Formulation Factors Affecting Capsule Brittleness

By: ACG North America

Gelatin capsules are a popular dosage form for numerous reasons, including faster speed to market and improved patient compliance. Brittleness is one of the common challenges associated with capsule performance. Capsule manufacturers often implicate poor performance of a capsule to manufacturing processes or storage conditions. However, it is important to realize that formulation parameters play an important role in overall capsule performance, including its tendency to become brittle.

Here’s looking at 4 major formulation factors that may have an impact on brittleness of capsule:

  1. Type of gelatin used

Gelatin is the main component of hard shell capsules and is derived from the chemical degradation of collagen. It behaves very differently depending on whether its macromolecules are in the collagen-like helical or coiled conformation. In the former case, the gelatin exhibits properties suitable for use at ordinary temperatures. However, in the latter case, gelatin is a typical rigid-chain polymer and behaves as a brittle impractical material. It does so because of the absence of water. Information about the performance of gelatin in terms of brittleness can be obtained by analyzing glass transition temperature and polymer crystallinity. Higher the crystallinity, the higher is the tendency of the gelatin to become brittle.

  1. Pigments

Pigments cause opacity and create a protective barrier to harmful radiation. However, they also play a significant role on mechanical properties of capsules; higher the pigment content, the higher is brittleness. Therefore, it is critical to formulate the capsule with optimum pigment content.

  1. Molecular weight

It is well known that molecular weight and molecular weight distribution can markedly affect the mechanical properties of a polymer. It is important to use the polymer of an optimum molecular weight: high enough for delivering good mechanical properties, but not too high that renders processability difficult.

Subjecting gelatin to higher temperatures for a long duration can cause polymer chains to fragment, reducing the molecular weight and deteriorating the capsule performance in terms of brittleness.  Therefore, it is important that processes that need gelatin to be heated are performed in the shortest possible time.

  1. Use of plasticizers

Plasticizers are often used to reduce the stiffness of a polymer by reducing the cohesive intermolecular forces along the polymer. The amount and choice of the plasticizer contribute to the hardness of the final product and may even affect its dissolution or disintegration characteristics, as well as its physical and chemical stability. For hard gelatin capsules, water acts as a plasticizer. Therefore, at low relative humidity, these capsules lose moisture and become brittle. Softgels capsules are more elastic owing to plasticizers such as glycerol or sorbitol and propylene glycol used in combination with glycerol.

In conclusion, numerous formulation parameters can affect the mechanical properties of raw materials and the capsule itself.  Extensive experience in the field of capsule manufacturing is needed to identify core fundamental properties that affect capsule performance. Therefore, it is important for manufacturers to also be cognizant of and have a stringent check over these parameters to improve the hard gelatin capsule performance.

With over fifty years of industry expertise, ACG is an integrated processing, manufacturing and packaging solutions provider to the global pharmaceutical industry. It is the world’s second largest manufacturer of high quality empty hard capsules. ACG’s capsule range is designed to provide customized solutions to the pharmaceutical and nutraceutical industry. 

 

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NJM to Exhibit Compact Filling & Closing Pharmaceutical Packaging Machine in NYC

By Marla, Marketing Manager, NJM Packaging

We’re always excited to showcase the latest in pharmaceutical packaging equipment at Interphex in NYC. This year, we’re bringing the Dara SX-310-PPD filling station down to the Javits Center next month to demonstrate how it handles automatic infeed, filling, and closing of injection vials.

The Dara SX-310-PP/D is a compact vial aseptic packaging machine that is suitable for cylindrical vials, both RTU (ready-to-use) and supplied in bulk, in glass, plastic, or metal. It can fill them with liquid, semisolid, and powder products in sterile areas or a clean room. Since the machine has been designed in compliance with cGMP and US FDA regulations, and in special accordance with industries that require the utmost accuracy and precision, it’s ideal for the pharmaceutical, biotech, and cosmetic packaging applications.

The versatile SX-310-PP filling station can be equipped with either stainless steel or ceramic valveless rotary piston pumps, or with SpeedFill® peristaltic pumps for liquid products, and with vacuum-pressure fill guns for powders. It features fully servo-driven automation and a compact footprint, and it offers accurate filling and precise stoppering and capping. The low-maintenance Dara SX-310-PP/D is easy to set up for new containers and achieves fast and easy changeover. When using CIP / SIP construction elements, it is not necessary to remove the product contact parts for their cleaning or sterilization.

