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IPC-USP 7th Annual Scientific Meeting
          February 6 - 7, 2008
Hyderabad International Convention Center
            Hyderabad, India



 USP’s Verification Programs:
     Experience to Date

             Richard Aleman
  USP Verification Programs Lead Auditor
Topics


   Pharmexcil MOU
   Dietary Supplement Verification Program
   (DSVP)
   Pharmaceutical Ingredient Verification
   Programs
     APIs
     Excipients
   Summary
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.
USP Dietary Supplement
      Verification
Look for the USP-Verified Mark on Your
Dietary Supplements


Your 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 Product
Verification


 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 Verification
Process


 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 on
Participating 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
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 DSVP

Ingredients 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: New
Opportunities to Assure Ingredient
Supplement

   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.
USP Pharmaceutical
Ingredient Verification
Proposed new programs: Drug Substance
and 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 Offered
Worldwide


For suppliers (ingredient manufacturers and
   distributors)
   1. Drug substance verification
   2. Excipient verification


For 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 Qualify
Items?

  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 Excipient
Verification 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, India



Performance 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 Bioavailability


Bioavailability is the rate and extent to which the active
ingredient or active moiety is absorbed from the drug
product and becomes available at the site of action




Hence, 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
Pharmaceutical Dosage Forms <1151>


Terminology
 1.    Aerosols                    15.   Lotions
 2.    Boluses                     16.   Lozenges
 3.    Capsules                    17.   Ointments
 4.    Concentrate for DIP         18.   Ophthalmic Prep.
 5.    Creams                      19.   Pastes
 6.    Elixirs                     20.   Pellets
 7.    Emulsions                   21.   Powders
 8.    Extracts & Fluid Extracts   22.   Premixes
 9.    Gels                        23.   Solutions
 10.   Implants                    24.   Suppositories
 11.   Infusions, Intramammary     25.   Suspensions
 12.   Inhalations                 26.   Syrups
 13.   Injections                  27.   Systems
 14.   Irrigations                 28.   Tablets
Classification of Pharmaceutical Dosage
Forms


         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 Forms
FIRST 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                         solutions


THIRD TIER CATEGORY   TYPE OF RELEASE [i.e. based on the RELEASE PATTERN OF THE ACTIVE]
Tiers 2 & 3 of Oral Dosage Forms

          Oral Dosage Forms



Solid oral dosage forms   Liquid oral dosage forms




Immediate 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 2




Maria 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
         Geometric
Assembly           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 Prednisone
Tablets – Quality Attributes and Experimental Variables Contributing to
Dissolution 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                                                                                                            80
Prednisone 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 Prednisone
Tablets – Quality Attributes and Experimental Variables Contributing to
Dissolution Variance, Pharm. Res. 2007
Variability due to Dissolution Vessels




Mark Liddell et al.: Dissolution Testing Variability: Effect of Using Vessels
from Different Commercial Sources, American Pharm. Review, Vol. 10(6)
Sept./Oct. 2007
USP Research on other Sources of
Variability 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 in
Dissolution 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 Guidance

USP 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 – Functionality
Specifications and
Monographs


S D Joag
Hon Gen Secretary, IPA
Director, Dr. M K Rangnekar Lab,
Mumbai
7th February 2008
At
USP 7th Annual Meeting, Hyderabad
Excipients

Pharmaceutical excipients are
substances other than API/APIs, or
prodrug that are included in a finished
pharmaceutical dosage form [IPEC]

Origin
ex·cip·i·ent (k-sp-nt) : Noun
An inert substance used as a diluent or vehicle for a drug.
[Latin excipins, excipient-, present participle of
excipere, to take out, exclude; see except.]
Excipients


 Excipients are used in virtually all drug
 dosage forms.
 They are essential to product
 performance.
Excipients

Product performance and functionality of
excipient are two sides of the same coin and
are inter-dependable
Right choice of the excipient/s makes the
product stable, safe and effective and
makes it superior than other products
Thus the formulation of excipients in many
cases is considered a trade secret
Some of the known Functional
Catagories of Excipients

Diluent / Filler
Lubricant
Surfactant (Emulsifying, Wetting and Solubilising
Agent )
Binder
Colorants
Suspending / Viscosity increasing Agents
Sweetening Agents
Glidant and or Anticaking Agents
Coating Agents
Some of the known Functional
purposes of Excipients


Vehicle – Pharmaceutical Water
Tonicity Agent
Plasticizers
Suppository Base
Ointment Base
Buffer
Disintegration
Flavors
Preservatives
Anti-oxidants
Excipient Origins

              From deep in the
              Earth
              Soil
Excipient Origins

              From crude oil to
              refined stage
              Petrolium
              Poly-glycols
              Starting materials
              for synthetic
              Chemistry
Excipient origins
Agriculture : Wheat, Corn,
Sugar Cane, Cotton etc.
Tallow oils to glycerin and fatty
acids
Agriculture derived
excipients

 Maize, , Potato, Wheat, Starches
 Sugar (Beet, Sugarcane)
 Dextrins
 Cyclodextrins
 Sorbitol
 Glycerin
Minerals &
Natural origin

Talc
Kaolin
Sodium chloride ( Sea Water)
Silicon Dioxide ( Silica - Aerosil)
Calcium Carbonate (Oyster Shell)
Processes


From 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
Excipients

A very diverse collection of materials
About 1200 ingredients are in use currently
in marketed pharmaceutical products as
excipients excluding colors and flavors
About 250 documented in the European
Pharmacopoeia
Now 60 monographs in the international
harmonization 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 useful
for formulators for consistent
excipient 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 of
Excipients

 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 grade
considerations
 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 in
Excipients
Issues with Excipient/s

 Source
 Quantity in formulation
 Purity / Grade
 Interactions with other excipient/s
 Degradation during shelf-life of the product
Impurities in
Excipients

 General

 impurities related to starting materials
 manufacturing processing aids
 Contaminants – storage, packing,

 To be controlled by GMP
Impurities in
Excipients

 Definition of the material: single or multiple
 component substance

 Related substances from the starting
 materials, the process or instability

 Additives, components added intentionally
Impurities in
Excipients

    Organic impurities
    Inorganic impurities
    Residual solvents
    Pesticides, anti-fungals
    Microbial contamination
Pharmacopoeial
Excipients


 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
Pharmacopoeial
Excipients, 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 pharmacopoeial
excipients
 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
Excipients
Critical Considerations
Challenges for Formulators



  Disintegration
  Dissolution/BA-BE
  Content uniformity
  Sustained / Delayed Release consistency
  Stability – Climatic conditions
  Patient compliance
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?
Security

What are the credentials of the provider?

What kind of quality system is in place?

