REGULATORY REQUIREMENTS FOR PREFORMULATION STUDIES

INTRODUCTION: Prior to nomination into full development, a candidate drug should undergo a phase traditionally called preformulation. Preformulation is the physiochemical characterization of the solid and solution properties of compounds. Preformulation encompasses all studies enacted on a new drug compound in order to produce useful information for subsequent formulation of a stable and biopharmaceutically suitable drug dosage form. These should focus on those physiochemical properties of new compound that could effect drug performance and development of an efficacious dosage form.

DEFINITION: “ A phase of a research and development process where the preformulation scientist characterizes the physical , chemical and mechanical properties of a new drug substance in order to develop stable , safe and effective dosage forms” GOAL: To establish the physico-chemical properties of a new drug To establish the data on drug-excipient compatibility To establish API ‘s kinetic rate profile.

REGULATORY REQUIREMENTS SMALL MOLECULES/General: 1. Q1A(R2) Stability Testing of New Drug Substances and Products (Issued 11/2003, Posted 11/20/2003); 2. Q1B Photo stability Testing of New Drug Substances and Products (Issued 11/1996, Reposted 7/7/1998); 3. Q1C Stability Testing for New Dosage Forms (Issued 5/9/1997, Posted 3/19/1998); 4. Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products (Issued 1/2003, Posted 1/15/2003); 5. Q3A Impurities in New Drug Substances (Issued 2/10/2003, Posted2/10/2003);

6. Q3B(R) Impurities in New Drug Products (Issued 11/2003, Posted 11/13/2003); 7. Q3C Impurities: Residual Solvents (Issued 12/24/1997, Posted 12/30/1997); 8. Q3C Tables and Lists (Posted 11/12/2003); 9. Q6A International Conference on Harmonization; Guidance on Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances (12/29/2000); 10. Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (Issued 8/2001, Posted 9/24/2001). Physicochemical and biological properties that might need to be examined include Solubility, Water content,

Particle size, Crystal properties, Biological activity, and Permeability. These properties could be inter-related and might need to be considered in combination. Some of these properties can change with time and require time studies. To evaluate the potential effect of the physicochemical properties of the drug substance on the performance of the drug product, the ICH Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products

One purpose of these comprehensive guidelines it to prepare for compliance with PROCESS ANALYTICAL TECNOLOGY (PAT), a recent initiative of the Food and Drug Administration (FDA; Ref. 1). PAT is intended to encourage drug makers to build quality into their development processes so they can anticipate the impact of changes on a final formulation. Although PAT is voluntary, the initiative is designed to promote a better understanding, among drug manufacturers, of the mechanics of their processes so that they can avoid failures and minimize the amount of testing required at the end of production. Preformulation studies support PAT by providing more information on an active pharmaceutical ingredient’s (API) characteristics to facilitate downstream efficiency and success. Drug manufacturers can eventually submit their documents to a special PAT group within the FDA, which can expedite regulatory approval.

The FDA considers PAT to be a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality. The goal of PAT is to enhance the understanding and control the manufacturing process, which is consistent with our current drug quality system This guidance facilitates innovation in development, manufacture, and quality assurance by focusing on process understanding. These concepts are applicable to all manufacturing situations.

PHYTOMEDICINES: In January 2004, the U.S. FDA issued a guideline for botanical products. The information discussed in section VII.A.1 of the guideline pertains to the initiation of characterization of the drug substance. It is important for the safe conduct of clinical trials to ensure the proper identity of botanical raw materials used in the trials. As there is no history of experience in United States with botanical raw materials marketed only outside the United States, a certificate of authenticity of the plant and plant parts should be provided for such materials. A trained professional who is competent to determine authenticity should sign this certificate.

The general method of preparation is provided under Sec312 The general method of preparation is provided under Sec312. 23(a)(7)(iv)(a). The EMEA provides the following guidelines for herbal (botanical as listed in United States) products: COMMITTEE FOR PROPRIETARY MEDICINE PRODUCTS (CPMP)/QUALITY WORKING PARTY (QWP)/2819/00 [EUROPEAN MEDICINES EVALUATION AGENCY (EMEA)/COMMITTEE ON VETERINARY MEDICINAL PRODUCTS (CVMP)/814/00] Note for Guidance on Quality of Herbal Medicinal Products (CPMP/CVMP adopted July 01). CPMP/QWP/2820/00 (EMEA/CVMP/815/00) Note for Guidance on Specifications: Test procedures and Acceptance Criteria for Herbal Drugs, Herbal Drug Preparations and Herbal Medicinal Products (CPMP/CVMP adopted July 01).

If no monograph for the herbal drug is given in a pharmacopoeia referred in directives 75/318/European economic community(EEC)and81/852/EEC Annexure 1 Analytical procedures not given in a Pharmacopeia should be validated in accordance with the ICH guideline “ validation of analytical procedures; methodology” (CPMPICH/281/95) and registration of veterinary products(VICH) guideline(CVMP/VICH/591/98) The information may be supplied either as part of the marketing authorization application or with the help of European drug master file procedure.

LARGE MOLECULE DRUGS: Proteins may be identified through genomics/proteomics activities or through more traditional medical research. One of the most challenging aspects of developing protein pharmaceuticals is dealing with and overcoming the inherent physical and chemical instabilities of proteins. Marketing considerations arise early in product development fro monoclonal antibodies(MAb’s). Typically MAb’s are needed at higher doses and are normally delivered ‘IV’. Thus, MAb’s must be available at high concentrations

at which they are viscous, making them difficult to administer conveniently. Hence preformulation activity that needs to be considered ia a concentration study investigating solubility behavior, effect of conc. on viscosity, increased potential for aggregation. International disagreement over preservatives in food and drugs may present problem at the preformulation stage. The US,EU and Japanese compendia standards differ regarding the timing of anti microbial tests for preservatives E.g.: Japan does not accept phenol, where it is commonly used in US. The European union is known to have the toughest acceptance criteria for preservatives.

RECOMBINANT DNA PRODUCTS: The USFDA provides a detailed description of the characterization of the substances obtained by recombinant DNA technique. Several guidelines of the ICH and other guidelines at the USFDA provide additional information on stability testing of biological products. A clear description of the drug substance should be provided which may include any of the following: Chemical structure Molecular weight Molecular formula Information from specific tests regarding identity, purity, stability and consistency of manufacture

of the drug substance should be provided of the drug substance should be provided. Eg: Amino acid analysis Amino acid sequencing Peptide mapping Determination of disulphide linkage Application should include description of - Relevant invitro and invivo biological testing - Bioassays - Storage conditions - Study protocols - Results supporting this section

REFERENCES: http://www.authorstream.com/Presentation/goutham.atla-426330-preformulation-education-ppt-powerpoint/ Hand Book of Preformulation

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