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

Felicity Thomas

Drug manufacturing laboratory equipment. | Image Credit:©Unique Vision - stock.adobe.com

Given the fact that pharmaceutical products command a high value, not only financially for the developer but also to the patients that require treatments, it is unsurprising that potential contaminants that can impede the integrity of such products must be avoided at all costs. If insufficient care is taken, contaminants can enter a drug product supply chain at multiple points, leading to costly failures and potential product recalls.

A fundamental part of good manufacturing practice (GMP) is the cleaning of manufacturing equipment. “Effectively cleaning process equipment on direct or indirect product contact surfaces is crucial to prevent cross-contamination or processing degradants contamination from the previously produced product, and introducing it into the next batch,” explains Walid El Azab, senior manager Technical Services for the Life Sciences Division of Steris. “Such degradants may include microbial or chemical elements that would negatively impact the subsequently produced product.”

There are multiple factors to consider when seeking to preserve the integrity of the manufacturing process. Manufacturers should bear in mind that contaminants can differ depending on the type of process, if a mono- or multi-product equipment train is being used, and the specified quality target product profile, El Azab remarks.

“In large campaigns, a shorter cleaning cycle (cleanup) may be employed between batches of the same product, aiming to prevent contaminants from exceeding acceptable limits and negatively affecting product manufacturing,” El Azab states. “The risk of cross-contamination within the same product is generally minimal to none unless there are special formulation-dependent concerns, such as a microbiological limit or chemical relic from the process that could adversely affect the next batch.”

Therefore, according to industry standard practices (1,2), when performing mono-product processes, visual inspection alone is considered to be adequate as part of the cleaning validation or verification, El Azab continues. However, for multi-product processes, there is a higher risk for cross-contamination, which means that for such operations, cleaning limits based on a scientific approach, such as the Health Based Exposure Limit (1,3,4,5,6), must be set and integrated into the shared equipment train, he specifies.

Additionally, there should be alignment of the level of control, including sampling and detection methods, with the product type and equipment visibility, El Azab adds (4,5). Further, the risk of contamination and patient safety must also be considered, he states (7).

“During both validation and routine processes, a combination of visual inspection and quantitative detection methods is typically required to confirm cleaning effectiveness in a multiple product setting,” El Azab explains. “However, in specific cases, scientifically justified, quantitative visual inspection alone may suffice.”

When dealing with sterile products, it is essential to put a robust contamination control strategy in place to show the effective prevention of product contamination, Azab confirms (8).“If this strategy confirms that the existing measures are sufficient to prevent contamination, the need for separate, dedicated equipment may not be necessary,” he says.

“To ensure the effective cleaning of equipment between products, it is essential to follow a structured procedure,” stresses El Azab. The first step is to map the process, he continues, which allows for the identification of potential sources of contamination and any variables that may affect the cleaning effectiveness and performance.

After mapping the process, manufacturers should gain an understanding of the contamination risks and then establish the appropriate corrective measures and associated controls that will need to be put into place, El Azab states. Then, pre-trial tests on a laboratory scale should be conducted, before the validation process, so that the optimal cleaning cycle can be established and any worst-case products identified, he adds.

Prior to starting the formal validation process, a trial should be performed when possible, and then the validation or verification runs can be executed as planned, El Azab highlights. A comprehensive cleaning cycle and procedure should be developed, he notes, with particular attention paid to critical points aimed at preventing cleaning failures. “For instance, during visual inspection, a best practice is to provide the inspector (or operator performing the visual inspection) with a defined path to follow,” El Azab says.

Final practices that should be adhered to include ensuring that personnel operating and cleaning the equipment are adequately trained to be able to perform the relevant procedures, and continuously assessing and monitoring cleaning performance over time, improving procedures where necessary, El Azab states. “In some cases (e.g., API manufacturing), the monitoring may require direct sampling after a routine cleaning of the equipment between product change over (9), except if properly justified based on historical data and assurance of the measures and controls in place preventing possible cross-contamination,” he asserts.

