing and exports:

  • The first was approval to set up three bulk drug parks, supported by a budget of INR 3,000 crore (about US $400,775) over the next five years. The Central Government of India will give grants-in-aid to states with a maximum limit of INR 1,000 crore (US $133,590) per park.
  • The second scheme creates production linked incentives (PLIs) to encourage the domestic manufacturing of 53 critical bulk drugs and intermediates in the country, with a budget of INR 6,940 crore (US $927,000) for the next eight years. Of these, 26 are fermentation-based and 27 are chemical-synthesis-based.

Future Trends
Despite some challenges, all signs point to a growing market need for new API business, both in India and worldwide. Original Abbreviated New Drug Application (ANDA) approvals have grown steadily from 2014 to 2019, a trend which looks set to continue creating new API opportunities.

Neuland continues to monitor these and other market drivers on an ongoing basis in order to keep you informed of key market changes. We’re also taking every possible step to protect your business from supply chain risks. Current and planned efforts include redundant manufacturing sites worldwide, multiple alternate facilities, maintaining our excellent regulatory track record, and bringing production of precursors and intermediates in-house.


Looking for an API Supplier? 5 Things to Consider (Updated)

Seven years ago – in March of 2013 – we published a blog post on 5 Things to Consider When Looking for an API Supplier. Because seven human years equals 100+ years in the pharma industry, we thought we’d revisit the topic now that the slight supply chain uncertainty some pharma execs were beginning to feel has grown and developed into a full-on global panic.

First of all – there is no need to panic! Everyone – and, full disclosure, this includes us – has been writing about the imminent supply chain crisis. Except, it isn’t quite a crisis, and very little (aside from recalls) happens ‘imminently’ in the drug industry. In fact, de-risking supply chains is nothing new, though in 2020 it seems to have risen to the top of pharma’s to-do list.

It is true there has been a shift in thinking – brought on first by quality issues, then by unexpected facility shutdowns, followed by increasing global trade nationalism, and finally capped off with a global pandemic that briefly impacted some supply chains.

No doubt, it has been a rough 7 years for globalism. Concern crept into the C-suite early in the period, but that has now officially been replaced by full-on ‘trade terror.’

No one – and nowhere – is immune: US-based companies, European firms, Japanese drugmakers and Indian manufacturers have all begun to re-evaluate the length and breadth of supply chains to identify (and hopefully begin the process of mitigating) risk. What is new is that governments have begun stepping into the fray, seeking ways to strengthen domestic production of key essential drugs and drug APIs which are most at risk.

The original post focused on 5 broad areas to consider when selecting an API supplier:

  1. Technical Capabilities
  2. Regulatory Capabilities
  3. Scalability
  4. Capacity
  5. Customer Relations

In our update to the earlier post (below), we have grouped the CMC-related categories of scalability & capacity together in order to make room for the once-emerging-but-now-absolutely-dominant factor: Supply Chain De-Risking.

Outsourcing production of APIs provides pharmaceutical and biotech companies the benefit of API scale-up and production expertise while allowing them to focus on their core business – the research and development of drugs.

With any successful business relationship, a great deal rests on the proper upfront due diligence. It is critical to choose an API supplier that can meet a whole host of important qualifications, from experience at various scales of production and available capacity to worldwide regulatory approvals and support as well as quality systems that mirror (or best) your own.

There are a number of criteria drug manufacturers evaluate when choosing an API supplier. Here are just a few of the key issues your company should be considering when making a decision to outsource API manufacturing.

