MENU

Home / Articles / 2013 / Proactive Compliance: Putting the "P" in CAPA

Proactive Compliance: Putting the "P" in

CAPA
Although there s been confusion about what s C and what s P out there, companies are gaining
clarity and reaping the benefits

By Doug Bartholomew
May 13, 2013

Pharmaceutical companies invest plenty of time and resources dealing with problems that occur in the
manufacturing process once they happen. But how much effort are they making to actually prevent quality issues
from occurring in the first place?

With much-publicized quality lapses surfacing at some big drug companies, it’s no wonder that pharmaceutical
manufacturers are concentrating more than ever on the corrective and preventive action (CAPA) process and the
systems they use to manage these events. At the same time, there is a growing emphasis on continuous
improvement to help integrate quality controls into manufacturing processes, thus preventing problems before they
occur. 

Nearly all drug firms have a corrective and preventive action process and system that ultimately strives to improve
manufacturing processes, reduce downtime and eliminate regulatory complaints. Many, however, view their CAPA
responsibility as a pure regulatory concern — in other words, identify the root cause of the problem, fix it, find a way
to prevent it from happening again, and get on with business. It’s only been in recent years that drug companies
have focused on making broader, more sweeping gains aimed at improving quality — what consultants refer to as
“continuous improvement.”

Wholesale Reluctance
A key reason many pharmaceutical firms have been reluctant to make wholesale changes on the plant floor is that
the amended processes must then undergo recertification, often a time-consuming ordeal in itself. “There are some
difficulties for pharmaceutical companies to really change their processes, because they have to go through the
recertification process,” says Catherine Converset, a partner at Productivity Group Europe in Paris, where she has
helped pharmaceutical industry clients with continuous improvement and lean manufacturing initiatives for more
than a dozen years. 
“Part of the challenge here is the regulatory concern,” agrees K. R. Karu, industry solutions director for the
pharmaceutical industry at Sparta Systems, a quality management and CAPA software vendor.

“Pharmaceutical companies tend to put handcuffs on themselves. They are resistant to change because they are
afraid the change is not going to be compliant.”

Those concerns are not unfounded. Every time pharmaceutical companies make substantive changes in processes,
procedures or systems — including just about every action workers perform on the plant floor — they must have
those changes approved by regulators. The smallest change in the way a product is produced triggers yet another
round of FDA review and authorization. It’s no surprise, then, that some manufacturers are wary of making major
changes in their manufacturing processes unless forced to do so.

Continuous Improvement Challenge
Converset says drug companies have been trying to adopt continuous improvement methods for at least a decade,
but only recently have they focused on improving their processes and process controls. “They are doing a lot of
work today on quality and on how to better monitor their CAPA process to be more efficient when handling a CAPA
event,” she adds. “The pharmaceutical industry understands that it has to make a lot of changes, and it is now really
challenged to make continuous improvement efforts.”

An impending challenge for the industry, Converset says, is the need for drug manufacturers to switch from batch
process production to continuous flow manufacturing. “Batch production is a structural limitation for the industry,”
she says. “The move to continuous flow requires a lot of changes, and it requires that companies have the ability to
closely monitor their processes.”

She recommends that companies embrace the concept of quality by design. This requires that companies carefully
define and monitor the parameters of the manufacturing process so that drug quality is guaranteed. “Quality is built
into the design of the process, but you need to constantly monitor the process,” she says. 

“We see some continuous improvement that is directly related to CAPA events,” Converset observes. “But a lot of
continuous improvement is aimed at reducing cost and lead time, reducing inventory and reducing errors.”

Admittedly, the pharma industry has embraced the concepts of continuous improvement and lean manufacturing
principles later than some other industrial sectors, most notably the automotive industry. “Pharmaceutical
companies have come to the lean party a little later than other manufacturers, but they are getting there,” Karu says. 

Of course, many pharmaceutical manufacturers have extensive controls in place to enable them to closely monitor
processes and receive alerts when something in a process starts to go out of specification.
“Pharmaceutical manufacturers leverage systems that offer thresholds and alert mechanisms to warn when the
process is moving outside the control limits, so that the appropriate actions can be put into place,” says Deborah
Kacera, regulatory and industry strategist at Pilgrim Software, a vendor of risk, compliance, quality management and
CAPA systems. 