“Over the past few years, the [equipment cleaning] market has seen the emergence of various technologies aimed at supporting sustainable initiatives,” El Azab remarks. “These [technologies] include rotary jet heads and devices for cleaning the underside of tank agitators, and improved formulated chemistries that reduce the cleaning cycle, water, and electricity consumption.”

Such technologies can also improve productivity, El Azab points out. For example, rotary jet heads can help “prevent product cross-contamination and preserve product quality” while devices designed to clean the underside of tank agitators can “eliminate confined space entry, making cleaning easier and boosting overall tank productivity,” he says.

“Notably, some pharmaceutical companies have adopted the approach of treating and recycling wastewater to lower costs and meet sustainability goals,” El Azab reveals. By way of example, he highlights the method of vacuum evaporation that allowed a laboratory to recover more than 90% of the water for re-use (10), whereas other pharma manufacturers are using other solutions, such as oil water separators, ultrafiltration, and reverse osmosis.

“Ultimately,” El Azab summarizes, “implementing suitable cleaning practices and validation procedures is crucial to maintaining the integrity of the manufacturing process and ensuring the high quality of the final products.”

Technical Report No. 49 (TR49): Points to Consider for Biotechnology Cleaning Validation

Guideline on Setting Health-Based Exposure Limits for Use in Risk Identification in the Manufacture of Different Medicinal Products in Shared Facilities,

Questions and Answers on Implementation of Risk-Based Prevention of Cross-Contamination in Production and ‘Guideline on Setting Health-Based Exposure Limits for Use in Risk Identification in the Manufacture of Different Medicinal Products in Shared Facilities.’

ISPE Risk-Based Manufacture of Pharmaceutical Products

Inspection of Health Based Exposure Limit (HBEL) Assessments and Use in Quality Risk Management

Annex 1: Manufacture of Sterile Medicinal Products

Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients

PRAB. Pharmaceutical Research Laboratory Reduces Wastewater Volume and Disposal Costs with Vacuum Evaporation. 


Vol. 47, No. 9
September 2023
Pages: 22–26

When referring to this article, please cite it as Thomas, F. Preserving Process Integrity: The Importance of Equipment Cleaning

Articles

A structured cleaning procedure is essential to ensure the effective cleaning of equipment.

Preserving Process Integrity: The Importance of Equipment Cleaning

Oil dropping, Laboratory and science experiments, Formulating the chemical for medical research, Quality control of petroleum industry products concept. Generative AI | Image Credit: © Jonatan - stock.adobe.com

For the past few years, with the advent of the COVID‑19 pandemic, there has been a rapid influx in investment into therapies that can treat and help alleviate symptoms of the respiratory disease, SARS‑CoV-2. Growth in the development and manufacturing of specialized vaccines has driven growth in the outsourced services markets, particularly for formulation development activities (1).

In addition to the driving force of the pandemic, new generation drug molecules are becoming ever present in the development pipeline to tackle the rising levels of chronic and difficult-to-treat diseases. This expanding proportion of complex compounds is also influencing a greater need for more specialized formulation approaches, the expertise for which is not always available as an internal resource at a company, leading to more reliance on outsourced service providers.

To learn more about the changes impacting the outsourced biopharmaceutical formulation development market, 

 spoke with Robert Gustines, senior vice president of Commercial Operations at Bora Pharmaceuticals, and Paresh Vadgama, fellow scientist, Biologics Product Development, Catalent.

 Could you provide an overview of the key drivers for the outsourcing formulation development market?

 Formulation development is a niche area within pharmaceutical drug development, with biologics formulation development in particular requiring specialized resources in terms of well-trained scientists, high quality ingredients, and advanced instrumentation. There are many drivers that fuel formulation development outsourcing, but two remain key.

First, there is an increasing demand for novel drugs to treat chronic and life-threatening disease conditions. Many new generation molecules require complex development and manufacturing processes, forcing the need for additional capital investment, including capability and capacity expansions. Additionally, more of these products are being marketed utilizing advanced delivery systems, such as auto-injectors, to help improve patient compliance.

