IPC-USP 7th Annual Scientific Meeting February 6 - 7, 2008Hyderabad International Convention Center Hyderabad, India USP’s Verification Programs: Experience to Date Richard Aleman USP Verification Programs Lead Auditor
Pharmexcil MOU Signed February 15, 2007 Purpose: Reinforce the links of understanding and cooperation between PHARMEXCIL and USP Understand the importance of access to good quality, safe and effective medicines, nutraceuticals, dietary supplements, and also other articles such as active and non-active ingredients used in the manufacture of health care products
Pharmexcil MOU, continued Recognize the importance of developing long-term strategies to ensure that medicines of assured quality, safety and efficacy are made available to individuals in the U.S., India, and other countries around the world Advance on the common goal of improving the quality of medicines, API’s, nutraceuticals, dietary supplements and their ingredients Coordinate complementary activities to continue first, second and third party monitoring to facilitate the achievement of that goal
Pharmexcil MOU—Implementation Work Group consisting of an equal number of representatives from both Pharmexcil and USP To evaluate and maintain activities undertaken by both parties related to the MoU objectives To develop annual work plans related to the objectives
MOU Objectives 1. Promote cooperation between the two parties 2. Improve transfer and exchange of information between the parties 3. Increase awareness of the importance of the quality, safety, and efficacy of medicine 4. Establish the basis for a long-term relationship by encouraging members of Pharmexcil to participate in the USP public health programs • USP revision process • USP Verification Programs 5. To develop standards and include to the extent possible the commonly used pharmaceutical raw materials in India under USP resulting in promotion of trade of such products in international markets
USP’s Verification Programs The Marks of Quality Good quality medicines meet official standards for identity, strength, purity, quality, packaging, and labeling.
Look for the USP-Verified Mark on YourDietary SupplementsYour assurance What’s on the label is in the bottle. The supplement does not contain harmful levels of contaminants. The supplement will break down properly to allow ingredients to dissolve in your body. The supplement has been made under safe, sanitary, manufacturing processes.
USP Dietary Supplement ProductVerification Products covered by this program Vitamin supplements Mineral supplements Amino Acid supplements Botanicals Non-botanical dietary supplements covered by DSHEA and legally marketed in the U.S. (e.g. fish oil, chondroitin sulfate sodium, glucosamine, etc.)
Rigorous Dietary Supplement VerificationProcess Participating companies go through many 1. Guidelines 2. Audit of from USP manufacturing months of Expert sites for GMP Committees compliance rigorous tests and reviews 3. Review of 6. Continuous documentation to meet USP’s off-the-shelf manufacturing, tests of QA, QC high standards products using the mark and earn the 5. Review of 4. Laboratory USP-Verified mark. conformance testing of with mark product usage samples guidelines
Off-the-shelf Testing USP will continuously test and examine selected lots and marketplace samples of approved products to ensure that The mark is being used in accordance with guidelines The product continues to meet the criteria to carry the mark The product has not been reformulated There have been no major changes in the manufacturing process, specifications, test methods, or any other critical quality parameters
Dietary Supplement Findings:1. Update specifications for raw materials and finished products to comply with USP-NF specification, where applicable.2. Reformulate and/or to introduce overages to formulation for ingredients to provide 100% of label claim throughout the shelf life of the product.3. Make numerous changes to the product labels. Some of these changes were made to ensure an accurate list of ingredient claims, corrections to the recommended daily intake, additional reference to chemical salt and sources, the addition of Latin binomial and plant part used for botanicals, etc…4. Establish proper stability study protocols, and subject their products to the studies to justify and/or determine appropriate expiration dating.5. Remove quantitative ingredient claims where no validated analytical method is available to support such claims. Additionally, have PC change quantitative ingredient claims to support the minimum requirement of meeting 100% of label claim.
List of Corrective Actions Imposed onParticipating Companies in DSVP – cont.6. Establish a standardized method of reporting analytical test results for products in units and percentages of label claim and clearly indicate units in the reporting form.7. Identify ingredients by more specific entity/marker compound(s) for proper identification and quantification of ingredients on label claim.8. Reformulate product which fails to comply with performance characteristics.9 . Remove ingredient claims that have not been approved by the USP-DSVP Executive Committee.10. Have appropriate validation for all method(s) used for quantification of ingredient claim(s) and use reference standard that are suitable for intended use and incorporate purity in calculation to provide accurate test results.
USP Dietary Ingredient Verification Voluntary participation by ingredient manufacturers Verification of ingredients manufactured and marketed to the dietary supplement industry in the U.S. and worldwide Procedures: same as DSVPIngredients covered by this program Vitamins Minerals Amino acids Powdered botanicals and botanical extracts Other non-botanical dietary ingredients legally marketed under DSHEA (e.g. fish oil, chondroitin sulfate sodium, glucosamine, etc)
Findings Lack of Personnel Training activities Lack of Equipment Cleaning validation procedures Lack of Validation of suppliers of raw materials Lack of validation of analytical methods Lack of analytical instrument calibration procedures
Natural Products Association: NewOpportunities to Assure IngredientSupplement Natural Products Association (NPA) , Washington DC representing hundreds of dietary supplements manufacturers signed a Memorandum of Agreement with USP in July 2007. Raw materials from China shipped to US customers will be analyzed at the USP China Lab in Shanghai and certificates of analysis provided to the NPA. This arrangement will minimize rejection rate of raw materials imported into the US.
Proposed new programs: Drug Substanceand Excipient Verification and Qualification
“Verification” and “Qualification”Defined“Verification” A procedure used to provide written assurance that a product, process, service or person’s qualifications conforms to specified requirements. USP Verification services will be sold to suppliers of drug substances and excipients.“Qualification” A Good Manufacturing Practices (GMP) concept required of dosage form manufacturers to assure the quality of materials received from suppliers. USP Qualification services will be sold to users of drug substances and excipients in the manufacture of drug products.
Four New USP Services to be OfferedWorldwideFor suppliers (ingredient manufacturers and distributors) 1. Drug substance verification 2. Excipient verificationFor users (dosage form manufacturer or other purchasers) 3. Drug substance qualification 4. Excipient qualification All four are applicable to drug substances and excipients currently used in pharmaceutical dosage forms. Participation in any program is voluntary.
What USP Will do to Verify or QualifyItems? AUDIT the manufacturing site REVIEW chemistry, manufacturing, and controls (CMC) documentation TEST samples for compliance with USP-NF monograph or, if no monograph exists, the manufacturer’s own analytical procedures REVIEW the manufacturer’s post-verification/qualification notification of changes RE-TEST items periodically after they first pass the initial verification/qualification lab testing RE-EVALUATE each article at least every third year USP will examine records and perform tests on drug substances and excipients to assure they are properly manufactured and they meet USP’s high standards for quality.
Pharmaceutical and ExcipientVerification Programs Drug substances Excipients Collaborate with Regulatory Authorities and other organizations Program should be helpful to: Suppliers Users (dosage form manufacturers) Regulatory Authorities Public Program is voluntary Global launch
Audit Criteria ICH Q7 Guideline Good Manufacturing Practices for Active Pharmaceutical Ingredients International Pharmaceutical Excipient Council/Pharmaceutical Quality Group GMP Guide for Pharmaceutical Excipients USP General Chapter <1078> Good Manufacturing Practices for Bulk Pharmaceutical Excipients
USP Mark and Certificate For articles meeting the USP drug substance or excipient verification requirements, the manufacturer may Display the USP Verified mark on containers Show customers a USP Verified certificate For suppliers meeting the USP qualification requirements for an article, USP will provide A report and a certificate indicating USP has qualified the supplier for that article
Audit Findings for APIs and Excipients QUALITY SYSTEM The Quality Unit is inadequate in that it does not function as an independent department. For example, the quality unit responsible for the release of finished APIs currently reported to the manager in charge of production. Review of several Batch Production Records for the manufacture of API XYZ reveal the lot # failed to meet the water content of finished product specification. The manager in charge of production made the decision to release the lot for commercial distribution despite the objections from Quality Control. The firm does not have a sufficient number of personnel to conduct finished API testing in a timely manner. For example, several lots of finished APIs testing were not fully completed and released prior to commercial distribution. There are an insufficient number of QA inspectors, or QA engineers to cover the quantity of products manufactured. For example, the firm manufactures over 200 bulk APIs, but only has five QA inspectors.
