Felicity Thomas is Associate Editorial Director of Pharmaceutical Technology, Pharmaceutical Technology Europe, BioPharm International.

Felicity Thomas

Despite March bringing in the start of the meteorological spring, northern Europe has been subjected to a late wintery surge, with falling temperatures and cold Arctic air mass (1). This latest drop in temperature is adding to the regional anxiety over soaring energy prices and shortages that have been impacting households, businesses, and industry since 2021 and exacerbated by the Russian invasion of Ukraine in 2022.

Some companies within the European bio/pharmaceutical industry, such as German behemoth Bayer, are being forced to reactivate the use of fossil fuels as a contingency should they be unable to fulfil the heating needs for production (2), even though plans were set out previously to move entirely to renewable energy sources. These types of ‘backward steps’ in terms of energy consumption will be a thorn in the side of the European Commission, which has hopes, as per its Green Deal (3), for the European Union (EU) to be climate neutral by 2050.

And these increasing energy cost pressures could not have come at a worse time, as companies are struggling with other challenges, including the rising demand for medicines, increasing instances of drug shortages, and expanding expenditures in other areas, such as for raw materials, logistics, and regulatory compliance. The generic-drug sector is particularly feeling the pinch, as highlighted by the open letter submitted to EU member states’ energy and health ministers in September 2022 by Medicines for Europe on behalf of its members, iterating the drastic price hikes some companies are facing—10-fold rise for electricity and between 50–160% rise for raw materials (4).

As alluded to by Richard Ettl, CEO of Swiss logistics company SkyCell, in an interview with 

® (which can be found on pages 25–26 of this issue), “Global businesses are entering what some are calling the ‘VUCA’ world—volatility, uncertainty, complexity, and ambiguity.” How should companies respond to these unsure times? They should be gaining visibility throughout the supply chain and taking action as soon as possible (5).

1. Hulton, F. and Feist, M. Weather Tracker: Northern Europe Facing Cold Snap. 

, 6 March 2023.
2. Hollinger, P.; White, S.; Speed, M.; Dunai, M. Will the Energy Crisis Crush European Industry? 

, 19 Oct. 2022.
3. EC. A European Green Deal. 

https://commission.europa.eu/strategy-and-policy/priorities-2019-2024/european-green-deal_en

(accessed 8 March 2023).
4. Burger, L. Europe’s Generic Drugmakers Say They May Cut Output Due to Energy Bills. 

, 28 Sep. 2022.
5. Thomas, F. Keeping Europe’s Medicines Stocked. 

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

When referring to this article, please cite it as Thomas, F. Feeling the Pinch. 

Articles

Soaring energy costs are compounding the challenges currently being faced by the European bio/pharma industry.

Feeling the Pinch

In this episode of the Drug Solutions podcast, Felicity Thomas, European/Senior Editor, catches up with Ana Ladino, Ashland’s Global Director—Regulatory Affairs, about the acceptance of a novel excipient onto CDER’s pilot review program, the next steps involved in progressing an excipient through the review program, and the change in industry’s mindset toward review programs in general.

Ana L. Ladino is Ashland’s Global Director-Regulatory Affairs

. As senior leader of the regulatory affairs function, she manages strategic direction and operational oversight for the regulatory activities for all Ashland’s Life Sciences products: excipients and other oral solid dosage ingredients and coatings, injectables, nutrition, nutraceuticals, agrochemicals, and medical devices. She oversees all FDA and other global regulatory authority interactions for Ashland’s products while ensuring a high level of integrity in regulatory and quality compliance. With 25 years of experience in the healthcare industry, she has extensive experience in drugs, combination products, medical devices, excipients, and API regulatory requirements. She has been involved in industry organizations such as RAPS, IPEC, AAM, ISO, NEMA, authored many global regulatory-related papers, and presents worldwide on various regulatory topics. She served on the Healthcare Businesswomen’s Association (HBA)—West Chester Board.

Ana holds a bachelor’s degree in electrical engineering and a master’s degree in biomedical engineering from Autonomous University of the West (UAO), in Cali, Colombia. In the past, she has worked for West Pharmaceuticals, Accellent, Siemens, GE Medical, and as a university professor.

