In December 2019, China issued a revision to their Drug Administration Law. It was the most wide-ranging modification of their laws since 2001. It marked a fundamental shift away from a company- or organization-based regulatory philosophy to one which is product-based.
The Marketing Authorization Holder (MAH) system is perhaps the most significant change to Chinese laws relating to drug products. It also brings the Chinese drug industry more in line with regulatory perspectives common in the U.S., E.U., India and elsewhere.
The new MAH system is expected to have an enormous impact on the country’s drug industry.
Why Shift to an MAH-based System?
The goal of a Marketing Authorization Holder-based system is to make it easier for drug developers to bring new drugs to market, while increasing their responsibility for the drug’s safety. The MAH will also seek to minimize some of the challenges China’s drug industry faces, including counterfeit drugs, substandard drugs and high drug prices.
Chinese regulators believe adoption of an MAH system will drive innovation for companies, research organizations & individuals. It will have other, residual impacts as well. Because MAHs are not restricted to manufacturing the drugs themselves, the outsourced contract research, analysis and manufacturing segments will see a significant boost. In turn, the ability to draw on the capabilities of these types of contract providers will further stimulate the growth of small- and mid-sized pharma companies in China.
Where companies previously focused on regulatory approval as the fundamental objective, they will need to shift to managing products across the entire lifecycle – pre-market to post-market. Smaller firms with fewer resources can turn their attention away from the necessity to build production capacity, and instead focus on their areas of expertise.
The MAH Was Already Partially in Place
While the December 1st rollout brought the Marketing Authorization Holder (MAH) system into widespread use, Chinese regulatory authorities had already been working with it for nearly five years.
It was first implemented on a trial basis in 10 provinces in 2016 – in which 3,239 product licenses were issued to 156 Marketing Authorization Holders. The trial period enabled pharmaceutical research institutions and individual researchers to submit clinical trial and marketing applications as drug registration applicants – which allowed them to become an authorization holder.
MAH Now Applies to All Companies in China
The MAH system now applies to all companies applying to register a drug in China. There are, however, some differences between China’s implementation of the MAH and other, existing arrangements around the world.
In China, each MAH must be considered a ‘legal entity.’ Examples include pharmaceutical or biopharmaceutical companies – or a research institute. This differs from existing regions which use an MAH system. In the EU, for example, it isn’t restricted to a company or organization – an individual can also be considered an MAH.
What Are the Roles of a Holder Under China’s New System?
Across the lifecycle of a drug, Marketing Authorization Holders have various responsibilities. These include:
The Holder is required to:
The Holder is required to:
Regulatory Implications of China’s MAH
Chinese regulators (the CFDA) will need to expand their focus from the safety, efficacy, and quality of drugs to include evaluation of each MAH’s quality & risk management capabilities. The CFDA will also need to establish standards and guidance for an MAH to follow concerning unit tracking, pharmacovigilance, and recalls.
China’s new MAH system represents another step towards harmonization of the global drug industry. The hope is that it will foster cross-pollination between R&D institutions and drug manufacturers to further encourage innovation, though we’ll have to wait and see.
The basic principle of pharmaceutical quality assurance is that a drug should be safe and effective for its intended use – and process validation plays a pivotal role in ensuring a drug’s quality.
Why? Because literally everything rests upon it and builds from it. Process validation establishes evidence that manufacturing processes consistently fall within acceptable limits. It’s the foundation upon which confidence in drug manufacturing rests.
We’ve discussed at length the importance of developing comprehensive process knowledge. In a post on the Importance of Understanding Critical Reaction Parameters, we noted that therapeutics in general – both biologics and synthetic drugs – have become more complex. “Some APIs require double-digit production steps, meaning understanding and controlling reaction parameters is essential to avoid failures or out-of-spec outcomes.”
This body of process knowledge which drug and API manufacturers must develop is the mainstay of process validation. Critical to the success of process validation is the use of analytical methods which provide reliable, and consistently repeatable, results.
Defining Process Validation
First proposed by FDA officials in the 1970’s as a one-time event to improve pharmaceutical quality, process validation evolved to encompass more proactive measures (“lifecycle process validation”).