Kacera says the annual product review undertaken by drug manufacturers typically will point to potential problem
areas where preventive actions should be undertaken on a proactive basis. “The annual product review is an
example of looking at all the data from various sources — from investigations of root cause analysis, batch record
reviews, change control reviews and other nonconformance reviews to see all the data systematically,” she says.
“This review consists of the ongoing vigilance, trending and aggregating of nonconformities to determine if there is
a pattern emerging that can be intervened. This type of information and its analysis can lead to preventive actions
that will improve both product and process control.”

Pharmaceutical firms also can take preventive action proactively by improving training for employees on the plant
floor. “Training is an essential element of a compliant workforce and a regulatory requirement,” Kacera asserts. “It is
critical for workers to be certified in the areas of best practices, the standard operating procedures they are
responsible for using, product information, problem solving, and whatever else is important based on their role and
responsibilities,” she adds. “Ongoing current good manufacturing practices training with effectiveness testing is an
essential part of the prevention equation.”

Confusion Within Industry

Complicating manufacturers’ efforts to take preventive action is the fact that CAPA itself is not clearly understood
within the industry. As a result, companies tend to interpret it in their own way. “The first thing I do when I meet with
pharmaceutical company executives is to ask them to define CAPA,” Sparta’s Karu says. “The reason is that there
are so many different ideas of what it is.” 

This relative lack of a clear definition, in turn, makes the definition of what constitutes a preventive action equally
unclear. According to the U.S. Food and Drug Administration, which regulates and enforces CAPA procedures for the
industry, corrective actions are those performed in response to an observed problem, while preventive actions are
taken to prevent such problems. 

But even the FDA recognizes that confusion exists within the industry over the difference between preventive and
corrective actions. “While industry typically has procedures that specify corrective and preventive actions taken in
response to a failure of some other unexpected event, these ‘preventive’ actions are really only corrective actions in
response to the event,” says Francis Godwin, Acting Branch Chief of the Generic Drug Manufacturing Assessment
Branch at the FDA. “A truly preventive action is one taken to improve a system or process before any disruptive
event occurs, and thus is not a reactionary action. 

“A preventive action is an action taken by a firm to prevent an occurrence of a nonconformity or undesirable

situation,” Godwin adds. “A corrective action is an action to eliminate the cause of an undesirable situation that has
been observed, and to ensure it does not recur.” Godwin says the specific definitions appear in the glossary of the
ICH “Guidance for Industry, Q10 Pharmaceutical Quality System,” which can be found at
http://www.fda.gov/downloads/Drugs/Guidances/ucm073517.pdf .

To sum up, a true preventive action focuses solely on reducing the possibility of things going wrong, without any
connection to a prior manufacturing inconsistency or other problem. Godwin says preventive actions can be
triggered by a variety of things, including continuous improvement initiatives, periodic product reviews, updated risk
assessments, trend analyses and other gains in knowledge.  

“Preventive action is when you don’t know what could go wrong,” concurs Pilgrim Software’s Kacera. Nonetheless,
she adds, once such a possibility has been identified, the company can apply the CAPA process to reduce or
eliminate the likelihood of its occurrence. “After the annual product review, if there could be a change made to a
product specification, then creating a preventive action CAPA is a way to help understand what has changed and
what can be done to mitigate the problem,” Kacera says. 
Once the root cause of a problem has been identified and corrected, says Sparta Systems’ Karu, there is the
opportunity for preventive action to follow. “The preventive part is twofold: first, to take steps to keep this from
reoccurring at this site, and second, to be proactive and make the same improvements at any other locations where
you use that same piece of equipment or process,” he says. 

“In my view, the biggest way companies can prevent manufacturing problems and do continuous improvement is to
apply the lessons they learn across the enterprise,” Karu adds. “This is about tribal knowledge versus institutional
knowledge — in other words, companies need to ask themselves where else could they possibly have the same
circumstances arise?”

Karu offered the experience of a large pharmaceutical firm with 50 manufacturing plants worldwide. “The customer
put a global CAPA system in place, and within a three-year period, the company reduced its manufacturing
deviations by 70%.”