 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

In this episode, Ana Ladino provides an update on the acceptance of a novel excipient onto CDER’s pilot program.

Drug Solutions Podcast: Progressing Excipients Through Review

Advanced therapeutic medicinal products (ATMPs) are experiencing a boom, with the global pipeline continuing to experience growth and more than 3700 ATMPs currently under development, according to data from the American Society of Gene and Cell Therapy. However, progressing such complex therapies that target niche disease areas through to commercialization produces a unique set of challenges.

Pharmaceutical Technology’s Bio/Pharma Outsourcing Innovation

Critically, the technical expertise required for the clinical research of ATMPs is something that can be lacking for developers in-house, driving demand for contract research organizations (CRO). In fact, the cell and gene therapy CRO market is forecast to experience continued and consistent growth until 2035.

In this feature, Rhonda Henry, president of Emmes BioPharma; Ching Tian, chief innovation officer, Emmes; and Raja Sharif, CEO Hataali, detail the challenges facing biopharma companies developing ATMPs and the role that CROs play in gaining a market advantage.

Pharmaceutical Technology's February 2023 Bio/Pharma Outsourcing Innovation eBook

Felicity Thomas is European/senior editor for Pharm Tech Group

When referring to this article, please cite it as Thomas, F. CROs Gaining a Competitive Edge. 

Pharmaceutical Technology's Bio/Pharma Outsourcing Innovation eBook 

Shifting toward more technological solutions and ensuring a greater understanding of the workforce’s needs will give both CROs and sponsors a market advantage.

CROs Gaining a Competitive Edge

Across Europe, a variety of cannabis or cannabinoid-based products used in pharmacotherapy are mainly indicated for the treatment of chronic pain, nausea, and vomiting as a result of chemotherapy (1). However, up until the time of writing, there has only been one cannabinoid-based pharmaceutical product (Epidyolex/Epidiolex, Jazz Pharmaceuticals) that has been granted approval by the European Medicines Agency (EMA) under the centralized procedure—meaning it can be marketed throughout the entire European Union (EU) (1,2).

As the cannabis pharmaceutical market is expanding around the world, with some forecasters projecting a compound annual growth rate of 18.6% between 2022 and 2027 for the global market (3), 

 spoke with Michael Sassano, CEO at SOMAÍ Pharmaceuticals—a next-generation biotech company—to learn more about the European market and how pharmaceutical applications will shape up in the future.

Could you provide an overview of the European medical cannabis market and the role of pharmaceutical applications within this sector?

Europe is at the forefront of medical and pharmaceutical cannabis. While the US [United States] and Canada paved the way for regional closed border recreational cannabis, Europe created a global cannabis market by regulating cannabis as a pharmaceutical API and adopting international standards of medicine EU-GMP [EU-good manufacturing practice] certification. By following the 

.), EU cannabis producers that conform to pharmaceutical GMP requirements can cross borders with cannabis so that doctors and patients can obtain a prescription for a multitude of indications like epilepsy, multiple sclerosis, and pain to name a few.

The EU market is small compared to the US market, because it started around 2017 and currently has roughly 350,000 patients in a few defined countries (4). Germany is the largest consumer market with approximately 200,000 patients, Italy the second largest market with approximately 65,000 patients, the UK [United Kingdom] with approximately 22,000 patients, Denmark with approximately 10,000 patients, the Netherlands approximately 9000 and smaller markets like Portugal, Czechia, Switzerland, to name a few. Only in the last two years has the European market started to transition from flower APIs to medicinal extracts which conform more to the medical and pharmaceutical standards. Most of the market is magistral prepared cannabis extract APIs, but advancements and normal course of development is showing the first signs of finished medicinal products.

 Will cannabis-based pharmaceuticals become more prominent in the future in your opinion?