Second, there is constant pressure to shorten the drug development timeline to bring therapies to patients faster, while remaining cost-effective. This pushes organizations to judiciously rationalize in-house activities, while outsourcing high capital and resource draining activities such as formulation development.

Biotech and pharmaceutical companies continue to look to outsourcing as a way to reduce risk, and save both time and money during drug development—especially in the earlier pre-clinical phases. What’s fueling growth in the formulation development space is the rising need for novel medicines as a result of a significant burden of infectious and chronic diseases, with oncology remaining a central focus and accounting for over a third of drugs in the pipeline globally.

 How has the increased attention on large molecule/biologics development impacted outsourced formulation services?

 Large molecule development requires specialized expertise due to the formulation challenges associated with increasingly complex, highly engineered protein molecules—typically involving maintaining stability, achieving appropriate drug delivery, and optimizing protein structures. As a result, there has been a growing demand for contract development and manufacturing organizations (CDMOs) that possess the necessary expertise and infrastructure to handle the formulation development of biologics. For example, high concentration formulations are becoming increasingly common, and it will, therefore, become important to have a partner with expertise in this area of formulation development.

Contract partners that offer formulation services have responded to growing demand by investing in specialized equipment, facilities, and analytical tools required for working with biologics. Expert CDMOs should be in a position to provide a comprehensive range of integrated services, including cell line development, process optimization, analytical testing, and regulatory support, all with the flexibility to meet the specific
requirements of their client’s drug substance and product.

 The COVID-19 pandemic served as a catalyst that brought significant changes. Organizations with novel technologies and scalable solutions grew rapidly, and CDMOs that were often seen as finished product suppliers, became recognized as product development partners. A further consequence was that regulatory bodies began to increasingly work in-tandem with developers, to ensure a rapid review of quality and safety data.

Though drug development is a lengthy and highly regulated, yet uncertain pathway, formulation development services are gaining greater attention. Small biotech companies, with limited capital and technical expertise, are particularly reliant on outsourcing partners to support the development of their product pipelines. Some CDMOs, such as Catalent, can provide a ‘one-stop-shop’ integrated approach to simplify this process for smaller sponsor companies, while also cutting product development costs.

The lessons learned from the COVID-19 crisis are fostering innovation-based ecosystems within CDMOs to stay agile as they tackle technologically superior, highly complex biologics such as antibody-drug conjugates, mRNAs [messenger RNAs]/lipid nanoparticles, and adeno-associated viruses, including their formulation development. There is clearly a growing market emerging for outsourcing partners in this area which will become increasingly apparent over the coming few years.

 Are there any best practices you could share for companies looking to outsource formulation development of large-molecule drugs to an outsourcing partner to ensure success?

 Some recommendations to ensure successful outsourcing of formulation development include careful selection of a partner depending on skillsets, reputation, and credibility, and working out a detailed plan in advance.

Scientific expertise and technical experience are the main elements of a product’s success. Careful selection of an outsourcing partner that has the right skillsets, is adaptable to project changes, has a successful delivery track-record, and is willing to innovate, is critical.

Ensuring that the chosen outsourcing partner has a reputation for clear and regular communication is of the utmost importance to build trust between both parties, especially during long-term projects involving
significant investments.

Identifying a credible outsourcing partner that will apply prior knowledge, published literature or improvements made outside of its organization to reduce potential risks and optimize costs for its client, is another vital practice.

Working out an early, detailed outsourcing plan with key milestones, timelines, and deliverables is definitely recommended. For example, having a quality target product profile helps to develop product characteristics and decision workflow.

 Companies looking to outsource the formulation development of large-molecule drugs to an outsourcing partner must evaluate a number of ‘hygiene’ factors first (i.e., fundamental requirements that must be met before a partnership should be considered).

Firstly, the CDMO must have relevant expertise and experience, and a proven track record in successfully developing formulations for large-molecule drugs and a portfolio of similar projects. Next, the CDMO must have (or be investing in or acquiring) the necessary infrastructure, equipment, and capabilities to support large-molecule formulation development. This includes technologies and analytical tools for characterization, facilities, and cleanrooms specified for handling sensitive molecules.

