Seven years ago – in March of 2013 – we published a blog post on 5 Things to Consider When Looking for an API Supplier. Because seven human years equals 100+ years in the pharma industry, we thought we’d revisit the topic now that the slight supply chain uncertainty some pharma execs were beginning to feel has grown and developed into a full-on global panic.
First of all – there is no need to panic! Everyone – and, full disclosure, this includes us – has been writing about the imminent supply chain crisis. Except, it isn’t quite a crisis, and very little (aside from recalls) happens ‘imminently’ in the drug industry. In fact, de-risking supply chains is nothing new, though in 2020 it seems to have risen to the top of pharma’s to-do list.
It is true there has been a shift in thinking – brought on first by quality issues, then by unexpected facility shutdowns, followed by increasing global trade nationalism, and finally capped off with a global pandemic that briefly impacted some supply chains.
No doubt, it has been a rough 7 years for globalism. Concern crept into the C-suite early in the period, but that has now officially been replaced by full-on ‘trade terror.’
No one – and nowhere – is immune: US-based companies, European firms, Japanese drugmakers and Indian manufacturers have all begun to re-evaluate the length and breadth of supply chains to identify (and hopefully begin the process of mitigating) risk. What is new is that governments have begun stepping into the fray, seeking ways to strengthen domestic production of key essential drugs and drug APIs which are most at risk.
The original post focused on 5 broad areas to consider when selecting an API supplier:
In our update to the earlier post (below), we have grouped the CMC-related categories of scalability & capacity together in order to make room for the once-emerging-but-now-absolutely-dominant factor: Supply Chain De-Risking.
Outsourcing production of APIs provides pharmaceutical and biotech companies the benefit of API scale-up and production expertise while allowing them to focus on their core business – the research and development of drugs.
With any successful business relationship, a great deal rests on the proper upfront due diligence. It is critical to choose an API supplier that can meet a whole host of important qualifications, from experience at various scales of production and available capacity to worldwide regulatory approvals and support as well as quality systems that mirror (or best) your own.
There are a number of criteria drug manufacturers evaluate when choosing an API supplier. Here are just a few of the key issues your company should be considering when making a decision to outsource API manufacturing.
5. Supply Chain Risk Mitigation
An API manufacturer should have in place a number of capabilities or solutions to help you de-risk supply chains. There are a number of diverse strategies that can be employed, ranging from ensuring multiple backup manufacturing locations to handle unexpected shutdowns or issues to bringing the manufacture of key APIs, intermediates and precursors in-house to reduce external exposure (backward integration). Your API supplier should be aware of their own supply chain risks, and be able to communicate them clearly to you in order to help you manage risk.
Selecting an API supplier for your drug candidate is about building a partnership. You need to be comfortable with your API manufacturer’s capabilities, capacities, approaches to regulatory matters, and how they will interact with you.
It’s probably not too early to say that COVID-19 has changed pharmaceutical drug discovery considerably. And why wouldn’t it have, since it changed almost everything else?
Roaring onto the scene in the first quarter of 2020, COVID-19 proceeded to shut down entire nations and continents in the second quarter, and now continues to dominate world news, global economies, and our everyday lifestyles (“Should we go shopping? Eat out? Return to campus?”) in the 3rd quarter.
So, yes…of course it has had an impact on drug discovery and development. What remains to be seen is whether it will be an enduring transformation or if we will return to a semblance of ‘pre-COVID normal’ at some point.
In June, Forbes captured the scope of the coronavirus challenge and the reason why we are seeing such an unparalleled effort to defeat a single disease:
“In the last eight months the pandemic has emerged with stunning suddenness to infect more than 6.5 million people world-wide—killing nearly 400,000. Cambridge University estimated that losses over the next five years would total nearly $27 trillion, more than 5% of global GDP. As the world hopes for salvation, how pharma responds will have a profound effect on its future.”
Emphasis: Coronavirus
By March 2020, drug discovery and development efforts had started to coalesce around two broad medicinal objectives: (1) find suitable therapeutic compounds & modalities for treatment, and (2) develop a vaccine.
