Over the last four decades, supply chains have gone from being measured in meters to miles – and ultimately to continents & hemispheres.
Without a doubt, drug industry globalization has been a key factor in our success here at Neuland. But it has also spawned a range of supply chain anxieties – quality concerns, thorny compliance & regulatory issues, increased threats of supply disruption, growing (and waning) trade worries, and more.
It’s no wonder pharmaceutical supply chains have become such a hot topic of late. January saw topical articles at ContractPharma, Pharmtech, European Pharmaceutical Review, Industry Week and elsewhere. It feels like supply chains are practically everywhere. Which – of course – they are.
Global Supply Chain Complexity
Today, a drug supply chain can stretch across numerous countries on multiple continents, sometimes moving back and forth. A drug may cross multiple borders – from research and discovery across Europe, Japan, North America and elsewhere, to manufacturing supply chains running from China to India and then onward, to distribution around the world.
Supply chains – while increasingly complex – are growing increasingly secure.
Are we there yet?
No, but we have made great strides. Many of our advances towards supply chain security can likely be traced to the increasing global standardization and harmonization of industry practices and regulations across borders – enabling streamlined compliance with multiple jurisdictions.
We’ve discussed standardization & harmonization efforts here on the blog in the context of the U.S.-E.U. Mutual Recognition Agreement, ICH Q12, and the Revised FDA CDER SSM. These and other industry changes are helping (or hopefully will help) to tear down borders and restructure how the industry operates.
Supply Chain Security Steps
Challenges certainly remain, though.
Supply chains may be more secure, but they aren’t (and perhaps won’t ever be) 100% fully secure. Pharma industry suppliers like Neuland are increasingly taking steps to ensure the security of their own supply chains. (In our case, we’ve adopted backward integration practices, and have established redundant manufacturing facilities to ensure continuity of supply.)
The introduction of Quality By Design, DoE as well as many other new practices and procedures in recent years have already aided in reducing the risk of manufacturing-related supply chain interruptions. But quality and compliance problems still arise around the world – highlighting the continued importance of selecting an outsourced pharma contract partner with a proven regulatory track record.
Serialization – a key step towards supply chain security – is still a relatively new art. It will certainly evolve up and down the supply chain in the coming years…both as our capabilities extend, and in response to future emerging threats or practices.
Macro challenges also exist (and will always continue to exist). These include environmental, trade and government-related supply chain uncertainties, all of which seem to have become hot-button topics for the drug industry in recent years.
The last few years have seen plant shutdowns due to pollution and emissions, government-ordered shutdowns due to construction, and the sudden threat of cross-border tariffs – all of which can impact pharma supply chain risk management.
On the Plus Side…
When you consider the relatively short span of time in which drug supply chains have evolved, the impacts have been tremendous. As mentioned earlier, a typical drug is likely to cross multiple borders in its path to market – an astounding logistics feat when compared to just 20 or 30 years ago.
Supply Chain Security Has ‘Joined the Ranks’
With shifting regulatory landscapes, ever-present global challenges and increasingly complex chemistry- & quality-related issues, supply chain security has risen to become a prominent issue in pharma boardrooms over the last decade. Now that it’s top-of-mind, it’s likely to remain a top consideration in the years to come as companies seek to proactively manage risk.
MORE ON: PHARMA SUPPLY CHAINS >
We’ve recently written extensively about nitrosamine impurities, including this in-depth analysis of what transpired with Valsartan, and some follow-up material, here and here.
Nitrosamine impurities have been receiving a great deal of scrutiny in the pharma industry over the last year, and they represent a turning point from a regulatory standpoint.
In 2018, NDMA and similar compounds known as nitrosamines were found in a number of blood pressure medicines known as ‘sartans’, leading to some recalls and to an EU review, which set strict new manufacturing requirements for these medicines.
The Impact of Genotoxic Nitrosamine Impurities
The contamination of Valsartan and other drugs has had a large – and growing – impact on pharma sales, operations and regulatory requirements. For example, Zhejiang Huahai – the Company involved in the initial contamination of valsartan – has stopped production of the drug in its entirety. Given the increasing calls from regulatory bodies to detect and quantify the presence (if any) of such contaminants, the impact is ongoing.
Because nitrosamine impurities are dangerous to human health. In addition, the preparation, detection and quantification of nitrosamine impurities is difficult, requiring high-end chemistry as well as high-end equipment, skills and analytical instrumentation, which some pharmaceutical companies may lack.