  1. Technical Capabilities
    Your API supplier should be comfortable with your project’s underlying science, and have appropriate development and analytical chemists and labs in-house to support the API in question. Ensure they have the specific capabilities your project may demand – whether it’s analytical chemistry for the detection of genotoxic impurities, route scouting & optimization, process engineering, the development of non-infringing processes, effluent reduction or another discipline necessary to ensure project success.
  2. Regulatory Capabilities
    Less than 5% of U.S. FDA Abbreviated New Drug Application (ANDA) applications for generic drugs receive approval. One leading reason why such applications fail is lack of appropriate documentation for an API’s chemistry. These “chemistry deficiencies,” as they are known, can be attributed to a number of factors including: failure to disclose the use of solvents, changes in the manufacturing process, and failure to identify potentially toxic impurities.Avoiding chemistry deficiencies comes with familiarity of regulatory matters. Make sure your partner routinely undergoes inspections from the various regulatory bodies (e.g., FDA or EU GMP) that are critical to your drug’s success. In some cases, ANDAs can be denied because your supplier was unsure exactly how to communicate with a regulatory agency. Remember, an API supplier is only valuable to your firm’s drug candidate if they can execute your project according to the various stringent regulatory criteria you must meet.
  1. Scalability & Capacity
    Many contract manufacturers claim capacities from lab to kilo scale. Make sure your manufacturer can actually translate production across multiple scales, and has done it before. Check their track record on DMFs they’ve filed, and similar products they’ve produced. Even if you don’t plan to outsource production long term, your contract manufacturer’s skills and expertise at various scales can prove invaluable during process transfer.Your plan for scaling and manufacturing your drug candidate is only as realistic as the capabilities of your respective partner. Many contract manufacturers have specialties – Neuland, for example, has focused on APIs for nearly 30 years. We are experienced in translating the manufacturing process across a broad range of scales and possess the knowledge of niche chemistry customers expect.Ask if your potential partner has the available capacity for your project – on your timeline. All too often, both scalability and capacity may be available – but not on a timeline that meets your needs.
  1. Customer Relations
    Can the API manufacturer provide you with the level of support and involvement your company needs or expects? You want to select an API supplier who believes customers can contribute meaningfully to solutions based on their experience and priorities, and encourages them to participate with clear, open lines of communications. Technology has reached the point where clients can track – in near-real-time – the progress of their project, and online project management systems are one tool that can help increase the integration of international teams based around the globe.

    5. Supply Chain Risk Mitigation
    An API manufacturer should have in place a number of capabilities or solutions to help you de-risk supply chains. There are a number of diverse strategies that can be employed, ranging from ensuring multiple backup manufacturing locations to handle unexpected shutdowns or issues to bringing the manufacture of key APIs, intermediates and precursors in-house to reduce external exposure (backward integration). Your API supplier should be aware of their own supply chain risks, and be able to communicate them clearly to you in order to help you manage risk.

Selecting an API supplier for your drug candidate is about building a partnership. You need to be comfortable with your API manufacturer’s capabilities, capacities, approaches to regulatory matters, and how they will interact with you.


Pharma Drug Innovation in 2020: From Novel Drugs to Drugs for Novel Coronavirus

Have other areas in drug discovery suffered because of COVID-19?

It’s probably not too early to say that COVID-19 has changed pharmaceutical drug discovery considerably. And why wouldn’t it have, since it changed almost everything else?

Roaring onto the scene in the first quarter of 2020, COVID-19 proceeded to shut down entire nations and continents in the second quarter, and now continues to dominate world news, global economies, and our everyday lifestyles (“Should we go shopping? Eat out? Return to campus?”) in the 3rd quarter.

So, yes…of course it has had an impact on drug discovery and development. What remains to be seen is whether it will be an enduring transformation or if we will return to a semblance of ‘pre-COVID normal’ at some point.

In June, Forbes captured the scope of the coronavirus challenge and the reason why we are seeing such an unparalleled effort to defeat a single disease:

“In the last eight months the pandemic has emerged with stunning suddenness to infect more than 6.5 million people world-wide—killing nearly 400,000. Cambridge University estimated that losses over the next five years would total nearly $27 trillion, more than 5% of global GDP. As the world hopes for salvation, how pharma responds will have a profound effect on its future.”

Emphasis: Coronavirus
By March 2020, drug discovery and development efforts had started to coalesce around two broad medicinal objectives: (1) find suitable therapeutic compounds & modalities for treatment, and (2) develop a vaccine.

