Creating Compliant, Smart, Scientifically Sound Specifications

More than 200 FDA warning letter citations for inappropriate specifications were issued in 2013, and this trend is continuing in 2014. 21 CFR 111, “Current Good Manufacturing Practice (cGMP) in Manufacturing, Packaging, Labeling or Holding Operations for Dietary Supplements," requires that specifications be created for raw materials, in-process materials, finished products and packaged products. To be compliant, each specification must ensure the quality of the material or product by addressing its identity, purity, strength, composition and lack of potential contaminants. Smart specifications are developed, maintained and implemented in an efficient manner. Scientifically sound specifications can be utilized to assure the dietary supplement manufacturer that the finished product will contain at least 100 percent of all nutrient amounts declared in the Supplement Facts Panel (SFP) of the label throughout shelf life.

Specifications are a set of defined parameters with associated acceptance criteria that, when combined, establish the characteristics and quality of a finished dietary supplement product. As a controlled document, each specification must be identified by a unique number (usually the assigned item number) that is managed through the change control (CC) system to ensure all revisions are tracked and monitored. Any controlled document, including ones that have specifications, must be reviewed and approved by the quality department. The testing requirements captured on the specification must include tests and examinations that will (1) unequivocally identify the material or product from any other that is in use or could be received at the manufacturing site, (2) assess the microbiological purity of the material, (3) determine the strength or concentration of the dietary ingredients, (4) evaluate the physical composition of the material or product, and (5) screen the material or product for any potential contaminants to demonstrate they are present at acceptable safety and regulatory levels.

Raw materials include dietary ingredients and components. Vitamins, minerals, botanicals (powders and extracts), amino acids, enzymes, probiotics and any other type of appropriate material that has a label claim on the SFP are all considered dietary ingredients. Components are non-dietary ingredients, such as excipients that are typically utilized as a manufacturing or process aid, but also include coating materials used for tablets, and hard and soft capsules. Packaging components that may come into contact with the finished dietary supplement must be demonstrated to be safe, suitable for their intended use, and non-reactive or absorptive, such that the product may be affected by the packaging. Dessicants and cotton, as well as the entire container closure system including pouches, films, cans, bottles, caps, lids, seals, neck bands, body sleeves and outer boxes, are all considered packaging components. Labels and inserts also fall into the category of a packaging component, and therefore, they must be verified as safe, suitable for use, and non-reactive or absorptive so as to affect the dietary supplement product. Specifications for all of these types of raw materials are referred to as raw material specifications.

In-process material specifications must be established for any point, step or stage of the manufacturing and packaging processes where control is necessary to ensure the consistent production of the dietary supplement as dictated in the master manufacturing record (MMR). In-process material specifications are generally focused on verifying the composition of the material, which is most frequently accomplished by a series of physical tests and examinations that vary depending on the product dosage form. However, the assessment of contaminants such as metal fragments are also performed in-process.

Finished product specifications detail the dietary supplement finished batch testing requirements. Every dietary ingredient listed on the SFP must be addressed on the finished product specification, and each must have a minimum acceptance criteria that is equivalent to at least 100 percent of the label claim in order to meet the requirements in the Nutritional Labeling and Education Act (NLEA) detailed in 21 CFR 101.9, “Nutrition Labeling of Food." Release specifications may even be set at a higher percentage to account for any overage amounts formulated into the product to ensure the 100-percent requirement is met throughout the product expiration or best by date. The latter is often referred to as a stability specification. Maximum acceptance criteria should also be set to ensure that no ingredient is present at a level that exceeds the tolerable upper intake level (UL) established by FDA, and to ensure the manufacturing process remained in control throughout production.

To demonstrate the designated packaging components and label were applied to the dietary supplement, packaging specifications must be developed for every packaging configuration (SKU) that is used.

Each specification (raw material, in-process material, finished product or packaging) must provide the attribute to be assessed, the acceptable range for the attribute and the particular laboratory (in-house or contract) test method that will be utilized to conduct the assessment. The test method assigned must be scientifically valid, which means it is accurate, precise, specific and robust for its intended purpose and matrix. This may be demonstrated through peer-reviewed scientific publications or designed verification experiments that are well documented. The organization of specifications to include sections of identity, purity, strength, composition and contaminants will ensure that all regulatory requirements governed in 21 CFR 111 are addressed. Raw Material Specifications should also detail the receipt, inspection, sampling and testing requirements of the material with their associated acceptance criteria. Additionally, supplier and manufacturer information should be provided on the raw material specification.

Upon the completion of all tests and examinations dictated on the raw material specification, in-process material specification, finished product specification or packaging specification, the results must be documented with reference to or with the raw data. In-process material specifications and packaging specifications are typically provided throughout the MMR because it is the controlled document that governs each stage of the manufacturing and packaging process. The results obtained are therefore recorded directly on the batch production record (BPR), which is executed with every product batch manufactured. Raw material and finished product specifications are stand-alone controlled documents. However, the use of single, combined specification and reporting form allows the results of each test and examination to be recorded directly onto the specification. This strategy also removes the potential of errors that occur due to the issuance of multiple documents with the same information, and it limits the number of controlled documents that must be generated and managed through the CC system.

Tara Lin Couch, Ph.D., has over 20 years of diverse laboratory and regulatory experience in academic, field, contract and manufacturing environments. She directed the quality control department at a pharmaceutical and dietary supplement manufacturing facility for many years. Currently, she is a senior consultant at EAS.

For more information on GMPs and laws that regulate the supplement and functional food industries, visit INSIDER’s Regulatory Content Library.