Noted Updates From ICH Q3D - Elemental Impurities (Step 2 to Step 4)

By Harley Everett Wilcox, MBA
www.abclabs.com

Implementation challenges persist with the ICH Q3D, elemental impurities, as the deadline for implementation is delayed and reported related to global implementation and industry feedback. IPQI suggests industry responses centered on Risk Assessment and amount of detail needed.  Global regulatory agencies, pharmacopeias, ICH and other stakeholder are involved and impacted by efforts to move away from USP <231>.

Some noted updates from ICH Q3D Step 2 to Step 4 include:

• Existing products have 36 months post step 4 publication for implementation.

• PDEs for iridium, osmium, rhodium, and ruthenium are based on palladium VS platinum.

• Additional detail prescribed to PDE assessment for other routes of administration beyond oral, parenteral, and inhalation—section 3.2.  Comment: Other routes may include rectal, topical, nasal, buccal, and transdermal. Section 3.2 suggests using available bioavailability data.

• Examples are provided for justification of higher levels than PDE using Modifying Factors.

• Parental Products section 3.4 now provides information for large parental dose and permissible PDEs.

• Selenium is now a class 2B vs 2A regarding element classification and excluded from risk assessment if not added to product.

• Class 4 has been renamed as “other elements.”

• Potential Sources of EIs Section: “known or suspected” container closure leachables changed to “Potential.” (See a recent webinar by ABC's own W. Rushing for more on this)

• ID of Potential EI’s –Section 5.3: Step 4 include more specific information for risk assessment base on route of administration i.e. oral and parenteral.

• The addition of Risk Assessment Summary includes a defined threshold based on PDE.

• Option 1, “permitted concentrations,” a change from MUST to SHOULD in regards following options 2a, 2b, or 3.

For more on this:

For more information from ABC (specifically on the implementation of new elemental impurities USP Chapters <232> and <233>), please visit this page on ABC Laboratories website which  has a link to download the working paper entitled "ABC Laboratories FormationsPaper on Implementation ofNew Elemental Impurities USPChapters <232> and <233>"

References:

PQRI.Org

S. Peterson, K. Wells, M. Silvey, L. Schrier, “ABC Laboratories Formations Paper on Implementation of New Elemental Impurities USP Chapters <232> and <233>.” ABC Laboratories, 2014.  www.abclabs.com.

ICH

ABC Company News: Downloads from 2014 AAPS Annual Meeting

CGMP Radiosynthesis for Early Phase Clinical Trials

Radiolabeled drugs are used in Human ADME and bio-availability studies. While the regulatory requirements for traditional “cold” clinical trial materials are well understood, the regulatory requirements for radiolabeled are much less understood by industry. The synthesis of radiolabeled compounds sometimes requires development of new synthetic pathways which can be significantly different from the traditional synthetic pathway. The radiolabeled drug can have significantly different stability and impurity profiles from the non-labeled drug and thus require special considerations. These special considerations may pose challenges in terms of ensuring CGMP compliance and safety for the patient during the clinical trial.

To download the whitepaper, click here.

How to Evaluate Manufacturer-Provided Extractable Information

Most pharmaceutical container/closure systems in use today are purchased from component manufacturers, who often provide material characterization information on their products. A common and often expensive misstep is to assume manufacturer-provided information will suffice as Extractables and Leachables (E&L) data. This paper will help you understand what information regulators require in your filing, provide questions to ask suppliers, and explain how to evaluate manufacturer-provided information relative to your unique product.

To download the whitepaper, click here.

ABC Company News: ABC Adds iCAP Q ICP-MS to Mass Spec Capabilities

To better meet new regulatory requirements for elemental impurities and other trace analysis, ABC Laboratories has added Thermo’s high performance iCAP Qc Quadrupole ICP-MS Spectrometer to its fleet of mass spectrometers. ABC’s newest ICP instrument enables single mode analysis that covers the mass range of 4-290 amu, while delivering low abundance sensitivity and ultra-fast scanning. This is the same instrument that USP used to help develop new chapters <232> and <233>.

“ABC continually evaluates its technology to ensure we are meeting our clients’ needs and enhancing operational efficiency,” said Joe Troxell, ABC Vice President of Product Development Services. “While this purchase is part of our ongoing capital program, it’s made particularly important by new regulatory requirements for metals analysis in pharmaceuticals.”

