In the world of pharmaceutical sales and marketing, the active pharmaceutical ingredient or API takes center stage. Consider Lipitor, the biggest selling drug on the planet. Lipitor netted $12.4 billion in revenue for Pfizer in 20081. The world’s attention is on the soon-to-expire patent of Lipitor’s API, atorvastatin. Atorvastatin is a miracle compound, inhibiting liver synthesis of cholesterol and prolonging the life and health of millions of consumers. But the effectiveness and safety of any drug product is not dependent solely upon the API. Is it reasonable to expect a patient to take an oral dose of 10 mg of pure atorvastatin daily? How would the API be protected from degradation by moisture, light, and heat between doses? How is the bioavailability of the API controlled once it’s been ingested?
The answer to all these challenges is excipient ingredients. Although Webster’s Dictionary defines excipients as “a usually inert substance that forms a vehicle as for a drug,” this definition somewhat depreciates the role of the excipient. Very often, a certain level of functionality is expected. And certainly the ingredients must be unadulterated. Excipients may play a “supporting actor role,” but the final drug product would not be the safe and efficacious dose it is without these top-performing “inert ingredients.”
Testing of incoming excipients with some frequency prior to blending is necessary to confirm final drug product safety and efficacy. This testing is not only reasonable form a business sense, but is of course a regulatory requirement. The FDA requires testing to verify the excipient’s identity as well as confirmation that the ingredient conforms to appropriate written specifications for purity, strength, and quality. While it is true that 21CFR211.84 (d)(2) allows the manufacturer to accept an excipient vendor’s Certificate of Analysis, this is only on the condition that A) the manufacturer performs at least one identity test and B) the manufacturer establishes the reliability of the supplier's analyses through appropriate validation of the supplier's test results at appropriate intervals.
In other words, the manufacturer must demonstrate some confidence in the vendor’s CofA by having its own historical test data to validate it against.
It is useful to make a distinction between functional testing and safety testing of an “inactive” ingredient. This distinction was made clear in 2007, when USP-NF proposed an informational chapter <1059> “Excipient Performance.” Although not official at the time of this writing, the informational chapter emphasizes a distinction between functionality testing with its focus on performance, and monograph testing, with its focus on identity, purity, strength and quality2. Critical physical and chemical properties that influence product performance are not defined in the excipient’s monograph, simply because of the vast diversity of the possible applications in different products. Consider for example the common excipient mannitol. It can function as a tablet binder, a capsule filler, a dosage sweetener, or a parenteral osmotic regulator. Each of these functional characteristics would require a different test to measure it. One might use USP <616> Bulk and Tapped Density if one were to use mannitol as a binder, but use USP <781> Optical Rotation USP if the mannitol is intended as a sweetening agent. Optical rotation might seem like a pointless test for a filler, but it is critical in flavor chemistry.
USP <1059> lists 14 different functional categories. They also recommend General Chapter tests that may be useful to ensure performance.
|Fig. 1: Comparison of Magnesium Stearate Tests|
||USP <32>||EP 6.5|
|Identification||• Mg ppt test
|• Freezing point
• Acid Value
• Mg ppt test
|Acidity or alkalinity||• Colorimetric test||• Colorimetric test|
|Chlorides||• Turbidimetric test||• Turbidimetric test|
|Sulphates||• Turbidimetric test||• Turbidimetric test|
|Cadmium||NONE||• Atomic Absorption|
|Lead||• Colorimetric test||• Atomic Absorption|
|Nickel||NONE||• Atomic Absorption|
|Loss on drying||• Gravimetric test||• Gravimetric test|
|Microbial||• Harmonized culture method||• Harmonized culture method|
|Specific area||• Gas adsorption||• Gas adsorption|
|Stearic and palmitic acid||• GC||• GC|
|Assay||• Complexometric test||• Complexometric test|
Multiple monographs, non-harmonized test methods, specialized equipment, technique sensitive wet chemistry — these are considerable obstacles for the global drug manufacturer to manage. Again, excipient ingredients may play a supporting actor role, but if they’re inadequately tested, the play becomes a tragedy. Contract testing laboratories are best positioned to confirm that the ingredient is safe and functional. A drug manufacturer may see 10 or fewer shipments of magnesium stearate a year, while a contract laboratory like ours receives 10 shipments from hundreds of customers during the same time interval. Three-quarters of the cost is in the setup and borne by the first sample. Aside from batching samples to get efficiencies, a contract laboratory will have all the equipment, staffing and training necessary to perform the test.
Testing is a contract laboratory’s core competency, therefore investment in an ICP MS for heavy metal testing is reasonable. But for a contract manufacturer, the volume of heavy metal testing will not result in a satisfactory return on investment, and the opportunity cost of not focusing on discovery could be even greater. A truly global GMP pharmaceutical analytical laboratory can match the local testing needs for the global manufacturing partner.
The excipient ingredients do not get the large print on the drug packaging or advertisement, but they play a crucial role. Nonfunctional excipients can impact the efficacy of the dosage, adulterated excipients can have an even worse impact. It is a regulatory requirement to test these components. As the marketplace becomes increasingly global, and as the methods begin to harmonize, partnering with a global contract laboratory is a sensible means to reduce cost and assure quality.
Anthony Grilli is General Manager of SGS Life Science Services — R&D/QC, a global provider of contract testing services.