Parenteral product quality is improving. Since 2014, when 

<790> “Visible Particulates in Injections” (1) became official, particle-related recalls of injectable products have dropped significantly (see 

	However, “I want to be cautious and not give all of the credit to 

 <790>,” says John G. Shabushnig, PhD, owner and principal consultant at Insight Pharma Consulting and leader of the Parenteral Drug Association’s (PDA’s) Visual Inspection Interest Group. “There was a lot going on during this period including significant recalls from compounding pharmacies; however, I do think having clear guidance on inspection and acceptance criteria was a contributor to this drop.”

<1790> “Visual Inspection of Injections” (2) is another positive influence. Shabushnig says, “

 <1790> provides a more complete picture of good practices when implementing and operating a visual inspection program. It also clearly discusses a lifecycle approach to inspection, with an emphasis on continuous process improvement and using inspection data to drive that process. Defect prevention should always be the primary goal.”

	In addition, there continues to be a shift toward lower acceptable quality limit (AQL) values for acceptance sampling after 100% inspection, according to a benchmarking survey (3) performed in 2014 by PDA. Shabushnig says, “This trend is especially true for critical defects, having moved from 0.10% to 0.065%. More firms are classifying particles as critical defects despite an implied classification as a major defect, which would have a mean AQL of 0.65%, in 

 <790>. The subsequent PDA benchmarking survey for difficult-to-inspect products also showed that many firms have not adopted the supplemental (destructive) testing specified for these products in 

<790>. Examples include reconstitution of lyophilized or powder products or dilution or filtration of opaque or strongly colored solutions.”

Figure 1. FDA recall notices for particles in injectable drug products, 2010-2017. Prepared by John Shabushnig with data obtained from the FDA Recall and Safety Alerts Archive, www.fda.gov/Safety/Recalls/default.htm, accessed March 13, 2018. Figure is courtesy of John Shabushnig.

	Wider adoption of automated inspection ranks as another positive force on product quality. This effort begins with container production. “Aiming for zero defects in our pharmaceutical packaging production, we employ an automated inspection system (AIS),” reports Michael Feldhaus, director of Technology at Schott Pharmaceutical Systems. “This 100% visual inspection technology examines all key surfaces of our vials and cartridges and merges cutting-edge machine vision technology with our decades-long glass-forming expertise.”

	Feldhaus explains, “Camera inspection allows for inline process control. The sensitivity and reliability of the system enable us to perform 100% cosmetic inspection for vials and pen cartridges, resulting in high-quality pharmaceutical containers. In addition, the data help us optimize process control.”

	With quality control demands escalating continuously, both the software and hardware used for cosmetic inspection have improved significantly. “For example,” Feldhaus says, “we have further developed our AIS software, which creates a 3D image of the container based on visual material from multiple cameras with different light settings. This process allows the container surface to be analyzed in a more comprehensive way. Moreover, machine learning technology helps detect patterns and improve the process further. On the hardware side, higher processing power and improved illumination enable systems to provide more data and sharper images. In addition to using improved machinery, our employees regularly take part in training to strengthen their overall quality awareness and ensure our products meet high quality demands.”

	Makers of parenteral packaging components such as closures and stoppers also rely on automated inspection. Datwyler Pharma Packaging Division uses advanced 100% camera inspection technologies and improved lighting sources to ensure product quality throughout its manufacturing process. Increased processing power permits use of more powerful detection algorithms, which improve detection capabilities and minimize false rejects. As a result, “some of the most critical production defects have been brought to the lowest level ever recorded,” reports Dirk Vander Mierde, Datwyler’s site director in Alken, Belgium. Potential defects caught by the system include the presence of foreign matter, deformation, or damaged coating. In addition, any rejects undergo additional inspection to help identify ways to improve the process.

	On parenteral packaging lines, automated inspection tends to be limited to high-volume operations due to capital and validation costs. As a result, manual inspection continues to dominate with approximately 50% of firms relying on it, according to the 2014 PDA benchmarking survey (3). Shabushnig reports, “Approximately 30% use automated inspection with the remaining 20% using semi-automated systems.” He notes, “This is actually a drop in the response rate for automated inspection since the 2008 survey (3). This does not, however, mean that fewer companies are using automated inspection; rather, there are differences in which companies respond to the survey each year. More importantly, the survey is structured so that each company/site has a single ‘vote.’ That vote counts the same if the company/site is making 10,000 or 100,000,000 units each year. If the results were normalized for units produced, I believe we would see more units inspected by automated systems. We should also note that manual inspection continues to be the reference visual inspection method in all of the pharmacopeias and that smaller-volume operations will continue to use manual inspection for the foreseeable future. Automated inspection does not ensure greater detection ability, and a well-run manual inspection process is very capable of delivering a high degree of security.”

	Meanwhile, automated inspection continues to evolve and protect product quality with enhanced lighting, flexibility, container handling, and speed.

	“LED lighting has provided a great improvement to our automatic inspection machine (AIM) in several ways,” reports Jose Zanardi, head of Vision Technology Engineering at Bosch Packaging Technology. LED lighting reduces downtime due to less frequent bulb changes and post-change verification. It also provides a consistent light level, eliminating the need for the inspection machine to compensate for light degradation. Compared to the halogen lighting it replaces, LED illumination generates less heat, eliminating concerns about product exposure to potentially damaging temperatures and the need for time-out programming for lamps.

	“LED lights offer both precision and flexibility,” says Christopher Nerreau, area sales manager at Laetus US, which introduced LED lighting for machine vision in 1994. Combining low cost and easy implementation, options address virtually any application with bicolored, ultraviolet, or standard LED illumination.

	Higher resolution cameras and customizable software also enhance flexibility. For example, Bosch’s Halcon vision system in its flagship AIM 8 series provides a standard vision tool that can be customized to maximize identification of visual defects. Zanardi notes customized inspection algorithms are essential to protect the quality of parenteral products. He explains, “Most of the medicines produced today pose challenges for inspection due to product clarity, viscosity, and fill volume, as well as container challenges such as dual chamber design, increased use of plastic, and influence of siliconized components, which attract both product and foreign particles.”

	Other new features on equipment from Bosch include a patented, dynamic puck material handling system. It eliminates glass-to-glass or glass-to-hard-surface contact and minimizes size changeover time via a semiautomatic puck exchange system. Finally, Bosch has developed a fourth-generation static division unit. The SD4 module inspects particles in motion and offers the highest reliability for solutions and light suspensions with easy-to-develop recipes and validation.

