product formulation and development

unit 1 product formulation and development

1. PHARMACEUTICAL PRODUCT DEVELOPMENT Dr. K. L.DEEPTHI, M.PHARM PH.D ASSOCIATE PROFESSOR DEPARTMENT OF PHARMACEUTICS A.KALYANI, B.PHARM

2. CONTENTS 1.Introduction to pharmaceutical product development 2.Objectives 3.Regulations related to Preformulation 4. Regulations related to formulation development 5.Regulations related to stability assessment 6.Manufacturing and quality control testing of different types of dosage forms .

3. INTRODUCTION Pharmaceutical product : when a new chemical entity(drug moiety) is discovered it is considered as an experimental drug whereby with the aid of various drug development teams enters the phases of preclinical & clinical trails approved by INDA & NDA respectively ; reaches the market being distributed across various states for its use.

4. Objectives : To design quality product and its manufacturing processes to consistently deliver the intended performance of the product. To generate an assurance that therapeutic moiety in the proposed formulation is suitable, safe and effective with no toxicity. To achieve a predictable therapeutic response of a drug. To investigate capability of large scale manufacturing with reproducible product quality. Early identification of associated risks. To identify material attributes and process parameters that affect the drug product quality attributes .

5. Regulations related to Preformulation Preformulation: It is defined as the phase of research and development during which the physico - chemical properties of the drug substance are characterized in order to develop safe, effective and stable dosage form. Objectives: To establish the physico-chemical parameters of a new drug entity. To determine its kinetics and stability. To establish its compatibility with common excipients. Helps to guide dosage form selection. It provides insight into how drug products should be processed and stored to ensure their quality.

6. ICH Guidelines For smaller drug molecules

7. ICH Guidelines for larger molecules Larger molecules such as proteins may be identified through genomic activities and marketing consideration arise for MAB’s. Typically these are needed at higher doses& delivered through I.V. Preformulation activity needed to considered is solubility behavior, effect of concentration on viscosity & increased potential for aggregation. The USA, EU& Japanese compendia standard differ regarding to the timing of antimicrobial tests for preservatives.

8. For phytomedicines: In January 2004, U.S FDA issued a guideline for botanical products. The European Medicine Evaluation Agency[EMEA] provides the following guidelines for herbal products. Committee for proprietary medicine products (CPMP)/Quality working party (QWP)/2819/00/committee on veterinary medicinal products. 2. CPMP/QWP/2820/00 note for guidance on specifications: Test procedures and acceptance criteria for herbal drugs, herbal drug preparations and herbal medicine products. If analytical procedures are not mentioned in pharmacopeia then developed method is validated in accordance with the ICH Guideline “ validation of analytical procedures; methodology”.

9. Regulations in formulation development: Pharmaceutical formulation development is the process in which different chemical substances including active drug are combined to produce final medicinal product. Formulation development is an area of product development that determines patentability, lifecycle and success of pharmaceutical product. It links the discovery of new substance to successful development of commercial drug product. All pharmaceutical products are formulated to specific dosage form for drugs to be effectively delivered to patients. Most appropriate route of administration; design of experiments(DOE); statistical analysis; process validation& process optimization are widely applied to formulation development.

10. The challenge of a formulation scientist is to determine the optimum choice of each excipient and its optimum levels. Physicochemical analysis can aid excipient selection, enable the stability of the drug substance and the product to be assessed, and ensure the critical material attributes(CMA) relating to formulation performance. All these formulation goals can be described as Target Product Profiles(TPP).It usually includes route of administration., dosage form & size., maximum and minimum doses of requirement etc. It guides formulation scientists to establish formulation strategies and develops efficient drug product.

11. Regulations at stability assessment Factors affecting stability comprise the drug stability, dru g excipient interaction, employed manufacture processes, type of dosage form ,packaging system of products environmental conditions encountered during shipment, storage and handling etc. Stability testing procedures include real time stability testing, accelerated stability testing, retained sample& testing cyclic temp .stress stability testing. These studies are carried out at each stage of the life cycle of a drug from very first stages of development to later stages of follow up studies. The ICH regulates safety, quality & efficacy of API & API containing products where standards are mentioned in USA,EU & Japan.

12. Main objective is to minimum CGMP for preparation of drug products for administration of drugs to humans or animals. 1. CGMP is present in 21 CFR part 211 that provides the requirements of stability testing programme for development of new drugs & new drug products. 2. For stability testing studies, SOP’s include documentation that includes stability profile and expiry of drug product. 3. This programme ensures maintenance of identity strength, quality, purity and efficacy of a drug/drug product.  