Companies need to verify that the outsourcing partner has a thorough understanding of the regulatory landscape and intellectual property protections in place.

 Could you outline the key benefits for outsourcing formulation development?

 Outsourcing demand for formulation development is shaped by several key drivers. For example, the economies associated with outsourcing to specialized partners rather than investing in establishing in-house capabilities. Outsourcing allows them to reduce infrastructure costs and access expertise, state-of-the-art technologies, equipment, and facilities without capital investment.

Speed-to-market is a crucial success factor in the life sciences. Outsourcing formulation development can expedite the drug development process by leveraging existing infrastructure, expertise, and streamlined processes. Additionally, CDMOs offer flexibility and scalability in resource allocation, allowing pharma and biotech companies to adjust their outsourcing requirements based on the specific needs of their development pipeline.

Finally, the understanding of regulatory requirements and quality assurance practices of CDMOs allows their clients to leverage this expertise to streamline their submissions, reducing the risk of regulatory hurdles and delays.

 Formulation development is a complex and expensive process, requiring comprehensive knowledge of excipients, dosage form characteristics and patient-specific drug delivery customization. Key benefits can be expected when outsourcing formulation development, including cost minimization, gaining a competitive advantage, and improved efficiency.

 Outsourcing provides easy access to highly specialized technologies and expertise, while reducing routine operational and capital expenses including laboratory rent, utilities, instruments, general maintenance, and employees’ salaries.

 Many outsourcing partners offer integrated, wide-ranging formulation development solutions that use high throughput screening and analytical technologies. Leveraging their vast prior knowledge and adopting the latest innovations, they look for continuous improvements. Customers can benefit from these advancements to make better decisions and stay ahead of their competitors.

 With platform approaches, qualified infrastructure, optimized inventory, and in-house expertise, an outsourcing partner can readily develop formulation solutions to move quickly into clinic. This allows clients, especially small/virtual companies, to focus on core areas and optimize cash flow while seeking growth opportunities.

To meet the rising demand for outsourced formulation services, especially in support of next-generation biologics, this sector will continue to see heavy investments and growth in the near future. Also, this space is rapidly experiencing the adoption of data analytics technologies, providing greater scientific insights for improved data-based decision-making.

Global Trends in R&D 2023.Activity, Productivity, and Enablers.


Volume 47, No. 9
September 2023
Pages 46-49

When referring to this article, please cite it as Thomas, F. Outsourcing Formulation Services for Biologics. 

The pandemic and shifting focus to more complex therapeutics are driving growth in the outsourced formulation development services market. 

Outsourcing Formulation Services for Biologics

Vaccine manufacturing within Europe is being supported financially as money flows into various operations through multiple veins. A prime example of such an investment was announced in early September by GSK, which is supporting manufacturing operations with €250 million being put up for a new facility in Belgium (1).

The British bio/pharma company’s plans are to create a new facility at its Wavre site in Belgium that will produce both non-living and live vaccines and seems to coincide with the launch of Arexvy—GSK’s new respiratory syncytial virus (RSV) vaccine. According to a news report, the new facility will be operational in 2027, with GSK expecting to manufacture tens of millions of doses per year at the site (1).

Other large American companies, such as Moderna and Pfizer, are also investing in European facilities. Moderna, for example, announced in March 2023 that it had selected Harwell Science Campus in Oxfordshire, United Kingdom, as the location for its new Moderna Innovation and Technology Centre (MITC) (2). The centre, which will incorporate R&D and a manufacturing facility, is expected to provide the UK public with access to messenger RNA (mRNA) vaccines for an array of respiratory diseases and should create hundreds of jobs for construction and then operation.

“When constructed, our facility at Harwell will harness mRNA science that aims to develop and deliver innovative vaccines to the UK public that address emerging threats from respiratory viruses facing our population,” said Darius Hughes, Moderna’s UK general manager, in a press release (2).

