Challenges, Sustainability, and Big Trends in Outsourcing Today

Drug Solutions

Understanding is crucial to ensure the right balance in manufacturing technologies and proccesses is achieved.

Balancing Change and Certainty in Manufacturing

Obstacles remain before broader application of intensified processes can be implemented.

Formulating Drugs for Continuous Processing

Limitations in production platforms have impeded continuous manufacturing for advanced therapies.

Small Footprint Automated Closed Production Platforms

Considering the differences between small- and large-molecule drug products can help determine analytical testing methods for E&L.

Considerations for Analytical Testing for E&L

Fundamental Constriction Points in Emerging Therapies

Drug Digest

Jill Wechsler is Pharmaceutical Technology's Washington Editor, jillwechsler7@gmail.com.

Confusion recently arose over whether and how Medicare will cover new Alzheimer’s treatments, but the fine print indicates that reimbursement for such medicines still will occur only with the completion of studies to support full FDA approval. And even with that imprimatur from FDA, the Centers for Medicare and Medicaid Services (CMS) will limit reimbursement to patients who enroll in physicians’ registries. While one treatment for this widespread condition may gain full approval next month, accelerated approval status remains insufficient to support reimbursement by the federal government.

 on June 1, 2023 that Medicare will cover drugs in this new class of Alzheimer’s treatment that receive “traditional approval” from FDA. However, the fine print stipulated that coverage will only apply to those who participate in a registry to collect real-world data that can further assess the usefulness of these drugs for elderly patients. CMS ignited controversy in 2022 when it decided to only pay for treatment of those few patients participating in confirmatory studies, under its coverage-with-evidence-development program.

The first drug likely to qualify for full approval is Leqembi from Eisai, which is scheduled for an 

of its confirmatory studies on June 9. FDA granted accelerated approval for the treatment in January, but CMS limited coverage to those patients enrolled in confirmatory trials, as it did earlier with Biogen’s Aduhelm. In addition, Eli Lilly hopes to provide sufficient data to gain full approval for its Alzheimer’s therapy by year-end.

 Alzheimer’s Association protested CMS’ requirement 

for registry enrollment as erecting “an unnecessary barrier” to coverage. While patient registries are “important tools for gathering much needed real-world evidence” to improve patient care, they should not be used to limit access to an FDA-approved treatment, the patient advocates stated.

(BIO) described CMS’ policy as reinforcing criticism of FDA accelerated approval and raised concerns that these challenges to accelerated approval will limit patient access to treatment and curb future innovation.Some members of Congress and patient groups agree with FDA on the importance of permitting broad access to potentially beneficial treatments, especially for severe conditions affecting small patient populations.

It really all comes down to money: the high cost of new Alzheimer’s treatments and potentially millions of patients likely to seek treatment would run up Medicare prescription drug budget exponentially.

Articles

Reimbursement for Alzheimer's medicines still will occur only with the completion of studies to support full FDA approval.

Medicare Still Won’t Pay for Alzheimer’s Drugs without Confirmatory Data

Adamis Pharmaceuticals announced the closing of its merger with DMK Pharmaceuticals on May 25, 2023.

The focus for the closing is the effort to increase sales of Adamis’s commercial products and advancing DMK’s lead clinical stage compound, DPI-125, which is being studied as a potential novel treatment for opioid use disorder (OUD). Further, the stock of Adamis will continue to trade on the Nasdaq Capital Market under the ticker symbol “ADMP.” In addition, Ebrahim Versi, CEO of DMK, was named CEO and Adamis and chairman of the Board of Directors at the close of the merger.

“We are very excited about this merger, as I believe that the combined company will make a significant contribution to saving and improving the lives of people suffering from opioid use disorder,” said Versi in the press release. “Too many lives are cut far too short, and families are devastated by this disease, and we need to act urgently to reverse this epidemic. ZIMHI, I believe, is the most effective naloxone medicine to reverse fentanyl overdoses and my goal will be to make this our flagship product and to build on that with our novel first-in-class compound, DPI-125. Not only does it have the potential to treat patients with opioid use disorder but also, I believe, to prevent it when used as a potent analgesic, thus obviating the need for use of opiates. The global opioid market in 2021 was reported as being greater than $22 billion. Given the differentiated profiles of these agents, along with our large portfolio of novel compounds, I see a bright future for the company.”

In preparation of the closing of the merger, which happened on May 22, 2023, Adamis effected a 1-for-70 reverse stock split of all its issued and outstanding shares of common stock. Further, all outstanding options, restricted stock unit awards, and warrants were proportionately adjusted, following their respective terms.

Adamis Pharmaceuticals Closes Merger with DMK Pharmaceuticals 

After more than a decade of debate and discussion, FDA has published a new system for providing basic and essential information on patient use of drugs and certain biologic products. A 

new one-page Patient Medication Information (PMI) guide

 would replace the more complex and lengthy Patient Package Inserts (PPIs) now distributed in pharmacies dispensing prescription medicines.

The aim of the new program is to reduce drug misuse and adverse reactions by providing accurate information on product indications and uses to help people take prescription medicines safety and effectively,

in unveiling the new proposal May 30, 2023. Currently, the different types of information on prescription drugs as now required can be confusing and prompt patients to stop taking medications or to use them inappropriately, leading to treatment failures, hospitalizations and even deaths.

a one-page document that highlights essential information on product use and would be given to patients with their medications, including certain biological products provided in outpatient settings. The information also will be available online for public access. FDA anticipates that by reducing duplicative information, the new system will be more cost-efficient for drug and biotech manufacturers. The new format also will support translation of PMI to other languages and facilitate the use of technologies to convert the information to additional formats. FDA estimates that its proposal would cost approximately $20 million a year to implement, but would yield greater benefits and savings, largely from safer and more appropriate use of medicines.

