USP (41) & (1251) Revision - Overview, 2013

Revision of USP
General Chapters 41 and 1251

Switzerland, May 2013
Dr. Klaus Fritsch
Manager Compliance
Global Business Area LabTec
Agenda
History
Revision of USP General Chapter 41
Summary of Technical Changes
Internal usage only
US Pharmacopeia
Founded 1820 by 11 physicians
The United States Pharmacopeia and The
National Formulary (USPNF) is a book of

public pharmacopeial standards. It contains
standards for chemical & biological drug
substances, dosage forms, compounded
preparations, excipients, medical devices,
and dietary supplements.
A drug product in the U.S. market or
imported in the U.S. must conform to the

standards in USPNF
1938 Federal Food, Drug & Cosmetics Act:
USP standards recognized, enforced by FDA
Scientific non-profit and non-governmental

organization
Internal usage only
Excerpt of USP General Chapter 41
Internal usage only
New USP General Chapters 41 & 1251

Publication of the Proposals
Pharmacopeial Forum PF38(5),

September 4th, 2012
THE PROPOSALS HAVE BEEN

APPROVED!
Official Publication: Second
Supplement to USP36-NF31
Release / Posting date: June 3rd, 2013

Official date: December 1st, 2013
Internal usage only
In memoriam Arthur (Thuri) Reichmuth
Internal usage only
USP Expert Panel

Convenor: Gregory Martin, Complectors Consulting
Scientific Liaison: Horacio Pappa, USP
Industry representatives:
-
Merck
Pfizer
Abbott
Genzyme (Sanofi)
Representative from NIST

Supplier representatives:
-
Mettler-Toledo AG (Arthur Reichmuth, Klaus Fritsch)

Sartorius (Dirk Ahlbrecht)
Internal usage only
Agenda
History
Internal usage only
New General Chapter 41 "Balances"

Scope
"States the requirements for balances used for materials that must be
accurately weighed (see General Notices, 8.20)."
Weighing of analytes for quantitative measures
Scope unchanged but better defined/explained
Requirements
"Weighing shall be performed using a balance that is calibrated []"

"[] and meets the requirements defined for repeatability and
accuracy."
"For balances used for other applications the balance repeatability and
accuracy should be commensurate with the requirements of its use."
Potential for selling more calibration certificates besides of the USP
certificate
Applications outside USP41 also need criteria => GWP Verification
9
Internal usage only
USP 41 - Requirement for Repeatability

Requirement
"Repeatability is assessed by weighing one test weight not less than 10

times."
"Repeatability is satisfactory if two times the standard deviation of the

weighed value, divided by the nominal value of the weight used, does not
exceed 0.10%."
"If the repeatability obtained is smaller than 0.41 d, where d is the scale
interval, replace this standard deviation with 0.41 d."
Additional Statement
"Because repeatability is virtually independent of sample mass within the

balances capacity, use of a small test weight, which may be difficult to
handle, is not required."
The rounding rule (0.41 d) stipulates a lower threshold for the
minimum weight which was previously not explicitly stated.
10
Internal usage only
Requirement for Repeatability

Example: Repeatability test with a semi-micro balance using a weight
with a nominal mass of 20 mg
Standard
deviation
s
Existing USP
criterion
3*s/m 0.1%
Pass /
Fail
Proposed new USP

criterion
2*s/m 0.10%
Pass /
Fail
0.005 mg
0.08% (0.1%)
Pass
0.05%
Pass
0.007 mg
0.11% (0.1%)
Pass
0.07%
Pass
0.009 mg
0.14% (0.1%)
Pass
0.09%
Pass
0.010 mg
0.15% (0.2%)
Failed
0.10%
Pass
0.011 mg
0.17% (0.2%)
Failed
0.11%
Failed
The effective requirement for repeatability essentially remains

unchanged from a practical perspective (changed coverage factor
and different rounding essentially compensate each other).
11
Internal usage only
USP 41 - Requirement for Accuracy

"The accuracy of a balance is satisfactory if its weighing value, when
tested with a suitable weight(s) is within 0.10% of the test weight
value."
"A test weight is suitable if it has a mass between 5% and 100% of the
balance's capacity."
Characteristic curve with

sensitivity deviation
Correct sensitivity
Indication
Not allowed
Stipulated
< 5%
5%
Capacity
Load
Internal usage only
Trueness (ISO/VIM) = Accuracy (USP/ICH)

imprecise:
values are dispersed
(random deviations)
precise (precision):
values are close
within each other
(good repeatability)
biased (bias):
average value is NOT
on target
(systematic deviation)
accurate
true (trueness):
average value is on
target (no systematic
deviation)
13
Internal usage only
USP Requirement for Repeatability and Accuracy

Requirement on
repeatability /
standard deviation
(0.10%)
repeatability & accuracy

Requirement on
accuracy / systematic
deviations (0.10%)
14
Internal usage only
New Certificate USP 41