What is the capacity to provide stable
quality in the amounts necessary
Openess

Is the provider open to discuss - under
confidentiality agreement
particulars of the ingredient,
the manufacturing process
Is the provider open to audit?
Is the provider interested in
co-development of improved quality
better 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 of
industry 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
USP 29/NF 24 functional categories



                            Table 1: USP 29 / NF 24 Functional Categories
 Tablet/capsule diluents              Tablet/capsule binders                          Colors
                                                                         Surfactants (Emulsifying, Wetting
         Lubricants                           Coatings
                                                                              and Solubilizing agents)

         Plasticizers              Anticaking agents and glidants                   Desiccants

 Antimicrobial preservatives                 Humectants                   Bulking agents for freeze-drying
  Acidifying, alkalizing and
                                            Antioxidants                        Antifoaming agents
      buffering agents
                                 Chelating, Complexing, Sequestering
    Alcohol denaturants                                                         Sweetening agents
                                               agents
      Ointment bases                       Tonicity agents                          Emollients
   Water repelling agents                 Suppository bases                     Aerosol propellants

        Filtering aids                        Sorbents                        Pharmaceutical Waters

          Solvents              Viscosity increasing/suspending agents               Vehicles
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 related
characteristics (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) variable
process = constant process



   Raw
     Materials                Process


                  Process




                  Control
Case Studies
        Lactose anhydrous
       Magnesium stearate
    Microcrystalline cellulose
         Lactose hydrous
Gelatin 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 of
anhydrous lactose from 2 different
suppliers
Comparison of sieve fractions of selected
lots of anhydrous lactose
Assessment of anhydrous lactose
variability 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
Assessment of breaking strength


 Breaking   % Dissolved   % Dissolved   % Dissolved
 strength   15 minutes    30 minutes    45 minutes

 10 Kps     97            99            100



 25 Kps     94            97            98



 30 Kps     91            96            98
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 hydrous
dense 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-Flo
lactose 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 hydrous
dense 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 microcrystalline
cellulose 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
Questions and Answers
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
Stability
Extensive chemical degradation: a substantial loss of
potency

Degradation products may result in adverse events or
be unsafe

Instability may cause

Undesired change in performance, i.e.
dissolution/bioavailability

Substantial changes in physical appearance of the
dosage form

causing product failures
                                                        2

Requirement 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 Degradation
Hydrolysis
 Esters
 Carboxylic acid esters
 Amides
 Imides


Dehydration
Isomerization and Racemization
Decarboxylation and elimination
Oxidation
Photodegradation

                                  4
Drug-Excipient Interaction
Excipients are usually biologically inactive, the same cannot be said from
a chemical perspective.      Excipients, and any impurities present, can
stabilise and/or destabilise drug products.

Considerations for the formulation scientist:
     Chemical structure of the API
     Type of delivery system required
     Proposed manufacturing process

Initial 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
      reaction

The objective of drug/excipient compatibility considerations and practical
studies is to delineate, as quickly as possible, real and possible interactions
between potential formulation excipients and the API. This is an important
risk 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       H
O                                                            O
                                                                                                6
Excipient Interactions

Reactions of amines with reducing sugars




                                           7
Excipient Interactions

      Transesterification Reactions

                                          O
                      Polyvinyl
                      acetate phthalate
H2N         COOC2H5                       N   COOC2H5

                                          O




                                                   8
Known Incompatibilities




                          9
Excipient Interactions
Excipient 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 Moisture
Physical state of water:

Weakly absorbed water: Loose water or surface water

Strongly absorbed water: Excipient having higher adsorption energy
decrease water reactivity, decrease in relative hydrolysis rates.

Moisture adsorption Equilibrium: Excipient that adsorbs more
moisture adsorbs more strongly, resulting less free water for strongly
adsorbing excipient before it is reaching equilibrium. Relative
reactivity is decreased.

Hydrated Drugs and excipient: Excipients can form hydrates may
enhance drug degradation by giving up their water of crystallization
during grinding.

Lactose hydrate enhances degradation of 4-Methoxyphenylamino
acetate hydrochloride upon grinding.
                                                                    11
Excipient Moisture

Mobility of water molecules :

Effect of water mobility on drug stability,       spin – lattice
relaxation time and spin-spin relaxation time by NMR and
dielectric relaxation time by dielectric relaxation spectroscopy.


Water mobility in polymer solutions/gels will effect the drug
degradation. Mainly used for polymeric excipients like Poly
vinyl pyrrolidone, Gelatin , PEG.



                                                                12
Excipient Interactions
   pH : Surface acidity of excipients contribute to
   drug degradation
Eg: 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 Interactions
Physical stability
Crystallization of amorphous drugs:
Nifedipine co precipitated with PVP undergoes partial
crystallization during storage.
Oxyphenbutazone converts to anhydrous form with lower
solubility during storage under conditions of high humidity
Haloperidone converts to crystalline in presence of HPC,MC,
HPMC and PVA.

Crystallization of amorphous excipients also occur during
storage effects the drug release.


                                                              14
Drug-Excipient Compatibility Testing
In the typical drug/excipient compatibility testing program,
binary (1:1 or customised) powder mixes are prepared by
triturating API with the individual excipients.

These powder samples, usually with or without added water and
occasionally compacted or prepared as slurries, are stored
under 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 thermal
methods, 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 be
misleading; false positives and negatives are routinely
encountered.                                                  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 Testing
Drug-excipient interactions can be studied using both approaches in a
complementary fashion. The first tier approach is to conduct short-term
(1-3m) stability studies using generic prototype formulations under
stressed 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 the
chemical interactions in more complex systems such as prototype
formulations, with a view towards establishing which excipients cause
incompatibility within a given mixture.
                                                                       17
Drug-Excipient Compatibility
Testing – 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
Detection & Characterization


  Thermal Analysis
     DSC, DTA, DTG & Isothermal calorimetry
 Chromatography
     HPLC, GC
  Diffuse reflectance spectroscopy
  IR, XRD
  LC-MS/MS,NMR
                                          19
Ibuprofen-Mg Oxide interaction
           by DSC




                             20
Excipient Interaction Study
       (Oxethazaine)




                              21
Excipient Interaction Study
       (Glimiperide)




                              22
Isothermal Calorimetry




                         23
Levocetirizine- Lactose anhydrous
    interaction study by HPLC




                                    24
Rosuvastatin with Ac-Di-sol
    (Cross carmasol)




                              25
Rosuvastatin with Ac-Di-sol
    (Cross carmasol)




                              26
Ropinirole interaction with
with colloidal silicondioxide




                           27
Atorvastatin with Meglumine




                          28
Drug Combinations
Objective is to minimise incompatibilities: Degradation pathways of the
two APIs could be different, so a stabilisation strategy for API #1 could
destabilise API #2.
In this situation, first intent strategy could be to prepare, separate
compression blends of each individual API and compress as a bi-layer
tablet
 – Disadvantages: adds complexity and bi-layer rotary presses are
    expensive
Alternatively, could compress one of the APIs and over-encapsulate this
into 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 station




Prepare: Increase the Scope of Your Study
• Test a variety of excipients and excipient compositions
for compatibility with a range of drug/API concentrations/loadings.
• Create, schedule, and replicate sample stressing
conditions including temperature, time/duration,
humidity/moisture level, pH, and light exposure.
                           www.symyx.com
                                                                      30
Concluding Remarks

Drug-excipient studies are an important foundation tool early in the
development 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
Thanks…….




