QUALITY BY DESGN APPROACH Page 88
16.0 QUALITY BY DESIGN (QbD) Quality by design is a systematic scientific approach for the development that involves the identification of the critical parameters, critical quality attributes (CQA) (of both product & process) and is characterized by the establishment of a design space, and enhanced process understanding. The aim of pharmaceutical development is to design a quality product and its manufacturing process to consistently deliver the intended performance of the product. Information from pharmaceutical development can be a basis for quality risk management. 16.1 Quality target product profile (QTPP) The pharmaceutical development and manufacturing strategy for Acitretin Nanoemulsion and Telmisartan Nanoemulsion drug product is guided by the products quality target profile (QTPP). Note: The quality target product profile (QTPP) is a prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality, taking in to account safety and efficacy of the drug product. The QTPP is an essential element of a QbD approach and forms the basic of design for the development of the product. Table- 23 PRODUCT TARGET Is this a JUSTIFICATION ATTRIBUTE CQA Dosage form Acitretin: Hard Gelatin capsules filled with solid Nanoemulsion Yes Pharmaceutical equivalent requirement same dosage form Telmisartan: Soft gelatin capsule filled with clear fill Identification Positive for active Yes Though identification is critical for safety and efficacy, this CQA can be effectively controlled by the quality management system and will be monitored at drug product release. Formulation and process variables do not impact identity. Page 89
Assay of Drug ±5% from the Label claim Yes Affect patient safety and Efficacy Route of administration Oral administration Yes Pharmaceutical equivalent requirement same route of administration as that of RLD Dosage strength Acitretin: 25 mg Telmisartan: 80 mg Yes Pharmaceutical equivalent requirement same dosage strength Container closure Acitretin: Blister pack Telmisartan: HDPE Pack Yes Needed to achieve the target shelf life and to ensure the product integrity during shipping. Shelf life 24 months below 25ºc Yes Equivalent to or better than RLD shelf life. Administration Similar as RLD Yes Generic product requirement Alternate method None Yes None are listed in the RLD label of administration Drug product Description Yes Pharmaceutical equivalence quality attributes Identification Yes requirement must meet the same Assay Yes compendial standards or other Related substances Yes applicable standards Particle size Yes To control for the better/desired Zeta potential Yes product performance Upper globule size determination Yes in lipid Disintegration Time Pharmacopoeal requirement Yes To give the desired release profile CQA: Critical Quality Attribute Page 90
16.2 Critical Material Attributes: Initial risk assessment for input materials based on Prior Knowledge applied to CQAs Table- 24 Drug product Appearance Solubility ID Test RS Assay Flow Residual quality properties solvents attributes Particle Size Distribution Description High Low Low Low Low Low Low Low Assay Low High High High Low Low Low Low Related Low Low Low Low Low Low Low Low substances Particle size Low High Low Low Low High Low High Zeta Low Low Low Low Low Low Low High potential Globule size determinatio n in lipid emulsions High Low Low Low Low Low Low High 16.3 Justification for initial risk assessment Table- 25 CPPs CQAs Justification and initial statergy Dispersion of Surfactants in aqueous phase Appearance/Description Polysorbate 80 and Cremophor EL is used as an emulsifier for emulsions containing triglycerides as the dispersed phase and uniform dispersion of Surfactant/CoS is required for a stable emulsion formation. The risk of dispersion may impact the drug product CQAs like appearance and Dispersion characteristics Page 91
Primary emulsion formation (operating condition for in-line mixer) Fine emulsion formation (By high pressure homogenization) Filling/Encapsulation Appearance/Description Assay Particle Size Zeta potential Upper globule size determination USP <729> ph Assay Related substances Sterility Particle Size The risk of primary emulsion formation to impact the drug product appearance is high. Formation of fine emulsion is carried out by high pressure homogenization. The ph of the fine emulsion is carefully controlled. The risk of fine emulsion formation to impact the drug product CQAs like assay of drug, particle size, upper globule size and ph are high. To get the desired fill volume. The risk of filling to impact the drug product CQAs like assay, RS and sterility are high. 16.4 Selection of the components of the drug product: 16.4.1 Drug Substance The target profile for Acitretin solid emulsion is met by the investigation and selection of Acitretin which is the input API for the product. The chemical name of Acitretin is alltrans-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid and available as yellow colored fluffy powder, with the pka of 5 and molecular weight 326.44, Acitretin is insoluble in water and slightly soluble in acetone and alcohol. The Target Profile for Telmisartan Nanoemulsion is met by the investigation and selection of Telmisartan which is the input API for the product. The chemical name of Telmisartan is 2-[4-[[4-methyl-6- (1-methylbenzimidazol-2-yl)-2-Propylbenzimidazole-1-yl] methyl] phenyl] benzoic acid and available as white crystals, with pka of 4.5 and molecular weight 514.6169. Telmisartan is practically insoluble in water and sparingly soluble in strong acid and strong base. Page 92