At NJM Packaging, we’re proud to have this machine as part of our pharmaceutical packaging lineup, and we can’t wait to show you how you can integrate it onto your packaging floor.  Learn more about the Dara SX-310-PP/D aseptic filling, stoppering, and capping machine for vials on our website, or visit us at Booth #2353 at Interphex NYC 2017 at the Jacob Javits Center from March 21-23. 

Register for Interphex for free here, and come check out the new Dara SX-310-PP/D or learn more about how NJM Packaging’s machines can improve your packaging line.

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A Vision for Full Scale, Isolator-Based Aseptic Filling Systems

By Paul Valerio
Director, Process Technology/ Associate
IPS-Integrated Project Services, LLC

It will be possible to design a large proportion of full scale, isolator-based aseptic filling lines with most required systems and utilities under the typical 10 feet (3 meters) clean room ceiling in the near future.

Will you join me in this vision? I am sure other stakeholders in aseptic fill-finish manufacturing share this desire.

Such an achievement will be highly valuable to the pharmaceutical industry. Current solutions and trends in process technology indicate it is feasible, and perhaps around the corner.

The industry has benefitted greatly from early pioneers of advanced aseptic technology: companies and individuals that pushed the envelope in the past. New filling lines provide greater flexibility, reliability, and higher yields through improved component handling, more accurate dosing, advanced automation, and minimization of waste. Isolator systems provide a quality environment that separates people from aseptic processes and the systems perform automated bio-decontamination cycles, now under two hours. An isolated filling line with state-of-the-art functionality has become feasible for more and more companies, whether they are branded, CMO or generic injectable drug manufacturers.

More progress is needed.

There are still many pharma manufacturing sites, some say hundreds to thousands worldwide, that perform aseptic manufacturing in traditional Grade A clean rooms, relying on fully gowned operators to perform their trained aseptic technique with consistency. They have limited capital, or perhaps limited knowledge of today’s possibilities. World regulatory agencies are applying pressure for barrier technology to make this history. Today, manufacturers with legacy facilities planning upgrades are often looking past Restricted Access Barriers (RABS) and choosing isolator technology once they understand how much isolator design robustness and affordability have improved.

Despite advances in isolator-based filling lines, the need to position significant air handling equipment above the machine adds cost and required space, making this option out of reach for some companies.

I see equipment suppliers already embarked on the vision for more compact full-scale lines. Significant strides in aseptic processing and filling technology are flashing before the pharma industry quite rapidly these days. Transformation of leading suppliers from pure equipment builders to solution providers has a lot to do with the significant progress. Gone are the days when a supplier would react with an attitude of, “you want me to make your machine do what?” Instead, suppliers understand the quality and process requirements of the pharma industry. Not only are they eager to meet the challenges requested of them today but they also have stepped up to proactively advance process technology in collaboration with drug manufacturers.

One such collaboration spawned the development of small-scale, modular systems with a ‘plug and play’ approach. Bausch + Stroebel partnered with isolator supplier, SKAN, to develop VarioSys®. The initial concept used a sterility testing isolator platform designed to fit into lab spaces, i.e. below the ceiling, allowing companies to fill vials one day and syringes the next, all on one platform. A new solution was born. Filler supplier, groninger, and Franz Ziel now offer a similar combined product, called FlexPro. Vanrx Pharmasystems designed its small-scale robotic and isolator-based filler from the ground up, neatly designed for easy installation.

Meanwhile, advances in isolator design for full-scale lines have resulted in more efficient and compact air handling. Bus-sized air handlers from the past have become compact modules. Some solutions already incorporate all air handling on top of the isolator footprint, albeit above the ceiling.

One can see a natural progression, making isolators for full-scale lines look more and more like those used for the smaller scale systems. There are technical challenges to make the full scale filler/isolator systems even more compact, but recent developments clearly show that solution providers are up to the task. Just as the modular systems have opened up isolator-based filling to many companies on a smaller scale, the proposed step change for more compact full-scale lines will also have a significantly positive impact on the industry.

The vision I put forth is not a ‘man on the moon’ moment. My colleagues and I have a few ideas of our own, and the star wheels are already in motion with current design trends. It is simply a matter of time and priority. Let’s do what our industry does best and collaborate to make it happen.

Join my colleagues and me to meet the innovators of the small scale/modular system suppliers mentioned above at the Advanced Small-Scale Aseptic Technology Tour, hosted by IPS at INTERPHEX in New York on 22 March 2017.

