How Virtual Businesses Can Leverage Strategic Outsourcing

Finding ALL the Right Contract Development & Manufacturing Companies (CDMOs) for Your Project

Sure, it’s tempting to select and deal with just one CDMO and press on with your project. However, finding a single CDMO that meets all the science, technology, and equipment needs of your product development and manufacturing project is highly improbable. For instance, say you picked a vendor for your initial phase trials to develop and produce an active ingredient based on its capability to produce and process only enough GMP material at a 5-kilo scale.

Fortunately, your clinical trials proceeded smoothly. As a result, you find yourself forecasting the need for increased lots of your active ingredient at 10- and 20-kilo scales. However, your vendor’s equipment can’t handle more than 5 kilos per lot and have six separate lots to meet your needs. It takes two months to produce, test, and ship each 5-kilo lot and a total of a year to complete all six lots. Not only does this delay your schedule, but now you must find another vendor who can make the material in single lots of 10 or 20 kilo scales. If you had known about this need ahead of time and found a second vendor with the necessary equipment, you would have been able to meet your deadline. Before starting any project, you must be aware of and understand your vendor’s capabilities and limitations. Doing so will help you mitigate risks and production downtime to stay on schedule and successfully meet all your objectives.

Testing Active Ingredients with Analytical Methods

Analytical methods are necessary to identify and determine an active ingredient’s purity, potency, and quality. Analytical testing methods won’t exist for new drug substances, so determining these methods will be required to start. Keep in mind that the product looks worse the better the methods are, and since you need to know everything there is to know about the active ingredient, this is a positive thing. While competent methods can offer information on impurities and probable byproducts of an active ingredient, superior methods isolate these impurities from the active peak to identify and measure them. Never skimp on method development, as it will pay dividends when it comes time to produce the product’s dosage form in volume.

Retesting an Active Ingredient

An active ingredient’s retest date needs to be established based on data collected from storing the active ingredient under regulated temperature and humidity conditions and assessing its quality attributes at specific intervals using its manufacturer’s suggested methods (reference ICH guideline Q1A [R2], Stability Testing of New Drug Substances and Products, and ICH guideline Q1E, Evaluation of Stability Data for details). In the event of a failed test during the stability study, the retest date for the active ingredient may be needed sooner than anticipated, as was the case for a recent EQC client.

Three university professors formed their company without prior pharmaceutical industry experience. They relied heavily on their API supplier to define the parameters for the stability research. Because this was a new API, there wasn’t much information regarding its physical and chemical properties. Unfortunately, the customer naively agreed to the manufacturer’s stringent criteria for the stability research.

Two months into the stability research, test findings for moisture content failed in both the accelerated environment (25°C/60% relative humidity) and the recommended storage state (refrigerated). The client permitted the stability study to continue due to a lack of regulatory experience, which resulted in failed results throughout a year of testing and was made worse by the manufacturer’s failure to conduct failure investigations. The customer needed clinical research to start within a month, so it was then that I was introduced to them and asked to do anything I could to save their project. This marked the start of a time-consuming process that included a thorough safety evaluation and a retro-specific study of each testing failure. The lesson here is that you, not the manufacturer, are ultimately in charge of the circumstances defined for your compound. Consult an expert if you have no prior experience in this area.

Developing Pharmaceutical Formulations

Product production is an exciting moment for the sponsor since it signifies product distribution to clinics and patient dosages are nearing completion. However, this is one of the most challenging phases. Unless the clinical product is in a basic dose form, such as a non-formulated API in a capsule, the active component must be coupled with additional elements designed to aid production and product shelf life.

Pharmaceutical formulations are comprised of both active and inert substances (also called excipients). Excipients are inactive components chosen for their particular capabilities as product diluents, binders, compression aids, granulation agents, disintegrants, glidants, and lubricants. When the correct amount of each excipient is determined, these materials aid in the flow of powdered blends over stainless-steel manufacturing equipment rather than clumping or clinging to the surfaces, and they can preserve the active component from deterioration. An expert formulator’s experimentation can be the difference between a successful manufacturing campaign and an expensive disaster.

Several years ago, a sponsor with whom I briefly collaborated believed himself to be a formulation scientist despite having never worked in this field. With the production deadline rapidly approaching, he provided the CDMO with a formulation created from a Google search of widely used excipients (no, I’m not joking). The CDMO strongly warned that the selected excipients and their percentages were unsuitable for his product and that the likelihood of success was low. He ignored the warning and authorized the CDMO to continue manufacturing. The tablet press manufactured tablets with a high frequency of capping as it progressed (e.g., the top or cap of the tablet splits or fractures from its body). The CDMO assessed that an inadequate or improper binder was most likely the cause of this issue. The production got canceled, and the sponsor incurred significant time and financial losses. Contracting a CDMO with seasoned scientists to correctly create the dosage form for manufacturability and stability is far preferable to launching an unsuccessful campaign with a poorly prepared product.

Evaluating the Final Product With Analytical Methods

I recently explained to a client that the analytical methods for an active ingredient would most likely not be acceptable for evaluating the product. The client was surprised and proceeded to describe the amount of money they had spent on API methods and the benefits of those methods in testing an active ingredient. While I was sympathetic to his point of view on the matter, I felt obligated to explain my reasoning.

Formulated products have a distinct analytical profile from non-formulated products due to the combination of excipients with the API. Each excipient has specific UV absorbance, contaminants, and stress-degradation potential. Once the product is formulated, new methods must be established and validated before testing of the product can begin. Additionally, many additional dosage-form-specific tests, including dissolving and content uniformity methods for tablets and capsules, are required, which were not necessary for API testing. CDMOs often treat method formulation and qualification as a last-minute activity, failing to create solid procedures that offer repeatable and trustworthy outcomes. During method development and qualification, hasty testing sometimes produces erroneous, unclear, and out-of-specification results.

Be sure to take the time to visit and chat with the quality control (QC) team of a CDMO. Ask them to offer examples from their own lives in which they were obliged to research and solve challenging situations. Discuss with supervisors and managers how they teach quality control personnel to solve analytical problems. Employ a credible consultant to supervise routine testing and failure investigations and audit and certify the laboratory.