16.4.2 Excipients: Excipients used in the preparation of Acitretin nanemulsion are Capmul MCM, Tween 80, Transcutol HP, Neusilin and sodium hydroxide. Each components performs a specific function in forming the formulation. Capmul MCM holds the bulk of the Acitretin in a medium that can be stabilized and dispersed, Tween 80 serves as an emulsifier to stabilize the small Acitretin-Capmul MCM droplets in aqueous dispersion, and Transcutol maintains the formulation stable. The Neusilin used as the carrier material. Excipients used in the preparation of Telmisartan Nanoemulsion are Myglyol 812, cremophor EL, PEG 400 and Meglumine. Myglyol holds the bulk of the Telmisartan in a medium that can be stabilized and dispersed, Cremophor EL acts as an emulsifier to stabilize the small Telmisartan-Myglyol droplets in aqueous dispersion, and PEG 400 maintains the formulation stable Meglumine acts as a basifier to keep the solubility values on the higher side. 16.5 Establishing Boundaries Of The Design Space 16.5.1 Identify Product Failure Modes The most common approach to develop a stable emulsion is to identify an control the processing conditions and variables which destabilize the emulsion. Stable emulsion is considered to be one in which the dispersed droplets retain their initial character and remain uniformly distributed throughout the continuous phase for desired shelf life. There should be no phase changes or microbial contamination on storage, and the emulsion should maintain elegance with respect to dispersion characteristics, and consistency. Instability in emulsion may arise from both chemical and physical origin. Chemical instabilities, such as the development of rancidity in natural oils due to oxidation by atmospheric oxygen, depolymerization of macromolecular emulsifiers by hydrolysis, microbial degradation, increased acidity and presence of electrolytes destabilize emulsion by neutralizing the repulsive negative charge on the droplet surface. Physical instability may be attributed to increase in temperature, agitation and freeze thawing which attributes to increased droplet size with a greater tendency to coalesce. Page 93
16.5.2 Identify Product-Imposed Boundary on the Design Space Droplet size distributions and presence of surface charge (zeta potential) in Acitretin emulsion droplet and important from both stability and biopharmaceutical considerations. The larger particle size, the greater the tendency to coalesce and further increase droplet size. Thus, fine particles generally promote better stability, also the more negative the zeta potential is the greater the net chare on the droplets and the more stable emulsion is, the droplet size and surface charge distribution represents the boundary of the design space imposed by the characteristics of the formulation. 16.5.3 Identify Equipment-Imposed Boundaries on the Design Space: Differences in manufacturing techniques such as the rate of the heating and cooling cycle, the extent and order of mixing can cause variations in the consistency and rheology of the resulting emulsions. The initial particle size of the emulsion depends on the emulsifiers used, the emulsification equipment, the addition speed, and the phase volume. If the surfactants is paced in one of the phase prior to emulsification, it will migrate to the other to establish equilibrium. Thus, emulsification temperatures and cooling rates are important and the time of the mixing should be sufficient to allow the surfactant to migrate to and equilibrate at the interface throughout the process. 16.6 Summary : It is very important to view product and process development for a stable nanoemulsion formulation which is an integrated process rather than as a collection of independent activities. Drug formulaion, the development scientist must be aware of the type of equipment to which the product will be transferred in the next stage of development. The scientist must also understand the capability of equipment and must take into account the processing condition which becomes particularly important in developing emulsion with a droplet size distribution below 1000nm. Page 94
17.0 STABILITY STUDIES: the design of the stability was in compliance with the ICH guideline, stability storage conditions are selected as follows. Stability storage conditions Table- 26 Study Storage condition Time period Long term 25 ºC ± 2 ºC / 60% RH ± 5% 6 months RH Accelerated 40 ºC ± 2 ºC / 75% RH ± 5% RH 3 months Page 95