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USP Chapter 41 Updates and Breakdown

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By: Fred Algieri Jr., Atlantic Scale Company

USP Chapter 41 has updated their testing requirements to determine the suitability of balances. Here is a quick reference on the important aspects and updates:

Chapter 41 is a REQUIREMENT for QC analysis measurements.

There are two required tests in Chapter 41, Accuracy and Repeatability. Both tests have tolerances of 0.10%.

The Accuracy requirement is applicable between 5% and 100%.

Calibration weights being used in the Accuracy check must have an accuracy of NMT 1/3 of the balance tolerance for that respective test point. This can be the tolerance of the nominal value of the weight or it can be the uncertainty of measurement for the weight when applying the actual weight value from the certificate.

The Repeatability test consists of 10 replicate weighings. The resulting standard deviation is to be used in the following calculation:

(2 × SD) ÷ Desired Minimum Sample Weight ≤ 0.10%

The coverage factor is now 2. Previously it was 3.

The denominator in the calculation is now stated as the “Desired Minimum Sample Weight”, not the weight applied as previously stated.

There is also now a “standard deviation floor” of 0.41d (d being the scale interval or the readability of the unit). This means if the determined standard deviation from the replicate test is less than the 0.41d value then the 0.41d value will need to be used in the assessment calculation.

The 0.41d (standard deviation floor) limits the low end measuring range to the below:

  • 8.2 mg minimum sample weight (lowest possible) 5-place (0.00001 g) analytical balances
  • 82 mg minimum sample weight (lowest possible) 4-place (0.0001 g) semi-analytical balances
  • 820 mg minimum sample weight (lowest possible) 3-place (0.001 g) toploading balances
  • 8.2 g minimum sample weight (lowest possible) 2-place (0.01 g) toploading balances

Again, the above values are the lowest possible minimum weights. The determined standard deviation needs to be at or lower than the 0.41d value to obtain the above results. This usually requires a very good environment. Most test results for on-site repeatability testing is as follows:

  • 10 mg – 20 mg minimum sample weight (commonly determined) 5-place (0.00001 g) analytical balances
  • 100 mg – 200 mg minimum sample weight (commonly determined) 4-place (0.0001 g) semi-analytical balances
  • 1 g – 2 g minimum sample weight (commonly determined) 3-place (0.001 g) toploading balances
  • 10 g – 20 g minimum sample weight (commonly determined) 2-place (0.01 g) toploading balances

Successful repeatability testing mostly depends on the balance quality, the controlled environment it is in, and also the balance operator’s dexterity and experience in performing the repeatability test.

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Pneumatic Blending

Pneumatic blending offers numerous advantages over mechanical mixing. It incorporates a series of controlled compressed gas (or air) pulses into the bottom of a conical hopper to mix dissimilar materials into a homogeneous blend. As the compressed gas expands back to atmospheric pressure, it drives the material at the bottom of the bin upward through the material bed above, causing the blending action. Continue reading

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Productivity in Upstream Processes

By Ken Clapp, Upstream Product Manager, GE Healthcare

Although keeping a better-faster-cheaper mindset, the bioprocessing industry cannot sacrifice quality. Over the past few decades, tremendous improvements have been made, including the industrialization of Chinese hamster ovary (CHO) cells and biologics titers.

Less than 20 years ago, single-use bioreactors were not part of our biomanufacturing vernacular. Such systems have become synonymous with offering improved product quality, faster turnaround times, and cost-effective operations. Single-use bioreactors continue to find new processes in product development and manufacturing worldwide. The convergence of this technology, the higher titers, and better product specificity fostered an environment to reassess the conventional ways of biologics manufacturing. Continue reading

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Designing for Operational Excellence

Kristina Pumphrey, PE – CRB
Associate / Operational Improvement Specialist

It seems counterintuitive to wait until a facility is in operation to apply Lean/ Six Sigma techniques to improve operational efficiency.  There are many decisions made during design that affect operations.  The facility layout affects travel paths and the distance traveled to move material and personnel throughout the facility.  When developing the layout it is important to look at adjacencies and frequencies of operations in order to optimize the layout and ensure there is no excessive movement.  Equipment sizing sets the batch size and expected throughput in the facility.  Small batch sizes help to make the process more responsive to product demands and tend to reduce inventories.   Large batch sizes help to minimize non-value adding activities such as set ups, cleaning, quality testing, etc.  Weighing the pros and cons of these items can help to optimize batch sizes and assist in minimizing product lead times. Room air classifications have a large impact on energy consumption in the facility.  Reducing room sizes and downgrading air classification can reduce airflow and energy consumption in the facility.  Continue reading

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