	Despite advancements in software, off-line image storage and analysis, and inspection speed, automated inspection systems using machine vision still pose challenges related to tuning and validation complexity. “Machines also have difficulty in managing the ‘normal’ variation found in many container closure systems,” says Shabushnig. “This difficulty is especially true for molded vials, which results in a high false reject rate (i.e., acceptable units that the machine rejects to assure that true rejects are detected with sufficient sensitivity and certainty).”

	In addition, challenges remain with line integration and interpreting inspection results. Shabushnig explains, “In most cases, a scratch and a crack look the same to a machine yet have differing risks to patients (critical vs. minor). This limitation makes analyzing reported inspection results difficult and often requires a reinspection of rejected units to assess the type of defects found in the batch.”

	For optimum line performance, automated inspection must integrate with equipment before and after filling. Nerreau notes, “There is a wide variety of parenteral products requiring vision solutions. Some examples include: using color identification to recognize color-coded needles, pattern matching to identify missing products in the package, optical character recognition to identify expiration dates on vials, and serialization for security.” Each application poses challenges for machine integration. 

	Prior to filling, inspection equipment typically connects to exterior washing or capping machines. After filling, the typical connection is to container closure integrity testing equipment using high voltage or laser headspace or vacuum technology, or to a re-nester/re-trayer for syringe applications. “Ensuring proper container transfer with sensors to manage product flow is essential to the integration process,” says Zanardi. In projects where glass-to-glass contact must be eliminated, precise design engineering is necessary to assure that container handling and machine starts and stops do not damage the product or the machine.

	“To perform complex image processing tasks in quality control environments, it is essential that the camera and lighting systems are tailored to the specific application,” says Nerreau, adding, “It is imperative for any machine integration to include extensive discussions and intensive consultations early on, along with a personal survey of the production environment.”

	With the industry focused on quality improvement, visual inspection continues to be a hot area, reports Shabushnig. A project at PDA is addressing visible particles in injectable products, with a current focus on improvements to the primary packaging materials. It seeks to better understand the risks as well as methods to detect and control particles in these components. This project is supported by both pharmaceutical manufacturers through the Pharmaceutical Manufacturers Forum and a number of primary packaging component manufacturers.

	PDA’s Visual Inspection Interest Group meets in April 2018 in the United States and in Europe to discuss the draft revision of Annex 1 (4). “Changes included significant expansion of sections associated with visual inspection and container integrity,” says Shabushnig. In addition, PDA continues to provide hands-on training in the area of visual inspection in the US, Europe, and Brazil. 

	Meanwhile USP continues to review comments and Â­suggestions for 

 <790> and <1790>. “Current topics of interest include the selection and use of sampling plans for 

 <790> and using risk-based methods to set alternative acceptance criteria for particles,” reports Shabushnig. “The Expert Panel responsible for these chapters is always interested in feedback to improve the understanding and use of these chapters,” he concludes.

	1. USP, USP General Chapter <790>, “Visible Particulates in Injections” (US Pharmacopeial Convention, Rockville, MD, 2014).
	2. USP, USP General Chapter <1790>, “Visual Inspection of Injections” (US Pharmacopeial Convention, Rockville, MD, 2017).
	3.  J. Shabushnig, “PDA Survey: 2014 Visual Inspection”  (Parenteral Drug Association, 2015).
	4.  EC, Consultation Document for Revision to EudraLex Volume 4: Good Manufacturing Practice Guidelines, “

Annex 1, Manufacture of Sterile Medicinal Products


	Vol. 31, No. 4
	April 2018
	Pages: 32–35

	When referring to this article, please cite it as H. Forcinio, "Improving Visual Inspection," 

Articles

Features

RGtimeline/Shutterstock.comParenteral product quality is improving.

Improving Visual Inspection

The purity (aggregates, host-cell proteins, host-cell DNA, etc.) and structure (sequence of amino acids, post-translational modifications, folding, etc.) of proteins directly impact the safety and efficacy of any formulated drug product based on them. Because proteins are generally produced as a mixture of similar but different biomolecules using living cells and subjected to extensive purification steps, variations in their structure and purity can occur from batch to batch.

	The International Council for Harmonization (ICH) guidance Q6B, 

Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products

 (1) established guidelines for setting specifications for biologic drug substances, including determination of their composition, physical properties, and primary and higher-order structures, using appropriate methodologies. Comprehensive characterization of proteins is often challenging, however, given their complexity. In many cases, singular analytical methods cannot provide the complete picture for specific attributes. Orthogonal methods-different methods intended to measure similar attributes-are often necessary to provide independent confirmation of protein properties. Protein particle characterization is no exception.

	The key when selecting orthogonal analytical methods is to choose technologies that overlap in complementary ways to provide a complete characterization of the protein in question, according to Kent Peterson, president and CEO of Fluid Imaging Technologies. The first step is to identify the information that is required for protein characterization and which techniques can provide that information-and the information that each cannot provide. “It is important to keep in mind that different techniques may provide the same information, but produce different results due to their varying technologies,” Peterson says.

	Proteins, as well as all types of monoclonal antibodies and gene and cellular therapeutics, differ in terms of their structures, biological activities, and purity profiles. Consequently, while different sets of orthogonal technique strategies may be used for different biologics, true “toolbox” approaches or platforms may not be completely successful, according to Mike Merges, director of strategic growth for Catalent Biologics.

	As a result, Catalent, when developing strategies for assay or method development and optimization, considers a combination of one factor at a time (OFAT) to define individual factors, at least initially, and design of experiment (DoE) to look at multiple and interacting factors. “The use of fractional factorial DoE as soon as is practical allows for a more rapid and robust development of a set of orthogonal methods,” Merges adds.

	When it comes to particle analysis, Peterson notes that different techniques rely on different detection principles ranging from fairly basic (visual/microscopic inspection) to high-tech methods (resonant mass measurement [RMM], analytical ultracentrifugation [AUC]) and cover a wide range of particle sizes. “No single technique provides all of the answers. Two different techniques provide more data than just one,” he observes.

	Effective sets of orthogonal methods “follow-the-molecule,” according to Merges. Timeliness, cost-effectiveness, and accuracy are other important factors, according to Peterson.

	In addition, Merges notes that the ability to validate the techniques and transfer them from the development phase/lab to the quality control phase/lab or even to an outside contract research organization are essential.

	“Validation is accomplished in a phase-appropriate manner,” Merges continues. The overall guidance for all phase-appropriate levels is ICH Q2 (R1) (2), although different technical platforms (e.g., enzyme-linked immunosorbent assay [ELISA] or bioassay potency tests) may have specific levels of adherence to the ICH guidelines and/or other pieces of guidance, such as 

	“The establishment of appropriate validation acceptance criteria should be based upon data-driven decisions. Those data are best generated via a pre-validation exercise conducted prior to the drafting of each phase-appropriate validation protocol,” he explains.

