Grant Playter

Bio/pharmaceutical companies operate in an industry known for its rigorous, exacting standards; companies place significant, implicit trust in any outside party they involve in their supply chain. Consequently, one could be forgiven for thinking that outsourcing materials for biologics production, which by design are much more complex than their small-molecule counterparts, would be infrequent because of concerns regarding quality control.

However, biologics outsourcing is a major industry that is, in concert with the rising demand for biologics throughout the industry, poised for rapid growth. A market report from IQ4I Research & Consultancy forecasted that this niche is expected to grow at a double-digit compound annual growth rate from 2022 to 2030. Additionally, the authors anticipated the industry reaching a $106.7 billion valuation by 2030 (1).

Outside of the growing demand for biologics, one can point to various reasons for this rise. For one, building a new biopharmaceutical manufacturing facility takes, on average, 5–10 years before it is operational, and can cost up to $2 billion (2). For small-to-mid-sized organizations, this cost is already an untenable expense, especially for products that are still in early-to-mid development phases. That said, even companies who have their own manufacturing facilities tend to dabble in outsourcing, as it allows them to leverage a contract manufacturing and development organization’s (CDMO’s) existing knowledge and experience with biologics production—for many companies, this is uncharted waters. In this vein, outsourcing can ultimately smooth out production irregularities and reduce time-to-market.

This begs the question: what is the state of this emergent industry? 

 spoke with Kasper Møller, chief technical officer at AGC Biologics, a CDMO specializing in protein-based biologics and advanced therapies, to outline the keys to a successful outsourcing platform, explore ongoing trends in biologics outsourcing, and much more on the topic.

When speaking with Møller, the core mantra that he repeatedly stressed was that biologics CDMOs need to be flexible. Because outsourcing companies are working with various companies on wildly different biologics requiring often disparate approaches—for instance, the needs of mammalian-derived therapeutics are different than those of microbial-derived proteins—versatility must be built into the framework of one’s solutions.

“Flexibility is key to adding value to each project and within each modality, facility, and manufacturing line,” said Møller. “Longer-term planning for projects can help address [this problem], but potentially more important is the use of flexible technology systems. With single-use technology and materials, it is possible to change the configuration of a manufacturing line, exchange or add unit operations, and cover various scales of operation.”

In Møller’s case, AGC Biologics developed “the 6-Pack single-use manufacturing concept,” which helps vary batch sizes within the same manufacturing line. This is achieved through combining harvests of parallel 2000-L single-use bioreactors, allowing the company to run anywhere from 2000-L–12,000-L batches at a time. Varied batch sizes allow customers to scale at their own pace, providing more time to evaluate product demand.

Møller also noted that this flexibility should also extend manufacturing agreements. For instance, in cases where high capacity is needed but the timing is uncertain, customizing a deal to provide a fully dedicated line, a partially dedicated line, or a line based off of a “rolling forecast” where products can be exchanged and manufacturing slots moved via a forecasting mechanism (Møller likened the last one to commercial manufacturing), can be helpful for fulfilling customer expectations while maintaining peak operational efficiency.

While biologics come in many forms—vaccines, recombinant proteins, gene therapies, etc.—Møller emphatically stated that he believes protein therapeutics will continue to be the top dog for years to come. Monoclonal antibodies (mAbs) in particular, he stressed, are something that AGC is focused on supporting, which the company facilitated by expanding its existing facilities in Copenhagen, Denmark in 2021 (3). According to Møller, this investment doubled their mammalian single-use system capacity at the site, adding a new manufacturing line with eight 2000-L single-use bioreactors for mammalian protein projects, a new 500-L perfusion bioreactor, and two downstream purification lines. Similarly, the company acquired a commercial-grade large-scale 20,000-L mammalian protein manufacturing facility in Boulder, Colo., in 2020 (4).

However, while mAbs are the king of the hill, they are not without competition. A key area of growth that Møller identified was cell and gene therapies, particularly in North America. In 2022 alone, FDA approved five novel cell and gene therapies, including Zyntelgo (betibeglogene autotemcel), Hemgenix (etranacogene dezaparvovec), Skysona (lisocabtagene maraleucel), Adstiladrin (nadofaragene firadenovec), and Carvykti (ciltacabtagene autoleucel); these 2022 approvals comprise roughly one-fifth of the total number of FDA-approved cell and gene therapies to date (5).

Møller’s observations are mirrored by many others in the industry: in 

 annual survey of bio/pharma workers, approximately half of them felt the biggest opportunity in the entire industry lay in cell and gene therapies (6). As companies race to compete in this rapidly growing niche, biologics-oriented CDMOs such as AGC will move to accommodate them. In the case of AGC, one such decision the company made was the acquisition of a of an established Italian cell and gene company, MolMed, in 2020 (7), as well as a Colorado facility containing viral vector and cell therapy production and manufacturing capabilities in 2021 (8).

