[co-author: Tara Lin Couch]

Even the best company is not perfect. Mix ups, mathematical errors, transposing numbers, forgetting to sign a batch production, a supplier mix-up, or any one of an almost infinite potential glitches in the very complex processes involved in making a dietary supplement can occur because human beings are not perfect. These events can range from the benign (transposing the last two numbers of the expiration date on a bottle of vitamin C) to potentially life threatening (a mix up resulting in the presence of an undeclared major allergen in protein powder). Managing this kind of event in a manner that preserves consumer confidence and avoids regulatory entanglements can be challenging but establishing a quality system using the roadmap provided by the dietary supplement current good manufacturing practices regulations (cGMPs) will provide for an orderly process most likely to lead to a successful outcome.

Discovering What Went Wrong (and Trying to Ensure It Won’t Happen Again)

One of the most important aspects of any quality management system (QMS) intended to meet the principles of cGMPs is its investigatory piece that is used to evaluate and address problems and quality issues. For dietary supplements, this Quality Incident System within the cGMP QMS is dictated in Subpart F – Production and Process Control System: Requirements for Quality Control of 21 CFR 111, cGMP in Manufacturing, Packaging, Labeling or Holding Operations for Dietary Supplements. Specifically, 21 CFR 111.113 lays out the requirements for quality control operations to conduct a material review and make a disposition decision for materials and/or products impacted, or potentially impacted by quality incidents. These incidents include:

• Out of specification (OOS) results from testing materials or products;
• A deviation from a master manufacturing record (MMR);
• An unanticipated occurrence during manufacturing operations;
• A deviation from any other part of the production and process control system;
• An instrument calibration or control problem that may have impacted the quality of batch(es); and
• When a dietary supplement is returned.

Consumer complaints, with requirements provided in Subpart O – Product Complaints of 21 CFR 111; and the separate statutory requirements of the Dietary Supplement and Nonprescription Drug Consumer Protection Act of 2006, may also be part of this Quality Incident System. In addition, the Corrective and Preventative Action (CAPA) process may be utilized at any point, when necessary, during an investigation within the quality incident system.

Establish a Plan and Follow It

A practical and efficient quality incident system engages all the facility, not just the quality control team, and is organized in a tiered fashion to ensure that critical and complex incidents are appropriately escalated. The flowchart on page 8 illustrates the quality incident system of 21 CFR 111.

Regardless of the organizational strategy, to be meaningful an investigation must be thorough, timely, unbiased, well-documented and scientifically sound. This statement is an excellent excerpt from the U.S. Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER), Guidance for Industry: Out of Specification (OOS) Test Results for Pharmaceutical Production, issues initially in October 2006 and then updated in 2021. This is the only guidance provided by the FDA on investigatory practices and processes, which also makes it clear that even if a material or product is eventually rejected, a thorough and complete investigation is necessary to determine if the result impacts other materials or products. To accomplish these investigatory goals, written procedures must then be developed and implemented for each tier of the quality incident system; and there must be associated controlled form(s) to document every step of the investigation and indicate who performed it and when to fulfill the requirements of 21 CFR 111, Subpart P – Records and Recordkeeping, overall good documentation practices (GDPs), and the FDA expectations for records that are attributable, legible, contemporaneously recorded, original or true copy, and accurate (ALCOA).

Out of Specification (OOS) Investigation

An OOS investigation is performed whenever a specification established in accordance with 21 CFR 111.70 is not met. However, an investigation should also be undertaken for results that are out of trend (OOT) or unusual. This applies to raw materials, in-process materials, packaging components, labeling and finished products. The purpose of the OOS investigation is to determine if the result obtained is valid. This determination may be accomplished by assessing the accuracy of the result non-experimentally, reviewing historical data, re-analyzing the sample, re-testing the sample and performing additional experiments, if needed. It is vital though to ensure that deference is always given to the original result. Results within the specification would be accepted without question, so disregarding unfavorable results is not an acceptable practice. Neither is the practice of “testing into compliance” where repeated analysis or testing is performed until a favorable result is obtained. Significant scientifically valid evidence must be generated to invalidate an OOS, OOT or unusual result. Validated OOS results then lead to a material review. It is recommended that analytical and microbiological OOS investigations are segregated due to the strategic differences required during the investigations. Analytes are generally uniformly distributed while the growth of bacteria, fungi and mold microorganisms is quite variable.

