GMP Cannabis simplified into 11 steps

Sometimes it’s best to take a step back, and explain basic concepts of the bigger picture – to take a look at the forest instead of just the trees. Good Manufacturing Practices (GMPs) are complicated systems that assure customer safety. Despite being complicated, you can break them down to a simplified concept of what they are, why they exist, and what it looks like for an operator or technician executing a Standard Operating Procedure (SOP).

What is GMP?

GMP stands for Good Manufacturing Practices. It is also commonly referred to as cGMP, meaning that it is the “current Good Manufacturing Practice” that meets GMP requirements as they are currently regulated. They are the set of regulations that describe all of the operations required to call a drug product, a GMP certified product. Any drug you buy at the pharmacy is produced under GMP conditions.

Why are there GMP regulations?

GMP’s are a way to ensure the public’s safety for manufactured drugs, in order to prevent public health crises. It helps prevent the distribution of adulterated drugs, due to poor manufacturing practices, from reaching consumers that whose health could potentially be harmed.

For example, there was a time before GMPs, where a manufacture could substitute whatever they wanted into their “miracle elixers” that were good for soothing all aches and pains. There was no basis for their efficacy, and the ingredients were completely unregulated. This all changed around 1906 when Upton Sinclair wrote “The Jungle,” where he described the filthy and unsanitary conditions of meat packing plants in Chicago. This completely changed how people thought about how things are manufactured.

What does it mean to operate under Good Manufacturing Practices?

Things have changed since the early 1900’s, and we now have processes in place to make sure that no drug or food substance goes out the door of a factory without having close control over the process. There are many concepts packed into an SOP, and many systems that all work together to make the process work.

So, “from the ground up,” here’s what is looks like when a technician or operator works through a GMP process using their SOP’s. Imagine a technician producing and extract using a Supercritical CO2 process or a Cannabis chef producing an edible with a purified extract.

Obtain the proper and current Standard Operating Procedure (SOP) before starting the job. The SOP will guide the technician through the procedure step-by-step, greatly reducing the chance of operator error.
Thoroughly read through the SOP before starting to make sure that nothing has changed for the procedure, and that the right procedure is being used for the right starting materials.
Follow the instructions exactly, and do not change them or deviate from them.
Work accurately and precisely, paying close attention to the details of each step.
Prevent any contamination or mix-up of materials. Do not have two separate batches of raw materials of in-process materials in the same are without being labeled.
Make sure that no products are mislabeled.
Use equipment that’s been cleaned, calibrated, and is the right tool for the job. All equipment should be well maintained and ready to use. If something is not working, it should be labeled “out of service” until it’s ready for use.
Document your work as it is being done, with initials and dates on the SOP for each step.
Keep your workspace clutter free and clean.
Any documented work may not be destroyed – it can be corrected, but never discard it.
If anything does not go according to the SOP, it must be reported to direct supervisors and the deviation must be documented and analyzed for any risks posed to the end user.

These are the most general guidelines for what GMP looks like in practice. While GMPs are a new concept to the recreational and medical cannabis industry, they’re not new to the pharmaceutical industry. It will take time for the industry to catch up, but it’s not hard to do once a company commits to a culture of quality management systems and cGMPs.

If you have more questions, check out www.oriongmp.com and get a free consultation on putting together your Cannabis related Good Manufacturing Practices and Quality Manufacturing Systems.

Compliance vs. Good Manufacturing Practices

Just to clarify, there is a difference between Compliance and Good Manufacturing Practices (GMPs). To put it simply, Compliance covers the laws that allow a company to manufacture cannabis and its products, while GMPs provide a framework for how you do it.

Compliance is presently defined as the state by state rules for manufacturing cannabis and cannabis products. It covers the regulations, required transparency, laws, policies, requirements, and standards for manufacturing cannabis. This sets the legal framework for how businesses in their respective states can operate.

Good Manufacturing Practices, on the other hand, are guidelines that come from the Food and Drug Administration and the International Conference on Harmonization. Both provide the requirements for a pharmaceutical manufacturing operation to produce drugs that will be ingested by human beings. They set the operational framework for how to manufacture drugs that are safe for human consumption.

