Usp 2008track2combined

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.


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.


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).


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.


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.


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.


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.


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.


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.

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

Stirring rate

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
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


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

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

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

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


Reactions of amines with reducing sugars

7


Transesterification Reactions

O
Polyvinyl
acetate phthalate
H2N COOC2H5 N COOC2H5

O

8

Known Incompatibilities

9

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

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

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


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 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

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.


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


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

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

Usp 2008track2combined

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