Published on IVT Network (http://www.ivtnetwork.

com)

Analytical Instrumentation
By Amjad Ganma Jan 6, 2013 2:58 pm PST

Getty Images
I. Introduction
In order to ensure the quality and reliability of data produced by a laboratory, it is necessary to use a systematic method of
qualifying and calibrating the instruments in a way that is appropriate for the type of instrument and which takes the type of
use into consideration. Because reliable data is a key component of GMP, it is covered throughout global regulations and
guidelines.
II. Major Regulatory Guidelines
Code of Federal Regulations Title 21 Part 211 Section 160 Subpart I: Laboratory Controls
The calibration of instruments, apparatus, gauges, and recording devices at suitable intervals in accordance with an
established written program containing specific directions, schedules, limits for accuracy and precision, and provisions
for remedial action in the event accuracy and/or precision limits are not met. Instruments, apparatus, gauges, and
recording devices not meeting established specifications shall not be used. [43 FR 45077, Sept. 29, 1978, as amended
at 73 FR 51932, Sept. 8, 2008]
Read full guidance.
The FDA is very clear and concise in this section. The expectation is simple: instruments used for GMP testing must be
calibrated on a regular schedule, following a specific procedure, using written acceptance criteria and providing instructions for
what when the results do not meet the specifications. Instruments are not to be used for GMP testing if the calibration testing
does not meet specifications. Although this is generally accepted and followed, one point that is frequently missed is
specifying what should be done, etc.
B. European Medicines Agency
Eudralex Volume 4, Annex 15
Planning for Validation

2. All validation activities should be planned. The key elements of a validation programme should be clearly defined and
documented in a validation master plan (VMP) or equivalent documents.
3. The VMP should be a summary document which is brief, concise and clear.
4. The VMP should contain data on at least the following:
(a) validation policy;
(b) organisational structure of validation activities;
(c) summary of facilities, systems, equipment and processes to be validated;
(d) documentation format: the format to be used for protocols and reports;
(e) planning and scheduling;
(f) change control;
(g) reference to existing documents.
5. In case of large projects, it may be necessary to create separate validation
master plans.
Download the full guidance.
C. International Conference for Harmonisation
ICH Q7: Good Manufacturing Practices for Active Pharmaceutical Ingredients
5.3 Calibration
5.30 Control, weighing, measuring, monitoring and test equipment that is critical for assuring the quality of intermediates
or APIs should be calibrated according to written procedures and an established schedule.
5.31 Equipment calibrations should be performed using standards traceable to certified standards, if existing.
5.32 Records of these calibrations should be maintained.
5.33 The current calibration status of critical equipment should be known and verifiable.
5.34 Instruments that do not meet calibration criteria should not be used.
5.35 Deviations from approved standards of calibration on critical instruments should be investigated to determine if
these could have had an impact on the quality of the intermediate(s) or API(s) manufactured using this equipment since
the last successful calibration.
Download the full guidance.
III. Other Regulatory Guidances
American National Standards Institute
ANSI/NCSL Z540-I-1994,Calibraion laboratories and measuring test equipment-General requirement
International Standards Organization
ISO 10012-1:19929(E),Quality assurance requirements for measuring equipment Part 1:metrological confirmation system for
measuring equipment

European Directorate for the Quality of Medicines and Healthcare

EDQM Quality management guideline: It includes many documents related to qualification of analytical instruments
Japanese Pharmacopoeia
Japanese Pharmacopoeia 16th edition: General Information: Physics and Chemistry: System Suitability
World Health Organization
WHO: Quality Assurance of Pharmaceuticals: Relationship between Validation and Qualification
United States Pharmacopoeia
United States Pharmacopoeia Chapter <1058>
The Validation is the action of proving, in accordance with the principles of GMP, that any procedure, process, equipment,
material, activity or system actually leads to the expected results, while the qualification is the action of proving that any
premises, systems and items of equipment work correctly and actually lead to the expected results Validation and qualification
are essentially components of the same concept.
The term qualification is normally used for equipment, utilities and systems, and validation for processes. In this sense,
qualification is part of validation
IV. Discussion Topics
Commentary from the Subject Matter Expert
USP <1058> is a separate general chapter for instrument qualification came into operation in August 2008 dealing with the
qualification of analytical instruments in the Pharmacopoeial Forum was published in the first supplement of the USP 31 / NF
28 (2008).
The pharmaceutical industry is glad that, with this chapter, it has now an official regulatory basis for the qualification of
equipment in pharmaceutical quality control. Up till now, the qualification approaches had to be deduced and adopted from
general recommendations, e. g. from Annex 15 to the EC GMP Guide (Qualification and Validation). With General Chapter
<1058> there is now a solid basis for analytical instrument qualification on the part of the pharmacopoeias
The new USP chapter recommends the well-established qualification phases also for analytical instruments:
Design Qualification
Installation Qualification
Operational Qualification
Performance Qualification
One interesting fact is that, by performance qualification, the periodic checks of the instrument in defined intervals are meant,
i.e. performance qualification now includes the regular calibration activities, preventive maintenance and necessary repairs
over the whole runtime of the individual device - naturally taking change control into consideration.
The USP's proposal of a stepped model for different categories of instruments. It suggests three categories were helpful for
daily practice:
Group A (Simple Equipment)
Group B (Among Others For Thermometers, Ph Meters, Refractometers)

Group C (computer-based devices, like HPLC, GC, NIR, etc.)

