Having grown up in the eras of “unisex” and “one size fits all” clothing, I am aware of the problems of trying to make one shirt, dress, trousers, or any garment to fit all body sizes. The result is almost always a compromise. And, by definition compromise means no one is happy. In many cases, just to make life easier, we used to say, “The fit is good enough.” However, in analytical methods, especially under FAD or EMA jurisdiction, good enough is simply not good enough, or good, at all.

Now, do not get me wrong. I used to wear a button that stated,“Several months in a lab can save a few hours in the library.” I believe that it is never wrong to research earlier work and methods when attempting to develop an analytical SOP for a new product; someone may well have solved your analytical problem for you, already. However, just because a sample prep and/or analysis method is published in a reputable journal article or a methods compendium such as ASTM International Handbook or the USP (United States Pharmacopeia), does not mean it will automatically work for every dosage form or chemical entity.

One particular example shows that, even when a method is developed by a “real” R&D Analytical lab, problems could occur. The case in point was an immediate-release, solid dose ergot alkaloid assay. At the six-month stability point, it appeared that the product lost almost 60% of its activity. Since the API (active pharmaceutical ingredient) was also used in other products in the same company and competitors as well as similar to several other products in their portfolio, the loss seemed an anomaly. Making matters worse, the stability-indicating HPLC assay showed no breakdown products.

After aggressive sonication, shaking, and even heating, the remaining API was finally recovered. It seems that the new formulation used in this dosage form was not thoroughly tested for long-term stability. The API was physically bound to one or more of the excipients in the tablet. Of course, the responsible R&D developers were “too busy” to correct a method already sent to QC, so their suggestion was to add an internal standard that also stuck to the excipients, making the assay look sufficient. Needless to say, we changed and validated a new extraction method for the assay, especially after considering what an FDA inspector might say about this solution. Fortunately, the dissolution times didn’t change with time on stability, just the assay values, so the dissolution method could be retained.

Far too often, I have seen a supposedly trained chemist assume that, because the API is the same one as in another company’s product, the analytical method, including extraction from the matrix, has to work the same. You must ask yourself, “If the blood levels of a generic dosage form can be influenced by the choice of excipients, e.g., mannitol vs. sorbitol, why wouldn’t the analytical method be affected by the matrix?” Unfortunately, even the most comprehensive pre-formulation studies seldom account for extraction characteristics changing over time. The common wisdom is that, should that happen, the dissolution profile will change. It may change, but the specifications do not, in the case of an immediate release, look at a profile, but often only a Q80 is seen—a time point at which at least 80% of the API is released. Seldom is there a system in place to track changes in percent released over time, so, unless the number is finally a failing value, there is often no record to alert a supervisor.

There are other painfully obvious examples. The assay for saponification value is a simple reaction with a caustic solution, followed by a back titration with acid to ascertain the amount of OH- consumed. Since a number of APIs are esters and the test has been around for more than a century, this is one excellent wet method in the toolbox. However, one lab in which I consulted was following the saponification method exactly as written in the ASTM manual, even though the material being tested was not soluble in the solvent system being used. In some cases, this may be accounted for by the reaction product being solubilized by the reaction, but that has to be determined ahead of the test and accounted for with any modifications. In other words, method development needs to be done!

A contract lab, not having massive lab resources, may be inclined to declare that it is the job of the initiator company to supply well-documented, validated analytical methods with the MMF (master manufacturing formula). Remember the first example of the API not being extracted? That was a validated method at a major company, included in the NDA (new drug application) and accepted by the FDA. And, as I have mentioned in other columns, the more versatile and responsive to potential difficulties your lab is, the better chance of attracting new business you have.

Another reason is that, while the good, old compendial methods have been good enough for past clients, the larger companies who are more and more turning to CMOs, have been developing their products and methods with an eye to new Guidances and Guidelines (FDA and EMA) and ICH (International Conference on Harmonization) Guidances. One striking example is the new ICH Q3D Guideline, “Guideline for Elemental Impurities.”