To realize such gains, sponsors of new drugs will seek FDA approval of PPIs as part of new drug applications (NDAs) or biologics licensed applications (BLAs). In addition, manufacturers of already approved medicines will have to revise existing patient information documents and file supplemental applications to gain PMI approval. The greater burden on industry will involve updating systems for printing and packaging PMIs with medicines, an undertaking that has generated objections to previous FDA proposals for revising required information for patients. To facilitate these changes, the agency outlines a five-year implementation schedule, as it calculates that sponsors would have to submit labeling supplements for more than 2600 existing drugs and more than 1600 new drug applications.

Generic-drug makers face added complexities in converting current medication information to the new format, as they will have to refer to new PMIs of their reference listed drugs, once those are submitted to and approved by FDA. The agency says it will facilitate this process by creating PMI templates for approved abbreviated new drug applications if the reference drug has been withdrawn or lacks an approved PMI.

In recognition of the issues raised from past proposals, FDA requests comments from industry on the usefulness and appropriateness of this latest patient information plan, the accuracy of the agency’s estimate of the burden and cost of providing the requested information, ways to improve the PMI proposal, and strategies for a reducing the burden of collecting the requested information. Industry has six months to submit comments.

Jill Wechsler is Washington reporter for 

FDA has published a new system for providing basic and essential information on patient use of drugs and certain biologic products. 

FDA Proposes Streamlined Medication Handouts

In a competitive outsourcing market, contract development and manufacturing organizations (CDMOs) are always searching for the best ways to serve their clients. CDMOs and other contract organizations will look to industry to determine where they should invest in their services and facilities, and successful CDMOs will pivot to meet industry needs.

In this vein, successful CDMOs are perhaps one of the best sources for insight into trends not only into the outsourcing sphere, but the entire pharma industry. This article will explore the factors CDMOs view as important in landing pharmaceutical clients, and what one can infer regarding the state of the industry from them.

A stray observer attending just about any pharma conference would likely be struck by a phrase CDMO representatives seem to repeat again and again: end-to-end services. In 

®’s coverage of the 2023 DCAT conference alone, representatives from Thermo Fisher Scientific (1), CordenPharma (2), and Quotient Sciences (3) stressed that their company offered end-to-end services. Sarah Stevens, senior vice-president and head of Drug Product Development & Manufacturing at Quotient Sciences, even made the case that we would see this marketing increase further over the course of the next few years.

“Thinking about it from the CDMO and pharmaceutical services perspective, I think we will see this continuing direction of travel towards offering a fully integrated end-to-end service,” said Stevens (3). “I think almost all CDMOs will be at least claiming to offer integrated, end-to-end services.”

In large part, end-to-end services are receiving abundant attention because they satisfy two interconnected core criteria: supply chain anxiety and flexibility. Existing issues of the just-in-time supply chain model were shattered by the COVID-19 pandemic, leaving manufacturers who were dependent on multiple companies in multiple countries for different steps of the drug development, manufacturing, and packaging process scrambling to maintain their manufacturing processes (4).

This situation presented CDMOs with a unique opportunity: companies offering both drug substance and drug product services could now pitch themselves on the virtue of supply chain redundancy, which was now in demand. While this hasn’t necessarily been entirely transformative—many CDMOs, in particular small-to-mid sized operations, will almost certainly continue to specialize in certain steps of the manufacturing process—it has become an increasingly viable way to get one’s foot in the door. And should the pitch land, it presents a stronger value proposition for the CDMO, as they have the added leverage because they are more deeply integrating themselves into their partner company’s operations.

However, as Stevens somewhat alluded to in her quote, an end-to-end service needs to satisfy the many complex needs of its partner company. While many companies advertise their end-to-end capabilities on paper, they often do not have the existing capabilities to serve all potential clients. In a DCAT roundtable on the topic, Enrico Polastro, vice-president and senior industry specialist, Global Pharmaceutical and Fine Chemicals Practice, Arthur D. Little, noted that end-to-end companies are “unlikely to be able to offer the full range of molecule building and formulation capabilities covering the entire spectrum of pharmaceutical products” (5).

This is where manufacturing flexibility comes into play. While it is difficult to cover the full spectrum of needs, the more one can offer, the more enticing that becomes to potential clients, as it allows the partner company to operate more broadly and trust that changes can be made on the backend to accommodate any necessary changes. Furthermore, establishing a relationship with an outsourcing company that can address various needs may be desirable for companies who anticipate expanding into various types of drug products, as it gives them the option to return to a familiar process that has previously addressed their needs.

“Outsourcing partnerships that prioritize flexibility enable companies to quickly adapt to market changes,” says Nandu Deorkar, senior vice-president, Research & Development, Avantor. “In a fast-paced industry like pharmaceuticals and biotech, market demands can change rapidly, and companies that can quickly adapt have a competitive advantage. By having a flexible outsourcing partner, companies can adjust their operations promptly to meet changing market demands and stay ahead of the competition.”

This flexibility can take many forms. For instance, according to Deorkar, manufacturing agility, scalability, and collaboration are all crucial factors, in addition to technical expertise and demonstrated capability. Ultimately, what is crucial is starting a dialogue that enables an outsourcing company to efficiently and capably respond to the needs of its partner; end-to-end capabilities are one such answer in the current broader pharmaceutical market.

Another corporate structure that has received increased attention among CDMOs is the push toward sustainability operations. On the surface, this move works well purely from a public relations perspective; a 2021 Pew Research study found that 80% of respondents in 17 advanced countries were willing to make “a lot” or “some” changes to how they lived or worked in order to fight climate change (6). Even as it pertains to the United States, which has historically fought over the issue, as of April 2023 69% of Americans believe the country should invest in renewable resources and strive toward carbon neutrality by 2050 (7), and the United States government has passed major legislation geared toward energy sustainability (8).

“Outsourcing companies are placing an emphasis on their sustainability practices to showcase their commitment to social responsibility, which can also improve their reputation and brand image,” says Deorkar. “Consumers are becoming more aware of environmental issues, and they prefer to purchase products and services from companies that prioritize sustainability.”