	Orthogonal techniques for particle characterization

	When it comes to particle characterization, Petersen points out that collection of imaging data is one of the accepted techniques for acquiring size, shape, and other morphological information used to differentiate protein aggregates from other particles in the formulation. “The nature of the particles in protein formulations and the small sample volumes pose a challenge in that throughput, accuracy, and specificity are met by very few technologies, however,” he comments.

	Different techniques have different strengths and weaknesses for addressing these challenges. “For example,” Petersen observes, “particle count can be obtained by various particle analyzers, including single-function particle counters, light obscuration (LO) instruments, and flow imaging microscopes (FIMs). However, only some FIMs offer light and dark pixel thresholding that enables the detection of translucent proteins, while these proteins go undetected by other technologies.” 

	More specifically, LO provides particle count and concentration for large sample volumes. It provides the ability to analyze large volumes relatively quickly, has been around for a long time, and is seen as the first step in particle analysis, according to Peterson.

	It does not capture morphological information about the particles contained in the sample, however, nor does it accurately detect or record translucent to semi-translucent particles, according to Peterson. “In LO, the signal from each particle is converted to a sphere of correlative size, and what is actually measured is the equivalent spherical diameter (ESD) of the generated sphere. We know, however, that not all protein particles are spherical in shape, so this method does not produce the most accurate size distribution,” he explains. LO is an inexpensive and quick method that has been in use for decades despite these limitations due mostly to the fact that it remains a USP compendial method.

	FIM, on the other hand, enables the detection of particle sizes ranging from 300 nm-5 mm and reveals morphological characteristics of the particles imaged. In addition, FIM can detect translucent, semi-translucent, and opaque particles and allows for the differentiation of protein aggregates and non-proteinaceous particles.

	Currently, light obscuration and membrane microscopy are required by USP regulations, and flow imaging microscopy is being rapidly embraced globally, according to Peterson. The combination of technological advancement and the industry’s acceptance of the need for a better method to fill the gap where methods like LO left a lot of unanswered questions-specifically for smaller micro- and nanoparticle analysis-have paved the way for newer methods to become widely accepted, he explains. “Better data from imaging flow microscopy provides morphological characteristics of the particles analyzed and answers these questions while providing a more detailed analysis,” he says.

	Nanoparticle analysis lacks many orthogonal components. Historically, imaging in flow could not address this size range, according to Peterson, so information on size and shape and transparency through the imaging of nanoparticles had been missing. Newer technologies such as nano-flow imaging from his company are addressing this need. Automated membrane microscopy from HALO Labs and hyperspectral imaging from Spheryx are also offering promising solutions. “Until recently, there has been no imaging capability for flow imaging microscopy of particles in the nanometer size range. The FlowCam Nano imaging instrument from Fluid Imaging Technologies is an oil immersion flow microscopy technique that provides optical resolution down to the hundreds of nanometers,” Peterson says.

	The breakthrough technologies described herein are examples of solutions being developed by instrument manufacturers in response to the needs of formulation development scientists for orthogonal analytical techniques for protein characterization. Bringing them to the market is increasingly difficult, however, according to Peterson. “There seems to be a growing lag time between commercial implementation and regulatory acceptance and requirements. These delays may be jeopardizing the timely, widespread use of technologies that can significantly contribute to the safely and efficacy of biotherapeutic drugs,” he asserts.

Test Procedures and Acceptance Criteria for Biotechnological/Biological Products

, Step 4 version (ICH, 1999).
	2. ICH, Q2(R1) 

Validation of Analytical Procedures: Text and Methodology

, Step 4 version (ICH, 1994) (Complementary Guideline on Methodology dated 6 November 1996 incorporated in November 2005).
	3. 

 General Chapter <1033>, “Biological Assay Validation” (US Pharmacopeial Convention, Rockville, MD, 2010).
	4. 

 General Chapter <1034>, “Analysis of Biological Assays” (US Pharmacopeial Convention, Rockville, MD, 2012).


	Vol. 31, No. 4
	April 2018
	Pages: 20–24

	When referring to this article, please cite it as C. Challener, "Multiple Views Deliver Complete Characterization of Protein Particles" 

Access to multiple analytical techniques is essential for fully characterizing complex protein formulations.

Multiple Views Deliver Protein Particle Characterization

Continuous chromatography processes use the same resin and buffer systems as batch counterparts, but in a smaller footprint with less resin and buffer consumption. Switching from batch to continuous allows for improved resin capacity utilization through continuous loading (overloading, in fact) of the column or membrane for increased process efficiency. It is particularly attractive for sensitive biomolecules that need to be rapidly separated from the other components in bioprocess solutions.

	Some regulatory aspects must still be addressed, however, and for companies with extensive existing infrastructure, switching to continuous chromatography might not be cost-effective.

	In batch chromatography, one large column is used. In continuous multicolumn chromatography, the large column is effectively split into a number of much smaller columns that operate in series over a larger number of cycles. While product is loaded on some columns, other columns in the set are going through the wash, elution, and regeneration phases. By allowing simultaneous operation on many columns, continuous chromatography is more efficient with time and resin, according to Michelle Najera, senior development scientist for downstream product development for AGC Biologics. “The load phase can be split into two columns in series as well, allowing more product to be applied to a given volume of resin since unbound product from the first column is easily collected by the second column in the load phase,” she adds.

	Different vendors offer different formats; in some cases up to eight columns can be used, according to Peter Levison, senior marketing director for downstream processing at Pall Biotech. “Multicolumn chromatography has long been an accepted continuous purification practice by small-molecule manufacturers, but is just now gaining traction in the biomanufacturing space,” he says.

	Continuous chromatography systems are designed to be loaded continuously, which is a useful approach when the purification step is connected to an upstream perfusion bioreactor. There are several different techniques available, including simulated moving bed (SMB) and periodic counter current chromatography (PCC). The aim is the same for all: to achieve a continuous (over) loading of the columns or membranes, and thereby improve the process efficiency through increased resin capacity utilization, according to Lotta Molander, senior product manager with GE Healthcare Life Sciences. “This approach also allows a chromatography step to be run with less safety margins than would normally apply in a traditional batch process without loss of product,” she says.

	Some systems come with flow paths that are designed to be cleaned and reused, while others are flow paths that are single-use. Some systems come with dynamic control functionality-process analytical technology (PAT)-that enables the continuous chromatography unit operation to better adapt to changes in feed concentration (when connected to a bioreactor) or differences between columns in real-time, assuring steady state operations and a robust/stable output from the chromatography step, Molander notes.

