PharmTech Annual Event Highlights Process Optimization, Product Quality

This week's PharmTech AnnualEvent (www.pharmtechevent.com)in Somerset, New Jersey, targeted approaches to improving drugdevelopment and quality through optimizing processes, managing risk,and controlling variations in manufacturing operations.

The event included keynote presentations on regulatory compliance andinitiatives, process analytical technology (PAT), and applications ofmodel-based designs while conference sessions highlighted areas such ascontinuous processing, identifying critical process parameters andquality attributes. Attendees also had opportunities to attendindividual tracks on ingredients, formulation and development,analytical, manufacturing, information systems and technology, andoutsourcing.

Reducing variability
Identifying the cause of and controlling variability during mixing andblending operations presents unique challenges to manufacturers, saidFernando Muzzio, director of chemical engineering and director of thepharmaceutical engineering program at Rutgers University (NewBrunswick, NJ, www.rutgers.edu)in a presentation on failure modes in content uniformity. Weightvariability, insufficient mixing, segregation, agglomeration, and falsecauses (e.g., sampling,analytical) all contribute to variations in content uniformity.

Mistakes in sampling, for example, are not uncommon, especially when asample thief is used. "Thiefs were not designed to be precision tools,"said Muzzio, and failures such as sample transfer or material stickingmay contribute significantly to variability in results. Developingpredictive process understanding (i.e.,PAT) by identifying critical inputs and outputs, characterizingmultivariate relationships, implementing predictive control models, anddesigning processes for continuous feedback control also plays a partin reducing variability. "But it all depends if the process iscontinuous or batch," says Muzzio, "most important, what you measureand how you measure depends on the process, not the other way around."Statistics are useful for handling changes in processing conditions andingredient properties that may lead to process failures, he said, but"implementing the correct design of experiments to distinguish amongthe many possible causes for poor performance is very important."

Reducing variability through proper bulk drug characterization was atopic of a presentation by Dina Zhang, senior investigator for MerckResearch Laboratory (Whitehouse Station, NJ, www.merck.com). Thediscussion reviewed the characterization methods for dry and wetgranulations and the benefits of analytical tools, including atomicforce microscopy and inverse gas-phase chromatography. "Physicalcharacterization is important in upstream and downstream development,"said Zhang. Morphology, particle size and flowability, which are part ofbulk drug optimization, help in process selection such as directcompression, roller compaction, or wet granulation, while physicalstability and dissolution studies facilitate formulation optimizationfor optimizing bioavailability.

Regulatory compliance, FDA initiatives
Controlling variability and managing risk are becoming increasinglyimportant as the industry faces changes in FDA's approach to ensuringproduct quality. In a keynote address, former FDA investigator andcompliance officer Philip Linderman cited failure investigations,standard operating procedures (SOPs), aseptic processing, andvalidation as the top four Warning Letter citations in biologics. Theseareas also were within the 10 most common 483 citations innon-biologics, and GMP violations were the top reason for drug recalls. Product safety and quality was a driver in FDA'srevised investigation process into six systems said Linderman, now asenior compliance consultant for JM Hyde Consulting, Inc. These systemsinclude quality, facilities and equipment, materials, production,packaging and labeling, and laboratory control. "You're only as strongas your weakest system," he said. "For FDA, the most important factorin deciding whether deviations are significant is whether theyrepresent a theoretical risk to the finished product or a danger to thepatient."

CDER is currently undertaking steps to advance principles detailed inFDA's final report of the 21st Century Initiative and to allowmanufacturers to "assume more ownership and accountability for themanufacturing controls that will improve drug quality," said Jon EdwardClark, Associate Director, Policy Development and GMP at CDER's Officeof Pharmaceutical Science. Among the areas under development is theadoption of an internal quality management system, adoption of qualityassessment system, wider use of PAT principles, and establishingstronger hamonization, including collaborations with PharmaceuticalInspection Cooperation Scheme (PIC/S) and leveraging the InternationalConference on Harmonization's Pharmaceutical Development (Q8) andQuality Risk Management (Q9) guidelines.

Ajaz Hussain, PhD, former Deputy Director of CDER's Office ofPharmaceutical Science and currently vice-president and global head ofbiopharmaceutical development at Sandoz, rounded out the keynotepresentations Thursday by updating attendees on the current state ofPAT in the industry and outlining remaining challenges. "PAT waspositioned as a system, not technologies," said Hussain. PAT itself hasmerged into Q8 and Q9. For "continuous improvement" PAT-Q9 principles,making up the "design space" in development, needs to be integratedinto manufacturing and quality assurance along with innovation andcontinuous improvement options.

The industry is currently in a state of limited and similar abilityamong competitors with regard to continuous improvement, noted Hussain.For a company to move to a state in which it has greater ability thanits competitors on continuous improvement, the company must build uponscience of design--that is, creating a fundamental, reusable designknowledge base--as well as enabling technology platforms, science andtechnology integration, and current and anticipated future customerneeds. Ultimately, said Hussain, the ideal state would involveachieving and ensuring product quality and performance, understandinghow formulation and process factors influence product performance, andbeing able to effect continuous improvement and continuous "real-time"quality assurance.