Preformulation and Quality Overall Summary - Regulatory Insights

Abstract

A detailed understanding of the properties of the drug substance is very essential to overcome the formulation problems in the later stages of drug development, to reduce drug development cost, and to decrease the overall development time. The goals of preformulation studies are to choose the correct form of the drug substance, to evaluate its physical properties and to generate a thorough understanding of the drug substance’s physico-chemical & chemical dynamics through stability under the conditions that will lead to development of an optimal drug delivery system. The preformulation studies are driven by three factors: the regulatory requirements, the commercial requirements and the technological development. However, prior to reviewing the various requirements that determine the scope of preformulation studies, it is important to review how the drug discovery models are rapidly changing and why there is a need for not just one, but several levels of exercise during preformulation studies. To overcome all these formulation hurdles, Regulatory agencies are continuously pushing the quality systems in the early phases of drug development to ensure the predefined product quality. Hence, several guidances have been published by USFDA & ICH to set regulatory specifications relevant to product quality. According to ICH, all technical requirements for the application of drug approval were harmonized in CTD format which are scientifically more elaborate by USFDA in QOS - QbR format. QbR is based on the principle of Quality by Design (QbD) which increased efficiency in the FDA review process.

Key Words: Drug substance, Preformulation, Quality by Design (QbD), Quality Overall Summary (QOS), Question based Review (QbR), Common Technical Document (CTD).

Introduction:

Drug Substance

It is an active constituent in the pharmaceutical product which is responsible for the overall product performance & pharmacological action.

Preformulation:

Prior to the development of major dosage forms, it is essential that pertain fundamental physical and chemical properties of the drug molecule and other divided properties of the drug powder are determined. This information decides many of the subsequent events and approaches in formation development. This first learning phase is known as preformulation.

Preformulation Study on Drug Substance:

Preformulation studies have a significant part to play in anticipating formulation problems and identifying logical path in both liquid and solid dosage form technology.

It describes the process of optimizing the delivery of drug through determination of physical, chemical properties of new drug molecule that affect drug performance and development of an efficacious, stable and safe dosage form.

Significance of Preformulation Study on Drug Substance:

• Establishing the identity & physicochemical properties of new drug molecule.
• Establish its kinetic rate profile.
• Establish its compatibility with common excipients.
• Establish its physical characteristics.
• Finally give innovative, stable, safe, cost effective dosage form capable of delivering the substance for its intended use.

Common Technical Document (CTD):

It is a common mode of submission developed by ICH for the harmonization of Drug approval application globally.

CTD Organization:

Module 1:  Administrative Information and Prescribing Information

1.1 Table of Contents of the Submission Including Module 1

1.2 Documents Specific to Each Region (for example, application forms, prescribing information)

Module 2:  Common Technical Document Summaries

2.1 Common Technical Document Table of Contents (Modules 2-5)

2.2 CTD Introduction

2.3 Quality Overall Summary

2.4 Nonclinical Overview

2.5 Clinical Overview

2.6 Nonclinical Written and Tabulated Summaries

Pharmacology

Pharmacokinetics

Toxicology

2.7 Clinical Summary

Biopharmaceutic Studies and Associated Analytical Methods

Clinical Pharmacology Studies

Clinical Efficacy

Clinical Safety

Literature References

Synopses of Individual Studies

Module 3:  Quality

3.1 Table of Contents of Module 3

3.2 Body of Data

3.3 Literature References

Module 4:  Nonclinical Study Reports

4.1 Table of Contents of Module 4

4.2 Study Reports

4.3 Literature References

Module 5:  Clinical Study Reports

5.1 Table of Contents of Module 5

5.2 Tabular Listing of All Clinical Studies

5.3 Clinical Study Reports

5.4 Literature References

Impact of the CTD:

• The ICH CTD represents one of the most ambitious and successful international harmonization activities undertaken.
• It will significantly reduce time and resources needed by industry to compile applications for global registration.