            32
Bioequivalence
 Bridge to Quality,
 Safety and Efficacy
for Generic Products
      Dr.Prashant Bodhe
  prashant.bodhe@gmail.com
Basic principles of QA
Quality safety and effectiveness must be built
into the product
Quality can not be measured or tested or
inspected into all finished product
Each step of the development and
manufacturing process must be controlled,
analyzed & performed to maximize the
probability that the finished product meets all
the 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 BA
Response is related to drug dose.
Response is better related to drug
concentration at site of action.
Plasma drug concentration reflects drug
concentration at site of action (systemic
exposure)
Bioavailability (BA) determines plasma
concentration profile
Bioavailability, Safety & Effect

Drug 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 site
of action
  In right quantity and right concentration
  In an intrinsically active conformation
  For required duration
Bioavailability CFR Definition
320.1 Definitions
Bioavailability means the rate and extent to
which the active ingredient or active moiety is
absorbed from a drug product and becomes
available at the site of action.

For drug products that are not intended to be
absorbed into the bloodstream, bioavailability
may be assessed by measurements intended to
reflect the rate and extent
Bioavailability: Regulatory Definition

 Rate and extent of absorption
 Rate
   Cmax
   Tmax
 Extent
   Area under the Curve (AUC)
Prescribable New Drug
New drug development program
leads to a new product
Clinical Trial Formulation
Stability Studies
Marketed Formulation
Prescribable
Generic Drug: Physicians Dilemma

 Can I replace innovators brand
 with generic?
 Are two products switchable?
 Yes! If
  they are bioequivalent
  And consistently bioequivalent
BE Principle
Bioequivalence
 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 Definition
Bioequivalence means the absence of a
significant difference in the rate and
extent to which the active ingredient or
active moiety in pharmaceutical
equivalents or pharmaceutical
alternatives becomes available at the site
of drug action when administered at the
same molar dose under similar
conditions in an appropriately designed
study.
Bioequivalence: Meaning
Essentially similar or NOT DIFFERENT
bioavailability
Regulatory definition: Comparable
Rate and extent of absorption
Rate
•   Cmax
•   Tmax
Extent
    Area under the Curve (AUC)
BE documentation
during the IND or NDA period to
establish 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 documentation
To Establish therapeutic equivalence or
similarity
To establish lack of food effect or proper
label claim w.r.t. food
To establish the claim of modified
release
To establish safety of MR
To establish lack of dose dumping
Assumptions in BE
Pharmaceutical Equivalent
Pharmaceutical Alternative
Pharmaceutical Equivalent

Contain identical amounts of the identical
API , i.e., the same salt or ester of the same
therapeutic moiety, in identical dosage
forms
Different inactive ingredients
Meet the identical compendial or other
applicable standard of identity, strength,
quality, and purity, including potency and,
where applicable, content uniformity,
disintegration times and/or dissolution
rates.
Pharmaceutical Alternative
contain the identical therapeutic moiety, or its
precursor, but not necessarily in the same
amount or dosage form or as the same salt or
ester.
Each such drug product individually meets
either the identical or its own respective
compendial or other applicable standard of
identity, strength, quality, and purity,
including potency and, where applicable,
content uniformity, disintegration times and/or
dissolution rates.
In vivo BABE studies
These are also Clinical trials, ICH E6 GCP
definition
1.12 Clinical trial/study: Any investigation in
human subjects intended to discover or verify the
clinical, pharmacological, and/or other
pharmacodynamic effects of an investigational
product(s), and/or to identify any adverse
reactions to an investigational product(s), and/or
to study absorption, distribution, metabolism, and
excretion of an investigational product(s) with the
object of ascertaining its safety and/or efficacy.
The terms clinical trial and clinical study are
synonymous
Clinical relevance of BA & BE
For Innovator Product
To be prescribable, a new product (T) (to
be marketed DF) must have the similar
BA as the reference product (R)
(Formulation used during clinical trials)
with which efficacy and safety were
proved
Process for Generics (ANDA) development
Identification



                               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 MONTHS


Note:               Generalised Timelines are for Products to US market
Clinical relevance of BA & BE
For Generic Product
To be approved for ANDA, a new
product [T] must have BA that is
equivalent to that of the reference
product [R]
To be switchable, a new product [T] must
have BA that is consistent and equivalent
to that of the reference product [R], in
this case a marketed product
Therapeutic acceptance of Products

 Innovator to generic product switch
Or
 New patient on a generic product
Variable Response in patient
Reduction in BP is variable when switched to
generic brand from innovator in otherwise
stable patient
  Patient factor? No
  Formulation effect? Possible
  But products are bioequivalent
Could be higher within subject variation
attributable to formulation, manufacturing,
process variable
Therapeutic Rejection of Products

Lack of consistent response or safety will
lead to
  Noncompliance
  Switch back to innovator
  Switch to another generic product
Lower market share
Relevant Questions
How does T compare with R on an
average (average BE or BEA )? √
How variable is T compared with R ×
(population BE or BEP )
Do the results vary more with T in some
subjects and more with R in others ×
(individual BE or BEI )
Compliance to regulations
Acceptable bioequivalence data and
comparable in vitro dissolution and CMC
data are required for approval of
abbreviated new drug applications
But it does not assure a successful market
life for the product
Validation & Verification of
  in vitro and in vivo Specifications
Pilot studies on different formulations
with different dissolution profile
Each formulation has been subjected to
discriminating dissolution testing
Process and formulation parameters have
been analyzed
Using complex statistical analysis and
matrices various correlations can be
established
Failed bioequivalence
Inappropriate study design
inadequate numbers of subjects in the
otherwise adequately designed and execution
of BE study
May be due to higher or lower measures of rate
and extent of absorption for test product
compared to the reference product or
because the performance of the test or
reference is more variable cf to each other or
Both reference and test are different or varying
in 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 products