For these different groups, the range of qualification measures can be laid down in a stepped way in the companies.
Moreover, this chapter also includes a brief statement on software validation. From a software perspective, the GAMP 5 Good
Practice Guide (GPG) for Laboratory Computerised Systems has wide recognition within the industry and regulators but it is
not consistent with some of the elements of <1058>. This USP General Chapter <1058> is currently under revision.
Components of Data Quality
Each layer mentioned below in the aspect of quality data adds to the overall quality. Analytical instrument qualification forms
the base for generating quality data. The other components essential for generating quality data are analytical method
validation, system suitability tests, and quality control check samples. They follow:
Quality control checks: Verifies accuracy of sample analysis
System suitability tests: Verifies that the system performs according to analysts expectations
Analytical methods validation: Proof that analytical procedures does what it purports to do
Analytical instrument qualification: Forms the base for generating quality data. Proof suitability of the instrument for
intended use.
Warning Letters/Citations
Inadequate Instrument Qualification Leads to FDA Warning Letter
In July and August 2011, the FDA conducted a 31-day inspection of a pharmaceutical company. In its findings, the FDA
observed that an on-line measurement system including TOC and conductivity was not compliant for the intended use based
on the fact that a performance qualification (PQ) was not documented. The data from the on-line analyzer and accompanying
recorder was being used to support an out-of-specification (OOS) incident and justify product lot release. This was a repeat
observation from the previous establishment inspection.
The finding points out the importance of analyzer PQ from the FDAs perspective. Performance qualification for analytical
instruments is defined as the documented collection of activities necessary to demonstrate that an instrument consistently
performs according to specifications, as defined by the user and is appropriate for the intended use.5 In the case mentioned
above, the on-line analyzers intended use was for real-time testing, and the premature closure of an incident investigation
lead to an improper product release. As described below in FDA Warning Letter regarding Missing PQ, the data from the online TOC instrument was invalid for its intended use without the PQ and accompanying validation of the data recorder system
Inadequate Method Comparison Leads to a Warning Letter
Improvements to analytical techniques and transfer of methods to at- or on-line applications emerged as important
opportunities to reduce risk and increase efficiency in todays modern manufacturing facility. A pharmaceutical company, cited
in 2011 for not adequately performing the required steps to support the transition to a new testing approach, was making these
improvements. In this case, there was no method comparison or equivalency study performed to show that the changes were
superior to the original approved method. The data in question for this new approach was used for OOS closure and lot
release.
In its 2004 guidance, PATA Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance,
the FDA describes the importance of equivalency testing, transfer, and comparison studies that are needed when improving
analytical methods which are used for critical measurements of the process. The FDA further stresses, in a more recent
guidance document on Process Validation,3 that analytical method validation and improvement is very important if these
methods are used to reduce risk (monitoring), provide process understanding (control), or release product based on the data.
Analytical methods supporting commercial batch release must follow cGMPs in parts 210 and 211. FDA Warning Letter
Regarding Inadequate Method Validation details the specific deviation from regulations.
Advice on Avoiding the Aforementioned Warning Letters

Aligning with Current FDA Guidance: To have Analytical Instruments in order and comply with rules and regulations; create
validation support packages (VSP) that aligns with the best practices of instrument qualification and methods validation. Below
Table highlights the validation characteristics and robust protocols. Validation Support Packages (VSP) and Real-time Testing
VSP (RTT VSP) that can help prevent the previously described scenarios in the warning letters. They also align with best
practices and international guidance from organizations such as the Tripartite International Conference on Harmonization
(ICH).

V. Conclusion
Companies are enhancing their compliance functions by adding resources, trying out different organizational structures, and
bolstering a culture of compliance. While companies are struggling with how to measure the effectiveness of these efforts,
they are well aware of the financial and reputational consequences of noncompliance. Companies are also testing different
approaches to their oversight of compliance, though the audit committee tends to take the lead. Moving forward, companies
will need to balance the increasing demands of compliance oversight with the continuing need for adequate attention to
broader strategy issues. This handbook will be a useful tool for the companies to be compliant with the current regulations
and assess drug regulation performance attributed to analytical instrument. By comparing and contrasting the drug regulation
by different regulatory bodies this handbook will help us to draw a conclusion about the components of drug regulatory
systems which constrain or facilitate the effectiveness of drug regulation.

Source URL: http://www.ivtnetwork.com/article/analytical-instrumentation