	Why should you move to continuous chromatography?

	Regardless of the technical solution used for continuous chromatography, it can offer advantages compared to traditional batch chromatography through the improved utilization of resin capacity, according to Molander. “Data indicate that more than one column offers better efficiency, and greater yield of product per unit volume of chromatography resin per unit of time. That means that because the columns are smaller, less resin volume is used, and it can be used much more efficiently, thereby saving cost,” Levison states.

	In turn, a decrease in the equipment footprint and floor space requirements in classified areas is possible, because unit operations can be downsized, particularly when two or more unit operations are connected in a fully or semi-continuous/hybrid production process, according to Molander. Buffer consumption is also reduced.

	Manufacturers are always trying to optimize their processes, particularly as product titers increase, according to Levison. In the case of antibodies, the industry is now working well above 3 g/L, even up to 5 g/L, with titers of 10 g/L being described. “To really maximize productivity, the kinetic effects of adsorption:desorption of protein to the resin become important, and drive demand for more columns in order to operate at high flow rates while maximizing the productivity benefits of continuous chromatography,” Levison observes.

	In the clinical manufacturing setting, Levison notes that users are looking for more efficient use of the resin lifetime by cycling more frequently compared to batch. “Clinical manufacturers are motivated to cycle as much as possible using fairly short residence times in order to use less resin early on when the future outcome for a given molecule is still unknown,” adds Najera. She points out that commercial manufacturers, on the other hand, may use a strategy where slightly longer residence times are used to reach high resin loading because the maximum number of cycles will eventually be reached for a commercialized molecule with steady demand for the drug. “The real benefit,” asserts Levison, “is overall greater productivity and improved process economics based on reduced resin requirements and reduced buffer usage.”

	As a contract manufacturer that produces a significant amount of clinical material, AGC Biologics’ current goal with continuous chromatography is to more efficiently use resin so that less is required to make clinical material, according to Najera. “The cost for resin makes up a significant portion of the cost to manufacture clinical material. Resin reduction is achieved by cycling the resin more intensively than traditional chromatography,” she explains.

	In addition to cost savings, Molander notes that the steady state operation that can be achieved with continuous chromatography can also give additional process robustness and control and lead to improved product quality levels, which can be particularly useful when processing unstable molecules.

	Access to single-use continuous chromatography systems is also advantageous, according to Levison. “With the ability to operate at higher titers or cell densities, there is a drive to reduce bioreactor volume. If a manufacturer can reduce its process to a 2000-L bioreactor, or multiple 2000-L bioreactors, facilities become much easier to build with shorter construction times and reduced cost. In this case, single-use chromatography becomes a very desirable component of the entire single-use process,” he explains. 

	Importantly, according to Jim Sulzberger, process chromatography consultant with Bio-Rad Laboratories, the advantages of continuous chromatography-increased utilization of chromatography media binding capacity, significant reduction in buffer consumption, increased adoption of single-use buffer pathways and pre-packed large columns, decreased capital costs, and lower real estate costs-can be achieved using all of the same types of media originally developed for batch processes. He also notes that the advent of new membrane chromatography devices and chromatography media with hydrophilic base beads and high ligand densities will maximize the impact of continuous operations.

	When should you move to continuous chromatography?

	Traditional chromatography steps can create bottlenecks in the process because they can be time and labor intensive. Continuous multicolumn chromatography, according to Levison, overcomes this barrier and can be applied to pretty much any batch process. “The transition is not difficult. The manufacturer just needs the right equipment and expertise; the processes use the same buffers and resins as used in their current batch processes,” he says. “Ultimately, if you want to work faster, continuous multicolumn chromatography is an excellent solution for both small- and large-molecule processes,” he states.

	Continuous chromatography can be an excellent choice when working with sensitive molecules, where continuously removing the molecule from a potentially harmful environment into the first purification step can be the only viable option, according to Molander. She adds that in scenarios where there is limited product demand (in kg), continuous chromatography using a higher number of cycles in the available time can allow significant reduction of the needed resin volume.

	For Sulzberger, continuous chromatography should be of interest for all processes that start with a capture step and where there is a desire for straight through processing. “The premise behind continuous bioprocessing is a decrease in consumable costs and an increase in process productivity. Process development is the same in terms of selectivity, but there are changes in terms of engineering concerns surrounding efficiency and capacity. For current commercial processes, however, many continuous chromatography platforms have software that aids in converting a batch process to a continuous process,” he comments.

	Protein A capture steps are the most common application for continuous chromatography at AGC Biologics. “The resin is expensive and therefore the potential cost of goods savings is substantial,” Najera observes.

	When considering continuous chromatography for a new process, Molander does add that the benefits from continuous processing should be balanced with the risk of delayed regulatory process applications and thereby time to clinical trials and market introduction. “Even though regulatory agencies are very supportive and collaborative when it comes to companies introducing different process intensification initiatives, there is still, to my knowledge, no approved biopharmaceutical product with a continuous chromatography step, and some aspects/questions in the area that could still benefit from further clarifications,” she says.

	Why you should not move to continuous chromatography

	Not all chromatography steps are suitable for continuous processing. For instance, when a manufacturer is using a chromatography adsorbent that requires a longer contact time between the ligand and ligate to get effective interaction, continuous multicolumn chromatography may not be the best option, according to Levison. He points to some affinity processes that need to have extended contact times and need to run slowly; the efficiencies of continuous chromatography would not be realized in these cases. Switching from batch to continuous chromatography would also not make sense for processes that are minimal or only run once per year.

	Continuous chromatography is not recommended when a chromatography step is not well understood, is expected to experience significant variability, or may be modified later, according to Najera. “One thing we like to remind ourselves is that we should fully understand all aspects of a process step run in batch mode before it is modified to a continuous step,” she notes.

	For companies with a large installed base of equipment and facilities plus well-established platforms and infrastructure, GE Healthcare sees an increased interest in addressing process efficiency initiatives in different ways,” according to Molander. “The producers want to maximize the use of existing resources with few changes to standard operating procedures, rather than invest in new equipment for continuous chromatography,” she says. 

	Contract manufacturers face other issues. AGC Biologics often has less ability to make modifications toward continuous chromatography for commercial processes, according to Najera. “Modifications to commercial processes may require additional regulatory filing activities. Making the switch to continuous chromatography at this stage is therefore less appealing for our clients,” she observes.

	Outside of increasing early adopters of continuous chromatography, there are two improvements that need to be addressed to keep continuous processing on the path to become the new purification paradigm, according to Sulzberger.

