Suspensions in medications have been around since at least the time of the writing of the Old Testament when the prophet Isaiah recommended that a ‘lump of figs’ be spread on King Hezekiah’s boil.

This may have been one of the first instances where problems inherent in the making of suspensions became apparent. The monarch may have realized that the seeds, pulp and skin of the fruit did not apply evenly on the affected area.

In the intervening years between treating King Hezekiah around 700 BCE and today, many of the fundamental analytical testing factors affecting ingredient quality of suspensions remain. Unlike biblical times, modern manufacturers of suspensions must also manage additional issues concerning production equipment and also considerations specific to scale-up from R+D batches to commercial production.

Ingredient challenges
Gravity is the enemy of effective production of suspensions. Quality suspensions must overcome the effects of gravity by mixing physical and chemical properties of excipients to create a uniform distribution throughout the product. 

Properties and qualification
The physical properties of the active pharmaceutical ingredient (API) in a suspension e.g., particle size and morphology, are key factors influencing successful scale-up from test environment to mass production. Supplier qualification for the API should include certificates of analysis for multiple batches that demonstrate consistent compliance with well-defined specifications.

In addition to chemical attributes of potency, impurities and the like, physical properties to be controlled for the API include the particle size distribution and a visual description of the particle morphology, such as color and description of the microscopic amorphous or crystalline structure. The ability of a formulation to create a proper suspension is dependent upon these criteria.

For example, a large proportion of small particles may reduce the sedimentation rate, however, if there is a broad size range between these small particles and the larger particles, this may adversely affect uniform API distribution within the suspension.

Scale-up
Successful small-scale results for R+D batches of suspensions is a preliminary step required for production of commercial quantities. Specifications for particle size and shape, product viscosity, density, relationship between active and inactive ingredients and macro and microscopic properties must be reproduced on a much larger scale to assure therapeutic effectiveness.

Equipment challenges
Processing variables that are successfully controlled during the transition from small R+D lab scale (a few liters) to “pilot” scale (dozens of liters) may become challenging to control at full commercial production scale (hundreds to over a thousand liters) if careful attention is not paid to verify the correct type, calibration and controls over the commercial manufacturing equipment.

The uniform taste and appearance of food at different locations of a well-run fast-food franchise restaurant are achieved utilizing the same equipment with the same specifications installed at every location. Extensive and ongoing training is required to help assure that the burger-making technology is transferred correctly to generate consistent results.

Technology transfer and scale-up of suspensions involves more numerous variables and a heightened degree of uncertainty compared with other industrial duplication strategies. These variables include differences in the human resources (expertise) as well as the engineering issues of process control and equipment settings, change parts and equipment cleaning and maintenance. For example, not all “homogenizers” or wet mills work the same or have the same controls.

Manufacturing process
Successful commercial manufacturing for suspensions requires detailed information that enables exact reproduction of the medication. The R+D department that produced the test batches must provide instructions about how to replicate successful results using specified types of equipment including proper settings for speed, time and internal mechanical controls. 

Methods utilized in the past, such as empirical trial and error experiments to reproduce results are no longer adequate because they do not systematically evaluate all significant sources of variation that could result in failure to meet specifications that assure safety, strength, quality and purity. A comprehensive Product Development Report (PDR) reduces risk by outlining where the potential variables are and proactively designing the formulation and process to preclude ‘failure modes’ and assure that scale-up procedures work effectively.

Homogenization
Formula One race cars are each built according to the same exacting standards, but finish the race at different times. The reason similar machines produce differing results is due to human and mechanical factors that vary between different race teams. A similar dynamic exists in technology transfer and scale-up when utilizing different equipment at separate locations to produce exactly the same pharmaceutical product. The unique manufacturing challenges for suspensions further complicate the process.

One indispensable piece of equipment in the manufacture of suspensions is the homogenizer. Sometimes an intermediate milling step is included prior to final homogenization. By these means the insoluble API is uniformly dispersed throughout the liquid phase with inactive ingredients during homogenization.

In homogenization, the suspension is pumped under high pressure where particles are dispersed throughout the liquid. High pressure homogenization produces a more stable product by optimizing the API/excipient mix, thereby increasing product stability and inhibiting settling of dispersed ingredients.

Processing equipment differences
The homogenization process is necessary for production of quality suspensions, however different makes and models of homogenizing equipment as well as the processes they utilize to complete their task vary greatly.

For example, inline homogenizers may reduce time and increase quality of suspensions compared with in-tank batch mixing by creating a continuous production process, easier equipment cleaning and minimizing batch-to-batch inconsistencies.

The transition from creating test batches in the laboratory with small capacity homogenizers to large-scale industrial homogenizers demands precise adjustment of settings between various brands of equipment to match desired results.

Proper calibration of speed and time must be balanced to create the same results among different types of machinery. Results may not be obvious. A speed setting at ‘2’ for one machine may not correspond to the same setting on another piece of equipment or even an older model of the same equipment. Time is another factor that must be adjusted when utilizing different machines. 

Often, multiple engineering batches are required to assure that the large-scale process matches the success of small-scale results. Suspensions are especially susceptible to changes in equipment speed, time and processing temperature to produce desired dispersion of active ingredient within the excipient medium.

Mixing problems
The time and speed settings between different machines to precisely match results between test batches and commercial production are further complicated by problems associated with the physical mixing of suspension ingredients.

Factors affecting the mixing of solid particles in a suspension include particle size, shape, density, porosity, volume and flow properties. The mixing process may alter the characteristics of the active ingredient particle in ways that may result in product failure.

For example, shear mixing involves movement of particles using shear force as the ingredients move through metal plates, rotors and spinning components. The physical relationship between the internal components of the homogenizer must be precisely adjusted to duplicate the results of test batch samples. 

