A 20 Year Retrospective: The Pharmaceutical Industry Then and Now

Introduction

As part of our celebration commemorating our 20th anniversary, American Pharmaceutical Review asked members of our Editorial Advisory Board and other industry and subject matter experts to reflect on the changes they have seen over the last twenty years and to take a peek at what the industry needs to do to grow in the future. Their responses are below.

A 20 Year Retrospective: The Pharmaceutical Industry Then and Now

Looking back over the last 20 years what have been some of the most significant industry developments/trends in the following categories:

Shaukat Ali, Technical Support Manager, BASF Corporation:

New classes of drugs

Drug discovery and development strategies for new drugs have changed in the past two decades. An early discovery requiring the high throughput combinatorial chemistry to synthesize the library of new chemical entities and to further optimize the structures to identify the targets for treatment of life threatening ailments, are new paradigms in the modern drug development process. In vitro and in vivo screenings of small and large molecules against biological targets, proteins and enzymes for diseases like cancers, anti-inflammatory and rare diseases to identify the lead candidates, supplemented with molecular modeling and collaborative research, have opened the avenues for modern therapies and yielded the opportunities for licensing new molecules and formulation technologies. Significant progress has been made over the years in areas of innovative formulation platforms that accelerate the development of new classes of drugs that improve safety and efficacy, alleviate dose associated toxicity and adverse effects, to benefit patient compliance. This progress has also enabled the industry to take the risks to meet unmet needs in multiple areas of therapy. Those include anti-body directed therapy, CAR-T cell therapy, immune-oncology drug delivery, siRNA technology, gene therapy among others.

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New manufacturing technologies

As the industry is poised to adapt innovative platforms to expedite formulation development for special disease classes, scaling up the synthesis for manufacturing molecules sensitive to temperature and pressure under cryogenic conditions, has been a subject of continued interest. For example, adapting continuous manufacturing has been a recent focus in discovery and development of NCEs. As the development of NCEs gets more complex. The industry is ready to take steps to expedite synthesis by shortening the number of manufacturing steps by adapting innovative heat transfer reactions and purification column technologies to maximize yields and reduce impurities.

With the continued rise in the number of poorly soluble molecules, the industry is embracing innovative formulation technologies to address the solubility and bioavailability challenges to save time and cost. Formulation technologies such as solid dispersions and lipid based liquid dispersions have been used to address modern drug development challenges. For example, hot melt extrusion, melt granulation, spray drying, co-precipitation, Kinetisol®, and lipid based emulsifying systems (SEDDS/SMEDDS) have all been used for such molecules, and with the advent of continuous manufacturing and 3D printing with continued support from regulatory agencies, the industry will adapt these modern technologies to reduce complexity and expedite development.

Regulatory initiatives

The regulatory landscape has changed as NCEs out of discovery become more challenging and complex in synthesis, scale up, formulation development and manufacturing. Employment of compendial methods for existing and new molecules and excipients for testing and qualification, will be mandated requirements by regulatory agencies. Excipient manufacturers and users are monitoring the new compendial methods to comply with the current changes in the United States, European or Japanese Pharmacopeias.

Likewise, the FDA is working together with industry, the United States Pharmacopeia and other agencies and organizations, to develop new guidance and monographs as more complex molecules are discovered and enabling technologies are sought to expedite the development of new drug candidates. This interaction of all stakeholders is vitally important to reduce redundancies so that development of quality products is uninterrupted. For example, with the modernization and implementation of Chapters <232> and <233> for elemental impurities in drug substances and drug products, drug manufacturers and excipient manufacturers are complying with the new changes as directed by the regulatory agency. With the FDA’s guidance, the United States Pharmacopeia is taking the appropriate measures to support the industry by offering quality reference standards, and providing expertise in harmonizing existing, new and pending monographs for excipients and drug molecules.

Industry globalization

The industry has experienced significant globalization over the last two decades. This is due, in part, to the increased number of service providers, CROs and CMOs as the industry looks to rationalize the development of pipelines. As the industry is poised to address modern dynamics and norms of new molecules, manufacturing technologies and processes are adapted and implemented quickly to capture the market and maximize the value of drug products. Although the United States remains the center of innovation for new APIs and technologies, more drugs are being manufactured globally in Europe and other countries to save time and cost. Excipient manufacturers are working with global partners to comply with all relevant pharmacopeias resulting in gains of raw material market share in those countries.