While the exact needs of any company are typically unique in some form or fashion, Møller noted that are two core themes he finds himself telling his potential partners. “Two of the biggest considerations AGC Biologics focuses on with drug developers of any size is reducing cost and process robustness,” he said. “As an outsourcing partner, these are key areas that we advise our customers to watch closely.”

While few skimp on the actual development of the treatment, according to Moller, companies often neglect the design of robust manufacturing processes and analytical methods in the early stages of development in an effort to reduce costs and hasten time-to-market. However, this short-term outlook can present problems down the line.

Regardless of a treatment’s effectiveness, if there isn’t a scalable manufacturing process associated with it, there will almost certainly be delays when the time comes for commercialization. By taking the time to consider the design of manufacturing processes early on, companies can ultimately save themselves time and money.

Biologics Outsourcing Global Market–Forecast to 2030

2. Longo N. Setting up a Pharmaceutical Manufacturing Supply Chain Is a Complex and Lengthy Process. 

3. AGC Biologics. AGC Biologics Announces the Groundbreaking of its New Facility at its Copenhagen, Denmark Site. Press Release, Aug. 20, 2021.

4. AGC Biologics. AGC Acquires Biopharmaceutical Commercial Facility in Colorado, USA. Press Release, June 2, 2020.

5. FDA. Approved Cellular and Gene Therapy Products. 

6. Playter G. Crossing the Same River Multiple Times. 

7. AGC Biologics. MolMed S.p.A Becomes AGC Biologics S.p.A Following the July Acquisition. Press Release, Oct. 27, 2020. 

8. AGC Biologics. AGC Biologics Enters Agreement to Acquire Facility in Longmont, CO, Eyeing to Significantly Expand Their Cell and Gene Therapy Capabilities and Offerings. Press Release, July 1, 2021.


Vol. 47, No. 3
March 2023
Pages: 48–49

When referring to this article, please cite it as G. Playter. The Logistics of Outsourcing Biologics. 

Articles

The trends shaping the growth of the biologics outsourcing industry demand attention.

The Logistics of Outsourcing Biologics

The exact state of computer software validation (CSV) can be tricky to pin down. While industry insiders can call it slow to change, attempting to sort through various complex procedures, approaches, and technologies to develop a truly validated process can be mystifying for those on the outside looking in.

 spoke with G. Raymond Miller, PhD, course director for Computer System Validation at The Center for Professional Innovation and Education. Miller spoke on various topics, including the rise of computer software assurance (CSA), how to contextualize new draft guidances from regulatory authorities, and common CSV pain points.

: FDA recently put together a draft guidance on CSA that describes a new validation approach. How does this work, where does it differ from historical approaches, and why is FDA implementing it?

: First, CSA is not replacing computer validation; it’s an alternative approach to the process that has evolved since the mid-1980s. For decades, CSV has been an effort in good documentation practice. The outcome has too often been perfect documentation that has little to do with correct system operation and ends up locked away in the event an investigator asks for it. The intent of CSA is to focus more on challenging system operations the way we intend to use them, not producing piles of beautiful but meaningless documentation.

General Principles of Software Validation

 points out (1), software doesn’t wear out; given the same inputs it will supply the same output. The results of computerized operations can vary when the inputs change. We don’t need to run a test multiple times with the same inputs; we need to inject a variety of inputs intended to generate errors if we can. We want to break it during testing, not in production, when errors might harm the public directly, or maybe through other impacts such as business disruption. CSA represents current thinking about how to make the CSV process value-added.

With regard to CSA challenges in testing, I’m still trying to wrap my head around testing without reviewable evidence. Not because of a perceived need for proof, but to overcome human nature to take the easy way out. Say it’s Friday afternoon, we’re tired and ready to head out for the weekend. We might be a little less diligent about noticing and investigating a discrepancy that occurs during testing; especially if we aren’t required to have documented evidence. I’ve seen this happen too many times over the years. If we must have documented evidence and sign for our actions, we’re not going to be able to bypass procedures and ignore those discrepancies. How can we focus more on testing and yet still ensure due diligence?

 The Center for Devices and Radiological Controls (CDRH) also put together a list of planned guidances for 2023 for computer validation of various devices (1). Broadly speaking, what are some of the key changes we can expect out of these guidances? How are companies preparing for this?

: My interests are in the CSV process itself; I see it as just good IT [information technology] business practice, so it really applies across the board. The guidance in CDRH’s list that stands out to me is Cybersecurity in Medical Devices. I see that as a documented awareness of the serious impact cybersecurity has on patient safety.

