Strategic Outsourcing For Virtual Companies — Lessons Learned In The Trenches

By Greg Weilersbacher

A virtual company advancing a drug candidate into product development faces a deluge of challenges. One of the biggest hurdles to overcome is expertise and experience: You can’t be an expert on everything.

You might have expertise in drug discovery with a unique talent for selecting the perfect molecule. Or maybe you’re a great synthetic organic chemist, formulator, analytical development scientist, or manufacturing engineer. If all these skills could be combined into a single person, we wouldn’t need to rely on others for help. The reality is you do need the assistance of pharmaceutical scientists and advice from industry professionals to help you navigate the twists and turns in the road.

New companies often start with an idea for a product to treat a rare disease, an asset purchased from a large company, or the goal of repurposing a drug for a different indication. The job ahead may involve development and production of the active ingredient; analytical method development; dosage form development and product formulation; production, release, and stability testing; container/closure selection; labeling, kitting, storage; and distribution. The list goes on and on. The following are some real-life lessons that can help you select the best outsourced solutions providers to help you achieve your goals.

SELECTING MULTIPLE CDMOS TO GET THE JOB DONE

With so many CDMOs to choose from, it’s tempting to go with a single CDMO to minimize your headache. However, the needs of the product dictate the science, technology, equipment, and scale required for product development and manufacturing, and very few CDMOs can satisfy all these needs. For example, you’ve chosen a vendor to develop and manufacture the active ingredient based on its technical ability to manufacture and process just enough GMP material at a 5-kilo scale to support Phase 1 trials.

You are fortunate, and the clinical trials go well. This leads you to forecast additional lots of active ingredient at 10- and 20-kilo scales. The vendor’s equipment train cannot accommodate lot sizes of greater than 5 kilos, so they suggest producing six lots to meet your requirements. Given that each 5-kilo production takes two months to make, test, and release, the vendor will complete the six productions in 12 months. This creates a major speed bump in your timeline, and now you’re faced with finding another vendor that can produce the material in single lots at 10- and 20-kilo scales. Had you anticipated this need in advance and lined up a second vendor with larger-scale equipment, you would have met your timeline. Understanding each vendor’s production scale before pressing the “go” button can reduce or eliminate the productivity downtime and keep your timeline on track.

ANALYTICAL TESTING OF ACTIVE INGREDIENT

Analytical methods are essential for determining the identification, purity, potency, and other quality attributes of the active ingredient. For new drug substances, methods will likely not exist and will require development. It’s important to remember that the better the methods are, the worse the product appears. This a good thing, because you need to know everything about the active ingredient. While good methods can provide data on the impurities and potential degradation products of the active ingredient, great methods resolve these impurities from the active peak so they can be identified and quantified. Don’t be penny wise and pound foolish when it comes to allocating budget dollars to method development, as this information will help you as the material moves into manufacturing of the product dosage form.

ESTABLISHING A RETEST FOR THE ACTIVE INGREDIENT

Active ingredients require establishing a retest date, which cannot be arbitrarily set but must be based on data. It’s accomplished by storing the API under controlled temperature and humidity conditions and testing the material’s quality attributes at defined intervals using methods developed by the API manufacturer (see ICH guideline Q1A [R2], Stability Testing of New Drug Substances and Products, and ICH guideline Q1E, Evaluation of Stability Data for details). A failing result for any test during the stability study may result in a shorter retest date for the material than expected. This recently occurred with one of my clients.

The company was formed by three university academics without experience in the pharmaceutical industry, and they relied heavily on their API supplier for guidance in setting specifications for the stability study. Since this was the first time the API had been manufactured, very little was known about the physical and chemical properties of the material. The manufacturer set extremely tight specifications for the stability study, which the client naively approved.

Two months into the stability study, failing results were obtained for moisture content at the recommended storage condition (refrigerated) and at the accelerated condition (25°C/60 percent relative humidity). Due to lack of regulatory experience, the client allowed the stability study to continue, generating failing results through 12 months of testing. To make matters worse, no failure investigations were conducted by the manufacturer. I was introduced to the client at this point to do whatever I could to salvage the project because the client wanted to start a clinical trial within the month. This began an arduous process of retro-specific investigation into each of the testing failures and a detailed safety assessment. Moral of the story: As the sponsor, you (not the manufacturer) are ultimately responsible for the specifications that are set for your compound. If you lack experience in this area, a consultant can help you.

FORMULATION DEVELOPMENT

Product manufacturing is an exciting time for the sponsor because it means that product distribution to the clinic and dosing of patients are close at hand. But this is the phase that is one of the most challenging. Unless the clinical product is a very simple dosage form, such as nonformulated API in a capsule, the active ingredient will need to be combined with other materials designed to assist processing during manufacturing and with the product shelf life.

Pharmaceutical formulations are mixtures of active and inactive ingredients (also called excipients). Excipients are inactive components selected for their unique properties as diluents, binders, compression aids, granulation agents, disintegrants, glidants, and lubricants for the product. When the optimal percentage of each excipient is identified, these materials help powdered blends flow well on stainless-steel production equipment rather than clumping or sticking to the surfaces and can protect the active ingredient from degradation. A good deal of experimentation from an experienced formulator can make the difference between a successful production campaign and a costly disaster.