0.8     1.25
Reasons for failure
High variability of PK parameters
Under-powered, N < than required
Cost??
Lower enrollment
Withdrawal
Missing 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                    Significance
e.g. Statistically Sequence effect in a single dose
   study of non-endogenous drug
1. Study was conducted as per appropriate design
   and all applicable guidelines and regulations
2. BE is established otherwise satisfactorily
3. Wash-out period is adequate
4. In second period all pre-dose values are zero
5. 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 evaluation
Disintegration test (1950)
Dissolution test (1968, apparatus 1)
Apparatus 1 to 7
Defining specification of dissolution
IVIVC
Model based approach
Dissolution Specifications
In vitro dissolution specifications have to
be established to ensure batch-to-batch
consistency and to signal potential
problems with in vivo bioavailability
Data available for Innovator 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 & range of dissolution values of several
production lots
BA results of one or more lots (relative BA trials,
BE trials)
Formulation, process variables on lots used and
not used in efficacy trials & / or BABE trials
Stability 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 testing
to assess batch-to-batch quality, where the dissolution
tests, with defined procedures and acceptance criteria, are
used to allow batch release
dissolution 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 all
product formulations investigated. Such efforts may
enable the establishment of an in vitro-in vivo correlation.
When an in vitro-in vivo correlation or association is
available (21 CFR 320.24(b)(1)(ii)), the in vitro test can
serve not only as a quality control specification for the
manufacturing process, but also as an indicator of how the
product will perform in vivo.
When Equivalence Studies are
      Not Necessary
Parenteral preparations – aqueous
solutions
Solutions for oral use
Powders for reconstitution as a solution
Gases
Otic or ophthalmic products prepared as
aqueous solutions
Topical products prepared as solutions
Aqueous solutions for nebulizer    VPShah-Ukraine-07


inhalation or nasal sprays
Documentation of equivalence is necessary
Oral 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 necessary

Non-oral and non-parenteral pharmaceutical
products designed to act by systemic
absorption (such as transdermal patches,
suppositories, etc.)
Sustained or otherwise modified release
pharmaceutical products designed to act by
systemic 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 Chapter
1088 IN VITRO AND IN VIVO EVALUATION
  OF DOSAGE FORMS
Characterization 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 MR
A single-dose crossover study should
include 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 Effect
whether a food effect is a result of
problems 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 be
conducted if the applicant were to label the
drug for administration with a meal that is not
fat-loaded. In this case, an alternative meal
composition should be considered
For delayed-release (enteric-coated) dosage
forms, bioavailability studies to characterize
adequately the food effects and to support the
dosing claims stated in the labeling should be
performed
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 B
Case B applies to a non-oral, modified-release
dosage form of an already marketed active
drug entity for which extensive
pharmacodynamic /pharmacokinetic data exist.
Case A studies (omitting the food effect
studies)
  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 C
Case C applies to a generic equivalent of
an approved modified-release dosage
form.
crossover single-dose and steady-state
studies.
For an oral modified-release dosage
form, the food studies described under
Case A should also be performed
CFR 320.27
  A multiple-dose study may be required
    to determine the bioavailability of a drug product in
    the following circumstances:
(i) There is a difference in the rate of absorption but not
    in the extent of absorption.
(ii) There is excessive variability in bioavailability from
    subject to subject.
(iii) The concentration of the active drug ingredient or
    therapeutic moiety, or its metabolite(s), in the blood
    resulting from a single dose is too low for accurate
    determination by the analytical method.
(iv) The drug product is an extended release dosage form.
    But CDER guidance generally recommends single-dose
    pharmacokinetic studies for both IR, MR drug
    products to demonstrate BE
CDER Guidance : MR ANDA
single-dose, nonreplicate, fasting study
comparing the highest strength of the test and
reference listed drug product and
food-effect, nonreplicate study comparing the
highest strength of the test and reference product
Because single-dose studies are considered more
sensitive in addressing the primary question of
BE (i.e., release of the drug substance from the
drug product into the systemic circulation),
multiple-dose studies are generally not
recommended, even in instances where nonlinear
kinetics are present
Food effect studies not required
             for IR
When both test product and RLD are
rapidly dissolving, have similar
dissolution profiles, and contain a drug
substance with high solubility and high
permeability (BCS Class I)
the product should be taken only on an
empty stomach
No food effect
SUPAC-IR (1995)
              and
     SUPAC-MR Guidances (1997)
            Summary
 (Equipment Addendum (1999); FDAMA (1997) and
“Changes Approved to an NDA or ANDA” Guidance
                     (2000)
General Aspects: (Change)
   Variables Covered
  Components and Composition
   Non Release Controlling
   Release Controlling
  Site
  Batch Size (Scale-Up/Scale-Down)
  Manufacturing
   Equipment
   Process
General Aspects: Supporting Data
           • Level I (Minor) change
Level of
Change
           • Level II (Moderate) change
           • Level III (Major) change
           • Chemistry (A/C test, Stability)
  Tests    • In Vitro dissolution/release
           • In Vivo bioequivalence test / IVIVC
           • Annual report
 Filing    • Change being effected supplement
           • Prior approval supplement
SUPAC- IR and MR SUMMARY

The following changes need a bio study
 & / or IVIVC):
 level 3 RC and NRC,
 level 2 RC for NTR drugs
 level 3 site change
 level 3 process change
Resourcefulness and Commitment
IPC-USP 7th Annual Scientific Meeting
                February 6 - 7, 2008
      Hyderabad International Convention Center
                  Hyderabad, India

  Developing Fixed-Dose Combination Drug
     Products to Treat HIV Disease: The
HHS/UNAIDS/WHO/SADC Principles Document
     and the FDA Guidance for Industry


         Darrell R. Abernethy, M.D., Ph.D.
               Chief Science Officer
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Usp 2008track2combined