In December 2022, Pfizer announced that it would invest billions (approximately €2.4 billion), to expand its manufacturing capacities in both Ireland and Belgium (3). The huge financial input, €1.2 billion for each location, will add hundreds of jobs and allow the company to produce new medicines, such as Pfizer’s vaccine for RSV.

Further adding to the influx of cash is funding from the Transformative Medicine Manufacturing programme, provided by the UK’s innovation agency, Innovate UK, being used for a multitude of projects, including vaccine manufacturing (4). These investments will undoubtedly prove to be a beneficial and protective shot in the arm for European vaccine manufacturing.

1. Pronina, L. GSK Invests €250 Million to Allow Freeze-Drying of Vaccines. 

, 30 Aug. 2023.
2. Moderna. Moderna Selects Harwell Science Campus in Oxfordshire to Develop Moderna Innovation and Technology Centre in the UK. Press Release, 5 March 2023.
3. Erman, M. Pfizer to Invest More than $2.5 Billion to Expand European Manufacturing. 

, 2 Dec. 2022.
4. UKRI. £13 Million to Help Transform Medicines Manufacturing. Press Release, 22 Aug. 2023.

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

When referring to this article, please cite it as Thomas, F. Booster Shot for Pharma. 

European vaccine manufacturing is being boosted with high level investments.  

Booster Shot for Pharma

Pharmaceutical research and clinical trials concept. Medicine vial bottle for injection with vaccine and new pharmacy drug in pills and syringe under magnifying glass. Image Credit: © strigana - stock.adobe.com

Prior to a pharmaceutical product making its way into the supply chain, companies must perform extensive inspections to check for any potential defects and ensure the utmost quality. The market is leaning toward more complex therapeutics, which are sensitive to a variety of environmental factors and expensive to develop, and continuous, automated processes. These developments are making efficient inspection of the finished product ever more pressing.

Traditionally, finished product inspection is still widely performed manually; however, automating the process, either fully or partially, can allow for increased efficiencies in both time and cost (1). In fact, according to market research, the fully automated inspection machines segment, which comprised 42.5% of the market share in 2022, is predicted to experience significant growth between 2023 and 2032 (2).

To learn more about the evolution of finished product inspection, the types of automated technologies available, regulations, challenges, and future trends in the field, Pharmaceutical Technology® spoke with Wolfram Schindler, global product manager for Inspection Technology at Syntegon.

 Could you provide a brief overview on the evolution of finished product inspection?

 The first electronic particle inspection system was developed by the pharmaceutical company Eisai Co., Ltd together with the Technical University of Tokyo and patented in 1970. The ‘static division’ or ‘SD’ sensor technology, now belonging to Syntegon, is based on transmission light and a diode array to detect moving foreign particles in liquids but neglects static particles on the container surface. Five years later, the first fully automated inspection machine AIM275 was introduced to replace manual inspection at a higher output. Along with technical progress in machinery and imaging technology, today automated visual inspection machines can reach speeds of 600/min and more—two orders of magnitudes higher than manual inspection. Automated inspection is following the general trend from ampoules, vials, and pre-filled syringes to even more complex container types. This evolution poses challenges in terms of mechanical handling and vision capability. Since the early 1990s, camera technology has extended inspection capability towards non-moving particles and cosmetic defects like cracks in the glass or container-specific defects (ampoule tip shape, vial crimp, syringe flange, and stopper side, etc.).

Manual inspection is still widely used, especially for difficult-to-inspect parenteral products. For 100% batch inspection in general, however, choosing between manual or fully automated inspection is rather a question of batch size than technical capability. Finally, semi-automated inspection machines may bridge the gap between manual and fully automated inspection systems for several applications, offering a good balance between cost, speed, and inspection performance. Sometimes inspection approaches are combined. In a customer case involving molded glass, the human eye first identifies glass defects. The downstream automated inspection machine, which in this case would lead to high false reject rates for cosmetic defects in the inhomogeneous glass, is activated only for moving particle detection.