These were not mere add-on discovery programs. Assets and resources were re-purposed from a variety of sources, and companies, organizations and governments were given free rein to find a treatment or cure.
In an article at Nature.com on how the coronavirus outbreak could make it quicker and easier to trial drugs, Kenneth Kaitin, director of the Tufts Center for the Study of Drug Development in Boston, Massachusetts discussed how the pandemic has touched nearly all aspects of the industry. “This has really turned upside down the whole drug-development process,” he says. “The entire investigative world is focused just on developing treatments for COVID-19.”
Single-Minded Global Focus on COVID-19
The world has adopted a singular focus – which is a rarity in drug discovery circles. Governments and organizations have, in the past, driven focus in specific therapeutic areas – think ‘cancer moonshot’ – but never to the exclusion of other development efforts as we are seeing today.
That’s not to say everything has stopped. While coronavirus research is taking precedence and has had an impact, other research continues, patents are being filed and deals are getting done. It does feel as though non-coronavirus news is sliding under the radar, and it’s to be expected: we’ve rightfully become preoccupied with COVID-related developments.
More notable than the global focus has been the intensity of worldwide, cross-border and cross-company collaboration. Industry watchers point to this extraordinary level of collaboration, in which the world’s best minds are sharing hypotheses, data, results and more – as perhaps being decisive in the fight against SARS-CoV-2. At the very least, such a model will significantly reduce duplicative efforts and compress timelines in the search for treatments or a vaccine.
Sharing SAR-CoV-2 and COVID-19 Resources
Drug discovery efforts in the fight against COVID-19 have benefitted from never-before-seen levels of information sharing. Collaborativedrug.com has a running list of the many shared COVID-19 drug discovery resources available, driven by both the global urgency to fight an emerging disease and a new model of open source scientific discovery:
“Publishers like the British Medical Journal (and in a moment of solidarity other publishers like Wiley and Elsevier) are providing information on the Coronavirus freely on the internet to spur short-term global response efforts and support long-term research.”
The list of organizations dedicated to working together is unprecedented. Just two of the initiatives include:
Impacts Beyond Drug Discovery
The discovery of novel therapeutic candidates is just one facet of the broader pharma industry, albeit a vital – and highly-visible – one these days. The impacts of coronavirus, however, have been felt across the breadth of the industry – from supply chain disruptions to later-stage clinical trials.
On the clinical trial front, COVID-related disruptions have become the rule rather than the exception.
“Since early March, hundreds of organisations that are acting as the sponsor, collaborator, or contract research organisation (CRO) have publicly announced disruptions to planned and ongoing clinical trials in their press releases, Securities and Exchange Commission (SEC) filings, and clinical trial registries, as well as on social media. Companies have delayed the initiation of planned trials or withdrawn these completely, as well as suspended enrollment in ongoing trials or terminated these trials.”
Most disruptions of clinical trials were due to suspended enrollment, followed by slow enrollment and delayed initiation. The availability of clinical trial sites (including hospitals) and investigators (many shifted efforts to COVID-related drug discovery or treatment) was severely curtailed, hampering trials. All told, about 1,000 organizations (and perhaps more at the time of this post’s publication) had publicly reported disruptions.
What are the implications? Without data from pivotal clinical trials, new drug filings will be delayed, meaning some important new medicines will take longer to reach the market.
Clinical trials, however, didn’t collectively just end. Thousands of COVID-19-related clinical trials are now ongoing, focusing on treatment of mild, moderate and severe cases, exposure prophylaxis, complication support, asymptomatic cases, critical care and vaccines. And – as mentioned above – other non-COVID-19 related work continues (including clinical trials), despite societal attention being focused elsewhere.
Setting Expectations
The pharmaceutical industry – for all its very public regulatory surveillance and consumer-facing marketing – has always been somewhat opaque. Companies historically have never updated the public on day-to-day progress in the lab.
Why?
It’s about setting expectations. Remember, for every 5-10,000 chemical compounds, only 2-5% will show any promise. Less than half of one percent will qualify for testing on humans, and – of that 0.25-0.5% which begin clinical trials – less than one in ten will be successful. From start to finish, that’s an overall success rate of something on the order of 0.05%. Announcing you’ve identified a chemical compound which could successfully treat a disease would not be rational expectation setting.