  • 1. IPC-USP 7th Annual Scientific Meeting February 6 - 7, 2008 Hyderabad International Convention Center Hyderabad, India USP’s Verification Programs: Experience to Date Richard Aleman USP Verification Programs Lead Auditor
  • 2. Topics Pharmexcil MOU Dietary Supplement Verification Program (DSVP) Pharmaceutical Ingredient Verification Programs APIs Excipients Summary
  • 3. 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
  • 4. 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
  • 5. 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
  • 6. 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
  • 7. USP’s Verification Programs The Marks of Quality Good quality medicines meet official standards for identity, strength, purity, quality, packaging, and labeling.
  • 8. USP Dietary Supplement Verification
  • 9. Look for the USP-Verified Mark on Your Dietary Supplements Your 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.
  • 10. USP Dietary Supplement Product Verification 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.)
  • 11. Rigorous Dietary Supplement Verification Process 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
  • 12. 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
  • 13. 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.
  • 14. List of Corrective Actions Imposed on Participating 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.
  • 15. USP Dietary Ingredient Verification
  • 16. 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 DSVP Ingredients 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)
  • 17. 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
  • 18. Natural Products Association: New Opportunities to Assure Ingredient Supplement 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.
  • 20. Proposed new programs: Drug Substance and Excipient Verification and Qualification
  • 21. “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.
  • 22. Four New USP Services to be Offered Worldwide For suppliers (ingredient manufacturers and distributors) 1. Drug substance verification 2. Excipient verification For 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.
  • 23. What USP Will do to Verify or Qualify Items? 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.
  • 24. Pharmaceutical and Excipient Verification 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
  • 25. 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
  • 26. 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
  • 27. 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.
  • 28. 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.
  • 29. 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).
  • 30. 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.
  • 31. 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.
  • 32. 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.
  • 33. 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.
  • 34. 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.
  • 35. 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.
  • 36. 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.
  • 37.
  • 38.
  • 39. IPC-USP 7th Annual Scientific Meeting February 6 - 7, 2008 Hyderabad International Convention Center Hyderabad, India Performance Verification Testing William F. Koch, Ph.D. Chief Reference Materials Officer
  • 40. 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
  • 41. Rate Process in Drug Bioavailability Bioavailability is the rate and extent to which the active ingredient or active moiety is absorbed from the drug product and becomes available at the site of action Hence, the rate of Dissolution is related to Bioavailability.
  • 42. 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)
  • 43. 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
  • 44. Pharmaceutical Dosage Forms <1151> Terminology 1. Aerosols 15. Lotions 2. Boluses 16. Lozenges 3. Capsules 17. Ointments 4. Concentrate for DIP 18. Ophthalmic Prep. 5. Creams 19. Pastes 6. Elixirs 20. Pellets 7. Emulsions 21. Powders 8. Extracts & Fluid Extracts 22. Premixes 9. Gels 23. Solutions 10. Implants 24. Suppositories 11. Infusions, Intramammary 25. Suspensions 12. Inhalations 26. Syrups 13. Injections 27. Systems 14. Irrigations 28. Tablets
  • 45. Classification of Pharmaceutical Dosage Forms Three-Tier System Delivery Route Dosage Form Release Category
  • 46. 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
  • 47. First Tier of Pharmaceutical Dosage Forms FIRST 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]
  • 48. 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 solutions THIRD TIER CATEGORY TYPE OF RELEASE [i.e. based on the RELEASE PATTERN OF THE ACTIVE]
  • 49. Tiers 2 & 3 of Oral Dosage Forms Oral Dosage Forms Solid oral dosage forms Liquid oral dosage forms Immediate Release Modified Release Extended Release Delayed Release
  • 50. 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
  • 51. 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)
  • 52. 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
  • 53. 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
  • 54. Dissolution Test Variability – Apparatus 2 Maria Glasgow et al.: The USP Performance Verification Test Part II: Collaborative Study of USP’s Lot P Prednisone Tablets, Pharm. Res. 2007
  • 55. Dissolution Test - Causes Of Variability The drug product under investigation Dissolution equipment, apparatus and assembly Environmental conditions Dissolution procedure Analytical method and procedure Analyst
  • 56. Experimental Variables Contributing to Dissolution Variance Statistical Analysis Summary for Apparatus 2 95% CV% Residual as Geometric Assembly 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 Prednisone Tablets – Quality Attributes and Experimental Variables Contributing to Dissolution Variance, Pharm. Res. 2007
  • 57. 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 80 Prednisone 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 Prednisone Tablets – Quality Attributes and Experimental Variables Contributing to Dissolution Variance, Pharm. Res. 2007
  • 58. Variability due to Dissolution Vessels Mark Liddell et al.: Dissolution Testing Variability: Effect of Using Vessels from Different Commercial Sources, American Pharm. Review, Vol. 10(6) Sept./Oct. 2007
  • 59. USP Research on other Sources of Variability 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
  • 60. USP Research on Sources of Variability in Dissolution 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
  • 61. 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
  • 62. USP Response to Draft FDA Guidance USP 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.
  • 63. 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
  • 64. 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
  • 65.
  • 66. Excipients – Functionality Specifications and Monographs S D Joag Hon Gen Secretary, IPA Director, Dr. M K Rangnekar Lab, Mumbai 7th February 2008 At USP 7th Annual Meeting, Hyderabad
  • 67. Excipients Pharmaceutical excipients are substances other than API/APIs, or prodrug that are included in a finished pharmaceutical dosage form [IPEC] Origin ex·cip·i·ent (k-sp-nt) : Noun An inert substance used as a diluent or vehicle for a drug. [Latin excipins, excipient-, present participle of excipere, to take out, exclude; see except.]
  • 68. Excipients Excipients are used in virtually all drug dosage forms. They are essential to product performance.
  • 69. Excipients Product performance and functionality of excipient are two sides of the same coin and are inter-dependable Right choice of the excipient/s makes the product stable, safe and effective and makes it superior than other products Thus the formulation of excipients in many cases is considered a trade secret
  • 70. Some of the known Functional Catagories of Excipients Diluent / Filler Lubricant Surfactant (Emulsifying, Wetting and Solubilising Agent ) Binder Colorants Suspending / Viscosity increasing Agents Sweetening Agents Glidant and or Anticaking Agents Coating Agents
  • 71. Some of the known Functional purposes of Excipients Vehicle – Pharmaceutical Water Tonicity Agent Plasticizers Suppository Base Ointment Base Buffer Disintegration Flavors Preservatives Anti-oxidants
  • 72. Excipient Origins From deep in the Earth Soil
  • 73. Excipient Origins From crude oil to refined stage Petrolium Poly-glycols Starting materials for synthetic Chemistry
  • 74. Excipient origins Agriculture : Wheat, Corn, Sugar Cane, Cotton etc.
  • 75. Tallow oils to glycerin and fatty acids
  • 76. Agriculture derived excipients Maize, , Potato, Wheat, Starches Sugar (Beet, Sugarcane) Dextrins Cyclodextrins Sorbitol Glycerin
  • 77. Minerals & Natural origin Talc Kaolin Sodium chloride ( Sea Water) Silicon Dioxide ( Silica - Aerosil) Calcium Carbonate (Oyster Shell)
  • 78. Processes From 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
  • 79. Excipients A very diverse collection of materials About 1200 ingredients are in use currently in marketed pharmaceutical products as excipients excluding colors and flavors About 250 documented in the European Pharmacopoeia Now 60 monographs in the international harmonization process, USP, JP and Ph Eur
  • 80. 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