A Growing Number of Affected Drugs
Awareness of nitrosamine impurities began with the sartans (e.g., Valsartan), but contaminants have been found in other popular products, as well. Two more key drugs were recently affected:
Ranitidine, an H2 (histamine-2) blocker, reduces stomach acid production by blocking histamine receptors. The FDA alerted patients and HCPs to voluntary Ranitidine recalls, because “they may contain unacceptable levels of N-nitrosodimethylamine (NDMA).”
The two products specified by the FDA are:
In September 2019, the FDA announced it had become aware of laboratory testing that found low levels of NDMA in the heartburn medicine, nizatidine. Nizatidine is also an histamine H2 receptor antagonist, and is commonly to treat peptic ulcer disease and gastroesophageal reflux disease (GERD). As with Ranitidine, the recalled prescription Nizatidine capsules may contain unacceptable levels of the nitrosamine, N-nitrosodimethylamine (NDMA).
Mylan Pharmaceutical announced a voluntary recall in January 2020 of 3 lots (150 mg and 300 mg strengths) due to trace amounts of impurities.
In early December 2019, the government in Singapore recalled three metformin drugs due to NDMA found above the acceptable level.
How Do Nitrosamine Impurities Happen?
Nitrosamine impurities are not a simple byproduct. They are quite complex. This complexity has its source in the formation of impurities, either through the introduction of certain reagents or solvents, or their degradation products.
The formation of nitrosamines can occur when secondary or tertiary amines react with nitrous acid. Nitrous acid itself is unstable and can be formed in situ from nitrites (NO2) under acid conditions.
In the case of the sartan compounds, most contain a tetrazole ring. Formation of this tetrazole ring employs the use of sodium nitrite. Coincidently the solvents employed in the cases where impurities were found either were amines or contained traces of amines. This likely produced the observed NDMA and NDEA contaminants.
Our current understanding of nitrosamine impurity formation is that it can occur under the following circumstances:
What Regulatory Standards Should You Follow for Nitrosamine Impurities?
Nitrosamine impurities are genotoxic impurities (GTIs). GTIs are taken very seriously by regulatory authorities, and they have responded to the Nitrosamine issue by mandating that pharma companies test for this impurity during production.
Over the last few months, regulatory agencies (including the U.S. FDA) have ramped up their response to these impurities. The FDA has been testing samples of affected drugs and has requested that manufacturers also conduct lab testing to determine NDMA levels in products. Manufacturers are also asked to send samples to FDA for testing. The agency will recommend a recall of nizatidine in cases where NDMA levels are higher than the acceptable daily intake limit (96 nanograms per day, or 0.32 PPM).
Unlike other genotoxic impurities in which limits are established based on maximum daily dose (MDD), regulatory bodies published nitrosamine limits in their guideline which are independent of MDD. The standard covers various nitrosamines (NDMA, NMBA, NDEA, NDIPA, NEIPA – see chart).
Here are the Guidelines & Methods Regulatory Agencies Established to Control Nitrosamine Impurities
The European Medicines Agency (EMA) and the Coordination Group for Mutual Recognition and Decentralised procedures – Human (CMDh) have both published documents (EMA/189634/2019 and CMDh/404/2019) outlining the processes API manufacturers should follow to determine the presence (and quantity) of nitrosamines. While recognizing that this issue is not likely to impact many drug substances, the European Directorate for the Quality of Medicines & HealthCare (EDQM) has also outlined a response to nitrosamines.
The EMA has indicated that companies should prioritize drugs for review based on a number of factors, including: maximum daily dose, duration of treatment, therapeutic indication and number of patients treated. Tools such as Failure Mode Effects Analysis (FMEA) and Failure Mode, Effects and Criticality Analysis (FMECA) can be used to perform the analysis of drug products at risk.
As outlined by European authorities, the general process for companies holding a CEP (Certificate of Suitability) follows 3 steps:
Step 1: Risk Evaluation
Step 2: Confirmatory Testing
Step 3: CEP Revisions
The FDA has also addressed nitrosamine testing, recognizing that the low levels of impurities present will create testing challenges. They recommend LC-HRMS (Liquid Chromatography High Resolution Mass Spectrometry) to test ranitidine, as the method involves lower temperature conditions (the higher temps of some test methods can lead to NDMA generation). The FDA has published several test methods which manufacturers may consider when assessing nitrosamine impurities.
