What is the role of the Quality Control Laboratory?
The Quality Control (QC) laboratory serves as one of the most critical functions in pharmaceutical manufacturing and control. The Code of Federal Regulations, 21 CFR 211, Subpart I-Laboratory Controls, outlines the requirements and expectations for the quality control laboratory and drug product testing.
The QC laboratory has the final say on product release based on adherence to established product specifications. A specification is defined as a list of tests, references to analytical procedures, and appropriate acceptance criteria that are numerical limits, ranges, or other criteria for the tests described. Specifications establish a set of criteria to which a drug product or drug substance should conform to be considered acceptable for its intended use. Conformance to a specification implies that the drug substance and/or drug product, when tested, will meet the established acceptance criteria. Specifications are proposed, justified, and approved as part of an overall control strategy to ensure the quality, safety, and consistency of a drug substance and/or drug product. Subsequently, the quality of a drug substance and/or drug product is determined by design, development, in process controls, Good Manufacturing Practice (GMP) controls, product and process validations, and the specifications applied throughout development and manufacture. These specifications are specifically the validated test methods and procedures and the established acceptance criteria for product release and throughout shelf life/stability studies.
21 CFR, Section 211.160-General Requirements, establishes the requirements for specifications, standards, conformance to established quality standards and specifications, sampling plans, test procedures, processes and procedures for the investigation of nonconformance, the calibration/validation and proper maintenance of laboratory equipment used for testing and recording of testing data, and that products are free from microbial and chemical contamination. Additionally, 21 CFR, Section 211.165-Testing for Release and Distribution identifies the quality control laboratory as the deciding entity for product conformance to established specifications and justification for release. The legitimacy of laboratory test results is confirmed through the execution of validated test methods and the comprehensive documentation of all testing data to ensure compliance to established specifications. (Reference Section 211.194-Laboratory Records.)
Over the Counter (OTC)
Data available on prescription drug use in the United States demonstrates that in 2012 nearly 3 out of 5 of American adults use prescription medication. Additionally, nearly 81% of American adults seek relief from Over the Counter (OTC) medications, and OTC medications provide relief to an estimated 60 million Americans, both adults and children. Americans willingly consume prescription drugs and OTC medications under the assumption that the safety and efficacy of these products have been tested and approved prior to their release to market. Americans can comfortably make that assumption due to the fact these products are meticulously regulated by the Food and Drug Administration (FDA). The FDA Guidance, Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products Chemical Substances, provides recommendations regarding testing procedures, the justification and determination of acceptance criteria, and the establishment of global specifications for new drug substances and new drug products.
Consumers of prescription drugs and OTC medications demand and expect the products they are purchasing are effective, acceptable for their intended use, and safe. Likewise, consumers of medical cannabis should have the same expectations and assurance about the products they are purchasing.
When is a drug a drug?
At what point does a drug substance and/or drug product warrant testing controls, standards, specifications, and scrutiny of a quality control testing laboratory? The simple answer is when there is enough data. The FDA’s Center for Drug Evaluation and Research (CDER) has the responsibility of ensuring both prescription and non-prescription drugs that are marketed in the United States are safe and effective. The FDA’s drug approval process is long and arduous, but unarguably necessary. The data generating step in this process, and probably the most critical to the approval of a drug product, is the drug sponsor’s clinical studies. These studies are generally referred to as clinical trials. Government agencies, such as the National Institutes of Health, the Department of Defense, and the Department of Veteran’s Affairs provide funding for the execution of clinical trials. Additionally, funding may come from private industry such as pharmaceutical and biotech companies, medical institutions, and non-profit foundations.
There are (3) phases of a clinical trial
Phase 1 emphasizes safety. A drug’s most frequent side effects and how long it takes to metabolize and be excreted in the body is tested in this phase. The typical number of volunteers for a Phase 1 clinical trial is 20-80 people. Phase 2 emphasizes effectiveness. Volunteer numbers are typically in the hundreds. In this phase, there are two populations of volunteers; a test group, which has the disease/condition for which the proposed drug is to be effective against, and a control group. The test group is administered the drug product being tested, and the control group receives a placebo or a different drug. Safety continues to be evaluated during Phase 2. Phases 1 and 2 are small scale studies, where the populations of volunteers are low. Phase 3 are large scale studies in which the population of volunteers may be in the thousands. In a Phase 3 clinical trial extensive data is generated and documented on the safety and effectiveness of the proposed drug product, the impact of use on different populations, use of different dosages, and the impact of use in combination with other drugs. This data is summarized and presented to the FDA through the New Drug Application (NDA) process. Once the NDA is reviewed, and the drug labeling and manufacturing facility are inspected and approved, the drug is approved for release to market.
