1-7.The ICH Q8 “Minimal Approach” to Pharmaceutical Development Satish Mallya January , 2011

Pharmaceutical Development Q8(R2) The aim of pharmaceutical development is to design a quality product and its manufacturing process to consistently deliver the intended performance of the product. The information and knowledge gained from pharmaceutical development studies and manufacturing experience provide scientific understanding to support the establishment of the design space, specifications, and manufacturing controls. January 19-22, 2011

Pharmaceutical Development Q8(R2) At a minimum, those aspects of drug substances, excipients, container closure systems, and manufacturing processes that are critical to product quality should be determined and control strategies justified. Critical formulation attributes and process parameters are generally identified through an assessment of the extent to which their variation can have impact on the quality of the drug product. January 19-22, 2011

ICHQ8 Empirical (Minimal) Essential product development for all products vs Enhanced (QbD) Quality by Design Critical understanding of product and process January 19-22, 2011

Approaches & Outcomes Minimal Enhanced Conducted one variable at a time – minimum product knowledge Multivariate experiments – extensive product knowledge Focus on optimization and reproducibility of process Focus on control strategy and robustness of process End product testing On line (PAT) tools utilized Primary control through FPP specifications FPP specifications part of overall control strategy FPP quality controlled by in-process and end product testing FPP quality ensured through risk based control strategy since product and process are well understood. Real time release testing with possible reduction of end product testing Quality over product life cycle managed through problem solving and corrective action Quality over product life cycle managed through preventive action and continuous improvement January 19-22, 2011

“Minimal” Approach Establish Quality Target Product Profile (QTPP) Identify Critical Quality Attributes (CQA) of the FPP Investigate quality attributes of the API and formulation ingredients Select an appropriate manufacturing process and establish the Critical Process Parameters (CPP). Outline pertinent control strategies. January 19-22, 2011

“Minimal” Approach Establish Quality Target Product Profile (QTPP) Identify Critical Quality Attributes (CQA) of the FPP Investigate quality attributes of the API and formulation ingredients Select an appropriate manufacturing process and establish the Critical Process Parameters (CPP). Outline pertinent control strategies. January 19-22, 2011

Quality Target Product Profile (QTPP) A prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the drug product. January 19-22, 2011

Quality Target Product Profile (QTPP) QTPP is the basis of design for the development of the product Considerations for establishing QTPP: Indication & route of administration Dosage form & strength(s) Container closure system Attributes affecting pharmacokinetic characteristics (e.g., dissolution) FPP quality criteria (e.g., sterility, purity, stability and drug release) January 19-22, 2011

Quality Target Product Profile (QTPP) The following are generally identified as elements of QTPP: Assay of API in the FPP Purity Content Uniformity of API in the FPP Disintegration/Dissolution of FPP Tablet Friability & Hardness Stability/Suitability of Container Closure System Bioequivalence Various formulations are investigated in order to obtain similar dissolution patterns as for the innovator product and to improve the disintegration time. On achieving satisfactory results in the lab scale batches scale up is undertaken to ensure reproducibility of results on larger scales. January 19-22, 2011

Quality Target Product Profile QTPP Attribute Target Product IR tablet, 300 mg Bioequivalence F2 > 50 Appearance Film coated scored Potency 95-105% Purity Impurity A – 0.2% Impurity B – 0.5% Total – 1.0% Content Uniformity Meet Ph. Eur. Dissolution NLT 85% in 30 minutes in pH 1.2, 4.5 & 6.8 Stability 24 months at RT in HDPE and blisters January 19-22, 2011

“Minimal” Approach Establish Quality Target Product Profile (QTPP) Identify Critical Quality Attributes (CQA) of the FPP Investigate quality attributes of the API and formulation ingredients Select an appropriate manufacturing process and establish the Critical Process Parameters (CPP). Outline pertinent control strategies. January 19-22, 2011

Critical Quality Attribute (CQA) A physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality. January 19-22, 2011

