By Tamika Cathey
Specifications Development, as defined in FDA’s Good Manufacturing Practices for dietary supplements (21 CFR §111) have posed one of the biggest challenges to industry since the inception of the requirements in June 2007. Specifically, 21 CFR §111.70 requires manufacturers to develop specifications for each component used in the manufacturing process and the finish product, including raw material components, in-process controls, packaging/labeling materials, and finished products. To be compliant with 21 CFR §111, each specification must ensure the quality of the material or product by addressing its identity, purity, strength or concentration, physical composition and lack of potential contaminants or ensuring that potential contaminants are present at acceptably safe levels. However, manufacturers continue to struggle with understanding specifications development and compliance. This is evidenced by the many Warning Letters and Form 483s issued by the FDA in the past ten years.
Certainly, the intent of specification requirements is well understood, at least conceptually by industry. The main purpose for requiring adequate specifications is to prevent product(s) adulteration and ensure that the finish product meets at least 100% of all nutrient claims declared on the Supplement Fact Panel (SFP) throughout its best by date or expiration date per 21 CFR §101.9 under the Nutritional Labeling and Education Act (NLEA). Once a specification is set, the specification must be verified using scientifically sound and justified testing analysis and/or visual examination analysis such as organoleptic, macroscopic, microscopic, chemical, or microbial. Recognized test methods can be obtained from compendial sources like USP monographs, AOAC, FCC, or NF and used a starting point in determining an appropriate method. Multiple tests and examinations are usually deployed to ensure specifications are met per 21 CFR §111.75 and 21 CFR §111.320. All of this ensures consistent reproducibility and reliability of a finished product that is either being manufactured or packaged.
A look at recent warning letters illustrates this lack of understanding with findings such as:
- A lack of or incomplete identity component specifications (e.g. dietary ingredients, excipients or process aids, coating materials etc.) for each component per 21 CFR §111.70(b)(1) and 21 CFR §111.70(b)(2).
- Lack of or incomplete specification(s) for in-process controls in manufacturing process per 21 CFR §111.70(a).
- Lack of or incomplete product specifications for finish products per 21 CFR §111.70(e) to include package/labeled products (e.g. 21 CFR §111.70 (d) & (f) & (g)).
Briefly, specifications are a set of defined parameters benchmarked against associated acceptance criteria providing characteristics and quality of a finish dietary supplement. The expectation is that when specifications are established, they will be written, managed in a controlled system with revision histories that are tracked, monitored, reviewed and approved by the Quality Department. This means materials and products being used from other sources will be unequivocally identified, the microbiological purity and other purity requirements will be assessed to determine strength and concentration of a dietary ingredient. The physical composition will be evaluated, and any potential contaminants will be identified.
When developing specifications, it is a good idea to begin as early as possible by identifying critical quality attributes of finish product(s) and the manufacturing process as a whole. These quality attributes are to be identified with acceptable ranges determined in order to assess the attribute. Scientifically sound/valid test methods and examinations are tools used to conduct the assessment. Each specification developed should address sections of identity, purity, strength, composition, and contaminants to meet regulatory requirements outlined in 21 CFR §111.
Dietary supplement manufacturers must consider component specifications, including dietary ingredients, as defined in 201(ff) of the FD&C Act and label claimed on SFP, and non-dietary ingredients such as excipients, capsules, and coating materials.
In addition, in-process specifications must be established for any point, step, or stage of manufacturing and packaging processes. Simply put, these specifications focus on verifying material composition thorough a series of physical tests and examinations such as in-process checks and metal detection. These specification requirements can be met by developing a comprehensive Master Manufacturing Record (MMR) as required in 21 CFR 111.210.
Packaging and labeling specifications for components including container closure systems and materials that may come in contact with finish product including desiccants, cotton, pouches, lids, outer cartons, labels, and inserts should include approved/qualified supplier information, name and description of item, and physical attributes such as material type, size, dimensions, and color. Physical attributes and item descriptions can be obtained from a reliable C of A. Keep in mind that packing specifications must be developed for every packing configuration used for finish products. Set process and control specifications within the MMR and set a requirement that visual examination for each batch will be performed.
Finally, finished product specifications (FP) establish the identity, purity, strength, composition, and limits of contaminates for each finished batch of dietary supplement. In short, the finish product specification details testing requirements for a finished batch. All dietary ingredients listed on the SFP must be identified on the FP specification and additional requirements of minimum and maximum acceptance criteria.
It is expected that the claimed SFP ingredients meet at least 100 percent of the label claim in order to meet the requirements NLEA detailed in 21 CFR 101.9. Release specifications may be set at a higher percentage to account for any needed overage amounts formulated into the product to ensure the 100-percent requirement is met throughout the product expiration date or best buy date.
In closing, specifications development can be established based upon acceptable ranges and values set forth by industry, academia, and scientific data/results from published journals, and/or product history in manufacturing. Refer to NLEA mandatory and voluntary labeling disclosure set forth by FDA 21 CFR 109 (j). Accredited laboratories and American Herbal Product Association can provide guidance for building the appropriate specification to include test method. Reference any sources used to determine appropriate specification. If further assistance is needed, manufacturers can also work closely with the qualified supplier(s), an accredited 3rd party laboratory, and/or qualified consultants to help with specification development.