Documente Academic
Documente Profesional
Documente Cultură
Focus on Quality
An Integrated Risk Assessment
for Analytical Instruments
and Computerized Laboratory
Systems
A risk assessment is presented for determining the amount of qualification and validation work
required to show that instruments and computerized laboratory systems are fit for their intended
purpose.
C. Burgess and R.D. McDowall
Table I: Increased granularity of existing USP <1058> instrument groups groups depending on its use. Intended
use is also an essential part of our risk
USP <1058> Group Suggested Qualification and Validation Approach
assessment presented in this column.
Group A (Apparatus)
However, the current weakness
No measurement or calibration requirements of the overall risk-based approach
Compliance by observation is the way in which software is as-
No user defined qualification or calibration requirements
sessed. Software is pervasive in group
Group B (Instruments) B instruments and group C systems.
Type 1: Instrument
Qualification of the instrument operating parameters Chapter <1058> currently references
Implicit validation of software functions through the the FDA guidance document, General
only
qualification of the instrument
Principles of Software Validation (9).
Qualification of the instrument operating parameters This guidance was written primarily
Type 2: Instrument Implicit validation of software functions through the
with embedded qualification of the instrument for medical device software, which is
calculations Explicit verification of the calculations used by individual neither configured (modified to the
laboratory business process by vendor supplied
Qualification of the instrument operating parameters tools) nor customized (writing soft-
Type 3: Instrument Implicit validation of instrument software functions ware macros or modules that are in-
with user-defined through the qualification of the instrument
tegrated with the application). Given
program capability User-defined programs require specification and
verification that they work as intended that many analytical instruments and
Group C (Systems)
systems are configured or customized,
this guidance does not fit well in a
Qualification of the instrument using the control software
Type 1: Low Documents user types and corresponding access privileges
regulated GXP laboratory environ-
complexity system System life cycle for nonconfigurable software or ment.
configurable software used with default settings In January 2012, we published a
Qualification of the instrument using the control software stimulus to the revision process in
Type 2: Medium Document user types and corresponding access privileges the on-line version of Pharmacopeial
complexity system Document software configuration Forum (13), in which we proposed an
System life cycle validation for configurable software
update for USP <1058>. In our pro-
Qualification of the instrument using the control software posal, instrument qualification was
Documents user types and corresponding access privileges
Type 3: High
Document software configuration integrated with computerized system
complexity system validation rather than being two
System life cycle validation for configurable software
Specification and verification of the custom modules or separate activities. This would pro-
macros vide regulated laboratories with the
opportunity to reduce the amount of
also referenced the FDA guidance for and validation of instruments and work and avoid potential duplication.
industry entitled General Principles computerized laboratory systems (The In this publication, we included a risk-
of Software Validation (9), which was GAMP GPG uses the term laboratory assessment flow chart for determining
written primarily for medical devices; computerized system in contrast to the the amount of work to perform to
the configuration and customization more common term of computerized qualify analytical instruments and,
of software is not mentioned tehre. laboratory system; however the two where appropriate, validate the soft-
terms are equivalent.) We have a paper ware functions and applications. From
GAMP Good Practice Guide for soon to be published that maps the the comments received, we updated
Laboratory Systems Updated two approaches and shows that they the flow chart. We present it here as a
The publication of the first edition of are very similar despite some differ- simplified method for classifying the
the GAMP Good Practice Guide for ences in terminology (12). apparatus, instruments, and systems
Validation of Laboratory Computer- in your laboratory.
ized Systems (5) had some problems. Progress Updating USP <1058>
However, in the recently published The original basis of USP <1058> was Why an Integrated Risk
second edition (6), the good practice the 2004 AAPS white paper Analyti- Assessment Approach?
guide was aligned with GAMP 5 (4) cal Instrument Qualification, which The basic risk assessment model in
and was updated to be risk-based focused on a risk-based approach to <1058> is the classification of any
(as reflected in the new title). Col- AIQ by classifying apparatus, instru- item used in a laboratory into group
laboration with us during the writing ments, and systems depending on the A, B, or C based on a definition of in-
enabled both the good practice guide laboratorys intended use. The defini- tended use. This is generally a sound
and the new draft of USP <1058> (11) tion of the intended use is the key part approach, because apparatus (group
to be more closely aligned and have of the process, because the same item A), instruments (B), or systems (C)
a unified approach to qualification could be classified in any of the three are easily classified. However, there is
w w w. s p e c t r o s c o p y o n l i n e . c o m November 2013 Spectroscopy 28(11) 3
1. Unambiguously differentiating 3.
version of USP <1058>. This will user programs programs complexity complexity
B and C.
