Biowaiver Implementation in Pharmacuetical Industry

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Biowaiver Implementation in Pharmacuetical Industry Miss. Manjusha A.Bhange. Pharmaceutics, Latur., Maharashtra Dr. Bhusnure O.G. Quality Assurance, Latur., Maharashtra Mrs. Giram P.S.

, Maharashtra ABSTRACT: From 1995 2000, biowaivers were limited to the approvals of supplements for scale up and other manufacturing changes of approved drug products.

1 Biowaiver Implementation in Pharmacuetical Industry Miss. Manjusha A.Bhange. Pharmaceutics, Latur., Maharashtra Dr. Bhusnure O.G. Quality Assurance, Latur., Maharashtra Mrs. Giram P.S. Pharmacology, Latur., Maharashtra Miss. Warad Tanuja A. Quality Assurance, Latur., Maharashtra ABSTRACT: From , biowaivers were limited to the approvals of supplements for scale up and other manufacturing changes of approved drug products. The FDA began implementation of the BCS paradigm as a regulatory tool in 1995, when the Guidance for Scale Up and Post Approval Changes (SUPAC) for immediate release (IR) products was issued In August 2000, The FDA issued the BCS guidance and extended the regulatory considerations for granting biowaivers for approval of drug products if the application was for an IR oral drug product containing a BCS class I drug substance. This study compared the in vitro dissolution behavior. It is important to accelerate drug approval and make generics available. A generic manufacturer must conduct clinical bioequivalence testing of the generic product. This is done by comparing it with an innovator product and establishing therapeutic equivalence. These studies can be extremely expensive and time consuming. Biowaiver procedure is a surrogate method of evaluating bioequivalence of generic products Just by belonging to Class I/III and/or fulfilling dissolution criteria does not entitle product eligibility for a biowaiver approval. Key words: Implementation of biowaiver, Bioequivalence, Biopharmaceutics, Guidelines involved, Regulatory application, Future opportunities. INTRODUCTION: Biowaiver means avoiding time consuming and costly pharmacokinetic studies and using in vitro dissolution test as a surrogate test to evaluate the bioequivalence of a test and reference product Advantages. Circumvent expensive and sometimes unethically questionable human testing. Reducing time in bringing product to the market. Reduce product cost. 1 BCS-classification: Biowaiver approval is based on the Biopharmaceutics Classification System (BCS) 54 Miss. Manjusha A.Bhange., Dr. Bhusnure O.G., Mrs. Giram P.S., Miss. Warad Tanuja A.

If the in vivo dissolution of a highly soluble compound is rapid and excipients used in the product do not affect absorption of the API then bioequivalence between the two pharmaceutically equivalent

2 TIMELINE FOR EVOLUTION OF BIOWAIVER GUIDANCES BCS BASED BIOWAIVER SUPAC Guidances BCS based Biowaiver Guidance for Immediate Release Dosage Forms Note for Guidance on the Investigation of

2 If the in vivo dissolution of a highly soluble compound is rapid and excipients used in the product do not affect absorption of the API then bioequivalence between the two pharmaceutically equivalent IR products need not be demonstrated using in vivo studies. 2 TIMELINE FOR EVOLUTION OF BIOWAIVER GUIDANCES BCS BASED BIOWAIVER SUPAC Guidances BCS based Biowaiver Guidance for Immediate Release Dosage Forms Note for Guidance on the Investigation of Bioavailability and Bioequivalence (Variations) Biowaiver Guidance Annex 8 TRS Guideline on Investigation of Bioequivalence Bioavailability and Bioequivalence Studies for Orally Administered Drug Products 2011 General notes on BCS based biowaiver applications (PQP Guidance document) Updates in progress to FDA biowaiver document. 2, 3 BIOWAIVER PROCEDURE: BCS-based solubility: Highly soluble: Dose/Solubility ratio 250mL in aqueous buffers phs (7.5) at 37 ± 1 C Dose is defined differently in different guidances: WHO- highest dose strength mentioned in the EML US FDA maximum dose strength that is marketed EMA- highest single dose that is administered. 3,4 Permeability Highly permeable APIs with a permeability of 85% ( 90%) of the administered dose are defined as highly permeable Primary data (in humans) Absolute bioavailability. Mass balance studies. Intestinal perfusion studies Secondary data. Perfusion studies in animals. In vitro permeability studies using CaCo-2 or MDCK cell lines along with reference substances Miss. Manjusha A.Bhange., Dr. Bhusnure O.G., Mrs. Giram P.S., Miss. Warad Tanuja A.