There are also some similarities. Both Compliance and GMPs can have Standard Operating Procedures (SOPs). SOPs are simply the documentation of any process that a company does. They range from simple to complicated. It can be an SOP for sweeping the floors, or an SOP for a 32 step organic chemistry synthesis of tetrahydrocannabinol.

Compliance is without a doubt, the most important first step to establishing your business. Without it, you can face serious legal consequences. Establish your company with a trusted attorney who specializes in compliance, and start manufacturing with peace of mind.

GMPs are the next best step to make your business stand out above the competition – being a GMP Certified facility creates a huge differentiation in your product. With a well defined GMP system in place, you can track improvements to your product over time using the scientific method, ensure consumer safety, and have fully traceable processes. Overall, it’s a win-win adaptation to your business because you improve your processes (and chances to be bought out) and you improve product safety and quality for the consumer (sell more product).

If you have more questions, check out www.oriongmp.com and get a free consultation on putting together your Cannabis related Good Manufacturing Practices and Quality Manufacturing Systems.

Validating SOPs for GMP Cannabis

The objective of validating a procedure is to demonstrate that the procedure is suitable for its intended purpose. This extends to all SOPs. They must be validated to prove that they accomplish their purpose. There are many different processes that can be validated in pharmaceutical operations. Some examples include, but are not limited to, process chemistry, analytical testing, lab facilities, cleaning, equipment, packaging, etc.

For the sake simplicity, this article will cover validation of analytical methods. Method development and validation are all about setting specifications and making sure that the method can reliably achieve those standards. The specifications are discovered during method development, where an analyst works by trial and error to find the right conditions, that are described by example below. It is a tedious process, but once the proper method for analysis is established (i.e. the right column, the right flow rates, the right wavelength, and right temperatures), you have data that should show a reproducible method. From there, it’s a matter of setting the amount of variance that is tolerable to still accomplish the method (i.e. validation parameters).

Analytical method development is the time when the robustness of a method is established. Robust in this sense, means that you can change parameters of the method without seeing variation in the results – that is, despite conditions being less than optimal, you still get good results. Validation checks the variation in methods – you must get the same results for a given method within a specified percentage or relative standard deviation. If a method has been proven to be robust, it has a much greater chance of passing validation (being within the specified variance).

There are three major types of analytical methods: identity tests, assays, and impurity tests. An identity test proves that a certain molecule is present in a sample. An assay shows how much of a molecule is present in a sample. An impurity test shows how much of the sample has degraded or the relative quantities of impurities present in a sample. There are 6 major parameters tested in the validation of analytical methods: accuracy, precision, specificity, detection limits, quantification limits, and range.

Validation parameters require qualified reference standards. Ideally they will be from a third party, manufactured in an ISO environment that ensures the purity. The qualified reference standards are how meaningful comparisons are made to assess each parameter.

accuracy – how close to the target value the method reliably achieves
precision – how close each measurement is to the other measurements in a series of measurements
specificity – identification of the exact molecule that’s being tested – i.e. the method can discriminate between molecules similar to the target molecule.
detection limit – the smallest quantity of a molecule that can be detected
quantification limit – the smallest quantity of a molecule that can be reliably quantified
range – the smallest and largest amount of a molecule that can be reliably quantified in an analytical test

Details of the method should be clearly listed and explained in the validation report. They are important because they clearly lay out the conditions to execute a given method. Here are a few examples of method conditions:

Description of the method – e.g. HPLC
Type of chromatography column – e.g. C18 Reverse Phase HPLC Column
Flow rate and method durations – e.g. 1mL/min – 20 min runtime
Detection Wavelength – e.g. 210nm
Column Temperature – e.g. 30C

If you have more questions, check out www.oriongmp.com and get a free consultation on putting together your Cannabis related Good Manufacturing Practices and Quality Manufacturing Systems.

Standard Operating Procedures for GMP Cannabis

Standard Operating Procedures (SOPs) are an essential component of Good Manufacturing Practices (GMP). If a process is to be done, it will have an SOP that describes how to do it. SOPs cover topics such as manufacturing, testing, training, management, documentation, lab facilities, cleaning, change control, deviations, and anything else you can think of. It might seem redundant from the outside looking in, but it is a major way for ensuring that pharmaceutical products are produced with consumer safety as the ultimate priority. For the sake of this article, it will mainly focus on manufacturing and testing.