These were not mere add-on discovery programs. Assets and resources were re-purposed from a variety of sources, and companies, organizations and governments were given free rein to find a treatment or cure.

In an article at Nature.com on how the coronavirus outbreak could make it quicker and easier to trial drugs, Kenneth Kaitin, director of the Tufts Center for the Study of Drug Development in Boston, Massachusetts discussed how the pandemic has touched nearly all aspects of the industry. “This has really turned upside down the whole drug-development process,” he says. “The entire investigative world is focused just on developing treatments for COVID-19.”

Single-Minded Global Focus on COVID-19
The world has adopted a singular focus – which is a rarity in drug discovery circles. Governments and organizations have, in the past, driven focus in specific therapeutic areas – think ‘cancer moonshot’ – but never to the exclusion of other development efforts as we are seeing today.

That’s not to say everything has stopped. While coronavirus research is taking precedence and has had an impact, other research continues, patents are being filed and deals are getting done. It does feel as though non-coronavirus news is sliding under the radar, and it’s to be expected: we’ve rightfully become preoccupied with COVID-related developments.

More notable than the global focus has been the intensity of worldwide, cross-border and cross-company collaboration. Industry watchers point to this extraordinary level of collaboration, in which the world’s best minds are sharing hypotheses, data, results and more – as perhaps being decisive in the fight against SARS-CoV-2. At the very least, such a model will significantly reduce duplicative efforts and compress timelines in the search for treatments or a vaccine.

Sharing SAR-CoV-2 and COVID-19 Resources
Drug discovery efforts in the fight against COVID-19 have benefitted from never-before-seen levels of information sharing. Collaborativedrug.com has a running list of the many shared COVID-19 drug discovery resources available, driven by both the global urgency to fight an emerging disease and a new model of open source scientific discovery:

“Publishers like the British Medical Journal (and in a moment of solidarity other publishers like Wiley and Elsevier) are providing information on the Coronavirus freely on the internet to spur short-term global response efforts and support long-term research.”

The list of organizations dedicated to working together is unprecedented. Just two of the initiatives include:

  • The COVID-19 Open Research Dataset (CORD-19): Allen Institute for AI, Chan Zuckerberg Initiative (CZI), Georgetown University’s Center for Security and Emerging Technology (CSET), Microsoft, and the National Library of Medicine (NLM) at the National Institutes of Health.
  • The COVID-19 Therapeutics Accelerator—launched by the Gates Foundation, Wellcome, and Mastercard. Companies participating in the collaboration include: BD, bioMérieux, Boehringer Ingelheim, Bristol-Myers Squibb, Eisai, Eli Lilly, Gilead, GSK, Johnson & Johnson, Merck (known as MSD outside the U.S. and Canada), Merck KGaA, Novartis, Pfizer, and Sanofi. Companies have agreed to share their proprietary libraries of molecular compounds that already have some degree of safety and activity data.

Impacts Beyond Drug Discovery
The discovery of novel therapeutic candidates is just one facet of the broader pharma industry, albeit a vital – and highly-visible – one these days. The impacts of coronavirus, however, have been felt across the breadth of the industry – from supply chain disruptions to later-stage clinical trials.

On the clinical trial front, COVID-related disruptions have become the rule rather than the exception. On the clinical trial front, COVID-related disruptions have become the rule rather than the exception.

“Since early March, hundreds of organisations that are acting as the sponsor, collaborator, or contract research organisation (CRO) have publicly announced disruptions to planned and ongoing clinical trials in their press releases, Securities and Exchange Commission (SEC) filings, and clinical trial registries, as well as on social media. Companies have delayed the initiation of planned trials or withdrawn these completely, as well as suspended enrollment in ongoing trials or terminated these trials.”

Most disruptions of clinical trials were due to suspended enrollment, followed by slow enrollment and delayed initiation. The availability of clinical trial sites (including hospitals) and investigators (many shifted efforts to COVID-related drug discovery or treatment) was severely curtailed, hampering trials. All told, about 1,000 organizations (and perhaps more at the time of this post’s publication) had publicly reported disruptions.