The FDA’s definition of a drug is “any product that is intended for use in the diagnostic, cure mitigation, treatment, or prevention of disease; and that is intended to affect the structure or any function of the body”.4 Isn’t that the intent of medical cannabis products? Why are medical cannabis products not considered drugs in terms of the FDA’s definition? The not so simple and unwavering answer of cannabis opponents is there isn’t enough data.
Cannabis, marijuana specifically, is considered a Schedule 1 Controlled Substance under the FDA’s Controlled Substances Act (CSA). Per the CSA, substances in this schedule currently have no accepted medical use in the United States, a lack of accepted safety for use under medical supervision, and a high potential for abuse. For nearly 50 years the federal government, specifically the National Institute on Drug Abuse (NIDA), has funded the sole program at the 12-acre farm at the University of Mississippi for the cultivation and research on marijuana. Historically, research reports generated by the University of Mississippi emphasize the negative health impacts of marijuana. However, due to strong and relentless advocacy for medical cannabis, and with more than half of the states in the United States having medical cannabis laws on the books, federal agencies have been forced to permit and have funded studies that report on the therapeutic benefits of medical cannabis. Additionally, in August 2016, the FDA’s Drug Enforcement Agency (DEA), opened the door for scientists, researchers, and cultivators to seek approval for the research and cultivation of marijuana at locations other than the University of Mississippi, but the government does not make the process easy. The number of licenses granted are restricted, and the rules and requirements to qualify for a license are strict and overwhelming, which may force many to avoid the process all together. However, with recent news reporting that the only available source of cannabis from the University of Mississippi for use in clinical research is contaminated with mold, there is a push from scientists to speed up the process for license approvals. This may subsequently cause a surge in the number of scientists, researchers, and cultivators applying for licenses to conduct scientific studies due to the lack of confidence in the unopposed data generated from previous cannabis studies.
It may appear that the DEA is softening its position on medical marijuana research, but there continues to be a lack of acceptance and approval based on the resounding objection to remove marijuana as a Schedule 1 drug. Therefore, scientists and researchers continue to struggle with the existing process and lack the federal backed funding necessary to support large-scale clinical trials. Without clinical trials, there exists no opportunity to generate and document data on the safety and efficacy of a drug product. As stated previously, data is the foundation for FDA drug approval. Without data to document and summarize there is nothing to submit for review per the NDA process. The absence of an NDA means no drug approval, and ultimately no existence of a legitimate, accepted drug to release to market.
Opponents argue the need for more research before accepting cannabis as a valid treatment for such conditions as Alzheimer’s disease, Parkinson’s disease, arthritis, epilepsy, chronic pain, and even cancer, but the truth of the matter is cannabis is the most investigated therapeutically active substances in history. Companies have sponsored privately funded research for decades on drug products made from marijuana. Regardless, scientists are continually restricted by the availability of samples they can obtain to conduct research and/or clinical trials. Samples must be obtained from a federally approved facility and/or program. This ultimately delays the progress of scientific research as it may take years to obtain samples. Despite the cumbersome process of privately funded research, and the government’s continued prohibition of cannabis, the U.S National Library of Medicine National Institute of Health’s website, PubMed.gov, contains over 25,000 published studies and reviews, documenting volumes of scientific and empirical data on the therapeutic effects and benefits of the plant and its components.5 To argue there is not enough scientific data to support a policy change for cannabis is simply absurd.
The medical cannabis industry is already a multibillion dollar industry, and it continues to grow exponentially. Product quality control, which includes a robust, reliable, consistent, and regulated analytical and microbiological testing program, is necessary and vital to ensure consumer safety and the understanding of the efficacy of the products for which they are purchasing.
Why the need for laboratory compliance?
There are several reasons compliant, standardized laboratory testing is necessary in the cannabis industry. First and foremost, the safety and efficacy of any commercially marketed drug product should be the intent of any company in the business of selling these products for use by an end consumer. The pharmaceutical industry’s heparin recall in 2008, which resulted in approximately 100 deaths in the United States due to adulterated raw heparin imported from China, forced the enlistment of laboratories throughout the nation to work with the FDA and the pharmaceutical industry to develop more robust and precise test methods for the identification of contaminants. Additionally, the contamination crisis heightened the awareness and resulted in more stringent regulations and requirements regarding supply chain, incoming raw material testing, the investigation of out of specification (OOS) results, consequences of not following proper GMP, and comprehensive product and process validations.
State run cannabis laboratories have adopted their own testing regulations and requirements for cannabis products, but most states require testing and labeling for potency (THC and CBD) and various contaminants such as residual solvents, microbial, heavy metals, and pesticides.
