Recently, the US Food and Drug Administration (FDA) cited a pharmaceutical manufacturer for not validating an analytical method. The drug maker’s answer was that the sample matrix was too complex for the method to be fully validated. As you would guess, this answer did not amuse the agency.
As we all know, analytical methods play a vital role in supporting all aspects of drug development and approval. Analytical method development and validation documentation is a key component in building the chemistry, manufacturing, and control (CMC) section of a drug marketing application. Why is that? The formulation work, process development, manufacturing, packaging, stability studies, dissolution studies, clinical studies, and even releasing manufactured batches of the commercial product are all connected and heavily rely on a reliable analytical method.
As a result, emphasis must be placed on development stages and feasibility studies by well-versed and highly competent scientists, since it’s much easier to validate a well-developed method. On the other hand, lack of validation can most certainly result in approval delays and possible rejection of data.
In addition, the effects of any changes in the production process/equipment or to individual product formulation components on associated analytical methods must be assessed.
Validation steps will depend on the stage a drug product is in. Drug products in early development phases (that is, preclinical) don’t have to have all parameters been validated. At that point, all you may need is just to validate for specificity, showing whether that substance is there or not.
Once you start progressing through the clinical trial phases, you’ll be adding more testing parameters, which have to be validated before using the analytical method. The FDA has a number of regulations and guidelines in this regard, which are available online.
You may be surprised when I tell you that developing and validating an analytical method is not the sole responsibility of the analytical department.The validation process requires inputs from
- The process development engineer to define the scope of the project
- Formulators to provide the formulation
- The toxicologist to set the limits of detection and quantitation based on the toxicity of the actives and excipients
- The chemist developing and validating the method
- The regulatory professional assisting in development and approval of the validation protocol
- The QA professional who will review and release the laboratory data and final reports.
The regulatory department must set all applicable criteria for each parameter, such as the actual limit of detection based on toxicological data, and purity specifications based on potency and end-use requirements. The analytical technique and instrumentation chosen will depend upon the degree of precision, linearity, range, and accuracy necessary to meet regulatory requirements. The analyte of interest, not the instrumentation available in the laboratory, determines the analytical technique. However, other regulatory requirements should also be taken into consideration.
For example, which instrument would you use for a drug product with two active substances; the sodium salt of an active substance and the potassium salt of another active substance. And what if the production specifications are set at +/- 2.0%? Will you use Inductively Coupled Plasma (ICP) or an Atomic Absorption (AA) instrument? Of course the AA instrument cannot provide that level of precision, so using the ICP is the right option.
Another consideration is the required detection limit. As we all know, the toxicity of a potential Impurity will impact the product specification for the impurity and therefore the required method’s limit of detection. When the potential for toxicity from an impurity is known to be low, the specifications may be set significantly higher with much tighter method precision requirements. For example, if you have a drug product that has isopropanol as a residual solvent from an active substance. And you have aluminum as a contaminant in that drug product that happen to be parental. How would you set the specifications? While methods developed for both components can be categorized as impurity determinations, the specifications for isopropanol should be set at much higher level (parts per million) than that for aluminum (parts per billion) because of the toxicity effect of the aluminum. Now, we all know that isopropanol can be tested by Gas Chromatography (GC) instrument, which might be used to quantitate the residual isopropanol with a precision of about +/- 5%. But how about the aluminum, with a specification limit of about 10 ppb? Should you use the AA that has precision of +/- 10%, or the Graphite Furnace that has a precision of +/- 25%? Of course, ICP will be the right option in this regard.
In addition, you can’t rely on stability of results, for example, if you don’t have a robust and reliable validated method. And you absolutely can’t release a batch of manufactured drug product unless you have fully validated analytical method in place.
Sometimes, people who are involved in analytical method development and validation struggle because they don’t know what to validate and what not to validate at each stage of drug development process. In fact, if you find that you’re taking months to develop and validate a method, that length of time indicates that either you are not getting the help you need from the other departments, or using the wrong instruments to meet tight specification requirements, or your validation staff doesn’t know enough about your product and methods.
At Synergy Bioscience, we have the expertise in developing analytical methods, validating the method, writing standard operating procedures (SOPs) and the protocols, transferring the method, providing training to analysts, and making sure everything is in order and on the right footing.
Now, we would love to hear from you. What issues do you have with your analytical methods? Tell us what challenges you’ve faced in developing, testing and documenting analytics and other methods. We’d love to hear from you.