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A Review of Exciting New Peptide Drug Research

According to the FDA’s 2019 Impact Story: Developing the Tools to Evaluate Complex Drug Products – Peptides: “As a class of drugs, peptides are increasingly important in medicine. FDA is developing the scientific tools to facilitate evaluations of these drug products and proposed generic equivalents.”

The agency reports having seen a “rapid increase in the number of new drug applications submitted for peptide drug products.” They recognize the need to overcome the challenges involved in the detection, analysis and control of peptide-related impurities, and ensure equivalence between generic and innovator versions of peptide drugs.

Peptide drugs continue to offer significant benefits, though delivery challenges remain. In an earlier post on the promise of peptide drugs, we discussed some of the advantages peptides can offer:

“Compared with proteins and antibodies, peptides have the potential to penetrate further into tissues owing to their smaller size. Moreover, therapeutic peptides, even synthetic ones, are generally less immunogenic than recombinant proteins and antibodies.”

We also touched on some of their traditional challenges, namely:

  • high production cost & infrastructure requirements
  • rapid degradation profiles in the human body
  • corresponding lack of oral dosing delivery mechanisms
  • other pharmacodynamic limitations (short half-life, high hydrophilicity, rapid hepatic clearance, etc.)

Despite these challenges, however, novel strategies have “turned peptide therapeutics into a leading industry with nearly 20 new peptide-based clinical trials annually. In fact, there are currently more than 400 peptide drugs that are under global clinical developments with over 60 already

approved for clinical use in the United States, Europe and Japan.” (A Comprehensive Review on Current Advances in Peptide Drug Development and Design)

Here are some abstracts of exciting peptide research currently making the news:

A new antibiotic to combat drug-resistant bacteria is in sight
An international team of researchers, with the participation of scientists from Justus Liebig University Giessen (JLU), has now discovered a novel peptide, that attacks gram negative bacteria at a previously unknown site of action.

Oral Proteins and Peptides Market to reach $8.23 billion at a CAGR of 11.7% by 2028.
However, high cost associated with drug development and low bioavailability of these drugs restraint the growth to certain extent.

Arch Biopartners Provides Interim Update on Phase I Trial for LSALT Peptide: https://www.globenewswire.com/news-release/2019/11/07/1943014/0/en/Arch-Provides-Interim-Update-on-Phase-I-Trial-for-Metablok-LSALT-Peptide.html

Antimicrobial Peptide May be Effective Against MRSA
Researchers from Germany have identified a new antimicrobial peptide that demonstrates significant activity against a variety of bacteria, including multiresistant human strains such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE).

Synthetic Corkscrew Peptide Kills Antibiotic-Resistant Gram-Negative Bacteria
An engineered peptide provides a new prototype for killing an entire category of resistant bacteria by shredding and dissolving their double-layered membranes, which are thought to protect those microbes from antibiotics.

Antibacterial Peptide Could Aid in Treating Soldiers’ Burn Wound Infections
An antibacterial peptide developed at Temple’s College of Science and Technology looks to be a highly effective therapy against infections in burn or blast wounds suffered by soldiers.

Nanoparticles enable oral insulin delivery in mice
The particles help insulin, a peptide, to slip through the intestinal wall and into the bloodstream.

Advances in Lipid and Metal Nanoparticles for Antimicrobial Peptide Delivery
Antimicrobial peptides (AMPs) have been described as excellent candidates to overcome antibiotic resistance. Frequently, AMPs exhibit a wide therapeutic window, with low cytotoxicity and broad-spectrum antimicrobial activity against a variety of pathogens.

What are you working on? Share your thoughts here.


2020: Looking Forward & Listening to Customers to Address Pharma Needs

2020 is here and we’re starting the New Year off right. We’re listening closer to – and learning more from – you, our customers.

Last November’s CPhI Frankfurt provided valuable insight into the challenges pharma companies either already face or want to head off.