What are the implications? Without data from pivotal clinical trials, new drug filings will be delayed, meaning some important new medicines will take longer to reach the market.

Clinical trials, however, didn’t collectively just end. Thousands of COVID-19-related clinical trials are now ongoing, focusing on treatment of mild, moderate and severe cases, exposure prophylaxis, complication support, asymptomatic cases, critical care and vaccines. And – as mentioned above – other non-COVID-19 related work continues (including clinical trials), despite societal attention being focused elsewhere.

Setting Expectations
The pharmaceutical industry – for all its very public regulatory surveillance and consumer-facing marketing – has always been somewhat opaque. Companies historically have never updated the public on day-to-day progress in the lab.

Why?

It’s about setting expectations. Remember, for every 5-10,000 chemical compounds, only 2-5% will show any promise. Less than half of one percent will qualify for testing on humans, and – of that 0.25-0.5% which begin clinical trials – less than one in ten will be successful. From start to finish, that’s an overall success rate of something on the order of 0.05%. Announcing you’ve identified a chemical compound which could successfully treat a disease would not be rational expectation setting.

The COVID-19 era has seen a sea change in how we set expectations. Johnson & Johnson is even planning to air a reality television series showcasing their COVID-19 efforts. As STATNews noted in a May article: “The narrative emerging from the Covid-19 pandemic is that the market is responding to rescue us from global catastrophe, a public relations coup for an industry that has long known about the potential for another pandemic but hasn’t meaningfully invested in research until now.”

However, as Forbes noted in their June article, this poses a serious challenge for the industry. When NIAID Director Anthony Fauci expressed hopefulness that a vaccine could be produced by the end of 2020, many in the pharma industry thought it over-optimistic. The ‘world record’ for vaccine development – at six years – is currently held by Ebola. Equally concerning to those who want to manage public expectations: to date there has never been a successful vaccine for any coronavirus – whether SARS, MERS or the common cold.

At the same time, however, there has never been such a massive global collaborative effort to find one. And there is some reason to be optimistic. After all, the pharma industry is a 150-year-old chronicle of successful ‘firsts’…stretching from morphine to metabolomics. Innovation and discovery are the actual purpose of our industry.


While the U.S. Worries Over Supply Chains, India Seeks Solutions: Atmanirbhar Bharat

Starting in March, PPE – personal protective equipment, including gloves, gowns and face masks – became as valuable as gold…and nearly as rare. During a media briefing on March 27, the World Health Organization’s Director-General said the chronic, global shortage of personal protective gear “is one of the most urgent threats to our collective ability to save lives.”

But what if a country could build its own billion-dollar PPE industry virtually overnight?

India in Action
In response to the global pandemic and the resulting shortages of PPE worldwide, some Chinese manufacturers raised prices while other countries sought to outbid each other for supplies – driving prices into the stratosphere. Combined with long import timeframes and a lack of domestic suppliers, India launched its own PPE manufacturing efforts.

The result? In the span of 60 days, India became the world’s second largest supplier of PPE – creating a nearly $1 billion industry in just 2 months. Prior to March of this year, India had zero PPE production. By late May, the country had ramped up production to more than 200,000 PPE kits per day (a ‘PPE kit’ consists of a mask, eye shield, shoe cover, gown and gloves).

A “New” Atmanirbhar Bharat
Atmanirbhar Bharat, the concept of a self-reliant India, is experiencing a renaissance. First promoted during announcements of the COVID-19 economic relief packages in May, it also traces its roots back to earlier India-centric business strategies – including the successful 2014 Make in India movement.

Is India Moving Towards Protectionism?
With the rise of nationalist trade policies spreading around the world, the threat of trade protectionism is very real. The emergence of SARS-CoV-2 from China’s Hubei province amplified this mindset – from New Delhi to Washington, to the European capitals and beyond – as supply chains sputtered and began to collapse.

