Victories in Manufacturing and Regulatory Compliance

In December 2006, DSM Pharma Chemicals (DPC) manufactured the millionth kilogram of the active pharmaceutical ingredient in WelChol, distributed through Daiichi Sankyo, which is licensed through Genzyme, a cholesterol-lowering drug that helps thousands of people every day. Behind the milestone achievement for WelChol is a story of victories in manufacturing and regulatory compliance – and of a great business relationship.

The story began in 1995 when scientists at GelTex, a small public company with about 30 employees, patented colesevelam (CSV) hydrochloride, an oral polymeric, lipid-lowering agent. At first GelTex asked DSM scientists in Linz to manufacture only 25 kilograms of CSV, just enough to test the drug in clinical trials in humans. DSM has been manufacturing the API on a commercial scale since the drug’s US marketing approval in 2000 and European approval in 2004.

Scaling Up: manufacturing victories

Scaling up a chemical process from a lab setting into a robust commercial process meant thinking in tons, not grams.

Processing CSV was one of the trickiest aspects. Imagine having to cut an amorphous, gooey gel into clearly defined, 2-cubic-millimeter pellets. DSM engineers were up to this challenge with an innovative outside-the-box approach, decided to adapt an industrial cheese cutter to do the job. Their modified device cut the gel into just the right size without adversely affecting the chemistry or clogging filters. Their ingenuity not only vastly improved the process but also earned them a patent.

Scale-up is only one part of the story; continual process improvements create the ability to increase production capacity. Utilizing virtually the same equipment, the DSM team was able to make improvements that have produced eight to tenfold throughput increases.

“The chemistry is important, but engineering the process in a cost-efficient manner is what allows you to make a marketable product. The team at DSM did just that,” says Dr. Harry Mandeville, who invented CSV while with GelTex. Joe Tyler, then the head of manufacturing at GelTex, adds: “In my 25 years of working with contract chemical manufacturers for pharmaceutical products, the DSM site at Linz is the best I have ever worked with. The DSM Linz team did an extraordinary job.”

Acing the test: regulatory compliance

The Food and Drug Administration (FDA) completes a rigorous pre-approval inspection of all equipment used to produce ingredients used in pharmaceutical products. Walter Finster and Erich Steinwender of DSM led the CSV inspection efforts. The FDA’s team of eight inspectors was on-site for six days. Walter recalls: “They looked at our manufacturing processes, quality controls, laboratories; it even seemed like they examined our bathrooms!” The FDA’s post-inspection report noted “no deficiencies”, a perfect score.

During the planning and audit periods we worked closely with Scott De ‘Aeth, then the head of quality for GelTex and now VP Quality with Genzyme. The relationship with our customers has always been integral component in success. Rob Blanks, Scott De ‘Aeth’s predecessor as head of quality at GelTex, says: “We couldn’t have had the product approved in the short time we did (five years) without the excellent work of DSM.”

“We continue to work together with DSM and the team in Linz to improve the CSV process. DSM has shown the highest level of commitment to Genzyme, and I consider this to be one of our most successful partnerships: truly win/win,” comments Jim Shuman, Senior VP of Materials Management at Genzyme.

Being able to technically manufacture active pharmaceutical ingredients is very different from being able to help your customer become profitable. DSM is committed to providing innovation and expertise to every customer’s product we manufacture. We only promise what we can deliver and we deliver on those promises.

From start to finish

DSM is the only API manufacture that adds even more value to their customers by providing extended manufacturing value through the relationships within DSM’s contract manufacturing organization, DPC and the DSM Pharmaceuticals, Inc. (DPI) business unit. The DPI unit in Greenville, NC, provides custom manufacturing services in the areas of sterile injectables (aseptic liquids and lyophilization), solid dose form manufacturing (tablets and capsules) and is DEA approved for the manufacture of scheduled compounds. Additions to these services added this year are CTM PI-PIII manufacturing, formulation development services and sterile cytotoxic manufacturing.

This relationship has been a great value in providing complete CMO services. We may be one of only a few CMOs worldwide who can pride themselves on the fact that they only provide manufacturing services. DPP does not own any pharmaceutical products that compete for capacity. The ability to manufacture APIs and provide dosage form manufacturing delivers a complete solution chain for our customers. This is beneficial for pharmaceutical companies as they will be able to avoid the higher costs of future tech transfers by starting their API manufacturing with DSM and finishing with commercial dose form manufacturing at DSM.

About the author

Kristine Senft joined DSM Pharmaceutical Products in March 2007 as Senior Vice President, Marketing and Sales, DPC NA. Based in Parsippany, NJ, Senft’s focus within DPP is to lead the US commercial marketing and sales organization of DPC’s custom chemical manufacturing services focusing on complex intermediates and active ingredients targeting the large and emerging pharma markets.

Ms. Senft has more than twenty-five years of experience in progressively responsible positions in chemical marketing & sales management spanning many industries and covering many global regions – the last 8 years which has focused on the pharmaceutical industry. Prior to joining DSM, Ms. Senft spent the last 17 years with Albemarle Corporation in Baton Rouge, LA. Most recent positions held were as Global Business Director, Pharmaceutical Actives and prior to this as Sales Director, Fine Chemicals and Global Strategic Account Manager. She also has 10 years experience with Kaiser Aluminum and Chemical Company in various sales and marketing roles. She is a member of SOCMA and DCAT.

Ms. Senft is originally from the Chicago area, graduating from Eastern Illinois University with a BS in Chemistry. Ms. Senft lives in Randolph, NJ with her husband Patrick and their 2 children, Haley and Sean.