Proper test method development is a critical component to the operation of a quality run laboratory. The purpose of executing testing against validated test methods and procedures is to ensure a robust and repeatable process, which will guarantee reliable and trusted test results. Often test methods executed in a cannabis testing laboratory are developed by inexperienced laboratory technicians, or by individuals who lack the scientific education and expertise in test method development. Many laboratories consult testing methods that are readily available for pharmaceutical drugs and/or medical devices per standards such as the United States Pharmacopeia (USP), or the International Organization for Standardization (ISO). However, without the appropriate scientific knowledge and experience, there exists the potential of misinterpretation and improper execution of these standards. Additionally, there has been no accepted specifications for the minimum tests states require, therefore, states may have different acceptance criteria for the same test performed. There are some states that still do not require state mandated testing for cannabis products.
Legitimate laboratory testing in any industry comes at a cost. Laboratory equipment and testing reagents are expensive, the price per test may be up to $100 each, laboratory accreditation may be pricey, and to obtain experienced, educated laboratory technicians and managers laboratory owners must offer competitive wages and salaries. In an industry where regulations don’t apply, consumers run the risk of receiving product that did not undergo legitimate, quality testing, which may have been conducted by unqualified individuals. For example, testing for potency can present a challenge for cannabis testing laboratories. Many laboratories are pressured to test samples submitted from growers that may not adequately represent the entire batch of product, but are selected because they know they will test with the highest level of THC. Laboratories may blindly test these samples as the growers are not required to divulge the fact they have “cherry picked” their sample, or laboratories knowingly and willingly test these samples strictly for guaranteed profit.
Many laboratories operate a legitimate business. Consumer safety is top priority. They recognize the need for properly executed laboratory testing and accurate, reliable test results. Those that are managed by experienced and skilled analytical chemists and microbiologists have an advantage and will most likely sustain the rapid changes in the industry. There are many laboratories struggling to figure out how to maintain a hold in the cannabis space. They may be limited and at a disadvantage due to inexperienced and uneducated staff, a lack of expertise and knowledge on test method development and execution, and because the industry is deficient in guidance and regulation. These laboratories will be able to survive the storm if laboratory owners and management take the necessary steps to make their laboratory compliant through accreditation programs and complying with regulations like MCRSA (Medical Cannabis Recreation Safety Act), AUMA (Adult Use Marijuana Act) and ISO 17025, General Requirements for the Competence of Testing and Calibration Laboratories. Those laboratories that have developed their own proprietary methods with little to no information sharing among other laboratories, and/or those that are operating on the sole purpose of profit will most likely crumble as the industry becomes more standardized and regulated.
Consumers have become more educated about the products they are purchasing. Consequently, this is challenging the integrity of testing laboratories and pressuring them to be compliant and ethical. Consumers are interested in other components of cannabis such as cannabinoids and terpenes, where historically consumers wanted the most “bang for their buck” and thought the best product was that which contained the highest THC content. Medical cannabis patients are learning that they need to ensure their products are free from microbial contamination. The recent death of an immunocompromised cancer patient in California due to the consumption of product that was contaminated with bacteria and fungi is an example of why consumers need to fully understand what they are buying, and they can understand and interpret the test results provided for that product.
Currently competition is high among cannabis testing laboratories, but only the compliant will survive this rapidly growing and changing industry. If laboratories want to earn the same trust and respect as quality control laboratories in the pharmaceutical industry, then they need to operate a legitimate testing business. Medical cannabis is a means to provide an alternative, homeopathic treatment to conditions traditionally treated with pharmaceutical drugs, which may be highly addictive and/or generate a host of negative side effects. Laboratories must not let greed or refusal to accept change get in the way of the end goal; to provide consumers safe and effective product.
- Code of Federal Regulations: 21 CFR Parts 210 and 211
- U.S. Food and Drug Administration: Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products Chemical Substances
- Bradley Dennis (2015), Nearly 60 percent of Americans — the highest ever — are taking prescription drugs. The Washington Post
- Consumer Health Care Products Association (CHCP): Statistics on OTC Use
- Consumer Health Care Products Association (CHCP): Regulation of OTC Medicines
- U.S. Food and Drug Administration: Drug Approval Process
- U.S Food and Drug Administration: The FDA’s Drug Review Process: Ensuring Drugs Are Safe and Effective
- Debra Borchardt (2017), Cannabis Lab Testing Is The Industry’s Dirty Little Secret. Forbes
- Marijuana and Cannabinoid Research at NIDA (2016). National Institute on Drug Abuse
- Recent Research on Medical Marijuana. Norml Library
- DEA ends its monopoly on marijuana growing for medical research (2017). Los Angeles Times
- The Highs and Lows of Cannabis Testing (2016). The American Oil Chemists Society (AOCS)
- Lindsay MaHarry (2017), The Complex World of Cannabis Lab Testing: Ethics, Regulations, and Lack Thereof. Merry Jane
- Contaminated Medical Marijuana Believed To Have Killed California Cancer Patient (2017). CBS Los Angeles
- The Heparin Contamination Crisis. Heparin Science