But I also think the current thinking has broader implications to CSV in general, increased emphasis on hazard analysis, risk mitigation, and scenario testing regarding cybersecurity and data integrity. The identification of ‘intended functions’ for validation should include functions intended to mitigate hazards through risk management, including more robust testing. These are just good IT business practices. Companies should be proactively building appropriately controlled systems, not waiting for guidance documents to be finalized to start planning actions.

: Would you characterize computer validation as a segment of the pharmaceutical industry that is regularly seeing significant changes in technology or approaches, or is it more incremental? Outside of the changes FDA is outlining, do you know of any recent technologies or approaches that are shifting the way computer validation is handled?

: I would describe it as punctuated evolution. There is a fear of change, so companies stick with legacy, that is, documentation-focused validation, ‘just to be sure!’ They wait for others to show it’s okay to evolve. Often, the perspective is that there’s only one way to validate because, ‘That’s how we did it at company XYZ’. We must cultivate awareness of the need to adapt to the fact that different systems need different approaches: browser accessed, databased apps vs. data acquisition, and processing apps vs. real-time process control apps are three general categories that have different validation approaches.

In this vein, less emphasis is being placed on everything we intend a system to do and is instead shifting toward the intended uses around data integrity and security risks. We used to revalidate if we moved an instrument from one lab bench to another. Today we may not validate a change that impacts only a graphical user interface if there is no impact on data integrity and security.

: Periodic review of good practices (GxP) systems is often not considered in discussions surrounding computer validation. Why is this needed, how does it differ from initial validation, and how does it factor into the bigger picture of ‘achieving validation’?

: I'm surprised that periodic review might not be considered as part of the post-implementation operation and maintenance procedures—it is! Validation includes ensuring there are procedural controls around operation and maintenance of systems during use. GXPs expect that people are trained on those procedures before they are authorized to use the computerized systems. EU Annex 11 for GMPs [good manufacturing practices] and Q7 for APIs both address periodic review.

The concept is that, once a system is validated for use in regulated operations, there should be procedures for maintaining it in the validated state. Change control is one procedure: a change may not be made without an evaluation of the impact of the change and suitable validation activities to return the system to its validated state if the change is allowed to proceed. The concept of periodic review is more of a QA [quality assurance] activity to evaluate the effectiveness of the operation and maintenance procedures, and if there is any evidence that the system might no longer be operating in the validated state. Any discrepancies should be documented, and a change control action initiated for resolution. Periodic review does not often result in revalidation unless the change control procedures are not being followed.

: What are some of the most common pain points in computer validation? What, if anything, is being done to resolve them?

: One is company culture: there is a targeted delivery date, but the project sees too many delays. Less and less time is available for testing and finalization. Effective project management up-front helps so that stakeholders are aware that failure to follow procedures will result in schedule delays, not substandard actions.

Something I’ve also seen frequently is that QA is not brought into the process until the project is in its final stages. There is either the need to stop progress for corrections or pressure for QA to accede and reluctantly approve. Prevention comes from procedures and education on the importance of following the procedures. I’ve told some in the past, ‘Retrospective validation is just acknowledgement that proper validation and software development life cycle procedures were not followed from the beginning.’

Another is inadequate testing such that serious defects are encountered at a late stage or even in production. This can be mitigated through hazard analysis and risk management starting at the requirements stage. Use the results to proactively define the intended testing and data sets to catch the problems before the impact is even worse.

Finally, waiting until the validation is mostly completed to prepare the summary report. People must reread and summarize the actions, resulting in long delivery times and pressure to release the system for use, causing even further delays in the summary report. Instead, draft the summary report sections in the beginning and add to them as the validation proceeds. As soon as the last action has been completed, there is only one item to be completed in the summary report and it is ready for approval, releasing the system for use in regulated operations.

: Do you have any other thoughts you’d like to share on computer validation?

: One final recommendation that I have made over the years and where CSA concepts are already having an impact on testing: write test cases to tell the tester what to do, not how to do it! Legacy test case-writing practices have test authors run through the software, recording what steps they had to take to test the system (heavily scripted test cases). There are many problems with this:

However, testing in front of the software tests what it does, not what it should and should not do. This usually calls for running through the scenario to get the steps written correctly, and dry-run testing then takes time to make sure the test case was written correctly. Then the test case is reviewed and approved by others before it can finally be executed by someone else, for the ‘official’ test documentation. There is no value in dry-running the test cases; eliminating them saves much time and effort.

And if we write the test case from the requirement risk assessment telling the tester what to do but not how to do it, we get many benefits. Because we’re testing what we intend it to do, not confirming what it actually does, we have a better chance of finding defects. There are also no test navigation steps written incorrectly or questionable execution, so errors are usually real system issues. Additionally, the test authors can write the test cases while the system is in development, the test cases could possibly be used to direct development or mitigate issues up-front, and the tester is free to explore the system operation as the test proceeds and track down anomalies.