Besides visual inspection, physical methods for automated container closure integrity testing (CCIT) have been available on the market for decades, including high voltage leak detection (HVLD), the vacuum/pressure method and, for about 20 years, headspace analysis.

 What are the different types of automated finished product inspection technologies?

 The most common machine concept is pretty similar to the 50-year-old patent—a turret with inspection stations. Up to this day, an advanced version of the SD sensor technology is available, which various customers use for moving particle detection.

However, nowadays visual inspection is mainly based on matrix camera stations. Technical specifications of such stations may significantly differ in terms of frame rate, resolution, or dynamic range. Line scan cameras are another option (e.g., for 360° views without distortions). Depending on the requirements, one or more imaging technologies can be combined on the same machine. Particularly for lyophilized products, NIR [near infrared] spectroscopy or X-ray imaging may serve as a supplementary technology but are not that common.

Regarding CCIT, HVLD is widely used for leak detection of containers filled with conductive liquid. Another option for leak detection is the vacuum or pressure decay method. Laser-based head space analysis (HSA) is particularly suitable to identify both active and temporary leaks in lyophilized product vials. Beyond pure leak indications, the HSA measurement values such as total pressure, oxygen, moisture, or CO2 are important quality attributes per se.

 Are there any specific current trends impacting automated finished product inspection or any future trends that you could highlight?

 Finished product inspection should identify all relevant defective units from a quality standpoint but keep the false reject rate as low as possible from an economic and ethical perspective (e.g., think of blood plasma products). This ever-lasting key question is not trivial. Automated visual inspection and CCIT is best solved, according to Syntegon, through strong collaboration between client and vendor.

Difficult-to-inspect parenteral products, such as lyophilized products, are currently being addressed with novel technology. The challenge with lyophilized products is based on product characteristics like opacity, which makes it hard to detect particles as they do not appear on the products’ surface. Moreover, because lyophilized cakes often are not homogeneous but show cracks and rough surfaces, the distinction between particles and shadows is difficult. Product splashes on the containers’ wall also need to be clearly distinguished from particles or glass defects.

Deep learning (DL) approaches using artificial neural networks (ANN) are on the rise and will significantly improve within the next years with each new data set. DL holds the potential of further increasing detection rates and decreasing the number of false rejects compared to standard image processing tools, particularly for products with high variability among good samples (like lyophilized products).

For low outputs, robotic vision solutions together with artificial intelligence (AI) open a new path to inspect complex product-package combinations where classic automated approaches are not sufficient. When high machine speeds are required, accurate timing of cameras and lights, image processing time, and sensor signal accuracy are areas that need to be continuously optimized. Just like other advanced vision tools, AI will be increasingly considered and is currently undergoing feasibility studies in a growing number of projects.

The adequate use of the equipment is equally important, including a firm method development and validation strategy. The compilation of adequate test kits, as well as regular performance checks and re-calibration plans are vital for reliable detection processes.

In the future, there will be continuous expansion of inspection machines portfolios that combine visual and CCIT technologies at increased speed. New systems will incorporate advanced vision tools, and some CCIT sensor technologies are currently being developed further to be integrated into those solutions.

 How are regulatory bodies adapting to automation of finished product inspection? Are there any new guidelines that companies should be aware of?

 There has recently been an increasing awareness for calibration topics and a data-driven, scientific approach. Machines therefore include tools for trending and the recording of data, a dedicated sampling channel or special test modes to assist the users.

It is notable that the new EU GMP [European Union good manufacturing practice] Annex 1 (effective since August 2022) addresses visual inspection and CCIT with doubled text length compared to the 2008 version and highlights the importance of process knowledge. The guidance also stresses the need to generate a defect library, to categorize defects and to trend defect types and quantities.

Moreover, Annex 1 clearly advises to verify the equipment performance using representative defects before the start of inspection and during the batch. Finally, according to Annex 1, visual inspection alone is not seen as an acceptable integrity test method, which leads to the conclusion that it has to be combined with dedicated CCIT methods for that purpose.

