With dietary supplements becoming more and more popular throughout the world, quality has become even more critical for companies involved in the manufacture of nutritional products. FDA’s (Rockville, MD) forthcoming current good manufacturing practices (CGMPs) for dietary supplements will set the rules that all companies must follow.
We all know the importance of raw materials to a high-quality product. Raw materials are in fact the foundation of a qualified final product. Without a qualified material, all efforts at producing a good product would be like building a palace on a sandy base.
|Photo courtesy of Pure World Botanicals Inc.|
With hundreds, if not thousands, of items produced in a manufacturing facility, it is very difficult for a company to handle materials from the very beginning to the end of the final product fulfillment. We are relying more and more on our suppliers to provide high-quality materials for our manufacturing of finished products. Taking herbal products as an example, a typical flowchart may include herbal growing or collecting; crude-herb distributing; bulk-material manufacturing, such as milling and extracting; and consumer product manufacturing.
With materials flowing from stage to stage of the material trading chain, it is important to have the material clearly and correctly identified and elucidated. In addition to material and container labels, the certificate of analysis (C of A) serves as an identification document for the status of the material. The C of A provides more-detailed information that a label generally cannot provide. The C of A conveys information from a material supplier to a material user about the identity, quality, and purity of that specific material. It is very important for a material supplier to show its customer a trustworthy C of A so that the customer can understand what kind of material is received. The material user can also compare the information provided on the vendor’s C of A against its specifications to see whether the material meets the required criteria.
WHAT TO EXPECT ON A CERTIFICATE OF ANALYSIS
A trustworthy C of A must reflect the true and representative properties of the subject material. Normally, a C of A will list each item of analysis required by the specifications of the material and report actual analytical data against the specification point or range of the corresponding analysis. Depending on material type and process stage, as well as the user’s requirements, a general C of A may include the following common information:
- Product identity: product name, item number, lot/batch number, manufacturer, manufacturing date, and expiration date.
- Product source: country of origin, scientific/botanical name, plant part (root, stem, leaf, flower, fruit, seed, resin, etc.) if from a botanical source.
- Product type: crude material, cut, powder, granular, whole herbal extract, standardized extract, and whether the item has an official monograph.
- Identification method: microscopic, TLC, FT-IR, HPLC, GC, etc.
- Physical property: color, odor, taste, appearance, bulk density, particle size, pH value, solubility, moisture content, loss on drying, viscosity and refractory index (for liquid materials), flow-ability, compressibility, etc. For pure ingredients: melting/boiling point, specific rotation, etc.
- Chemical assay and method: active or marker compounds, purity or specified ranges, titration, UV-Vis, HPLC, GC, etc.
- mpurities: foreign matter, total ash, acid-insoluble ash, heavy metals, natural toxins, pesticide/fungicide residues, etc. You may also have concerns on genetically modified organisms, allergens, and gamma-ray irradiation process if your product is regulated by some foreign government rules.
If it is for a sterile material, a C of A should also include microbiological data, including total plate count, yeast, molds, total coliforms, E. coli, salmonella, staphylococcus, pseudomonas, etc.
Finally, the C of A should be signed and dated by a quality control or quality assurance person representing the manufacturing or testing company.
DEVELOPING A TRUSTWORTHY C OF A
A responsible material supplier will develop a trustworthy C of A with meaningful information representing the material covered by the C of A. A lot of work needs to be done to fulfill this task. First, the supplier must develop a thorough and practicable specification for the designed material based on the scientific and customer requirements. Second, the supplier will develop and manufacture the material meeting the established specifications. Third, the quality control or quality assurance personnel of the material supplier will collect representative samples of the specific batch of the material, go through a thorough scientific analysis of the samples against the established specifications, and present actual data for each criterion set up in the specifications.
If the analytical data meet the specification requirements, a C of A can be generated to release the material for delivery or further usage. If the analytical data do not meet the specifications, the material shall be redeveloped or remanufactured.
FDA’s proposed CGMP standards do not apply to a person or entity engaged solely in activities related to the harvesting, storage, or distribution of raw agricultural commodities that will be incorporated into an ingredient or product by other persons or entities. Normally, these raw agricultural materials can be easily identified by their macroscopic properties without a C of A. However, some physical (e.g., color) and chemical properties may vary by plant part, harvesting season, or even cultivating site. If a specification is set for a specific range of the desired compounds, an analysis of the raw material, and therefore, a consequent C of A, becomes necessary.
In the nutritional industry, there are some broker companies engaged solely in trading without physically processing the materials. They shall convey exactly the original C of A from the manufacturer to their customers without changing even the lot numbers. This way, the C of A can reflect the original data from the manufacturing fact. In some cases, a material importer may reassign the whole cargo of material as a single lot even if the cargo contains several original manufacturing batches. Since there was no reprocess of the different lots, you may see physical and chemical variations from container to container of this “same-lot” material. This is something to be aware of.