Audit Findings for APIs and Excipients FACILITIES AND EQUIPMENT STSTEM FACILITIES The firm does not a written SOP regarding the general cleaning and maintenance of the building facilities utilized in the manufacture of APIs. For example, the warehouse storage facilities for both raw materials and finished APIs was noted to be crowded with the accumulation of debris which could serve as rodent/insect harborage areas and prohibited audit in several area of the warehouse. The design of the building is inadequate in that it does not allow for the flow of materials and personnel without creating a potential cross contamination problem. For example, the manufacture of API XYZ is being conducted in a manufacturing suit located in the middle of the building with the raw material storage area located in the adjacent room. This situation requires that upon the receipt of raw materials, that they be transported prior to release, through the manufacturing suit creating a potential for cross contamination.
Audit Findings for APIs and Excipients The firm does not have a written SOP describing the use of rodenticides, fungicides, insecticides, cleaning and sanitizing agents for the facility. Utilities such as steam, gas, compressed air, heating, ventilation, and the air conditioning (HAVAC) system used in the manufacture of APIs have not been qualified (IQ, OQ).
Audit Findings for APIs and Excipients PROCESS EQUIPMENT Installation Qualification (IQ), Operational Qualification (OQ), and Performance Qualification (PQ), has not been conducted on critical process equipment used in the manufacture of APIs. Equipment surfaces used in the manufacture of APIs have not been tested to ensure that they are not reactive, additive, or adsorptive. Piped raw materials used in the manufacture of APIs were not identified as to flow direction and content.
Audit Findings for APIs and Excipients MATERIALS SYSTEM The firm does not have separate areas identified as quarantined, in process, and released for the storage of incoming raw materials. For example, different lots of raw materials are not identified as quarantined, in process, and released all stored next to each other commingled. The firm’s does not have a separate room for the sampling of incoming raw materials. Raw materials are sample in the opened warehouse, which could pose a cross contamination concern.
Audit Findings for APIs and Excipients The firm’s Inventory Materials Management Computerized System has not been validated nor qualified. A challenge of the materials computerized system revealed that it is not always accurate. For example, a review of the computer system for Lot XYZ of an API, stored in warehouse slot # 135 revealed that there were 150 containers, 25 lbs. per container. A physical count of the contents in slot # 135 revealed that there were 300 containers. This discrepancy was investigated and determined to have been caused by human error.
Audit Findings for APIs and Excipients PRODUCTION SYSTEM Review of Master Manufacturing instructions for the five of seven APIs manufactured by the firm revealed that they were not approved by the Quality Unit. For example, the firm’s production manager stated that the company manufactures too many products and that review of master instructions by the quality unit was taking too much time to approve. The president of the firm and the production manager simply decided to remove the quality unit from the approval process. Review of completed batch production and control records revealed that for the past nine months, production has been approving the batch records for final commercial distribution and not the quality unit.
Audit Findings for APIs and Excipients PACKAGING AND LABELING SYSTEM Bulk product packaging room was not identified as to status e.g., in use, to be cleaned, etc. During the audit of the product label cage, the auditor observed in some cases, approved rolls of product labels without the approved green sticker per SOP #000, Label and Product Box Receipt. Weigh scale used during the filling operations of bulk API was observed not to have a calibration sticker, and no written documentation was provided to confirm that it had been previously calibrated. The API Certificate of Analysis, for each finished lot of API, does not list the date of manufacture nor the expiration date.
Audit Findings for APIs and Excipients LABORATORY CONTROL SYSTEM No sample logbook is maintained by, the QC laboratory which shows the sample number, date of receipt, status of testing, initial of person who obtains the sample and tests the sample, completion date, and number of samples received by the laboratory. Review of the laboratory’s sub sampling practice regarding finished products was noted to, be accomplished, without the benefit of formal documentation. Discussion with the laboratory technician performing this sub sampling revealed that she was merely taking approximation of samples without specific measurements, and without a formal Standard Operating Procedure. Audit of the Laboratory’s refrigerator used to store standards and reagents, revealed the storage of standards and reagents passed their expiration dates or without expiry dates and use before date.
Summary Pharmexcil MOU and USP’s ‘third party certification programs’ create opportunity to promote Indian exports of: Dietary Supplements (AYUSH Medicines) Dietary Ingredients APIs Excipients USP’s certification efforts are valuable to sponsors directly—support improvements in advance of stringent regulatory inspections The joint manufacturer-USP activities also support USP’s public monographs and reference materials, which in turn also support manufacturers The certification will benefit from regulatory recognition—USP is working on this but for now has no regulatory recognition for its third party programs.
IPC-USP 7th Annual Scientific Meeting February 6 - 7, 2008 Hyderabad International Convention Center Hyderabad, IndiaPerformance Verification Testing William F. Koch, Ph.D. Chief Reference Materials Officer
Drug Product Performance Formulation performance is defined as the release of the drug substance from the drug product leading to bioavailability of the drug substance and eventually leading to one or more pharmacologic effects, both desirable and undesirable. Dale Conner, PharmD, FDA/OGD, 2004
Rate Process in Drug BioavailabilityBioavailability is the rate and extent to which the activeingredient or active moiety is absorbed from the drugproduct and becomes available at the site of actionHence, the rate of Dissolution is related to Bioavailability.