So what were our customers & colleagues thinking about at CPhI?

What we heard from attendees echoed many of the themes we’ve been discussing throughout 2019, including:

  • The increasing complexity & importance of regulatory compliance.
  • The gains made in the field of peptides.
  • Heightened attention to supply chain security.

Stronger Supply Chains
Much ink has been spilled on trade wars, Brexit and the general sense of uncertainty that seems to have settled upon global business decision-making these days. It has led to an uptick in supply chain security awareness, even among smaller pharma companies with relatively simple supply chains. Backward integration, secondary supplier qualification and multi-facility redundancy have all become increasingly important when evaluating options to strengthen supply chains.

Top-of-Mind Qualities
At CPhI Frankfurt, we heard that some of the traits which fundamentally set Neuland apart happen to also be top-of-mind among the decision-makers with whom we spoke. This was true of quality, certainly, and Neuland’s regulatory track record has always been a strength.

But it’s also true of Neuland’s business focus as a “pure-play” API provider. The fact that we don’t ever compete generically with our clients matters. It’s even more essential now in the vendor selection process as companies assess their supply chains. While for us it’s a 30+ year old approach to contract pharma, increasing trade ambiguities have raised the significance of our model in the eyes of our customers.

CPhI 2019 Had Laser-Focused Attendees
This year, customers visiting Neuland’s booth at CPhI tended to have a very clear idea of products and services they wanted to discuss. As buyers, they were further along the decision-making process, and it was clear they had done a great deal of prep work. Customers were very focused on well-defined agendas regarding the products & services they wanted. Attendees at CPhI spent more time in the Formulators section than the Regulatory section– an indicator that drug compound formulation challenges were a primary concern at the show.

Growing Opportunities in APAC and MENA
It’s always wonderful to catch up with our U.S. and E.U. customers. A large number of visitors from both the Asia Pacific (APAC) and Middle East & North Africa (MENA) regions also stopped by our booth.

With the MENA pharma market set to grow to $60 billion, the region is characterized by “population growth, increased life expectancy, greater prevalence of lifestyle-related diseases such as diabetes, and a greater prioritization of healthcare services among governments in the region.”

APAC has, of course, long been a growth market – and China has been a key driver in this. This is expected to continue, since China accounts for 20% of the world’s population but only represents 1.5% of the global drug market. There was an increased amount of APAC interest in our peptide APIs and peptide capabilities (discussed below). From Korea, in particular, we saw a great deal of interest in Rotigotine, a Parkinson’s compound. Some discussions we held centered around its potential use in patch formulations.

APIs & Indications of Interest at CPhI
What APIs and indications interested our customers the most? Many of the compounds in our portfolio and R&D pipelines were in great demand with requests for samples & DMFs, including:

Paliperidone
Paliperidone is an atypical antipsychotic used to treat schizophrenia and schizoaffective disorder.

Edoxaban
Edoxaban is an oral anticoagulant drug used to reduce the risk of stroke and blood clots in people with an irregular heart rate (nonvalvular atrial fibrillation).

Aripiprazole
Aripiprazole is an atypical antipsychotic used to treat certain mental or mood disorders (e.g., bipolar disorder, schizophrenia and Tourette’s syndrome), and – when combined with other medication – can be used to treat depression.

Rotigotine
Rotigotine is a dopamine agonist medication used for the treatment of Parkinson’s disease and restless leg syndrome.

Apixaban
Apixaban is an oral anticoagulant medication used to treat and prevent blood clots, and to prevent stroke in people with atrial fibrillation.

Rivaroxaban
Rivaroxaban is an anticoagulant medication used to treat deep vein thrombosis and pulmonary emboli, and prevent blood clots in atrial fibrillation or following hip or knee surgery.

Varenicline Tartrate
Varenicline Tartrate is a medication used to treat nicotine addiction. It is a high-affinity partial agonist for the α4β2 nicotinic acetylcholine receptor subtype (nACh).

