Software-based validation of processing systems

in accordance with FDA 21 CFR Part 11

With pharmaceutical manufacturing processes under tight governmental scrutiny and
regulation, it helps to have assistance in meeting the FDA’s requirements for data collection
and compliance validation.

By Matthias Bruns and Karlheinz Büscher, Siemens AG

Introduction
As a result of scandals in the food industry, the manufacturing process in the pharmaceutical
and food and beverage industries are now subject to very specific restrictions. For example,
companies must ensure that only authorized persons are able to modify the manufacturing
process, and every modification must be recorded in a way that reliably protects it against
manipulation. Before it goes into operation, a production plant must be validated by
authorized inspectors, who test the plant to make sure that it complies in every way.

In the past, documents and signatures had to be committed to paper. Today, after fulfilling
specific prerequisites, data which has been electronically collected and stored also fulfill the
conditions required for validation. The U.S. Food and Drug Administration (FDA) defines
these prerequisites in the directive "FDA 21 CFR Part 11."

The Simatic WinCC SCADA system supports compliance with these regulations for
electronic records and electronic signatures. Quickly and easily implemented, the system
optimizes the manufacturing process and improves quality.

This article discusses the fundamentals of the FDA 21 CFR Part 11 anticipated for the global
market, and shows how WinCC can be used to fulfill these and other mandatory regulations.
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Validation and FDA 21 CFR Part 11
The U.S. market is by far the biggest as well as the leading market for pharmaceutical
products. There are few medicines that are not sold on this market. It is therefore hardly
surprising that the regulations governing this market circulate very quickly throughout the
world. It is for this reason that the majority of European pharmaceutical companies comply
with the regulations issued by the FDA so that they can export their products to the U.S.

The FDA formulates very clearly the conditions under which pharmaceutical products must
be manufactured. FDA validation of a plant serves as proof that the plant complies with FDA
regulations.

Because modern manufacturing plants are highly automated, all important information is
available in electronic form. The FDA 21 CFR Part 11 regulation defines how and under what
conditions electronic records and signatures can be validated. Mr. Joseph C. Famulare, the
FDA employee responsible for this regulation, describes the job of the FDA as follows:
In essence, FDA 21 CFR Part 11 describes the use of electronic records and electronic
signatures. As seen by a SCADA system, this results in a series of very concrete demands:

1. Access control unequivocally defines operator privileges. Access is restricted

through security mechanisms.

2. An electronic signature must have the same degree of validity as a handwritten

signature. The system must allocate the electronic signature to a procedure or
document in such a way that it cannot be adulterated.

3. Operator activities during runtime must be recorded in a way that makes it impossible
for the recorded information to be adulterated, and so that the information tells the
reader who modified or acknowledged what when, and why (audit trail).

4. There must also be clear access mechanisms for application software engineering.
There must be a record of who modified what when, and why (change control).

5. Existing electronic data must be archived and must be able to be read at a later time.

Prerequisite in all the above cases is the possibility for unequivocal recording and allocation
of the date and time (time stamp)

Simatic WinCC V6 supports the above-mentioned requirements, simplifying validation of the

system as a whole. This benefits not only the producers, but also the system integrators and
the machine builders. Full compliance with FDA 21 CFR Part 11 is achieved, along with
additional administrative and procedural controls. The functions are described in detail in
Figure 1 below.

Figure 1: Requirements of FDA 21 CFR Part 11

Access control and electronic signature
Access control is a safety-related and thus a critical instrument for quality control. It must be
ensured that only authorized persons can make changes related to their own particular
sphere of responsibility. Moreover, it is of interest to the FDA that actions taken in the plant
be assigned to specific persons. It is for this reason that the FDA stipulates the recording of
the logins and logouts of authorized persons. In addition, there is a large number of
additional directives which require compliance, such as the two-component demand for user
ID and password, password expiration, and the blocking of certain users. All prescribed
functions are fully supported by WinCC in combination with the Simatic Logon Service
option. This applies to both stand-alone systems and client/server structures.