Drug Product Attributes:Quality and Performance Product quality, as measured by: Chemistry, manufacturing and controls (CMC) Microbiology Identity, strength, quality, purity and potency of drug product Product performance, as indicated by: Drug dissolution (for many dosage forms)
Goals of Dissolution Testing Prediction of bioavailability, the surrogate- parameter of therapeutic efficacy Evaluation of the drug product’s robustness, as a parameter of the drug product-related safety Evaluation of critical manufacturing variables Evaluation of uniformity and stability Manufacturing Storage
Classification of Pharmaceutical DosageForms Three-Tier System Delivery Route Dosage Form Release Category
Pharmaceutical Dosage Form Taxonomy First Tier: classification by route of delivery oral dosage forms topical/transdermal parenterals (by injection) mucosal or other membranes Inhalation Second Tier: classification by physical state solid liquid gaseous Mixed Third Tier: classification by release pattern conventional modified
First Tier of Pharmaceutical Dosage FormsFIRST TIER CATEGORY: DELIVERY ROUTE - based on region of the body to which active delivered Gastro-intestinal Tract Mucosal Membranes Lungs Body Tissues or Fluids Skin surface IV [by injection] IM etc SC nasal otic vaginal trans- dermal dermal oral rectal ophth- urethral topical almic oro- phary ngeal SECOND TIER CATEGORY: DOSAGE FORM [i.e. based on the general type of dosage form]
Tiers 2 & 3 of Mucosal Dosage Forms Mucosal Membranes oro- rectal pharyngeal SECOND TIER CATEGORY DOSAGE FORM [i.e. based on the general type of dosage form] solids semi-solids solids liquids liquids powders gels suppositories solutions pastes suspensions gums semi-solids tablets chewable tablets solutionsTHIRD TIER CATEGORY TYPE OF RELEASE [i.e. based on the RELEASE PATTERN OF THE ACTIVE]
Tiers 2 & 3 of Oral Dosage Forms Oral Dosage FormsSolid oral dosage forms Liquid oral dosage formsImmediate Release Modified Release Extended Release Delayed Release
Compendial Use of the Dissolution Test The Dissolution Test provides the compendial correlation to Drug Product Performance for the following dosage forms: Solid oral dosage forms Topical, dermals Mucosal Injectables – parenterals
USP Chapters <711>, <724>USP apparati Apparatus 1 (basket) Apparatus 2 (paddle) solid oral dosage forms Apparatus 3 (reciprocating cylinder) various dosage forms Apparatus 4 (flow-through cell) Apparatus 5 (paddle over disk) Apparatus 6 (cylinder) topical dosage forms Apparatus 7 (reciprocating holder)
Critical Elements of Dissolution Testing Relevant influenced by the design of Predictive the method, procedure, and Discriminating dissolution equipment Reproducible influenced also by the performance of the Transferable dissolution equipment and Rugged execution of the procedure Hence, there is a need for verification of the performance of the entire system
USP Performance Verification Tests USP General Chapter <711> Dissolution Apparatus 1 and 2 • Disintegrating Tablets for USP Dissolution Performance Verification Test: Prednisone RS Tablets, lot P0E203 • USP Dissolution Calibrator, Non-disintegrating Type: Salicylic Acid Tablets RS, lot Q0D200 Apparatus 3 • USP Drug Release Calibrator for Apparatus 3: USP Chlorpheniramine Maleate Extended Release Tablets RS lot G0B259 Apparatus 4 • to come Apparatus 5, 6 and 7 • to be specified
Dissolution Test Variability – Apparatus 2Maria Glasgow et al.: The USP Performance Verification Test Part II:Collaborative Study of USP’s Lot P Prednisone Tablets, Pharm. Res. 2007
Dissolution Test - Causes Of Variability The drug product under investigation Dissolution equipment, apparatus and assembly Environmental conditions Dissolution procedure Analytical method and procedure Analyst
Experimental Variables Contributing to Dissolution Variance Statistical Analysis Summary for Apparatus 2 95% CV% Residual as GeometricAssembly Confidence Between Between Between Residual Total % of Total Mean Limits Analyst Position Experiment Variance Alpha 58.7 (51.1–67.4) 6.6% 11.1% 1.6% 11.8% 17.7% 45.0% Beta 48.4 (46.5–50.3) 0.0% 3.7% 1.0% 11.6% 12.3% 90.3%Gamma 44.9 (41.4–48.6) 6.3% 1.0% 0.7% 4.3% 7.8% 30.8% Delta 48.0 (43.2–53.3) 6.2% 2.3% 2.3% 8.1% 10.7% 57.4%Epsilon 46.9 (43.0–51.0) 5.4% 3.9% 0.3% 8.7% 11.0% 63.2%Gang D, et. al.: The USP Performance Verification Test Part I: USP Lot P PrednisoneTablets – Quality Attributes and Experimental Variables Contributing toDissolution Variance, Pharm. Res. 2007
Variability of Different Assemblies Individual results obtained with Apparatus 2 on two different assemblies Apparatus 2 - Assembly Alpha Apparatus 2 - Assembly Gamma 85 85 80 80Prednisone Dissolved Percent (%) Prednisone Dissolved Percent (%) 75 75 70 70 65 65 60 60 55 55 50 50 45 45 40 40 35 Min Max 35 30 Mean Min 30 Max 25 Mean 25 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 0 1 2 3 4 5 6 7 8 9 10111213141516171819202122232425262728293031 Experiment # Experiment #Gang D, et. al.: The USP Performance Verification Test Part I: USP Lot P PrednisoneTablets – Quality Attributes and Experimental Variables Contributing toDissolution Variance, Pharm. Res. 2007
Variability due to Dissolution VesselsMark Liddell et al.: Dissolution Testing Variability: Effect of Using Vesselsfrom Different Commercial Sources, American Pharm. Review, Vol. 10(6)Sept./Oct. 2007
USP Research on other Sources ofVariability in Dissolution Testing Dissolved gases (e.g. oxygen) published in Dissolution Technologies 13(3), 2006 Geometry of the dissolution vessels published in Dissolution Technologies 14(1), 2007 Stirring rate published in Dissolution Technologies 14(1), 2007
USP Research on Sources of Variability inDissolution Testing - Conclusions Based on USP research, data and statistical analysis, it is the USP position that: the variability due to the Prednisone Tablets contributes no more than 5% to the total variability the suitability of the Prednisone Tablets RS for the Performance Verification Test (PVT) for the Apparatus 2 (paddle) has been demonstrated
Draft FDA Guidance issued October 2007 The Use of Mechanical Calibration of Dissolution Apparatus 1 and 2 - Current Good Manufacturing Practice (CGMP) The draft Guidance argues that only mechanical calibration without PVT is needed http://www.fda.gov/cder/guidance/7232dft.htm
USP Response to Draft FDA GuidanceUSP maintains that: Both PVT and mechanical calibration are critical to the dissolution procedure, and Mechanical calibration alone cannot ensure the validity of dissolution results.USP emphasizes: That mechanical calibration is a necessary but not sufficient means of ensuring consistency and comparability of measurements obtained with a dissolution test system. The importance of a periodic performance verification test (PVT) together with careful mechanical calibration to ensure that the combined experimental study yields consistent results.USP acknowledges that: Improvements to the mechanical specifications are required. New approaches to assess drug product performance in vitro are needed.
Current Activities at USP:Oral Dosage Forms Investigations on the influence of vibration on the PVT results Revision of the General Chapter <711> regarding the specifications of some instrument parameters Manufacturing and evaluating a new batch of Prednisone Tablets RS
Future Research Directions at USP Investigate the “ideal” Reference Standard for oral dosage form PVTs Develop Performance Verification Tests (PVT) and Reference Standards for other dosage forms and apparati. Topical/transdermal Parenterals (by injection) Mucosal or other membranes Inhalation Investigate new approaches to assess drug product performance in vitro
Excipients – FunctionalitySpecifications andMonographsS D JoagHon Gen Secretary, IPADirector, Dr. M K Rangnekar Lab,Mumbai7th February 2008AtUSP 7th Annual Meeting, Hyderabad
ExcipientsPharmaceutical excipients aresubstances other than API/APIs, orprodrug that are included in a finishedpharmaceutical dosage form [IPEC]Originex·cip·i·ent (k-sp-nt) : NounAn inert substance used as a diluent or vehicle for a drug.[Latin excipins, excipient-, present participle ofexcipere, to take out, exclude; see except.]
Excipients Excipients are used in virtually all drug dosage forms. They are essential to product performance.