The COVID-19 era has seen a sea change in how we set expectations. Johnson & Johnson is even planning to air a reality television series showcasing their COVID-19 efforts. As STATNews noted in a May article: “The narrative emerging from the Covid-19 pandemic is that the market is responding to rescue us from global catastrophe, a public relations coup for an industry that has long known about the potential for another pandemic but hasn’t meaningfully invested in research until now.”
However, as Forbes noted in their June article, this poses a serious challenge for the industry. When NIAID Director Anthony Fauci expressed hopefulness that a vaccine could be produced by the end of 2020, many in the pharma industry thought it over-optimistic. The ‘world record’ for vaccine development – at six years – is currently held by Ebola. Equally concerning to those who want to manage public expectations: to date there has never been a successful vaccine for any coronavirus – whether SARS, MERS or the common cold.
At the same time, however, there has never been such a massive global collaborative effort to find one. And there is some reason to be optimistic. After all, the pharma industry is a 150-year-old chronicle of successful ‘firsts’…stretching from morphine to metabolomics. Innovation and discovery are the actual purpose of our industry.
Starting in March, PPE – personal protective equipment, including gloves, gowns and face masks – became as valuable as gold…and nearly as rare. During a media briefing on March 27, the World Health Organization’s Director-General said the chronic, global shortage of personal protective gear “is one of the most urgent threats to our collective ability to save lives.”
But what if a country could build its own billion-dollar PPE industry virtually overnight?
India in Action
In response to the global pandemic and the resulting shortages of PPE worldwide, some Chinese manufacturers raised prices while other countries sought to outbid each other for supplies – driving prices into the stratosphere. Combined with long import timeframes and a lack of domestic suppliers, India launched its own PPE manufacturing efforts.
The result? In the span of 60 days, India became the world’s second largest supplier of PPE – creating a nearly $1 billion industry in just 2 months. Prior to March of this year, India had zero PPE production. By late May, the country had ramped up production to more than 200,000 PPE kits per day (a ‘PPE kit’ consists of a mask, eye shield, shoe cover, gown and gloves).
A “New” Atmanirbhar Bharat
Atmanirbhar Bharat, the concept of a self-reliant India, is experiencing a renaissance. First promoted during announcements of the COVID-19 economic relief packages in May, it also traces its roots back to earlier India-centric business strategies – including the successful 2014 Make in India movement.
Is India Moving Towards Protectionism?
With the rise of nationalist trade policies spreading around the world, the threat of trade protectionism is very real. The emergence of SARS-CoV-2 from China’s Hubei province amplified this mindset – from New Delhi to Washington, to the European capitals and beyond – as supply chains sputtered and began to collapse.
India’s move towards self-reliance was driven less by protectionism or distrust of trading partners than by the new realities of necessity and supply & demand. Nirmala Sitharaman, India’s Finance Minister, has said that “self-reliant India does not mean cutting off from rest of the world.” The Law and IT Minister, Ravi Shankar Prasad, related that Indian self-reliance doesn’t mean “isolating away from the world. Foreign direct investment is welcome, technology is welcome.” He relates a self-reliant India to becoming a more influential component of the global economy.
Reaction to Increased Foreign Dependence
In boardrooms and policymaker offices around the world, COVID-19 has amplified the concerns of supply chain dependency and risk. Nowhere is this more pronounced than in the life science and health sectors.
In 2020, Chinese pharma suppliers increased prices by 20%. But that was only one aspect of supply chain risk. Logistics play a major role, as well, with longer shipment times and higher costs. A final piece of the puzzle: government restrictions on exports of certain medications and supplies. In April, the U.S. Chamber of Commerce reported:
“More than 60 governments around the world have adopted export restrictions on medical supplies and medicines in an effort to ensure sufficient domestic supply during the COVID-19 crisis. These export restrictions can take the form of nonautomatic licensing requirements, consularization requirements, as well as outright bans on exports. In various instances, transparency is insufficient, administration is ambiguous, and no end date is given.”
In India (and elsewhere around the world), there have been calls to boycott Chinese products, but this isn’t a realistic solution.