Also of interest to attendees were some of Neuland’s other APIs, including:

Crisaborole
Crisaborole is a nonsteroidal topical medication used for the treatment of mild-to-moderate atopic dermatitis (eczema).

Elagolix Sodium
Elagolix is an oral GnRH antagonist medication used to treat pain associated with endometriosis. It is also under development for the treatment of uterine fibroids and heavy menstrual bleeding.

Tafamidis
Tafamidis is a medication used to delay loss of nerve function in adults with familial amyloid polyneuropathy (FAP).

Peptides in Great Demand
We’ve been seeing growing demand for peptides, and CPhI was no exception. It’s not a surprise, given the industry’s increasing attention on their potential capabilities and pharma’s growing ability to resolve challenges with bioavailability while increasing the range of functional dosage forms.

We’ve talked a lot about peptides here on our blog (for example, check out this Guide to Sourcing Pharmaceutical Peptide APIs). This year, however, interest & demand has finally caught up to the potential of peptides. At the show, we had a great deal of interest in two of our R&D pipeline peptides – Liraglutide and Semaglutide – both of which are targeted at antidiabetic indications. We also experienced increased interest in Neuland’s peptide capabilities from other generics developers and contract manufacturers.

Interested in learning more about any of these APIs? Contact Neuland today.


A Few Words on Pharma Innovation…

The field of advanced process chemistry is, by its very nature, a tale of innovationAt just about the same time we were going to write on the state of peptides (key takeaways: yes – still growing, lots of promise, more drugs in the pipeline), I read a piece from Karen Langhauser – pharmamanufacturing.com’s Chief Content Director – on defining ‘innovation.’ (This was in reference to their cover article for the month, on their 2019 Innovation Awards.)

In her editorial, Langhauser makes the case that persistent, incremental improvements are the ‘bread and butter’ of pharmaceutical advancement:

“As B2B editors, much of our time at industry events is spent learning about new equipment and services designed to meet the specific needs of pharma. We hear all the stories behind this innovation and thus truly understand and appreciate the investment pharmaceutical equipment vendors put into developing and improving their products. We believe all types of innovation, whether earth-shattering or incremental, should be recognized.” (emphasis mine)

Innovation in Action
The article got me thinking about innovation, and how we see it play out in our everyday lives. For example, here at Neuland we’re surrounded by innovative people – people who spend their days discovering solutions to the challenges of drug commercialization.

Pharmaceutical scientists and process chemists are often confronted by the ‘two-steps-forward-one-step-back’ process of scientific discovery. Modifying or adding a specific chemical to a reaction, for example, may create X benefit, but result in Y or Z consequences.

Innovation in Drug APIs
Because of this, the field of advanced process chemistry is, by its very nature, a tale of innovation (or, more aptly, a series of tales).  And while it is easy enough to cast aside the generic portion of the market to shine the innovation spotlight on novel APIs, the generic portion of the market is also teeming with innovation.

Sure, it isn’t as sexy as “The Latest Great New Scientific Discovery!!!!!,” but the generic drug space – by virtue of its hyper-competitiveness – demands innovation. This often takes the form of manufacturing advances. And usually, they are incremental improvements designed to move the needle enough to establish or improve profitability… unquestionably critical achievements in a hyper-competitive market.

Indeed, it is often those ‘persistent, incremental improvements’ which pave the way for vast leaps forward in our ability to cure or manage various health conditions. Numerous small improvements add up – whether it’s an efficient peptide purification method which allows us to reimagine the economies of scale for peptide drugs, or a novel analytical method (or technology…or even knowledge) which allows the industry to identify a previously-unknown contaminant or impurity.

This latter scenario was the case with Valsartan and our (still) emerging understanding of detection and mitigation of its potential contaminants (NDMA and NDEA). While it is common outside of the pharma industry to view such recall incidents as failures, sometimes they are not. They serve to remind us how limited our scientific knowledge and capabilities can be.