All that said, while the preferences of the general public should be noted—particularly as public opinion places a key role in shaping legislation—their direct impact on business-to-business interactions is difficult to directly
link. However, an understated impact of sustainability measures is in how they confer an economic benefit to businesses that use them.

, Pierre Luzeau, CEO of Seqens, an outsourcing company specializing in pharmaceutical synthesis and specialty, noted that customers were specifically looking for partners who could help them reach sustainability goals like carbon-zero (9). Luzeau argued that it was such a strong factor in business decisions that failing to hit that benchmark, or at least work toward it, could be a death sentence.

“We are convinced that the selection of suppliers will be based on the best supplier from that standpoint,” said Luzeau. “If you are not capable of proposing the best solution as far as [corporate social responsibility] is concerned, you will disappear in the 10 years’ timeframe—this is for sure.”

The economic reasons for this are multi-faceted. First, as public opinion continues to favor environmental sustainability measures, the likelihood of government-subsidized energy programs and fines for energy inefficient processes rises. Companies that cannot get ahead of anticipated regulations in a timely manner will be deemed more inflexible in that regard than their competitors.

From a strictly cost-savings perspective, energy initiatives reduce energy consumption and waste. Sustainability and efficiency are inextricably tied, and there are measurable savings that occur from energy and waste reduction.

For example, while the fixed costs on solar panels are significant at the beginning, with enough time one can recoup those costs and more. Furthermore, anticipated advances in energy-saving technology could pave the way for “alternative energy” to simply become “energy,” as Jason Lomberg, North American editor at Power System Designs, succinctly notes in “The Elusive ‘Break-Even’ Point for Alternative Energy.”

“In the very near future, solar—and other technologies with an unforeseen ‘break even’ point might shed the ‘alternative’ label and just be an extremely viable form of energy,” said Lomberg (10).

While this article has tackled what CDMOs are placing an emphasis on, one might notice one factor that is not being discussed: cost. In many private sector negotiations, regardless of other qualifications, the lowest bid often gets the job. However, pharma
marketing tends to steer clear of this topic—no CDMO is publicly advertising
themselves as a “budget” option.

There are multiple reasons for this. George Ntortas, partner at Fuliginous Management Consulting, a consulting firm that works with companies operating in the CDMO space, neatly summarized the inherent variability of the CDMO pricing structure in a feature he wrote on LinkedIn. In the feature, Ntortas explained that various factors, including the type of manufacturing being performed, the degree of difficulty of the task, whether competitor’s have similar capabilities, and dozens of others all impact price in some form or fashion. Production for a generic paracetamol tablet might only need to be
sold at a 60% mark-up, whereas lyophilized patented vial may be in more of a ballpark of 90% (11).

“Margin is not the only factor affecting what is the willingness of a pharma company to pay. Culture, location, quality, cooperation, responsiveness, and flexibility of the CDMO also affect customers’ willingness to pay,” said Ntortas. “If the pharmaceutical company is satisfied with the service level they get from a CDMO, if they feel that they are important and their supply is secured, they are probably ready to sacrifice part of their margin as opposed to choosing a CDMO with a lower price but also a lower service level and higher supply risk.”

It is because of the inherent variability of the types of projects, customers, and deadlines that CDMOs deal with that leads to cost differentials. If a CDMO were to advertise itself at one price, it would almost certainly be wildly overcharging or undercharging most of its clients; either way, it would soon be out of business. While cost might not be pushed to the forefront of marketing, it is still very much a consideration—but it is one that is dependent on variables that need to be ironed out in negotiations.

“While cost is undoubtedly an essential factor to consider in outsourcing partnerships, it should not be the sole focus,” says Deorkar. “Successfully bringing a drug to market or clinic requires more than just cost reduction. Technical expertise, scalability, and flexibility are also crucial capabilities that can significantly impact the success of an outsourcing partnership. Companies may sidestep cost discussions in public because it’s a sensitive topic, but it’s still an important consideration in the decision-making process.”

1. Playter, G. Discussing the Growing Role of CDMOs with Anil Kane. 

, March 29, 2023.
2. Playter, G. Illuminating the State of Outsourcing with Stephen Houldsworth. 

, March 27, 2023.
3. Playter, G. Exploring the Future of Outsourcing with Sarah Stevens.

, April 28, 2023.
4. Spivey, C. Drug Solutions Podcast: Securing Manufacturing Independence Through Re-shoring Facilities to USA. 

, March 1, 2022.
5. DCAT Value Chain Insights. Straight Talk: End-to-End CDMO/CMO Business Models. 

 July 24, 2019.
6. Bell, J.; Poushter, J.; and Kennedy, B. In Response to Climate Change, Citizens in Advanced Economies Are Willing To Alter How They Live and Work. 

, Sept. 14, 2021.
7. Tyson, A.; Funk, C.; Faigan, M.; and Huang, C. What the Data Says About Americans’ Views of Climate Change. 

, April 18, 2023.
8. H.R.5376, US House of Representatives, 117th Congress, 130th Session (Washington, DC), Sept. 27, 2021
9. Playter, G. Setting Sustainability Goals with Pierre Luzeau. 

, March 30, 2023.
10. Lomberg J. The Elusive “Break-Even” Point for Alternative Energy. 

, May 30, 2017.
11. George Ntortas. Pricing in the Pharmaceutical CDMO Environment. 

Pharmaceutical Technology
Vol. 47, No. 6
June 2023
Page: 16-18

When referring to this article, please cite it as Playter, G. Governance of Future Pandemics. 

What factors do CDMOs consider vital to their success?

The Outsourcing Success Story 

Editor of Pharmaceutical Technology Europe

By the end of 2022, biologic-based drug approvals accounted for a slightly larger proportion of approvals than the number of small-molecule new molecular entity approvals (1). With this shift in focus for the industry toward more complex molecules that are prone to degradation comes an increased need for more careful manufacturing processes that can ensure contamination-free end products are made.