Critical Quality Attribute (CQA) Additional CQAs for APIs, raw materials and intermediates: properties that affect FPP CQAs (e.g., particle size distribution, bulk density) . Potential drug product CQAs are utilized to guide the product and process development. The list of potential CQAs may be modified as product knowledge and process understanding increase. Pertain To Affect API Excipients In-process PP Potency Purity Drug release Stability Sterility January 19-22, 2011

“Minimal” Approach Establish Quality Target Product Profile (QTPP) Identify Critical Quality Attributes (CQA) of the FPP Investigate quality attributes of the API and formulation ingredients Select an appropriate manufacturing process and establish the Critical Process Parameters (CPP). Outline pertinent control strategies. January 19-22, 2011

Quality Attributes of the API API Characterization Physical Chemical Biological For FDC products, evaluate the compatibility of the APIs with each other. The knowledge gained from the studies investigating the potential effect of API properties on FPP performance can be used to justify tests in the API specification January 19-22, 2011

API Characterization Physical properties: Appearance Particle size Bulk and tap densities Crystalline form Hygroscopicity & water content Solubility and pH profile of solution/dispersion January 19-22, 2011

API Characterization Chemical properties Stability temperature humidity oxidative photolytic Biological properties permeability partition coefficient BCS January 19-22, 2011

Excipients Function in formulation Affect on performance of FPP Stability Bioavailability Affect on manufacturability of FPP Ability to perform during shelf-life Disintegrants Preservatives Antioxidants Safety of Novel Excipients January 19-22, 2011

FPP Identification of attributes critical to the quality of the drug product Justification for choice of drug product components properties of the drug substance Properties of excipients Suitability of container closure system Justification for choice of the manufacturing process Summary of formulations used in bioequivalence studies justification for changes between the proposed commercial formulation and those formulations used in bioequivalence batches and primary stability batches Justification for score line Justification for overages January 19-22, 2011

Container Closure System Rationale for selection of the container closure system Safety of packaging material Suitability of the container closure system for storage and transportation, including the storage and shipping container for bulk PP Compatibility of the FPP with packaging materials Integrity of the container and closure Justification for the use of secondary packaging materials January 19-22, 2011

Compatibility Compatibility of the drug product with reconstitution diluents Range of diluents Range of dilutions Container types Storage recommendations Compatibility and stability of admixtures obtained from further dilution of reconstituted products prior to administration. January 19-22, 2011

Microbiological Attributes Rationale for performing or not performing microbial limit testing for non sterile drug products Evidence of effectiveness of preservative At the lowest specified concentration Over shelf-life Antimicrobial effectiveness of products that are inherently antimicrobial January 19-22, 2011

“Minimal” Approach Establish Quality Target Product Profile (QTPP) Identify Critical Quality Attributes (CQA) of the FPP Investigate quality attributes of the API and formulation ingredients Select an appropriate manufacturing process and establish the Critical Process Parameters (CPP). Outline pertinent control strategies. January 19-22, 2011

Manufacturing Process Development Justification for the selection of the manufacturing process and in- process controls; Appropriateness of the equipment used; Identification of critical process parameters (CPP); Justification for differences between the manufacturing processes used to produce batches for bioequivalence studies or primary stability studies and the commercial process. Collection of process monitoring data during the development of the manufacturing process can provide useful information to enhance process understanding. January 19-22, 2011

Critical Process Parameter (CPP) A process parameter whose variability has an impact on a critical quality attribute (CQA) and therefore should be monitored or controlled to ensure the process produces the desired quality. January 19-22, 2011

Critical Process Parameter (CPP) Blending Granulation Drying (LOD) Compression Filtration Sterilization January 19-22, 2011

“Minimal” Approach Establish Quality Target Product Profile (QTPP) Identify Critical Quality Attributes (CQA) of the FPP Investigate quality attributes of the API and formulation ingredients Select an appropriate manufacturing process and establish the Critical Process Parameters (CPP). Outline pertinent control strategies. January 19-22, 2011

Control Strategy A planned set of controls, derived from current product and process understanding that ensures process performance and product quality. Is intended to ensure that a product of required quality will be produced consistently Sources of variability that can impact product quality should be identified, thoroughly understood and appropriately controlled January 19-22, 2011

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