“The calls for India to boycott (and promote an Atmanirbhar Bharat instead), are practically difficult in the short term for India as India imports $75 billion worth of goods every year from China, to the extent that parts of Indian industry are dependent on China.”
Atmanirbhar Bharat – Digital India & Pharmacist to the World
The emergence of a vast PPE industry in India is only the latest example of a self-reliant India in practice. Two other industries are also excellent examples of this, though the phenomenal growth of both occurred over years – rather than days: the electronics & semiconductor industry and the pharmaceutical industry.
With pharma, India has become known as the ‘pharmacist to the world,’ and is globally the top manufacturer of generic drugs. In more recent years, efforts have shifted towards innovator molecules and biotechnology.
KPMG: Establishing Indian Self-Sufficiency in APIs
KPMG’s April 2020 Indian API Industry – Reaching Full Potential report discusses the need for India to “proactively boost the manufacturing of APIs, intermediates and KSMs in the country and reduce dependence on imports.”
The report lays out in detail policy recommendations to strengthen the sector. Among the categories of recommended changes stretching over the next several years:
The Future of Self-Reliance
As a response to supply chain concerns, the concept of self-reliance is sound. It has, in fact, become a rallying cry in capitals across the world. As a practical matter, the reality is somewhat murkier. The electronics and pharmaceutical industries – shining examples of Indian innovation and in shoring – remain heavily-dependent on foreign suppliers despite efforts to limit supply chain risk. (Neuland has taken a number of steps to do just that, which we discussed most recently in this post.)
Objectively, being self-reliant reduces risk. As we’ve seen in the current pandemic, access to drugs, protective equipment and masks is critical to successfully confronting the virus – and the absence of these products can have considerable negative life-threatening consequences.
Realistically, however, we live in a global world in which we’ve become increasingly interdependent. And while building local infrastructure can create jobs, strengthen economies, and ensure stability of supply, positive results are not always possible. Some products will likely remain offshore for years to come.
There has been a flood of articles recently on how companies have adapted to our new reality in a coronavirus-affected world. As an essential services manufacturer and lab, Neuland has tackled some unique challenges as we’ve navigated through the pandemic. In this post, we’ll share some of the steps we’ve taken, and review some of the common practices pharma businesses around the world are using to mitigate the spread of COVID-19.
Perhaps the best example of steps manufacturing businesses have taken in the modern era can be found during the flu pandemic of 1918. Many of those actions have resembled those we’ve taken to fight SARS-CoV-2:
“During the 1918-19 H1N1 “Spanish” influenza pandemic, which infected one fifth to one third of the world population, and during which 50 million people died worldwide,1,2 including an estimated 675,000 Americans, the United States has adopted a range of nonpharmaceutical (public health) interventions. These measures, which were similar to those currently adopted, included closure of schools and churches, banning of mass gatherings, mandated mask wearing, case isolation, and disinfection/hygiene measures.3
These measures were not implemented at the same time or for the same duration in different cities, however, nor were they uniformly followed. A recent analysis concluded that in some cities (San Francisco, St Louis, Milwaukee, and Kansas City) where the measures were implemented early, these measures reduced transmission rates by up to 30% to 50%.3 Cities that implemented such measures earlier had greater delays in reaching peak mortality, and had lower peak mortality rates and lower total mortality.”
Also similar to our current situation, manufacturing across industries was largely curtailed. In the case of the 1918 flu, many employees fell ill – necessitating the shutdowns. In 2007, researchers at the Federal Reserve Bank of St Louis reported that the Spanish Flu caused manufacturing to decline by 18% in 1918-19, a result of declines in both supply and demand.
What Are Governments Recommending for COVID-19?
In the U.S., OSHA’s (the Occupational Safety & Health Administration’s) COVID-19 guidance shared a series of recommendations for manufacturers. Agencies such as the CDC have issued additional guidance, such as Implementing Safety Practices for Critical Infrastructure Workers Who May Have Had Exposure to a Person with Suspected or Confirmed COVID-19.
Common recommended steps include:
It has been reported that “Social distancing and employee safety measures put an additional level of pressure on manufacturers, as 40%-50% of their workforce will be unavailable to perform their functions on-site.”