	The first issue relates to sensor and PAT for enhanced process -monitoring and real-time release of the product to next-unit operation, according to Molander. “PAT and analytical methods that allow a process to continue running while providing feedback on critical quality attributes of a particular purification step have not evolved at the same rate as their process science counterparts,” Sulzberger says. Since PAT is not yet a viable reliable option, he notes that how often and when to have hold steps to perform quality checks is a required discussion.

	Reporting and analysis tools for time-based data (i.e., chromatograms) need some improvements as well, according to Najera. “We are going from chromatograms for just a few cycles to often over 100 eluate peaks per continuous sublot. There needs to be a way to analyze and report these data seamlessly, as well as detect adverse trends in performance,” she explains. 

	Regulatory aspects are the second area of concern. Here, Levison believes that advances can be made as more data are generated. “In this instance, there is a great benefit of starting from the process development step to document scalability,” he notes. 

	The discussion topic for Sulzberger focuses on whether there is sufficient guidance from regulatory agencies on how a ‘batch’ is defined. “If there is a truly continuous process, when are lot numbers assigned during the process? If there is ever a recall of a drug product, how large of a batch would need to be recalled given lot definition and how far back in the process should the proper investigation be extended?” he asks. 

	“Collaboration between industry leaders, early adopters of continuous chromatography and continuous processing in general, and regulatory agencies will be paramount in appropriately defining such guidelines and requirements,” Sulzberger asserts.

	Finally, Molander notes that the industry is in the early days of adoption of connected processing techniques in the biomanufacturing workflow. “More modular, plug-and-play equipment designs that can fit in seamlessly to different automation backbones would help accelerate that transition,” she observes.

	As with all new technologies, Sulzberger notes that there will be a learning curve, with some scientists/companies quick to adopt continuous chromatography. “Early adopters of continuous chromatography will see more efficient production, and by extension lower cost of goods for their final products. Additionally, they will be able to construct smaller production sites due to the reduction of skids and columns required to produce a given number of batches of a particular pharmaceutical product,” he says.

	“It comes down to adoption,” agrees Levison. “Open access to real-world experimental data that demonstrate the efficiencies of continuous multicolumn chromatography is essential. As more large-scale applications get published, there will be more demonstrations of scalability, which will advance adoption,” he concludes.


	Vol. 31, No. 4
	April 2018
	Pages: 14–18

	When referring to this article, please cite it as C. Challener, "Making the Move to Continuous Chromatography" 

Early adopters are benefiting from lower costs and increased productivity.

Making the Move to Continuous Chromatography

Keystone Folding Box has added a new line of secondary packaging systems for injectable pharmaceutical products. The products are available in custom all-paperboard and plastic-hybrid designs for prefilled syringes, auto-injector pens, vials, and ampoules.

	The systems are suitable for automated or manual production, as well as for clinical trials and full-scale commercialization. Keystone states that the product materials are compatible with low-temperature exposure, making them appropriate for typical temperatures associated with the cold-chain distribution of injectable products.

	The collection includes the Vial Pack line of cartons for packaging single or multiple vials or ampoules and Injectable Packs suitable for prefilled syringes or auto-injector pens, which can be designed to include ancillary items such as sterile wipes, according to the company. The InjectaSlide package includes a thermoformed tray that slides inside a carton and into a locked position. The locking function is enabled by a lock-release button that must be pressed to unlock and slide the tray forward for access to each dose.

	Additional features include child-resistant functions for several of the products and dosage-scheduling functions for in-home use of multi-dose packs, which can remind patients to administer the correct dose at the proper date and time.

Product Spotlight

Keystone Folding Box has added a new line of secondary packaging systems for injectable pharmaceutical products.

Secondary Packaging Solutions for Injectables

The Concentrating Pipette Select from InnovaPrep is a small automated benchtop instrument that can concentrate contaminates from large volumes of liquids for improved detection. The instrument allows for contamination screening of liquid samples up to 5L and lets users choose from six versions of interchangeable, high-flow filtered pipette tips that feature different specifications to concentrate proteins, viruses, DNA, bacteria, whole cells, fungal spores, or other particles. Recovered particles are delivered in seconds and ready for analysis using user method of choice, according to the company.

	Applications for the pipette include biological and particulate contamination monitoring in the environment, as well as monitoring the integrity of various ingredients including water, intermediate products such as cell culture media, and finished products including parenteral fluids and compounded drugs.

	According to InnovaPrep, when used as a front-end to rapid molecular methods for quality assurance/quality control monitoring, the instrument allows for sample-to-answer within a single shift, improving detection of trace contamination. 

The Concentrating Pipette Select from InnovaPrep is a small automated benchtop instrument that can concentrate contaminates from large volumes of liquids for improved detection.

Automated Benchtop Pipette

Q. I work in the warehouse and am responsible for maintaining the paperwork associated with incoming and outgoing shipments, including the certificates of analysis (CoA). Can you explain what should be on CoAs and how they relate to GMP compliance?

	A. The International Pharmaceutical Excipients Council defines a CoA as “a legal document that certifies the quality of the excipient and demonstrates the batch conforms to defined specifications, has been manufactured under excipient GMP, and is suitable for use in pharmaceuticals” (1). The same definition can also apply to finished product. Basically, it is a document that confirms a product (an API, excipient, or final product) meets defined and expected criteria that render it suitable for use. It is typically issued by the quality assurance department and lists the actual test results performed as compared to the specification range for the various parameters tested. In addition to the test results and specification range, the CoA should also list the batch number or lot number of the material, the manufacturer and their location, the date the material was produced and, if applicable, the expiration date of the particular material associated with the CoA. It should also have the identity and signature of the person who approved the certificate along with the date of approval. The World Health Organization (WHO) has a document on their website titled, “Model Certificate of Analysis”. This document has a comprehensive list of information suitable to be included in a CoA. The model CoA was developed in conjunction with the 

Guidelines on the Implementation of the WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce

	The CoA plays an important role in GMP compliance. The safety of the pharmaceutical supply chain is of concern to regulators, manufacturers, practitioners, and patients. The process of assuring the suitability of suppliers of pharmaceutical ingredients or products typically starts with an audit. Once the audit is completed and the supplier has been approved, the purchasers need to be able to monitor the credibility of their suppliers. CoAs help because they assure the continued quality of the product by providing “a summary of testing results on samples of products or materials together with the evaluation for compliance to a stated specification” (3). The European regulations require that “Authentic Certificates of Analysis should be issued for each batch ….” (4).