A sponsor I briefly worked with a several years ago fancied himself as a formulation scientist despite never working in this capacity. With the manufacturing date fast approaching, he sent the CDMO a formulation he derived from a Google search of commonly used excipients (I’m not kidding). The CDMO strongly advised that the chosen excipients and their percentages were not appropriate for his product and that the odds of success were slim to none. Ignoring the warning, he instructed the CDMO to move forward with production. As it proceeded, the tablet press produced tablets with a high frequency of capping (e.g., the top or cap of the tablet splits or fractures from the body of the tablet). The CDMO determined that the most likely cause of this problem was an insufficient amount of binder or the use of an incorrect binder. The production was terminated, and the sponsor lost considerable time and money. Your dollars are much better spent contracting a CDMO with seasoned scientists to properly formulate the dosage form for manufacturability and stability rather than jumping into an ill-fated campaign with a poorly formulated product.

ANALYTICAL METHODS FOR THE FINAL PRODUCT

Recently, a client was surprised when I mentioned that the analytical methods for the active ingredient would likely not be appropriate for testing the product. The client went on to explain how much money was spent on the API methods and that the methods were very useful in testing the active ingredient. I was sympathetic to his position on the subject but was compelled to explain the logic behind my statement.

A product that has been formulated has a different analytical profile than a non-formulated product due to the excipients that have been combined with the API to make the product. Each excipient has its own ultraviolet (UV) absorbance and impurities and, when stressed under stability conditions, may produce degradation products. The analytical methods used to test the product must be able to detect this degradation. Once the product has been formulated, new methods need to be developed and qualified prior to being used to test the product. Additionally, several new dosage-form specific methods are required, such as dissolution and content uniformity methods for tablets and capsules, that were not needed for API testing. While the product’s manufacturer is likely to be the best source for the method, there is a strong tendency for CDMOs to treat method development and qualification as a last-minute activity and to not spend adequate time producing robust methods that yield consistent and reliable results. Rushing method development and qualification leads to testing results that are confusing, misleading, and often out of specification.

Take time to visit and speak with the CDMO’s quality control (QC) staff. Ask them to provide real-life examples that required them to investigate difficult problems and arrive at solutions. Speak with supervisors and managers to determine how they train QC in analytical problem solving. Finally, employ a reputable consultant to audit and qualify the lab and manage routine testing and failure investigations.

PRODUCT MANUFACTURING

This stage represents the culmination of the previous activities and is typically the most stressful for the sponsor. If it’s the first time the product has been manufactured, expect problems to occur during production. This is normal. The sponsors and the CDMO should discuss potential processing issues and evaluate likely solutions before initiating production. This helps to calibrate the sponsor’s expectations regarding a picture-perfect production and is a good exercise for the CDMO regardless of its experience level.

Several years ago, one of my clients had a campaign scheduled for its clinical-stage tablet product. Its CDMO had developed the formulation using an engineering lot of API and had also developed and qualified analytical methods prior to the start of the production. The API manufacturer shipped the GMP active ingredient to the product manufacturer, who performed an identification test and released it for production. The API was blended with the chosen excipients, and samples were taken for blend uniformity testing. The results were highly variable and did not meet specification requirements. The batch record instructed to reblend and take additional samples for testing. The results were similar to the previous tests. An investigation examined the QC testing, the manufacturing process, and production equipment, but no error was identified.

Finally, the certificates of analysis (COAs) supporting the engineering lot and GMP lot of API were examined to identify any differences between the lots. The COAs revealed that the GMP lot had much larger particles than the engineering lot. The larger particle size caused the blend to stratify (e.g., excipients with small particles sifted to the bottom of the blender, while the GMP API lot with large particles remained at the top of the blender). Nothing could be done to remedy current production, and the product was rejected. The CDMO proposed initiating a new campaign that would jet mill the API prior to blending with excipients to reduce the particle size of the active ingredient. This solved the problem and yielded a product that met product release testing specifications.

It’s a given that problems will happen during production. The real value a CDMO provides is its experience handling complicated production issues rather than looking to the sponsor to provide solutions. This highlights the importance of careful selection of your CDMO: Your timelines, outsourcing dollars, and product are at stake.

THE TAKEAWAY

Virtual companies have unique challenges when it comes to outsourcing production and testing, much of which comes down to expertise and experience. The selection of several active ingredient manufacturers able to produce at varying scales will help to minimize the impact on your timelines when your primary vendor’s capacity is limited. The analytical methods developed by the API manufacturer will likely not be applicable to the product dosage form, which will require new methods to be developed and qualified. A robust formulation that yields material that flows well on production equipment and results in a stable product is time and money well spent. Finally, identifying a final product manufacturer with extensive experience working through highly technical problems will minimize stress on the sponsor when problems arise during first-time productions.

GREG WEILERSBACHER is the founder and president of Eastlake Quality Consulting, a GMP consulting firm. Over the last 25 years, he has held director and VP positions leading quality assurance, quality control, analytical chemistry, materials management, GMP facilities, and product manufacturing in biotech and pharmaceutical companies.