Contract manufacturing process aids – Oft-overlooked tools for success

Insider Takes

For over a quarter century, the dietary supplement industry has been regulated under federal law and regulations which require minimum steps for compliance with current good manufacturing practices (cGMPs). These rules and regulations were promulgated by FDA fully 10 years after the signing into law of the Dietary Supplement Health and Education Act of 1994 (DSHEA) and phased into utilization by the agency based on the size of the company being evaluated.

Even today, a substantial percentage of companies engaged in this industry have at least one significant enough deficiency to warrant the issuance of a Form 483—a report of observations requiring corrective action or at the very least, a fuller explanation to satisfy the regulators that what is being done can be documented and repeated with the intent to keep the finished product safe for human consumption and free of contaminants or foreign materials.

Logically, one would think companies would want to create an environment where problems could be identified early in the process of receiving or storing goods for later production. Unfortunately, without adequate standards of reference—or without segregating testing areas so as to prevent or mitigate cross-contamination of materials—errors in the primary test of verifying identity of the substance in question just leads to compound issues and even recalls of finished products.

Some of the process aids that should become widespread in our industry are mobile testing stations with high-efficiency particulate air (HEPA) or protected filtered air flow to allow for a “clean” environment to sample inbound materials for further evaluation by the quality unit. In addition to having this segregated protected area, the personnel conducting the sampling should have proper fitting personal protective clothing and apparati in use to prevent accidental contamination of the material being sampled. Finally, good documentation of the opening of the material container, the size of sample, the date and time taken, and the reclosure of the container with double signatures of the process should be maintained in a robust database and in a writing that accompanies the sample raw material to the laboratory or other testing station.

Once a sample has been taken and placed in an appropriate container with labeling affixed and witnessed by a member of the quality unit for verification, the sample then needs to be evaluated against a variety of optional reference standards using added processing aids. If the material is a known substance with a monographed profile established by the U.S. Pharmacopeia (USP), Food Chemicals Codex (FCC) or other reputable quality organization, it should go through an identification process. At the very least, this would involve one or more of the process aids utilized to calculate melting point temperature, color (using colorimeter), infrared “fingerprint” pattern, atomic weight, chromatographic fingerprint or spectrophotometric recognition.

Melting point calculations can be achieved by simple chemistry involving Thiele tubes, capillary tubes or more sophisticated equipment such as a Vernier Melt Station. Melting point is most often used to identify the purity of a substance, and is useful in doing quick qualifications of raw material samples by research and development (R&D) staff for consideration of approval of a new vendor for what may be a commodity item.

Melting point evaluations of expensive materials such as coenzyme Q10 (CoQ10) are very useful and quick. I have personally witnessed where maltodextrin, Yellow No. 5 and a small quantity of rutin was used to “adulterate” true CoQ10 powder, thereby altering the melting point to outside the accepted range of 48 to 52 degrees Centigrade. Maltodextrin melts at 240 degrees Centigrade. Rutin melts at 242 degrees Celsius. When the “purported CoQ10 powder” did not produce evidence of melting at 150 degrees Celsius, it was apparent economic adulteration was present, if not outright fraud. These process aids are invaluable additions to any dietary supplement finished product producer.

Another essential for conducting identification of inbound materials is Fourier transform infrared (FTIR) spectroscopy, which is a technology used to collect the infrared spectrum of absorption or emission of a solid, liquid or even gas. By collecting high spectral resolution data over a wide range, the reading can be compared with a reference standard which was independently validated and verified by a separate laboratory or commercial vendor of reference standards. One significant mistake often cited by inspectors under DSHEA is that it is not GMP to use prior receipts of materials as the “reference standard” by which the currently tested material is being evaluated.

In the case of botanical materials involving either powders of plant components or extracts thereof, the need for more sophisticated process aids is clearly present. The emergence of or high-performance thin-layer chromatography (HPTLC) equipment to facilitate routine testing of botanical compounds through the accepted method of chromatography against recognized reference standards has become of profound importance in creating evidence of identification testing in master production records and resulting batch records. Should a problem be identified post-consumer use, one can be certain of an inquiry for these records should the quality of the material be called into question in a court proceeding. Additional steps can also be taken to verify findings or clear up anomalies encountered by HPTLC testing, involving DNA testing (limited) and HPLC testing to identify collateral compounds that may be unwanted and present in the subject material.

Consider the current situation with CBD products, many of which are in edible preparations, and which regrettably also contain levels far in excess of that permitted for THC. While FDA continues to ponder the correct regulatory framework for supplements containing CBD, if any, rest assured that companies that do not provide the basic minimums of adequate identification tests for the materials used in the finished products will be very busy in defending litigation should their materials be found contaminated—this is true for both the producer and the finished product reseller.

When dealing with natural products, careful attention needs to be paid to bioburden, or the concentrations of bacteria or other potentially pathogenic organisms that could be present in the raw material. Specifications need to be set authorizing positive release or rejection criteria when dealing with yeast, mold or bacteria present in the material. Unless the substance has gone through a steam sterilization or some other mechanism of reducing the bioburden, it is wise to conduct a microbiological test on the material to identify content and, if necessary, identify species of the bacteria present. Failure to do this could lead to serious consequences. To that end, high-quality manufacturers have internal microbiological testing capabilities which they deploy prior to releasing or rejecting material for use in supplements. Consider at this point that several pieces of equipment or process aids have been identified, all of which are essentially diagnostic tools for identification, which is the primary step in a quality system designed to militate against fraudulent or contaminated materials entering the supply chain of the industry.

Once received and cleared for general use, additional steps must be taken to assure purity and potency, not to mention suitability for manufacturing and ultimate stability or shelf life. Process aids which are often overlooked are simple items such as temperature and humidity recorders for warehousing or production facilities that are often environmentally controlled. Failure to provide records of those readings in a subsequent product complaint or recall investigation can be introduced as evidence of failure to take appropriate care.

For companies with international certifications such as those from Australia’s Therapeutic Goods Administration (TGA), the presence of an “air shower” for removal of foreign materials prior to entering a controlled environment is a requisite for certification. While that is not generally a requirement for U.S. producers, it does provide an added layer of safety from exposing in-process ingredients in a weighing or blending environment to cross-contamination.

Additional process aids to be considered as essential in operations of dietary supplement facilities and processes involve sieving capabilities to identify and remove foreign materials, metal detectors to prevent contamination, weight checkers on process equipment to provide written evidence of oversight and care, and tablet or capsule de-dusters to rid finished product of debris prior to packaging or subsequent coating. In packaging operations, simple installation of Plexiglas protectors over open containers on a filling line can retard potential environmental contamination of the finished goods. Also helpful is placement of electronic eyes, weight checkers and digitally controlled jet printers for date, lot and expiry coating, with final metal detection equipment present to further safeguard the consumer.

Of course, one of the most important process aids for manufacturing is actually scheduling and performing the recurrent training and accurate utilization of personal hygiene methods and equipment, gowning procedures and application of personal protective equipment (PPE) in affected areas of operations. When conducted routinely, documented and retained, training on the proper mechanisms of washing hands, gowning and affixing of PPE is an often-overlooked component in critical evaluations of manufacturing facilities in the supplement industry.

Mark A. LeDoux is founder, chairman and chief executive officer of Natural Alternatives International Inc. an organization established in 1980 with facilities in the U.S. and Switzerland engaged in the research, design and manufacture of nutritional supplement programs and products for multinational clients. He is a proud member and leader of many industry organizations.