Largely driven by this exponential increase in demand for biopharmaceuticals, the aseptic pharmaceutical processing market is estimated to grow at a compound annual rate of 7.9% between 2021 and 2031 (2). “During the past few years, sterile drug development and production has grown significantly as a consequence of the type of products that are coming to the market—biological drugs, advanced therapies, and so forth,” concurs Rafael Beaus, global consultancy manager, Telstar.

For David Stevens, global chief commercial officer, Kindeva Drug Delivery, a combination of factors is impacting aseptic and sterile drug manufacturing. In response to the increased focus on more challenging molecules, innovators have been using more advanced formulation strategies, he explains.

“Additionally, the need to optimize production costs of medicine, including even the most innovative biologics, has been further heightened by recent global inflation, which has ratcheted up pressure on the pricing power of pharmaceutical marketers already being challenged by government downward pressure on drug reimbursement costs,” Stevens continues. “Even in the [United States], historically, the most amenable to pharma drug pricing—payors—have consolidated their buying power, and pharmaceutical companies and healthcare industry-wide are having to adjust to the reality of a more cost-conscious environment.”

As a result, Stevens notes, growth in more specialized, targeted, and precision treatments is being seen, as these types of therapies can provide options for previously untreatable conditions or offer payors more sustainable value for their therapeutic costs. “The implication for sterile drug product manufacturers is a growing shift toward products that require meaningfully smaller production batch sizes and more complex manufacturing processes,” he says.

In addition, the recent COVID-19 pandemic has hastened the uptake of patient self-management, leading innovators toward development of novel products that differentiate them from their competitors and allow patients to administer therapies at home with the same level of safety as in the clinical setting, Stevens remarks. “This [trend] has propelled growing interest and demand for pre-filled syringes and autoinjectors, which provide patients with the convenience and simplicity of user-friendly devices with pre-defined volumes and efficient low-waste doses outside of a clinical setting, which in turn offers reduced cost and differentiating proof points for patients and payors,” he states.

Looking at technology, Joerg Zimmermann, vice president Vetter Development Service, External Affairs, reveals that there is a clear trend toward more automation and the introduction of robots in aseptic manufacturing, along with digitalization of all processes via the Internet-of-Things or Pharma 4.0. “All this [change] is leading to even more robust and safe processes for manufacturing sterile drug products,” he says.

Keeping people, who are the main contamination source in aseptic manufacturing, out of the critical areas where a product is exposed is becoming a more pressing concern for industry, stresses Beaus. “This [demand] means that automation is being required more in aseptic processes, as well as the use of closed systems and engineering solutions to provide maximum safety to products,” he adds.

“Obviously within GMP [good manufacturing practice], there is a continuous pursuit of greater levels of patient safety, which, for injectable medicine, translates to pursuing even greater levels of sterility assurance that naturally leads to engineering innovations to minimize direct human intervention in the production process,” specifies Stevens. “Most notably, however, the EU [European Union] GMP Annex 1: Manufacture of Sterile Medicinal Products update, published in August 2022, clarified expectations for sterile products that reinforced contamination control requirements and emphasized the role of engineering out associated risks using technology where possible” (3).

The issuance of the revised Annex 1 guidance came after two long commenting phases and will be largely coming into effect in August 2023, Zimmermann reveals. “While some say that it is nothing new in terms of content, the regulation has become much more prescriptive, and this is currently raising the question of what the right interpretation is,” he says. “As Annex 1 is not only published by the EU, but also adapted almost identically by WHO [World Health Organization] and PIC/S [Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme], this will be the global standard going forward.”

Interpreting the revised Annex 1 guidance document will prove to be the biggest challenge for companies dealing with aseptic manufacturing in the near future, Zimmermann stresses. “While the consultations between regulators and members of the industry were successful on several issues, some paragraphs can be misunderstood. It is therefore of the utmost importance to understand the intent, and this is being worked on in conferences, seminars, and symposiums,” he states.

Beaus adds that, in light of the revised guidance, companies will need to improve their know-how of new facility design to ensure they are fully compliant moving forward. Furthermore, challenges will arise when existing facilities are upgraded to meet the new regulatory expectations while also maintaining sufficient production, he emphasizes.

“With greater regulatory compliance demands, including the wide-ranging aseptic processing and contamination control strategy implications of updated GMP Annex 1 guidance, pressure on older facilities with older lines will be appreciably felt, accelerating a shake-up of market players that is likely to increase pressure on already limited high-quality capacity,” agrees Stevens. In anticipation of the impact these regulatory changes will bring, pharma innovators have already started to demand the use of best-in-class fill/finish technology within internal and external manufacturing supply chains, particularly for innovative pipeline products, he confirms.

Another obstacle that has impeded the industry over the past few years, particularly during the pandemic, has been shortages of certain materials, such as single-use systems, bags, filters, and so forth, in the supply chain, notes Zimmermann. Although, this issue has mostly been resolved now, he states.

The shortage of gamma-sterilization capacity has also caused some difficulties, Zimmermann continues. “The combination of higher demand and the scarcity of cobalt-60 have led to a fundamental rethinking of the choice of sterilization methods. Alternatives are being introduced, with X-ray sterilization becoming a popular choice,” he says.

“While a lot of large-scale capacity was brought quickly into the market during the pandemic, there is a lack of capacity for smaller, more specialized products, particularly when looking at the rise of mRNA [messenger RNA] therapeutics and other newer modalities,” confirms Stevens.

Newer modalities, such as advanced therapeutic medicinal products (ATMPs), which include cell and gene therapies, pose unique challenges for manufacturers, Zimmermann points out. “Many [ATMPs] are autologous, meaning that patient-derived cells are being modified and reapplied to the patient. This is the so-called batch-size 1, and the processes are more comparable to microbiological lab processes than industrial processes,” he says.

“Finally, acute downward pressure on generic injectable medicines, as reflected in the drug shortage list, has created an imperative toward improving manufacturing efficiency, further amplifying the need to adopt high-throughput, faster lines that take advantage of automation and isolator technology,” Stevens emphasizes.