The Government of the Indian state of Telangana has extended all the necessary support and assurance for smooth functioning of both pharmaceutical manufacturing and R&D.
In Telangana, functional work sites – which come under pharmaceutical manufacturing and R&D per G.O. No: 45 and 46 of Government of Telangana – have been declared exempt from the lockdown by both the Central and State Government authorities. Companies which are operating per the exemptions must take steps to ensure the health and safety of employees.
What Has Neuland Labs Been Doing?
For the last several months, Neuland has implemented the guidelines specified by the Government of Telangana as well as the National Directives for COVID-19 Management referenced in Circular No. 40-3/2020-DM-I-A. We are committed to serving the needs of the healthcare sector without compromising the health and safety of all Neuland employees – which is our first priority. We’ve taken a number of preventive measures at all work sites over the last four months:
Neuland is continuously striving to make the workplace safer every day during this global health crisis. We are providing personal protective equipment to our employees, and have adopted enhanced personal hygiene and social distancing measures. We’ve also created a 24/7 helpline number which employees can call to express any concerns with respect to COVID-19.
Around the world, pharma and biopharma – along with all of the supporting industries, from suppliers and research organizations to outsourced providers – have been exclusively focused on COVID-19. With good reason – since its impacts are being felt in virtually every aspect of our lives…social, political, economic and beyond.
The conversations usually range from discussions centered around vaccines, to treatments, to the ancillary issue of too-long supply chains increasing the risk of drug shortages or other issues.
Non-COVID-Related Business Moves On
While the life sciences industry as a whole rose to the challenges posed by the pandemic, believe it or not, other science continues to move forward. So – as a (partial) break from our coronavirus-laden science news streams – here’s a roundup of some of the research and scientific discovery happening in the field of peptides. Much of this may have gone unnoticed, but merits attention.
Oral Dosing with Peptides on the Horizon?
There is growing promise (finally!) of oral dosing routes for peptides. This is a potential gamechanger for the peptide segment, since a lack of solid dosage forms was considered to be one of the major factors preventing peptide drugs from gaining traction.
The oral dosage route has long been the holy grail of peptide drugs. Historical routes of administration – namely, injectables – have lower adoption and compliance rates.
With 60+ peptide drugs currently approved and on the market, very few (e.g., plecanatide and oral semaglutide) are available in solid dosage forms. This is attributable to the ease with which they are broken down in the gastrointestinal tract. They are, however, well-suited to oral delivery, given the size of the molecules. Identifying methods by which peptide therapeutics could retain their efficacy when taken orally has always been a priority.
In a study published in Nature Biomedical Engineering in May, researchers at the Ecole Polytechnique Fédérale de Lausanne (EPFL) developed a method “for the generation of small target-specific peptides (less than 1,600 Da in size) that resist gastrointestinal proteases,” overcoming the traditional issues of metabolic instability and limited intestinal uptake.
An article at Genetic Engineering & Biotechnology News discussed the near-term objectives of the EPFL research:
“[The] group is developing oral peptides that act directly on gastrointestinal targets, meaning that they don’t need to travel into the bloodstream. ‘We are focusing on chronic inflammatory diseases of the gastrointestinal tract like Crohn’s disease and ulcerative colitis as well as bacterial infections,’ Heinis noted. ‘We have already succeeded in generating enzyme-resistant peptides against the interleukin-23 receptor, an important target of these diseases, which affect millions of patients worldwide without any oral drug available.’”
Peptides & COVID-19
Therapeutic peptides have been receiving a great deal of attention lately for their role in SAR-CoV-2 research and treatment.
A publication on the preprint server bioRxiv describes a number of peptides which interfere the early stages of SARS-CoV-2 viral attack. An article about the research paper, New database catalogs peptides that may halt SARS-CoV-2 cell infection, discusses the use of peptides to inhibit protein-protein interactions:
“SARS-CoV-2 is genetically closely related to SARS-CoV responsible for the original SARS outbreak in 2002, and both viruses use the angiotensin-converting enzyme 2 (ACE2) receptor as a keyhole to infect the cells. The binding occurs via the receptor-binding domain (RBD) found on the spike protein, and utilizes transmembrane serine protease enzyme known as TMPRSS2.”
