Stability: Using Sorbents to Ensure Drug Product Integrity and Mitigate Risk

As pharmaceutical manufacturers seek to fill dwindling pipelines, they are developing new chemistries that are sometimes difficult to stabilize over the desired shelf life. Traditional moisture management alone is often insufficient, because many new drug products exhibit multiple, different degradation pathways. This article reviews how degradation occurs and how sorbents work. It also provides advice about screening vendors and overcoming quality upsets. Understanding the top risks can help ensure product integrity and eliminate delays or disruptions in getting the product to market quickly. Time to market remains a key issue both for innovators launching a drug product and generic drug manufacturers seeking first-to-file advantage and the 6 months of market exclusivity that the HatchWaxman Act provides.

Controlling Degradation with Sorbents

From cracked tablets and capsules to reduced shelf lives and potency losses, drug product degradation can be disastrous and might even prevent your product launch. An increase in moisture, for example, can cause chemical changes that reduce the potency of a product in several weeks when it should typically have a shelf life of 2 years. Given the pressure to innovate and get to market quickly, identifying the causes of degradation and the best approaches to slow them can be a challenge. 

That’s where sorbent technologies can help. They slow the mechanisms of degradation in drug products and significantly improve stability, enabling you to obtain the shelf life required. Supported by Quality-by-Design simulations, sorbents are an inexpensive and fast way to stabilize drug products. In fact, the predictive ability of simulations can eliminate costly sorbent ranging studies and shorten the time to market. To see how sorbent technology can help, it’s important to understand the mechanisms of degradation and how they affect drug product stability. 

Degradation Pathways 

Pharmaceuticals are subject to a variety of degradation pathways that can shorten shelf life and raise safety issues. Hydrolysis is the most common degradation pathway, accounting for 60 to 80 percent of all reactions, followed by oxidation at 20 to 30 percent (most of them moisturemediated)¹. Other pathways include isomerization, photo-degradation, and elimination. Determining the mechanisms of degradation solely for the active pharmaceutical ingredient (API) requires studying its solution kinetics (sensitivity to temperature and pH). But when the API is formulated into a tablet or capsule, solid-state degradation comes into play, and that is more complex and difficult to predict. 

Critical factors involved in solid-state degradation include: moisture level, excipient incompatibilities, nucleation, and auto-catalysis from degradants that have high entropy and reactivity. Other possible factors include the drug product’s formulation, the processes used to manufacture it, how it is packaged, and the type of environments to which it’s exposed during storage and transportation. 

Impact of Formulation

In addition to the API, tablets and capsules typically include a variety of excipients, including binders, disintegrants, lubricants, and coatings. All contain some free moisture and, depending on how the product is made, moisture levels can increase, such as during the wet granulation process. Very few tablets have an optimal free-moisture level when they leave the press. 

Plus, when molecular mobility is sufficient to allow solid-state reactions, any additional free moisture will increase molecular mobility and thereby accelerate degradation. In fact, molecular mobility is directly related to the formulation’s moisture content: The higher the moisture content, the faster the reaction rate and the greater the likelihood of auto-catalysis. 

Impact of Packaging

How a product is packaged also affects its moisture level, and imperfect seals are typically the largest-single contributor to the ingress of moisture. But moisture can also pass through the plastic packaging itself, typically expressed as the moisture vapor transmission rate (MVTR) and denoted in grams per square meter per day. Other sources of moisture include the internal packaging material (dunnage) and the air within a bottle’s initial headspace (Figure 1). Although high-barrier packaging materials—primarily films for blister packs—reduce the ingress of moisture and oxygen, they are also more expensive than high-density polyethylene bottles that incorporate sorbents. 

The Value of Sorbent Simulations 

Sorbents reduce moisture and therefore molecular mobility, slowing the rate of degradation and improving drug product stability. (The greater the stability, the longer the shelf life.) Whatever the pathways of degradation happen to be, there are several key issues to consider, including the water activity (aw) of the drug product, the packaging configuration, the MVTR of the packaging material, the storage conditions, and the desired shelf life. Depending on the drug product, the oxygen transmission rate may also require consideration. 

Traditionally, manufacturers have conducted forced degradation studies to determine whether a sorbent is required, followed by sorbent-ranging studies to identify and optimize the type and quantity of sorbent required to ensure stability. Now, however, QbD-based pseudo-empirical modeling² offers a quick way to predict stability outcomes, including how much desiccant is required to prevent moisture- and oxygen-induced degradation. 

In practice, the pseudo-empirical modeling takes any given set of external conditions and calculates the conditions within the drug product’s package. The calculations— based on the integration of variable internal and constant external equilibrium relative humidity (ERH) conditions over time—take into account the conditions at the time of packaging (i.e., headspace), the package’s MVTR, and isotherms of the sorbent and drug product. 

The proven accuracy and speed of pseudo-empirical modeling make desiccant ranging studies unnecessary and simulations can shorten development time by 6 to 12 months. That enables pharmaceutical manufacturers to expedite regulatory filings and get their stabilized product to market faster. 

Pseudo-empirical modeling also allows you to test sorbents in a variety of formats that accommodate almost any packaging design. Formats include sachets and canisters dropped into the package; low-profile formats that affix to the packaging; and other configurations that are built into the package as a static structural component, such as a container wall, or as a mechanical component, such as a lever used to dispense the drug product. 

Like the pharmaceuticals they protect, many of these formats have improved over the years. For example, our company offers a drop-in canister that delivers 2.0 grams of functional silica gel desiccant in a canister that traditionally held only 1.0 gram of desiccant (photo). That enables pharmaceutical manufacturers to protect products even in space-constrained packages.