India’s move towards self-reliance was driven less by protectionism or distrust of trading partners than by the new realities of necessity and supply & demand. Nirmala Sitharaman, India’s Finance Minister, has said that “self-reliant India does not mean cutting off from rest of the world.” The Law and IT Minister, Ravi Shankar Prasad, related that Indian self-reliance doesn’t mean “isolating away from the world. Foreign direct investment is welcome, technology is welcome.” He relates a self-reliant India to becoming a more influential component of the global economy.

Reaction to Increased Foreign Dependence
In boardrooms and policymaker offices around the world, COVID-19 has amplified the concerns of supply chain dependency and risk. Nowhere is this more pronounced than in the life science and health sectors.

In 2020, Chinese pharma suppliers increased prices by 20%. But that was only one aspect of supply chain risk. Logistics play a major role, as well, with longer shipment times and higher costs. A final piece of the puzzle: government restrictions on exports of certain medications and supplies. In April, the U.S. Chamber of Commerce reported:

“More than 60 governments around the world have adopted export restrictions on medical supplies and medicines in an effort to ensure sufficient domestic supply during the COVID-19 crisis. These export restrictions can take the form of nonautomatic licensing requirements, consularization requirements, as well as outright bans on exports. In various instances, transparency is insufficient, administration is ambiguous, and no end date is given.”

In India (and elsewhere around the world), there have been calls to boycott Chinese products, but this isn’t a realistic solution.

“The calls for India to boycott (and promote an Atmanirbhar Bharat instead), are practically difficult in the short term for India as India imports $75 billion worth of goods every year from China, to the extent that parts of Indian industry are dependent on China.”

Atmanirbhar Bharat – Digital India & Pharmacist to the World
The emergence of a vast PPE industry in India is only the latest example of a self-reliant India in practice. Two other industries are also excellent examples of this, though the phenomenal growth of both occurred over years – rather than days: the electronics & semiconductor industry and the pharmaceutical industry.

With pharma, India has become known as the ‘pharmacist to the world,’ and is globally the top manufacturer of generic drugs. In more recent years, efforts have shifted towards innovator molecules and biotechnology.

KPMG: Establishing Indian Self-Sufficiency in APIs
KPMG’s April 2020 Indian API Industry – Reaching Full Potential report discusses the need for India to “proactively boost the manufacturing of APIs, intermediates and KSMs in the country and reduce dependence on imports.”

The report lays out in detail policy recommendations to strengthen the sector. Among the categories of recommended changes stretching over the next several years:

  • Improve the ease of doing business
  • Create incentives and subsidies
  • Focus on infrastructure development
  • Encourage innovation & technical capabilities.

The Future of Self-Reliance
As a response to supply chain concerns, the concept of self-reliance is sound. It has, in fact, become a rallying cry in capitals across the world. As a practical matter, the reality is somewhat murkier. The electronics and pharmaceutical industries – shining examples of Indian innovation and in shoring – remain heavily-dependent on foreign suppliers despite efforts to limit supply chain risk. (Neuland has taken a number of steps to do just that, which we discussed most recently in this post.)

Objectively, being self-reliant reduces risk. As we’ve seen in the current pandemic, access to drugs, protective equipment and masks is critical to successfully confronting the virus – and the absence of these products can have considerable negative life-threatening consequences.

Realistically, however, we live in a global world in which we’ve become increasingly interdependent. And while building local infrastructure can create jobs, strengthen economies, and ensure stability of supply, positive results are not always possible. Some products will likely remain offshore for years to come.


Pharma Manufacturing Operations in the Time of COVID-19

There has been a flood of articles recently on how companies have adapted to our new reality in a coronavirus-affected world. As an essential services manufacturer and lab, Neuland has tackled some unique challenges as we’ve navigated through the pandemic. In this post, we’ll share some of the steps we’ve taken, and review some of the common practices pharma businesses around the world are using to mitigate the spread of COVID-19.

