Ajaz S. Hussain, Ph.D. Deputy Director Office of Pharmaceutical Science, CDER, FDA An Example of Process Understanding Directed Risk Based CMC Regulatory Oversight of Post-Approval Change

Process Understanding Physical, chemical, microbiological, and engineering focus –Critical attributes and causal links to quality –Process control strategy (including environmental conditions) –Limitations of analytical methods Quality system capabilities –QC/QA, IQ, OQ, PQ…. –Change control –Training –OOS investigations - Continuous learning –Other aspects

Risk-Based Risks of uncontrolled post approval changes –New impurities, shorter shelf-life, bio-in- equivalence Risk of too restrictive post approval change policies –Low efficiency and high cost of manufacturing –Questionable and possibly minimal difference between quality of acceptable and rejected batches –Potential for eroding credibility of pharmaceutical quality system Likelihood of occurrence, severity of consequence, mitigation strategies

CMC Regulatory Oversight Prior Approval Supplement (PAS) –High risk Changes Being Effected in 30 Days (CBE-30) and Changes Being Effected (CBE) –Moderate risk Annual Report –Low risk

Post-Approval Changes Scale-Up, site of manufacturing, equipment and process, components and composition –Levels of changes Analytical methods, packaging, and other types of changes Why change? –Marketing needs, mergers and acquisitions,.. –Improving the process (voluntary, a good thing, but..) –Improvement demanded by FDA (e.g., consent decrees)

Process Understanding Post approval change Risk CMC regulatory oversight Company’s Quality system cGMP regulatory oversight

Process Understanding Post approval change Risk CMC regulatory oversight Company’s Quality system cGMP regulatory oversight Process Understanding Risk CMC regulatory oversight Company’s Quality system cGMP regulatory oversight Post approval change

An Example: References Ullah, I., Wiley, G. J. and Agharkar, S. N. Analysis and simulation of capsule dissolution problem encountered during product scale-up. Drug. Dev. Ind. Pharm. 18(8): (1992). Heda, P. K. A comparative study of the formulation requirements of dosator and dosing disc encapsulators, simulation of plug formation, and creation of rules for an expert system for formulation design. Ph.D. Dissertation, University of Maryland, School of Pharmacy, SUPAC-IR: Immediate-Release Solid Oral Dosage Forms: Scale-Up and Post-Approval Changes: Chemistry, Manufacturing and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation. November Immediate-Release Solid Oral Dosage Forms: Scale-Up and Post-Approval Changes: Chemistry, Manufacturing and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation

Change: Scale-Up of a developmental product using encapsulation equipment of different design Development Product –Capsule product containing x-mg of drug Y (“freely water soluble”) and 1% magnesium stearate was developed using a Zanasi LZ-64 capsule-filling machine. –Initial development experiments identified a link between blend time and dissolution rate. Capsules prepared with powders blended for 5 minutes exhibited a more rapid dissolution rate (~95% dissolved in 10 minutes) compared to powders blended for 40 minutes (~90% dissolved in 45 minutes). A 10-Kg lot was blended for 15 minutes in a V-blender. Under these conditions the resulting capsules conformed to an in vitro dissolution acceptance criteria of Q75% in 45 minutes (in 900 ml water at 37oC, USP Basket 100 rpm).

Scale-Up: Challenges Initial trial for scale-up utilized a batch size of 570 Kg; Hoflinger & Karg GFK-1500 capsule filling machine (H&K), a V- blender and the mixing time was set to 15 minutes. –Poor dissolution –“Overblending” with magnesium stearate? Not in the blender –During encapsulation on the H&K machine powder was being sheared (during the tamping steps, not during auger-feeding process), resulting in an unacceptable dissolution rate. –Using a shear simulation approach, optimal level of magnesium stearate of 0.3% was identified for the H&K machine that satisfied encapsulation (e.g., content uniformity) and dissolution and weight uniformity

How relevant is this example? The selected example represents a class of SUPAC that may be relevant for a number of companies. The other critical aspect of this case deals with changes in amount of magnesium stearate, the most widely used excipient in tablet and capsule formulations. Therefore, information developed in this analysis should be useful beyond this particular case study. –The choice of encapsulation equipment design, dosing disc vs. dosator type machines, is about equally divided with about 18% companies using both types of machines, i.e., about 40% of companies only use one type (design) of machine –64% use equipment of the same design and operating principles for development/pilot and production batches, and about 18% develop pilot formulations on equipment of different design from the production machines. –tailored for equipment of different design. In today’s global economy, developing capsule formulations that can be encapsulated using equipment of different design can be advantageous