ExcipientsProduct performance and functionality ofexcipient are two sides of the same coin andare inter-dependableRight choice of the excipient/s makes theproduct stable, safe and effective andmakes it superior than other productsThus the formulation of excipients in manycases is considered a trade secret
Some of the known FunctionalCatagories of ExcipientsDiluent / FillerLubricantSurfactant (Emulsifying, Wetting and SolubilisingAgent )BinderColorantsSuspending / Viscosity increasing AgentsSweetening AgentsGlidant and or Anticaking AgentsCoating Agents
Some of the known Functionalpurposes of ExcipientsVehicle – Pharmaceutical WaterTonicity AgentPlasticizersSuppository BaseOintment BaseBufferDisintegrationFlavorsPreservativesAnti-oxidants
ProcessesFrom very simple to complex e.g. Talc: mining -- drying -- milling Sugarcane -- Refined sugar Sorbitol -- Maize -- 20 steps -- Sorbitol Bones -- Gelatin (Animal Based) Tallow oils -- glycerin and fatty acids
ExcipientsA very diverse collection of materialsAbout 1200 ingredients are in use currentlyin marketed pharmaceutical products asexcipients excluding colors and flavorsAbout 250 documented in the EuropeanPharmacopoeiaNow 60 monographs in the internationalharmonization process, USP, JP and Ph Eur
Excipients Successful manufacture of robust product requires well-defined excipients and processes. Pharmacopoeial Monographs: 14 out of 40 functional categories identified in USP 30 - NF 25 EP (EDQM) plans to list specific functionality related characteristics in some of its excipient monographs
USP General Chapters usefulfor formulators for consistentexcipient performance <616>Bulk and Tapped density <695> Crystallanity <699> Density of solids <731> Loss on Drying <786> Particle size distribution- sieving <846> Specific surface area <911> Viscosity
Pharma use ofExcipients Contrary to APIs, excipients are not specifically made for use in medicinal products e, g. Cellulose Propellants Sugar Glycerin Starch Colors Flavors
Types of Excipients Excipients also in use as API: usually one pharma grade is made e.g. Di-calcium Phosphate, Calcium Carbonate Excipients developed and manufactured specifically for pharma use: special grade or grades
Excipient gradeconsiderations Material should be fit for its intended use Food grade material usually acceptable for (oral) pharma use, however consider : functionality, interactions, stability issues due to inconsistency in quality Special grades needed for parenterals, inhalation and speciality products
Impurities inExcipientsIssues with Excipient/s Source Quantity in formulation Purity / Grade Interactions with other excipient/s Degradation during shelf-life of the product
Impurities inExcipients General impurities related to starting materials manufacturing processing aids Contaminants – storage, packing, To be controlled by GMP
Impurities inExcipients Definition of the material: single or multiple component substance Related substances from the starting materials, the process or instability Additives, components added intentionally
PharmacopoeialExcipients Monograph in general sufficient to distinguish technical grades from pharma Monograph represents acceptance criteria for general use Debate on functionality related characteristics on going 14 high-priority functional categories have been identified in USP 30 – NF 25
PharmacopoeialExcipients, issues Genotoxic impurities Heavy metals (residues of catalysts) Heavy metals test not satisfactory Mycotoxins
Some examples Inorganic impurities Heavy metals in minerals Hydrogenated fats Gelatin, Acacia, Stearates Polymers Liquids (containers)
Non pharmacopoeialexcipients Well known substances: reference to literature Novel excipients: Stringent Regulatory requirements for approval follow ICH guidance as for API but look for quality, safety and functionality
Some examples Inorganic impurities sulfites processing aid starches and refined sugars radioactive nuclides
Some examples Organic impurities proteins e.g. gluten, prion, protein additives e.g. Silicon dioxide BHT/BHA Tocopherol Hydrogen peroxide
Some examples Organic impurities: monomers and processing aids in polymers, special instructions on ethylene oxide residues residual solvents pesticides
Some examples Organic impurities microbial contamination mycotoxins residues from antimicrobial treatment
Conclusions Definition of substance composition, very important Knowledge of origin and main use of the Excipient Apply general ICH guidance philosophy for novel materials Strictly adhere to monograph specifications Devise additional functionality tests and specifications as in-house
Questions to be asked What is excipient? A Commodity, a very special product, main use in the world, grades available? Who is the provider? A manufacturer, a distributor, a trader, a broker...? Is the provider a specialist in the pharma world?
SecurityWhat are the credentials of the provider?What kind of quality system is in place?What is the capacity to provide stablequality in the amounts necessary
OpenessIs the provider open to discuss - underconfidentiality agreementparticulars of the ingredient,the manufacturing processIs the provider open to audit?Is the provider interested inco-development of improved qualitybetter performing ingredients ?
IPC-USP 7th Annual Scientific Meeting - India Functionality Testing and Characterization of Excipients Helps Build Quality into the Drug Product Dr. Ashok Katdare, Ph.D.Vice-Chair, Excipients Monograph I Expert Committee
Outline What is Quality? Cornerstones of FDA’s Pharmaceutical GMP initiative for the 21st century ICH Q8, Q9 and Q10 Quality by Design (QbD) QbD considerations for excipients Excipient selection and control Excipient functionality Case studies Questions and Answers
What is Quality? Compliance with specifications Active Ingredient Excipients Drug Product Packaging components Predictable and consistent Robust process-ability and yield Reproducible functionality and utility Sum total larger than addition of individual parts
The desired state: A mutual goal ofindustry and the regulators A maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high quality drug products without extensive regulatory oversight Manufacturers understand their products well in terms of critical product and process parameters and quality attributes Manufacturers strive for continuous improvement No manufacturing supplements are needed Patients are assured access to high quality, high performing drug products
How to achieve the desired state? Three key concepts Quality by Design (QbD) and the design space concept (ICH Q8) Quality risk management (ICH Q9) Robust quality systems (ICH Q10)
ICH Q8 – first element of the road-map Why adopt ICH Q8 Quality can not be tested into a product, it has to be designed and built into it from the initial concept through to all elements of production • Without QbD industry could be validating processes without understanding • Without QbD there is no way to know if the process is changing • Industry could be wasting precious resources (time and money)
Advantages of adopting ICH Q8 Product quality and performance achieved predictably and assured by design of effective and efficient manufacturing processes Product and component specifications based on mechanistic understanding of formulation and how manufacturing unit operations are impacted An ability to practice continual improvement and ‘real time’ assurance of quality
Quality by design (QbD) QbD is a key component of the FDA’s Pharmaceutical GMP initiative for the 21st century Quality should be built by design and not simply tested in final product Rather than fixed process parameters and stability data, developers can demonstrate broader understanding of the formula and process to support design space, specifications and controls demonstrating robustness
Quality by Design QbD (cont) Manufacturing within the design space relieves the manufacturer of filing post- approval changes Tools include design of experiments (DOE), miniaturization, use of process analytic technologies (PAT), robust quality systems to establish design space and control systems QbD is not necessarily a new concept, what is new is its utility in the regulatory arena i.e. granting regulatory flexibility and relief allowing enhanced efficiency, cost benefits and ability to respond to short term market needs
What’s an excipient? Pharmaceutical excipients are any substance other than the active drug product which has been appropriately evaluated for safety and is included in a drug delivery system to either aid processing of the system during manufacture or protect, support or enhance stability, bioavailability, or patient acceptability or assist in product identification or enhance any other attribute of the overall safety and effectiveness of the drug product during storage and use.
What’s the origin of excipients? Mining of minerals Vegetation, plants and crops Chemical synthesis Formulated products Biotechnology Animal by-products Only a small percentage finds use in pharmaceuticals Quality and level of control can differ from lot-to-lot supplier-to-supplier
QbD considerations for excipients What is critical to functioning of the drug product? What are the critical process parameters? What variances can be tolerated by the process, still ensuring predictable, high quality, reproducible product? Will the excipient specs ensure product performance with desired quality attributes? What specification ranges can the process tolerate and still produce product with desired critical performance attributes?
