How FDA regulations are shaping the pharmaceutical manufacturing sector

Jonathan Wilkins of
European Automation examines the implications of the latest update CFR21/11 to 21
CFR part 11 of Code of Federal Regulations made by the US Food and Drug
Administration (FDA). The FDA requires anyone designing, manufacturing and
testing pharmaceuticals to abide by these rules. Since the enforcement of 21
CFR part 11 a few years ago, chemicals and pharmaceuticals manufacturers have
had to adapt and improve automated procedures at their manufacturing plants
across the US and Europe.

When 21 CFR part 11
came into effect, significant discussions followed among manufacturers, contractors,
systems integrators and the FDA concerning the interpretation and
implementation of the regulations. The discussions specifically focussed on electronic
records, electronic signatures, validation, time stamps, maintenance of
electronic records and traceability.

The audit trail is central
to the control imposed by the FDA. The guides state that:

‘Even if there are
no predicate rule requirements to document, for example, date, time, or
sequence of events in a particular instance, it may nonetheless be important to
have audit trails or other physical, logical, or procedural security measures
in place to ensure the trustworthiness and reliability of the records. We
recommend that you base your decision on whether to apply audit trails, or
other appropriate measures, on the need to comply with predicate rule
requirements, a justified and documented risk assessment, and a determination
of the potential effect on product quality and safety and record integrity. We
suggest that you apply appropriate controls based on such an assessment. Audit
trails can be particularly appropriate when users are expected to create,
modify, or delete regulated records during normal operation.’

Though initially met
with scepticism, the regulation has actually brought significant benefits by
encouraging better electronic record keeping in good manufacturing practice

Robotics and robot
vision can help record keeping and positively contribute to improving
procedures. In addition, the data acquired through robotic vision can be fed to
a PLC (Programmable Log Controller), HMI (Human Machine Interface) or SCADA (Supervisory
Control and Data Acquisition) system to be analysed. This data can also be
easily interrogated and acted upon in the event of a recall.

The validation
requirements of the pharmaceutical industry mean that when a component breaks
down, simply introducing a new part from a different manufacturer, even if it
achieves the same objective, isn’t really an option. Similarly, re-designing
the system is not only expensive but also causes complex traceability and
validation issues.

European Automation offers
to the pharmaceutical sector the capability to find and deliver nearly any
component in a record time, irrespective of its rarity or obsolescence since
the original installation.

The audit trail

A comprehensive
audit trail is compulsory when generating data; it also has to be completely
secure, automated and time-stamped so that it records the date and time of

The criteria
described by CFR21/11, which include standardisation, increased use of
electronic transactions and automation can translate to significant cost
reductions for manufacturers. Abiding by these requirements also boosts the
credibility of the entire pharma industry. Regulating issues such as serialisation,
electronic pedigree and authentication, the CFR21/11 update welcomes electronic
submissions in new drug applications alongside electronic logs for safety

In 2007 the FDA
managed to get the National Drug Code (NDC) passed in the United States. This
type of serialisation has since been applied to all pharmaceuticals. The NDC
contains a unique numeric or alphanumeric code not exceeding twenty characters,
which allows for the creation of an electronic pedigree and helps trace the
product’s journey from the point of manufacture to the point of dispensing.

The European
Federation of Pharmaceutical Industries and Associations (EFPIA) is also
recommending that manufacturers use a data matrix containing a unique serialisation
number for each secondary packaging unit distributed and sold in Europe.

Designed to protect
both end users (patients) and manufacturers, the regulation compels
manufacturers to create robust procedures and controls to guarantee the
authenticity, integrity and confidentiality of electronic records.

From a lean
perspective, CFR21/11 also offers minimum guidelines for Current Good
Manufacturing Practice (CGMP) for preparation of drug products. The key areas
for CGMP are aseptic processing, automated procedures, scans and cleanroom

A risk based approach

manufacturers wishing to comply with CFR 21/11 can sometimes over-engineer
their procedures, with negative consequences on staff and productivity. Manufacturers
fall into the over-validation trap when they try to test and assess every
aspect of the traceability procedures at hand.

A healthier, risk-based
approach should be considered by the manufacturers. Instead of using a
bottom-up approach, manufacturers are advised to focus on critical records and
thus identify and define electronic records and signatures. The next steps are
based on the predicate rules, criticality of the process and risk to product
and patient safety.

The risk-based
approach leaves out the testing of areas or systems that have been
pre-qualified by their manufacturer, making room for more important areas and
in which failures would result in downtime or significant infringement of GAMP.
It also offers manufacturers the opportunity to improve their systems and
comply with regulations while recognising that zero risk is impractical and

Though CFR 21/11 is a
US regulation, it must be observed by any company wishing to sell medical
devices, components or pharmaceuticals to North America and Europe. In a
globalised market, manufacturers cannot afford to ignore product quality and
safety guidelines. Embracing them and further improving one’s procedures is the
only way to remain competitive in an ultra-tough market. 

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