  • 81. USP General Chapters useful for formulators for consistent excipient 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
  • 82. Pharma use of Excipients Contrary to APIs, excipients are not specifically made for use in medicinal products e, g. Cellulose Propellants Sugar Glycerin Starch Colors Flavors
  • 83. 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
  • 84. Excipient grade considerations 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
  • 85. Impurities in Excipients Issues with Excipient/s Source Quantity in formulation Purity / Grade Interactions with other excipient/s Degradation during shelf-life of the product
  • 86. Impurities in Excipients General impurities related to starting materials manufacturing processing aids Contaminants – storage, packing, To be controlled by GMP
  • 87. Impurities in Excipients Definition of the material: single or multiple component substance Related substances from the starting materials, the process or instability Additives, components added intentionally
  • 88. Impurities in Excipients Organic impurities Inorganic impurities Residual solvents Pesticides, anti-fungals Microbial contamination
  • 89. Pharmacopoeial Excipients 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
  • 90. Pharmacopoeial Excipients, issues Genotoxic impurities Heavy metals (residues of catalysts) Heavy metals test not satisfactory Mycotoxins
  • 91. Some examples Inorganic impurities Heavy metals in minerals Hydrogenated fats Gelatin, Acacia, Stearates Polymers Liquids (containers)
  • 92. Non pharmacopoeial excipients 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
  • 93. Some examples Inorganic impurities sulfites processing aid starches and refined sugars radioactive nuclides
  • 94. Some examples Organic impurities proteins e.g. gluten, prion, protein additives e.g. Silicon dioxide BHT/BHA Tocopherol Hydrogen peroxide
  • 95. Some examples Organic impurities: monomers and processing aids in polymers, special instructions on ethylene oxide residues residual solvents pesticides
  • 96. Some examples Organic impurities microbial contamination mycotoxins residues from antimicrobial treatment
  • 97. Excipients Critical Considerations Challenges for Formulators Disintegration Dissolution/BA-BE Content uniformity Sustained / Delayed Release consistency Stability – Climatic conditions Patient compliance
  • 98. 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
  • 99. 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?
  • 100. Security What are the credentials of the provider? What kind of quality system is in place? What is the capacity to provide stable quality in the amounts necessary
  • 101. Openess Is the provider open to discuss - under confidentiality agreement particulars of the ingredient, the manufacturing process Is the provider open to audit? Is the provider interested in co-development of improved quality better performing ingredients ?
  • 102.
  • 103. 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
  • 104. 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
  • 105. 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
  • 106. The desired state: A mutual goal of industry 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
  • 107. 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)
  • 108. 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)
  • 109. 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
  • 110. 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
  • 111. 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
  • 112. 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.
  • 113. 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
  • 114. 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?
  • 115. 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
  • 116. 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
  • 117. 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
  • 118. 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
  • 119. 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
  • 120. USP 29/NF 24 functional categories Table 1: USP 29 / NF 24 Functional Categories Tablet/capsule diluents Tablet/capsule binders Colors Surfactants (Emulsifying, Wetting Lubricants Coatings and Solubilizing agents) Plasticizers Anticaking agents and glidants Desiccants Antimicrobial preservatives Humectants Bulking agents for freeze-drying Acidifying, alkalizing and Antioxidants Antifoaming agents buffering agents Chelating, Complexing, Sequestering Alcohol denaturants Sweetening agents agents Ointment bases Tonicity agents Emollients Water repelling agents Suppository bases Aerosol propellants Filtering aids Sorbents Pharmaceutical Waters Solvents Viscosity increasing/suspending agents Vehicles
  • 121. 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
  • 122. Examples of functionality related characteristics (FRCs) Particle shape, size and size distribution Crystallinity Moisture content Specific surface area Powder flow Compaction properties Viscosity Molecular weight, weight distribution Rheological behavior
  • 123. 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>
  • 124. 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
  • 125. 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
  • 126. Variable Raw Material + Fixed Process = Variable Product on Raw Materials Process Process Control
  • 127. Variable raw material + (anti) variable process = constant process Raw Materials Process Process Control
  • 128. Case Studies Lactose anhydrous Magnesium stearate Microcrystalline cellulose Lactose hydrous Gelatin in lyophilized dosage form
  • 129. 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
  • 130. 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
  • 131. Physical characterization of 7 lots of anhydrous lactose from 2 different suppliers
  • 132. Comparison of sieve fractions of selected lots of anhydrous lactose
  • 133. Assessment of anhydrous lactose variability 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
  • 134. 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
  • 135. 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
  • 136. 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
  • 137. 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
  • 138. 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
  • 139. Assessment of breaking strength Breaking % Dissolved % Dissolved % Dissolved strength 15 minutes 30 minutes 45 minutes 10 Kps 97 99 100 25 Kps 94 97 98 30 Kps 91 96 98
  • 140. 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
  • 141. 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
  • 142. 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
  • 143. Comparison of several lots of hydrous dense lactose from 2 different suppliers
  • 144. 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
  • 145. Effect of normal variability of Fast-Flo lactose on drymix properties
  • 146. 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
  • 147. 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
  • 148. Substitution of Fast-Flo with hydrous dense lactose
  • 149. 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
  • 150. 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
  • 151. Effect of varying grade of microcrystalline cellulose on power mix and tablets
  • 152. 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
  • 153. 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
  • 154. 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
  • 155.
  • 157. 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
  • 158. Stability Extensive chemical degradation: a substantial loss of potency Degradation products may result in adverse events or be unsafe Instability may cause Undesired change in performance, i.e. dissolution/bioavailability Substantial changes in physical appearance of the dosage form causing product failures 2 Requirement for approval by regulatory agencies
  • 159. 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
  • 160. Chemical Degradation Hydrolysis Esters Carboxylic acid esters Amides Imides Dehydration Isomerization and Racemization Decarboxylation and elimination Oxidation Photodegradation 4
  • 161. Drug-Excipient Interaction Excipients are usually biologically inactive, the same cannot be said from a chemical perspective. Excipients, and any impurities present, can stabilise and/or destabilise drug products. Considerations for the formulation scientist: Chemical structure of the API Type of delivery system required Proposed manufacturing process Initial 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 reaction The objective of drug/excipient compatibility considerations and practical studies is to delineate, as quickly as possible, real and possible interactions between potential formulation excipients and the API. This is an important risk reduction exercise early in formulation development. 5
  • 162. 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 H O O 6
  • 163. Excipient Interactions Reactions of amines with reducing sugars 7
  • 164. Excipient Interactions Transesterification Reactions O Polyvinyl acetate phthalate H2N COOC2H5 N COOC2H5 O 8
  • 166. Excipient Interactions Excipient 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