Robert Dream, Managing Director, HDR COMPNY LLC:

New classes of drugs

The past decade has seen a significant shift in the nature of the products being manufactured and sold by the innovative biopharmaceutical industry. The global biopharmaceutical portfolio today reflects increased therapeutic competition, a greater prevalence of large molecule drugs, expansion in the number of personalized or targeted products, and a rise of treatments for many orphan diseases. These trends have given rise to biopharmaceutical products with extremely limited production runs, highly specific manufacturing requirements, and genotype-specific products. This fundamental shift in the overall product mix and a focus on continuing to improve the efficiency and effectiveness of production is spurring an evolution in the technologies and processes needed to support advanced biopharmaceutical manufacturing. Innovation in manufacturing technology is helping to drive improved economics, flexibility and quality while potentially benefiting patients both directly and indirectly.

Technologies such as:

  • Gene therapy involves inserting genes into the cells of patients to replace defective genes with new, functional genes. The field is still in its experimental and clinical stages but has grown greatly since the first clinical trial in the 1990.
  • Stem cells are unspecialized cells that can mature into different types of functional cells. Stem cells can be grown in a lab and guided toward the desired cell type and then surgically implanted into patients. The goal is to replace diseased tissue with new, healthy tissue.
  • Nanomedicine aims to manipulate molecules and structures on an atomic scale. One example is the experimental use of nanoshells which convert infrared light into heat energy to destroy cancer cells.
  • New drug delivery systems include microscopic particles called microspheres with holes just large enough to dispense drugs to their targets. Microsphere therapies are being investigated for the treatment of various cancers and diseases.

New manufacturing technologies

Biopharmaceutical manufacturers are generally making investments in the following areas:

  • Continuous manufacturing to improve scalability and facilitate time to market, while lowering capital and operating costs and enhancing quality.
  • New process analytical tools to improve process robustness accelerate scale-up to commercial production and drive more efficient use of resources.
  • Single-use systems to increase flexibility and reduce production lead times, while lowering capital investment and energy requirements.
  • Alternative downstream processing techniques to improve yields while lowering costs, green chemistry to reduce waste.
  • New vaccine and therapy production methods to increase capacity, scalability, and flexibility.
  • New types of products are coming to market that help increase the effectiveness of medicines and support patient compliance, such as products that reflect improvements in drug delivery systems and drug device combination products.

Regulatory initiatives

Regulatory has come a long way in the last two decades. Regulatory bodies are making strides to mirror the industry in the more forward thinking, development and technologies that have been evolving over the last two decades. Today the regulatory bodies promotes advanced technologies and encourage manufacturers to implement new technologies to improve the quality, efficacy, and safety of drugs manufactured; and in the meantime reduce cost of the unit dose manufactured to the patient; e.g., Scott Gottlieb, M.D. blog posted on December 11, 2017 covey as such effort: https://blogs.fda.gov/fdavoice/index.php/2017/12/advancing-policies-to-promotesafe-effective-medtech-innovation/

Industry globalization

The rise of advanced manufacturing technologies, modularization, closed system manufacturing, small footprint factory requirements, and global-local manufacturing demand gave rise to the expansion of large firms to start manufacturing locally within many countries and many local grassroot companies came to life to manufacture and do business locally as well. These are positive benefits impacting societies by benefiting patients, the environment, and nation standing as a leader in innovation.

Maik Jornitz, President & CEO, G-CON Manufacturing Inc.

The main changes we have seen in drug classes, was the manifestation and rapid rise of biologic drugs and its broad spectrum of treatment possibilities. Now, a new class of drugs is on the rise, which is cell and gene therapies. As with biologics, the processing technologies and spaces for cell and gene therapy will change drastically, but with it the opportunity to improve and optimize. Both classes represent a major improvement to patient care and treatment. It is encouraging to see higher remission rates and remedies for formerly deadly diseases.

The other change we experienced is in manufacturing technologies, where higher expression rates created the possibilities to process lower volumes in single-use process technologies creating the opportunities to reduce cleanroom footprint and revisit cleanroom designs.

Eric S. Langer, Managing Partner, BioPlan Associates, Inc.:

A number of the biomanufacturing technologies being developed today have their early roots established many years ago. This includes microbial production platforms, single-use bags, perfusion technologies, stem cell technologies, novel chromatography approaches, and many others. While this points to the exceptionally long development timeframe required in the biopharma industry for new product development, it also suggests that novelty may not always be what creates opportunities. Incremental improvements is how these decades-old technologies are re-emerging as viable routes to more efficient, lower cost, and higher quality bioprocessing. Many believe that regulators may scrutinize novel materials, with product contact differently from tried-and-true devices. So a key question any new technology developer needs to ask is ‘how will regulators perceive this material and technology’? Given that the majority of this industry continues to express the need for better process efficiency, as the single most important trend over the past five years, any new manufacturing technology will necessarily need to demonstrate efficiency, and be regulator-friendly.

Girish Malhotra, PE, EPCOT International:

New classes of drugs:

Some of these are improvements and others are innovations.

  • Asthma
  • Cholesterol
  • Diabetes
  • HIV/AIDS
  • HCV
  • Cancer/orphan disease cures

Drugs in each of the categories have helped and improved life.