Jennifer Walsh captured this sentiment in the title of an article at Pharmaceutical Engineering in 2019: “The Evolution of Process Validation: From Box-Checking to Lifecycle Approach to Biologics Continuous Manufacturing.”
The title isn’t an overstatement – and most quality assurance professionals would (perhaps begrudgingly) admit to the once-simplistic ‘box-checking’ aspect of process validation. Back in 1987, the FDA defined it as “documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its predetermined specifications and quality attributes.“
Our understanding of process validation differs today, since it isn’t considered a ‘once-and-done ‘event but rather an ongoing practice. Here’s a definition of process validation from learnaboutgmp.com:
“Process validation is defined as the collection and evaluation of data, from the process design stage throughout production, which establishes scientific evidence that a process is capable of consistently delivering quality products.”
What Does Regulatory Guidance Say?
Process validation is a legal requirement in the drug industry (among others). Governing regulations include current good manufacturing practices (cGMP) for finished pharmaceuticals, as described in 21 CFR parts 210 and 211.
GMPs require drugmakers to determine that manufacturing processes can consistently meet finished product quality requirements, including those characteristics impacting the quality, purity and potency of a compound. This means your CMO must understand:
As the FDA makes clear in their Guideline on Process Validation: General Principles and Practices, this typically involves teams with “expertise from a variety of disciplines (e.g., process engineering, industrial pharmacy, analytical chemistry, microbiology, statistics, manufacturing, and quality assurance).”
What are the Three Key Process Validation Stages?
Process validation is broken down into stages, as follows:
Stage 1: Process Design
In this first stage, the manufacturing process is designed to ensure a consistent ability to meet target quality attributes. The key to sound process design is thorough documentation, which becomes essential in subsequent stages. Process design often includes Design of Experiment (DoE) studies, risk analysis tools and the results of verification runs at lab or pilot scale. This collective information can help predict performance of commercial scale processes.
Stage 2: Process Qualification
Process qualification refers to the qualification of both facility, equipment & utilities and the manufacturing processes themselves. Once the facilities and equipment have been individually qualified, the process performance qualification (PPQ) can occur. Process qualification assesses the data gathered from all relevant studies, including experiments, lab-, pilot- and commercial batches. Successful qualification demonstrates that commercial manufacturing processes will perform as expected.
Stage 3: Continued Process Verification
Stage 3 relates to the ongoing activities that occur, reflecting the ‘lifecycle process validation’ approach in use today rather than the one-time approach common years ago. The objective of continued process verification is to ensure the process remains validated, that it is still in a “state of control.” To confirm this, drug and API manufacturers need systems in place to detect nonconformities in processes. One outcome of this stage is often process improvement or optimization strategies, though these are often subject to additional regulatory approval or further process validation.
Are you interested in learning more about process validation? Check out the U.S. FDA’s Guideline on Process Validation: General Principles and Practices or contact Neuland Labs today.
Coronavirus has impacted drug supply chains.
At first blush, people will likely read that sentence to mean drugs aren’t arriving at their intended destination. That precursor chemicals, intermediaries, APIs, or finished dosages – either by virtue of plant closures or government intervention –are not making it to where they need to go.
I don’t mean to say that shortages haven’t happened in various countries around the world (hydroxychloroquine, anyone?), but the reality is actually more subtle. It’s a tale of risk, and how companies are struggling – in very short time frames – to minimize and control it.
Neuland has explored this topic before – but it was never widely regarded as an urgent subject until recently. The reality is everyone is feeling this crunch. While Neuland actually has a leg up on this issue (more on that later), the reality of complex, multinational, interdependent supply chains means this issue affects the industry en bloc.
The Focus on China
China – widely presumed to be the originating source of the novel coronavirus – has been the focus of supply chain attentions, most notably in the West but also in countries like India.
Pharma – collectively, as an industry – have become heavily reliant on China over the last few decades. Precursor chemicals, intermediates for APIs and APIs themselves are often sourced from China. And while popular reports that as much as 80% of drugs come from – or rely in some fashion upon – China haven’t been substantiated, there is considerable dependence on Chinese manufacturers.