The spike protein referenced above has become a key target of peptides. New York-based Hoth Therapeutics has likewise focused on this target – licensing technology and intellectual property for a novel peptide therapeutic to prevent spike protein binding and potentially slow COVID-19’s transmission.
Synthetic Peptides: Promising Candidates for COVID-19
Beyond Hoth Therapeutics, there are many more peptide drugs in development for COVID-19. From PharmaceuticalTechnology.com:
“Over 400 drugs are in development worldwide for the treatment of Covid-19 (Table 1). Five synthetic peptide candidates are already being tested in patients with Covid-19: four candidates in Phase II and one in Phase I. The pipeline also includes one investigational new drug (IND)/clinical trial application (CTA) filed stage candidate, two preclinical stage candidates, and six discovery stage candidates.
According to GlobalData’s Pharma Intelligence Center Pipeline Drugs Database, there are currently 21 peptide drugs in development for the treatment of COVID-19, including 15 synthetic peptides in development for the treatment of Acute Respiratory Distress Syndrome (ARDS), a life-threatening condition where the lungs cannot provide the body’s vital organs with enough oxygen, and other respiratory illnesses caused by SARS-Cov-2 infection.”
While we wait for the results of these various studies, it’s clear that peptides continue to be seen as strong contenders for therapeutic indications.
Learn more about peptide manufacturing and Neuland’s peptide capabilities in our Guide to Sourcing Pharmaceutical Peptide APIs.
In December 2019, China issued a revision to their Drug Administration Law. It was the most wide-ranging modification of their laws since 2001. It marked a fundamental shift away from a company- or organization-based regulatory philosophy to one which is product-based.
The Marketing Authorization Holder (MAH) system is perhaps the most significant change to Chinese laws relating to drug products. It also brings the Chinese drug industry more in line with regulatory perspectives common in the U.S., E.U., India and elsewhere.
The new MAH system is expected to have an enormous impact on the country’s drug industry.
Why Shift to an MAH-based System?
The goal of a Marketing Authorization Holder-based system is to make it easier for drug developers to bring new drugs to market, while increasing their responsibility for the drug’s safety. The MAH will also seek to minimize some of the challenges China’s drug industry faces, including counterfeit drugs, substandard drugs and high drug prices.
Chinese regulators believe adoption of an MAH system will drive innovation for companies, research organizations & individuals. It will have other, residual impacts as well. Because MAHs are not restricted to manufacturing the drugs themselves, the outsourced contract research, analysis and manufacturing segments will see a significant boost. In turn, the ability to draw on the capabilities of these types of contract providers will further stimulate the growth of small- and mid-sized pharma companies in China.
Where companies previously focused on regulatory approval as the fundamental objective, they will need to shift to managing products across the entire lifecycle – pre-market to post-market. Smaller firms with fewer resources can turn their attention away from the necessity to build production capacity, and instead focus on their areas of expertise.
The MAH Was Already Partially in Place
While the December 1st rollout brought the Marketing Authorization Holder (MAH) system into widespread use, Chinese regulatory authorities had already been working with it for nearly five years.
How?
It was first implemented on a trial basis in 10 provinces in 2016 – in which 3,239 product licenses were issued to 156 Marketing Authorization Holders. The trial period enabled pharmaceutical research institutions and individual researchers to submit clinical trial and marketing applications as drug registration applicants – which allowed them to become an authorization holder.
MAH Now Applies to All Companies in China
The MAH system now applies to all companies applying to register a drug in China. There are, however, some differences between China’s implementation of the MAH and other, existing arrangements around the world.
In China, each MAH must be considered a ‘legal entity.’ Examples include pharmaceutical or biopharmaceutical companies – or a research institute. This differs from existing regions which use an MAH system. In the EU, for example, it isn’t restricted to a company or organization – an individual can also be considered an MAH.
What Are the Roles of a Holder Under China’s New System?
Across the lifecycle of a drug, Marketing Authorization Holders have various responsibilities. These include:
Pre-Marketing
The Holder is required to:
Post-Marketing
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.