However, their affordability for the masses due to high prices is becoming increasingly limited.

Regulatory initiatives

FDA has issued guidelines that I believe have created more stress when it comes to manufacturing technology innovation. They have not created platforms to simplify existing manufacturing operations and introduce better technologies. In addition, FDA has not tried to simplify the filing process and reduce approval times.

Examples of this are the FDA’s suggestion to adopt QbD1,2 and continuous manufacturing3 for the manufacture of Active Pharmaceutical Ingredients (APIs) and their formulations. It is necessary to mention that the fundamentals of chemical engineering that have been outlined in McGraw Hill Chemical Engineering Series4 and earlier versions going back to the early fifties have been practiced in the manufacture of chemicals, pharmaceuticals being a subset. They detail the fundamentals that are the building block of every chemical manufacturing process, have been practiced since inception, but are being labeled as the new “coming”1,2 necessary for quality products.

The mere suggestion to incorporate QbD is indirectly telling they that companies have short comings in their process design and don’t employ the right talent. However, one should know that without incorporation of design fundamentals repeatable quality product cannot be produced. If the companies do not build their manufacturing on this basis, they will continue to fail on cGMP practices. There will be continuing data integrity issues. In recent years we have seen these through increasing 483 issuances.5 FDA might have to take a stricter stance to curb such excursions. I just have to ask ourselves did we fail to practice what has been penned and taught by our elite educationalists.

A 20 Year Retrospective: The Pharmaceutical Industry Then and Now

The FDA is suggesting adoption of continuous manufacturing when it does not understand the fundamental established definition of “continuous manufacturing” that has existed and has been practiced for over 100 years. What is FDA’s definition and is it established? There is not a response from FDA on this subject.6 Is FDA’s definition established by personnel who have developed, designed, commercialized and managed continuous manufacturing of APIs and formulations? It seems FDA is promoting CM as “fool’s gold”. CM can work for API (active pharmaceutical ingredients) if there is product volume demand to operate 8,760 hours per year. It is real for certain formulations that meet demand requirements outlined above. If CM’s value is not understood and applied properly, the industry on the whole will end up spending billions with most likely no return. Spent monies can only be recovered via higher priced drugs.

Continuous improvement is an ongoing exercise at every organization. FDA has been preaching it but has mot practiced it. Case in point is that FDA has not done much to simplify drug or approval of manufacturing processes. A recent proposal to bring the time to eight to ten months has been suggested. Even that has issues. My question is why not complete the whole task in three months. Benefits will be tremendous i.e. lower costs and selling prices and competition. Pharma needs these. Only best of the best will survive.

New manufacturing technologies

Manufacturing technology innovation comes from the companies that produce products. In the last 20 years very little of new manufacturing technologies and for that matter continuous improvements, my conjecture, has taken place on the pharma landscape that are able to lower brand and generic manufacturing costs and selling prices. I believe regulations, extended approval procedures, and time are the cause. I also believe that caution within the companies, regulators who take too long to approve improvements and better technologies, are also a reason for lack of any innovation within the companies.

I believe there is more following of FDA guidances/suggestions rather than companies taking internal initiatives that will improve product quality, profitability and drug affordability. A latent reason for all this could be high profitability with existing less than efficient processes and methods.

Industry has to take the lead on manufacturing technologies. The current global pharma landscape, and that includes the regulatory landscape, will need significant change to get there.7

Industry globalization

Hatch-Waxman Act8 and WTO9 changed global pharma landscape. When nearing patent expiration not much effort through efficient processes, which could slow down or prevent generic entry, has been made by the brand companies to retain manufacture of drugs in the developed countries. As a result most of the generic drugs are being manufactured and supplied by India and China. Selling prices of the generics are lower compared to the brand drugs. Hatch-Waxman and

WTO helped. However, the selling prices of the same generic drugs are significantly, by a magnitude, lower in the developing countries compared to the developed country prices. This price differential is raising many questions about loss of intellectual property, an unfair question. The main reason for the high prices is exorbitant price hikes by the supply chain participants10,11 especially in the United States to facilitate drug distribution.

Donald Singer, GSK Senior Fellow, Microbiology, R&D:

Globalization has impacted our industry in a big way. We have become very dependent on new supply chains for excipients and active ingredients that can include parts of the world that have different perspectives and culture relating to quality. Inconsistencies in approaches to quality, or lack thereof, also complement different approaches to ICH guidance (ICH Q8, 9, 10, 11 and 12; developed in mid-2000’s) which helped offer learning/direction of the importance of quality management systems that can assure pharmaceutical quality is robust and consistent.