Selecting Vendors to Avoid Supply Chain Disruptions 

Supply chain interruptions can delay and disrupt production and cause your company to lose sales and brand equity. Even a seemingly inconsequential component can delay product deliveries. As development costs continue to rise, don’t jeopardize your investment: Make a plan to avoid a broken supply chain and a second plan to mitigate its effects. 

According to a recent Tufts study, the cost of developing a new branded drug can exceed $2.6 billion³. A similar study by the Canadian Generic Pharmaceutical Association estimated that developing a generic drug product costs more than $4 million and takes 3 to 6 years⁴. Whatever the exact numbers, development is time consuming and costly. Don’t squander more time fighting to sustain your supply chain. 

The first step: Make a business-continuity plan. Next, ask each of your suppliers to do the same or to share their plan for minimizing disruptions. Follow up regularly during your audits to confirm a sound plan is in place. 

Here are some topics to cover: 

• Manufacturing sites How many different manufacturing sites do you operate? How quickly can another site produce what I need if a political, economic, or natural disaster disrupts business as usual? 
• Redundant manufacturing Can each manufacturing site supply the exact same product? Do the sites meet the same standards and use the same processes? How will turnaround time be affected? 
• Vendor-managed inventory Are you willing to maintain and manage reserve inventory to support my operations and/or to accommodate a surge in demand? 
• Ramping ability How quickly can you increase production to supply what we need for new products or an increase in production?  

Preventing and Managing Quality Mishaps

It’s costly when quality is called into question. In the biotechnology industry, a single quality mishap is estimated to cost $10,000 to $50,000⁵. And that doesn’t factor in the potential for loss of brand equity, product disruptions, and lower sales and revenue. So it pays both to reduce the chance of a quality upset and to prepare for one. 

Start by making a plan before you install new equipment. Sorbent dispensers, for example, differ greatly in how they perform. Investigate all the options during procurement to determine which unit will meet your quality requirements and how it will help you during a quality mishap (photo).

First, identify the regulatory requirements you must meet. Next, find out how the equipment and sorbent system you’re considering meets those requirements and your company’s own quality standards. Questions may include: 

• Are the materials that contact the sorbent sachet or canister FDA compliant? 
• Do all sorbent products have a Type III Drug Master File? 
• Does the dispensing equipment offer first-in/first-out (FIFO) control? 
• Are the sorbents manufactured in a facility that complies with ISO 9001 and GMP, especially 21 CFR parts 210 and 211? 

While it’s easy to see how most of these criteria affect quality, the importance of FIFO is sometimes overlooked. FIFO operation is prudent because it minimizes the sorbents’ exposure and thus the loss of sorbent capacity (quality). A good way to ensure FIFO operation is to use dual hoppers and alternate running them. That ensures continuous operation. It’s also more efficient than using a single feed bowl where fresh sorbents mix with old ones. That could leave old sorbents in the bowl too long and/or require you to run the bowl empty and then pause production to refill it. 

Traceability and the ability to bracket a potential issue are also part of a comprehensive quality management system. If you can capture and transmit data directly into a SCADA-based quality system, so much the better. That makes information immediately available. 

In the case of sorbent dispensers, seek equipment that can transmit data—including lot number, manufacture date, and quantity, for example—from the packet spool to the dispenser. That information becomes a powerful tool when quality is questioned, because it shows whether the finished products were packaged with the correct sorbent and provides full traceability to the spool number within a product lot. If there is any question, you can bracket down to the spool and quickly isolate the products, which could mean you need look at just 15 cases instead of 1,500. It’s just one example of how you can expedite investigations and mitigate quality upsets. Vendors as Partners 

Vendors who focus on the short term expose you to risks, including the risk of manufacturing substandard products and the inability to resolve problems quickly. That means the cost and disruption associated with quality upsets, inferior products, and machine downtime can escalate. 

To avoid those problems, ask the vendor about: 

• Commitment to innovation and its track record of supporting new drug product formulations; 

• Ability and willingness to act as a consultative partner to resolve complex challenges; 

• Ability to customize products to meet your needs; 

• Experience in the industry; 

• Reliability of the services and products offered; 

• Business continuity planning to minimize disruptions and manage your inventory; 

• Ability to respond to spikes in your demand; 

• Total cost of ownership versus per-piece pricing; 

• Processes and systems used to resolve quality events; and 

• Number of manufacturing sites and whether each site can supply the exact same product. 

The objective is to reveal the correlation of quality, reliability, and cost. Per-piece pricing, for example, can be deceptive because it doesn’t factor in the cost of disruptions, decreased quality, or inefficiency. The diminished productivity of faulty or underperforming equipment is another hidden cost. By contrast, vendors committed to your long-term success are happy to explain how they will help you overcome challenges. 

Drug product stability is too important to settle for anything but the optimal sorbent and dispensing equipment. That’s how you ensure drug product integrity and quality while also meeting your goals regarding quality, reliability, and cost. 

References 

1. Gupta, Pardeep. “Drug product stability and shelf life.” Course, Center for Professional Advancement, East Brunswick, NJ. 

2. SimulSorb and SimulOx from Multisorb Technologies, Buffalo, NY. 

3. DiMasi, JA. “Briefing: Cost of developing a new drug.” Tufts Center for the Study of Drug Development, November 18, 2014, Boston. http://csdd.tufts.edu/files/uploads/Tufts_CSDD_briefing_ on_RD_cost_study_-_Nov_18,_2014..pdf. Accessed December 4, 2015. 

4. “Generic prescription drug development.” Canadian Generic Pharmaceutical Association. July 30, 2015. www.canadiangenerics.ca/en/resources/docs/DDBookletWebEng.pdf. Accessed December 4, 2015. 

5. “PDA survey: Business case for pharmaceutical quality.” Parenteral Drug Association, 2012.