	The veracity of the CoA, however, still needs to be confirmed by the purchaser. When a supplier is new, the results of the CoA are usually confirmed for each shipment of the material by performing independent verification of the CoA results. Once a history of reliable and accurate results from the supplier is established, the purchaser will often perform skip lot testing, in which they verify the CoA results on a defined periodic basis, with the exception of the identity test, which should be performed for each shipment of material received (5).

	Not all materials need to have the results of the CoAs retested to assure their accuracy. Some latitude is given for drug product containers and closures. Some of the tests that need to be performed to verify the results on the CoA for containers and closures may not be practical for the purchaser to perform. In this case, the CoA becomes the evidentiary proof that the material was safe for use. The 21 

 states, “Containers and closures shall be tested for conformity with all appropriate written specifications. In lieu of such testing by the manufacturer, a certificate of testing may be accepted from the supplier, provided that at least a visual identification is conducted on such containers/closures by the manufacturer…” (6). The purchaser still needs to establish the reliability of the container/closure suppliers through the audit process, but CoAs can be used to help determine the consistency of the supplier over a period of time by comparing and trending the CoA results. 

	CoAs are important documents for ensuring the safety of the supply chain. They allow users of pharmaceutical ingredients to monitor and trend the reliability of their suppliers over time and they provide information to the practitioner and patient that the product they are prescribing has meet the necessary requirements. The information contained in these documents is important for establishing the suitability of all the materials and their suppliers (API, excipients, components, containers, closures) used to manufacturer a pharmaceutical product. Using the CoA to track all your suppliers’ reliability over time just makes good business sense.

Certificate of Analysis Guide for Pharmaceutical Excipients, International Pharmaceutical Excipients Council 

EudraLex Volume 4, Good Manufacturing Practice, Medicinal Products for Human and Veterinary Use

, Part I, Basic Requirements for Medicinal Products, Chapter 4: Documentation (EC, 2010).
	4. European Commission, 

EudraLex Volume 4, Good Manufacturing Practice, Medicinal Products for Human and Veterinarian Use

, Part II: Basic Requirements for Active Substances used as Starting Materials (EC, 2014).
	5. 21 

 211.84(d)(2), Testing and approval or rejection of components, drug product containers, and closures.
	6. 21 

 211.84(d)(3), Testing and approval or rejection of components, drug product containers, and closures.


	Vol. 31, No. 4
	April 2018
	Page: 45–46

	When referring to this article, please cite it as S. Schniepp, "CoAs Help Secure the Supply Chain" 

Ask the Expert

Certificates of analysis can be used to monitor the reliability of products and their suppliers, says Susan Schniepp, distinguished fellow at Regulatory Compliance Associates.


CoAs Help Secure the Supply Chain

	A lethal influenza outbreak this past winter has spotlighted the importance of improving and accelerating vaccine discovery and production. Reports that this year’s flu vaccine was only 36% effective have raised concerns about continued use of egg-based production systems that appear outdated and less reliable. And the imperative to combat infectious disease outbreaks and deadly conditions such as malaria and tuberculosis emphasizes the need to modernize and streamline vaccine testing and manufacturing. 

	A source of optimism is continued development of new, more effective inoculations. In 2017, FDA’s Center for Biologics Evaluation and Research (CBER) approved GlaxoSmithKline’s new Shingrix vaccine against shingles and a new recombinant hepatitis B preventive from Dynavax Technologies featuring a new adjuvant to boost immune response. A 

 from the Pharmaceutical Research and Manufacturers of America (PhRMA) in late 2017 lists 264 vaccines in development, including 137 for infectious diseases and more than 100 for cancer (1). And while vaccines are expensive in the United States, costs in low- and middle-income countries are dropping as regional producers such as India’s Bharat Biotech gain World Health Organization (WHO) prequalification for important preventives. 

	Vaccine discovery, however, remains challenging and unpredictable for the biomedical research community and industry. Even though increasingly effective vaccines are eliminating diseases such as polio and diphtheria and helped stem the Ebola outbreak three years ago, promising candidates often fail. Sanofi recently halted distribution of its dengue fever vaccine in the Philippines after some patients developed the disease following injection (2). 

	Such setbacks fuel anti-vaccine campaigns around the world, as seen in attacks on inoculation programs to combat a yellow fever outbreak in Brazil and on measles vaccines in the United States and Europe. Rumors of health risks continue to discourage vaccination of teens against human papillomavirus (HPV) despite evidence that it can prevent cancer. 

	FDA Commissioner Scott Gottlieb, MD, voiced strong support for vaccines at his Senate confirmation hearing in April 2017, where he dismissed as groundless claims of a causal link between vaccines and autism, distancing himself from earlier challenges to vaccine safety by President Trump. In an announcement of spending priorities for 2019, Gottlieb highlighted the importance of advancing manufacturing technologies for drugs and biologics, including vaccines. He

that continuous manufacturing platforms can help ramp up vaccine supply on short notice and that FDA clarification of its requirements and standards should encourage industry investment in new technologies and opportunities (3). 

	FDA support is important in maintaining an efficient development and review process to deliver vaccines that meet high standards to ensure product safety and quality. FDA is applying lessons learned from Ebola to streamline vaccine development, noted Philip Krause, deputy director of CBER’s Office of Vaccine Research & Review (OVRR), at the January 2018 WCBP symposium in Washington, DC. Krause emphasized how FDA strives to review and approve submissions and manufacturing supplements in a “sensible” way that emphasizes good science. CBER also encourages manufacturers to meet with FDA staff to address chemistry, manufacturing, and controls (CMC) issues before filing an application.

	Robin Levis, deputy director of OVRR’s Division of Viral Products, further described how FDA’s Fast Track and priority review programs facilitated development of Ebola vaccines and other preventives. To keep pace with accelerated clinical testing of potential Ebola preventives, FDA collaborated with other regulatory authorities and WHO to gain convergence on key issues, such as exceptions to product characterization and testing procedures, and where certain aspects of process validation could be abbreviated. While FDA licenses only those vaccines supported by adequate and well-controlled studies and able to be manufactured in a consistent manner, Levis noted that there may be flexibility when combating epidemics, such as accepting supportive CMC data from platform-related products and specifications based on related products. Test vaccines also may be used prior to obtaining real-time stability data, especially for early clinical trials. 

	An accelerated pathway for vaccine testing, however, “puts the squeeze on the CMC window” for process definition, characterization, and qualification, commented Natalie Christian, integrated development and supply team lead at Merck, at the January WCBP symposium. Vaccine development may be even more challenging, she observed, due to limited platform technologies for these products, potential for process change during technology transfer, scale-up difficulties, and a need for additional qualification lots. Similarly, Cristiana Campa of GSK Vaccines in Italy emphasized that the complexity of vaccine development makes it important to define a control strategy for identifying critical quality attributes as early as possible to help screen and select adjuvants and to identify attributes to be tested in clinical studies. 