From the growing inconsistencies the regulators have become more aware of patient safety issues, and actively implemented broader inspection capabilities (e.g. finalizing mutual recognition agreements), broader drug oversight accountability (e.g. new compounding pharmacy guidance), and deep diving into integrity of data systems.

The partnering for development of global harmonization by the large pharmacopeias have provided more efficient and modern monographs that allow a single testing criteria for meeting USP, EP and JP requirements for excipients and some drug product release tests.

David Elder, Principal Consultant, David P. Elder Consultancy:

New classes of drugs

Building on the success of the established nucleoside reverse transcriptase Inhibitors (NRTIs), and non-nucleoside reverse transcriptase inhibitors (NNRTIs); the last 20 years have seen huge developments in anti-HIV therapy. These include new generations of less toxic NRTIs and NNRTIs, new classes of anti-retroviral drugs, as well as many new combinations of these different classes of drugs.

Various new classes of anti-retroviral drugs have been developed. These include protease inhibitors (PIs) which are targeted at blocking HIV protease, an enzyme essential for the replication of the virus.

Fusion inhibitors (FI) and post-attachment inhibitors (PAI), both blocking HIV from entering the CD4 cells of the immune system, have also been developed. Furthermore, integrase inhibitors (II), which block HIV integrase, preventing the virus from replicating, have recently seen increased promise. Finally, CCR5 antagonists, which block these receptors on the surface of certain immune cell, have also been commercialized.

Combination therapy has seen a proliferation of combinations of these various different classes of HIV drugs. Typically, combinations of three / four drugs, from at least two different drug classes, are employed, i.e. Triumeq (abacavir (NRTI) / dolutegravir (II)/ lamivudine (NRTI)). As a consequence of these major advances, HIV is no longer considered a “death sentence” in the developed world; although in Sub-Saharan Africa it still causes many fatalities.

New manufacturing technologies

Continuous manufacturing is defined as processes where the input materials are continuously charged at the beginning of the process and the product is continuously discharged at the end. Continuous manufacturing reduces the number of process steps versus a classical batch-based process, allowing smaller equipment and a smaller manufacturing footprint to be used. Processes will normally run 24/7/52, with a small planned maintenance downtime, i.e. 1-2 weeks. There are substantial advantages in terms of cost, efficiency, robustness, reduced failure rates and decreases in level of ‘stockouts’, as well as allowing significant manufacturing flexibility. As a consequence of the increased in-process monitoring via process analytical technology (PAT) tools, there is an increased probability of generating “real time” quality data, potentially resulting in “real time release testing” (RTRT).

FDA is extremely keen on modernizing pharmaceutical manufacturing using continuous manufacturing and other related principles. FDA sees these initiatives as part of the long-term resolution to avoiding drug shortages, which have plagued the US market in the recent past.

Regulatory initiatives

There has been an increased focus on the control and management of impurities in medicinal products. The international conference on harmonization (ICH) first introduced safety based limits during the mid-90s. ICH Q3A(R2) and ICH Q3B(R2) were subsequently issued in 2006 addressing impurities found in new drug substances / drug products and their controls.

ICH Q3C(R6) provides guidance on permissible limits of common residual solvents. ICH Q3C(R6) identifies three different solvent classes based on toxicological considerations in order of decreasing toxicity; i.e. class 1 > class 2 > class 3. ICH Q3C(R6) recommends substitution and avoidance of highly toxic solvents (Class 1) unless their use is warranted via risk-based evaluations.

The two most recent guidelines include ICH Q3D and ICH M7(R1). ICH Q3D provides safety based guidance on allowable limits of residual elements within pharmaceuticals using risk based principals. Similarly, ICH M7(R1) addresses the thorny issue of very toxic, I.e. mutagenic impurities. Unlike the other guidelines, ICH M7(R1) is clearly applicable during clinical development. However, the other ICH Q3 guidelines are also routinely applied and interpreted (misinterpreted?) during clinical development even though that was not the original intention and regulatory expectations during these development phase often in excess of any meaningful safety considerations.

Industry globalization

ICH was the first major initiative that attempted to harmonize global approaches to the regulation of medicines. In some areas, such as impurities (see above) and the concept of Quality by Design (QbD) (i.e. ICH Q8-Q10) the ICH guidelines have been truly transformative. In other areas, such as pharmacopeial harmonization the outcome has been less positive. Indeed, the ICH Q4 guidance is longer being updated and has been replaced by the efforts of the pharmacopeial discussion group (PDG). This is perhaps reflective of the inherent challenges of trying to harmonize the outputs of a national (JP), multinational (Ph. Eur.) and a private (USP) pharmacopeia. Similarly, in the manufacturing arena the outcomes have been mixed. Early adoption of globalization of manufacturing of APIs (in particular) to China and India, i.e. outsourcing was followed by recent initiatives to in-source many programs. Many companies now operate a mixed model with early phase outsourcing, followed by insourcing at Phase III and during the early years of production, followed by a subsequent outsourcing as the financial returns from the product diminish. For some reason, outsourcing of drug product development has never being viewed as positively as with API outsourcing.