 With the advent of extracted and formulated [cannabis-based] APIs and finished products, Europe has entered the true pharmaceutical space. There are already examples of pharmaceutical products like Dronabinol, Epidiolex, and Sativex, which have undergone clinical trials commensurate to standard pharmaceutical products. But there is also the herbal medicinal market, which is a global US $150 billion (€139 billion) market (5), that cannabis has entered with plant-derived extracts. The herbal extract market will be the largest explosion in growth for EU cannabis over the next few years and long run. And there is the OTC [over the counter] market or adult use that is also being explored in Europe and is already a US $35 billion (€33 billion) global OTC/recreational cannabis market today (6). Cannabis has a place in all three pharmaceutical pillars for clinical trial products, herbal extracts, and OTC.

Demand by patients is driving the early entrepreneurs to develop the infrastructure needed to support the growing European market. The trend in Europe for cannabis is largely skewed to a safer and better way to relieve pain and has an average age of 50-years-old. Whereas mature OTC markets, like the US, have an average age of 30, and although pain is still the largest sector, people are using cannabis for many more reasons like stress, anxiety, sleep, and much more. This [variance] is primarily because there are not enough clinical trials to prove efficacy for EU doctors to prescribe for other indications. For a more robust European medical market to expand, more studies and education for doctors is needed and that will come as the number of patients looking for relief expands in Europe.

 Are European pharma companies already participating in the cannabis market?

 Already in the past two years since the UN [United Nations] voted to classify cannabis as a medicine in December 2020, there have been major acquisitions by pharmaceutical companies: Jazz Pharmaceutical bought GW Pharmaceutical for US$6.7 billion (€6.2 billion) in early 2021 (7), which was followed up at the end of that year with Pfizer purchasing Arena Pharmaceutical also for US$6.7 billion (€6.2 billion) (8); Teva Pharmaceuticals entered the distribution of cannabis products (9); Dr. Reddy’s, an India based pharmaceutical company, bought German distributor Nimbus Health (10); and the large Netherlands API manufacturer DSM bought cannabis API manufacturer Brains Bioceutical (11). This [activity] is only the tip of the iceberg for pharma players, and nearly every company, whether API producers, clinical trial companies, herbal medicine producers, distributors, generics, or Big Pharma looking for complimentary therapies, are all looking to find their position [in the market].

Europe has an advantage because companies must follow more robust pharma EU-GMP regulations, while the US and Canada follow either novel foods GMP or even less robust restaurant quality regulations. To be global and to be attractive for pharma, the EU standards are a bullseye. And Europe is far ahead of the curve.

 Are there any differences between European countries in terms of interest/investment into the cannabis market?

 Each country has unique positions in Europe for cannabis. The largest consumer market, which benefits distributors of medical cannabis, is Germany. The main driver was the 2017 German health reformation, which gave doctors the freedom to choose cannabis as a therapy for their patients (12). [In 2022], Switzerland followed the same path as Germany and doesn’t require doctors to get federal approval before prescribing cannabis. The UK requires doctors to have tried at least three other therapies before prescribing cannabis, which greatly hinders adoption. And even more restrictive are countries like Denmark and Ireland, which limit use to major ailments only, epilepsy, multiple sclerosis, and stage III cancer-related issues. Without pain and other less serious indications, cannabis cannot get widespread adoption as the pool of eligible patients is very limited.

Other countries like Portugal have become the EU leader in cultivation and manufacturing cannabis flower and extracts. The Portuguese regulatory environment treats cannabis in line with Ph. Eur. on herbal APIs and extracts and allows for the market authorization of cannabis finished extracts. Couple that with a highly educated population and most reasonable wage structure for western Europe, Portugal will be the leader of cannabis exports for the foreseeable future with already 21 licensed facilities and home to the biggest cannabis companies like Tilray. Small countries like Malta and Luxenberg have embraced the more social aspect of OTC adult use but it’s small and hasn’t really started.

 Might certain countries be at risk of being left behind in the pharmaceutical cannabis market?