	Advances in designing small footprint, single-use bioreactors will provide vaccines quickly at greatly reduced cost, predicted Benjamin Damien, director of business development at Belgium-based Univercells. He said these developments will “transform the biopharmaceutical industry” by boosting local production and supply of high-quality vaccines in developing countries, while also expanding capacity for rapid response to epidemics and global threats. 

	Many of these initiatives have support from the Bill & Melinda Gates Foundation, which has led efforts for the past decade to spur vaccine development to combat global diseases. To enhance the process, Gates established the Medical Research Institute (Gates MRI) in Boston to work closely with scientists and biopharma companies on identifying, selecting, and optimizing production of novel vaccine candidates. Gates veteran Penny Heaton is building the MRI with the aim to eradicate malaria, accelerate the end of the tuberculosis epidemic, and prevent diarrheal deaths in children through developing new drugs, vaccines, biologics, and diagnostics. Heaton outlined plans at the WCBP symposium for supporting early clinical testing of products that then can be passed on to manufacturers for late-stage development and commercialization. She anticipates a strong focus on CMC issues, which she described as often the “number-one bottleneck” in vaccine development.  

	Meanwhile, the race is on to discover a universal flu vaccine that doesn’t require reformulation every year. A dozen candidates are undergoing preclinical and clinical testing at research institutions and commercial labs. This coincides with efforts to shift from egg-based to cell-based and recombinant DNA production technologies. In commenting on the effectiveness of this year’s flu vaccine, 

 that products made with cell-based methods appear more effective in protecting against the H3N2 virus than egg-based products (4). 

	Seqiris, a unit of Australia’s CSL, plans to produce 20 million flu vaccine doses this year using cell culture at its North Carolina facility, and Sanofi has linked with South Korean vaccine maker SK Chemicals to tap its cell-based vaccine production technology. A live attenuated intranasal FluMist vaccine from AstraZeneca’s MedImmune division, an alternative to painful sticks, is back on the US recommended list after a two-year suspension due to data indicating low efficacy.

	Despite the shortcomings of annual flu vaccination, health authorities continue to stress the importance of regular immunization to prevent thousands of deaths from influenza each year, particularly in children and the elderly. Hopefully, the research community will devise a more reliable and effective universal flu vaccine before the next, much-feared influenza pandemic strikes. 

	1. A. Powaleny, “New Report and Event Examine the New Era of Vaccines,” 

, Nov. 9, 2017.
	2. Sanofi, “Sanofi Updates Information on Dengue Vaccine,” Press Release, Nov. 29, 2017.
	3. FDA, Statement from FDA Commissioner Scott Gottlieb, M.D., on 

Administration’s Request for New FDA Funding to Promote Innovation and Broaden Patient Access through Competition

, Feb. 13, 2018.  
	4. FDA, Statement from FDA Commissioner Scott Gottlieb, M.D. on the 

Efficacy of the 2017-2018 Influenza Vaccine


	Vol. 31, No. 4
	April 2018
	Page: 8–9

	When referring to this article, please cite it as J. Wechsler, "Modern Manufacturing Key to More Effective Vaccines," 

Regulatory Beat

Accelerated development of new preventives raises challenges for efficient CMC evaluation and production.


Modern Manufacturing Key to More Effective Vaccines

Many new biological entities use unique processing flows and steps that can require non-traditional thinking about process validation. Large-molecule drug products and attendant manufacturing processes often involve complex syntheses and purification steps that differ substantially from those employed for small-molecule pharmaceutical products. In fact, it has been said that for biotechnology products, “The product is the process.” Traditional small-molecule drug products have well-defined chemical structures and can be analyzed to ensure conformance to specifications. Biopharmaceuticals are often complex molecules, or mixtures of molecules, produced in biological systems and it is not always possible to fully characterize these products in the laboratory. Therefore, the manufacturing and purification processes become critically important in ensuring the “sameness,” quality, efficacy, and safety of these products.

Process validation is documented process understanding and control that begins when it is determined that a cell, molecule, or compound may have clinical significance and ends when the product is no longer viable in the marketplace. Each product and process may have different validation formats and structures and may not fit the traditional validation models. Validation requires careful thought and planning. It is not a stack of protocols and reports designed to satisfy regulatory expectations. It is not following by rote a series of “qualifications” such as design (DQ), installation (IQ), operational (OQ), and performance qualification (PQ) studies. It is not hiring a validation company to develop the protocols, perform the studies, and write the reports. 

The need for formal process validation became evident following a series of incidents beginning in the early 1960s. Thalidomide, a widely prescribed drug for morning sickness in pregnancy, was determined to have caused birth defects, leading to the 1962 Kefauver-Harris Amendment to the US Federal Food, Drug, and Cosmetic Act, which among other provisions, authorized FDA to issue good manufacturing practice (GMP) regulations for “manufacturing, packaging, or holding of finished pharmaceuticals.” Those regulations were finalized in 1963 as 21 

) 133 “Drugs; Current Good Manufacturing Practice in Manufacture, Processing, Packing, or Holding” (1).

During the period 1966-1972, a series of incidents at Evans Medical Ltd., Liverpool, England, led to the deaths of five people due to microbially contaminated infusion fluids. The contamination was found to be due to problems with the autoclaves used to process terminally sterilized parenterals (2).

From 1970-1973, a series of septicemia events in hospitals throughout the United States due to contaminated IV fluids were linked to inadequate container-closure systems and terminal sterilization conditions for large-volume parenterals (LVPs) produced by several manufacturers. Following a series of inspections, FDA questioned the manufacturers’ ability to ensure sterility of these products, leading to the promulgation of GMP regulations for LVPs in 1976 (3). Although the LVP GMP regulations were never finalized and were ultimately withdrawn, they established formalized requirements for the validation and monitoring of critical processes such as sterilization.

When the US GMP regulations underwent a major revision in 1978, validation requirements for sterilization processes were included (4). Subsequent revisions to US and international regulations and guidance documents stressed the need for process validation and quality management systems to ensure pharmaceuticals and biopharmaceuticals are safe and effective. 

In May 1987, FDA issued a draft process validation guidance document for comment (5). That draft guidance was followed by two more, one in 2008 (6) and one in 2011 (7). Each of these guidance documents was intended to clarify FDA’s expectations regarding process validation.

