1-7.The ICH Q8 “Minimal Approach” to Pharmaceutical Development

1-7.The ICH Q8 “Minimal Approach” to Pharmaceutical Development

Satish Mallya

January , 2011

Satish Mallya January 20-22, 20102 |

Pharmaceutical Development Q8(R2)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

Satish Mallya January 20-22, 20103 |

Pharmaceutical Development Q8(R2)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

Satish Mallya January 20-22, 20104 |

ICHQ8ICHQ8

Empirical (Minimal)

Essential product

development for

all products vs

Enhanced (QbD) Quality by Design

Critical understanding of product and

process

January 19-22, 2011

Satish Mallya January 20-22, 20105 |

Approaches & OutcomesApproaches & Outcomes

MinimalEnhanced

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 testingOn line (PAT) tools utilized

Primary control through FPP specificationsFPP 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

Satish Mallya January 20-22, 20106 |

“Minimal” Approach“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

Satish Mallya January 20-22, 20107 |

“Minimal” Approach“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

Satish Mallya January 20-22, 20108 |

Quality Target Product Profile (QTPP)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

Satish Mallya January 20-22, 20109 |

Quality Target Product Profile (QTPP)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

Satish Mallya January 20-22, 201010 |

Quality Target Product Profile (QTPP)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

Satish Mallya January 20-22, 201011 |

Quality Target Product ProfileQuality Target Product Profile

QTPP AttributeTargetProductIR tablet, 300 mg

BioequivalenceF2 > 50

AppearanceFilm coated scored

Potency95-105%

PurityImpurity A – 0.2%

Impurity B – 0.5%

Total – 1.0%

Content UniformityMeet Ph. Eur.

DissolutionNLT 85% in 30 minutes in pH 1.2, 4.5 & 6.8

Stability24 months at RT in HDPE and blisters

January 19-22, 2011

Satish Mallya January 20-22, 201012 |

“Minimal” Approach“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

Satish Mallya January 20-22, 201013 |

Critical Quality Attribute (CQA)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

Satish Mallya January 20-22, 201014 |

Critical Quality Attribute (CQA)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

Satish Mallya January 20-22, 201015 |

“Minimal” Approach“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

Satish Mallya January 20-22, 201016 |

Quality Attributes of the APIQuality 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

Satish Mallya January 20-22, 201017 |

API CharacterizationAPI 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

Satish Mallya January 20-22, 201018 |

API CharacterizationAPI Characterization

Chemical properties– Stability

• temperature• humidity• oxidative• photolytic

Biological properties– permeability – partition coefficient– BCS

January 19-22, 2011

Satish Mallya January 20-22, 201019 |

ExcipientsExcipients

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

Satish Mallya January 20-22, 201020 |

FPPFPP

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

Satish Mallya January 20-22, 201021 |

Container Closure SystemContainer 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

Satish Mallya January 20-22, 201022 |

CompatibilityCompatibility

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

Satish Mallya January 20-22, 201023 |

Microbiological AttributesMicrobiological 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

Satish Mallya January 20-22, 201024 |

“Minimal” Approach“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

Satish Mallya January 20-22, 201025 |

Manufacturing Process DevelopmentManufacturing 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

Satish Mallya January 20-22, 201026 |

Critical Process Parameter (CPP)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

Satish Mallya January 20-22, 201027 |

Critical Process Parameter (CPP)Critical Process Parameter (CPP)

Blending

Granulation

Drying (LOD)

Compression

Filtration

Sterilization

January 19-22, 2011

Satish Mallya January 20-22, 201028 |

“Minimal” Approach“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

Satish Mallya January 20-22, 201029 |

Control StrategyControl 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

Thanks