 Many major European countries are addressing the issue of how to regulate cannabis use in their country. Spain was expected to come out with comprehensive regulation like Germany by Q4 2022 but has yet to do so. France has been running a pilot programme and is very eager to adopt rules once they see Germany and Spain movements for 2023. Greece, although initially being an early pioneer for producing cannabis, has opened their first facility recently and still has hopes to compete as a producer like Portugal, albeit they are far behind and [it] doesn’t look very promising given poor regulation adoption. Additionally, Greece is in transition from government-controlled distribution to pharma distribution. Italy has been actively changing the rules for bigger adoption and is also going away from government-controlled distribution and focusing to pharmaceutical standard distribution.

As more and more countries adopt pharmaceutical standard manufacturing and distribution, and the sooner they allow for doctors to be educated and help their patient, the larger the EU cannabis markets gets. [The year] 2023 will prove to be the most expansive and news-filled year for such developments as the largest countries pave the way for rules that smaller countries can adopt.

 What regulatory hurdles must pharma companies consider for the cannabis market?

 There is a big shift right now from magistral preparation compounding at pharmacies to finished cannabis medicines with market authorization. Initially, cannabis products were treated as an API that pharmacies would then purchase and compound to give to patients. This was clearly a path pushed by pharmacists so they could charge a higher margin than finished products. It was also the quickest path for regulators to certify APIs that could get to patients quicker than the longer road of registered medicines.

Since the advent of extracts and formulated products, the shift is towards these products because they are more cost effective for the patients and they are produced and regulated at a much higher quality standard than pharmacy-made products. That transition is occurring as countries like Portugal have adopted the standard EU herbal pharmacopoeia to manufacture extracts and allow for finished form dosages like gel caps, sprays, drops, and other pharmaceutical standard delivery devices. The consumer will benefit greatly because there are fixed increases that pharmacies and distributers can charge for medicines. Volumes will increase to offset any lost margin. But we aren’t there yet; countries like Germany and Italy, the two largest markets, are magistral.

 What should industry expect for the future?

 Europe will no doubt be the second largest cannabis market in the world next to the US. But the high standards of pharma EU-GMP will make Europe the only global powerhouse far surpassing the US for pharmaceutical manufacturing. Standardization and a large population to serve will be a hotbed of pharmaceutical transactions over the next coming years and the future while countries [whose regulatory standards for cannabis‑based products are akin to those for] novel foods like Canada and even lower restaurant standards for the US will not participate significantly in the global medical markets.

1. Lipnik-Štangelj, M.; Razinger, B. A Regulatory Take on Cannabis and Cannabinoids for Medicinal Use in the European Union. 

EMA.europa.eu/en/medicines/human/EPAR/epidyolex

 (accessed 18 Jan. 2023).
3. Research and Markets. 

Global Cannabis Pharmaceuticals Market (2022–2027) by Brand, Product Type, Distribution Channel, Application, and Geography, Competitive Analysis and the Impact of COVID-19 with Ansoff Analysis

. Report, September 2022.
4. Prohibition Partners. 

The European Cannabis Report: 7th Edition

. Report, March 2022.
5. Fortune Business Insights. 

Herbal Medicine Market Size, Share, and COVID-19 Impact Analysis, by Application (Pharmaceutical and Nutraceutical, Food and Beverages, and Personal Care and Beauty Products), by Form (Powder, Liquid and Gel, and Tablets and Capsules), and Regional Forecast, 2022–2029

. Report, July 2022.
6. BDSA. BDSA Reports Global Cannabis Sales to Jump 22% in 2022; Forecasts $61 Billion by 2026. Press Release, 2 March 2022.
7. Jazz Pharmaceuticals. Jazz Pharmaceuticals Completes Acquisition of GW Pharmaceuticals plc. Press Release, 5 May 2021.
8. Pfizer. Pfizer Completes Acquisition of Arena Pharmaceuticals. Press Release, 11 March 2022.
9. Hasse, J. Exclusive: One of the Largest Pharma Companies in the World has Made a Big Move in Cannabis. 