For new facilities, more importance is being placed on isolators and automatic processes, with many manual operations being replaced, Beaus remarks. “All-in-all, new facilities are being designed to allow visitors to view the main operations from the outside,” he says.

In the case of existing facilities, however, companies need to upgrade the existing equipment, revamp areas, and implement automated solutions to continue production that complies with new requirements, Beaus adds. “There’s room for increasing the automation level in existing facilities to be able to skip most of the current manual operations. The balance between investment needed and product safety is what is difficult, as automation is quite expensive, making it difficult to justify the return on investment,” he states.

As an example, Stevens highlights Kindeva Drug Delivery’s newly constructed aseptic manufacturing facility in Bridgeton, Mo., where the company has adopted isolator technology as standard to offer optimum aseptic operating principles for the manufacture of sterile injectables. “Single-use technology has also been a game-changer for multiuse/multi-product facilities in terms of room turnaround and the elimination of reliance on cleaning methods, assuring there is no carryover from product contact surfaces,” he specifies.

“There is a trend to move toward more automation of aseptic processes,” concurs Zimmermann. “Transfers between processing steps can be realized with robots or automatic transfer systems, and there is a clear recommendation in Annex 1 to automate the loading and unloading of lyophilizers.”

Decontamination of cleanrooms is another area where automated solutions are providing benefits, Zimmermann remarks. Using Vetter as an example, he highlights the Vetter Cleanroom Technology, V-CRT, which is a fully automated system designed to fully decontaminate conventional restricted access barrier systems grade A/B rooms, allowing for optimized contamination control in critical zones.

“While gloveless isolators were first introduced a decade ago, there are further developments being done to optimize the systems with even more automation, including robotized microbiological environmental monitoring and avoiding contact of H

 [hydrogen peroxide] with the packaging components,” Zimmermann continues.

In the future, manufacturers will face hurdles as a result of the growing number of small-batch targeted biologics entering the pipeline because most commercial capacity has been designed for larger, recurring volumes, Stevens specifies. “Additionally, the complex and expensive drug substance production processes required for high-value biologics, such as mRNA and viral vectors, will further drive the goals of maximizing sterility assurance to minimize risk of batch failures,” he says.

Although in agreement that personalized medicines, developed in small facilities close to or even inside hospitals, with significantly high-value products will be a certain trend requiring flexible facilities, Beaus also believes development will occur for more common products too. “There will be [highly] efficient specialized facilities, that are [significantly] automated, where most common aseptic and sterile products are produced as commodities, with maximum safety for product, but at the same time achieving low cost per every produced unit,” he says. “This trend may be applicable to vaccines, large volume parenterals, or some other general sterile products.”

“Further trends are definitely in the artificial intelligence space, particularly regarding automated visual inspection,” Zimmermann states. Currently, the naked eye remains a reference point within this area of the process, so digital camera systems will offer huge assets in the future, he notes.

“Manufacturers face the challenge of being flexible to stay in touch with evolving requirements for new drug-delivery approaches, be that in more complex formulations or in administration methods,” Stevens concludes. “For manufacturers, the task is figuring out how flexible they need to be to meet this trend.”

1. Senior, M. Fresh from the Biotech Pipeline: Fewer Approvals, but Biologics Gain Share. 

, 41 (2), 174–182.
2. Research and Markets. 

Aseptic Pharma Processing Market—Global and Regional Analysis: Focus on Product, Technology, Regional, and Country Analysis—Analysis and Forecast, 2021–2031

Volume 4, Guideline, Final Version, Aug. 22, 2022.

Felicity Thomas is the European/senior editor for Pharmaceutical Technology Group.

When referring to this article, please cite it as Thomas, F. Facing the Future of Aseptic Manufacturing. 

Manufacturers must figure out how flexible they need to be to meet the numerous new requirements of the changing therapeutic and regulatory landscapes.

Facing the Future of Aseptic Manufacturing

James Vesper, PhD, MPH  is director, Learning Solutions at ValSource,
Jvesper@valsource.com.

Amanda McFarland, MSc is senior QRM and Microbiology consultant at ValSource.

Quality risk management (QRM) is being performed more frequently in the pharmaceutical industry due to expanded requirements by health authorities like FDA, the European Medicines Agency (EMA), and members of the Pharmaceutical Inspection Cooperation/Scheme (PIC/S).Because of this, it is reasonable to anticipate that stakeholders and leaders within a pharmaceutical organization would want to examine indicators related to how well the risk management process is progressing, ways to improve the execution of risk assessments, and the impact that a particular risk assessment had—or did not have—on the affected product, process, or business unit.Evaluation of a QRM exercise is not a stated requirement in either International Council for Harmonisation (ICH) Q9R1 or in the ICH Q10 Pharmaceutical Quality System document. Evaluating a QRM activity would, however, be an effective way to help demonstrate management’s commitment to quality and the organization’s quality system that is stated in ICH Q10:

(1)Participate in the design, implementation, monitoring and maintenance of an effective pharmaceutical quality system; …

(5)Conduct management reviews of process performance and product quality and of the pharmaceutical quality system;

(6)Advocate continual improvement” (1).

Evaluating QRM actitivies can also aid decision makers in achieving the objectives outlined in ICHQ9R1 (2).

Take responsibility for coordinating quality risk management across various functions and departments of their organization

Assure that a quality risk management process is defined, deployed, and reviewed and that adequate resources and knowledge are available

Assure that subjectivity in quality risk management activities is controlled and minimized to facilitate scientifically robust risk-based decision making” (2).

While several methods have been described for evaluating the components or maturity of a risk management program within an organization (3–5), a structured method to evaluate a single risk management activity (including assessment, evaluation, reduction, communication, and review/monitoring) has yet to be published. To be useful, an evaluation approach should have the characteristics of being objective, simple to use, not requiring a significant increase in workload, addressing the life cycle of a risk management exercise, and providing reliable feedback that could be used to improve the risk management process.Such an evaluation approach could be based on an evaluation method well known to those involved in training: the Kirkpatrick Model.