  • 167. Excipient Moisture Physical state of water: Weakly absorbed water: Loose water or surface water Strongly absorbed water: Excipient having higher adsorption energy decrease water reactivity, decrease in relative hydrolysis rates. Moisture adsorption Equilibrium: Excipient that adsorbs more moisture adsorbs more strongly, resulting less free water for strongly adsorbing excipient before it is reaching equilibrium. Relative reactivity is decreased. Hydrated Drugs and excipient: Excipients can form hydrates may enhance drug degradation by giving up their water of crystallization during grinding. Lactose hydrate enhances degradation of 4-Methoxyphenylamino acetate hydrochloride upon grinding. 11
  • 168. Excipient Moisture Mobility of water molecules : Effect of water mobility on drug stability, spin – lattice relaxation time and spin-spin relaxation time by NMR and dielectric relaxation time by dielectric relaxation spectroscopy. Water mobility in polymer solutions/gels will effect the drug degradation. Mainly used for polymeric excipients like Poly vinyl pyrrolidone, Gelatin , PEG. 12
  • 169. Excipient Interactions pH : Surface acidity of excipients contribute to drug degradation Eg: 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
  • 170. Excipient Interactions Physical stability Crystallization of amorphous drugs: Nifedipine co precipitated with PVP undergoes partial crystallization during storage. Oxyphenbutazone converts to anhydrous form with lower solubility during storage under conditions of high humidity Haloperidone converts to crystalline in presence of HPC,MC, HPMC and PVA. Crystallization of amorphous excipients also occur during storage effects the drug release. 14
  • 171. Drug-Excipient Compatibility Testing In the typical drug/excipient compatibility testing program, binary (1:1 or customised) powder mixes are prepared by triturating API with the individual excipients. These powder samples, usually with or without added water and occasionally compacted or prepared as slurries, are stored under 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 thermal methods, 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 be misleading; false positives and negatives are routinely encountered. 15
  • 172. 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
  • 173. Drug-Excipient Compatibility Testing Drug-excipient interactions can be studied using both approaches in a complementary fashion. The first tier approach is to conduct short-term (1-3m) stability studies using generic prototype formulations under stressed 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 the chemical interactions in more complex systems such as prototype formulations, with a view towards establishing which excipients cause incompatibility within a given mixture. 17
  • 174. Drug-Excipient Compatibility Testing – 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
  • 175. Detection & Characterization Thermal Analysis DSC, DTA, DTG & Isothermal calorimetry Chromatography HPLC, GC Diffuse reflectance spectroscopy IR, XRD LC-MS/MS,NMR 19
  • 177. Excipient Interaction Study (Oxethazaine) 21
  • 178. Excipient Interaction Study (Glimiperide) 22
  • 180. Levocetirizine- Lactose anhydrous interaction study by HPLC 24
  • 181. Rosuvastatin with Ac-Di-sol (Cross carmasol) 25
  • 182. Rosuvastatin with Ac-Di-sol (Cross carmasol) 26
  • 183. Ropinirole interaction with with colloidal silicondioxide 27
  • 185. Drug Combinations Objective is to minimise incompatibilities: Degradation pathways of the two APIs could be different, so a stabilisation strategy for API #1 could destabilise API #2. In this situation, first intent strategy could be to prepare, separate compression blends of each individual API and compress as a bi-layer tablet – Disadvantages: adds complexity and bi-layer rotary presses are expensive Alternatively, could compress one of the APIs and over-encapsulate this into 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
  • 186. Symyx work station Prepare: Increase the Scope of Your Study • Test a variety of excipients and excipient compositions for compatibility with a range of drug/API concentrations/loadings. • Create, schedule, and replicate sample stressing conditions including temperature, time/duration, humidity/moisture level, pH, and light exposure. www.symyx.com 30
  • 187. Concluding Remarks Drug-excipient studies are an important foundation tool early in the development 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
  • 189. Bioequivalence Bridge to Quality, Safety and Efficacy for Generic Products Dr.Prashant Bodhe prashant.bodhe@gmail.com
  • 190. Basic principles of QA Quality safety and effectiveness must be built into the product Quality can not be measured or tested or inspected into all finished product Each step of the development and manufacturing process must be controlled, analyzed & performed to maximize the probability that the finished product meets all the quality, safety and efficacy parameters
  • 191. 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?
  • 192. Evolution of BA Response is related to drug dose. Response is better related to drug concentration at site of action. Plasma drug concentration reflects drug concentration at site of action (systemic exposure) Bioavailability (BA) determines plasma concentration profile
  • 193. Bioavailability, Safety & Effect Drug 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
  • 194. 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 site of action In right quantity and right concentration In an intrinsically active conformation For required duration
  • 195. Bioavailability CFR Definition 320.1 Definitions Bioavailability means the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action. For drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent
  • 196. Bioavailability: Regulatory Definition Rate and extent of absorption Rate Cmax Tmax Extent Area under the Curve (AUC)
  • 197. Prescribable New Drug New drug development program leads to a new product Clinical Trial Formulation Stability Studies Marketed Formulation Prescribable
  • 198. Generic Drug: Physicians Dilemma Can I replace innovators brand with generic? Are two products switchable? Yes! If they are bioequivalent And consistently bioequivalent
  • 199. BE Principle Bioequivalence 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
  • 200. BE: CFR Definition Bioequivalence means the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.
  • 201. Bioequivalence: Meaning Essentially similar or NOT DIFFERENT bioavailability Regulatory definition: Comparable Rate and extent of absorption Rate • Cmax • Tmax Extent Area under the Curve (AUC)
  • 202. BE documentation during the IND or NDA period to establish 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.
  • 203. BE documentation To Establish therapeutic equivalence or similarity To establish lack of food effect or proper label claim w.r.t. food To establish the claim of modified release To establish safety of MR To establish lack of dose dumping
  • 204. Assumptions in BE Pharmaceutical Equivalent Pharmaceutical Alternative
  • 205. Pharmaceutical Equivalent Contain identical amounts of the identical API , i.e., the same salt or ester of the same therapeutic moiety, in identical dosage forms Different inactive ingredients Meet the identical compendial or other applicable standard of identity, strength, quality, and purity, including potency and, where applicable, content uniformity, disintegration times and/or dissolution rates.
  • 206. Pharmaceutical Alternative contain the identical therapeutic moiety, or its precursor, but not necessarily in the same amount or dosage form or as the same salt or ester. Each such drug product individually meets either the identical or its own respective compendial or other applicable standard of identity, strength, quality, and purity, including potency and, where applicable, content uniformity, disintegration times and/or dissolution rates.
  • 207. In vivo BABE studies These are also Clinical trials, ICH E6 GCP definition 1.12 Clinical trial/study: Any investigation in human subjects intended to discover or verify the clinical, pharmacological, and/or other pharmacodynamic effects of an investigational product(s), and/or to identify any adverse reactions to an investigational product(s), and/or to study absorption, distribution, metabolism, and excretion of an investigational product(s) with the object of ascertaining its safety and/or efficacy. The terms clinical trial and clinical study are synonymous
  • 208. Clinical relevance of BA & BE For Innovator Product To be prescribable, a new product (T) (to be marketed DF) must have the similar BA as the reference product (R) (Formulation used during clinical trials) with which efficacy and safety were proved
  • 209. Process for Generics (ANDA) development Identification 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 MONTHS Note: Generalised Timelines are for Products to US market
  • 210. Clinical relevance of BA & BE For Generic Product To be approved for ANDA, a new product [T] must have BA that is equivalent to that of the reference product [R] To be switchable, a new product [T] must have BA that is consistent and equivalent to that of the reference product [R], in this case a marketed product