, 12 Sep. 2019.
10. Dr. Reddy’s. Dr. Reddy’s Laboratories Enters into Definitive Agreement to Acquire German Medical Cannabis Firm Nimbus Health GmbH. Press Release, 3 Feb. 2022.
11. DSM. DSM and Brains Bioceutical Form Exclusive Global Partnership to Unlock the Therapeutic Potential of Cannabinoids in Early-Stage Drug Development. Press Release, 22 June 2021.
12. Gunelius, S. Inside the European Cannabis Industry. 


Vol. 35, No. 2
February 2023
Pages: 28–30

When referring to this article, please cite it as Thomas, F. Advantageous Positioning for Europe in Pharmaceutical Cannabis. 

The European bio/pharma industry’s high regulatory standards and GMP requirements are set to position the region as a frontrunner for pharmaceutical‑grade manufacturing of cannabis-based medicines.

Advantageous Positioning for Europe in Pharmaceutical Cannabis

Gender equality and diversity is an issue that has been more prevalent in discussions and considerations across the professional landscape over recent years. For women, striving to reach the top positions in company boardrooms or even advancing up the career ladder can be a seemingly insurmountable task, with many prejudices and obstacles still causing problems.

As 11 February marked the passing of another annual observance of the United Nations’ International Day of Women and Girls in Science—which aims at promoting female participation in science, technology, engineering, and mathematics subjects and careers (1)—it seemed pertinent to review how the pharmaceutical industry stands up in the global scale of gender diversity in the upper corporate echelons.

According to the 2021 Gender Diversity Index (a study of 668 companies, produced by the non-profit Brussels-based organization, European Women on Boards), the healthcare and pharma sector has a gender diversity index (GDI) value of 0.61. This value means the industry ranks third out of eight sectors that were specified by the analysts in the study and is an improvement from the 2020 ranking, when the sector only reached fifth and had a GDI of 0.56 (2).

The top three companies for the healthcare and pharma sector were GN Store Nord, a telecommunications and hearing instruments business based in Denmark; MorphoSys, a biopharmaceutical company from Germany; and AstraZeneca, a research-based biopharma company based in the United Kingdom. Of these three companies, only one (GN Store Nord) has a female CEO and none have women as chairs of the board (2).

Sadly, progress in gender diversity at the top levels across all industry sectors has been slow going. As alluded to by Jane Kennedy, chief business officer of Discovery Park in Kent, UK, the difficulties within the science sectors not only lie in getting girls attracted to the subject matter to begin with but also in preventing women from quitting a science-based career once they have gotten through the door. This latter problem is particularly challenging when women realise there is a significant pay gap between them and their male counterparts (3).

Further change is needed! Diversity needs to improve with more speed than has been happening in recent times, not least of all to comply with new European Union rules (4) but also to ensure innovation and market growth can be unlocked—something that is possible through diverse leadership (5).

International Day of Women and Girls in Science, 11 February

UN.org/en/observances/women-and-girls-in-science-day

Gender Diversity Index of Women on Boards and in Corporate Leadership

. 2021 Report (January 2022).
3. Kennedy, J. 

Bench to Boardroom—Why Can’t Women Make the Leap?

Council Approves EU Law to Improve Gender Balance on Company Boards

. Press Release, 17 Oct. 2022.
5. Hewlett, S.A.; Marshall, M.; Sherbin, L. How Diversity Can Drive Innovation. 

When referring to this article, please cite it as Thomas, F. Getting Personal. 

Although some headway is being made into more gender-diverse executive levels in pharma, much more work is still needed.

Improving Gender Diversity

Within the bio/pharma industry, there is a certain expectation for companies to maintain required levels of cleanliness within their facilities to ensure products that are manufactured are at minimal risk of contamination. All cleaning processes must also be validated for effectiveness and reproducibility.

As drug products become more complex and sensitive to potential contaminants, there is an increasing demand for cleaning validation throughout industry. According to market research, the cleaning validation market is forecasted to grow by a compound annual growth rate of 5.7% between 2021 and 2027 (1).

Of course, the requirement for manufacturing equipment to be clean is nothing new; as Andrew Kolbert, PhD, senior leader, Technical Solutions, Element, points out, this facet of drug production has been a necessity for 70 years since the introduction of the 21 Code of Federal Regulations (CFR) 210 Part 133.4 (2). “Early efforts [in this field] were focused on avoiding microbiological contamination or just filth, as seen at food manufacturers,” he states.