For those involved in organizational training, learning, and development, two important activities are assessment and evaluation. While assessment and evaluation can be done in various ways, a well-accepted schema was developed in the 1950s by a then PhD student, Donald Kirkpatrick (6). The “Kirkpatrick Model” as it is known today consists of four levels (

) that can provide information concerning what the participant(s) has learned, the instructors, the course itself, how participants are applying the learnings in their work activities, and the effect that the learning has had (or not) on the organization. The most recent version of the model is quite similar to the original but has been updated to clarify the terms and its application. Unifying these four levels is the concept of “return on expectations” that connects the learning event with the goals (i.e., expectations) that both learners and leadership have of the event.

Table I. Four levels of the Kirkpatrick Model of Assessment and Evaluation (6).

The Kirkpatrick model can be used in different ways, specifically in formative (making improvements) and summative (making decisions) applications. When used formatively, the results help improve the process of learning (e.g., obtaining feedback on how easily [or not] a user was able to move through an e-learning course and then making changes to make the interface more intuitive and easier to use). In a summative application, decision makers look at outcomes (e.g., determining if the learner has met a defined standard and is qualified. Or, for instance, deciding if the learning solution or training course should be released for wide-scale use). 

presents Kirkpatrick levels and questions asked for formative and summative applications related to training.

Table II. Four levels of the Kirkpatrick Model of Assessment and Evaluation applied in formative and summative situations.

As mentioned earlier, practitioners of QRM and leadership have an interest in determining if the outcomes of QRM are successful in their organizations as well as finding ways of improving the execution of a risk assessment and ensuring that subjectivity is minimized. Making simple modifications to the Kirkpatrick model and applying those to the risk-management lifecycle is discussed as follows.

While other models and tools exist to support business process and software development and improvement such as the Capability Maturity Model Integration (CMMI) (7), the approach presented here is narrower in scope, simpler to use, can be adapted easily to the specific needs of an organization, and does not require external resources for support.

The initiation and risk assessment phases typically involve a team of subject matter experts that is often led by a trained facilitator.The results of the assessment are evaluated to determine which risks meet the criteria of “significant” risks requiring reduction through the application of controls and mitigations.Monitoring and review are incorporated to determine if the controls are effective and if any of the facts or assumptions used in the risk assessment have changed.

QRM practitioners and leaders who oversee the risk management process and the execution of specific risk assessments might ask a number of formative and summative questions concerning the QRM activities.These can be placed into four categories that are similar to the four levels of the Kirkpatrick Model and are shown in 

Table III. A four level evaluation model applied to quality risk management (QRM).

The example questions above and elsewhere in this paper are based on what a risk management practitioner might ask; however, leadership at a particular organization might have other success criteria or indicators that they believe to be important.Perhaps, for example, it might be that each team member participated in 90% of the risk team meetings or that the report was reviewed and approved in a given time period. These expectations can be easily included in the evaluation process to track and trend metrics.

When evaluating learning outcomes as well as risk management outcomes, one is looking for evidence or indirect measures, not necessarily “proof” or direct measures. Obtaining qualitative and quantitative data from a variety of methods and from different perspectives can provide a multi-dimensional understanding of how well the methods, processes, and activities are meeting the desired goals.Examples of methods that can be used for the four levels are described as follows. As will be shown, some of the activities are already included in the risk management life cycle but are not used in evaluation of a specific risk assessment to make improvements.

Surveys can be taken at multiple time points during an extended risk assessment (for large projects, risk assessments sometimes last for months) providing the facilitator information to make team meetings more effective.Reaction surveys can also be done at the end of the project with the results applied to the next risk assessment performed to aid lessons learned and knowledge management. Level 1 evaluations can be either paper-based or e-surveys using a Likert Scale of 1 to 5 with 5 being the best and asking questions about the assessment process, such as:

Are the goals of the overall risk exercise clearly explained?

Do all members of the risk assessment team have an opportunity to contribute to the assessment?

Are all participants prepared to contribute to the assessment?

Is the facilitator prepared to contribute to the assessment?

Does the facilitator effectively facilitate (i.e., make the assessment process as simple as it could be)?

The questionnaire could also ask for specific examples of good practice and suggestions or ideas of where improvements could be made. As mentioned above, other stakeholders may have additional expectations to include in the evaluation.

 This evaluation would be completed at the end of the risk assessment and when risk reduction controls have been prescribed.When the risk assessment phase has been completed, an experienced risk assessor or expert could examine the spreadsheets or reports from the team to determine if a risk question was properly written and used; and if the team logically and consistently identified the hazard (the source of harm), what caused that hazard to be expressed (the hazardous situation), and the impact of the harm.The expert could also review the key-word scales that were used to determine if they were applied consistently. Subjectivity can be minimized through the use of well-defined scales and reviewing their application is crucial to ensuring that heuristics and bias did not skew the outcome of the assessment.

After the risk evaluation and risk reduction phases, an expert could look at the causes of the harm and the controls to determine if they are properly aligned, that is, if the controls are appropriate and matched to the causes. This phase is also an important step to ensure that a robust set of controls have been identified to address the root cause of the hazard and that the team adequately brainstormed a combination of controls, where necessary, to aid in continuous process improvement.

In a summative mode, if the documentation met the requirements, it could be approved; in a formative mode, ways to improve the process through a redesign of the forms used to collect knowledge obtained through the risk assessment or by incorporating additional guidance in a job aid could be noted.In practice, the quality unit typically gives what amounts to a summative evaluation when they officially approve the risk documents.

 This level of evaluation considers if the results of the risk management exercise, specifically the risk controls that have been identified to reduce the risks, have been successfully implemented. This is often done through the corrective action/preventive action (CAPA) system which is integrated with a change control process.

This evaluation could consider the timeliness between identification of the controls and their being fully implemented.For those controls that would take considerable time (e.g., designing, constructing, installing, and qualifying a piece of complicated equipment), interim controls may be appropriate to reduce risks to some degree and maintain a state of control.Qualification activities that show the method or equipment works as intended, that training was provided and applied by personnel, and that relevant procedures were revised and approved could also be indicators (i.e., evidence) of successful implementation.