No GMP Group B Group B Group B Group C Group C Group C
Item 2 is a fundamental nonpe- relevance
excluded
Validate
software
Group A
apparatus
Type 1
instrument
Type 2
instrument
Type 3
instrument
Type 1
system
Type 2
system
Type 3
system
priate, the department and location 2. Shipment of material, such as data 7 is yes then the organizations vali-
of the item as well as an inventory or loggers? dation procedures for computerized
asset number if available. 3. Nonclinical laboratory studies in- systems should be followed. Again,
The next, and most important, part tended for submission in a regula- this question is included to ensure
of this preparation phase is to describe tory dossier? completeness of coverage of the risk
the intended use of the item. This is 4. Clinical investigations including assessment questionnaire for all
the key to the whole risk assessment. supply of clinical supplies or phar- laboratory instruments, systems, and
It is essential to be as accurate as pos- macokinetics? software.
sible and also to indicate if there are 5. Generation of, submissions to, or If the answer to question 7 is no,
any records created by the use of the withdrawal of a regulatory dos- then it is necessary to determine if
item (for example, paper printouts or sier? the item is apparatus (group A) as
electronic records). The intended-use 6. Backup, storage, or transfer of opposed to instruments and systems
statement should also indicate if the electronic records supporting any (USP <1058> group B or group C).
item will be connected to the network of the above?
or will stand alone. If all responses are no then Step 3: Is the Item an Apparatus (in
Some people may consider simpli- qualification and validation are not Group A)?
fying the intended use statement, but necessary because the item has no The third step in the risk assessment
this is the most important part of this GxP function and is documented as is to differentiate between apparatus
stage. Failure to define the intended requiring no qualification or valida- and instrumentation or systems. USP
use adequately means that the only tion. This is highly unlikely to happen <1058> defines group A as standard
person who is fooled is you. Ensure within a GMP-regulated quality con- apparatus with no measurement capa-
that the intended use is defined well. trol laboratory. However, if the labo- bility or user requirement for calibra-
For example, if an instrument has ratory is on the boundary between tion (3). Therefore, we ask three closed
90% of its work involved in research research and development there may questions (questions 810) to identify
and only 10% with GxP work, it is nat- be some interesting issues to man- items of apparatus:
ural to focus on the research element. age. If the majority of work is carried 8. Is there any measurement capabil-
However, it is the 10% of the GxP out for research and a minority of the ity of the item?
work that is critical and determines work for development (say a 90:10 split 9. Is the item user calibrated after
the overall level of control required. of activities) do we focus on the 90% purchase?
or the 10%? Because there is a high 10. Does the use of the item require
Step 1: Determine GMP Relevance probability that the 10% will end up in more than observation?
The first stage of the risk assessment a regulatory dossier, we need to focus If the answer to each question is
is to determine if the item is carrying on the 10% to ensure the instrument no, then the item is classified as USP
out GMP work. For the sake of com- and any software output are correct. <1058> group A. On the other hand, if
pleteness of the risk-assessment model Furthermore, if procedures developed one or more answers are yes, then we
we have included the possibility of using the instrument or system are to move to step 4.
laboratory instrumentation and sys- be transferred to other laboratories
tems being present that are not used later in the lifecycle, we need to ensure Step 4: Is the Item an Instrument (in
for regulatory purposes. Based on the the item is under control and the out- Group B) or a System (in Group C)?
