As regulations governing active pharmaceutical ingredients (APIs) and excipients — including propylene glycols — tighten across the globe, pharmaceutical companies are requiring in-depth quality reviews of the entire supply chain processes for their pharmaceutical raw materials. These companies are considering a variety of solutions, ranging from centralized and decentralized data management systems to risk-based scrutiny and third-party certification. In all cases, the ultimate goal is to strengthen the safety and integrity of the global supply chain while making the most efficient use of resources. Third-party certification holds perhaps the greatest promise as a solution that can help achieve this goal.

Why the Increased Emphasis on Supply Chain?

In 2010 alone, there were several serious adverse events – recalls, shortages and defects – traced to the supply chain.

Historically, contamination of propylene glycol USP/EP has occurred with the presence of diethylene glycol (DEG) or monoethylene glycol (MEG) because of their similar properties and difficulty in analytical separation. Most contamination occurs during the supply chain process, well after purity has been established during manufacturing.

As a result of supply chain contaminations, strict guidelines in line with GMPs (good manufacturing practices) and GDPs (good distribution practices) have been established to ensure proper storage, handling and transportation of excipients. As shown in Figure 1, there are numerous opportunities for contamination throughout the highly complex supply chain.  
A product certified to be pure after initial manufacture can encounter multiple sources of contamination before it reaches a pharmaceutical company’s production site. Here are some of the areas third-party auditors may examine as part of the certification process for PG USP/EP.

Some steps to reduce contamination risk for PG USP/EP include:

• Handling with special precautions such as shipping in approved lined tank cars and stainless steel tank trucks
• Dedicated, food-grade loading and unloading lines
• Protection storage tanks from atmospheric moisture using nitrogen as a pad gas or an air dryer on the tank ventilation system
• Drums must be of suitable material as required by GMPs
• Discouraging the practice of storing PG USP/EP in milled steel containers (to prevent iron contamination)
• Avoiding handling PG USP/EP with porous plastic materials and rubber

Third-Party Auditing of PG USP/EP Holds Great Promise

As could be expected, a great deal of debate surrounds each of the solutions to the challenge of ensuring supply chain purity. Using data management systems raises the issue of whether centralization or decentralization is best for a global, highly fragmented industry where standards differ from country to country, region to region — and even state to state. Risk-based scrutiny has its limitations, as well. Data inputs can come from various sources, an approach that bears a striking similarity to the historic “honor system” still followed in some parts of the industry.

To further complicate things, government agencies are attempting to monitor an ever-expanding number of imports with dwindling people resources. For example, the U.S. Food and Drug Administration (FDA), which oversees millions of regulated imports each year, is only able to test and/or sample a fraction of those imports (see “Monitoring Ingredient Quality an Issue of Global Proportions” sidebar).

In response to the industry’s call for improved quality throughout the supply chain — and as an added convenience to customers — propylene glycol and other excipient manufacturers are now considering certification of compliance to GMPs with third-party organizations like International Pharmaceutical Excipients Auditing, Inc. (IPEA).

Third-party certification is a resource-efficient way to ensure pharmaceutical and food companies can continue to benefit from the outstanding and versatile performance of propylene glycol in their products. The certifications primarily focus on product manufacturing, but may also be expanded to ensure compliance within all aspects of the supply chain process. In addition, the common “trust but verify” practice that involves periodic audits of suppliers to ensure they are indeed following GMPs is no longer necessary for third-party-certified manufacturers. Already, pharmaceutical-grade propylene glycol manufacturers adhere to regulations and standards from the U.S. FDA and similar agencies around the globe.

The International Pharmaceutical Excipients Council (IPEC) was created in 1991 to develop, implement and promote global use of appropriate quality, safety and functionality standards for pharmaceutical excipients and excipient delivery systems. IPEC provides unified global excipient standards and promotes supply chain security through its current federation, which is made up of four independent but functionally related associations: IPEC-Americas, IPEC-Europe, IPEC-Japan and IPEC-China. IPEA is a subsidiary of IPEC-Americas, and currently a leading third-party auditor with an American National Standards Institute (ANSI) accredited GMP certification program.

At the time of this writing, two North American propylene glycol manufacturing facilities — both operated by The Dow Chemical Company — have received IPEA certification stating substantial conformance to GMPs as defined in the current “Joint IPEC-PQG Good Manufacturing Practices Guide for Pharmaceutical Excipients.”

There is no disputing that strengthening the safety and integrity of the global supply chain requires a multifaceted approach. Data management will play a part. So will risk-based scrutiny. And there’s certainly nothing wrong with honor and trust — as long as they are founded on following sound, scientific practices. But experience shows that each of these solutions has drawbacks.

According to IPEA, its independent third-party evaluation process helps ensure that excipients and related components in finished pharmaceutical products meet only the highest appropriate IPEC GMP standards throughout their manufacturing process. When purity matters — a given in the pharmaceutical industry — third-party auditing may promise tremendous value for those committed to the highest levels of quality throughout the supply chain.

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Monitoring Ingredient Quality an Issue of Global Proportions

These figures, indicative of the situation globally, help illustrate limitations of relying on government regulations alone to catch quality issues in pharmaceutical imports. Monitoring the full spectrum of ingredients – including excipients – is even more complex.

• Nearly 24 million shipments of FDA-regulated products are expected to arrive at U.S. ports in 2011 (vs. six million in 2001)
• 130,000 importers from more than 300,000 foreign sites in 150 countries
• Up to 40% of drugs Americans take are manufactured outside of the U.S.
• Up to 80% of APIs in those drugs are manufactured outside of the U.S.
• Only 1.3% of imports are sampled by the FDA
• Only 0.3% of imports are tested by the FDA

Adapted from “A Vision for Total Excipient Control,” presented at Excipient Fest Americas 2011, May 10, 2011. (Author: Steven Wolfgang, Ph.D., U.S. FDA)

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Propylene Glycol USP/EP: A Primer

Pharmaceutical grades of propylene glycol, or PG USP/EP (United States Pharmacopeia / European Pharmacopeia), require a purity of 99.5% to earn the USP/EP designation. That specification provides an added measure of confidence to manufacturers who include propylene glycol USP/EP as an ingredient in medications, personal care products and food applications.

As a functional excipient, propylene glycol helps to solve formulation problems and create simpler, more effective formulations. While not considered an active ingredient, propylene glycol USP/EP works to solubilize and homogenize the active ingredient in a formulation so that each dose or cream-based application contains a consistent and correct amount of active ingredient. Because of this property, propylene glycol USP/EP is an excellent solvent and extractant for a wide range of active ingredients in vitamins, vaccines, therapeutic drugs, antiseptics and local anesthetics.

With a low degree of toxicity and a metabolic pathway similar to that of sugar, there are currently no official hazard classifications for propylene glycol USP/EP, and it has been approved for pharmaceutical use as listed in most global Pharmacopeia. The FDA lists propylene glycol USP/EP as generally recognized as safe (GRAS) for use in food, animal feed, cosmetics, personal care products and pharmaceuticals.

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Vincent Lacoste is global strategic marketing manager for propylene glycols at The Dow Chemical Company and leads Dow’s PG third-party GMP quality certification efforts around the globe. He can be reached at vlacoste@dow.com.