In practice, these activities are often considered when confirming a CAPA has been successfully completed through what is known as an “effectiveness check.”

This is the most challenging level when considering a QRM exercise because, if the risk management activity was successful, you would not see a deviation, failure, or other unwanted events. Specifying the goal(s) (or stakeholder expectations) of the risk management exercise at the outset can make this step easier. In the ICH Q9 model, this is done during the risk review/risk monitoring phase, an activity that is often overlooked or given short-shrift (8).

If there has been a historical rate of the unwanted events, say a specific root cause resulting in a deviation or product recall, that rate could be compared to the rate after the new controls were put in place. Another view of results would be if new hazards or failure modes were found after the risk assessment was completed that could indicate the assessment team did not have sufficient experience with the process under review at the initial onset of the assessment. If the results of the risk management exercise could be applied to other sites, products, or platforms, or if a risk assessment would contribute to process understanding, these could be positive indicators of success and benefit.

For learning professionals, it is rare to apply all four levels to all learning solutions or training courses. Level one is most widely used, and to a lesser extent, level two. Level three, transfer/implementation is sometimes determined not by learning personnel but by auditors and inspectors who discover if the training in a task or procedure is being properly used back in the workplace. In a QRM setting, the amount of evaluation could be based on the importance of the risk management activity being executed.

For decades, the Kirkpatrick Model has helped learning professionals make formative and summative decisions.This model can be adapted and applied to QRM programs and meets the criteria of being simple to use (i.e., answering basic questions); not requiring a significant increase in workload (i.e., some of actions are already taking place during review/approval and monitoring), addressing the life cycle of a risk
management exercise (i.e., done at multiple points), and providing information that could improve the risk management process (i.e., through the use of formative questions).

As regulators increase their requirements on the use of QRM in the pharma and biopharma industry and be more proactive and less reactive, it is important that the industry execute these assessments as efficiently and effectively as possible. Using the four-phased method described here can contribute to continual improvement and meeting the expectations of both the organization and the regulators.

Appreciation to Hal Baseman, Dr. Umit Kartoglu, and Dr. Kelly Waldron for their valuable comments on early drafts of this article.

, Step 4 (ICH, 2008). ICH.org(accessed Jan. 23, 2023).

. (accessed Jan. 23, 2023).Management Study Guide. Risk Management.

https://www.managementstudyguide.com/evaluation-of-risk-management-plan.htm

PIC/S. Aide Memoire:Assessment of Quality Risk Management Implementation.2021.

Waldron, K. Managing Risk to the Patient: Recoding Quality Risk Management for the Pharmaceutical and Biopharmaceutical Industries. 2017.

Kirkpatrick Partners. Where Did the Kirkpatrick Model Come From? 

https://www.kirkpatrickpartners.com/the-kirkpatrick-model/

Vesper, J. and O’Donnell, K.Current Challenges in Implementing Quality Risk Management. 

 2016 36 (6), pp 73-80(accessed Jan. 20, 2023).

James Vesper, PhD, MPH (corresponding author) is director, Learning Solutions at ValSource, Jvesper@valsource.com. Amanda McFarland, MSc is senior QRM and Microbiology consultant at ValSource.

This article was peer reviewed by a member of 

 Editorial Advisory Board.
Submitted: March 30, 2023.
Accepted: May 2, 2023.

When referring to this article, please cite it as Vesper, J. and McFarland, A. A Four-Phased Approach for Evaluating a Quality Risk Management Activity. 

Using the four-phased method to assess QRM can ensure continual improvement and that regulatory requirements are met.

A Four-Phased Approach for Evaluating a Quality Risk Management Activity

Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.

Numerous pharmaceutical companies from startups to well-established firms are exploring the potential of cannabinoid-based drug substances as therapeutic agents for the treatment of a wide range of disease indications. Developmental cannabinoid medications must follow the same approval pathway established for all other small-molecule drug candidates. Early in 2023, the agency also determined that a new regulatory pathway for cannabidiol (CBD) products is needed that “balances individuals’ desire for access to CBD products with the regulatory oversight needed to manage risks” (1). “Smart companies,” says Jordan Tishler, president and CEO of inhaleMD, President of the Association of Cannabinoid Specialists, and an Instructor of Medicine at Harvard Medical School, “will see the value of following the pharmaceutical pathway and pursuing clinical trials and FDA approval, while the rest will simply make recreational products.”

Regardless of whether companies are seeking to develop therapeutics or dietary supplements based on cannabinoids, they face the challenge of realizing effective delivery of these highly hydrophobic compounds. “Cannabinoids present many of the same difficulties that other poorly soluble and/or absorbable APIs present,” states Gavin Chandler, CEO of Trokie, a company working on novel delivery systems for cannabinoids for use as dietary supplements in strict compliance with FDA and Federal Trade
Commission (FTC) rules.

In addition to being highly lipophilic molecules, cannabinoids can also undergo extensive first-pass metabolism, which creates difficulties for dosing and titration and impacts the speed of therapeutic onset, according to Chandler. He points to testosterone and triptans as being examples of other APIs that share these difficulties.

Furthermore, Tishler notes that bioavailability of cannabinoids is poor regardless of route of administration, and it is also quite variable, particularly for oral delivery. The challenge, agrees John A. MacKay, founder and CEO of Synergistic Technologies Associates, is to get nonpolar cannabinoids into some type of media or delivery vehicle that will enable sufficient quantities of them to be transported across membranes to targeted areas.

Growing numbers of patent filings and publications regarding the pharmacodynamics of cannabinoid delivery using novel technologies indicate high interest in addressing the shortcomings of cannabinoid products delivered via the standard oral routes of administration, according to Chandler. Technologies of interest include buccal, intra-nasal, and transdermal delivery systems, as well as the use of various nanoscale approaches to enable improved oral delivery.