These are just my current thoughts on computer validation from experience with many hundreds of computer validation projects over the years. Not everyone will agree with them, but I hope they will consider the merits and offer useful alternatives. I’m always open to new approaches and improved processes with the general goal of keeping computer system validations practical yet defensible.

General Principles of Software Validation; Final Guidance for Industry and FDA Staff

CDRH Proposed Guidances for Fiscal Year 2023

Grant Playter is the associate editor for 


Vol. 47, No. 2
February 2023
Page: 32-33

When referring to this article, please cite it as G. Playter. The Punctuated Evolution of Computer Software Validation. 

Shifting guidance and the growing prominence of computer software assurance exemplify the state of computer software validation.

The Punctuated  Evolution of Computer Software Validation

Jill Murphy, editor, and Grant Playter, associate editor, discuss the results from Pharmaceutical Technology’s latest employment survey. This survey, which polled approximately 300 members of the pharmaceutical industry, is designed to gather insights on topics like the broader state of pharmaceutical employment, trends going on in the industry, and predictions for its future. In this episode, Jill and Grant take a deep dive into these statistics and discuss what underlying factors might be at the root of it all.

 presents the Drug Solutions podcast, where the editors will chat with industry experts from across the pharmaceutical and biopharmaceutical supply chain. Join us as experts share insights into your biggest questions—from the technologies, to strategies, to regulations related to the development and manufacture of drug products.

Podcasts

Jill Murphy, editor, and Grant Playter, associate editor, discuss the results from Pharmaceutical Technology’s latest employment survey.

Drug Solutions Podcast: Surveying Pharma Workers on Employment Trends

 conduct a survey (1) designed to measure the state of the bio/pharma industry. More specifically, the survey assesses various employment metrics, thoughts on ongoing trends, and predictions for the future of the industry. The intent is to not only create a snapshot of the bio/pharma industry as it exists in 2022, but to also encapsulate the thoughts and feelings of those within.

In recent years, this has been dominated by the specter of a generational pandemic. While most are reluctant to declare the end to COVID-19—the continual discovery of new variants would stay the hand of even the boldest of public health officials—its influence has nonetheless diminished, even in an industry that has become inextricably tied to the virus.

However, in this year’s survey, consisting of 296 respondents in the bio/pharmaceutical industry, almost all key metrics that concern COVID-19’s importance to daily operations (

) decreased. One of the largest practices, social distancing, dropped to 28.2%, less than half of the percentage in last year’s survey (2). And while remote work remained prominent, with approximately 58% still engaging in the practice—especially notable given that many pharmaceutical positions require working on-site—it still had an approximate 10% drop from last year’s sample. Of the eight measures, the only pandemic-related metric that saw a rise in use was “assuming additional responsibilities,” which saw a modest increase of approximately three percentage points.

While the reticence to banish COVID-19 will continue to permeate through society, it is clear that the pharmaceutical industry is de-escalating many of the practices associated with it. Setting aside the validity of this approach, this shifts industry discussion to other aspects of the pharmaceutical market and what the future may hold.

Among survey respondents, wage growth appeared to stagnate relative to last year’s survey. As seen in 

, 72.8% of respondents indicated that their salary remained “approximately” the same, almost twice as much as last year’s 39.0%. Similarly, just 22.1% of respondents indicated a significant increase in salary, less than half of last year’s 55.4% number. Salary decreases also had a modest reduction, as they did in 2021, dropping from 8.1% to 5.1%.

Approximately 24.3% of respondents felt some increase in job security, a slight dip from the 30.4% number observed in 2021; the percentage of those who felt no change in job security dropped just three tenths of a percentage from 52.6% to 52.3%. As seen in 

, these modest reductions appear to have funneled into a slight increase in those who felt less secure, from 17.0% to 21.3%. As it pertains to job satisfaction, while those who felt somewhat satisfied or unsatisfied with their jobs remained similar to 2021’s numbers, those who felt fully satisfied dropped from 23.7% to 14.5% and those who felt mostly satisfied increased from 39.2% to 51.4%, resulting in a slight drop to the weighted average.

Interestingly, this only appears to have corresponded with a slight decrease in overall salary satisfaction. While those who were fully satisfied with their salary did drop from 18.8% to 14.9%, there was an increase from 37.7% to 41.9% in those who were mostly satisfied; this means the total number of those who responded positively to the question (i.e., fully or mostly satisfied) actually increased slightly. It is worth noting that the survey slightly changed the wording of the pay assessment question to include the word “significantly” to prevent raises designed to keep pace with inflation from being considered a metric of real wage growth. This change could result in some degree of variance among responses in the survey population, especially given the otherwise bullish market for employees in the greater economic landscape.