There are cases where the homogenization process to produce suspensions on a commercial scale must be completed multiple times. This process, called cycling, comes into play when initial homogenization produces partial dispersion. Cycling initiates additional homogenization until the suspension reaches the proper level of dispersion.

The cycling or looping process adds a risk component to successful scale-up of suspensions because excessive processing may alter the size, shape or viscosity of the essential particle, reducing effectiveness and resulting in failure. A well-defined homogenization process may require quick, real-time sampling and in-process testing, where the feedback of the results actually determines how many ‘cycles’ through the homogenizer are needed to reach the process end point relative to specifications for particle size or viscosity.

Equipment scale-up
Many things change when moving from equipment used to create successful test batches in the laboratory to commercial production. Multiple challenges must be overcome for correct transition from small-scale to large-scale machinery. Adjustments must be carefully made to reflect the type of equipment used, specifications, settings for time, speed and other mixing issues. 

This process is made more difficult during production of suspensions, because the active ingredient must be uniformly dispersed in large production tanks and also in each primary package to assure effective therapeutic benefit. After successful production of a bulk suspension, the time, temperature and method of continuous low-shear mixing during the process of bottle filling still must be controlled to assure batch uniformity.

Analytical methods
“If you can’t measure it well, you can’t manage it well.” Analytical components of the PDR provide crucial guidance as to the correct materials and methods required for the quality control and microbiology laboratory teams to achieve robust, reproducible, acceptable results. The PDR specifies the correct validation acceptance criteria for methods by which quality control testing should be conducted. Successful validation of analytical methods that have been transferred between sites or between companies is critical for commercial production.

Stability
Suspensions contain insoluble particles distributed in a liquid. The composition of the inactive ingredients to effectively disperse the active ingredient with uniform results over the shelf life of the product depends on particle size/morphology, viscosity, rheology and surface chemistry of the API. For example, in most cases, increasing suspension viscosity decreases sedimentation rate. Stability is also influenced by the electrostatic charge between API particles and the suspending medium, which can enhance uniform distribution of API in the suspension when the excipients are well chosen and appropriately mixed.

The macroscopic and microscopic profile of the API within the formulation must be duplicated between test and production batches. Results must align in a dry, pre-mixed state and also in wet mixed suspension. Re-suspendability properties of the formulation over the shelf life must also be assessed to assure that the end user can obtain a dependable dose after a reasonable amount of shaking the bottle before use.

Successful technical transfer requirements
The process of moving from R+D batches to commercial production requires a transfer of information optimized with a detailed PDR using a Quality by Design (QbD) approach. QbD is a scientific approach to formulation design and manufacture using cGMP principles to identify risks, weaknesses and specifications for taking production to a larger scale.
The FDA requires that QbD principles be followed in order to achieve approval for commercialization. An incomplete QbD PDR may result in unsuccessful scale-up efforts, loss of time and resources, or even a refusal to approve by FDA.

Central to the QbD approach is the identification of Critical Process Parameters (CPPs) and Critical Quality Attributes (CQAs). CPPs address the manufacturing variables to be controlled for successful commercial production. CQAs address the final required chemical and physical qualities to be achieved as measured by validated QC analytical methods.

Corporate culture
When checking ingredients for successful technology transfer and scale-up, company culture is often left off the list. The ability of separate teams from different organizations to understand each other and work well together significantly eases potential problems. A language barrier is one obvious cultural issue that could derail a scale-up project. More subtle cultural areas involve regular working hours, decision-making hierarchy and personality traits that differ in hires from different companies.

Team integration is particularly important for the successful scale-up of suspensions. The additional challenges inherent in the production of suspensions demands close coordination between the organization developing the formulation and the partner that is producing commercial quantities that may be requesting FDA approval for the finished product.

Unanticipated delays have occurred when the company attempting to make commercial quantities of a suspension does not reproduce results that were successfully created at smaller scale by the R+D organization. When the problem is checked against a PDR that is inadequate, the document may fail to identify the risk which may have caused the failure. 

Often, the origin of the problem can be found in poor channels of communication between the two organizations. Although open lines of communication are not emphasized as much as equipment or ingredient specifications, regular interaction between development and commercial scientists is vital to address potential quality, regulatory and manufacturing challenges that may affect production timelines.

Conclusion
The large-scale manufacturing of medications from small-scale test batches is fraught with ingredient and equipment challenges to assure promised therapeutic value and patient safety within cost parameters. 
Few formulations pose as many of these challenges as the production of suspensions, where an active dry substance must be uniformly dispersed throughout a liquid according to exacting specifications.

Critical Process Parameters (CPPs) and Critical Quality Attributes (CQAs) covered in a comprehensive Product Development Report according to Quality by Design (QbD) guidelines identify risk factors and solutions for manufacturing and analytical hurdles posed by ingredient properties and qualification, scale-up, equipment challenges, processing equipment differences, mixing problems, analytical methods, stability and successful technical transfer.

Sometimes forgotten or minimized by scientific priorities, team integration and compatible corporate cultures between R+D and commercial operations are also important factors determining successful scale-up of suspensions to commercial scale production. 

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Robert A. Falconer is Principal Consultant at Falcon Pharma, LLC. He has held executive positions over 44 years at four Rx branded product firms, two Rx generic firms, and as principal in his own consulting practice. His experience spans Technical Operations, Regulatory Affairs and Quality Assurance, including numerous international projects involving both investigational and marketed drug products.

Angela Holley is Director of Business Development at WDPrx – Woodfield Pharmaceutical, LLC.  Her expertise includes sales, marketing, business development and administration for traditional and virtual manufacturers. From start-ups to global businesses, Holley is familiar with the marketing cycles of everything from standard cough and cold remedies to specialty pharmaceutical products and orphan drugs.