Of the more than 120 different phytocannabinoids that have been identified, Δ9-tetrahydrocannabinol (Δ9-THC, or THC) and CBD are the most abundant and most investigated (2). Many synthetic cannabinoids have also been produced and evaluated. Most cannabinoids that have been shown to be pharmacologically active are Class II compounds under the Biopharmaceutics Classification System, which are considered to have low water solubility and high lipophilicity.

Inhalation gives best bioavailability, but presents many problems

Although inhalation of cannabis-derived products is the most common method of administration and does generally provide the best bioavailability and fast onset of action (5–10 minutes) as well bypasses first-pass metabolism (2), smoking and vaping oil extracts supply the cannabinoids in conjunction with toxic byproducts. In addition, the bioavailability still only reaches 20–30%. “The best solution to date,” says Tishler, “is a flower vaporizer, but this device is costly and the results are typically very user-dependent.”

Inhalation must be done appropriately, too, adds Mackay. “If patients don’t inhale correctly, the cannabinoids can be delivered into the mouth instead of the lungs. In addition, some people experience a gag-reflex when using an inhaler.” Due to the “stickiness” of these hydrophobic compounds, Tishler adds that it is difficult to put them in metered-dose inhalers because the devices fail after just a few uses.

Buccal and intranasal delivery could be alternatives

Buccal and intranasal delivery are other approaches to avoiding first-pass metabolism. These delivery methods also may offer reduced variability compared to oral administration of cannabinoids, according to Chandler. “We see increasing clinical evidence coming out in various publications both domestically and internationally that these types of formulations provide higher and more reliable absorption of cannabinoids that will benefit clinicians and their patients,” he observes. He does, stress, however, that there is still much work to do.

Whether one form of administration is better than another remains to be seen. In addition, Chandler remarks that cannabinoids are a diverse set of molecules, so what would be an advantage for one might be a disadvantage for another depending on the specific attributes of the cannabinoids. “On the purely theoretical side, buccal formulations are potentially easier to use because they are solids rather than liquids,” he comments.

On the other hand, intranasal delivery, based on the results with other similar APIs, could have slightly faster speed of onset at the expense of total absorption because of the washout down the throat, according to Chandler. There are concerns, however, about irritation of the nasal mucosa and mucociliary clearance, and it has been suggested that this route of administration may be most appropriate for highly potent APIs that require small dosage amounts (3).

Separately, depending on the cannabinoid, buccal or intranasal might provide for better patient tolerability, as some cannabinoids can be either very bitter or spicy, and where one technology or the other might provide a better patient experience. “We need more clinical data, but I expect there will be a place for both technologies depending on the clinical context and specific cannabinoids,” Chandler says.

For buccal formulations specifically, Chandler notes that analogous cases such as buccal delivery of testosterone show that buccal improves total absorption and reliability. Similarly, improvement of efficacy has been reported when going from oral gastric tablets of triptans to sublingual or intranasal delivery. The published literature on buccal delivery of cannabinoids, he continues, suggests that there is evidence that buccal delivery improves total absorption with pharmacokinetic (PK) profiles swinging from predominantly first-pass metabolites towards more non-metabolized actives in patients. “These papers, however,” says Chandler, “describe small trials with only a handful of patients and not powered or controlled at a level to really address the question of variability.”

Developing buccal formulations (orally disintegrating tablets, buccal mucoadhesive tablets, films and patches, sublingual disintegrating thin films, sprays, chewing gum, and lozenges) can be challenging for cannabinoids because buccal delivery comprises a group of technologies, all of which might not be suitable for all cannabinoids, according to Chandler. In addition, he notes that cannabinoids have diverse flavor profiles, which can be an issue.

“Buccal delivery tends to involve greater residence times in the mouth, and depending on the unit dose they can be highly concentrated,” Chandler explains. Furthermore, the small size of the oral cavity limits the volumes that can be comfortably delivered compared to traditional tablets/capsules. Some cannabis and hemp extract products are in development.

It is worth noting that buccal and intranasal delivery are just two forms of transmucosal drug administration, which is intended to deliver drug substances through the mucosal epithelium into systemic circulation. Others include rectal and vaginal delivery. Several different cannabinoid candidates are being developed as transmucosal products, with many of them based on THC or CBD and most as oromucosal formulations (2).

Nano products claim to tackle GI tract absorption issues

Given that oral delivery via tablets and capsules is generally the preferred route of administration due to simplicity, many developers of cannabinoid medicines are focused on overcoming the poor absorption of these molecules in the gastrointestinal (GI) tract, which is typically 15–20%. Nanoscale solutions are receiving the greatest attention, according to Tishler, but solid data has yet to be supplied, he says.

Nano-based technologies are attractive because they have the potential to not only improve solubility and bioavailability, but increase stability and provide mechanisms for controlled- and other types of modified-release profiles and taste masking (2,4).

Various solutions are being developed, including those based on lipid and polymeric nanoparticles (2,4). Other lipid-based formulations such as nanomicelles, nanoemulsions, lipid nano capsules, and nanostructured lipid carriers, self-micro emulsifying drug-delivery systems, and self-nano emulsifying drug-delivery systems are being explored, as are ethosomal systems containing phospholipids, ethanol, and water; complexation by cyclodextrins; extracellular vesicles or exosomes; mesoporous silica; and electrospun fibers (2,4).

Nanoemulsions are particularly popular, according to MacKay, with different companies using a number of different approaches to generate them. “The challenge is selecting the right emulsifiers and emulsification technology (for example, controlled cavitation) for a given cannabinoid to achieve nanoemulsions of the correct particle size that maintain their emulsified state for throughout shipment, storage, and use,” he contends.

Stability is essential, as formulations in which the emulsion has degraded will not have a consistent concentration of the cannabinoid active throughout the entire solution. The particle size is important because it not only determines how efficiently the nanoparticles will cross membranes, but which cells are targeted and how the nanoparticles interact with them, Mackay observes.

Nanotech-based delivery technologies are receiving significant attention.