Application of QbD to excipients Increased understanding of formula and process desire for greater understanding of excipients Science and risk-based approach Focus on meaningful tests • Tests that provide knowledge and improved understanding of impact on formula, process and product • Meaningful specifications Design space and QbD does not mean tightening of specification
Excipients - basic understanding Excipients come from variety of sources is acknowledged Normal variability from batch-to-batch is recognized and accepted Understanding of the ‘normal’ variability and its potential impact on processes through meaningful tests is achieved Formulators and engineers need to work with this variability, rather than against it Excipient manufacturers should engage in science and risk-based concepts
Excipient selection - considerations Excipient compatibility testing allows to determine the level of interaction between a given active pharmaceutical ingredient (API) and a selection of excipients Intent is to proactively eliminate or minimize risk(s) in selection of a formula for the drug product as early as possible in the process of new drug delivery system development
Excipient selection and control Selection is based upon following considerations: What functionality is required Desired Drug delivery system Physical, chemical and biopharmaceutical attributes of API Physical, chemical attributes of excipients Design and Control Manage normal variability Understand interactions and their impact on key processing unit operations, critical process parameters and critical product attributes
What is excipient functionality? A desirable property of a material (excipient) that improves manufacturability, quality and performance of the drug product. Most excipients impart different types of functionality depending on their use in a particular product and dosage form Functionality related characteristics (FRCs) cannot be defined by ‘type’ or ‘use’ of an excipient
Examples of functional mechanisms Diluents impart desirable manufacturing properties (like powder flow, compaction strength, mitigation of overlubrication tendency etc) or performance attributes (like disintegration, dissolution) Lubricants (boundary type) adhere to solid surfaces, reduce particle-particle or particle-metal friction where as fluid- film lubricants melt under pressure creating a thin film around particles reducing friction Surfactants reduce interfacial tension through a variety of mechanisms allowing emulsification, and wetting pH modifying agents adjust and maintain pH during processing or shelf-life
Examples of functionality relatedcharacteristics (FRCs) Particle shape, size and size distribution Crystallinity Moisture content Specific surface area Powder flow Compaction properties Viscosity Molecular weight, weight distribution Rheological behavior
USP general chapters relevant to FRCs Crystallinity <695> Crystallinity determination by solution calorimetry <696> Particle size distribution by analytical sieving <786>; light diffraction measurement <429> Specific surface area <846> Powder low <1174> pH <791> Saponification and acid value <401> Gel strength for gelatin <1081>
Context of excipient functionality Excipient functionality can only be assessed in the context of a particular formulation and manufacturing process It depends on the following Active ingredient properties Manufacturing process Function it serves (relative to other excipients) and trade-offs Intended use (dosage form) and patient population Many other factors
Relevance of compendial compliance Compendial monographs primarily focus on purity and safety Mainly chemical with a few physical tests Functionality related characteristics (FRCs) in USP and Pharm Eur Physical testing can be useful but provides insufficient guarantee of functionalities And then there are excipients with multiple functionalities
Variable Raw Material + Fixed Process =Variable Product on Raw Materials Process Process Control
Variable raw material + (anti) variableprocess = constant process Raw Materials Process Process Control
Case Studies Lactose anhydrous Magnesium stearate Microcrystalline cellulose Lactose hydrousGelatin in lyophilized dosage form
Case study 1 Formula 26% active ingredient (highly soluble) 40% microcrystalline cellulose 32.5% Lactose anhydrous 1% superdisintegrant 0.5% Magnesium stearate Manufacturing process Direct compressible powder mixture followed by tabletting
Design space Anhydrous lactose was identified as a critical excipient with respect to flow of drymix Note that it is added to the formulation to improve flow of the drymix (containing API) Scope also included comparison of lots from two main suppliers Flowability of drymix was determined to be the critical process parameter for evaluation
Physical characterization of 7 lots ofanhydrous lactose from 2 differentsuppliers
Comparison of sieve fractions of selectedlots of anhydrous lactose
Assessment of anhydrous lactosevariability on dry mix Rate of flow Lot 1 Lot 2 Lot 3 of lactose anhydrous In seconds 13 34 76 (bulk API alone was 150 sec) Rate of flow Dry mix 1 Dry mix 2 Dry mix 3 of dry mix (with API) In seconds 24 27 26
Summary conclusions The API, by itself. Exhibited poor flow As expected, significant variability was noted among lots and between suppliers Excipient levels were selected to circumvent poor flow of drug Despite lot-to-lot variability (of almost 6 fold), very little effect was noted on flow of drymix Formula was determined to be robust with respect to Composition Normal variability of a key excipient
Design space Magnesium stearate is identified as a key component of the formula because of its potential adverse impact on dissolution Level in formula was already optimized Specific surface area (2X range) Lubrication time (2X range) Effect on dissolution rate was assessed
Assessment of lubrication parameters Specific % Dissolved % Dissolved % Dissolved surface area 10 minutes 20 minutes 30 minutes and mixing times 4.9 m2/gm 98 98 98 5 minutes 10.3 m2/gm 95 95 95 5 minutes 10.3m2/gm 93 93 94 10 minutes
Summary conclusion Formula was shown to be robust with respect to 2X range in specific surface area 2X range in lubrication time Dissolution profile remained acceptable despite stressing ‘the system’ to limits
Design space Impact of increase in breaking strength of tablet was assessed. Hardness of the tablet was varied 3X (10-30 Kps) Dissolution profiles were evaluated
Overall summary conclusions for Case 1 Formula is robust Design space includes a rather broad range Variability in excipients (broad specs justified) Alternate suppliers Lubrication time Hardness Critical process parameters are insensitive to normal variability in key excipients (within the design space studied) Manufacturing process is rugged
Case study 2 Formula 33.3% active ingredient (moderately soluble) 35% Microcrystalline cellulose 17% Lactose hydrous dense 14% Pregelatinized starch 0.7% Magnesium stearate Manufacturing process Directly compressible powder mix followed by tabletting
Design space Identification of key components Lactose from the perspective of flow and sticking Microcrystalline cellulose from the perspective of flow Impact of using different grades was evaluated Formula composition was arrived at from a formal statistical design of experiments
Comparison of several lots of hydrousdense lactose from 2 different suppliers
Design space As expected, wide variations in lot-to-lot flow properties were noted Lots covering a range of 8X were evaluated Differences in control of physical characteristics were noted Impact on flow of drymix was evaluated since a good flow is essential to tablet production for direct compression processes Karr indices were evaluated as a potential surrogate
Effect of normal variability of Fast-Flolactose on drymix properties
Summary conclusion Despite selecting lots of lactose covering a range of 8X with respect to flow properties, the drymixes behaved indistinguishably It can be concluded that The optimized formula is robust and can easily accommodate normal lot-to-lot variability in Fast-Flo lactose
Design space Once the formula was proven to be robust with respect to normal variability of lactose, impact of different grades (suppliers) was assessed In addition to drymix characterization, tablet properties were also evaluated
Substitution of Fast-Flo with hydrousdense lactose
Summary conclusion Despite some differences in performance, different grades of lactose (from two different suppliers) were established to be acceptable Fast-Flo lactose, as expected, exhibited better compressibility and friability A less expensive grade (hydrous dense) allowed achieving cost-optimization goals
Design space Microcrystalline cellulose is commercially available in several grades Avicel PH200 was customized to have better flow (essential for direct compression mixes) Two different grades (Avicel PH200 and PH102) were evaluated for interchangeability Flow properties of drymix as well as tablet properties were evaluated
Effect of varying grade of microcrystallinecellulose on power mix and tablets
Summary conclusion The formula is robust to allow use of different grades of microcrystalline lactose Processing characteristics (drymix evaluation) as well as tabletting properties easily met critical desirable attributes Interchangeability of grades is possible Paved the way for switching to a less expensive and more widely available grade
Summary Idea of Quality by Design (QbD) is not entirely new FDA’s new initiative provides a basis and framework to create a ‘win-win’ situation for both industry and regulatory authorities Regulatory flexibility and relief Better science and understanding Robust formula, rugged processes and high quality drug products Benefits to patients • Predictability of high quality supply
