A critical component for the brand owner is ensuring its supplement contains the ingredients specified in the formula at the appropriate amounts. The cGMPs (current good manufacturing practices) are clear about the requirement for both ingredient and finished product specifications to be created for each item to identify it and quantify potential adulterants or contaminants. Historically, the brand owner delegated the responsibility for testing the raw materials to the designated contract manufacturer, and often relied on the contract manufacturer’s finished product certificate of analysis (CoA) as evidence of the finished product compliance with the required specification(s).
With all of this done out of sight of the brand owner, what assurances are available to ensure the cGMP testing requirements are being met? Does the contract manufacturer have an in-house lab sufficient for the scope of its business model? Does the contract manufacturer outsource some or all its testing? All too often, this key analysis is overlooked or only given a cursory inspection during a plant visit or audit. A nice room, decorated with fancy looking instruments and staff in lab coats and safety glasses usually provides the blanket assurance to the brand owner that the contract manufacturer can handle the job–and, unfortunately, the deficiencies in the lab or its operations only become apparent after there is an issue. Thus, time spent upfront understanding how testing on a product is done is well worth the effort in the long run.
Frankly speaking, the contract manufacturer’s in-house lab is unlikely to either have the expertise, equipment or time to run every test required to meet specifications. Contract manufacturers usually manage a mix of in-house testing coupled with the use of qualified third-party labs. Of course, if a contract manufacturer does not operate an in-house lab, everything must be outsourced, which is fine so long as the third-party lab(s) can perform the required testing.
Contract Manufacturer’s In-House Lab
Many contract manufacturers have made the investment to bring a lot of their routine testing in-house. While this certainly saves time, it is an investment that takes time to achieve a return. However, for most quality contract manufacturers, the peace of mind in having a competent in-house laboratory offsets the investment in millions of dollars of equipment and trained staff. Additionally, the turn-around time from a third-party lab and the additional costs of using one can often put the contract manufacturer at a competitive cost disadvantage.
For instance, the cGMP required testing for raw material identity, potency testing and contaminants can easily run from US$0.25 to as much as $1 per bottle of supplement. The more ingredients in the formula, the more testing that is required. Also, the order quantity impacts the testing cost per bottle—$2,000 in testing costs spread over a 2,000-bottle order impacts the cost per unit much greater than it does on a 10,000-bottle order.
To help offset this cost, many contract manufacturers have worked to minimize the amount of testing required on incoming raw materials by qualifying their vendors. With sufficient procedures, this allows the contract manufacturer to test the incoming raw materials on a “skip lot” basis and not test every lot. There are pros and cons to skip lot testing (which we won’t get into here), but it’s an avenue most contract manufacturers will explore as time goes on.
A basic lab needs to have a means to test the identity and potency of the incoming raw material as well as the active or biomarker compounds in finished products. The lab should be able to test for known adulterants outside of the normal heavy metal and microbiological contaminants.
Identity testing: A contract manufacturer’s lab should have means to test for raw material identity. This can be done by:
- Organoleptic methods,
- FTIR (Fourier transform infrared spectroscopy),
- FTNIR (Fourier transform near infrared spectroscopy),
- HPTLC (high-performance thin layer chromatography), and/or
- HPLC (high-performance liquid chromatography) and/or UPLC (ultra-performance liquid chromatography).
There are certain raw materials that may require a mass spectrometer (MS) to test the material, but if this is required, the contract manufacturer will probably outsource the testing. Mass specs are expensive to buy ($200,000 to $500,000) and to operate.
Regardless of the identity technique used, the key to this process is the reference standards. The first lot of material received from a vendor is not a reference standard unless the vendor can show proof the material lot sent to the contract manufacturer was fully characterized. Using the first lot of material as a standard, if it’s not fully characterized, is a weak foundation for any lab. If the material is wrong or mischaracterized, all future lots will be flawed, as well. A strong contract manufacturer’s in-house lab is one that has invested in a library of reference standards.
Organoleptic identity testing works if there is a trained person on staff, and the raw material lends itself to this type of testing. However, it may not be the best approach to identifying adulterants.
Historically, FTIR is a fast, inexpensive way to compare two materials. The problem is sensitivity. FTIR is not sensitive enough to pick up some of the materials used in economically motivated adulteration. Be cautious about any lab using FTIR as the sole means of testing identity.
A good contract manufacturer lab will use FTNIR, HPTLC and/or HPLC/UPLC to do the identity testing. Again, having reference standards is the key to detecting the presence to the correct material. FTNIR is fast and can detect adulterants, but can give some false negative results. HPTLC and HPLC/UPLC are the best for identifying raw materials, but the testing can be time consuming. If the contract manufacturer relies on HPTLC or HPLC/UPLC for testing, make sure it has adequate equipment and staff to handle the volume of samples. HPTLC can take a day to run test a sample. HPLC can take one to three hours to run one sample. UPLC is significantly faster and can run a sample in 30 minutes or less.
If the contract manufacturer receives/uses 200 different ingredients and makes 20 finished products a day, that amounts to a lot of necessary testing. Simple math will dictate whether the lab has the capacity to do what’s needed, so a brand owner should review the lab’s daily workload and confirm this information, including the chemist’s ability to interpret the results.
Contaminants testing: Typical contaminants are heavy metals and microbiological. However, more botanicals and botanical extracts are being adulterated. If the contract manufacturer does identity testing using FTNIR, HPTLC or HPLC/UPLC, it should be able to identify adulteration of the raw material.
Heavy metals and microbiological contaminant testing are routine tests and can be done by an in-house lab or outsourced. These are usually run concurrent with the identity and potency tests to save time.
Potency testing: This is a cGMP test requirement if potency of the raw material is part of the specification. For example, if a brand is using a Rhodiola rosea extract and making a Rosavins content claim on the product label, then the contract manufacturer will be testing for the Rosavins content in the raw material as a key identity marker. In most cases, this quantifying of active or biomarker compounds is usually performed using a HPLC/UPLC method.
Finished product testing: In this case, the contract manufacturer cannot rely on anyone else’s data or information. It must either perform the test or contract it to a third-party lab. The lab techniques are much the same as those used for the potency testing, i.e., HPLC/UPLC, ICP- MS for mineral testing, which is same equipment used to identify heavy metal contamination.
One issue that has been on the radar in the industry is “dry- labbing.” Contract manufacturers with an in-house lab that is under-staffed or does not offer adequate capability or certain third-party labs will sometimes “dry lab” results, which is creating numbers to push the items through the lab and out the door. This causes issues with cGMP compliance, and risks the brand owner’s good name and industry standing.
Material and product specifications and testing for such is a cGMP requirement that cannot be shirked or ignored. Any contract manufacturer that cuts corners to reduce delivery times or save money by offering to overlook these requirements isn’t doing a brand any favors. Correct, robust testing done by the contract manufacturer and/or qualified third-party lab helps ensure the viability of the product and safety of your consumers.
Michael Finamore is CEO of Gemini Pharmaceuticals Inc., a contract manufacturer of both dietary supplements and over-the-counter (OTC) pharmaceuticals for more than 30 years. All Gemini production is carried out in a pharmaceutical cGMP (current good manufacturing practice) environment.