CRITERIA FOR BIOWAIVERS: a) If the drug product is a parenteral solution intended solely for administration by injection or an ophthalmic or otic solution.

3 CRITERIA FOR BIOWAIVERS: a) If the drug product is a parenteral solution intended solely for administration by injection or an ophthalmic or otic solution. b) If the drug product contains same active and inactive ingredients in the same concentration as a drug product that is the subject of an approved full new drug application. 5, 6 REQUIREMENTS FOR A BIOWAIVER STUDY: a) Dissolution Test in 3 different media which are: Buffer ph 1.2, simulated gastric fluid (SGF) without enzymes or 0.1N HCl Buffer ph 4.5 Buffer ph 6.8 or simulated intestinal fluid (SIF) without enzymes, all in 900 ml and at 37 C b) 12 samples in each media, paddle rotating at 50 rpm or basket at 100 rpm c) Sampling times are 10, 15, 20, 30, 45 and 60 minutes. 6 d) The profiles of the test and reference products must be similar in all three media. e) The products are similar if the similarity factor f2 50 and both products show 85% dissolution in 15 min. 7 DATA TO SUPPORT REQUEST FOR BIOWAIVERS: Quantities of data to support a request for biowaivers have to be submitted. The drug substance for which a waiver is being requested should be highly soluble and highly permeable. Sponsors requesting biowaivers based on the BCS should submit the following information to the Agency for Review by the Office of Clinical Pharmacology and Biopharmaceutics (for NDAs) or Office of Generic Drugs, Division of Bioequivalence (for ANDAs). 7 A. Data Supporting High Solubility The following information should be included in the application: a) Description of test methods including information on analytical method and composition of the buffer solutions. b) Information on chemical structure, molecular weight, nature of the drug substance (acid, base, amphoteric or neutral) and dissociation constants (pka). B. Data Supporting High Permeability The following information should be included in the application: a) For pharmacokinetic studies- information on study design and methods used along with the pharmacokinetic data. b) For direct permeability methods- information supporting the suitability of a selected method that encompasses a description of the study method; criteria for selection of subjects, animals or epithelial cell line; drug concentrations in the donor fluid. 56 Miss. Manjusha A.Bhange., Dr. Bhusnure O.G., Mrs. Giram P.S., Miss. Warad Tanuja A.

4 C. Data supporting rapid and similar dissolution for submission of a biowaiver requesting an immediate release (IR) product should be rapidly dissolving. The following information should be included in the application: a) A brief description of the IR products used for dissolution testing including information on batch or lot number, expiry date, dimensions, strength, and weight. b) Dissolution data obtained with 12 individual units of the test and reference products using recommended test methods. D. Additional Information the manufacturing process used in the production of test product should be described briefly to provide information on the method of manufacture (e.g., wet granulation vs. direct compression). a) List of excipients along with amount used and their intended functions should be provided. In addition, excipients used in the test product should have been used previously in FDA-approved IR solid oral dosage forms. 8,9 BIOWAIVER REGULATORY GUIDANCE IN VARIOUS COUNTRIES: A. United States the US biowaiver guidance is based on the widely known BCS system which is briefly described in (Table 1). Biopharmaceutics classification system (BCS). Class Description 1 High solubility, High permeability 2 Low solubility, High permeability 3 High solubility, Low permeability 4 Low solubility, Low permeability B. European Union Like US, Europe also allows biowaivers for BCS 1 only, whereas, the proposed guidelines permit BCS 1 and 3 biowaivers. 9 THE BIOPHARMACEUTICS CLASSIFICATION SYSTEM: When combined with the dissolution of the drug product, the BCS takes into account three major factors that govern the rate and extent of drug absorption from IR solid oral 48 dosage forms: (1) Dissolution. (2) Solubility. (3) Intestinal permeability. (4) According to the BCS, drug substances are classified as follows: Class 1: High Solubility High Permeability Class 2: Low Solubility High Permeability Class 3: High Solubility Low Permeability Class 4: Low Solubility Low Permeability A. Solubility: The solubility class boundary is based on the highest strength of an IR product that is the subject of a biowaiver request. A drug substance is considered highly soluble when the highest strength is soluble in 250 9, 10 ml or less of aqueous media over the ph range of Miss. Manjusha A.Bhange., Dr. Bhusnure O.G., Mrs. Giram P.S., Miss. Warad Tanuja A.