Rodolfo J. Romañach, Ph.D., Site Leader C-SOPS, Recinto Universitario de Mayaguez, Department of Chemistry:

I was told 20 years ago that we had nice academic projects but FDA would never approve a near infrared spectroscopic method. This has certainly changed, and there is even an FDA guidance for submission of NIR methods.

Is the current state of the industry what you imagined it might be 20 years ago? What do you see as some positive industry developments and what do you think the industry can do better?

Ali: As we reflect 20 years back, many of the new developments are beyond the scope of belief for our industry. Technologies such as continuous manufacturing to streamline the online testing process analytical tools (PAT) to expedite drug development and innovations in 3D printing to make personalized medicines did not exist. As the population continues to age, the industry continues to develop technologies and medicines that improve and extend the quality of patients’ lives. That said the industry must continue to address shortages of medicines for life-threatening diseases like cancers among others. This coupled with the manufacturing costs for drug substances under cGMP, and finding reliable manufacturers for quality raw materials, have all been a focus to avoid future risks by implementing robust processes and working ethics as partners within the industry. Gaps in certain areas of development have been addressed by stakeholders building consortiums to identify and achieve desired solutions, mutually beneficial for healthy relationships for unmet needs. Excipient manufacturers, have launched numerous ingredients to meet the industry needs to help expedite drug development including the development of products for taste masking of bitter APIs, increasing solubility and bioavailability of poorly soluble drugs, directly compressible Ibuprofen, dry binders, functional coating polymers amongst others.

Dream:

  • Yes, I did imagine that 20 years ago! I wrote few articles depicting such developments. One of the articles I wrote was published in CEP Magazine, November 2005, Titled: “Customized Medicine Beyond Designer Drugs.”
  • What I see as positive industry development is, many of the technologies we are discussing here are still young and in development… I could see some of these technologies further develop and improve the drug manufacturing outlook.
  • Furthermore, the use of Industry 4.0/IIoT will further modernize the manufacturing world in general as well.

Jornitz: I would say the advances in biologics and the resulting process technology improvements were on the horizon 20 years ago and therefore one could see the changes within particular applications and advances in technologies. I find it very encouraging to see that new technologies, for example single-use process technologies were adopted, although it took 15 years to be widespread accepted and implemented.

I would have envisioned a more intense push for cell culture vaccine processes and improvements in efficiencies in that area. It would be good to see more technology advances in some of the vaccine applications, especially when one thinks about upcoming pathogenic threats.

The cell and gene therapy applications were not on my radar and these new treatment possibilities are a very encouraging surprise. We see more experimental treatments see the limelight, treatments which can address diseases to which we had no answer to.

I see our industry being dedicated to serve the patient and with it has done a tremendous development job in treatments and manufacturing processes. These advances could be faster when technology improvements can be realized quicker.

Langer: Twenty years ago, the bioprocessing industry was in some ways the ‘wild west’ with the greatest concerns being burnrate of a company’s investments; this resulted in the urgent need to focus on getting a product to the next phase of clinical trials. Production efficiency and use of the best technologies were not nearly as important as simply getting a biologic manufactured at clinical scale. Worries about how this will scale-up were secondary, at best. This led to inefficient production using, for example, labscale devices, which were then scaled-out. Today, the positive developments in bioprocessing have demonstrated that companies have learned from the past. The focus on efficiency is an outcome of that constant learning.

Malhotra: Not really.

Industry seems to have lost its mojo in developing breakthrough therapies for mass needs. It has produced marginally better drugs that it can sell at much higher prices to keep its revenues and profits growing. High prices have helped revenue and profit growth. With waning growth, industry has focused on cancer therapies, where it has made significant advances, and on orphan drugs. Demand especially for cancer drugs is significant. However, industry has to figure out how to make these drugs affordable. The big question is “Can the industry sustain its current business model?”

Companies selling brand drugs in the developing countries at significantly lower prices are causing consternation in the developed countries. There are too many examples to enumerate. That gives the perception in the developed countries that the developing countries are stealing intellectual property. Reality is very different. Since the brand pharma cannot sell the drugs at the developed country prices, they sell the same drugs at significantly lower prices to recoup some of their fixed expenses. Since the major suffering population could be in the developing countries, it would be beneficial if the brand companies used ‘economies of scale’ to sell the drugs all over at lower prices and amortized their investment over a longer period. This could be considered an alternate business model.