To learn more about implementation of new elemental impurities UPS Chapters <232> and <233>, download this working paper.

ABC Webinar Archive: "The Critical Role of CMC in Your IND Submission"

Early stage drug developers generally have their sights firmly set on the initiation of clinical trials, focusing on toxicological and pharmacological studies. Often, the importance of Chemistry, Manufacturing and Control (CMC) data is underestimated. But the CMC package is critical to IND approval, and meeting all FDA requirements demands careful planning and sound execution.

This discussion will focus on the primary CMC requirements for a biopharmaceutical IND submission. It will cover the risk/reward criteria for determining the level and degree of method validation, reference standard characterization and formulation; as well as potential pitfalls and ways to streamline the entire development process.

"The Critical Role of CMC in Your IND Submission"

Featured Presenter:
Glenn E. Petrie, Ph.D., Senior Scientific Advisor, ABC Laboratories

Metabolite Profiling and Identification - (More Than) 150 Years of Good Advice

 

Over the past few months I have been writing a chapter on "Metabolite Profiling" for the forthcoming book, New Horizons in Predictive Drug Metabolism and Pharmacokinetics (Royal Society of Chemistry, 2015).

I began the chapter with one of my favorite quotes related to drug metabolism:

“In order to understand the actions of drugs it is an absolute necessity to have knowledge of the transformations they undergo in the body…we must not judge drugs according to the form and amount administered, but rather according to the form and amount which actually is eliciting the action.”

From where did this sage advice arise? Another recent book on metabolite profiling? No. A regulatory guidance document? No.

In fact, this statement was written more than 150 years ago, in 1859, by Rudolph Buchheim (1820-79), a pioneer in experimntal pharmacology.

The quote appeals to me for several reasons; first, as someone interested in the history of chemistry and science; second - and more important - because it lays out as elegantly as any modern statement the very mission and importance of drug metabolism ("form") and pharmacokinetics ("amount") and pharmacology ("action"), especially the role of metabolite profiling and identification.

Though the basic mission has not changed over the past 150 years, what has evolved is the tools at our disposal to execute that mission.  I've witnessed some of that evolution in my nearly 30-year career in xenobiotic metabolite profiling, isolation, characterization, and identification, especially the shrinking footprint (and cost) of high resolution mass spectrometry and improved in silico tools for data mining and prediction.

What do you see as potential advances (or unmet needs) in metabolite profiling and identification technologies in the coming years?

ABC Webinar Archive: "Are Extractables and Leachables Going Phase Appropriate?"

Not long ago, it was more or less conventional wisdom that E&L studies should be performed late in the development cycle—even after the final container/closure system is known. But current regulatory trends suggest that, like many things GxP, expectations for early E&L data are on the rise. 

In recent years, multiple drug sponsors have been required by authorities to provide detailed E&L packages or address specific questions during phase I/II. It’s not only clinical trial material containers causing concern, but also the equipment used in manufacturing and dosing devices. As a result of these new expectations, several programs have been put on a clinical hold pending E&L data, causing significant delays and unplanned expense.

Click here to watch now.

CGMP Radiosynthesis - Will Your CRO Be There When It Counts?

Expert ¹⁴C radiolabeling for human clinical programs requires extensive training and experience. Having supported radiolabeled studies for more than 30 years, ABC Laboratories was one of the first to produce ¹⁴C-labeled API and formulate CTMs under CGMP requirements. Our experienced radiosynthethic chemists have worked with many drug candidates so we can help guide you through the detailed CGMP process. We work in tandem with your chemistry, regulatory, and QA personnel to ensure that a high-quality API or drug product CTM, that meets your specifications, is delivered to the clinic on time.

We know you're counting on us

ABC's experienced scientists have worked on both sides of the outsourcing relationship, so we understand the criticality of meeting timelines while supplying high quality products and data. ABC maintains a dedicated Quality Control and Quality Assurance staff with extensive experience specifically supporting isotopically labeled compounds. Nowhere will you find a team with more skill in developing efficient synthetic routes, commitment to delivering your labeled drug candidate, batch records and Certificates of Analysis in the agreed-upon time at the level of quality needed to meet today's high standards.

click here for more.