5 B. Permeability: The permeability class boundary is based indirectly on the extent of absorption (fraction of dose absorbed, not systemic BA) of a drug substance in humans, and directly on measurements of the rate of mass transfer across human intestinal membrane. C. Dissolution: An IR drug product is considered rapidly dissolving when 85 percent or more of the labeled amount of the drug substance dissolves within 30 minutes, using United States Pharmacopeia (USP) Apparatus I at 100 rpm (or Apparatus II at 50 rpm or at 75 rpm when appropriately justified (see 99 section III.C.) 10 RECOMMENDED METHODOLOGY FOR CLASSIFYING A DRUG SUBSTANCE AND FOR DETERMINING THE DISSOLUTION CHARACTERISTICS OF A DRUG PRODUCT The following approaches are recommended for classifying a drug substance and determining the dissolution characteristics of an IR drug product according to the BCS. A. Determining Drug Substance Solubility Class An objective of the BCS approach is to determine the equilibrium solubility of a drug substance under physiological ph conditions. Maximum dose divided by 250 should be greater than or equal to the lowest solubility observed over the entire ph range of 1-6. B. Determining Drug Substance Permeability Class (i) When the absolute BA is 85 percent or more. (ii) When 85 percent or more of the administered drug is excreted unchanged in urine. (iii) When 85 percent or more of the administered drug is recovered in urine as parent and metabolites with evidence indicating stability in the GI tract. 11 C. Determining Drug Product Dissolution Characteristics and Dissolution Profile Similarity: The dissolution testing apparatus used in this evaluation should conform to the requirements in USP (<711> Dissolution). Selection of the dissolution testing apparatus (USP Apparatus I or II) during drug development should be based on a comparison of in vitro dissolution and in vivo PK data available for the product. The USP Apparatus I (basket method) is generally preferred for capsules and products that tend to float, and USP Apparatus II (paddle method) is generally preferred for tablets. 12 f2 = 50 log {[1 + (1/n)Σt=1n (Rt - Tt)2] } BIOWAIVERS BASED ON BCS: For BCS class 1 drug products, the following should be demonstrated: The drug substance is highly soluble. The drug substance is highly permeable. The drug product (test and reference) is rapidly dissolving, and the product does not contain any excipients that will affect the rate or extent of absorption of the drug (see section V.A.) 13 For BCS class 3 drug products, the following should be demonstrated: The drug substance is highly soluble The drug product (test and reference) is very rapidly dissolving Miss. Manjusha A.Bhange., Dr. Bhusnure O.G., Mrs. Giram P.S., Miss. Warad Tanuja A.

6 ADDITIONAL CONSIDERATIONS FOR REQUESTING A BIOWAIVER: When requesting a BCS-based biowaiver for in vivo BA/BE studies for IR solid oral dosage forms, sponsors/applicants should note that the following factors can affect their request or the documentation of their request. A. Excipients (i) BCS class 1 drug products: Excipients can sometimes affect the rate and extent of drug absorption. In general, using excipients that are currently in FDA-approved IR solid oral dosage forms will not affect the rate or extent of absorption of a highly soluble and highly permeable drug substance that is formulated in a rapidly dissolving IR product. 14 (ii) BCS class 3 drug products: This is due to the concern that excipients can have a greater impact on absorption of low permeability drugs. The composition of the test product must be qualitatively the same and should be quantitatively very similar to the reference product. B. Prodrugs: Permeability of prodrugs will generally depend on the mechanism and (anatomical) site of conversion to the drug substance. When the prodrug-to-drug conversion is shown to occur predominantly after intestinal membrane permeation, the permeability of the prodrug should be measured. C. Fixed Dose Combinations: a. If all active components belong to BCS class 1: (i). If there is a PK interaction, the excipients should fulfill the considerations outlined in section V.A. (ii). Otherwise, in vivo bioequivalence testing is required. b. If all components of the combination belong to BCS class 3 or a combination of class 1 and 3. D. Exceptions: 15 REGULATORY APPLICATIONS OF THE BCS A. INDs/NDAs: Evidence demonstrating in vivo BA or information to permit FDA to waive this evidence must be included in NDAs (21 CFR (a). A specific objective of such BA information is to establish in vivo performance of the dosage form used in the clinical studies that provided primary evidence of efficacy and safety B. ANDA: BCS-based biowaivers are appropriate for IR test products that meet the criteria for BCS class 1 or 3 as discussed above, provided that the reference listed drug product also meets those criteria and the 464 test product exhibits similar dissolution profiles to the reference listed drug product (see sections II and III). 16 C. Supplemental NDAs/ANDAs (Post approval Changes): BCS-based biowaivers are appropriate for significant post approval changes (e.g., Level 3 changes in components and composition) to an IR test product that meets the criteria for BCS class 1 or 3 as discussed above, and both pre- and post-change products exhibit similar dissolution profiles (see sections II and III). Develop science-based risk calculations to make the biowaiver decision more Objective: 1) Since biowaiving is a surrogate for the in vivo proof of bioequivalence, accepting the in vitro biowaiver inherently has some risk that the biowaiver decision is not correct i.e., the two products are actually bioequivalent to each other but application of the BCS based biowaiver concludes that they are not bioequivalent. 2) Conversely, the two products are not bioequivalent to each other but application of the BCS based biowaiver concludes that they are bioequivalent with each other Miss. Manjusha A.Bhange., Dr. Bhusnure O.G., Mrs. Giram P.S., Miss. Warad Tanuja A.