My conjecture is that the development of new drugs and the high price strategy has worked well and might work for few more years for about 17% of the global population. Brand pharma have catered minimally to the remaining 83% of that population that also needs drugs but at affordable prices. Addressing needs of such a big population mass12 could give pharma companies significantly higher total revenue and profits compared to the current business model. It would require a model change. Industry may be forced to consider it if the fast pace growth of yester years stalls.

Industry and the regulators have to figure out how to reduce drug development and approval time and costs. The question we need to ask and address is that are we over analyzing the drug development and their commercial processes and as a result delaying new drug introduction at affordable costs. Industry needs to consider a 7.2 billion population as the market rather than 1.2 billion. It should be obvious that the revenue from 7.2 billion would be much bigger number. Are the companies missing on simple laws of economics?

Singer: Improvements to design of sterile manufacturing have definitely progressed quickly, albeit the ‘Grade A-continuity’ regulatory era for aseptic processing had something to do with that, and I hope it continues. Paving the way for operator-less filling operations is important for microbiological control and patient safety. Modern equipment and designs are available for removing humans from sterile operations, yet there is a heterogeneous uptake of some technologies globally, so culture needs to change in this respect to improve. Use of the terminal sterilization overkill approach (i.e. moist heat sterilization) rather than consideration and development of bioburden cycle development for small molecules is a paradigm that is still waiting for a path to pave. An important culture change that I am glad to see has occurred across all aspects of our pharma industry, is the acceptance of quality as the foundation of everything we do. It took a while to catch up with other high tech industries, but we are there.

Elder: “More with Less” seems to be a reasonable summary of the current state of the industry. In addition, the innovative engine of the industry that was driven by an extensive network of small and medium sized companies has been lost, to be replaced by huge multi-national conglomerations; which because they have grown by a process of mergers and acquisitions have lost their souls as well as their innovative expertise. Now the innovative engine is being driven by small virtual companies that outsource their development activities to large CMDOs and then sell off their wares to big pharma at a later stage of development. Poor drug like properties caused by an over-reliance on high throughput and combinatorial chemistry have led to significantly increased attrition. One positive outcome that has emerged is a greater understanding of the need for better physicochemical properties in drugs, particularly aqueous solubility, leading to the birth of biopharmaceutics as a discipline in its own right.

Romañach: The pharmaceutical industry has adopted process analytical technology and continuous manufacturing, and made them a reality. The progress in pharmaceutical manufacturing has been much greater than I ever imagined.

Looking ahead what does the industry need to do to address growing concerns over cost, time to market, government/regulatory scrutiny, and quality/safety of products?

Ali: The future of pharmaceutical industry looks brighter than ever as more drugs go off the patent cliff. Generic drug manufacturers are stepping in to capture the market for affordable medicines. As the number of new drugs go off patent, ethical pharma continues to devote the resources required to build robust pipelines of small and large molecules as well as biologics drugs. Regulatory agencies and health insurers will continue to play an important role in fueling the growth of generics making them easily accessible to the general patient population at a nominal cost.

As the cost for development of NCEs continues to climb to over $1 billion (from synthesis, formulation development and marketing), many in the industry are building partnerships with startups and biotech companies, and/or licensing the molecules for development to build the pipelines for future medicines. It is expensive, but significantly improves development time and speed to market. Thus, we find many of the block buster drugs today are either acquired or licensed from biotech companies or developed in mutual collaborations with an understanding of taking risks and milestone payments or a long-term royalty fee. So, as the price tag of development continues to rise, fewer new drug molecules are being launched every year. As branded drugs continue to come off patent, generic manufacturers are playing an important role as first to file to capture the market or developing the NDA drugs under 505 (b)(2) by adapting the new formulation technologies and/or for different therapeutic indications. To alleviate the safety and regulatory concerns, the generic manufactures are building their rapport by taking the appropriate measures to follow the agency’s guidelines to avoid delays and capture the market faster.

Dream:

  • Improving the technologies under development
  • Development of better controls and automation system, digital sensing devices and better manufacturing equipment to support the new developing and growing technologies at hand. In simple terms: smart machines and smart factories in the manufacturing envelop.
  • Regulatory need to train regulators to be able to respond, review, and inspect newer manufacturing portfolios and factories.

Jornitz: Our industry is a very conservative industry often clinging to legacy technologies and sticking with the known. This type of attitude is motivated by regulatory scrutiny, changes can be only implemented with lengthy, costly and tedious investigations and global filing needs. Surveys have found that one of the major hurdles for new technology implementation is post-approval changes, which can take many years to be approved globally. Such multi-year approval process does not encourage anybody to neither look into nor implement new technologies. Other industries, with less regulations show us all the time how processes can be optimized and made more efficient.

Only such improvements can lower costs and make sure that drug shortages are becoming a topic of the past.