Deviations

A deviation from the MMR or other controlled process may be planned or unplanned, but both types of deviation must be investigated. The purpose of the investigation is to determine the root cause of the deviation and whether material and/or product has been or will be impacted. Planned deviations are not expected to be permanent or re-occur for a significant amount of time, and this investigation should also evaluate why the deviation should not be permanent. A permanent deviation is a change that must be managed through the change control process. Unexpected occurrences or events that result in variations from an MMR or other process are unplanned deviations. An unplanned deviation requires an investigation that provides an assessment of all relevant background information needed to understand the incident, interviews personnel involved, reviews pertinent procedures and documentation, and includes a historical review and trend assessments to determine the root cause of the deviation. A material review follows each deviation in order for a material or product disposition decision to be made.

Returns Investigation

Subpart N – Returned Dietary Supplements of 21 CFR 111 dictates that a returns investigation is conducted to evaluate the reason for the return and assess whether the quality of the product batch or any related batches have or may have been impacted. This is accomplished by examining the returned product and reviewing manufacturing and packaging records for that product. Returns may be salvaged if the reason for the return is unrelated to quality, or if the product can be reprocessed to ensure that it meets all product specifications thereafter. However, consideration must be given to the storage conditions and security of the product while it was in transit and not within the control of the product brand owner. The disposition decision for a return may be to dispose of the returned product, salvage the product either as is or after reprocessing, or if quality has been impacted conduct a market withdrawal or product recall. All of which will be documented as part of the material review.

Quality Investigation

A general quality investigation of an unexpected occurrence or event that may have impacted the quality of a material is performed for instrument calibration issues, equipment control problems, inappropriately identified or damaged materials, and any other non-OOS, deviation or returns incidents. The premise of the quality investigation is the same as that of a deviation and includes an examination of all relevant background information needed to understand the incident, the performance of personnel interviews, a review of pertinent procedures and documentation, and a historical review and trend assessments such that a root cause can be ascertained. A subsequent material review is then conducted to make a disposition decision for all impacted materials or products.

Material Review

A material review is an evaluation of a material or product that has been impacted by a specification failure or unexpected occurrence to determine whether the quality of the material has been compromised in terms of its identity, purity, strength, composition or limits of potential contaminants. The purpose of the review is to make a scientifically sound disposition decision for the material. When the first-tier investigation, OOS, deviation, returns investigation or quality investigation, is thorough and detailed, and a root cause has been assigned, no further investigation is necessary at the material review stage. However, further investigation can be conducted, as necessary, to make a disposition decision. Ultimately, the investigation and material review should encompass a review of the MMR and executed batch production record (BPR), master formulation and bill of materials (BOM), pertinent processes and procedures, product label and previous quality issues and historical trends. Personnel interviews should also be performed as part of the material review. Additional testing, retesting, resampling and increased inspections may be incorporated also, as necessary, to determine the root cause of the incident. The disposition decision must be to either accept the material as is or to reject it. If the material is rejected, it may be reprocessed if reprocessing can ensure that material will meet its specification in terms of its identity, purity, strength, composition or limits of potential contaminants. The latter should also be determined as part of the material review. Although appropriate subject material experts (SMEs) should be consulted when making this disposition decision, per 21 CFR 111 only the quality control team is allowed to make the final disposition decision.

Conclusion

Conducting a thorough quality investigation is never easy. It requires a significant amount of critical self-evaluation, a willingness to acknowledge that systems currently in place might not have worked properly and the initiative to take steps to implement necessary changes. Companies that can undertake this process with an open mind (rather than a predetermined outcome that whatever happened was someone else’s fault) will find that they are better off for it, and management should be able to sleep better at night with the knowledge that these systems are in place.

This article appeared in the August 1, 2024, issue of Nutrition Industry Executive and was co-written by Tara Lin Couch, PhD, the owner of TLC Regulatory and Laboratory Consulting.