SOPs are meant to be followed exactly as they are written. Improving a manufacturing process is an ongoing goal of GMP. In order to improve a process, procedures must be performed exactly the same way every time the process is performed. The process is treated like an experiment, where all variables are controlled for, as best as possible. Following SOPs is the way of controlling the variables. When a process is repeated, observations of variations will inevitably be made. It’s from observing deviations and variance that changes can be made and improve the process over time.

Improving the process is important, but the primary reason for following SOPs is to ensure that a quality product is manufactured. Following SOPs to the letter is how this is accomplished. This assumes that the SOPs are well written and specify what a quality product is. With a well written SOP that guides an employee step by step, the chance for mistakes that would compromise the quality of the product are reduced.

As mentioned above, there are many different types of SOPs. While documentation, facilities, etc. are important processes to have SOPs for, processes like manufacturing and testing are most pertinent. This is because manufacturing and testing SOPs have a direct impact on product quality.

For a company adopting GMPs into their process, this is the place to start. In both manufacturing and testing, the SOPs will describe exactly how processes are performed. Every piece of equipment used in the manufacturing process has its own SOP associated with it. It clearly describes how to use the equipment, how to service/qualify the equipment, and describes the equipment maintenance schedule. With the operating procedures for every piece of equipment, the processes that follows are clear.

While SOPs describe how to use the equipment, methods are the documents used to describe the execution of manufacturing and testing. A method is a written document, just like an SOP, that guides the manufacturing and testing, step by step. It is the ultimate guide for the process down to the details of manufacturing a drug substance. As an employee works through the method, they initial and date each step as proof that they completed the step exactly as it is written.

With SOPs and methods describing processes, the amount of variance is reduced. Employees will be performing tasks the same way, day to day, instrument to instrument. Reducing the variance improves the product quality, and reduces the chance for a compromised product. With SOPs and good training, there is a great reduction in opportunities for making mistakes. There are nearly no excuses for mistakes, aside from equipment failure, but that’s another story and another SOP.

If you have any comments or questions, please post them in the comments section or email andrew@hemphacker.com.

GMP Training for Cannabis Manufacturing and Testing

GMP training is an important part of manufacturing and testing pharmaceutical products. It is the means of ensuring employees can properly perform their job to specified standards. Those standards ensure products are manufactured consistently, in a controlled manner, and to defined quality specifications. Training employees on a regular schedule, with job specific instruction, and thorough documentation help companies meet their standards of manufacturing and testing of their pharmaceutical products.

The first component to a quality training program is that training occurs on a recurring basis. When a new employee joins a company, it is necessary for them to learn, understand, and be tested on their job specific duties. After initial training they are qualified to do their job. They will then be required to perform refresher training that makes sure they are still up to date with any changes to the processes used for their job. For example, if a process is changed, the employee needs to have documented training on the change, proving they understand the change and can employ the process properly.

The second component to a quality training program is that the training covers the scope of an employee’s job. Each employee has their own specialized tasks in a manufacturing or testing facility, and they are responsible for knowing their job as it’s defined by the company. For example, a quality control chemist does not need to know the intricacies of a process chemist’s job, and vice versa. Each respective chemist needs to fully understand their own job so they can perform it up to the standards set in training.

Recurring training is a standard element of any quality process in the pharmaceutical industry. The proof of that training is in documentation. Documentation consumes a large amount of time in a quality manufacturing and testing environment. It is not fun and few people like it. It can take more time than the work itself. Still, without documentation, there is no proof of what has been done. It is important that companies have a documented training program that outlines each job in the company. Each job will have specific duties associated with it, and each duty requires training.

This article isn’t meant to touch on the qualifications of individuals bring to a job, but it grazes an interesting point. People who may not be qualified to start in a job can become qualified. An employee may not know how to operate a Gas Chromatography (GC) instrument when they start the job, but if they know how to operate an HPLC, there’s little reason why they can’t be trained to run a GC. On the job training (OJT) is a viable way to build up your employees’ capabilities and careers. When OJT is well documented, it’s the proof of a person’s education. It’s not only important to prove that your process is being executed by properly trained employees, but it’s also important to your employees’ careers.

If you have more questions, check out www.oriongmp.com and get a free consultation on putting together your Cannabis related Good Manufacturing Practices and Quality Manufacturing Systems.