Having said this, legacies are also upheld by functions within the industry. The known creates comfort and therefore keeping inefficient processes become entrenched. New technology scouting respective implementation is not a primary goal, as it might mean one has to venture into something new. We experienced this attitude with single use process technologies, which took 15 years to become the leading, more optimized technology and nowadays with prefabricated cleanroom units and turnkey facilities. With conservatism and short sightedness, the traditional is often favored over the optimal.

Langer: Continual learning and flexibility in a ‘whitewater’ environment is the hallmark of a healthy business. As the biopharma industry evolves, and begins to produce, for example, biosimilars at remarkably lower COGS, and higher titers, the cost per gram, and per patient will decrease.

This learning is already being transferred into the manufacturing strategy for early pipeline innovative products. So when the next generation of biologics emerge, the costs of production will be dramatically lower.

While this may not translate to dramatically lower cost of the therapies, it certainly is moving in the right direction. Further, by lowering costs of biosimilars through more efficient manufacturing, these products will be made more available to emerging economies, where, at present, many are simply prohibitively expensive.

Malhotra: Reduction in time to market is essential for the long-term viability of brand pharmaceutical companies. Regulators have to facilitate the process. This would require a major revamp in the workings of the regulators especially the US FDA. Every year gain in the life of a brand drug will have a significant impact on the P&L statement of every company. Revamp would require a major re-do at the regulators and it would/might require a legislative interference. If they don’t, as discussed later, “creative destructors”13,14 will change the current model.

Early in 2018 a new initiative was launched by Amazon, Berkshire Hathaway and JPMorgan12 to lower drug costs to their employees. If they are successful and they should be, it is going to be a major perturbation to make/improve drug affordability in the developed countries.

Global quality and safety of drugs is paramount. First time issuance of a 483 citation could be taken as a reflection of oversight or not crossing every “t” and dotting every “i” in their manufacturing process. However, repeated 483’s at the same company should be taken as a ground for deliberate negligence and considered for shutting the operation. Only financial hurt will prevent repeated offences.

FDA has initiated a process to reduce the approval time needed from 8-10 months. However, it is still long and needs to be reduced to three months. Reduction to three months would be an incentive for the company to get to the market sooner. To achieve such a reduction in time FDA will have to create templates and facilitate applicants. There could be internal resistance within FDA and other regulators. My conjecture is companies will like this as profits are a good incentive to achieve goals.

Companies will have to comply with every FDA requirement and have to have fool proof compliance regimen. If they do not, FDA should stop manufacturing at the site. Inspection and approval time could be extended beyond three months. Reducing time to three months will be an internal challenge at FDA. Totally different thinking will have to implemented.

Companies have to do an internal introspection of their own practices so that they do not suffer the wrath of 483s. Every step of the manufacturing process they have to have an absolute command. One may think that this is difficult. It is difficult only if one does not have command of the processes. They have to think that if a manufacturer is expecting quality, they should deliver the same, no less.

Tea leaves about the pharmaceutical industry have been written,15,16 read and will continue to be written. They let us imagine, suggest us of possibilities and opportunities. We just have to decipher the maze, strive and to get there to write our own tea leaves that could be used by others to learn and innovate. It is not difficult.

Dr. Ghulam Shabir, CSci, CChem, FRSC, Managing Director, DGS Pharma Consulting Ltd: I have seen the industry suffer due to a lack of skilled workers that are in key leadership jobs. They cannot deliver the leadership skills needed within agreed targets which cost more to the company. There is an absence of skilled workers getting into the job, this is especially seen in higher positions. When industries recruit the wrong person into the key job these industries fail to perform and market their products. Operations become more complex, which causes delays in delivering product to market. 

Going forward the industry must need fairer recruitment policies for hiring people, especially key roles based on diversity, merit, and talent, those who can contribute and deliver an excellent performance.

Industries need talented people who can bring innovative ideas to introduce new products with low cost to the market. Industries need to simplify their operations processes, which will help fast delivery to the market. The industry also must not recruit or promote their staff based on friendship, grouping or politics. Industries need to develop a quality culture within their operations and must have common goals to produce defect free products with zero waste and zero accidents/incidents. Also, industries need to make quality decisions risk based (ICH Q9) alongside, with standard written procedures to avoid unnecessary scarping of products in case of any quality issues occurred during the operation. Companies must not compromise with the quality of their products and need to make sure their products are safe to the end users. This will reduce the cost to the company and improve the business and reputation. Finally, regulations, by the regulatory bodies/government need further improvements in the harmonization process through ICH globally for registration of new drugs, this will reduce major cost to the industry in registration of their products into different countries.