13. VARIOUS ICH STABILITY GUIDELINES

14. ICH Guidelines for stability testing of Biologics/biotechnological products ICH guideline Types and objectives of stability testing Q5A VIRAL SAFETY Q5B GENETIC STABILITY Q5C stability testing of biotechnology products Q5D Derivation & characterization of cell substrates. Q5E Comparability of biotech products to changes in manufacturing process

15. Climatic zones for stability assessment Climatic zone Climate/ definition Major countries/regions Mean annual partial water vapour pressure Long term testing conditions 1 Temperate UK; Northern Europe; Russia& US <15 0 C/11hPa 21 0 C/45%RH 2 Subtropical & Mediterranean Japan & southern Europe >15-22 o C/ >11-18hPa 25 0 C/60%RH 3 Hot & dry Iraq, India >22 o C/<15hPa 30 0 c/35%RH 4a Hot & humid Iran , Egypt >22 o C/ >15-27hPa 30 0 C/65%RH 4b Hot & very humid Brazil & Singapore >22 0 C/>27hPa 30 0 C/75%RH

16. Environment Sampling time points (months) Method & climatic zone 25 C /60 %RH 3,6,9,12,18,24,36 Long term for zones 1& 4 30 C /35%RH 3,6,9,12,18,24,36 Long term for zones 3 30 C/65%RH 3,6,9,12,18,24,36 Long term for zone 4a;or immediate condition for zones 1&2 30 C/75%RH 3,6,9,12,18,24,36 Long term for zone 4a;or immediate condition for zones 1&2 40 C/75%RH 3,6 Accelerated conditions for all zones Stability testing of new products

17. Accelerated stability testing A product is stressed at several higher temperatures and the amount of heat input required to cause product failure is determined. This is done to subject the product to a condition that accelerates degradation.it is used to predict shelf life.in addition to temperature other stress conditions employed include moisture; light; agitation etc The concept of stability testing is based on Arrhenius equation which is given by InK = InA - E/RT Where K = degradation rate/s A = frequency factor/s E = activation energy(KJ/mole) R = universal gas constant(0.00831KJ/mole) T = Absolute temperature(K)

18. Regulations in manufacturing : CDSCO & Indian ministry of health and family welfare are the main regulatory bodies. A new drug is defined as a drug that has not been used in India to any significant extent under the conditions prescribed, recommended or suggested in the products labeling and has not been recognized by the appropriate licensing authority of India. CDSCO regulates DTAB,DCC & CLAA for manufacturing , importing , sale & distribution of pharmaceuticals regulated under D&C act 1940;rules 1945.

19. Regulations at quality control testing Guidelines for quality control testing : The term quality control refers to the sum of all procedures undertaken to ensure the identity and purity of a particular pharmaceutical product. Q.C procedures are intended to ensure that a manufactured product adheres to defined set of quality criteria/meet the requirements put forth by regulatory agencies. The WHO provides detailed guidelines on all aspects of laboratory testing in 1984, the committee Has set up pharmaceutical Q.C testing labs. WHO ECSPP(Expert committee on specifications for pharmaceutical products) in 1999 adopted guidelines entitled WHO Good practices for national pharmaceutical control laboratories. These guidelines provides advice on QMS within analysis of API’s; excipients pharmaceutical products.

20. Quality control testing of dosage forms Example: Tablets 1. Weight variation test : weigh 20 tablets, calculate the average weight of the tablets and is compared to individual weight with the average wt. The tablet meets the USP test if “if not more than 2 tab are out of % limit”. 2. Content uniformity : 30 tablets are selected randomly where 10 of them are individually assayed, and 9 out of 10 tab. should have potency within 15% of labelled drug content. 3. Tablet hardness : it is the hardness at which the tablet crushes. Limit: 5kg/sq. Inch 4. Friability : few of the weighed tablets are taken and placed in Roche friabilator

21. And are subjected to abrasion & shock at 25 rpm for 20 min. Dusted & weighed. Limit : conventional compressed tablets – weight loss should lie in 0.5-1%. 5. D isintegration test: one tablet is placed in each tube, and a standard motor moves the basket containing simulating biological fluid, up and down for certain time. USP disintegration test will be passed if all the tablets disintegrate and the particles passed through the #10 mesh screen within the specified time. Maximum disintegration time for uncoated tablets is 30min and for enteric coated tablets is 2hrs. 6. Dissolution test : A single tablet is placed in a small wire mesh basket and immersed in the dissolution medium contained in a 1000 ml flask at 37 0.5 C., rotated as specified. Limit : A value of t 90% (i.e. 90% drug release) within 30 minutes is often considered satisfactory.

22. References: 1. Hand book of Preformulation 2. Theory and practice of industrial pharmacy by Lachman & Liberman. 3. product formulation and development by Nirali prakashan.

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