However, in tandem with work wages, job security, and overall job satisfaction metrics dropping, concerns of the survey population (

) revolved around finding proper staff. More specifically, over half of the respondents indicated that either an insufficient number of staff with specialized training (35.0%) or number of staff in general (22.8%) were their biggest concerns. Taken together, this could suggest that the pharmaceutical industry is struggling between attracting skilled talent and raising compensation for existing workers, an especially difficult task with inflation in countries like the United States outpacing many company’s
standard annual raises.

Alternatively, given decreases in job security metrics and the fact that just 26.4% of the respondents have changed jobs in the past two years, this could perhaps indicate a reluctance to re-enter the job hunting market. While it is generally understood that pay bumps from job to job will be, on average, higher than those within the same company, the uncertain state of the market could be staying the hands of those who would otherwise pursue new opportunities. In conjunction with high inflation and the perceived need for spending on additional staff, this could result in fewer raises and lower wages.

While wages and employment remain in a murky place, the other questions on the survey—those concerning past trends, future trends, and how they might intersect—painted a clearer picture of where the future of the industry might be headed.

In last year’s survey, the pharma industry had begun its recovery from the lows of COVID-19 and responses corresponded with that. Approximately 53.2% of respondents felt the industry had performed better than anticipated, while 47.4% thought the same about their company’s performance. As one would expect, those numbers both dropped significantly this year, as seen on 

However, there were only modest increases in those who felt it did worse than expected, an especially notable statistic in light of the fact that over half of the 2021 respondents expected increases in the industry. This affirmation of last year’s inclinations toward continued growth in the industry could perhaps explain the continued optimism in this year’s sample. As shown in 

, nearly half of respondents believe their individual company’s and the industry itself will continue to improve in the following year, while only a small fraction of the sample (10.9% and 11.5%, respectively) believe that things will get worse.

This, however, begs the question of where this growth may occur. The editors selected several intriguing areas of opportunities for participants to choose between, and as shown in 

, just under half (47.3%) chose cell and gene therapies. While chimeric antigen receptor-t cell therapies have been drawing increased interest from companies since tisagenlecleucel’s approval in 2017, this interest can also be explained by the rise of mRNA vaccines. Following their accelerated development in wake of the COVID-19 pandemics, there have been many vocal proponents for their use in personalized vaccines, in particular for conditions like cancer. In addition to cell and gene therapies, machine learning and artificial intelligence (22.3%) also drew significant interest from the survey population.

In total, while this year’s employment survey did shine a light on some intriguing trends throughout the industry, it has also reiterated, as it almost always does, that the industry continues to be in a state of flux. While there is continued optimism and hope for promising technologies, struggles among employees and business could easily boil to the surface. Employees may continue to face wage stagnation, while businesses may face struggles to maintain proper staffing for current operations, let alone branch out into new technologies of interest.

To get a coda on this from the survey respondents, we asked every respondent to submit one word that they felt best described the industry as it currently stands. While there were a variety of responses, two words kept popping up: “Challenging” and “Evolving.”

Will this prove true? Only time will tell—see you next year.

. Employment and Trends in the Pharma Industry Survey 

2. G. Playter, “The Long Path to Normal,” 

Grant Playter is the assistant editor for 

When referring to this article, please cite it as G. Playter. Crossing the Same River Multiple Times. 

Cautiously setting aside pandemic practices, pharma workers appear ready for flux, change, evolution, and expanding molecular diversity.

Crossing the Same River Multiple Times

Predictive analysis is a tricky business–it’s difficult to find experts who can not only thoroughly document trends of the past year, but also understand the underlying market forces at work that are causing them. Thankfully, the annual CPHI market report is an invaluable resource for those looking for experts who can not only document key trends but also extrapolate meaning from them.

In CPHI’s 2022 report, key takeaways included a bottoming out of the biotechnology market, the upswing in psychedelics interest, and the continued emergence of India (1). 

 spoke with various experts on the topics covered by the report to get their insight into the ghosts of pharma past, present, and future, including Tara Dougal, content director—pharma, Informa Markets; Ramesh Subramanian, PhD, chief commercial officer, Aragen; Steffanie Wilson, PhD, vice-president of Neuroscience Therapeutic Research Unit, Emmes; and Pushpa Vijayaraghava, Life Sciences lead advisory, Sathguru.

 One finding from the CPHI market report highlighted how there’s a common perception that we’ve hit a ‘bottom’ in terms of value in the biotech market. Can you discuss some of the factors that led to this, and what is changing that is leading to optimism? Why do you feel that contract development and manufacturing organizations (CDMOs) and contract research organizations (CROs) are particularly poised to benefit from this?