Consists of Requirements for Repeatability and Accuracy
Miracal and LARS II Version of the new USP certificate will be

deployed from June, however need Windows7 (DSM3.2).
15
Internal usage only
Agenda
History
Project "Robin Hood" Go to Market Strategy
16
Internal usage only
Scope of USP General Chapter 1251

All USP Generel Chapters with a number equal or larger than 1000 are
for information only and not legally binding.
Provides information on
-
Installation and Operational Qualification

Performance Qualification and Balance Checks
Minimum Weight
Balance Operation
Important Statement at the beginning of the chapter: "The information

given in this chapter is applicable not only to balances used for materials
that must be accurately weighed (see Balances 41) but also to balances
used in all analytical procedures."
General Chapter 1251 is considered as an information chapter for
essentially all weighing applications.
17
Internal usage only
USP 1251 - Frequency of PQ and of Balance Checks

"The balance check is performed at appropriate intervals based on
applicable standard operating procedures. The frequency of the balance
check depends on the risk of the application and the required
weighing tolerance."
"Checks with external weights can be replaced partially using (automatic

or manually triggered) adjustment by means of built-in weights."
USP 1251 is no cooking recipe but needs user-specific implementation

=> GWP Verification
18
Internal usage only
Performance Qualification as per GC

1251
"Table 1 provides a list of the most important balance properties that should be
assessed during performance qualification. Depending on the risk of the
application and the required weighing process tolerance, some of these tests
may be omitted. Tests also can be omitted if there is evidence that the property
in question has only minimal effect on the weighing performance."
Property
Sensitivity
Examples
The test load at or sufficiently close
to the capacity of the balance.
Linearity
From 3 to 6 points over the range of the balance.
Eccentricity
Performed in the center of gravity and the four quadrants [].

Test load usually should be 30% of the capacity of the balance
or higher.
Repeatability
10 replicate weighings (using a test weight that is a few

percent of the nominal capacity of the balance).
19
Internal usage only
USP 1251 - The Concept of Minimum Weight

"The minimum net sample weight, mmin, of a balance can be expressed
by the equation:
mmin = k*s/required weighing tolerance
For materials that must be accurately weighed, Balances 41 stipulates

that repeatability is satisfactory if two times the standard deviation of the
weighed value, divided by the nominal value of the weight used, does
not exceed 0.10%. For this criterion the equation above simplifies to:
mmin = 2000*s
If not subject to the requirements of Balances 41, the minimum weight

value may vary depending on the required weighing tolerance and the
specific use of the balance."
This is the first official introduction of minimum weight within a

Pharma compendium and not restricted to applications of USP
Internal usage only
20
41.
Which Test Weight for Repeatability?

Indication
Smaller weight:
Feasible, but
difficult to handle
(especially for micro
and analytical
balances)
Test weight up to a few percent of

the balance's capacity.
Load
5%
5%
"To facilitate handling, the test weight that is used for the repeatability
test does not need to be at the minimum weight value but can be larger
because the standard deviation of repeatability is only a weak function
of the test weight value."
Internal usage only
Routine Test of Balances

Indication
Indication
Not allowed
Stipulated
< 5%
5%
Capacity
Load
Load
5%
5%
Internal usage only
USP 1251 - The Concept of Minimum Weight

"In order to satisfy the required weighing tolerance, when samples are
weighed the amount of sample mass (i.e., the net weight) must be equal
to or larger than the minimum weight. The minimum weight applies to
the sample weight, not to the tare or gross weight."
The net sample weight

has to fulfill the
minimum weight
requirement.
USP 1251 wants to overcome the misconception that a tare weight

can be used to fulfill the minimum weight requirement.
23
Internal usage only
The Concept of Minimum Weight

"Factors that can influence repeatability while the balance is in use
include:
- The performance of the balance and thus the minimum weight can vary over
-
time because of changing environmental conditions

Different operators may weigh differently on the balancei.e., the minimum
weight determined by different operators may be different
The standard deviation of a finite number of replicate weighings is only an
estimation of the true standard deviation, which is unknown
The determination of the minimum weight with a test weight may not be
completely representative for the weighing application.
The tare vessel also may influence minimum weight because of the
interaction of the environment with the surface of the tare vessel."
"For these reasons, when possible, weighings should be made at larger

values than the minimum weight."
The above information stipulates the application of a "safety factor".
24
Internal usage only
Variability of Minimum Weight Safety Factor

Minimum weight
Smallest net weight
adjustment
(by service)
SAFETY
calibration period
calibration period
time
Calibration
at Installation
As-found calibration
25
As-left calibration
Internal usage only
Environmental Influences Installation Problem Samples

"Potential facility issues:"
- Air currents
- Temperature changes
- Low or high humidity; electrostatics
- Vibration
- Corrosive materials
- Fume hood
- Magnetic influences
- Direct sunlight
"In situations when the balance is located near equipment or systems

that induce vibration, drafts, electromagnetic radiation, magnetic fields,
or changes in temperature or humidity, the assessment should be
conducted with those systems operating in order to duplicate a worstcase scenario."
26
Internal usage only
Types of Weighing Selected Example