The Official Medicines Control Laboratories (OMCLs) of the Council of Europe has also published various methods to test for nitrosamines, available here.
Does Neuland Manufacture Products with Nitrosamine Impurities?
No – Neuland does not manufacture any products containing Nitrosamine impurities. But as a responsible pharma company, we have begun proactively evaluating all APIs to report to the relevant regulatory authorities. We’ve also incorporated reporting of impurities in the development process of the molecules.
The International Council for Harmonisation (ICH) is an organization which brings together the pharmaceutical industry and regulatory authorities to improve the synchronization of industry regulations. The organization’s ultimate goal is to ensure the development, production and registration of safe, effective and high quality medicines.
In November 2019 the ICH held its assembly in Singapore, where they formally adopted several guidelines:
The objective of ICH Q12 is to “promote innovation and continual improvement in the pharmaceutical sector, and strengthen quality assurance and reliable supply of product, including proactive planning of global supply chain adjustments.“
Some Challenges With Q12 Rollout
Q12’s approval and rollout, however, have met with some pushback. Among the concerns which have been aired, it has been termed “another quasi-management-based regulatory guideline” which could yield “additional confusion and more work from a vaguely defined, potentially duplicative system that will likely further inhibit the industry from achieving excellence.”
In an ironic twist, one chief concern regarding Q12 has been the potential loss of harmonization it might create. As things stand, ICH Q12 is complementary to ICH Quality Guidelines Q8 through Q11. The FDA has also indicated that Q12 is fully-harmonized with existing regulations & frameworks, while in the EU “revision of local regulations (e.g. the EU Variations Regulation) will have to be performed to fully implement the concepts of Q12.”
The article at GMP News (EMA Publishes Comments on ICH Q12) discussed the cross-Atlantic discrepancy, pointing out that when the EMA published ICH’s original version of the draft guideline, they included the statement: “These concepts will, however, be considered when the legal frameworks will be reviewed and, in the interim, to the extent possible under the existing regulation in these ICH regions.” The FDA, meanwhile, simply noted that “the ICH Q12 guidance is fully compatible with the established legal framework. Therefore, the concept of Established Conditions and supporting Product Lifecycle Management document are fully supported by the U.S. FDA as described in this guidance.”
Earlier in 2019, Lachman Consultants mentioned at a meeting on The Future of Post-Approval Changes is Coming – Are You Ready for ICH Q12?: “Speakers from CBER were skeptical about the applicability of the enhanced approach (as defined in the Q12 guideline)” to their applicable CBER products, while “CDER’s outlook was a bit more positive and it has received the nine applications and supplements that it solicited” from a pilot program.” But the meeting report also noted:
“Among the concerns raised were the complexities of managing multiple applications in a global regulatory environment if each regulatory body approves a different set of ECs [editor’s note: Established Conditions. See ‘What is the Purpose of ICH Q12?’ below], challenges in knowledge management elated to justification of ECs and non-ECs, the need for efficient IT systems to track ECs for different applications in different countries, the need to establish standards within the company for justifying ECs and non-ECs and how to document them in applications, and how to utilize ECs in Accelerated Development situations.”
So Q12 may or may not be a problem, presumably depending on where you are, what markets you serve, and who is regulating you.
But what, exactly, is Q12? What does it mean for pharma companies, and how will it impact current manufacturing & compliance practices?
What is the Purpose of ICH Q12?
Q12 aims to improve management of post-approval chemistry, manufacturing and controls (CMC) changes, with the goal of making it a more efficient & predictable process across a product’s lifecycle.
According to the FDA, various sections of Q12 “focus on the categorization of post-approval CMC changes, established conditions, post-approval change management protocols, product lifecycle management, pharmaceutical quality system and change management, the relationship between the regulatory assessment and inspection and post-approval changes for marketed products.”
The FDA has discussed how Q12 could potentially improve product & process knowledge, ultimately leading to fewer regulatory submissions and lower costs. They also feel it may help decrease product variability and potential CMC- & quality-related shortages.
The International Council for Harmonisation also focuses on potential quality and supply chain benefits, stating ICH Q12 will “strengthen quality assurance and reliable supply of product, including proactive planning of supply chain adjustments.”
What Are Some of the Expected Benefits of ICH Q12?
One of the key potential benefits of ICH Q12 is reduced costs – for both regulators and industry. Others include standardization of ‘supportive information’ for regulatory submissions and “the greater application of innovative technologies in manufacturing and control (i.e. analytical methods) in a timely manner.”