“In 1978, the GMPs [good manufacturing practices] were amended to 21 CFR Part 210.67, which specifically addressed the issue of cross contamination, as opposed to mere unsanitary conditions, with particular focus on manufacturers that made penicillin and other pharmaceutical products on the same equipment train,” Kolbert continues. The issue of cross contamination was brought to the fore by a case in 1988, he highlights, where a drug product, Cholestyramine Resin, was recalled due to contamination with pesticides as a result of insufficient cleaning of solvent drums (3).

“Cleaning validation is a subject that receives a great deal of attention within biopharmaceuticals, not least due to the risks presented in terms of product adulteration from cross-contamination and, hence, patient harm from improperly cleaned surfaces (and noting additional concerns such as operator protection),” specifies Tim Sandle, head of microbiology at Bio Products Laboratory (BPL) in Elstree, UK.

Sandle also highlights microbial proliferation as an area of importance because of the risk it poses in terms of the numbers of organisms adhering to surfaces and the release of microbial toxins. “Under the least desired conditions, a combination of organic residues and the presence of microorganisms can lead to a biofilm developing,” he says. “Biofilms are difficult to detect, and they are challenging to remove.”

Therefore, it is expected, by the regulatory bodies, such as FDA, that a drug manufacturer has a cleaning process in place for all equipment to ensure that no drug residue exceeds the maximum allowable carryover (MACO) level—a level that is determined based on toxicological risk—and that there are no cleaning agent residues and so forth, Kolbert asserts. “The cleaning process must also be validated to ensure it is consistently reproducible and effective. The exact form of this validation depends on the nature of the equipment as well as the cleaning process,” he says. “If cleaning is to be done manually, the reproducibility across workers will be need to be explored. If solvents or detergents are used, reduction to an acceptable level must be demonstrated.”

“Approaching cleaning validation should always begin with a risk assessment,” emphasizes Sandle. “To be effective, the risk assessment needs to be built upon a thorough understanding of the equipment to be cleaned and the cleaning reagents and mechanisms.”

Additionally, any residue(s) that needs to be removed must be identified and the optimal method to remove the residue(s) must be considered, Sandle continues. “For example, some residues are best cleaned by either an alkaline or acidic cleaner (or both types of cleaning agent may be required). To ensure the designed process has a greater chance of being effective, it is also important to understand how the residue is actually being removed (which requires detail of the residue chemistry),” he states.

“The next step is whether to use product residues or an alternative soil to challenge the designed cleaning process,” Sandle adds. “Users need to assess whether product residues are suitable for the cleaning validation because some process soils pose little challenge to the cleaning system, and it may be more appropriate to use a surrogate with greater viscosity and binding characteristics.”

Furthermore, Sandle points out that consideration should be made to how much residue may be permitted to be left, which will impact the level of cleaning that is required. “This [consideration] means selecting appropriate sampling methods, typically based on rinsing and swabbing, and the appropriate test methods for microbial and chemical analysis,” he says. “With methods, there needs to be an understanding about the metrology of the test instruments and the likelihood they can quantify the minimum acceptable residue. In addition to typical analytical method validation parameters (specificity, accuracy, linearity, limit of detection, precision), the actual sampling procedure must be qualified.”

For Kolbert, swabbing all of the drug product contact surfaces along the manufacturing train using the simplest analytical finish that will achieve an appropriate limit of detection is the most common approach. “If the drug product has a chromaphore, HPLC [high-performance liquid chromatography] or even UV [ultraviolet]/vis [visible] may be sufficient,” he says. “It is important to detect not only the drug product but any degradants or by-products that may be created.”

Also, if a detergent mix or solvent is required for the cleaning process then merely analyzing the rinsate does not suffice, Kolbert admonishes. “The product path components must also be tested for residue by direct swabbing,” he states. “A commonly used metaphor is if you are cooking in a pot, it is not enough to analyze the water rinse, you also need to look at the pot for old product residue that may break off over time.”