Benefits of the CTD:

• More “reviewable” applications.
• Complete, well-organized submissions.
• More predictable format.
• More consistent reviews.
• Easier analysis across applications.
• Easier exchange of information.
• Facilitates electronic submissions.

Question based Review (QbR):

QbR is a general framework for a science and risk-based assessment of product quality.
It contains the important scientific and regulatory review questions to;

• Comprehensively assess critical formulation and manufacturing variable.
• Set regulatory specifications  relevant to quality
• Determine the level of risk associated with the manufacture and design of the product.

QbR Questions Provides a Roadmap:

• Questions guide reviewers

•  
  • Prepare a consistent and comprehensive evaluation of the ANDA
  • Assess critical formulation & manufacturing variables

• Questions guide industry
  • Recognize issues OGD generally considers critical
  • Direct industry toward QbD

• Questions inform readers of the review

•  
  • How QbD was used in the ANDA
  • Provide the basis for a risk assessment

Quality Overall Summary (QOS):

A Summary that follows;

• Scope and outline of the Body of Data in Module 3
• Emphasize and discuss critical key parameters of the product
• Discuss key issues to integrate information from Module 3 and other modules

Quality by Design (QbD):
QbD means designing and developing formulations and manufacturing processes to ensure a predefined quality.
Quality by Design requires;

• Understanding how formulation and manufacturing process variables influence product quality.
• Proposed post approval changes management

Quality by Design ensures;

• Product quality (along with ICH Q9 and Q10).

Pre-Formulation Research Projects or Bulk Substance Characterization:
Investigate critical physico-chemical factors that assure Quality, Safety & Efficacy aspects of drug substances via investigating stability, chemistry & processing performance at the preformulation stage, as well as changes in analytical methodology used to assess such factors. Also, investigate properties of bulk drug substances which demonstrate "sameness", processibility and eventual product performance and quality (e.g., particle size, polymorph, hydrate/solvate, crystal habit, impurity profile).
Objective of this phase is Quantitation of physical and chemical properties that will assist in developing generic formulation which is,

• Stable
• Safe
• Bioequivalent

FDA recommended product development report should be submitted in 2.3.P.2 according to Question based Review in CTD format. This shall include detailed information on pre formulation and experience of early development stage.
2.3.P.2.1 Components of the Drug Product
2.3.P.2.2 Drug Product
2.3.P.2.3 Manufacturing Process Development
2.3.P.2.4 Container Closure System
Under ‘2.3.P.2.1 Components of the Drug Product’ the drug substance attributes that were considered during product development were:
1. The drug substance solubility and its pH dependence.
2. The multiple polymorphic forms of the drug substance.
3. The drug substance stability
4. The flow properties of the micronized drug substance
5. The particle size of the drug substance
6. The compatibility between the excipient and the drug substance
7. The drug substance density

1. The drug substance solubility and its pH dependence.

Drug substance solubility and its pH dependence is one of the two basic factors directly influencing bioavailability of the formulation. Based on physiological considerations its recommended to establish solubility of a drug substance at a pH range from 1.2 to 8.

Poorly soluble compounds represent an estimated 60% of compounds in development and many major marketed drugs. It is important to measure and predict solubility and permeability accurately at an early stage, and interpret these data to help assess the potential for development of candidates. This would further help in establishing dissolution specifications and formulation approach.

2. The multiple polymorphic forms of the drug substance

Polymorphic forms due to its different structural arrangements possess different physicochemical properties which can substantially differentiate its stability and dissolution performance from other polymorphs. Characterization of possible polymorphs and selection of polymorphs shall be critically evaluated at early development stages to avoid last minute surprises. For example, needle-shaped crystals tend to entangle and often do not flow well in manufacturing equipment. This can cause formulation of “hot spots,” with high concentrations of the API in some areas and deficits in others. A very large number of pharmaceuticals are shown to exhibit polymorphism, with solubility being affected by the nature of the polymorph for several drugs including diflunisal, chloramphenicol palmitate, glibenclamide, ketorolac, ranitidine, and ritonavir.