And then, of course, industry makes an incremental advance to step us beyond the challenge.  Accurate HIV detection – and the later introduction of combinatorial drug therapy – are likewise examples of incremental, progressive steps towards a solution. (Note: While HIV is not, by any means, ‘solved,’ it has evolved into a manageable, treatable chronic condition in certain geographies.)

The “Next Pinnacle of Scientific Knowledge”
The limitations of our knowledge often lead us to declaring a particular emerging field the answer to understanding human health. In the late 1990’s, as the Human Genome Project and Celera Genomics raced towards human genome sequencing, genomics was declared the pinnacle. In the ensuing years, more “pinnacles” followed – proteomics, glycomics, metabolomics, lipidomics, transcriptomics and more – each holding the promise of unlocking the keys to human health.

Each one has turned out to be incredibly important to our overall understanding of human health, but none are the final answer in and of itself. Such is the nature of incrementalism – what you thought mattered actually did matter…but as part of a greater whole.

The pharmamanufacturing.com article captured this sentiment perfectly, stating that the 2019 Pharma Innovation Awards winners “offer slices of innovation.”

It’s a great way of describing it, and it extends beyond the pharmaceutical equipment & services brief of the article. Slices of innovation also includes the vast number of human health, medical & drug discoveries happening all the time, the organizations focused on the healthcare delivery side of the industry, and everything in-between…including contract pharma organizations

like Neuland who offer constantly-evolving (yes – incrementally) process development & scale-up expertise.

What do you think are the most important pharma innovations still-to-come?

What’s on your wish list?

Share your thoughts with us on LinkedIn, Twitter or Facebook.


Fostering a Quality Culture to Support Drug Manufacturing

As an API manufacturer, when it comes to product safety in the pharmaceutical space the stakes couldn’t be higher. We’ve written a few posts recently on modifications to regulatory inspection regimes (here and here) that are likely to impact – in some fashion – global drug manufacturers.

In their Life Sciences Regulatory Outlook, Deloitte writes: “Life sciences companies exist to help patients and save lives. Regulatory compliance provides guardrails to ensure all companies play by the same rules.”

Well stated, Deloitte. We’re in the business of making drugs that improve people’s lives, and regulators are there to ensure we’re doing it safely in accordance with current best practices.

The last few years have seen major changes to the ways in which drug companies and their regulators go about ensuring the safety and efficacy of drugs. We’re in an era of significant change: scientific knowledge – whether human biology or complex synthetic chemistry – continues to advance.

Most companies are undertaking (and some have completed) the transition to digital data collection and retrieval. Processes are being streamlined and automated wherever possible.

Modernization is affecting everything from analytical instrumentation and process monitoring to risk management practices. Globalized supply chains continue to expand, even in light of recent trade uncertainties.

All of these factors – globalism, science & technology advances, the shift towards digitalization – play a role in the growing ‘complexity of compliance’…as well as the importance of compliance.

A commitment to regulatory excellence matters not because a failure can be expensive (it can, both both financially and in terms of reputation), but because – as Deloitte pointed out – we are in the business of improving people’s lives.

At Neuland, we’re proud of our quality accomplishments and quality system capabilities. We have a strong regulatory track record, with all three of our manufacturing units inspected and approved by regulatory agencies from around the world. (Our Unit 1 and Unit 2 manufacturing facilities have respectively undergone six U.S. FDA inspections.)