The International Council for Harmonization (ICH), an organization composed of regulatory authorities from the US, Europe, Japan, Canada, Switzerland, Brazil, China, and the Republic of Korea, and representatives of pharmaceutical industry organizations, has published a series of documents that, among other things, relate to process validation: Q6B for setting specifications for biotechnological and biological products (8), Q7A for active pharmaceutical ingredients (9), Q8 for pharmaceutical process development (10), Q9 for quality risk management (11), Q10 for pharmaceutical quality systems (12), and Q11 for drug substance development and manufacture (13). 

In 2007, ASTM International published E2500, 

Standard Guide for Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment

, which describes an alternative to conventional process validation (14).

The literature is full of references to process validation, and many of them seem to be contradictory. What is process validation, really? To understand this, we need to define “process” and “validation.”

Process has been defined in a number of ways. One dictionary definition is “a particular method of doing something, generally involving a number of steps or operations” (15). Another definition is “a series of actions that you take to achieve a result” (16). However, these definitions do not adequately consider the factors influencing the operations, actions, and steps that constitute a process. Those factors include the processing system itself, the inputs that drive the system, and the system outputs.

Scherkenbach, a student of W. Edwards Deming, defines process broadly yet concisely.  “In its simplest form, a process is a blending or a transformation of inputs such as people, materials, equipment, methods, and environment into outcomes. Some of these inputs do the transforming and some of them are transformed” (17). This definition considers important process influences lacking in dictionary definitions. The keys to the effectiveness of this definition are the identified influences on the inputs and outputs. Those influences must be defined, evaluated, and controlled to ensure the process performs as intended.

, based on Scherkenbach’s work, presents a process definition applicable to pharmaceutical and biopharmaceutical validation. Specifically, a process is inputs operating through a processing system to produce outputs. The inputs and outputs are influenced by people, material, equipment, procedures, and the environment in which they operate.

Processes may be discrete or linked so that the output of one process becomes the input to another, or multiple process outputs may serve as inputs to another. For example, a drug substance is an input to a process that produces a drug product, along with other components that result from other processes. And the drug substance itself is likely the result of multiple process inputs and outputs.	 

Validation of pharmaceutical processes was codified in the mid-1970s. That does not mean that earlier pharmaceutical processes were not validated. Pharmaceutical manufacturers had quality control programs that ensured the robustness of their manufacturing processes and the quality of the pharmaceuticals they produced. However, the scope of those programs depended on individual manufacturers resulting in variable effectiveness. Codification of validation expectations and requirements was intended to reduce that variability.

The 1978 CGMP regulations (4) discussed validation in terms of automatic, mechanical, and electronic equipment (21 

 § 211.68), validation of supplier’s test results for components, drug product containers, and closures (21 

 § 211.84(d)(2)), and validation of any sterilization process (21 

 § 211.113). However, the word validation was not explicitly defined.

FDA’s 1987 process validation guideline defined validation as “Establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes” (5).

In 2000, ICH Q7A defined validation as, “A documented program that provides a high degree of assurance that a specific process, method, or system will consistently produce a result meeting pre-determined acceptance criteria” (9). 

The concepts presented in the definitions of validation and process can be combined to form a meaningful definition of process validation applicable to the production of pharmaceuticals and biopharmaceuticals. FDA’s 2008 draft process validation guidance document defined process validation as “the collection and evaluation of data, from the process design stage throughout production, which establishes scientific evidence that a process is capable of consistently delivering quality products” (6).

The 2008 definition falls short in several areas, not the least of which is that the process is capable of delivering quality products instead of that it does deliver quality products-and does so consistently and reproducibly. Also, the term “quality products” is nebulous. Does quality relate to meeting regulatory requirements? Or, does it relate to product safety and efficacy?

ICH Q8(R2) provides an excellent description of process validation vis-à-vis product development (10).

Process validation, based on the combination of the definitions of the words process and validation, is establishing, documenting and verifying that the inputs, operating through the processing system, result in outputs that consistently meet pre-determined acceptance criteria and quality attributes. This definition is remarkably similar to FDA’s original 1987 definition of validation. In essence, process validation is documented process understanding.

Validation is necessary throughout a product’s lifecycle, from initial development through commercialization, to ensure it is safe and effective. The molecule originally identified as possibly having clinical significance must be fully characterized and its synthesis routes developed with the aim of scalability. Formulations to be used in clinical trials must be developed. The clinical formulations must be scalable to commercial production, retaining their effectiveness and safety attributes. Commercial production processes must be robust and reliable to ensure consistent product quality, maximize efficiency, and minimize cost. Process validation should-read must-begin at the very beginning to ensure the finished product can be manufactured and controlled to provide requisite levels of clinical effectiveness and patient safety. Products manufactured with validated processes almost invariably meet all regulatory expectations and quality requirements.

Start by thinking about the goals: What is the purpose of the study; what should it show, or prove, or demonstrate? Successful validation efforts often follow the 80-20 rule-80% of the effort should be thinking, evaluating options, and planning, and 20% should be devoted to performing the study. This optimizes the chances of success. Often, however, the reverse percentages are employed, resulting in wasted resources and yielding validation reports that do little to support the effectiveness of the processes they were intended to validate.

A process consists of inputs operating through a processing system resulting in outputs. The inputs, outputs, and the processing system, are influenced by people, materials, equipment, procedures, and the environment in which the process operates. All of these things must be considered and evaluated before developing the validation strategy and writing the validation protocol. Each process is unique, and no validation approach is universally applicable. Validation of a purification process for monoclonal antibodies differs substantially from validation of a steam-sterilization process for a drug product in its final container. Terminal sterilization does not work as a model for validation of a pharmaceutical water system.

Commercial production processes must be robust and reliable to ensure consistent product quality, maximize efficiency, and minimize cost.

A few simple guidelines will help to simplify validation planning and execution:

Define the inputs, the processing system, and the expected outputs.

Define critical and non-critical process attributes and parameters.

This is the first of a series of three articles about validation and technical transfer in the bio- pharmaceutical industry.

BioPharm International-04-01-2018

Improving Visual Inspection

Multiple Views Deliver Protein Particle Characterization

Making the Move to Continuous Chromatography

Secondary Packaging Solutions for Injectables

Automated Benchtop Pipette

CoAs Help Secure the Supply Chain

Modern Manufacturing Key to More Effective Vaccines

Understanding Validation and Technical Transfer, Part I

Single-Use Systems Advance Upstream Processing

Outsourcing Analytical Processes in Biologics Development

When One Therapy No Longer Fits All

Wearable Injection Devices Address Delivery Challenges

BioPharm International, April 2018 Issue (PDF)