Perhaps the best example of steps manufacturing businesses have taken in the modern era can be found during the flu pandemic of 1918. Many of those actions have resembled those we’ve taken to fight SARS-CoV-2:

“During the 1918-19 H1N1 “Spanish” influenza pandemic, which infected one fifth to one third of the world population, and during which 50 million people died worldwide,1,2 including an estimated 675,000 Americans, the United States has adopted a range of nonpharmaceutical (public health) interventions. These measures, which were similar to those currently adopted, included closure of schools and churches, banning of mass gatherings, mandated mask wearing, case isolation, and disinfection/hygiene measures.3

These measures were not implemented at the same time or for the same duration in different cities, however, nor were they uniformly followed. A recent analysis concluded that in some cities (San Francisco, St Louis, Milwaukee, and Kansas City) where the measures were implemented early, these measures reduced transmission rates by up to 30% to 50%.3 Cities that implemented such measures earlier had greater delays in reaching peak mortality, and had lower peak mortality rates and lower total mortality.”

Also similar to our current situation, manufacturing across industries was largely curtailed. In the case of the 1918 flu, many employees fell ill – necessitating the shutdowns. In 2007, researchers at the Federal Reserve Bank of St Louis reported that the Spanish Flu caused manufacturing to decline by 18% in 1918-19, a result of declines in both supply and demand.

What Are Governments Recommending for COVID-19?
In the U.S., OSHA’s (the Occupational Safety & Health Administration’s) COVID-19 guidance shared a series of recommendations for manufacturers. Agencies such as the CDC have issued additional guidance, such as Implementing Safety Practices for Critical Infrastructure Workers Who May Have Had Exposure to a Person with Suspected or Confirmed COVID-19.

Common recommended steps include:

  • temperature pre-screening of employees
  • wearing masks
  • social distancing
  • enhanced cleaning and disinfection of work spaces
  • attention to personal hygiene.

It has been reported that “Social distancing and employee safety measures put an additional level of pressure on manufacturers, as 40%-50% of their workforce will be unavailable to perform their functions on-site.”

The Government of the Indian state of Telangana has extended all the necessary support and assurance for smooth functioning of both pharmaceutical manufacturing and R&D.

In Telangana, functional work sites – which come under pharmaceutical manufacturing and R&D per G.O. No: 45 and 46 of Government of Telangana – have been declared exempt from the lockdown by both the Central and State Government authorities. Companies which are operating per the exemptions must take steps to ensure the health and safety of employees.

What Has Neuland Labs Been Doing?
For the last several months, Neuland has implemented the guidelines specified by the Government of Telangana as well as the National Directives for COVID-19 Management referenced in Circular No. 40-3/2020-DM-I-A. We are committed to serving the needs of the healthcare sector without compromising the health and safety of all Neuland employees – which is our first priority. We’ve taken a number of preventive measures at all work sites over the last four months:

  • Monitoring and Entrance to Facilities (e.g., guidelines for face masks, temperature checks, touchless recordkeeping, medical screening, transportation and more.)
  • Social Distancing & Travel Restrictions (e.g., meetings, social distancing measures, travel, site visitors, staggered schedules, seating arrangements, etc.)
  • Enhanced Sanitation Measures (e.g., increased cleaning frequencies in common areas and bathrooms, heightened awareness communications)

Neuland is continuously striving to make the workplace safer every day during this global health crisis. We are providing personal protective equipment to our employees, and have adopted enhanced personal hygiene and social distancing measures. We’ve also created a 24/7 helpline number which employees can call to express any concerns with respect to COVID-19.


Beyond COVID-19: What Else in Happening in Pharma?

Around the world, pharma and biopharma – along with all of the supporting industries, from suppliers and research organizations to outsourced providers – have been exclusively focused on COVID-19. With good reason – since its impacts are being felt in virtually every aspect of our lives…social, political, economic and beyond.

The conversations usually range from discussions centered around vaccines, to treatments, to the ancillary issue of too-long supply chains increasing the risk of drug shortages or other issues.

