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
Revision of USP General Chapter 1251
Summary of Technical Changes

1 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
2 Internal usage only
Excerpt of USP General Chapter 41

3 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

4 Internal usage only

In memoriam Arthur (Thuri) Reichmuth

5 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)

6 Internal usage only

Agenda

History
Revision of USP General Chapter 41
Revision of USP General Chapter 1251
Summary of Technical Changes

7 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
8 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.
9 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 Existing USP Pass / Proposed new USP Pass /

deviation criterion Fail criterion Fail
s 3*s/m 0.1% 2*s/m 0.10%

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).
10 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

Load
< 5% 5% Capacity Internal usage only
Trueness (ISO/VIM) = Accuracy (USP/ICH)
imprecise: precise (precision):
values are dispersed values are close
(random deviations) 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)

12 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%)

13 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).
14 Internal usage only
Agenda

History
Revision of USP General Chapter 41
Revision of USP General Chapter 1251
Summary of Technical Changes
Project "Robin Hood" Go to Market Strategy

15 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.
16 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
17 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 Examples
Sensitivity 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).

18 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 41.
19 Internal usage only
 Which Test Weight for Repeatability?

Indication

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

Load Load
< 5% 5% Capacity
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.
22 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".

23 Internal usage only
 Variability of Minimum Weight Safety Factor
Minimum weight
Smallest net weight

SAFETY adjustment
(by service)

calibration period calibration period

time
Calibration
at Installation As-found calibration As-left calibration

24 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 worst-
case scenario."

25 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."

26 Internal usage only

Agenda

History
Revision of USP General Chapter 41
Revision of USP General Chapter 1251
Summary of Technical Changes
Project "Robin Hood" Go to Market Strategy

27 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.

USP1251 GMP:
USP41 USP41
"All analytical All balances
"Quantitative Statement1
Analysis" procedures" 1)"For balances used for & scales2
other applications the 2)
balance repeatability and "Measuring equipment of
accuracy should be an appropriate range and
commensurate with the precision should be available
requirements of its use." 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
Scope of USP: Quality Control of Drugs Lab Balances only
Ensure quality & safety of drugs

Scope of GMP: Consistent Production and Quality Control All Scales and Balanc
Build quality into the process 28
to ensure quality & safety of drugs Internal 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.

29 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.

30 Internal usage only

 Revision of USP
General Chapters 41 and 1251

Switzerland, May 2013

Dr. Klaus Fritsch
Manager Compliance
Global Business Area LabTec