For companies, one big benefit will be increased clarity and process transparency, making it easier to categorize CMC changes to determine whether supplemental regulatory filings are necessary.
What Steps Are Companies Taking? What About Regulators?
Companies are at nearly every stage in terms of Q12 preparations. Some have opted to wait and see what local regulators will do (e.g., Europe), while others have embraced the framework and are moving ahead with preparations prior to its implementation.
At a minimum, most companies are establishing teams to address the various impacts of Q12 (e.g., Established Conditions).
At Neuland Labs, we’ve begun providing training on ICH Q12 at all locations to ensure straightforward, seamless implementation of the new guidelines. The FDA is likewise making preparations, and has begun training staff on some of Q12’s key principles.
Following up on our earlier post on the 2018 valsartan contamination, much has happened over the last six months.
In our original post, we discussed the appearance of impurities in valsartan to which no one had previously paid attention:
“Last year’s valsartan contamination and recall brought some surprising chemical synthesis issues to light in the pharma industry. While the reactions used in generic valsartan production are known to be a source of certain impurities, they were below current disregard limits and didn’t raise any red flags. It was the impurities that no one thought to look for, however, which led to the recall.”
The issue had come up when chemists didn’t realize their process – while successful at eliminating toxicity due to sodium azide – generated another toxic substance: the carcinogen N-nitrosodimethylamine (NDMA).
The manufacturer did do everything right, even imposing higher-than-required standards in some cases. The entire valsartan incident seems to be an indicator that the pharma industry has been focused on the quality of APIs, but wasn’t paying sufficient attention to the safety of chemical synthesis processes.
We concluded the article with:
“The troubling question is: How many NDMA, NDEA, ethyl mesilate and other highly toxic, low concentration, impurities might lie hidden in the hundreds of pharmaceutical ingredients made by thousands of manufacturers around the world?
Something needs to change in our quality management of pharmaceutical ingredients, not only to prevent similar contaminants in the future, but also to become aware of the ones which may be there – right now – in our medicines.”
Regulatory Response – Changes in Motion
We are already seeing changes. Regulators seemed to have reached the same conclusion our earlier post reached – and have expanded their inquiries to other drugs.
From the Regulatory Affairs Professional Society came news in August, 2019 of further contaminant-related enforcement: “The fallout from the N-Nitrosodiethylamine (NDEA) and N-Nitrosodimethylamine (NDMA) impurities fiasco continues as the US Food and Drug Administration (FDA) last week sent a warning letter to India-based Lantech Pharmaceuticals.”
November was a busy month for impurities, too. The FDA announced in had issued a warning letter to Mylan over valsartan manufacturing violations. Mylan had been one of several companies that issued recalls due to NDMA and NDEA impurities.
Also in November, the director of FDA’s Office of Compliance raised several concerns with the API industry – one of which was the presence of NDMA and NDEA in recent recalls.
This coincided with the release of an interim report from the FDA’s ongoing investigations of nitrosamine impurities in certain APIs. In FDA Updates Investigations into Impurities in APIs (November 2019), DCAT’s Patricia Van Arnum reported:
“The FDA is also asking manufacturers to continue conducting their own laboratory testing to examine levels of NDMA … Additionally, the FDA has requested that manufacturers of nizatidine test their drugs. The agency says it is still working with manufacturers to investigate the true source of NDMA and to understand the root cause of the low levels of NDMA present in the drugs.”
Grappling with nitrosamine contaminants seems to be a work in progress. Stay tuned.
Want to read our earlier piece detailing the valsartan incident? Here’s the post – How the Valsartan Contamination Happened: Its Context & Implications.
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.”
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 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:
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.
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 is an atypical antipsychotic used to treat schizophrenia and schizoaffective disorder.
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 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 is a dopamine agonist medication used for the treatment of Parkinson’s disease and restless leg syndrome.
Apixaban is an oral anticoagulant medication used to treat and prevent blood clots, and to prevent stroke in people with atrial fibrillation.
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 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 is a nonsteroidal topical medication used for the treatment of mild-to-moderate atopic dermatitis (eczema).
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 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.
At 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?
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:
Many of the Quality behaviours we’ve established are rooted in process and technology. For example, we employ:
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:
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:
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:
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).
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:
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.
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:
Not everything is covered by the MRA.
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:
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