Non-COVID-Related Business Moves On
While the life sciences industry as a whole rose to the challenges posed by the pandemic, believe it or not, other science continues to move forward. So – as a (partial) break from our coronavirus-laden science news streams – here’s a roundup of some of the research and scientific discovery happening in the field of peptides. Much of this may have gone unnoticed, but merits attention.

Is oral dosing with peptides on the horizon?Oral Dosing with Peptides on the Horizon?
There is growing promise (finally!) of oral dosing routes for peptides. This is a potential gamechanger for the peptide segment, since a lack of solid dosage forms was considered to be one of the major factors preventing peptide drugs from gaining traction.

The oral dosage route has long been the holy grail of peptide drugs. Historical routes of administration – namely, injectables – have lower adoption and compliance rates.

With 60+ peptide drugs currently approved and on the market, very few (e.g., plecanatide and oral semaglutide) are available in solid dosage forms.  This is attributable to the ease with which they are broken down in the gastrointestinal tract. They are, however, well-suited to oral delivery, given the size of the molecules. Identifying methods by which peptide therapeutics could retain their efficacy when taken orally has always been a priority.

In a study published in Nature Biomedical Engineering in May, researchers at the Ecole Polytechnique Fédérale de Lausanne (EPFL) developed a method “for the generation of small target-specific peptides (less than 1,600 Da in size) that resist gastrointestinal proteases,” overcoming the traditional issues of metabolic instability and limited intestinal uptake.

An article at Genetic Engineering & Biotechnology News discussed the near-term objectives of the EPFL research:

“[The] group is developing oral peptides that act directly on gastrointestinal targets, meaning that they don’t need to travel into the bloodstream. ‘We are focusing on chronic inflammatory diseases of the gastrointestinal tract like Crohn’s disease and ulcerative colitis as well as bacterial infections,’ Heinis noted. ‘We have already succeeded in generating enzyme-resistant peptides against the interleukin-23 receptor, an important target of these diseases, which affect millions of patients worldwide without any oral drug available.’”

Peptides & COVID-19
Therapeutic peptides have been receiving a great deal of attention lately for their role in SAR-CoV-2 research and treatment.

A publication on the preprint server bioRxiv describes a number of peptides which interfere the early stages of SARS-CoV-2 viral attack. An article about the research paper, New database catalogs peptides that may halt SARS-CoV-2 cell infection, discusses the use of peptides to inhibit protein-protein interactions:

“SARS-CoV-2 is genetically closely related to SARS-CoV responsible for the original SARS outbreak in 2002, and both viruses use the angiotensin-converting enzyme 2 (ACE2) receptor as a keyhole to infect the cells. The binding occurs via the receptor-binding domain (RBD) found on the spike protein, and utilizes transmembrane serine protease enzyme known as TMPRSS2.”

The spike protein referenced above has become a key target of peptides. New York-based Hoth Therapeutics has likewise focused on this target – licensing technology and intellectual property for a novel peptide therapeutic to prevent spike protein binding and potentially slow COVID-19’s transmission.

Synthetic Peptides: Promising Candidates for COVID-19
Beyond Hoth Therapeutics, there are many more peptide drugs in development for COVID-19. From PharmaceuticalTechnology.com:

“Over 400 drugs are in development worldwide for the treatment of Covid-19 (Table 1). Five synthetic peptide candidates are already being tested in patients with Covid-19: four candidates in Phase II and one in Phase I. The pipeline also includes one investigational new drug (IND)/clinical trial application (CTA) filed stage candidate, two preclinical stage candidates, and six discovery stage candidates.

According to GlobalData’s Pharma Intelligence Center Pipeline Drugs Database, there are currently 21 peptide drugs in development for the treatment of COVID-19, including 15 synthetic peptides in development for the treatment of Acute Respiratory Distress Syndrome (ARDS), a life-threatening condition where the lungs cannot provide the body’s vital organs with enough oxygen, and other respiratory illnesses caused by SARS-Cov-2 infection.”

While we wait for the results of these various studies, it’s clear that peptides continue to be seen as strong contenders for therapeutic indications.