10 Commandments for Cannabis Testing Facilities

GMP Cannabis, THC, and CBD are on their way to the market. This is a fact. In order for labs to stay on top of the market, they must adapt to the practices of the pharmaceutical industry. This is a basic list of 10 things cannabis testing labs should already be doing.

Thou shalt not perform analysis without proper training and understanding of the equipment. Qualifying a properly trained technician is dependent on the job they are doing. Have they been trained on the instrument? Have they taken sufficient analytical chemistry courses to understand how to interpret results? An analyst must know how to interpret the results, or figure out why the results they are get are inconsistent. If the results do not make sense, the analyst must troubleshoot the instrument based on what the data is telling them and then find out what went wrong. This type of critical and analytical thinking requires a thorough training program for all analysts.
Thou shalt not perform laboratory analysis without Standard Operating Procedures (SOPs) that are followed exactly as they are written. This assumes that a laboratory has done a good job of writing their SOPs in the first place. SOPs define exactly how a test will be performed; this reduces any variation in process that could affect the results. SOPs also define the technique that an analyst should use – for example, are all analysts in the lab using the same mass or volume measurement techniques? If there is variance in the process, there will be variance in the results.
Thou shalt not perform laboratory analysis using SOPs that have not been validated. In order to reduce variations in results, a method (e.g. the way you analyze your sample by HPLC) must produce the same results reliably. A validation is a set of experiments that is used to prove that the method does in fact produce the same results that are within the specifications of the desired method.
Thou shalt not perform laboratory analysis without accurately weighing and measuring the samples. This also falls under the category of training, but is perhaps the most important factor in accurately and reliably analyzing samples. This is also the most difficult technique to master, because there are so many variables. The best way to accurately weigh and measure samples is to perform any weighing and measuring the same way every time it is done. Exactly the same way – no excuses. Everyone in the lab should also weigh and measure samples with the exact same technique. This reduces the amount of variability in results throughout the lab.
Thou shalt not perform laboratory analysis without accurately documenting the results from weighing and measuring. This is self explanatory, but it may not be done this way in every lab. I have had the misfortune of seeing an analyst simply weigh out a sample, pour in ethanol up to an arbitrary line, shake it up, and inject the sample into an HPLC. He never recorded the weight of the sample or the volume of liquid that was added, and didn’t account for either of them… This kind of sloppiness is what makes labs untrustworthy.
Thou shalt only use analytical reference standards (ARSs) that have been produced by an ISO accredited lab. Creating in-house reference standards is possible, but it is highly unlikely that your lab has the capabilities of qualifying them. An accredited ISO lab synthesizes THC/CBD/etc and has exact ways of measuring the quantities that are in their ARSs. If you have variability, or uncertainty, in the amounts of THC/CBD/etc in your ARSs, your analysis will not be accurate. Reliable ARSs are the backbone of good analysis.
Thou shalt inject your ARS’s at a minimum of 5 times for any number of samples. This is how to determine if your instrument is working within its specifications/calibration, and includes the chromatography column and the instrument in general. If there is a poor Relative Standard Deviation (RSD), i.e. the 5 injections of the ARS are not within a specified percentage (think precision), the analysis of the samples is disregarded.
Thou shalt calculate the Relative Standard Deviation of the 5 ARS injections. This is done by taking the average of the response factors for a given peak (e.g. THC), dividing it by the standard deviation, and multiplying by 100%. For a very tight group of data, an analyst with good preparation technique and a well calibrated instrument will pull 2% RSD. RSD is the means of showing just how precise your techniques and instruments are running, and is a very important tool for tracking the performance of your work.
Thou shalt establish correction factors for different cannabinoids being analyzed. Not all cannabinoids will have the same response factor in the same chromatography instrument. This is particularly true for spectrophotometry (e.g. HPLC), that uses light to detect the presence of molecule. Since different molecules will absorb different amounts of light, the apparent amounts/concentrations will be thrown off if they are not corrected for.
Thou shalt document everything. All analysis must be documented with the weight or measures of the samples that are used, and contain all data collected from each test. The records must contain the calculations used to draw conclusions, and must make a statement of the results. The test results must be compared to qualified reference standards that clearly show identity, strength/potency, quality, and purity of the drug product.