Fraley, P. Automating Pharmaceutical Inspections for Efficient Delivery. Benchmark Brief, Burns & McDonnell, May 9, 2022.

Global Market Insights. Inspection Machines Market—by Product (Vision, X-Ray, Leak Detection, Checkweigher, Metal Detector, Software), Type (Fully, Semi Automated, Manual), Packaging (Ampoule, Vial, Syringe, Bottle), End-User, and Forecast, 2023–2032. Market Report (May 2023).


Vol. 47, No. 8
August 2023
Pages: 28–30

When referring to this article, please cite it as Thomas, F. Progressing Finished Product Inspection Through Automation. 

The industry is taking steps to automate the final product inspection process for complex therapeutics.

Progressing Finished Product Inspection Through Automation

Oral solid dosage (OSD) forms are commonplace within the pharmaceutical industry thanks to several advantages such a form can offer, including convenience of manufacture, ease of administration, and cost-effectiveness. According to market research, the OSD market outlook is favourable and expected to experience continued growth, driven by the low production cost—particularly within developing nations (1).

The manufacture of all pharmaceutical finished dosage forms, including OSD, must adhere to regulatory guidance and specifications to ensure quality and safety of the products are maximized. Current good manufacturing practices (CGMPs), for example, are the minimum standards that must be met and require a proactive quality approach be taken to the manufacture of finished products so that any risks, such as contamination, are minimized or eliminated (2).

CGMP requirements tend to be general and allow for manufacturers to implement quality controls on an individual basis. “The general expectations for CGMP, relating to OSD forms, revolve around ensuring consistent and acceptable product quality and safety,” confirms Dave DiProspero, senior fellow, Pharmaceutical Process, CRB. “This [practice] follows the traditional five Ps of GMP: people, premises, processes, products, and procedures. Regulatory guidance and good practices are based on these five Ps and focus on protecting the product from contamination and preventing any mix ups. Operations must be fully understood and in control.”

OSD regulatory guidance has been relatively current for many years, explains DiProspero, which is contrary to other areas of manufacturing, such as the sterile environment, where recent updates have been made via documents like Annex 1. “The US Food and Drug Administration (FDA) has issued various technical guidance documents [for OSD forms], most recently around continuous manufacturing; however, the most typical industry guidance is related to ISPE [International Society for Pharmaceutical Engineering Operations] OSD Baseline Guide Volume 2 and ISPE Good Practice Guide Continuous Manufacturing of OSD Forms” (3,4).

Within Europe, the European Medicines Agency’s (EMA’s) Committee for Medicinal Products for Human Use (CHMP) adopted updated manufacturing guidelines for finished dosage forms in 2017 (5). These updated guidelines addressed legislative requirements and followed the format of the common technical document (CTD) module 3 dossier. Additionally, the changes to manufacturing practices as related to the global, complex supply chains were reflected.

Although no major changes are expected to be made to GMP guidance for OSDs in the near future, DiProspero does point out that regulators are focusing more heavily on manufacturers of nutraceuticals and dietary supplements. “More guidance and closer alignment with [prescription] products are likely to occur in the years ahead,” he says. “Many of the major dietary supplement manufacturers are already greatly improving their facilities and processes to align with pharma facilities.”

“Continuous manufacturing has been the leading new processing platform paving its way in the development of new OSD products and conversion from traditional batch products,” notes DiProspero. It is known that regulatory authorities around the world have proactively supported the use of innovative manufacturing approaches, such as continuous manufacturing (6). “FDA have reacted very positively and strongly in advocating this platform and providing guidance on its use and implementation,” DiProspero confirms.

Recently, there has been greater harmonization around the regulation of continuous manufacturing, DiProspero continues. “The 2022 ISPE Continuous Manufacturing Good Practice Guide was heavily based on establishing a set of minimum equipment requirements for each type of system to function as a part of an integrated process train, making it easier for manufacturers and equipment suppliers to identify and define minimum attributes,” he says. “The March 2023 FDA guidance for industry (Q13 

Continuous Manufacturing of Drug Substances and Drug Products

) describes scientific and regulatory considerations for the development, implementation, operation, and lifecycle management of continuous manufacturing” (7).