This situation has been driven over the decades by a number of factors. Two of the biggest are environmental/pollution issues and increasing drug industry cost pressures.
Some of the cost advantages of manufacturing in China have faded. The closures and environmental-related issues mentioned above have revised some pricing – especially in relation to hazardous or polluting chemical production (for example, boron chemistry).
Despite China’s scale advantage, tightening restrictions have made it possible for India to re-emerge as a competitive alternative. This is especially true of precursors and intermediates in which process improvements can bend the cost curve to eliminate offshore advantages.
The Hot Question: Will the U.S. Bring Pharma Manufacturing Back Onshore?
The factors discussed above – and numerous others – led the shift away from domestic production in large parts of the world. As these points indicate, the conditions for their return to home countries – whether in the E.U., the U.S. or elsewhere – will likely never materialize en masse, though some repatriation is likely to occur.
However, labor costs won’t decline in the U.S. Environmental restrictions on large scale manufacturing won’t ease up in Europe. Neither region possesses either the infrastructure – or the muscle memory – for a quick repatriation and reboot of manufacturing.
In fact, some trends tend to indicate the opposite of repatriation is still happening. By the time this post publishes, Novartis will likely have closed a deal to offshore “about 300 generics drugs that it no longer felt were worth keeping, along with three U.S. manufacturing facilities.”
With all of this being said, it isn’t impossible for repatriation of manufacturing to occur…and COVID-19 may provide sufficient incentive to make it happen. Some reshoring is to be expected: higher volume, higher margin products may find their way back to domestic production.
There have been numerous articles about reducing reliance on overseas production of key critical drugs, though the definition of that category shifts depending on the condition or disease (antibiotics, for example, are considered critical, though they reportedly have no impact on viral diseases such as COVID-19).
A more likely outcome will be a shift towards redundancies – secondary manufacturers, backup facilities, multi-region supply arrangements, avoidance (wherever possible) of single-source providers and more. These tactics won’t focus solely on finished dosages, but will increasingly encompass the entire supply chain, starting with the furthest upstream precursor chemicals.
How Can Pharma Improve Supply Chain Security?
This is a question that will likely persist long after COVID-19 has run its course around the world – and it difficult to speculate what might happen. To shed some light, we can share some of the steps Neuland has taken – and where we see opportunities to further secure supply chains.
The temporary closures of Chinese factories in 2018 (referenced above) raised sufficient supply chain anxiety that we began effecting a shift in our own sourcing philosophy. Here is a brief survey of some of the steps we’ve either taken to address our own concerns and those of our customers around the world, or strategies we have seen gain prominence:
While reliance on China may fade, it won’t wholly disappear. This is the nature of global trade. With that being said, qualification of non-Chinese sources is likely to be a top-of-mind issue as the industry looks to de-risk global drug supplies.
The outbreak of COVID-19 has significantly impacted physical visits to drug manufacturing facilities. This raises a number of challenges, since many regulations — especially those relating to inspections — weren’t written with pandemic “social distancing” conditions in mind.
As a result, regulators and pharma companies are having to reinvent or temporarily change the methods they use to perform inspections and supplier audits. In many cases travel bans make in-person inspections impossible, but even when they do not, workers employed by regulatory agencies and pharma companies must be protected by limiting their potential for exposure to the virus. At the same time, quality controls must be maintained while minimizing risks posed by visitors to staff at pharma labs and production facilities.
Here’s how some of the key regulators in major markets are responding, and what you can do to ensure minimal disruption during this period.
U.S. Food & Drug Administration (FDA)
While the FDA has directed as many employees as possible to switch to teleworking, this isn’t possible for those who perform lab, manufacturing or warehousing activities, monitor imported products or other related tasks. In-person visits to most facilities outside the U.S. have been postponed through April. Inspections considered “mission-critical” by the FDA are still being looked at on a case-by-case basis. Routine surveillance visits inside the U.S. were also scaled back wherever possible.
The agency has stressed that inspections are just one of the tools it uses to maintain quality control, and that it “will continue to leverage all available authorities to continue to ensure the integrity of the products we regulate.”