How Neuland Labs Creates & Maintains a Pharma Quality Culture
To encourage regulatory excellence, we’ve fostered a culture in which quality & compliance are top priorities across all of our sites, 24X7. The key to ensuring a culture rooted in regulatory excellence lies in processes & procedures – driven by a motivated, quality-focused team. Among the practices we’ve adopted:

  • Quality Metrics by Management
    We hold weekly Quality Reviews at the plant level. These are led by the Quality Head with Plant, R&D, and RA teams. Monthly Quality reviews occur with top Management (including the CMD and CEO).
  • Continuing cGMP Education
    Continuous cGMP trainings are conducted with relevant employee teams to maintain up-to-date knowledge in accordance with current guidelines and regulations.
  • Constant Audit Readiness
    At Neuland, we experience approximately 100 customer audits each year at our facilities. While some companies approach audits or inspections as ‘special events’ which demand the team’s attention immediately prior to the audit, we’ve opted for an ‘all-the-time-audit-readiness’ approach. To this end, we perform continuous QA/CQA audits (both scheduled & walk through), and expect our units to be prepared for audits at any time, without forewarning.

Many of the Quality behaviours we’ve established are rooted in process and technology. For example, we employ:

  • Quality system automation: Electronic Quality Management systems have been implemented for Deviation, Change Control, CAPA, and Complaints across Neuland Units.
  • Routinely updated SOPs: Harmonised Procedures/SOPs & Systems are in place across all of Neuland’s Units. We ensure that SOPs are updated in line with current guidelines.
  • The latest most compliant instrumentation: Neuland’s Quality Control laboratories are equipped with the latest equipment and systems – including HPLCs, GCs, IR, UVs, SORs, KF titrators and more – to ensure compliance with 21 CFR Part 11 requirements.
  • Robust batch release systems: Our batch release systems ensure a thorough review of batch processing and analytical documentation by the site’s Quality Assurance department, in close cooperation internally between departments.

Would you like to read more about Neuland’s commitment to Quality culture? Learn about our Regulatory Affairs department, our Quality Control & Assurance team, or Contact Neuland Labs.

 

 


What the Revised FDA CDER SSM Really Means

Confused by the new FDA CDER Site Selection Model? Here’s what you need to know.

CDER – the U.S. FDA’s Center for Drug Evaluation and Research which regulates over-the-counter and prescription drugs – has altered their fixed minimum inspection routine. It now requires inspection of both domestic and foreign drug manufacturing establishments “in accordance with a risk-based schedule.” The FDA must consider a facility’s “known safety risks” when determining the inspection schedule.

This new Site Selection Model (SSM) allows the FDA to prioritize routine quality-based inspections (e.g., cGMP inspections). One of the SSM’s objectives is to create global inspection equivalency – in essence, sites with equivalent risk will face equivalent frequency inspections, wherever they may be located, and regardless of drug type (innovator, generic, OTC).

What is CDER’s SSM?
The Site Selection Model (SSM) prioritizes facility inspections by considering risks related to drug quality which could arise from violations of cGMP requirements.

Who Sets and Manages the SSM Schedule?
This is where things get a little complicated, but bear with me…

The CDER Site Surveillance Inspection List (SSIL), which prioritizes facilities for inspection, is produced by the Office of Surveillance (OS) in the Office of Pharmaceutical Quality (OPQ). The planning and carrying-out of inspections is performed by the Office of Regulatory Affairs (ORA). ORA is also the office which plans and conducts the inspections as assigned according to the SSIL. OS tracks the accomplished inspections and provides quarterly updates.

The SSM ranks sites by various risk factors. Higher-risk facilities are assigned for surveillance inspections.

How is this accomplished? The Office of Surveillance takes the current catalog of sites and applies risk factors and weights to produce site scores. The sites are then ranked by score to compile the SSM inspection schedule.

What Criteria does OS use to Prioritize Drug Manufacturing Facilities?
FDA CDER’s Site Selection Model evaluates a number of risk factors when determining how to prioritize inspections. These include:

  • Facility type (e.g., manufacturer, packager, lab).
  • Facility compliance history, inspection frequency and outcomes. This includes both FDA and foreign agency inspections (pursuant to section 809 of the FD&C Act, and also check out our FAQ post on the US-EU MRA), and the inspection history of foreign regulatory bodies deemed ‘capable.’
  • Time since last surveillance inspection (or whether the site has previously been inspected).
  • Information regarding recalls involving the facility.
  • Patient exposure and product risks, including dosage form, route of administration, API load, therapeutic classification, etc.
  • Other criteria as may be deemed necessary to allocate inspection resources.