Learn more about peptide manufacturing and Neuland’s peptide capabilities in our Guide to Sourcing Pharmaceutical Peptide APIs.


China Launches New Marketing Authorization Holder (MAH) System

In December 2019, China issued a revision to their Drug Administration Law. It was the most wide-ranging modification of their laws since 2001. It marked a fundamental shift away from a company- or organization-based regulatory philosophy to one which is product-based.

The Marketing Authorization Holder (MAH) system is perhaps the most significant change to Chinese laws relating to drug products. It also brings the Chinese drug industry more in line with regulatory perspectives common in the U.S., E.U., India and elsewhere.

The new MAH system is expected to have an enormous impact on the country’s drug industry.

Why Shift to an MAH-based System?
The goal of a Marketing Authorization Holder-based system is to make it easier for drug developers to bring new drugs to market, while increasing their responsibility for the drug’s safety. The MAH will also seek to minimize some of the challenges China’s drug industry faces, including counterfeit drugs, substandard drugs and high drug prices.

Chinese regulators believe adoption of an MAH system will drive innovation for companies, research organizations & individuals. It will have other, residual impacts as well. Because MAHs are not restricted to manufacturing the drugs themselves, the outsourced contract research, analysis and manufacturing segments will see a significant boost. In turn, the ability to draw on the capabilities of these types of contract providers will further stimulate the growth of small- and mid-sized pharma companies in China.

Where companies previously focused on regulatory approval as the fundamental objective, they will need to shift to managing products across the entire lifecycle – pre-market to post-market. Smaller firms with fewer resources can turn their attention away from the necessity to build production capacity, and instead focus on their areas of expertise.

The MAH Was Already Partially in Place
While the December 1st rollout brought the Marketing Authorization Holder (MAH) system into widespread use, Chinese regulatory authorities had already been working with it for nearly five years.

How?

It was first implemented on a trial basis in 10 provinces in 2016 – in which 3,239 product licenses were issued to 156 Marketing Authorization Holders. The trial period enabled pharmaceutical research institutions and individual researchers to submit clinical trial and marketing applications as drug registration applicants – which allowed them to become an authorization holder.

MAH Now Applies to All Companies in China
The MAH system now applies to all companies applying to register a drug in China. There are, however, some differences between China’s implementation of the MAH and other, existing arrangements around the world.

In China, each MAH must be considered a ‘legal entity.’  Examples include pharmaceutical or biopharmaceutical companies – or a research institute. This differs from existing regions which use an MAH system. In the EU, for example, it isn’t restricted to a company or organization – an individual can also be considered an MAH.

What Are the Roles of a Holder Under China’s New System?
Across the lifecycle of a drug, Marketing Authorization Holders have various responsibilities. These include:

Pre-Marketing
The Holder is required to:

  • provide compliant pre-clinical, clinical and manufacturing data.
  • identify a qualified person who acts as the contact for product releases.
  • guarantee the quality of any outsourced operations or providers.
  • establish a pharmacovigilance system to detect, assess and prevent adverse effects.

Post-Marketing
The Holder is required to:

  • establish a risk management plan.
  • conduct post-market evaluations to confirm safety, efficacy, and quality.
  • submit an annual report to list any changes that have occurred (Major changes, however, must be reported proactively, before they become effective).
  • stop the sale and distribution of any products for which safety-related problems are reported for one of its products, and launch recalls.
  • ensure the supply of drugs for ‘urgent needs’ (to be defined in subsequent regulations).

Regulatory Implications of China’s MAH
Chinese regulators (the CFDA) will need to expand their focus from the safety, efficacy, and quality of drugs to include evaluation of each MAH’s quality & risk management capabilities. The CFDA will also need to establish standards and guidance for an MAH to follow concerning unit tracking, pharmacovigilance, and recalls.

China’s new MAH system represents another step towards harmonization of the global drug industry.  The hope is that it will foster cross-pollination between R&D institutions and drug manufacturers to further encourage innovation, though we’ll have to wait and see.