intended-use statement from the prep- put is verified. Group B includes standard equipment
aration stage, we ask the six closed and instruments providing measured
questions (questions 16). These have Step 2: Is the Item values as well as equipment control-
been taken from the Society for Qual- Standalone Software? ling physical parameters (such as
ity Assurance (SQA) Computer Vali- At step 2 only one closed question is temperature, pressure, or flow) that
dation Initiative Committee (CVIC) asked (question 7) to determine if the need calibration. In contrast, group
risk assessment questionnaire (14). item is standalone software: C systems include instruments and
This questionnaire posed 15 closed 7. Is the item only software that per- computerized analytical systems,
questions to determine if a comput- forms a GxP function or creates where user requirements for function-
erized system carried out any GxP GxP records? ality, operational, and performance
activities. We have taken only the rel- This question should be applied limits are specific for the analytical
evant laboratory questions and used not only to recognized software ap- application. These systems typically
them in this <1058> risk assessment. plications such as statistical software are controlled by a standalone com-
The questions asked are related to or a laboratory information manage- puter with specific software for in-
what is the item used for. Is the item ment system (LIMS), but also Excel strument control and data acquisition
used for (Microsoft) spreadsheets and Access and analysis (3). To determine which
1. Testing of drug product or API for (Microsoft) databases used within the items belong in these two groups, at
formal release? laboratory. If the answer to question step 4 two closed questions are asked
w w w. s p e c t r o s c o p y o n l i n e . c o m November 2013 Spectroscopy 28(11) 5
category
software
acquisition? Low or
GAMP
If both answers are yes then the 4 Medium Medium
medium
item is considered a system and falls
under USP <1058> group C. However,
if the answer to question 12 is no Low or
3 Low Low
then the item is considered an instru- medium
ment and falls under USP <1058>
group B. The exact group B instru- Low Medium High
ment subclassification (I, II, or III) is
determined by asking three further Record impact
closed questions regarding customiza-
tion and configuration in step 5. Figure 2: Subclassification of USP <1058> group C systems by software category and record
impact.
Step 5: Group B Instrument
Subclassification cess could be controlled by a standard Guide Compliant Part 11 Records and
At step 5 the three remaining ques- operating procedure so that user- Signatures (see reference 15 for this
tions are asked (questions 1315) to defined programs developed after the classification). Second, the complex-
determine the subcategory of group initial qualification can be validated ity of the system is determined by the
B that the instrument belongs to (see on the operational system. Ideally, nature of the software used to control
Table I). The closed questions are as the user defined programs should be the instrument and to acquire, pro-
follows: controlled to prevent change by un- cess, store, and report results. Here,
13. Are there any built-in calcula- authorized persons or without change we use the GAMP 5 software classifi-
tions used by the instrument that control. It is possible that Type 3 in- cation (5).
cannot be changed or configured? struments could also have embedded
14. Can you configure the built-in calculations, where the answer to Q14 Determination of Record Impact
calculations in the instrument? was also yes, which would result in The GAMP Part 11 guide (15) identi-
15. Can you write a user-defined pro- these calculations being verified the fies three types of records generated
gram with the instrument? same way as Type 2 instruments. in the pharmaceutical industry:
Group B, Type 1 instruments are Let us return to the intended use High impact: Records typically have
indicated only if question 13 is an- statement in the preparation step dis- a direct impact on product quality,
swered yes because this is an instru- cussed earlier. The instrument may be patient safety, or could be included
ment without any calculations or the capable of performing embedded cal- in a regulatory submission for ex-
ability for the user to define programs. culations or have the ability for users ample, batch release, stability stud-
Therefore, only qualification of the to define programs. However, if these ies, method validation records
instruments functions is required to functions are not intended to be used, Medium impact: Records typically
demonstrate its intended purpose. then they do not need to be verified. have an indirect impact on product
Group B, Type 2 instruments are Hence, you can see the importance of quality or patient safety for ex-
designated if the answers to questions the intended use statement that was ample, supporting records such as
14 and 13 are yes and to question written in the preparation stage of the calibration, qualification, or valida-
15 is no. Therefore, in addition to assessment. tion records
qualification of the instrument the Low impact: Records typically have
embedded calculations need to be Step 6: Group C System a negligible impact on product qual-
verified in the way that they are used Subclassification ity or patient safety and are used to
by the laboratory. As noted in Table I, there are three support regulated activities but are
Group B, Type 3 instruments are types of group C systems that need to not the key evidence of compliance
classified if the answer to Q15 is yes be differentiated. System complexity for example, plans for qualifica-
and the remaining two answers are for systems in group C is determined tion or calibration activities (15)
no. This type of instrument requires by two factors. The first is the im- Note that most of the records gener-
qualification of the instrument plus pact of the records generated by the ated in a QC laboratory will typically
specification and verification of any system. Our risk assessment uses the be high impact. However, in an ana-
user defined programs. The latter pro- scheme in the GAMP Good Practice lytical development laboratory there
6 Spectroscopy 28(11) November 2013 w w w. s p e c t r o s c o p y o n l i n e . c o m
may be more of a mixture of high- to cations that are either category 3 low complexity systems, using an
low-impact records. In this case, the or 4. SOP for validation or qualification
worst case scenario should be taken to of simpler systems could be an easier
avoid understating the risk offered by Determination of Group C Complexity and more efficient approach (16). Fig-
the system. When the impact of the records gen- ure 2 can also be used in a different
erated by the system and the software way, to identify the risk elements in
Determination of category or categories has been deter- the different software components of
GAMP Software Category mined, it is compared with the grid a system. Components with custom
The subclassification of USP <1058> in Figure 2 to determine the system software require more control than
group C systems is completed by complexity. This will also determine those that are configured compared
determining the GAMP software the amount of qualification and vali- with those that are not configured.