SUPAC- Change Category Full production batch (1100 Kg) was produced on the H&K machine using 0.3% magnesium stearate, and a blend time of 15 minutes. With respect to magnesium stearate in IR products, SUPAC-IR guidance recommends a quantitative change to the extent  0.25 % be considered as a Level 1 and changes within  0.5 % are considered as Level 2. In this example, the target amount of magnesium stearate was 1% and was changed to 0.3% (i.e., -0.7%), which exceeds the recommended range for Level 2. Therefore, this change may be considered as Level 3 (High Risk)

Regulatory Oversight Stability tests: –Significant body of information available: One batch with three months accelerated stability data reported in supplement; one batch on long-term stability data reported in annual report. –Significant body of information not available: Up to three batches with three months accelerated stability data reported in supplement; one batch on long-term stability data reported in annual report. Dissolution Documentation: Case B dissolution profile In Vivo Bioequivalence Documentation: Full bioequivalence study.

Process Understanding as a means for Mitigating risk From a CMC perspective we have two prong approach to mitigate risk: –Testing + Reporting requirement –Process understanding may be used to address both –For example, reduce reporting requirements while maintaining the same testing requirements reduce reporting requirements and testing requirements

Risk: Likelihood and severity of consequence In this example a focus on process understanding will ask –What is the risk of shorter shelf-life? Mechanism of degradation? Recipient compatibility? Control of moisture? … –What is the risk of bio-in-equivalence? Is dissolution rate limiting? How reliable is dissolution test? Control pf particle size? ….

Change Management Strategies and Risk Likely to be based on a number of technical and economic factors. An important consideration for this decision should be an understanding of impact on product performance and the risk of product failure (i.e., failure to meet established dissolution and other specifications) during routine production. It is postulated that the risk of product failure during routine manufacturing is likely to be in the order (a)>(b)>(c). –Reduce shear on powder by adjusting the pin settings on the H&K machine? –Optimize (reduce) the level of magnesium stearate to satisfy content uniformity and dissolution acceptance criteria? –Change formulation to facilitate plug formation and/or minimize undesirable effects of magnesium stearate (e.g., addition of a wetting agent such as sodium lauryl sulfate)?

Risk of Bio-in equivalence? Clinical NDA vs ANDA Post-approval Biopharmaceutics considerations –Drug substance and drug product attributes, absorption mechanism –Relevance of dissolution test

Some observations “There is no known medically significant bioinequivalence problem with articles where 75% of an article is dissolved in water or acid at 37° in 45 minutes in the official basket or paddle apparatus operated at the usual speed, that is, USP First Case.” “A majority of monographs have such requirements.” “USP First Case performance is recognized as a reliable formulation objective in the United States and bears attention worldwide for product development where in vivo bioavailability testing is not readily available.” “It obviates wasteful biostudies.” “Medically significant cases of bioinequivalence rest mainly on four causal factors: inappropriate particle size of an active ingredient; magnesium stearate in excess as a lubricant- glidant; coatings, especially shellac; and inadequate disintegrant. Each of these factors is reactive to dissolution testing.”

Formulation attributes for optimal encapsulation on machines of different design vary Changing Zanasi to H&K requires a reduction in the amount of magnesium stearate –To maintain a low weight variation, optimum values of Carr’s index (CI) is in 25 to 35 range for Zanasi and 18<CI<30 for H&K –Based on plug ejection forces, a relatively lower level of lubricant (about ½) is sufficient for H&K machines compared to Zanasi. Heda. Ph.D. Dissertaion, Univ. Maryland, 1998

Recognizing “Robust formulations” with respect to “overblending”? In a FDA sponsored study it was found that the impact of magnesium stearate on drug dissolution and bioavailability of piroxicam (a low solubility drug) from capsule formulations (encapsulated on Zanasi LZ-64) containing a wetting agent was negligible. Sodium lauryl sulfate level and piroxicam particle size were the most important main effects affecting dissolution Pharm. Dev. Technol. 3: (1998).

Ajaz Hussain.In “Process Scale-Up in Pharmaceutical Industry,” Editor Michael Levine, Marcel Dekker. 2001