“[Further,] FDA’s guidance builds on existing International Council for Harmonisation (ICH) quality guidance (Q13), providing clarification on continuous manufacturing concepts and describing scientific approaches and regulatory considerations specific to continuous manufacturing of drug substances and drug products,” DiProspero adds (8).

Ensuring compliance and quality in modern practices

Currently, to ensure compliance and improved quality of modern finished products, companies are working on improved process containment and closed or integrated systems, DiProspero highlights. “It has always been common to contain and close when dealing with hazardous/potent compounds, but [there are now] improved systems and operations for non-potent and non-hazardous,” he remarks. “Minimizing dust, controlling feed, and improving ergonomics and operator safety are among some of the most common best practices being seen in modern powder handling and OSD manufacturing operations.”

Baseline Guide Vol. 2: Oral Solid Dosage Forms 3rd Edition

. Guidance Document, November 2016.
4. ISPE. 

Good Manufacturing Practice Guide: Continuous Manufacturing of Oral Solid Dosage Forms

. Guidance Document, March 2022.
5. EMA. 

Guideline on Manufacture of the Finished Dosage Form

. Guidance Document, July 2017.
6. Wahlich, J. Review: Continuous Manufacturing of Small Molecule Solid Oral Dosage Forms. 

Q13 Continuous Manufacturing of Drug Substances and Drug Products

. Guidance for Industry, March 2023.
8. ICH. Q13, 


Vol. 35, No. 8
August 2023
Pages: 32–33

When referring to this article, please cite it as Thomas, F. Ensuring OSD Quality and Safety. 

Current good manufacturing practices for oral solid dosage forms protect the product from contamination and potential errors.

Ensuring OSD Quality and Safety

As Europe experiences extreme weather conditions—with sweltering temperatures in Southern areas, wildfires destroying parts of the Greek islands, and deadly storms affecting other parts of the region—it is becoming clear that more action needs to be taken to tackle climate change. For the pharmaceutical industry, tackling climate change is not just about cutting emissions but also about combatting the adverse effects on health that are linked to the warming world.

In 2021, the World Health Organization (WHO) reported that “climate change is the single biggest health threat facing humanity” and predicted that, between 2030 and 2050, it will cause approximately 250,000 extra deaths per year (1). Shortly after WHO’s report, during the United Nations Climate Change Conference of the Parties (COP26), held between 31 Oct. and 13 Nov. 2021, a public-private partnership—the Sustainable Markets Initiative (SMI) Health Systems Task Force—was launched, aimed at speeding up the delivery of net zero healthcare (2).

Members of the Task Force, who include CEOs of large biopharmaceutical companies and public bodies, collaborated on industry commitments that will help support the transition to sustainable healthcare. A year later, during the COP27 meeting in 2022, the Task Force set out some core commitments, actions, and recommendations for industry that focused on three priority areas—“supply chain, patient care pathways decarbonization, and the use of digital innovation in clinical research” (2).

The joint action of the members involved in the Task Force has continued with a further scaling up of targets for suppliers in the industry to try and reach a net zero target. Most recently, Task Force members published an open letter stressing the criticality of action on climate change within the industry, which laid out minimum supplier targets for climate and sustainability across the value chain (3).

Ultimately, climate change is already impacting global health negatively and only a significant collaborative effort is going to reduce that effect. As the Task Force members wrote, “Healthcare supply chains must become greener, more efficient, and circular … Shifting to net zero, climate resilient health systems cannot be achieved in siloes. We must collaborate, across the sector and across borders, to secure a healthier tomorrow” (3).

Open Letter on Supplier Targets from Members of the Sustainable Markets Initiative Health Systems Task Force

When referring to this article, please cite it as Thomas, F. A Healthier Tomorrow? 

Only a significant joint effort across the supply chain will help to make healthcare more sustainable and reduce the impact of climate change on global health.  