  • 211. Therapeutic acceptance of Products Innovator to generic product switch Or New patient on a generic product
  • 212. Variable Response in patient Reduction in BP is variable when switched to generic brand from innovator in otherwise stable patient Patient factor? No Formulation effect? Possible But products are bioequivalent Could be higher within subject variation attributable to formulation, manufacturing, process variable
  • 213. Therapeutic Rejection of Products Lack of consistent response or safety will lead to Noncompliance Switch back to innovator Switch to another generic product Lower market share
  • 214. Relevant Questions How does T compare with R on an average (average BE or BEA )? √ How variable is T compared with R × (population BE or BEP ) Do the results vary more with T in some subjects and more with R in others × (individual BE or BEI )
  • 215. Compliance to regulations Acceptable bioequivalence data and comparable in vitro dissolution and CMC data are required for approval of abbreviated new drug applications But it does not assure a successful market life for the product
  • 216. Validation & Verification of in vitro and in vivo Specifications Pilot studies on different formulations with different dissolution profile Each formulation has been subjected to discriminating dissolution testing Process and formulation parameters have been analyzed Using complex statistical analysis and matrices various correlations can be established
  • 217. Failed bioequivalence Inappropriate study design inadequate numbers of subjects in the otherwise adequately designed and execution of BE study May be due to higher or lower measures of rate and extent of absorption for test product compared to the reference product or because the performance of the test or reference is more variable cf to each other or Both reference and test are different or varying in different ways
  • 218. 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 products 0.8 1.25
  • 219. Reasons for failure High variability of PK parameters Under-powered, N < than required Cost?? Lower enrollment Withdrawal Missing data, Outliers
  • 220. 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
  • 221. Statistical Clinical significance Significance e.g. Statistically Sequence effect in a single dose study of non-endogenous drug 1. Study was conducted as per appropriate design and all applicable guidelines and regulations 2. BE is established otherwise satisfactorily 3. Wash-out period is adequate 4. In second period all pre-dose values are zero 5. All the variables and restrictions were same in both periods
  • 222. 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.”
  • 223. 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."
  • 224. In vitro, In vivo evaluation Disintegration test (1950) Dissolution test (1968, apparatus 1) Apparatus 1 to 7 Defining specification of dissolution IVIVC Model based approach
  • 225. Dissolution Specifications In vitro dissolution specifications have to be established to ensure batch-to-batch consistency and to signal potential problems with in vivo bioavailability
  • 226. Data available for Innovator 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 & range of dissolution values of several production lots BA results of one or more lots (relative BA trials, BE trials) Formulation, process variables on lots used and not used in efficacy trials & / or BABE trials Stability data
  • 227. 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
  • 228. Expectations from Dissolution testing to assess batch-to-batch quality, where the dissolution tests, with defined procedures and acceptance criteria, are used to allow batch release dissolution 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 all product formulations investigated. Such efforts may enable the establishment of an in vitro-in vivo correlation. When an in vitro-in vivo correlation or association is available (21 CFR 320.24(b)(1)(ii)), the in vitro test can serve not only as a quality control specification for the manufacturing process, but also as an indicator of how the product will perform in vivo.
  • 229. When Equivalence Studies are Not Necessary Parenteral preparations – aqueous solutions Solutions for oral use Powders for reconstitution as a solution Gases Otic or ophthalmic products prepared as aqueous solutions Topical products prepared as solutions Aqueous solutions for nebulizer VPShah-Ukraine-07 inhalation or nasal sprays
  • 230. Documentation of equivalence is necessary Oral 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.
  • 231. Documentation of equivalence is necessary Non-oral and non-parenteral pharmaceutical products designed to act by systemic absorption (such as transdermal patches, suppositories, etc.) Sustained or otherwise modified release pharmaceutical products designed to act by systemic absorption. Fixed combination products
  • 232. 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.
  • 233. USP General Chapter 1088 IN VITRO AND IN VIVO EVALUATION OF DOSAGE FORMS Characterization 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
  • 234. Case A : IR & New MR A single-dose crossover study should include 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).
  • 235. Evaluating Food Effect whether a food effect is a result of problems with the dosage form? a single-dose crossover study comparing the solution (or immediate-release dosage form) under fed and fasting conditions
  • 236. 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
  • 237. Alternative appropriate studies could be conducted if the applicant were to label the drug for administration with a meal that is not fat-loaded. In this case, an alternative meal composition should be considered For delayed-release (enteric-coated) dosage forms, bioavailability studies to characterize adequately the food effects and to support the dosing claims stated in the labeling should be performed
  • 238. 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
  • 239. Case B Case B applies to a non-oral, modified-release dosage form of an already marketed active drug entity for which extensive pharmacodynamic /pharmacokinetic data exist. Case A studies (omitting the food effect studies) 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)
  • 240. Case C Case C applies to a generic equivalent of an approved modified-release dosage form. crossover single-dose and steady-state studies. For an oral modified-release dosage form, the food studies described under Case A should also be performed
  • 241. CFR 320.27 A multiple-dose study may be required to determine the bioavailability of a drug product in the following circumstances: (i) There is a difference in the rate of absorption but not in the extent of absorption. (ii) There is excessive variability in bioavailability from subject to subject. (iii) The concentration of the active drug ingredient or therapeutic moiety, or its metabolite(s), in the blood resulting from a single dose is too low for accurate determination by the analytical method. (iv) The drug product is an extended release dosage form. But CDER guidance generally recommends single-dose pharmacokinetic studies for both IR, MR drug products to demonstrate BE
  • 242. CDER Guidance : MR ANDA single-dose, nonreplicate, fasting study comparing the highest strength of the test and reference listed drug product and food-effect, nonreplicate study comparing the highest strength of the test and reference product Because single-dose studies are considered more sensitive in addressing the primary question of BE (i.e., release of the drug substance from the drug product into the systemic circulation), multiple-dose studies are generally not recommended, even in instances where nonlinear kinetics are present
  • 243. Food effect studies not required for IR When both test product and RLD are rapidly dissolving, have similar dissolution profiles, and contain a drug substance with high solubility and high permeability (BCS Class I) the product should be taken only on an empty stomach No food effect
  • 244. SUPAC-IR (1995) and SUPAC-MR Guidances (1997) Summary (Equipment Addendum (1999); FDAMA (1997) and “Changes Approved to an NDA or ANDA” Guidance (2000)
  • 245. General Aspects: (Change) Variables Covered Components and Composition Non Release Controlling Release Controlling Site Batch Size (Scale-Up/Scale-Down) Manufacturing Equipment Process
  • 246. General Aspects: Supporting Data • Level I (Minor) change Level of Change • Level II (Moderate) change • Level III (Major) change • Chemistry (A/C test, Stability) Tests • In Vitro dissolution/release • In Vivo bioequivalence test / IVIVC • Annual report Filing • Change being effected supplement • Prior approval supplement
  • 247. SUPAC- IR and MR SUMMARY The following changes need a bio study & / or IVIVC): level 3 RC and NRC, level 2 RC for NTR drugs level 3 site change level 3 process change
  • 249. IPC-USP 7th Annual Scientific Meeting February 6 - 7, 2008 Hyderabad International Convention Center Hyderabad, India Developing Fixed-Dose Combination Drug Products to Treat HIV Disease: The HHS/UNAIDS/WHO/SADC Principles Document and the FDA Guidance for Industry Darrell R. Abernethy, M.D., Ph.D. Chief Science Officer