Who Will the SSM Impact?
The CDER maintains a Catalog of Manufacturing Sites, which includes facilities that commercially manufacture finished pharmaceuticals, as well as in-process materials and APIs for use in human drugs.

There are a number of cases in which a firm’s facility may not be included in the site selection model, including:

  • Sites in which the last inspection was classified as open, or final official action indicated (OAI), are removed from routine surveillance inspection planning. For example, in the case of an OAI, re-inspection is determined as part of the enforcement effort.
  • Sites currently on Import Alert are removed from routine surveillance inspection planning.
  • Newly-registered sites (or those without prior routine surveillance inspection) are typically inspected within 30 days (and/or as a for-cause assignment).
  • Sites can also be removed from the SSIL by request of the ORA, and subsequent investigation & confirmation by the Office of Surveillance. An example of this type of removal from the inspection list would be a recent inspection performed after the SSIL was generated. In such a case, the facility would be removed pending confirmation that the cGMP inspection had been completed.

What are the Objectives of the Site Section Model Program?
The program’s objectives include determining whether inspected firms (e.g., sites, facilities) are operating in compliance with applicable cGMP requirements. Additional goals include:

Improving Safety
In cases in which they are not in compliance, the program’s objective is to provide the evidence for actions to prevent adulterated products from entering the market (or – as appropriate – to remove adulterated products from the market and to take action against persons or firms responsible).

Improving Compliance
The program aims to help drug manufacturers by providing input during inspections which can improve their compliance with regulations.

There are some longer-term goals, as well – including gaining a better understanding of current practices among drug manufacturers in order to update cGMP requirements, regulatory policy, and guidance documents.

FDA Inspection Classifications
After a SSM inspection, the FDA determines if the areas evaluated are in compliance with applicable laws and regulations. The FDA uses one of three classifications:

  • No Action Indicated (NAI): No objectionable conditions or practices were found during the inspection (or the objectionable conditions found do not justify further regulatory action)
  • Voluntary Action Indicated (VAI): Objectionable conditions or practices were found but the agency is not prepared to take or recommend any administrative or regulatory action
  • Official Action Indicated (OAI): regulatory and/or administrative actions will be recommended.

Better Outcomes, With Lower Risk
This new inspection model holds the hope of creating a new common denominator for drug manufacturers, while improving the overall safety & compliance of those facilities manufacturing human medicines. It shines light on potential manufacturing deficiencies, and takes steps to ensure safer, more efficacious medicines reach the market.


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 > http://www.pharmtech.com/standing-test-time-0

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?, pharmamanufacturing.com’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 > https://www.pharmamanufacturing.com/articles/2019/whats-behind-all-the-m-and-a-deals-in-pharma/

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 in-pharmatechnologist.com shares how the Swiss Agency for Therapeutic Products is revising testing protocols > https://www.in-pharmatechnologist.com/Article/2019/08/09/Switzerland-to-boost-detection-of-sartan-impurities?utm_source=copyright&utm_medium=OnSite&utm_campaign=copyright

Brexit & Supply Chains
Pharmaceutical-technology.com 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 > https://www.pharmaceutical-technology.com/sponsored/life-sciences-supply-chain-brexit/

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.”
https://www.supplychainbrain.com/articles/30066-pentagon-sees-security-threat-in-chinas-drug-supply-dominance

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 > https://packagingeurope.com/is-blockchain-the-key-to-a-secure-supply-chain/

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. https://pharmafield.co.uk/in_depth/a-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. http://www.pharmatimes.com/magazine/2019/julyaugust_2019/the_promised_land

 

 


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.