If you have any comments or questions, please post them in the comments section or email andrew@hemphacker.com.

The quality control practices your Cannabis Testing Laboratory doesn’t want you to ask about…

Running a pharmaceutical manufacturing operation requires planning, standardization, and structure. This article explains the basic operating parameters quality control (QC) lab in compliance with Good Manufacturing Practices as described in the 21 CFR 211 – i.e. the Code of Federal Regulations that govern the production of pharmaceutical products.

This article aims to describe the basic controls for running a quality control facility. The planning and standardization required is dependent on individual situations – types of samples, the source of the samples, and whether the is independent or part of manufacturing. This is a overview of the guidelines, not an executable process. An executable process can be developed with the help of a consultant. If you need an experienced GMP consultant, you’ve come to the right place. Without one, you will very likely waste a significant amount of time and money trying to implement GMPs.

Quality Assurance (QA) and Quality Control (QC)

Any pharmaceutical manufacturing operation is centered around QA and QC. QA is the department responsible for reviewing the testing process after it is completed. They are to review the all records associated testing, and store them. QA coordinates all maintenance and calibration activities of equipment, and ensures that all QC systems are in accordance with GMPs as defined by the company’s SOPs.

The QC unit is responsible for approving or rejecting any pharmaceutical product. QC reviews production records to ensure that no mistakes were made during manufacturing, and if errors were made, that they were properly investigated and corrected. All procedures pertaining to the QC unit are to be in writing and followed as written. All QC personnel are to be trained in current GMP regulations (cGMP’s) as applicable to the employee’s job. QC personnel training must be administered by qualified individuals on an on-going basis.

Laboratory controls and general requirements

Step 1 is having a quality control manager (QCM). The QCM is the person who manages the operations of a testing laboratory. They are the person who establishes all specifications, standards, and testing procedures. They ensure all standards are followed and documented. If there is a deviation from the standards, they are required to document and justify why the deviation occurred and determine if the deviation affects the quality of the product.

All the specifications, standards, and testing procedures must be scientifically sound. They must be based on experiments that prove the tests accurately determine the identity, strength, quality, and purity of the product. All the tests must be fully documented and executed according to procedure.

The tests must show that samples conform to the defined written specifications of identity, strength, quality, and purity. During testing, all samples need to be properly labeled and describe the sampling and testing procedures used to determine conformity to the standards. If the samples do not pass testing standards, they must be rejected for use. Samples may be retested, but they must pass all testing standards.

All equipment must be calibrated at suitable intervals and a service history must be maintained for each instrument. A written program for equipment calibration will be maintained and executed that contains specific instructions for maintenance schedules, limits for instrument accuracy and precision, and directions for action if specifications are not met. Any instrument that does not meet established written specifications will not be used for testing.

Testing and releasing samples as safe for consumption

Each set of samples that arrives in the laboratory should be assigned a batch number. If the QC unit is in the same company as manufacturing, the batch number should be known from the point the seeds or clones are first planted, and traced all the way through final testing, packaging, and distribution. Traceability is very important in quality control, and everything must be documented along the way.

For each batch of drug product, the specification criteria must be met to determine that batch conforms the product specifications – i.e. that testing proves the proper identity, strength, quality, and purity of each active ingredient. All testing performed for identity, strength, quality, and purity will be described in written procedures (test plans). All test plans must be established, validated, and documented to prove accuracy, sensitivity, specificity, and reproducibility.

The testing will define how many samples need to be taken in proportion to the size of the batch. The testing must be sufficient to prove appropriate specifications for approval and release from testing. In addition to the standard testing, all batches must pass sterility testing that proves it to be free of microbiological contamination. Any batches that fail to meet the specifications and criteria must be rejected as not safe for consumption. Retesting may be performed, but the samples of the drug product must meet all specifications and criteria.

Stability testing and establishing shelf life

Stability testing is used to determine the expected shelf life of a drug product. This is a tricky subject for the marijuana industry at the moment. Over time, THC degrades to CBN. This means that one of the active ingredients is no longer working at full efficacy for a given product. This changes from strain to strain, and the type of product – e.g. flowers or extracts. That said, this will be a challenge for many companies to implement, but is in fact the direction the industry must go towards to move up to the standards of the FDA.