"Gravimetric DosingGravimetric dosing typically is used for sample
and standard preparations or capsule filling. For such weighing the
analyst places the volumetric flask, vial, or capsule shell on the balance;
tares the balance after the balance display stabilizes; adds the solid or
liquid components into the receiver by means of dosing units; and
records the respective weights."
27
Internal usage only
Agenda
History
Project "Robin Hood" Go to Market Strategy
28
Internal usage only
Scope of USP and GMP

Conclusion for x-divisional go to market strategy:
Use the specific & practical guidance of USP and GWP as a reference to
help customers manage weighing equipment in GMP production in an
equivalent way as in quality control.
USP41
"Quantitative
Analysis"
GMP:
USP1251
USP41
All balances
"All analytical
Statement1
& scales2
) "For balances used for
procedures" other
applications the
1
balance repeatability and

accuracy should be
commensurate with the
requirements of its use."
) "Measuring equipment
of an appropriate range
and precision should be
available for production
and control operations.
Measuring, weighing,
recording and control
equipment should be
calibrated and checked at
defined intervals by
appropriate methods.
EC Guide to GMP, Chapter
3.40/3.41
2
e of USP: Quality Control of Drugs Lab Balances only

Ensure quality & safety of drugs
of GMP: Consistent Production and Quality Control All Scales and B

Build quality into the process 29
to ensure quality & safety of drugsInternal usage only
Impact of the proposed new GC 41 and 1251

The applicability of GC 41 ("used for materials that must be accurately
weighed") is now clearly defined.
Two independent tests with their respective test limits are described
(repeatability and accuracy).
Change of the coverage factor k from three to two reflects current

metrology practice (as e.g. in calibration certificates).
The change of the repeatability test limit from 0.1% to 0.10% affects the
rounding of the test result.
The effective requirement for the repeatability essentially remains

unchanged from a practical perspective (changed coverage factor and
rounding essentially compensate each other).
The use of 0.41d as the minimum repeatability value accounts for the
rounding error of digital indications as already incorporated in
international guidance documents for calibration of non-automatic
weighing systems.
30
Internal usage only
Impact of the proposed new GC 41 and 1251

An alternative method is described to determine the minimum weight of
balances, using a larger test weight than the minimum weight.
It is clearly stated that the minimum weight applies to the sample weight,
not to the tare or gross weight.
As repeatability fluctuates over time, when possible, weighings should

be made at larger values than the minimum weight (safety factor).
It is not permitted to carry out an accuracy test using a test weight with a
mass of smaller than 5% of the balance's capacity.
A daily balance assessment or check is not described anymore. Risk

analysis determines the frequency of any test.
Checks with external weights can be replaced partially using (automatic

or manually triggered) adjustment by means of built-in weights.
31
Internal usage only
Revision of USP
General Chapters 41 and 1251
Switzerland, May 2013
Dr. Klaus Fritsch
Manager Compliance
Global Business Area LabTec

USP (41) & (1251) Revision - Overview, 2013

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Revision of USP

General Chapters 41 and 1251

Internal usage only

National Formulary (USPNF) is a book of

A drug product in the U.S. market or

imported in the U.S. must conform to the

1938 Federal Food, Drug & Cosmetics Act:

USP standards recognized, enforced by FDA

Scientific non-profit and non-governmental

Internal usage only

Excerpt of USP General Chapter 41

Internal usage only

New USP General Chapters 41 & 1251

Pharmacopeial Forum PF38(5),

THE PROPOSALS HAVE BEEN

Release / Posting date: June 3rd, 2013

Internal usage only

In memoriam Arthur (Thuri) Reichmuth

Internal usage only

USP Expert Panel

Representative from NIST

Mettler-Toledo AG (Arthur Reichmuth, Klaus Fritsch)

Internal usage only

Internal usage only

New General Chapter 41 "Balances"

"Weighing shall be performed using a balance that is calibrated []"

Potential for selling more calibration certificates besides of the USP

Internal usage only

USP 41 - Requirement for Repeatability

"Repeatability is assessed by weighing one test weight not less than 10

"Repeatability is satisfactory if two times the standard deviation of the

"Because repeatability is virtually independent of sample mass within the

Internal usage only

Requirement for Repeatability

Proposed new USP

The effective requirement for repeatability essentially remains

Internal usage only

USP 41 - Requirement for Accuracy

Characteristic curve with

Trueness (ISO/VIM) = Accuracy (USP/ICH)

Internal usage only

USP Requirement for Repeatability and Accuracy

repeatability & accuracy

Internal usage only

New Certificate USP 41

Miracal and LARS II Version of the new USP certificate will be

Internal usage only

Internal usage only

Scope of USP General Chapter 1251

Installation and Operational Qualification

Important Statement at the beginning of the chapter: "The information

Internal usage only

USP 1251 - Frequency of PQ and of Balance Checks

"Checks with external weights can be replaced partially using (automatic

USP 1251 is no cooking recipe but needs user-specific implementation

Internal usage only

Performance Qualification as per GC

From 3 to 6 points over the range of the balance.

Performed in the center of gravity and the four quadrants [].