: Looking at the data, venture capitalists and private equity have well documented cycles for the capital they deploy. This means there is a limit to how long they can/will sit on reserve capital [the CPHI report identified hundreds of billions of ‘parked capital’]. It’s therefore inevitable that this money will flow into biotechs soon, and, for CPHI audiences, this is hugely positive because outsourcing is where biotech spends its money.

On the back of this trend, at CPHI we are introducing more content specifically for investors looking at the opportunities CDMOs present. On a more anecdotal level, if you spoke with our exhibitors last month you would hear how positive the outlook is. The event is a crucial platform for meeting the partners that will fill this increased capacity many CDMOs are building. Certainly, the next 18 months to two years look extremely robust, and that’s with macro and inflation headwinds factored-in.

 Our industry is cyclical, and we do go through regular corrections—we are potentially in one such regime. But the drug discovery industry has consistently demonstrated resilience and always comes back with an even better outlook for the mid-term future. Even during these times, though, there are always opportunities for CROs and CDMOs that can adapt and provide value to their partners. In the discovery space, with early assets being put on hold, potential opportunities exist for CROs that can advance those assets forward. CROs with integrated discovery capabilities that blend medicinal chemistry and biology, and have a team of drug hunters, can now create value for their partners by driving these programs cost effectively until the biotech partner is ready to bring the program back in. This creates significant value for both the biotech and the CRO.

On the early development front, with cost rationalization and less personnel, biotechs may prefer engaging with integrated development partners that offer drug substance and drug product capabilities since it reduces the management team and provides better cost metrics due to increased buying power. At Aragen, we view this as an interesting opportunity, since we provide both drug substance and drug product solutions through the clinic, but also combine that with toxicology support that includes access to non-human primates. The ability to rapidly and cost effectively drive programs into IND [investigational new drug] is always of high interest to our biotech partners.

Can you discuss the potential you see in the psychedelics market? Historically, what barriers have prevented the pharma industry from entering the space? Which of these do you expect to come down, and what will remain a challenge?

 There has been a historical reluctance in the psychedelics field to look closely at these compounds’ potential because of culture rather than the strength of science. This barrier I think we can see is falling away quickly with the psychedelic renaissance, and we see new market entrants all the time. That said, we are yet to see Big Pharma putting its considerable resources into this area directly, and most trials are undertaken by smaller biotechs or research group collaborations. It’s such an exciting time for the field, and we have worked on several large multicenter IND trials already.

In general, the results for psilocybin and 3,4-Methylenedioxymethamphetamine have been hugely promising, but there are still areas in psychedelic clinical trials that present challenges, notably around optimal dose, maintenance of the study blind, and length of therapeutic effects. As one of the few CROs with experience in these still novel trials, we are now getting many more enquiries, and it’s probably only a matter of time before we see Big Pharma making a more concerted effort at research.

The other exciting aspect is that, while there are a number of high-profile trials approaching potential approvals, we are still very much in the early stages of this research; we are learning all the time. In addition to the indications which have been the focus of recent trials such depression and PTSD [post-traumatic stress disorder], I think there are other psychiatric and neurological applications—from pain to headache disorders to addiction—where we are seeing increased interest. So that is what we expect in the next year, an increasingly wide and diversified psychedelic research space.

We put together some compelling content sessions for CPHI audiences this year on the potential of the psychedelics market, which is reflective of the increased interest we are seeing. If you heard the keynote address at CPHI Frankfurt—from Dr. David Erritzoe of Imperial College London—you would see that from a trial standpoint we are getting incredibly close to new approvals. The Multidisciplinary Association for Psychedelic Studies and COMPASS Pathways studies in the United States are likely to see approvals of both psilocybin and MDMA, and 70% of the global industry we surveyed expects an approval inside the next three years.

For our content programming and the CPHI annual report, we have focused on what else should be addressed to realize the potential of this sector. Our reports and experts both indicated that the lack of healthcare coverage for the accompanying psychotherapy is perhaps the biggest challenge to wider adoption post-approval. So, initially, we might see approvals but limited patients treated. From a manufacturing point of view, CDMOs with existing schedule 2 licenses will be the biggest beneficiaries, particularly if a payment mechanism can be built into healthcare, as these therapies are likely to be taken over an extended period of time. Then, as synthetic compounds with patent protection come through, profits will increase quickly.

One of the key findings discussed in the CPHI report was the growth of India in key metrics such as competitiveness and finished product manufacturing quality. What is your perspective on India’s potential going forward? How do you feel it compares to the other key raw materials (i.e., APIs and excipients) in China?

