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.

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.

  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.