Summary (cont) Functionality of excipients exists only in the context of a specific formulation Lot-to-lot variability in excipients is to be fully expected; therefore formulas and processes need to be designed accordingly Product developers must make a good-faith effort in building quality into the product Excipient manufacturers are encouraged to adopt QbD, continuous improvement and quality risk management systems
Drug - Excipient interactions USP ASM 2008 Dr.A.Lakshmi Prasad Senior Manager (Analytical Research) Sun Pharma Advanced Research Co.Ltd Tandalja ,Vadodara. International Convention Center February 7, 2008 1
StabilityExtensive chemical degradation: a substantial loss ofpotencyDegradation products may result in adverse events orbe unsafeInstability may causeUndesired change in performance, i.e.dissolution/bioavailabilitySubstantial changes in physical appearance of thedosage formcausing product failures 2Requirement for approval by regulatory agencies
Factors Affecting Formulation Stability• Drug & Excipient • Formulation • Environment Chemical structure Drug : excipient ratio Temperature Impurity profile Processing method Relative humidity Physical form Mixing/milling Packaging Moisture content Powder packing Light Particle size Oxygen Surface area Morphology 3
Chemical DegradationHydrolysis Esters Carboxylic acid esters Amides ImidesDehydrationIsomerization and RacemizationDecarboxylation and eliminationOxidationPhotodegradation 4
Drug-Excipient InteractionExcipients are usually biologically inactive, the same cannot be said froma chemical perspective. Excipients, and any impurities present, canstabilise and/or destabilise drug products.Considerations for the formulation scientist: Chemical structure of the API Type of delivery system required Proposed manufacturing processInitial selection of excipients should be based on: Expert systems; predictive tools Desired delivery characteristics of dosage form knowledge of potential mechanisms of degradation, e.g. Maillard reactionThe objective of drug/excipient compatibility considerations and practicalstudies is to delineate, as quickly as possible, real and possible interactionsbetween potential formulation excipients and the API. This is an importantrisk reduction exercise early in formulation development. 5
Excipient Interactions Reactions of Bisulfate OH SO 3- HO CH2NHCH3 HO CHCH2NHCH3 H HSO3- / SO32- HO HO O O OH OH CH 2 OP CH 2 OP O ONa ONa CH 3 O HO OH CH 3 HO OH CH 3 SO 3- CH 3 CH 3 H CH 3 H HSO 3- F H F HO O 6
Excipient InteractionsReactions of amines with reducing sugars 7
Excipient Interactions Transesterification Reactions O Polyvinyl acetate phthalateH2N COOC2H5 N COOC2H5 O 8
Excipient InteractionsExcipient Moisture Amount of water: High moisture content of poly vinyl pyrrolidone and urea enhances Aspirin hydrolysis. Decreased drug stability for ascorbic acid, dry syrups of cephalexin, powders of cysteine derivatives and urea-linolic acid inclusion complex. Ascorbic acid and silica gel Thiamine hydrochloride tablets : Magnesium stearate and MCC Propantheline bromide : Sodium alluminum gel 10
Excipient MoisturePhysical state of water:Weakly absorbed water: Loose water or surface waterStrongly absorbed water: Excipient having higher adsorption energydecrease water reactivity, decrease in relative hydrolysis rates.Moisture adsorption Equilibrium: Excipient that adsorbs moremoisture adsorbs more strongly, resulting less free water for stronglyadsorbing excipient before it is reaching equilibrium. Relativereactivity is decreased.Hydrated Drugs and excipient: Excipients can form hydrates mayenhance drug degradation by giving up their water of crystallizationduring grinding.Lactose hydrate enhances degradation of 4-Methoxyphenylaminoacetate hydrochloride upon grinding. 11
Excipient MoistureMobility of water molecules :Effect of water mobility on drug stability, spin – latticerelaxation time and spin-spin relaxation time by NMR anddielectric relaxation time by dielectric relaxation spectroscopy.Water mobility in polymer solutions/gels will effect the drugdegradation. Mainly used for polymeric excipients like Polyvinyl pyrrolidone, Gelatin , PEG. 12
Excipient Interactions pH : Surface acidity of excipients contribute to drug degradationEg: Isomerization of vitamin D2 Oxazolam degrades in the presence of MCC may be attributed to carboxylic acid groups on the cellulose surface in addition to effect of water. Melting : Effect of sterate in Aspirin is due to change in melting behavior. Oxidation: Dye excipients enhance oxidation and photodegradation Catalysis : Metal ions used as Pharmaceutical excipients or present as impurities catalyze drug degradation. Triggers oxidation and photodegradation 13
Excipient InteractionsPhysical stabilityCrystallization of amorphous drugs:Nifedipine co precipitated with PVP undergoes partialcrystallization during storage.Oxyphenbutazone converts to anhydrous form with lowersolubility during storage under conditions of high humidityHaloperidone converts to crystalline in presence of HPC,MC,HPMC and PVA.Crystallization of amorphous excipients also occur duringstorage effects the drug release. 14
Drug-Excipient Compatibility TestingIn the typical drug/excipient compatibility testing program,binary (1:1 or customised) powder mixes are prepared bytriturating API with the individual excipients.These powder samples, usually with or without added water andoccasionally compacted or prepared as slurries, are storedunder accelerated conditions (80°/75%RH, 60°C/ambient RH,40°/75%RH) and analysed by stability-indicating methodology,e.g. HPLC.Alternatively, binary samples can be screened using thermalmethods, such as DSC/ITC. No need for stability set-downs;hence cycle times and sample consumption are reduced.However, the data obtained are difficult to interpret and may bemisleading; false positives and negatives are routinelyencountered. 15
Drug-Excipient Compatibility Testing Prototype formulations: The amount of API in the blend can be modified according to the anticipated drug-excipient ratio in the final compression blend. However, the binary mix approach takes time and resources and….it is well known that the chemical compatibility of an API in a binary mixture may differ completely from a multi- component prototype formulation. This is a more complex system to interpret. 16
Drug-Excipient Compatibility TestingDrug-excipient interactions can be studied using both approaches in acomplementary fashion. The first tier approach is to conduct short-term(1-3m) stability studies using generic prototype formulations understressed conditions, with binary systems as diagnostic back-up: Chemical stability measured by chromatographic methods Physical stability measured by microscopic, particle analysis, in vitro dissolution methods, etc. The idea is to diagnose any observed incompatibility from the prototype formulation work then hopefully identify the “culprit” excipients from the binary mix data. Hopefully, a prototype formulation can then be taken forward as a foundation for product development.Can apply statistical models (e.g. 2n factorial design) to determine thechemical interactions in more complex systems such as prototypeformulations, with a view towards establishing which excipients causeincompatibility within a given mixture. 17
Drug-Excipient CompatibilityTesting – More predictive Model Storage of 200 mg drug excipient blends in a closed vials at 50°C with 20 % added water. Study reveals: role of chemical nature of excipient, ratio of drug-excipient blend, pH, role of moisture , temperature, humidity, light. This approach avoids late stage development surprises. 18
Drug CombinationsObjective is to minimise incompatibilities: Degradation pathways of thetwo APIs could be different, so a stabilisation strategy for API #1 coulddestabilise API #2.In this situation, first intent strategy could be to prepare, separatecompression blends of each individual API and compress as a bi-layertablet – Disadvantages: adds complexity and bi-layer rotary presses are expensiveAlternatively, could compress one of the APIs and over-encapsulate thisinto a capsule product, along with the powder blend from the second API – Disadvantage are that capsule size could be large, it requires specialised encapsulation equipment to fill tablets and blend… process is more complex and expensive 29
Symyx work stationPrepare: Increase the Scope of Your Study• Test a variety of excipients and excipient compositionsfor compatibility with a range of drug/API concentrations/loadings.• Create, schedule, and replicate sample stressingconditions including temperature, time/duration,humidity/moisture level, pH, and light exposure. www.symyx.com 30
Concluding RemarksDrug-excipient studies are an important foundation tool early in thedevelopment of drug products. They influence stability by …. Drug dissolution Melting time of suppositories Drug release rate Drug leakage Aggregation, precipitation & conformation Moisture adsorption Discoloration mechanical strength Know more about your drug and excipients to minimize Late stage development surprises 31
Bioequivalence Bridge to Quality, Safety and Efficacyfor Generic Products Dr.Prashant Bodhe firstname.lastname@example.org
Basic principles of QAQuality safety and effectiveness must be builtinto the productQuality can not be measured or tested orinspected into all finished productEach step of the development andmanufacturing process must be controlled,analyzed & performed to maximize theprobability that the finished product meets allthe quality, safety and efficacy parameters
Questions during Drug Development How do we build quality into products that are tested in the clinic to establish safety and efficacy? How do we utilize product development and also manufacturing experience to establish appropriate specifications for the to be marketed product?