7 3) Biowaiving is an in vitro surrogate for the in vivo proof of bioequivalence. In the former case, the applicant is refused a biowaiver based approval and must perform an in vivo assessment of bioequivalence to obtain product approval, costing time and money, and the patient is deprived of the advantages of having more products available. 18 CONCLUSION: BCS is employed to waive in vivo bioequivalence testing (i.e. provide "biowaivers") for new and generic drugs. Granting biowaivers under systems such as the BCS, eliminates unnecessary drug exposures to healthy subjects and provides economic relief, while maintaining the high public health standard for therapeutic equivalence. Using the rationale of BCS, it can be argued that biowaivers can also be granted on the basis of standard pharmacokinetic data. REFERENCES: 1) Kortejarvi H, Urtti A, Yliperttula M. Pharmacokinetic simulation of biowaiver criteria: the effects of gastric emptying, dissolution, absorption and elimination rates. Eur J Pharm Sci. 2007; 30: ) Midha KK, Rawson MJ, Hubbard JW. The bioequivalence of highly variable drugs and drug products. Int J Clin Pharmacol Ther 2005 Oct; 43(10): ) García-Arieta A, Gordon J. Bioequivalence Requirements in the European Union: Critical Discussion. AAPS J 2012; in press. 4) Rolli R. Automation of Dissolution Tests for Biowaiver Studies. Accessed at: 5) Dahan A, Miller JM, Amidon GL. Prediction of solubility and permeability class membership:provisional BCS classification of the world's top oral drugs. AAPS J. 2009; 11: ) Criteria for biowaivers. Accessed at Com/site/upload /site/generateur/williamsrogers.pdf. 7) World Health Organization (WHO) 2006 Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms Accessed on January 10, 2011 at 8) Additional guidance for organizations performing in vivo bioequivalence studies. In: WHO 9) Technical Report Series, No. 937, Annex 9, Geneva; World Health Organization: ) Chandra sekaran AR, Han CY, Chung ACY, Cheang LW, Ping LS. Post market in vitro equivalency evaluation of paracetamol tablets in kedah, Malaysia. Int J Pharm Sci Nanotech, 2011; 4(2): ) Bhide MM and Nitave SA. Comparative in vitro evaluation of commercial Aceclofenac tablets. World J Pharm Pharm Sci, 2014; 3(8): ) Kortejarvi H, Yliperttula M, Dressman JB, Junginger HE, Midha KK, Shah VP, Barends DM Biowaiver monographs for immediate release dosage forms: Ranitidine Hydrochloride. J Pharm Sci 94: ) Rohilla S, Rohilla A, Nanda A. Biowaivers: Criteria and requirements. Int J Pharm Bio Arch, 2012; 3(4): ) Kumar A, Meenakshi N. Case studies In: Marketing management, New Delhi; Vikas Publishing house., 2008; ) Additional guidance for organizations performing in vivo bioequivalence studies. In: WHO Technical Report Series, No. 937, Annex 9, Geneva; World Health Organization: ) Chandrasekaran AR, Han CY, Chung ACY, Cheang LW, Ping LS. Post market in vitro equivalency evaluation of paracetamol tablets in kedah, Malaysia. Int J Pharm Sci Nanotech, 2011; 4(2): ) Bhide MM and Nitave SA. Comparative in vitro evaluation of commercial Aceclofenac tablets. World J Pharm Pharm Sci, 2014; 3(8): ) Sudan Medicine and Poison Law. Khartoum; the Federal Ministry of Health Miss. Manjusha A.Bhange., Dr. Bhusnure O.G., Mrs. Giram P.S., Miss. Warad Tanuja A.

BCS Guidance and Biowaivers BCS Monographs

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