Over the last two years, there has been significant thrust on API manufacturing in India, and this is likely to continue. The trend includes Indian companies securing their own value chain by localizing API production as well as private equity funds and strategic investors prioritizing investments in API manufacturing in India. Several Indian companies have strengthened overall competitiveness in API by enhancing the level of backward integration. N-1 is no longer a viable strategy. Sustained competitiveness is likely to be driven by greater value chain strength as well as upstream innovation. Several companies are pursuing opportunities for biotransformation and the sustainability focus is getting more pervasive. For customers seeking to address the Scope 3 goals, this is going to be paramount.

Fair to say, therefore, that India is placed competitively to gain from the current preference and to reduce exposure to Chinese operations. However, in the last two years, contract manufacturing has gained greater favor than direct investment. In addition to API, India is also likely to gain in biologics manufacturing (both drug substance as well as fill-finish) as well as rest of world focused formulations. CDMOs with capability in biologics manufacturing as well as an integrated development platform converging discovery, medchem,

Segment fundamentals in India are being strengthened by upstream investments. However, we are also staring into a looming recession, and, in the post-COVID world, several countries/regions around the world have explicitly laid down plans for domestic manufacturing for pharma to shore up health security. This is likely to result in API investments expanding to global regions not earlier perceived as dominant hubs and the emergence of unforeseen competition. I envision these trends playing out together; and Indian industry is poised for an exciting phase of growth provided they can manage the macroeconomic challenges with foresight, upstream innovation, and astute execution.

Global diversity is now a must have, for any robust supply chain initiative. Hence, there is interest in both India and the West to ensure that clinical trials and commercial supply of medicines remain unaffected by any issues in China. At Aragen, we have had customers come in requesting an independent India-centric manufacturing supply chain that back integrates all the way to the starting material. This ensures security of supply even when a part of the globe gets impacted. India is known globally for its process research and development capabilities and its leadership in the generic supply chain. The same skills translate well for supplying APIs and/or intermediates for innovative therapies.

: We recently polled pharma industry professionals about avenues for potential growth, and two key areas they identified were cell and gene therapies and machine learning and artificial intelligence (AI). Do you agree with these findings? Are there any other technologies in particular that you feel are primed for market growth?

: We have seen similar data in our own CPHI surveys, and it remains a key focus of our content programs. From a manufacturing standpoint, the use of automation and smart factories could be next—while AI is being used to improve hit-to-lead rates in discovery. All of which has been well covered at CPHI in the past few years, the other areas undoubtedly maturing in the next two years are the use of continuous processing in solid dose drugs and improved manufacturing efficiencies in biologics with much better titers.

Another area I would point to, highlighted in our ‘Future of Outsourcing—Strategies for Partner Selection’ report from earlier this year, is the shift away from phase-appropriate development. What this means in practical terms for CDMOs [contract manufacturing and development organizations] is that Phase I is rarely the goal, but rather Phase II and beyond. It means CDMOs now look much further into development when designing processes and chemical pathways. It’s also in some ways a reflection of the way biotechs are spending their funding. So, the CDMO opportunity here is to offer more integrated services—both product and substance—up until Phase II. We already see evidence of this in brand marketing at CPHI Frankfurt and understand that many CDMOs are investing to broaden these capabilities.

We also published another 2023 trend report in which we identified that CDMOs are competing in new ways, with talent acquisition and sustainability now marketed as USPs in addition to typical development services. Perhaps less surprisingly, our report also identified an arms race of acquisitions underway amongst bigger CDMOs for cell and gene therapy manufacturing capacity, and, finally, supply chain technologies are likely to be another big breakthrough trend in the next year.

For more from Dougal and other contributors on their bio/pharma market research, check out 

CPHI Annual Report 2022: Psychedelic Approvals, VC Driven Contract Services Boom and Next Generation Manufacturing

When referring to this article, please cite it as G. Playter. Predicting Pharma’s Future. 

Experts weigh in on trends in the biotechnology market, psychedelics, and India.

Predicting Pharma’s Future

Preventing contaminants from interfering with pharmaceutical operations is critical for the safety of the workers handling the materials and the consumers to whom the final product is delivered. Apart from the self-evident health risks brought about by contamination, the financial risks can be just as dire; management firm McKinsey found that, on average, recalls cost the industry between $2.5 billion and $5 billion per year through non-routine costs and lost sales of new and existing products (1). Moreover, if product contamination results in a recall, the damage will be more than monetary; latent effects, such as consumer and investor confidence in a company, brand, or product must also be considered.

This naturally raises the question of what is being done to prevent contamination in the pharmaceutical field. The following reviews key areas of the pharmaceutical production process to look at what novel techniques, technologies, and policies are being implemented to mitigate the chance of contamination.

When a process is repeated in stainless steel, sterilization is necessary between batches to ensure product quality. Regardless of how this is done, whenever a system is exposed to multiple batches (and, in the case of manually cleaned systems, human intervention) the chance that the process fails to fully sterilize the system exists. This is especially true for lower-grade systems or ones that require complex clean-in-place/sterilize-in-place (CIP/SIP) procedures that require significant, specialized training to correctly perform.