category or categories that are used dation work required. The system life cycle to be fol-
to control the instrument and acquire As presented in Figure 2, there are lowed and the documented evidence
and process data from it (4). The three three types of systems possible in required for qualification of instru-
categories that we consider in this group C: ments and validation of the software
portion of the risk assessment are Group C, Type 1 system: A low should be defined in a validation plan
Category 3: Nonconfigurable soft- complexity laboratory computerized or SOP. The details of this are outside
ware in which the software cannot system where the instrument is con- the scope of this column, and readers
be changed to alter the business trolled by category 3 software that should refer to existing approaches
process automated. There is limited generates low-, medium-, or high- (4,6).
configuration such as establishing impact records or unconfigured
and managing user types and the category 4 software that generates Summary
associated access privileges of each low-impact records. In this column we have presented a
one, report headers, and location of Group C, Type 2 system: A medium comprehensive risk assessment pro-
data storage of records. However, complexity system consists of an cess for classifying apparatus, instru-
this limited configuration does not instrument controlled by category ments, and computerized laboratory
change the business process auto- 4 configurable software generating systems used in regulated laborato-
mated by the software. low-, medium-, or high-impact re- ries. The intention is to demonstrate
Category 4: Configurable software cords. An alternative classification clearly that an integrated approach to
that uses tools provided by the sup- for a laboratory computerized system analytical instrument qualification
plier to change the business process with category 3 software that gener- and, where appropriate, computer-
automated by the application. The ates high-impact records is that the ized system validation, is more ef-
tools can include entering a value system can be medium complexity. ficient than separating the two tasks.
into a field (such as reason for Group 3, Type 3 system: A high The risk assessment also ensures that
change within an audit trail), a but- complexity system is one with an laboratories qualify or validate all
ton to turn a function on or off, or a instrument controlled by category intended use functions in an item and
supplier language. In the latter case, 4 software that has category 5 soft- aims to minimize regulatory exposure
the configuration should be con- ware modules or macros. It can gen- from omitting work.
sidered under custom software. erate low-, medium-, or high-impact
Category 4 with category 5 custom records. It is the incorporation and References
modules or macros: In this case, use of the custom or category 5 (1) US Food and Drug Administration,
we have the configurable software software that makes the system high Guidance for Industry: Good Manu-
above, but with either custom complexity, because this software is facturing Practices for the 21st Cen-
modules programmed in a widely unique and needs more control. tury (FDA, Rockville, MD, 2002).
available language or macros for The approach to the control of (2) International Conference on Harmo-
automating the operation of the these systems is through a combina- nization, ICH Q9, Quality Risk Man-
application that are devised and tion of qualification of the analytical agement (ICH, Geneva, Switzerland,
written by the users using tools instrument with the validation of 2008).
within the application. Category 5 the application software (that is, an (3) General Chapter <1058> Analytical
is the highest risk software because integrated approach). The controlling Instrument Qualification in United
it is typically unique to a labora- document for this work is either a States Pharmacopeia 36 National
tory or an organization. We will standard operating procedure (SOP) Formulary 31 (United States Pharma-
not consider custom applications or a validation plan. Because of the copeial Convention, Rockville, Mary-
in this risk assessment because the wide variation of systems, the first land, 2012).
overwhelming majority of systems option would be a validation plan for (4) ISPE, Good Automated Manufactur-
used in the regulated laboratory high and most medium complexity ing Practice (GAMP) Guide, version
are commercially available appli- systems. For some medium and most 5 (International Society of Pharma-
w w w. s p e c t r o s c o p y o n l i n e . c o m November 2013 Spectroscopy 28(11) 7