3. The drug substance stability

Drug substance stability has big commercial & safety related impact on the project. A highly unstable protein drug cannot be placed in anything but a highly preserved and protected parenteral form, as an example. The development of stability testing protocols start with the development of stability indicating methods, the details of which can be readily found in any pharmaceutical analysis text or through the website of the US FDA.

The Q1A R2 (Stability Testing of New Drug Substances and Products) is a good starting place. Similar guidelines are provided for biotechnology and botanical products.

4. The flow properties of the micronized drug substance

The flow properties of a powder will determine the nature and quantity of excipients needed to prepare a compressed or powder dosage form. This refers mainly to factors such as the ability to process the powder through machines. To make a quick evaluation, the compound is compressed using an infrared (IR) press and die under 10 torr of pressure with variable dwell times, and the resulting tablets are tested with regard to their crushing strength after storing them for about 24 hours. If longer dwell times result in higher crushing strength, then the material is likely to be plastic; elastic material will show capping at low dwell times; and the brittle material will not show any effect of dwell times. It is recommended that the compressed tablets be subject to XPRD to record any changes in the polymorphic forms. Angle of repose, compressibility index and Huesners’ ratio shall be evaluated at early development stage.

5. The particle size of the drug substance

The particle size of a new drug substance is a critical parameter, as it affects every phase of formulation by impacting uniformity, flow, compressibility, dissolution, stability & bioequivalence. Appropriate particle size is required to achieve optimal dissolution rate in solid dosage forms, and to control sedimentation and flocculation in suspensions. Examples of some drugs that demonstrate varying drug absorption with particle size include griseofulvin, phenacetin, digoxin, and nitrofurantoin. The gastrointestinal absorption of ultramicrocrystalline griseofulvin, a fungistatic agent is reportedly 1.5-fold greater than that of the microsize griseofulvin. Increased absorption due to a reduction in the particle size allows for the administration of lower doses with the ultramicrocrystalline compound (500 mg vs. 375 mg, once daily for the microsize griseofulvin).

6. The compatibility between the excipient and the drug substance

The drug excipients shall be evaluated by forced degradation & stability studies at various temp/humidity conditions. Whereas the choice of excipients starts with the stages of formulation, some excipients are historically used in specific drug formulations; for example, if the newly discovered drug is a cephalosporin for use as an intravenous product, compatibility with arginine or sodium carbonate would be advised as these are the most commonly used active excipients used for solubilization.

7. The drug substance density

Particle attributes, such as density and morphology may have significant effects on material properties and tablet attributes.

For solids, the density will also vary with the crystal structure and degree of crystallinity. If the solids are amorphous, the density may further depend upon the history of preparation and treatment. Therefore, unlike fluids, the densities of two chemically equivalent solids may be different, and this difference reflects a difference in solid-state structure. The density of constituent particles is an important physical characteristic of pharmaceutical powders.

Conclusion:

For designing safe, stable and bioequivalent generic product, vigilant and thorough preformulation study should be executed in accordance with the regulatory guidances. Solubility, polymorphism, particle size and flow property were the most critical attributes of drug substance, including excipient compatibility, as described in QbR-CTD format. For minimizing regulatory hurdles, in the approval process of generic drug application, implementation of QbD for efficient execution of QbR system should be required, which utilize experience and knowledge.

Acknowledgements

Our sincere thanks to Amneal Pharmaceutical Co. Pvt (I) Ltd., Ahmedabad.

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About Authors:

Apexa V. Patel and Alpesh R. Chudasama

Apexa V.Patel
Executive – Regulatory Affairs, Amneal Pharmaceuticals Pvt (I) Ltd. , Ahmedabad .

Alpesh R. Chudasama
Research Associate - Regulatory Affairs, Amneal Pharmaceuticals Pvt (I) Ltd