Figure 2: Simatic Logon Service

It is important following batch production to confirm through the signature of the person
responsible that production complied with regulations. The FDA permits this signature to be
an electronic signature entered via the control system. The signature is produced in
conformance with the previously described user management system with user ID and
password, and is also made available as a service by Simatic Logon. Prerequisite is the
existence of a written directive equating the electronic signature to the handwritten signature.

Figure 3 : Electronic Signature

Audit trails for runtime

An audit trail records all GMP-relevant runtime operator activities (GMP stands for Good
Manufacturing Practice). WinCC's Audit option allows easy, user-friendly configuration of the
relevant actions, both those relating to individual objects (see Figure 4) and those of a
general nature (see Figure 5).
Figure 4: WinCC Audit – Selection of GMP-relevant objects

Figure 5: WinCC Audit - Runtime auditing

In addition to the recording of operator activities, the starting and modifying of recipes
(customer-specific tables) also become part of the audit trail. And using an Audit Entry
function, the plant operator can also choose to include activities of a completely individual
nature in the audit trail, such as the moving of sliders or the activation of function keys.
WinCC Audit thus enables the plant operator to create complete, gap-free documentation on
who changed what in the plant, and when. The FDA requirement relating to the traceability of
modifications made in the plant is thus well-fulfilled.

WinCC Audit provides a viewer for analyzing the audit trail which can execute on any
Windows-capable PC and which provides a number of filtering and selection options (see
Figure 6).
Figure 6: WinCC Audit viewer - Runtime

The question now is, which data are supposed to become part of the audit trail? A small
selection of audit information is listed below:

o Time and date of the modification

o Project ID, PC and database name
o Old value and new value
o User name
 o Event / Function
o Comments / Reason for modification.

WinCC Audit makes a large amount of heterogeneous audit information available in order to
give the plant operator the option of selecting the information he/she considers relevant.

Change control for engineering

In addition to the recording of changes made at runtime, WinCC also makes it possible to
create an audit trail for all engineering changes. This allows the plant operator to view the
runtime changes and the engineering changes in chronological order. This is particularly
advantageous for the analysis of bad batches in order to save valuable production time.

WinCC Audit makes a distinction between configuration changes performed with the WinCC
Explorer and so-called Document Control. Comprehensive monitoring is easy and user-
friendly to activate.

Figure 7: WinCC Audit – Configuration Auditing

Document Control includes plant displays, scripts, protocol layouts and customer-specific
documents. All these documents and files can be monitored for changes by WinCC Audit. In
addition, binary files are generated from the temporary versions of the documents and stored
in a separate SQL database. This allows the plant operator to build on older temporary
versions. In order to be able to manage the files automatically, the users are led through so-
called Check-in, Check-out and Rollback functions.

Figure 8: WinCC Audit Viewer – Document Control

Every change in the plant, whether in Runtime mode, engineering or Document Control can
be traced conclusively.

Audit Trails are stored as log files in an SQL database and are therefore protected against
manipulation. This WinCC Audit database can be easily organized in either a centralized or
distributed configuration on any network PC in the client/server network. The database can
be swapped out and archived, satisfying the main FDA requirement that modification data
must be held available over the entire life of a plant and beyond.

Summary and conclusion

Today, process optimization and simultaneous compliance with FDA regulations is the main
requirement in the pharmaceutical industry. The use of electronic records and electronic
signatures to FDA 21 CFR Part 11 serves this objective. The WinCC V6 SCADA system in
combination with the Audit and SIMATIC Logon options makes the application "Ready for
validation."

Additional information can be found on the Internet at: www.siemens.de/wincc-fda

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About the Authors

Matthias Bruns (e-mail: matthias.bruns@siemens.com) is Manager, HMI Sector

Development, Chemical & Pharmaceutical Industry, and Karlheinz Büscher (e-mail:
karlheinz.buescher@siemens.com) is Product Manager, HMI with focus on FDA, at Siemens
AG, Automation and Drives Group, Nuremburg, Germany.