The agency has also acknowledged that new product approvals could be delayed by the inability of the agency to perform inspections.
In the interim, the FDA is weighing alternative ways to conduct inspection-related work. For example, under certain conditions the agency might evaluate a firm’s records in lieu of an onsite inspection. More details can be found in the FDA’s press announcement.
European Medicines Agency (EMA)
The EMA plays a key role in coordinating the EU’s Good Manufacturing Practice (GMP) inspections of pharma manufacturing sites, as well as facilitating cooperation between Member States for inspections of manufacturers in third countries.
In cases where onsite audits are not currently possible, the EMA suggests that “a risk-based supplier qualification process can be supported by a remote or virtual audit.” And while the benefits of onsite tours of facilities, warehouses, and laboratories are impractical at this time, the agency suggests other audit procedures — such as interviewing personnel and reviewing documents — could still be handled remotely.
UK Medicines and Healthcare Products Regulatory Agency (MHRA)
Near the end of March, the MHRA announced that it would only be conducting “essential” on-site inspections, and that it expects pharma companies to maintain GxP compliance. In other cases, alternative approaches such as office-based assessment will temporarily replace some aspects of on-site inspections. Unannounced in-person visits are still a possibility, however, if the organization considers it necessary to protect public health. The MHRA has published its thoughts in more detail in a blog post titled MHRA Good Practice (GxP) inspections during the COVID19 outbreak.
Pharmaceutical Inspection Cooperation Scheme (PIC/S)
The Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S) are co-operative arrangements between 53 participating Regulatory Authorities in the field of Good Manufacturing Practice (GMP) for medicinal products for human or veterinary use.
In 2018, long before the outbreak of COVID-19, the PIC/S outlined a process for desktop assessment of GMP compliance. This non-binding guidance was issued in response to concerns that demand for inspecting pharmaceutical manufacturing facilities far exceeds what any one Competent Authority (CA) can accomplish.
While the original purpose of these guidelines was to address the growing complexity of the global pharmaceutical industry, they have taken on a new importance for the 53 members of the PIC/S during the response to COVID-19. The procedure serves as both a structure and a resource for remote inspections of some international suppliers. As a result, some regulators that have not previously permitted remote inspections are now turning to it as a model.
The Common Theme: Take Ownership of Quality
While no one is claiming they will rely exclusively on self-regulation by the industry, most authorities have issued direct appeals to pharma companies to take ownership of maintaining high quality standards and industry best practices. Documentation will be more critical than ever during this historic time — both to facilitate remote inspections where applicable, and as a record of compliance when onsite inspections resume.
The pharma industry should be prepared to use teleconferencing and other remote communication methods in new ways, and to exercise flexibility when working with regulators in order to minimize business disruptions.
According to the American Lung Association, chronic obstructive pulmonary disease (COPD – which includes chronic bronchitis and emphysema) is the third-leading cause of disease-related death in the U.S. It affects more than 15 million people in the U.S. and 250+ million globally.
Overall the number of COPD cases is expected to continue to rise, and the market for drugs and treatment options will grow. According to research composed by GlobalData, the COPD market is expected to increase from $9.9 billion to about $14.1 billion by 2025.
There are a range of treatments & medications used to treat the various symptoms of COPD. Inhalers (typically bronchodilators) are considered a primary treatment option. Bronchodilators – either long-or short-acting beta2-agonists or anticholinergics – are commonly used to relieve breathlessness.
Indacaterol is a long-acting beta2-agonist indicated for long-term, once-daily maintenance bronchodilator treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.
Indacaterol is dispensed as a powder-filled capsule which is pierced to allow inhalation via a special inhaler (e.g., the Arcapta Neohaler and the Onbrez Breezhaler). It’s used to control shortness of breath, chest tightness and coughing caused by chronic obstructive pulmonary disease (COPD). The drug relaxes the air passages in the lungs, which makes breathing easier.
Where is the Opportunity?