Stability testing is similar to the testing used to release a drug product as safe for consumption. The difference is that stability testing uses stored samples of approved batches, and tests them periodically to find the rate of degradation.

Stability testing is a separate written program from testing. In addition to regular testing, it defines the sample size and testing intervals, storage conditions, validated test plans, and testing the sample in the same containers used as received by consumers. The testing must be performed on multiple batches (of the same strain) in order to determine an appropriate expiration date. Accelerated degradation studies (e.g. higher temperature and humidity conditions) can be performed in order to extend the expiration dates.

Testing and approval (or rejection) of drug products

This pertains to the process of testing. It is the control of the samples during testing, and is used to make sure there are no mix-ups in samples or results. The samples must be placed in an appropriate container that is labeled and has associated test plans that follow along with it through the process.

The identity and quantity of each sample will be placed on a label of the container for each batch that is being tested. The label should include the name of the supplier, batch number, and the location of manufacturing. Records must be kept that show the results of each test and be maintained for a period of time after the expiration.

When a sample or set of samples pass testing, they may be released for consumption. If any of the tests do not pass, the batch is rejected. If a batch is rejected, an investigation is performed to determine the root cause of the failure. The approval process is completed when the QCM signs off on all test plans and the specification summary sheet for a particular batch.

Laboratory records and reports

Laboratory records are exceptionally important to QC testing. It is the documentation that proves a product is safe for human consumption. The QA and QC divisions are the the checks and balances of the pharmaceutical industry. The QA division gives all final approvals for releasing drug products after reviewing completed testing from an entire batch, and maintains all documentation of records and completed testing.

There are several requirements for laboratory records. The must describe the sample, its source, the quantity, batch number, date of sampling, and date of testing. A statement of results for each test plan must be tabulated in a specification summary sheet; it should indicate the location of testing and all the methods. The methods, as mentioned before must meet the standards of accuracy and reliability established by the QC division.

The test plans must document the weight or measures of the samples that are used, and will contain all data collected from each test. The records must contain the calculations used to draw conclusions, and must make a statement of the results. The test results must be compared to qualified reference standards that clearly show identity, strength/potency, quality, and purity of the drug product.

Each step of the test plan must be initialed and dated by the QC analyst (QCA) to ensure that each step of the test plan was performed without deviation. All test plans must be checked for accuracy by a second QCA or QCM. Any changes to a test plan must include a reason for the change, and be approved by the QCM.

GMP Cannabis and the Marijuana Industry – a short introduction

Current Good Manufacturing Practices (cGMPs) is the pharmaceutical industry’s term for summarizing all the practices involved in manufacturing drugs that are safe for human consumption. The sum of the practices are called “quality systems.” It’s not just the pharmaceutical industry that uses cGMPs – the food industry does as well. cGMPs is a new concept to the marijuana industry, but there are a few companies that have already embraced it. The most prominent one that comes to mind is APHRIA, hailing from the breadbasket of Canada, in Southern Ontario.

Early adaptation to cGMPs are important to the industry. When medical and recreational cannabis become federally regulated and legalized, cGMPs will be required to ensure product and consumer safety. The evolution of GMP had good reason behind it – people were dying as a result of bad manufacturing practices. On average, the industry has more people hurting themselves while attempting to manufacture drug products, rather than consuming them. This, however, does not mean that the products are all safe for human consumption. The companies that take the time to implement cGMPs from the beginning of their business will have a drastic advantage over those that try to retool their process and standard operating procedures (SOPs). The benefits of GMP go beyond the minimum requirement of having a safe to consume product – it also builds the reputation of your company’s brand and its image.

GMP and ISO are both quality systems that are used to manufacture goods under specifications that either ensure consumer safety, or exact specifications guaranteed to be true. The difference is that GMP is a federal requirement for a drug product, whereas ISO is a voluntary certification. For example, a company manufacturing marijuana and concentrates will need to be a GMP facility in the future, whereas a marijuana testing facility would only need to be a ISO certified lab since they are only testing marijuana.

GMP Cannabis is the future of the industry. The early adopters of the practices employed by the pharmaceutical industry will be ahead of the regulatory curve and be best positioned for success in the market.

If you have more questions, check out www.oriongmp.com and get a free consultation on putting together your Cannabis related Good Manufacturing Practices and Quality Manufacturing Systems.

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