Singer: It is always about finding the right balance of what is important for the patient and what will sustain our ability to develop, get regulatory approval, and market products to the patient. Microbiological safety is a paramount factor for me. For microbiological oversight, communication and constant learning in science and technology of our products, we need to be actively looking for ways to make improvements that will relate to process robustness, along with ensuring accuracy and consistency of testing. There is a gap in excipient customer-supplier collaboration where we can build trust and improve the consistency of excipient quality we need and reduce costs. For drug manufacture, we still depend on testing as a final measure of quality, yet robustness in process design has so much more impact on assurance that quality criteria are met; the patients will benefit from real-time release thinking as the paradigm that we should be strongly considering. The growing field of cell and gene therapies and relevant development of robust manufacturing controls which lead to real-time release assurance can be a harbinger of the new paradigm.

Elder: The introduction of Breakthrough Therapies in the US, and the Medicines Adaptive Pathways to Patients (MAPPs) within Europe, give a clear perspective of future thinking. For products developed to meet pressing societal needs, i.e. new antibiotics, regulatory agencies will work collaboratively with Industry to provide a more rapid and flexible approach to developing and approval of medicines. The cost for both industry and healthcare providers could also be significantly decreased. However, although there has been a meeting of minds with respect to clinical development resulting in the adoption of adaptive clinical trial design, which can lead to the early authorization of a product focused on a well -defined and targeted population with a clear safety and efficacy profile; the same cannot be said within the CMC community.

Adaptive pathways do not change the standards for the evaluation and these novel approaches make use of the existing regulatory framework. Thus rather than support the approach of “QbD-light” dossiers which are continuously supplemented post-submission and the desired state is reached several years post-filing, the current regulatory climate appears to want the typical levels of a QbD submission but within an accelerated timeframe. Companies can only meet these conflicted expectations by significantly increasing the resource burden of these programs, which is surely contrary to the aspirational goals of these initiatives.

Romañach:

  1. We need to improve sampling in pharmaceutical processes. Sampling is the basis of all quality control.
  2. We can achieve much more through innovation ecosystems, and industry-university collaboration.

References

  1. Hussain, Ajaz, Pharmaceutical Quality by Design: Improving Emphasis on Manufacturing Science in the 21st Century, Pharmaceutical Manufacturing, August 5, 2004 Accessed August 28, 2018
  2. Yu, Lawrence, Pharmaceutical Quality by Design: Product and Process Development, Understanding and Control, Pharmaceutical Research, April 2008, Volume 25, Issue 4, pp 781–791 Accessed August 26, 2018
  3. Kopcha Michael, Ph.D., R.Ph., “Continuous Manufacturing” – Common Guiding Principles Can Help Ensure Progress, September 11, 2017, FDA Voice, Accessed August 28, 2018
  4. McGraw Hill Chemical Engineering Series Accessed August 24, 2018
  5. Unger, Barbara: An Analysis of 2017 Warning Letters on Data Integrity, Pharmaceutical Online, May 18, 2018 Accessed August 25, 2018
  6. Drug Making Email exchange with Dr. Janet Woodcock, FDA July 13, 2016
  7. Malhotra, Girish: Pharma’s future is putting innovations in the hands of innovators, CPhI Parma Insights, August 23, 2018 Accessed August 26, 2018
  8. Hatch- Waxman Act, Very Well Health, May 31, 2018 Accessed August 29, 2018
  9. TRIPS and pharmaceutical patents, September 2006, WTO.org, Accessed August 29, 2018
  10. Sood, N; Shih, T; Van Nuys, K; Goldman, D; The Flow of Money Through the Pharmaceutical Distribution System, June 14, 2017. http://healthpolicy.usc.edu/Flow_of_Money_Through_the_Pharmaceutical_Distribution_System.aspx, Accessed March 1, 2018
  11. Malhotra, Girish: Opportunities to Lower Drug Prices and Improve Affordability: From Creation (Manufacturing) to Consumption (Patient), Profitability through Simplicity, March 9, 2018 Accessed August 29, 2018
  12. Malhotra, Girish: An Alternate Look at the Pharmaceutical World and Drug Affordability, CPhI Annual Industry Report 2017, pgs 36-41
  13. Malhotra, Girish: Could Amazon (A), Berkshire Hathaway (B) and J.P. Morgan Chase (M) be the Anti Ballistic Missile (ABM) needed to Control/Curb Rising Healthcare Costs? Profitability through Simplicity, February 9, 2018 Accessed August 21, 2018
  14. Malhotra, Girish: Amazon PillPack Marriage can Alleviate Drug Shortages and May be Lower Drug Prices, Profitability through Simplicity, July 5, 2018 Accessed August 21, 2018
  15. Malhotra, Girish: Reading the Tea Leaves: Predictions for Pharma’s Future, Profitability through Simplicity, January 18, 2016 Accessed September 1, 2018
  16. Malhotra, Girish: Pharmaceutical Manufacturing Technology Innovation: Does Reading the Tea Leaves Matter? Profitability through Simplicity, December 22, 2017 Accessed September 1, 2018
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