VENDOR C OF A QUALIFICATION
As a material user, you hope to receive the material you expect, along with the information necessary for you to examine and understand the material before you can use the material in your products. You expect the C of A to provide the representative and actual data that meet your specifications. This is especially important if your company does not have a laboratory setup that can check each criterion and is relying on your supplier to provide material parameters for your product formulation and process. Even if your company has a state-of-the-art laboratory and tests every lot of materials received, an informative C of A can provide some necessary information for your operation scheduling and, in some cases, raise a flag in early stages when a questionable material is received.
To assure that your vendor’s C of A is trustworthy and the information within is meaningful to your operation, you need to make sure you understand the nature of your supplier’s company. Are they a broker or a manufacturer? Do they have laboratory capacity for data acquisition and analysis required by the specifications; do they use an independent lab; or do they not test at all? How do they get their data for the C of A—is it copied from their supplier’s C of A or calculated from input? Do they conduct random analysis for every 10 lots, or physically test each lot? Those key questions must be answered at the beginning of the vendor qualification process, and the best way to answer them is to conduct your own inspection and audit of their facility. By physically reviewing their processes and quality system, you can understand the checkpoints they have established for gathering and inputting data into their C of A, and you can decide for yourself whether these are acceptable practices for your company.
Please note that the C of A is only one of many factors that are related to the quality of the product. A comprehensive quality system based on CGMPs is very important to any manufacturer dealing with nutritional materials and products. If you have an established quality system that can guarantee the quality of your products, you may want your supplier to follow the same or a similar quality system and include that in your vendor qualification process.
Another important issue is to communicate clearly with your supplier regarding the specifications of the material you are expecting for your production. For the same material, you may require a particle size different from the one your vendor is producing. The vendor’s microbial threshold may be different from your requirements. A material passing its specifications with a trustworthy C of A may not be usable in your process.
PRESHIPMENT SAMPLE QUALIFICATION
The second stage in qualifying a C of A is through preshipment sample analysis. By demanding a preshipment sample, you can independently test your vendor’s product against its C of A. The material can then be examined for both chemistry as well as physical properties to ensure that it matches the vendor’s C of A. It is also a good idea to request multiple preshipment samples from different lots for testing when qualifying a new ingredient. This will allow you to see firsthand the consistency of your vendor’s material across multiple lots, and to see any variation that may be present in the material itself. This is especially important when dealing with botanical products, as numerous factors can impact the final chemical and physical properties of the plant. For instance, the color of echinacea can be green, yellow, or brown depending on the harvesting stage and drying process. Total fatty acids in saw palmetto powder may vary from 7 to 14%, depending on the mature status of the fruit. Establishing a history with a supplier allows you to see how these variations may or may not fall within the specifications outlined in the C of A. Practical preshipment examination of the real lot sample before each purchase may save you time and the cost of rejecting the whole shipment when a problem exists.
Once a vendor is qualified and material is received, correct and clear information needs to be communicated on the product itself; this information must match the C of A exactly to certify the reliability of this document, almost like a reverse check for the document. For example, container labels must match the C of A precisely, particularly for product name, vendor item number, and lot number. The use of bar codes on labels is especially convenient, because it allows you to track the inspection of the product as it was being manufactured, analyzed, and packed. A visual inspection of the contents of the containers should then verify the consistency of color, odor, and appearance, and reveal any significant deviation or contamination. Finally, scientific sampling procedures should be followed to allow representative samples to be collected for proper examination of the product itself. If a nonrepresentative sample is taken from the product, you cannot ensure that the entire batch of product sent truly matches that C of A.
The final stage in the certification process is to conduct a firsthand laboratory analysis of the product itself. Once a true representative sample is taken of the product, the material should be examined for physical, chemical, microbial, and other properties following the same assays denoted on the vendor’s C of A, and, more importantly, your own specifications. If a different assay is required, this should be communicated to your vendor prior to C of A submission, as assay methodology can change the outcome of the data.
The lab analysis can be conducted in-house, if you have the facilities, or can be conducted by outside laboratories. Primary lab analysis is also the best way to ensure that a material meets your quality standards. This final stage further corroborates your vendor’s C of A as a trustworthy document, certifying that your vendor is providing you with the material you had originally specified.
Even if you don’t have laboratory capacity and you believe that you have built a trustful vendor relationship, at least one analysis is recommended, since many things may go wrong when a material is conveyed from one stage to another. The simplest way is to build a reference sample library and compare each lot of the same item to the reference through visual and other simple examinations.
Once all of these criteria are met and a vendor’s material and C of A are certified, you can begin to establish a history with them as a supplier. This will lay the groundwork for quality assurance for your products because your raw materials are now coming from a trustworthy source with consistently reliable documentation. With this solid foundation, you will be able to work through your production quality system to bring the highest-quality products to your customers, building further trust in your product line.