Evolution of BAResponse is related to drug dose.Response is better related to drugconcentration at site of action.Plasma drug concentration reflects drugconcentration at site of action (systemicexposure)Bioavailability (BA) determines plasmaconcentration profile
Bioavailability, Safety & EffectDrug Safety & Effect Systemic exposure profile during early trials Fairly defined relationship Intrinsic property Plasma Levels Needs to be established BA and BE studies by innovator Bioequivalence studies for Generics Formulation
BA: What does it mean?Bioavailability Provides data on the fraction of drug absorbed, its subsequent distribution and elimination as documented by its systemic exposure profile.A drug is bioavailable if it is present at the siteof action In right quantity and right concentration In an intrinsically active conformation For required duration
Bioavailability CFR Definition320.1 DefinitionsBioavailability means the rate and extent towhich the active ingredient or active moiety isabsorbed from a drug product and becomesavailable at the site of action.For drug products that are not intended to beabsorbed into the bloodstream, bioavailabilitymay be assessed by measurements intended toreflect the rate and extent
Bioavailability: Regulatory Definition Rate and extent of absorption Rate Cmax Tmax Extent Area under the Curve (AUC)
Prescribable New DrugNew drug development programleads to a new productClinical Trial FormulationStability StudiesMarketed FormulationPrescribable
Generic Drug: Physicians Dilemma Can I replace innovators brand with generic? Are two products switchable? Yes! If they are bioequivalent And consistently bioequivalent
BE PrincipleBioequivalence Compares the systemic exposure profile of a test product (Generic) to that of a reference product (Innovator Brand) For the test product to be bioequivalent it should exhibit the same rate and extent of absorption as the reference product
BE: CFR DefinitionBioequivalence means the absence of asignificant difference in the rate andextent to which the active ingredient oractive moiety in pharmaceuticalequivalents or pharmaceuticalalternatives becomes available at the siteof drug action when administered at thesame molar dose under similarconditions in an appropriately designedstudy.
Bioequivalence: MeaningEssentially similar or NOT DIFFERENTbioavailabilityRegulatory definition: ComparableRate and extent of absorptionRate• Cmax• TmaxExtent Area under the Curve (AUC)
BE documentationduring the IND or NDA period toestablish links between early and late clinical trial formulations formulations used in clinical trial and stability studies, if different clinical trial formulations and to-be- marketed drug product; and other comparisons, as appropriate.
BE documentationTo Establish therapeutic equivalence orsimilarityTo establish lack of food effect or properlabel claim w.r.t. foodTo establish the claim of modifiedreleaseTo establish safety of MRTo establish lack of dose dumping
Assumptions in BEPharmaceutical EquivalentPharmaceutical Alternative
Pharmaceutical EquivalentContain identical amounts of the identicalAPI , i.e., the same salt or ester of the sametherapeutic moiety, in identical dosageformsDifferent inactive ingredientsMeet the identical compendial or otherapplicable standard of identity, strength,quality, and purity, including potency and,where applicable, content uniformity,disintegration times and/or dissolutionrates.
Pharmaceutical Alternativecontain the identical therapeutic moiety, or itsprecursor, but not necessarily in the sameamount or dosage form or as the same salt orester.Each such drug product individually meetseither the identical or its own respectivecompendial or other applicable standard ofidentity, strength, quality, and purity,including potency and, where applicable,content uniformity, disintegration times and/ordissolution rates.
In vivo BABE studiesThese are also Clinical trials, ICH E6 GCPdefinition1.12 Clinical trial/study: Any investigation inhuman subjects intended to discover or verify theclinical, pharmacological, and/or otherpharmacodynamic effects of an investigationalproduct(s), and/or to identify any adversereactions to an investigational product(s), and/orto study absorption, distribution, metabolism, andexcretion of an investigational product(s) with theobject of ascertaining its safety and/or efficacy.The terms clinical trial and clinical study aresynonymous
Clinical relevance of BA & BEFor Innovator ProductTo be prescribable, a new product (T) (tobe marketed DF) must have the similarBA as the reference product (R)(Formulation used during clinical trials)with which efficacy and safety wereproved
Process for Generics (ANDA) developmentIdentification Pilot Execution 3M Pivotal Product Product of ANDA Stability Development BE Exhibit Batches Data BE Filing 4-6 M 4-6 M 2-3 M 4-6 M 4-6 M 10 to 15 months 6 to 9 months 18 – 24 MONTHSNote: Generalised Timelines are for Products to US market
Clinical relevance of BA & BEFor Generic ProductTo be approved for ANDA, a newproduct [T] must have BA that isequivalent to that of the referenceproduct [R]To be switchable, a new product [T] musthave BA that is consistent and equivalentto that of the reference product [R], inthis case a marketed product
Therapeutic acceptance of Products Innovator to generic product switchOr New patient on a generic product
Variable Response in patientReduction in BP is variable when switched togeneric brand from innovator in otherwisestable patient Patient factor? No Formulation effect? Possible But products are bioequivalentCould be higher within subject variationattributable to formulation, manufacturing,process variable
Therapeutic Rejection of ProductsLack of consistent response or safety willlead to Noncompliance Switch back to innovator Switch to another generic productLower market share
Relevant QuestionsHow does T compare with R on anaverage (average BE or BEA )? √How variable is T compared with R ×(population BE or BEP )Do the results vary more with T in somesubjects and more with R in others ×(individual BE or BEI )
Compliance to regulationsAcceptable bioequivalence data andcomparable in vitro dissolution and CMCdata are required for approval ofabbreviated new drug applicationsBut it does not assure a successful marketlife for the product
Validation & Verification of in vitro and in vivo SpecificationsPilot studies on different formulationswith different dissolution profileEach formulation has been subjected todiscriminating dissolution testingProcess and formulation parameters havebeen analyzedUsing complex statistical analysis andmatrices various correlations can beestablished
Failed bioequivalenceInappropriate study designinadequate numbers of subjects in theotherwise adequately designed and executionof BE studyMay be due to higher or lower measures of rateand extent of absorption for test productcompared to the reference product orbecause the performance of the test orreference is more variable cf to each other orBoth reference and test are different or varyingin different ways
Failed Bioequivalence 1. Passing, ratio = 1, 0.8 < CI < 1.25 2. Passing, ratio < 1, 0.8 < CI < 1.25 3. Failed, ratio = 1, 0.8 > CI > 1.25 Highly variable drugs, can pass with >N 4. Failed, ratio > 1, 0.8 < CI > 1.25 Formulation effect, can pass with >N 5. Failed, ratio < 1, 0.8 > CI < 1.25 Formulation effect, can pass with >N 6. Failed, ratio > 1.25, 0.8 < CI > 1.25 Completely different products 7. Failed, ratio > 1, CI > 1.25 Completely different products0.8 1.25
Reasons for failureHigh variability of PK parametersUnder-powered, N < than requiredCost??Lower enrollmentWithdrawalMissing data, Outliers
Statistical Techniques help in identifying the sources of variability isolating these sources of variability measuring the variability due to different sources testing statistically if each variability is big or small - i.e. statistically significant or not
Statistical Clinical significance Significancee.g. Statistically Sequence effect in a single dose study of non-endogenous drug1. Study was conducted as per appropriate design and all applicable guidelines and regulations2. BE is established otherwise satisfactorily3. Wash-out period is adequate4. In second period all pre-dose values are zero5. All the variables and restrictions were same in both periods
The Concept of Pharmaceutical Quality Dr. Janet Woodcock, Pharmaceutical Review, 7, 10, 2004: "For the purposes of clinical use, the established drug quality attributes are generally adequate because they achieve much tighter control of the level of variability than could be detected in patients without extensive study.”
