Case Studies

These are a few examples of how an experienced CMC consultant assisted other firms in their regulatory, compliance and drug development programs.

NDA RTF (Refusal-to-File)

Challenge - This virtual company's first NDA was originally prepared by a small clinical CRO and was returned with a RTF letter.  No new clinical data was requested; only an expanded analysis of the data.  The FDA also requested that the firm provide substantial improvements to the organization of all the data.  There were numerous CMC deficiencies; including missing quality attribute tests, inconsistent information between sections, inaccurate data treatment and insufficient stability data.

Response - The entire CMC section was evaluated for compliance to contemporary FDA expectations and identified the data required to correct the deficiencies.  Scientific studies to address and provide the missing tests and data were conceptualized, outsourced to CMC contractors, monitored and summarized. Proposals to the Agency to allow the use of already manufactured batches for the generation of some of the new test data were based on science and precedent. The entire CMC section was streamlined and re-written.

Outcome - The re-submitted CMC section resulted in an approvable letter, thus salvaging a previously failed product.  At the pre-NDA meeting with FDA, the FDA CMC Division Director thanked the CMC consultant for arranging this meeting with the virtual company and for preparing a quality, easily-reviewable submission.

QP (Qualified Person) Audit and EU CTA

Challenge - A first-in-man clinical study was intended to be conducted in the UK and had three US CMC contractors.  The dosage form was a PIC (API powder in a capsule).  The EU clinical CRO had difficulty coordinating the manufacturing and import licenses and the inspections of the US manufacturing sites with a contract QP.

Response - The PIC activity was transferred to a UK CMC CRO with an in-house QP.  The CMC consultant's early discussion with the QP facilitated API supply, analytical methods transfer, PIC manufacturing, and packaging and labeling in compliance with both US and EU GMP.

Outcome - The elimination of QP audits of the US manufacturing and packaging contractors shortened the time frame for the preparation of clinical supplies and allowed an earlier start to the clinical study.

New Combination Product

Challenge - This virtual company had conducted a cardiovascular clinical trial using two 30-year old, generically available oral solid dosage forms, dosed separately and together. The clinical data demonstrated that the two products in combination were dramatically superior to either drug alone. Their intent was to market a fixed dose combination product using the 505 (b) (2) NDA approval pathway. At the EOP2 meeting, to everyone's surprise, the FDA indicated that the only additional clinical trial that would be necessary for approval would be a BE study using the individual generic tablets versus the firm's formulated combination product.  The identification of a clinical/commercial manufacturer and the formulation, analytical procedures, etc., for the combination product had not started. 

Response - The CMC development plan was conceptualized in less than one week. CMC contractors for supplying both APIs, formulation and manufacturing prototypes of the varying doses of the combination product and for developing analytical tools  reflecting contemporary regulatory requirements (e.g., stability-indicating assays, discriminating dissolution methodologies) were identified, selected and visited.  Pre-formulation and analytical method development proceeded in parallel with the conduct of GMP compliance audits.  Scale up batches were prepared and used for NDA stability and the BE study concurrently.

Outcome - The NDA was submitted 9 months after the EOP2 meeting containing 6 month stability data that was evaluated to project a 24 month expiry date.  (This drug, BiDil, was approved in 2005.)

Defining Packaging and Labeling Options for a Complex Titration Clinical Study

Challenge - The clinical group provided a proposed blister package design for a complex, global, up-titration, maintenance and down-titration placebo-controlled study involving four stratifications of subjects. The titration phases involved six distinct ascending or descending doses, each of which had a matching placebo control. At any stage of the study, if there were minor side effects, a subject's dose could be reduced. The proposed blister card design required 14 different card layouts, with different amounts of dosage units, with labels in 6 languages.

Response - The CMC consultant recommended a single blister card layout which provided uniformity in the number of dosage units taken at any stage of the study and minimized the variations of time-consuming card design. Common static text was preprinted on the cards themselves, while dynamic text was provided in a booklet label.

Outcome - The lead time for the single card layout, pre-printed static text and booklet labels was reduced by 6 weeks.  Costs of the modified approach were reduced by 25%.

Preserving the Historical Tox and Clinical Database for an Inherited Drug

Challenge - Two compounds (one oral, one IV) had been in the clinic in Europe ten years prior with academic sponsors and research CMC supplies. Each was being re-positioned for the current US oncology market.  The solid dosage form API was extremely water insoluble and required high dose levels (250-1200 mg).  The historical dosage form used in the European clinical trials was an unformulated PIC (powder in a capsule) where the API had a purity of >99.7%. The IV product was unstable in aqueous solution where only a rudimentary freeze-dried product was used previously. This API had high (~5%) levels of starting materials and impurities.  The sponsors of both compounds wanted to preserve the existing historical tox and clinical database.

Response - We reviewed the CMC databases and found them to be deficient to contemporary standards. We outlined, then placed, then monitored the necessary scientific studies, including preformulation, formulation development and analytical methods and tests. We met with the FDA and discussed our approaches to future CMC development. For the oral dosage form with the high purity API, we initially re-entered the clinic with a similar high purity API PIC, with a very lengthy and costly purification process. Simultaneously, we developed a more realistic and purification process and conducted qualifying toxicology studies on the new API. For the IV dosage form, we reduced and/or qualified the existing impurities. 

Outcome - We discussed our proposed approaches with the regulators at pre-IND meetings. We submitted new CMC sections to the regulatory authorities in the UK and in the US which were approved for new phase 1-2 trials. The tox and clinical databases for both compounds were preserved.

Successful FDA PAI (Pre Approval Inspections)

Challenge - Eight small, emerging pharma/biotech companies submitted their first NDA/BLA to FDA, listing a variety of CMC contractors.  These CMC contractors included API manufacturers, analytical labs, clinical manufacturing groups, clinical packaging, labeling and distribution firms and were located in the US, Europe and Japan. Most of the contract organizations had never had a FDA PAI.

Response - The CMC consultant visited 15 manufacturing sites that had never had a FDA inspection.  Each was evaluated for compliance to cGMPs for the specific operations they conducted for their clients. Deficiencies were identified along with options for corrective action.  The CMC consultant worked with the virtual companies and many of their CMC contractors to monitor progress of the various upgrades and improvements to systems and operations. 

Outcome - Each of the 15 manufacturing sites passed their first FDA PAI. (Note that the overall rate for FDA turndown is 15-20% and about 50% for first-time inspections).