Developed by Novartis, it was approved by EMA in November, 2009 and in the U.S. in July, 2011. NCE exclusivity of Indacaterol expired in 2016, with the product patent set to expire in 2025 (2024 in Europe).
With 4 to 5 years remaining before patent expiry in major countries around the world, an ample development & formulation ramp is in place for a drug company to prep an Indacaterol product for market.
Neuland is ready to supply Indacaterol for developmental purposes in accordance with Bolar provisions, followed by commercial quantities after expiration of relevant patents.
Neuland Labs: Sole DMF Holder, Granted Patents
Today, Neuland Labs is the sole DMF holder for the crystalline Q-alpha form of Indacaterol Maleate with a novel and non-infringing process. Process patents have already been granted to Neuland in the U.S. and Europe which don’t expire until December 2034.
Advantages of Neuland Indacaterol Process
With traditional Indacaterol production methods, obtaining high purity material can be challenging. One of the novel processing steps used by Neuland plays a major role in arresting impurities, improving yields while also eliminating additional processing steps. This key invention involves protecting the hydroxy group in stage-2.
Neuland’s novel non-infringing process avoids all major impurities, (e.g., dimer, ethyl hydroxy, Indacaterol oxy impurities and monoethyl Indacaterol). No single impurity is present in Neuland’s Indacaterol at greater than 0.15%
Neuland’s Indacaterol process is cost-effective and is easy to perform at bulk scales.
Neuland: Your Partner for Indacaterol Development
Interested in exploring this COPD generic opportunity? Contact us to discuss your novel long-acting beta2-agonist inhaler project.
Consistent – Yet Still Low – Clinical Success Rates
The number of drug candidates which are approved, get to market and subsequently become profitable for industry is pretty low. And they haven’t moved much over the past few decades.
What does it mean? The likelihood of a compound getting to Phase I trials is still hovering around 10%. Bottom line: the pharma industry is operating with a 90% failure rate.
An Emphasis on ‘Fail Early’
The numbers don’t – on their surface – look particularly good. One change, however is that drug development firms are constantly improving and refining activities to better identify the ‘losers’ as early in the process as possible.
At the same time, drug companies must plan ahead – the most efficacious and safe drug in the world isn’t likely to come to market if it’s manufacture isn’t scalable or cost-effective.
Process Scale-Up During Early Development
Early drug development activities tend to look at process viability from the standpoint of reproducibility. “Will this reaction yield the same outcome (molecule) each time it is performed?” is a key focus. As candidates move towards preclinical, traits of the molecule itself becomes the focus, including its safety and efficacy.
Quite often, we talk with potential customers who are suddenly nervous about a candidate heading into clinical studies because the synthesis process has yet to be adapted to a commercial approach. It worked at the bench, and scale-up issues took a backseat (or no seat at all) as the drug went through the early steps of demonstrating potential value. Now, faced with a pressing need for significantly larger quantities, the companies are in a rush to ‘get it up to scale.’
But it isn’t always that easy. Linear scale-up may be the holy grail of process chemistry, but it’s usually not that straightforward.
Scaling APIs for Success
Many of the challenges that emerge later in scale-up and commercialization barely attract notice at earlier stages. We discussed this previously in a post on process chemistry, in which we referenced how each step of a process may – in itself – scale up linearly, but when combined into a multi-step process, unseen complications arise.
“This is one of the reasons scale-up rarely leaps from micrograms to tons in a single bound, but rather requires multiple scaling stages (micro or milligram scale, gram scale, pilot scale prior to full production, etc.) to successfully translate bench processes to manufacturing. Scale-up is rarely a linear process (wouldn’t that be nice and convenient!), and at each scale new complications typically emerge that must be worked through.”
What are the top unseen API scale-up challenges that can disrupt clinical plans?
What happens at the bench isn’t necessarily what will transpire at commercial scales, or even along the scale-up pathway. The path to drug commercialization is fraught with risk, the probabilities of success are low and the costs of failure can be extraordinarily high.
These risks can be amplified by inadequate (or absent) planning and foresight. Incorporating scale-up planning and forecasting as early as possible into the R&D process can reduce the likelihood of unexpected challenges as products near the clinical stage.
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.