Excipient Testing in a Global Environment
By Anthony Grilli
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?
Photo courtesy of Bristol-Myers Squibb
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.”
Safety and Functionality
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.
USP Excipient Functional Categories
- Tablet/Capsule Diluents
- Suspending/Viscosity Agents
- Tonicity Agent
- Tablet/Capsule Binder
- Ointment Base
- Sweetening Agent
- Glidant/Anticaking Agents
- Coating Agent
- Pharmaceutical Water
- Suppository Base
The European Pharmacopeia takes a similar approach to USP. General Chapter 5.15, “Functionality-Related Characteristics of Excipients,” became official April 2008, and underscored the importance of the functionality testing of excipients. Although the intent is the same as USP, the presentation of the information in the individual compendia is different. The European approach is to include the functional tests in the actual monographs, whether they be mandatory or not. The USP and JP approach is NOT to include them in the monograph unless they are mandatory. It is interesting that EP5.15 ends with a paragraph stressing that this difference in format should in no way slow down harmonization of excipient monographs, and that the “different legal environments of the 3 pharmacopeia allow for different formats of the monographs without affecting the international harmonization status.”
Global Marketplace and Excipient Testing
It is encouraging news that harmonization is proceeding unimpeded by regional preferences for monograph styles. Choosing the proper tests to qualify excipients in a global marketplace is no easy task. As already indicated, one must tailor tests to match the ingredient’s intended function. What about local requirements for testing? The tests required by the same ingredient often differ in Europe, U.S., and Japan. Continued harmonization of the three major pharmacopeia will help resolve this dilemma. Unfortunately, harmonization is a slow process.
USP <1196> Pharmacopeial Harmonization outlines how the Pharmaceutical Discussion Group (PDG), representatives from the European Directorate for the Quality of Medicines, The USP Convention, and the JP Ministry of Health and Welfare drive the harmonization process:
Stage 1: Identification
Based on input from users, PDG identifies monographs and general test chapters worthy of harmonization. One of the three pharmacopeia is assigned as coordinating pharmacopeia for that assignment.
Stage 2: Investigation
Coordinating Pharmacopeia collects information of the three existing specs, grades of marketed products, and analytical procedures. It then prepares a harmonized monograph, along with rationale and validation data.
Stage 3: Expert Committee Review
Each of the three P’s take the draft and forward to their respective expert committees. Comments are collected, and a commentary on the comments is assembled and sent to the secretariats of the other pharmacopeia.
Stage 4: Official Inquiry
The draft and commentary are published in each pharmacopeia’s respective forums. Readers send their comments, comments are reviewed by each pharmacopeia, which in turn analyzes, consolidates, and submits comments to coordinating pharmacopeia. The coordinating pharmacopeia then prepares another draft and another commentary on the comments.
Stage 5: Consensus
The draft is now reviewed and commented by the other two PDG pharmacopeias. All three now struggle for consensus.
Stage 6: Regional Adoption and Publication
If there is consensus, each pharmacopeia incorporates the harmonized draft to its own procedures. Users are appropriately informed. Once the text is official in all three pharmacopeia, the chapter or monograph is considered harmonized.
Stage 7: Inter-Regional Acceptance
Coordinating pharmacopeia provide documents to ICH Q4B EWG, which are evaluated and formal acceptance is posted by ICH.
Sixty-one excipients were initially selected for harmonization, and 31 of them are now at Stage 6 Regional Adoption and Acceptance. Unfortunately, 31 excipients represents a very small fraction of the hundreds of non-API monographs in each of the compendia. And some of the most common excipients are proceeding very slowly. Magnesium stearate was at Stage 4 five years ago, and is only now at Stage 5. Gelatin is still at Stage 2, Crospovidone and sucrose are still at Stage 4, and stearic acid is still at Stage 5.
Until harmonization is complete, the global manufacturer is faced with multiple testing for the same quality or functionality tests. Magnesium stearate offers a good case study of the additional testing a pharmaceutical company must perform for a global market place. (See Fig. 1)
|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|
Although the magnesium stearate monograph is not fully harmonized, acidity, chlorides, sulphates, LOD, assay and stearic/palmitic acid are required by both compendia and the tests methods themselves are the same. This is good news, as one can simply run the sample once. Both compendia also agree that specific area is a functionality related test and can be omitted if it does not play a functional role it the final dosage form. However, cadmium and nickel are additional to EP, and lead content is conducted completely differently by USP and EP. These represent additional tests that must be performed to satisfy both markets. Finally, different reference standards are called out for stearic and palmitic acids.
Such is the case for all ingredient monographs that contain heavy metal tests. The test methodology described in the current USP <231> was originally designed more than a century ago. The USP admits that the method is not sensitive enough for many heavy metals, and can fail to detect mercury. The USP is in the process of updating the method and has been holding a series of workshops with industry. The forecast is for USP to publish a method in 2010, becoming official sometime afterward. A secondary benefit of the updated standards for metal impurity tests will be harmonization with Europe and Japan. Meanwhile, the manufacturer tests the same contaminant by two methods.
Perhaps the real success story in the magnesium stearate case study is the tests for microbial cleanliness, which was harmonized this year at the General Test level. Any raw material that must be screened for microbiological contamination must now be tested by the new harmonized methods USP <61> and USP <62>. An E. coli is an E. coli, whether it’s in Paris, in Tokyo and in NY. There is no scientific reason to culture them with different media in these different locations.
Managing Global Requirements and Change
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.
- Pfizer 2008 Annual Report. Appendix A page 4
- "Proposed New USP General Information Chapter, Excipient Performance <1059>", Pharmacopeial Forum Vol 33(6) [Nov.-Dec.2007]