Pharmaceutical development report (pdr)

pharmaceutical development report PDR is the one of the significant document of CTD (common technical document) which requires for in approval of new drug process

1. Pharmaceutical product Development Report (PDR) ( Effective ICH Q8 Pharmaceutical Development Reports) - By Atul Bhombe M.Pharmacy (RA) First yr. Sanjivani college of pharmacy education & research

2. Introduction The International Conference on Harmonization (ICH)  Common Technical Document (CTD) format is the  submission standard for new and abbreviated drug product  applications in the United States, the European Union and  Japan.  One of the significant sections of the CTD is the  Pharmaceutical Development Report (PDR).  A complete  PDR is essential to provide a comprehensive understanding  of the product and process for the FDA application  reviewers and inspectors . The information in the PDR is- based upon the documentation generated during the  formulation and process development phase of drug  development.   

3. The ICH Q8 and Q8(R1) Pharmaceutical Development  Report guidance documents provide the guidelines for the  PDR.1,2   As stated in the Q8 guidance, “The Pharmaceutical  Development section provides an opportunity to present  the knowledge gained through the application of scientific  approaches and quality risk management to the  development of a product and its manufacturing process.”   The PDR can, and should, be updated over the lifecycle of  the product as new knowledge of the product is obtained.

4. There are six critical sections to PDR development listed in  the Q8 guidance document. Each section addresses a  specific component or process in the development process,  including:  1. Components of the drug product  ( Api , Excipient ) 2. Information about the drug product formulation  development, overages, and physiochemical and  biological properties  3. Describes the manufacturing process development 

5. 4. Rationale for the choice of the drug product  container closure  5. Microbiological attributes 6. Compatibility of the drug product with  reconstitution diluents or dilution prior to  administration for labelling information

6. 1. Components of the drug product    The components thus include the API(s) and all the Excipients A) Active pharmaceutical ingredient : The physicochemical and biological properties of the drug substance that can influence the performance of the drug product and its manufacturability.” Examples of physicochemical and biological properties that might need to be examined include- Solubility , Water content,Particle size, Crystal properties, Biological activity, Permeability, melting range.

7. B) Excipients The characteristics and amounts of excipients that can influence the performance of the pharmaceutical product or its manufacturing capability should usually be discussed relative to the respective function. The ability of functional excipients, e.g. pH-adjusting agents, buffers, stabilizers (such as antioxidants and chelating agents), preservatives and dissolution modifiers (such as surface active agents), to perform throughout the intended shelf-life of the FPP should usually be demonstrated .

8. 2. Information about the drug product formulation  development, overages, and physiochemical and  biological properties   formulation development   A summary of formulations used in clinical safety and efficacy and in any relevant bioavailability or bioequivalence studies should be provided. Any changes between the proposed commercial formulation and those formulations used in pivotal clinical batches and primary stability batches should be clearly described and the rationale for the changes provided. Information from comparative in vitro studies (e.g., dissolution) or comparative in vivo studies (e.g., bioequivalence) that links clinical formulations to the proposed commercial formulation described. it should be summarized and a cross-reference to the studies (with study numbers) should be provided. Where attempts have been made to establish an in vitro/in vivo correlation, the results of those studies and a cross-reference to the studies (with study numbers) should be provided in the Pharmaceutical Development section. A successful correlation can assist in the selection of appropriate dissolution acceptance criteria and can potentially reduce the need for further bioequivalence studies following changes to the product or its manufacturing process.

9. Overages: In general, use of an overage of a drug substance to compensate for degradation during manufacture or a product’s shelf life, or to extend shelf life, is discouraged. overage to compensate for loss during manufacture should usually be provided in the PD, including the step(s) where the loss occurs, the reasons for the loss and batch analysis release data (assay results).

10. Physicochemical and biological properties: Parameters relevant to the performance of the FPP, such as pH, ionic strength, dissolution,reconstitution , particle size distribution, aggregation, polymorphism, rheological properties, biological activity or potency and/or immunological activity, should be addressed. (See also ICH Q6A Specifications: Test Procedures And Acceptance Criteria For New Drug Substances And New Drug Products: Chemical Substances; Decision Tree #4 (Part 3) and Decision Tree #7 (Part 1) or ICH Q6B Specifications: Test Procedures and Acceptance Criteria for Biotechnology/Biological Products. The discussion should crossreference any relevant stability data in 3.2.P.8.3.)

11. 3. Describes the manufacturing process development The selection, the control, and any improvement of the manufacturing process described (i.e., intended for commercial production batches) should be explained. It is important to consider the critical formulation attributes, together with the available manufacturing process options, in order to address the selection of the manufacturing process and confirm the appropriateness of the components. The rationale for the selection, controls,  appropriateness of components and equipment, and  process design is discussed.  The critical process  parameters, their monitoring and control, are presented in  this section as well as the justification for the drug product  specifications.

12.  As with the formulation, the differences  between the manufacturing processes used for the pivotal  clinical trial batches, the primary stability batches and the  commercial process are discussed. Data should be provided  to show the robustness of the process to reliably produce  the quality product

13. 4. Container closure The suitability of the container-closure system used for the storage, transportation (shipping) and use of the FPP should be discussed. This discussion should consider: The choice of primary packaging materials should consider, e.g., choice of materials, protection from moisture and light, compatibility of the materials of construction with the dosage form (including sorption to container and leaching), and safety of materials of construction. Justification for secondary packaging materials should be included, when relevant.

14. 5. Microbiological attributes The selection and effectiveness of preservative systems in products containing antimicrobial preservative or the antimicrobial effectiveness of products that are inherently antimicrobial. • The selection and effectiveness of preservative systems in products containing antimicrobial preservative or the antimicrobial effectiveness of products that are inherently antimicrobial • For sterile products, the integrity of the container closure system as it relates to preventing microbial contamination

15. •  This may include testing at the lowest  specification for the preservative(s) and testing simulating  patient use to justify the efficacy and safety such that the  minimum concentration of preservatives is used. The  results of the microbial testing substantiate the qualitative  and quantitative preservative requirements.  Although chemical testing for preservative content is the attribute normally included in the drug product specification, antimicrobial preservative effectiveness should be demonstrated during development.

16. 6. Compatibility The compatibility of the drug product with reconstitution diluents (e.g., precipitation, stability) should be addressed to provide appropriate and supportive information for the labelling . • This information should cover the recommended in-use shelf life, at the recommended storage temperature and at the likely extremes of concentration. Similarly, admixture or dilution of products prior to administration ( e.g.,product added to large volume infusion containers) might need to be addressed.

17. References ICH Q8 R2 Guideline “ Pharamaceutical Development” (https ://database.ich.org/sites/default/files/Q8_R2_Guideline.pdf) WHO Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme : quality part. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-sixth report. Geneva, World Health Organization, 2012, Annex 4 (WHO Technical Report Series, No. 970). https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q8r2-pharmaceutical-development