One major challenge in following the new Guideline is that it introduces new analytical technology, specifically inductively coupled plasma (ICP)-based techniques to replace the wet chemical heavy metals limit test, along with new and specific limits for individual elements. Perhaps the most significant challenge is related to the practical implementation of the guideline.

ICH Q3D advocates the use of a risk-based approach to assessing the potential presence of elemental impurities in drug products. While such assessments are common within other aspects of pharmaceutical development, application to elemental impurity assessment presents new challenges to routine QC or contract analytical labs. One specific challenge includes determining how to assess or quantify the risks associated with factors such as water, container-closure systems, and excipients. Defining where in the assessment process data may be required and identifying where risks can be determined to be negligible are done via a thorough scientific theoretical risk assessment. This risk-based assessment is not what most CMOs or CROs are equipped to perform.

The guideline introduces toxicologically relevant permitted daily exposure (PDE) limits to individual elements replacing non-specific 19th century wet chemical heavy metal limit tests. ICH Q3D advocates the use of a risk-based approach to assessing the potential for presence of elemental impurities in drug products. The process of executing and documenting the risk assessment is a major challenge both in terms of time and financially, primarily as a result of a limited global understanding about how to assess or quantify the risk associated with factors such as water, container-closure systems and excipients.

Clearly, business as usual attitudes cannot be taken by traditional laboratories—either independent or supporting R&D and manufacturing—if they wish to remain solvent and relevant in the 21st century. Several major changes must take place for these labs to remain viable:

1. The lab must not be seen as stand-alone any longer. It must become a partner with either production or development. That is, it must extend its reach into the physical domains that were heretofore black boxes that merely delivered samples to the lab for analysis. The QC/analytical lab needs to be actively engaged in the decisions of what process monitors are used and where they are to be placed. Since the QC/analytical lab must calibrate, validate, and maintain these monitors, they need to be included from day one. Another change in tradition is to stop justifying any purchase in the name of a single product or project. For example, justifying a new HPLC for product “X” implies that it will not be used for any other product; obviously not true. The piece of equipment must be defined and purchased with the present and all future uses in mind.

2. In a similar vein, the decision to fund a new technology that is new to the lab cannot be made based on today’s needs or products, but with an eye on which new products may be added because there are analytical abilities available. No sales team can sell a 1960s lab for 2016 products. The expense of adding a new technology, e.g., the ICP mentioned above, adding and training a technician to both run the instrument and develop methods may be more than offset by the new business a lab equipped with such technology could attract. In addition to meeting new Guidances and Guidelines, the mere presence of modern technologies encourages the lab personnel to move other analyses from the 20th to 21st century. This updating will be noticed by companies looking for CRO and CMO partners.

3. Training, training, training. For some unknown reason a large majority of U.S. and European Pharma companies seemed to earmark training and professional meetings as overhead, and mostly stopped sending lab personnel to courses. When a new instrument is added, too often only one analyst is trained on the technique. For example, I have seen a huge number of companies purchase a near-infrared instrument and allow only one person to work with it; and, when he/she leaves the department or company, stop using the equipment. In other words, some bean-counter decided that not using a $100,000 instrument was preferable to spending $2-3,000 to train a second analyst.

As much as I value hands-on experience, merely doing the same tests, year after year, does not do anything to bring a veteran analyst to par with a new graduate in terms of modern instrumentation. Sending staff to technical meetings is no longer an expensive luxury. In order to stay competitive in an increasingly lucrative market, any contract lab would do well to keep its cadre modern.

So, in short, one of the best ways for a contract organization to grow and remain relevant is to invest in its laboratory: hardware, software, and, especially personnel.

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Emil W. Ciurczak
DoraMaxx Consulting

Emil W. Ciurczak has worked in the pharmaceutical industry since 1970 for companies that include Ciba-Geigy, Sandoz, Berlex, Merck, and Purdue Pharma, where he specialized in performing method development on most types of analytical equipment. In 1983, he introduced NIR spectroscopy to pharmaceutical applications, and is generally credited as one of the first to use process analytical technologies (PAT) in drug manufacturing and development.