One way in which the industry has begun addressing this issue is through automation. Not only does this eliminate the need for direct human intervention, it simplifies many of the procedural steps that can indirectly affect the cleaning process. Alex Van Hagen, Life Sciences Sector Specialist at Watson-Marlow Fluid Technology Solutions, discussed the impact this can have on the manufacturing process in the “Sterilization’s Horizon: Improving Automation, Single-Use Technologies, and Annex 1” episode of 

t series (2). Van Hagen specifically highlighted the rise of vaporized hydrogen peroxide (H₂O₂) systems in aseptic processing, which has made key advances in its efficacy as a sterilization tool.

According to Van Hagen, companies historically used open-systems where human operators would go in and sterilize the machinery. However, this process opened the gates to massive amounts of contamination risk.

“If you are going to open it up and have people going in and cleaning it, that’s all [well and good],” said Van Hagen. “However, they’re using their hands. Our hands are [how] we interact with the world, it’s the highest bioburden-laden part of our body except for our mouths.”

This method, risky as it is, was one of the cheapest, fastest ways to sterilize bioreactors. However, when an existing patent that was preventing companies from developing faster ways of using H₂O₂ in aseptic production expired in 2002, H₂O₂ emerged as a potentially viable alternative; to this point, multiple days of cleaning were needed to use the chemical. Now, with the advances that have been made in its usage over the past 20 years, it can be done in as little as 30 minutes, making an automated system a feasible alternative to historical practices (2).

With single-use consumables, the chances of prior batch residue contaminating a fresh batch is removed, but the chances for extractables and leachables (E&L) to enter the product is introduced. Because they are made of various types of plastic, rather than stainless-steel, chemicals may now corrode the system and contaminate it, necessitating highly regulated E&L studies to determine what chemicals can be safely delivered through the system. Technological advancements have largely been in increasing the accuracy and speed of these studies. For instance, high-resolution, accurate-mass mass-spectrometers (HRAM-MS) have gained popularity as a tool to understand the structure of unknown compounds.

That said, the E&L field sees significant change through tightened regulatory oversight, albeit in a somewhat unconventional way. While direct changes to regulatory insight do occur, current guidance is not necessarily prescriptive; often, changes come down to changes in interpretation (3). To keep up with ongoing regulatory interpretations, self-governing bodies issue recommendations for E&L testing.

The Product Quality Research Institute (PQRI), one such institution, pushed for several changes in its most recent recommendations, most notably as it pertains to a justification and outline for toxicological evaluation of leachables in parenteral drug products (PDPs) (4). In addition to various other recommended procedures, the organization recommended that a qualification threshold (QT) of 5 µg/day is appropriate for orally inhaled or nasal drug products in the absence of supporting general toxicology data and an identified potential for irritation or sensitization in PDPs. Apart from PDPs, PQRI also issued guidance for unique considerations necessary for biologics (4).

Lastly, cleanroom technologies have also seen some advancements that are changing how researchers work in the cleanroom. Stephen Tierney, president, XiltriX North America, noted that certain technologies have begun to gain greater prominence in cleanrooms. One example of this is continuous particle counting measurements, such as volatile organic compounds, which are becoming more broadly incorporated. Similarly, he also noted that sensors are being put in a single system; analog magnehelic differential pressure sensors, for example, can now be digitally integrated into an environmental monitoring system alongside a room’s conditions and particle counters (5).

As it concerns cutting edge advancements, there are many promising advances that have not yet crested the horizon for widespread use. Alex McDaniel, Environmental Monitoring Program manager, Element, noted that while conventional microbiology testing methods are set to continue seeing use in the near future, rapid microbiology has begun garnering greater interest. Traditional microbiology methods take between 7–10 days, depending on duration of media dual incubation conditions, a painful timeframe that does not take into account the time it takes to identify and report microbial infection. Rapid methods would allow for quicker insight (hours, or even minutes) into the state of batch release for various forms of assays, including raw materials, sterility confirmation, water monitoring, and active air sampling (5).

The Business Case for Medical Device Quality, 

M. Rivers and F. Thomas, “Drug Digest: Sterilization’s Horizon: Improving Automation, Single-Use Technologies, and Annex 1,” 

F. Thomas, “Meeting E&L Expectations,” 

Safety Thresholds and Best Demonstrated Practices for Extractables and Leachables in Parenteral Drug Products (Intravenous, Subcutaneous, and Intramuscular),

G. Playter, “Advances in Environmental Monitoring,” 

Grant Playter is the Assistant Editor for 

Advances in contamination control are being to mitigate the presence of pollutants in drug products.