Our Ask the Experts Feature takes questions from our readers and poses them to our Editorial Advisory Board members and other outside experts. Visit www.contractpharma.com/ask-the-experts and submit your question! If it’s chosen as our Question of the Month, you’ll win a $100 American Express gift card, like Joe Tempio did!

—GYR

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Q: How do you deal with methods validation of analytical methods (i.e. HPLC) for comparator clinical dosage forms when innovator reference standards are not readily available for drug substance and impurities?

—Joe Tempio, JST PharmaServices

A: It could be very tedious process. It is recommended to degrade the API under the stressed conditions and analyze each degradants. If the references are not available from the API manufacturer, then it requires the synthesis of each impurity under investigation to establish a quantitative method.

—Shaukat Ali, BASF

A: It is usually possible to find out some aspects of the analytical method from the web or from pharmacopoeias. If the comparator is provided to the patient in the original packaging, then no data should be required (assuming it has been stored correctly during any marshalling at the clinical trial company). If the comparator has been manipulated in any way — i.e. overencapsulated or repacked or both — then analytical data will be required. This brings you to the central issue: how to compare with the baseline reference standard, a material that is usually unobtainable.

But let’s look at the role of the reference standard: it is to enable you to show that your sample has not deviated from its properties at ‘birth,’ or at least not outside the allowable limits described in the registered specification. In the case of the comparator, the ‘birth’ is the birth of the packed original product. The data for the comparator should treat the unadulterated original pack as its standard. You are setting out to show that the repacked product (now called the comparator) has not deviated from its original properties, i.e. those properties pertaining to the original packed product.

—Paul Titley, Aesica

Q: How do you expect the preclinical contract services market to shift as pharma recovers from the patent cliff and begins funneling additional R&D resources into biologics?

—Brad Miller, XenoTech, LLC.

A: I have spoken to many CMC experts, who are involved in outsourcing preclinical services to CROs from several Big Pharma companies lately. The major thrust of Big Pharma R&D is shifting towards biologics/biotherapeutics and away from small molecule R&D. There is a major paradigm shift that I am expecting over the next three to five years.

Major CROs that are involved in preclinical CMC activities are getting themselves ready and shifting more for working on biosimilars, peptides, monoclonal antibodies and the like. I believe that the emergence of companies like CMC Bio and other CDMOs for biologics will have a positive (high single-digit to a double-digit) growth rate, while those focusing on small molecule R&D programs will either decline or remain flat at the best.

—Mak Jawadekar, Ph.D.

Q: I am consulting with a company that is about to file an IND for a program it just licensed from a large pharma company. We intend to file our own independent IND for a Phase IIa study, instead of transferring the IND from the large pharma company. We have about three months of stability data on the drug product that we can file, but the large pharma cannot locate the excipient compatibility report for the study it had conducted. Are we required to conduct an excipient compatibility study to file in this IND, or can we simply use the stability data on the actual drug product in this IND filing?

—Mark Ginski, Virtual CMC Consulting

A: A pragmatic view would be that the stability data should tell you all you need to know. The compatibility data would inform the formulator which excipients to avoid or at least give you warning about storage conditions needed to maintain shelf life. We can assume that the compatibility data was used by the large pharma company to make decisions on formulation and storage conditions, but you are unlikely to convince a reviewer that although the data is missing those conclusions were valid! Three months’ stability data does not seem much, given the time between manufacture and actual administration to the patient. If the data from the accelerated stability condition looks rock solid, then the lack of compatibility data can be down played. If there are any datapoints that you have to ‘explain,’ then it is likely you will need more data (i.e. six months), or the missing comp data. It would be quicker to generate the comp data.

—Paul Titley, Aesica