The Concept of Pharmaceutical Quality Dr. Janet Woodcock, Pharmaceutical Review, 7, 10, 2004: “In contrast, for regulatory and manufacturing processes, the lack of detailed understanding of the real-world importance of quality attributes is a serious problem, leading to many disputes that might be resolved easily were relevant information available on the relationships between various quality parameters and clinical performance."
In vitro, In vivo evaluationDisintegration test (1950)Dissolution test (1968, apparatus 1)Apparatus 1 to 7Defining specification of dissolutionIVIVCModel based approach
Dissolution SpecificationsIn vitro dissolution specifications have tobe established to ensure batch-to-batchconsistency and to signal potentialproblems with in vivo bioavailability
Data available for Innovator ProductsDissolution results under a variety of agitationand media conditionsA method that provides (rapid) dissolutionprofileMean & range of dissolution values of bio lot(s)Mean & range of dissolution values of severalproduction lotsBA results of one or more lots (relative BA trials,BE trials)Formulation, process variables on lots used andnot used in efficacy trials & / or BABE trialsStability data
Data available for Generic Products Dissolution results under a variety of agitation and media conditions A method that provides (rapid) dissolution profile Mean & range of dissolution values of bio lot(s) Mean and range of dissolution values of Few production lots ?? N=smaller BA results of one or more lots (Pilot trial 0 to few) Lots used in efficacy trials (Rarely Available) Stability data Comparative In vitro data Formulation, process variables on lots used and not used in BABE trials
Expectations from Dissolution testingto assess batch-to-batch quality, where the dissolutiontests, with defined procedures and acceptance criteria, areused to allow batch releasedissolution testing is also used to (1) provide process control and quality assurance, and (2) assess whether further BE studies relative to minor postapproval changes be conducted, wheredissolution can function as a signal of bioinequivalence.In vitro dissolution characterization is needed for allproduct formulations investigated. Such efforts mayenable the establishment of an in vitro-in vivo correlation.When an in vitro-in vivo correlation or association isavailable (21 CFR 320.24(b)(1)(ii)), the in vitro test canserve not only as a quality control specification for themanufacturing process, but also as an indicator of how theproduct will perform in vivo.
When Equivalence Studies are Not NecessaryParenteral preparations – aqueoussolutionsSolutions for oral usePowders for reconstitution as a solutionGasesOtic or ophthalmic products prepared asaqueous solutionsTopical products prepared as solutionsAqueous solutions for nebulizer VPShah-Ukraine-07inhalation or nasal sprays
Documentation of equivalence is necessaryOral immediate release pharmaceutical products with systemic action, & Indicated for serious conditions requiring assured therapeutic response; Narrow therapeutic window/safety margin, steep dose- response curve; Pharmacokinetics complicated by variable or incomplete absorption or absorption window, nonlinear pharmacokinetics, presystemic elimination/high first- pass metabolism >70% Unfavorable physicochemical properties, e.g., low solubility, instability, metastable modifications, poor permeability, etc., Where a high ratio of excipients to active ingredients exists.
Documentation of equivalence is necessaryNon-oral and non-parenteral pharmaceuticalproducts designed to act by systemicabsorption (such as transdermal patches,suppositories, etc.)Sustained or otherwise modified releasepharmaceutical products designed to act bysystemic absorption.Fixed combination products
Documentation of equivalence is necessary Non-solution pharmaceutical products which are for non-systemic use (oral, nasal, ocular, dermal, rectal, vaginal, etc. application) and are intended to act without systemic absorption. In these cases, the bioequivalence concept is not suitable and comparative clinical or pharmacodynamic studies are required to prove equivalence. This does not, however, exclude the potential need for drug concentration measurements in order to assess unintended partial absorption.
USP General Chapter1088 IN VITRO AND IN VIVO EVALUATION OF DOSAGE FORMSCharacterization PK properties of Dosage forms Case A - applies to the original modified- release oral dosage form of an active drug entity already marketed in immediate-release form and for which extensive pharmacodynamic and pharmacokinetic data exist
Case A : IR & New MRA single-dose crossover study shouldinclude the following treatments: the modified-release dosage form administered under fasting conditions a dosage form that is rapidly available administered under fasting conditions modified-release dosage form administered at the same time as a high-fat meal (or another type of meal that has potential for causing maximum perturbation).
Evaluating Food Effectwhether a food effect is a result ofproblems with the dosage form? a single-dose crossover study comparing the solution (or immediate-release dosage form) under fed and fasting conditions
Effect of Timing on Food-Drug Effect four-way crossover study with the modified-release dosage form administered under the following treatment conditions: fasting, taken with a high-fat meal, 1 hour before a high-fat meal, and 2 hours after a high-fat meal
Alternative appropriate studies could beconducted if the applicant were to label thedrug for administration with a meal that is notfat-loaded. In this case, an alternative mealcomposition should be consideredFor delayed-release (enteric-coated) dosageforms, bioavailability studies to characterizeadequately the food effects and to support thedosing claims stated in the labeling should beperformed
Multiple-dose, Steady-state Studies STUDY I : IR with linear pharmacokinetics a steady-state study with the MR dosage form at one dose rate (preferably at the high end) using an IR dosage form as a control STUDY II: Nonlinear kinetics or no cf data a steady-state study with MR dosage form at Two dose rate (preferably at low & high end) using an IR dosage form as a control
Case BCase B applies to a non-oral, modified-releasedosage form of an already marketed activedrug entity for which extensivepharmacodynamic /pharmacokinetic data exist.Case A studies (omitting the food effectstudies) if the pattern of biotransformation to active metabolites is identical for the two routes. If the biotransformation patterns are different, then clinical efficacy studies should be performed with MR product In addition, special studies may be necessary to assess specific risk factors related to the dosage form (e.g., irritation and/or sensitization at the site of application)
Case CCase C applies to a generic equivalent ofan approved modified-release dosageform.crossover single-dose and steady-statestudies.For an oral modified-release dosageform, the food studies described underCase A should also be performed