Increasingly, companies are utilizing highly potent drugs in biopharmaceuticals, which is creating challenges in terms of cleaning validation, asserts Kolbert. These drugs have extremely low MACO, which has driven analytical limits of detection to barely achievable levels, he adds. As a result, it is becoming necessary to use liquid chromatography coupled with tandem mass spectrometry to hit the toxicologically driven thresholds, Kolbert states.

In Sandle’s opinion, the main challenges in cleaning validation are in relation to residue removal, which is partially dependent upon the required level of cleanliness and the level of cleanliness that can actually be achieved—which relates to the design of the equipment. “Ideally, equipment selection will have embraced quality-by-design and there will be no inaccessible parts,” he continues. “However, in reality, some areas of large items of equipment are easier to clean than others and the main challenges that arise are often cantered on developing cycles that can reach challenging locations [such as] narrow pipes, u-bends, valves, and so on.”

Another area that is sometimes neglected is consideration of the age of equipment, Sandle specifies. “Manufacturing activities have the potential to induce abrasion and corrosion,” he says. “Hence, consideration must be given to ageing equipment with any aspect of cleaning.”

Regulators expect companies to conduct a risk assessment, Sandle points out. “With the risk process, it is good practice to use a multi-disciplinary team. The team should assess indirect product contact pars in relation to: the ability to build-up residues and the ability to transfer residues to product contact sites,” he explains.

Additionally, there is an expectation from regulators that all sample locations selected are represented and that potential ‘worst cases’ are indicated, Sandle notes. “I have seen several regulatory findings for cleaning validation that has been undertaken using locations that are not sufficiently challenging,” he says.

“A common regulatory issue also relates to manual cleaning,” Sandle continues, “especially around verification [as to whether] the operators can continue to undertake manual cleaning to a reliably high standard.”

Essentially, the cleaning process needs to be documented and demonstrated to be valid as per the regulatory bodies’ guidance, such as FDA outlined in Validation of Cleaning Processes (7/93) (3), confirms Kolbert. “There are a number of pitfalls that must be avoided, such as an overreliance on rinse analyses instead of direct observation of the equipment product contact paths; lack of sufficient evidence of reproducibility of any manual steps in the cleaning process; and verification of the absence of cleaning agents at the conclusion of cleaning,” he emphasizes.

“Perhaps the most important lesson from regulatory findings is the importance of running a risk assessment to manage the process, focusing on the proactive identification of hazards, selecting the optimal process to reduce the risk presented by these hazards, and with that ensuring there is a suitable measure of detection in place to verify the outcome,” Sandle says.

Sandle hopes that there will be increased use of rapid methods in cleaning validation that can provide real-time assessments in the near future. 

“Adenosine triphosphate (ATP), protein residue, and glucose residue swabs are among the more useful rapid methods, although further development is required to improve accuracy and repeatability,” he highlights. “Of the different ‘PAT [Process Analytical Technologies] methods’, ATP bioluminescence technology offers a higher sensitivity compared with colorimetric methods.”

In terms of management of cleaning validation processes, software developments are piquing Sandle’s interest, including some that are employing artificial intelligence. “Such packages can help to sort equipment into types where a matrix approach is preferred, as well as enabling scheduling and for setting re-validation targets,” he states.

At its very essence, cleaning validation will require greater consideration, simply as a result of the evolving therapeutic landscape, Kolbert asserts. “The increased use of biological therapeutic agents in pharmaceutical manufacturing will require increased complexity of analytical techniques as activity of the residue is as important as chemical presence,” he summarizes.

1. MMR. Pharmaceutical Cleaning Validation Market: Industry Analysis and Forecast (2021–2027) by Product Type, Validation Test, and Region. Report,.October 2021.
2. CFR Title 21, 210 Part 133.4 (Government Printing Office, Washington, DC).
3. FDA. Validation of Cleaning Processes (7/93), Inspection Guide. Aug. 26, 2014.

Analytical techniques for validating cleaning methods must evolve to match the pace of an increasingly complex manufacturing landscape for new therapeutics.