REGULATORY REQUIREMENTS FOR PREFORMULATION STUDIES
INTRODUCTION:Prior to nomination into full development, a candidate drug should undergo a phase traditionally calledpreformulation.Preformulationis the physiochemical characterization of the solid and solution properties of compounds.Preformulationencompasses all studies enacted on a new drug compound in order to produce useful information for subsequent formulation of a stable andbiopharmaceuticallysuitable 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 thepreformulationscientist 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 thephysico-chemical properties of a new drugTo establish the data on drug-excipient compatibilityTo establish API ‘s kinetic rate profile.
REGULATORY REQUIREMENTSSMALL 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 andMatrixingDesigns 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 includeSolubility,Water content,
Particle size,Crystal properties,Biological activity, andPermeability.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 forcompliance with PROCESS ANALYTICAL TECNOLOGY(PAT), a recent initiative of the Food andDrug Administration(FDA; Ref. 1).PATis intended to encourage drug makers tobuild qualityinto their development processes so they can anticipate the impactof changeson a final formulation.AlthoughPAT is voluntary, the initiative isdesigned topromote a better understanding, among drug manufacturers, of the mechanicsof theirprocesses so that they can avoid failures and minimize the amount oftesting requiredat the end of production.Preformulationstudies support PAT byproviding moreinformation on an active pharmaceutical ingredient’s (API)characteristics tofacilitate downstream efficiency and success.Drugmanufacturers caneventually submittheir documents to a special PAT group within the FDA, which canexpedite regulatoryapproval.
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 systemThis guidance facilitates innovation in development, manufacture, andquality assuranceby focusing on processunderstanding. These concepts areapplicable toall manufacturing situations.
PHYTOMEDICINES:In January 2004, the U.S. FDA issued a guideline for botanical products.Theinformation 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.
Thegeneral method of preparationisprovided underSec312. 23(a)(7)(iv)(a).TheEMEA provides the following guidelines for herbal (botanical aslisted inUnited 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 Guidanceon Qualityof Herbal Medicinal Products (CPMP/CVMP adopted July 01).CPMP/QWP/2820/00 (EMEA/CVMP/815/00) Note for Guidance onSpecifications: Testprocedures and Acceptance Criteria for Herbal Drugs, HerbalDrug Preparationsand 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/EECAnnexure 1Analytical 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).TypicallyMAb’sare needed at higher doses and are normally delivered ‘IV’.Thus,MAb’smust be available at high concentrations
at which they are viscous, making them difficult to administer conveniently.Hencepreformulationactivity that needs to be considerediaa 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 thepreformulationstage.The US,EU and Japanese compendia standards differ regarding the timing of anti microbial tests for preservativesE.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 thecharacterization of the substances obtained byrecombinant DNA technique.Several guidelines of the ICH and other guidelines atthe USFDA provide additional information on stabilitytesting of biological products.A clear description of the drug substance should beprovided which may include any of the following:Chemical structureMolecular weightMolecular formulaInformation from specific tests regardingidentity, purity, stability and consistency of manufacture
of the drug substance should be provided.Eg: Amino acid analysisAmino acid sequencingPeptide mappingDetermination ofdisulphidelinkageApplication should include description of- Relevantinvitroandinvivobiological 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 ofPreformulation