It’s exactly those kinds of longer-term process gains that CAPA is designed to foster, the FDA’s Godwin says. “Both
the corrective and the preventive portion utilize increasing product and process knowledge to continually improve
the process: corrective to address events as they arise; preventive to take action before they arise,” he explains. “It is
in the manufacturer’s own interest to continually improve their processes, even if the process has yet to yield an
irregularity or undesirable event.”

 
Pharmaceutical Associates’ Experience
One drug firm that is using a CAPA system to enable better management of manufacturing issues is Pharmaceutical
Associates Inc. (PAI). The company manufactures and distributes a variety of liquid pharmaceuticals, including
contract-manufactured liquid products, private-label formulations, and PAI’s own line of generic pharmaceutical
liquids. In addition to the company’s 300,000-square-foot manufacturing plant in Greenville, S.C., PAI is building a
new state-of-the-art facility on the same site.  

PAI is using Pilgrim Software’s CAPA and complaints management system to track and trend exceptions, says Mark
Wita, corporate vice president for Quality Assurance and Regulatory Affairs. “Before we had numerous standard
operating procedures for investigations or inspections — nothing was uniform,” he says. “Everyone had their own
spreadsheets for handling these issues. The problem was how to handle complaints in a uniform manner. Pilgrim
unifies all the different areas involved with potential problems in your company.” 

In this case, the CAPA software is used to monitor only those issues that have been noticed and entered into the
system as a result of some complaint or quality issue that was brought to the company’s attention. At PAI, for
example, those events are entered into the system by plant supervisors, quality assurance staff and other
managers.  

PAI’s approach to handling a CAPA event is typical. “First, we define the problem and list the most likely probable
cause,” Wita says. “Next, we check to see what we did the last time if we had a similar issue. If not, we may have to
do some experimentation to see what might have caused the problem. Then we assign a root cause. Typically we
find that the cause of errors or anomalies can be traced to one of four sources — man, machine, material or
method. 
“Next we take corrective and preventive action. This could mean telling the vendor to replace the material. Or we
may need to change the inspection process, or make changes to the SOP or batch record. Then we train our people
on what needs to be done to bring about those changes. And we continue to monitor the process to make sure it
doesn’t happen again.”

Wita says he has heard workers claim that a certain manufacturing anomaly was just an “isolated” event. “But when
it happens three times in a year, it can’t be an isolated event,” he adds. 

Proactive Prevention
By closely examining the aggregated data the CAPA system puts together on nonconformances, Wita says he is
able to spot potential trouble areas where the company needs to take action early, instead of waiting for something
to go wrong. “You look at the process as a whole and look for trends,” he says. “Then you make a judgment on
whether something needs to be corrected. Finally, you monitor the process and review the data.”

Despite the apparent confusion that exists within the industry over the difference between a corrective and a
preventive action, Wita says PAI has been able to harness its CAPA system to help it prevent problems that have
already occurred as well as prevent some that could possibly arise down the road. “For us, it’s both,” he explains.
“You can predict some problems and prevent them, but there are some unforeseen problems that are going to crop
up.” 

As an example, while conducting PAI’s annual review process, Wita says the company has identified areas where
processes can be improved on a proactive, rather than reactive, basis. “With our annual review, we identified some
improvements we could make proactively to our processes.” Of course, he adds, “If you make a change, you might
have to revalidate that process.” 

PAI also is able to take preventive action by leveraging in-process monitoring to detect equipment that may be
starting to go out of specification. “We do in-process monitoring to make sure our processes are in control,” he says.
“Process controls should be well within the design controls for quality, so that you aren’t drifting outside your
regulatory requirements. If you see drift, it’s telling you there’s something wrong.”

Yet another way for pharmaceutical firms to apply continuous improvement to prevent manufacturing errors is
through improved training of employees, especially when it comes to overcoming employee attitudes that can
impact quality. “Good training can overcome any kind of cultural issues you may have,” he says. In other words, he
says, employees should be trained to believe that, as he puts it, “If you see something, say something. You want to
train people not to be afraid to bring forward any quality problems.”

Human error due to poor training, shoddy adherence to work standards, or carelessness on the job often are found
to be the root causes of manufacturing deviations or other quality problems. “If you need to do three CAPAs related
to weighing problems, then you may have a training problem,” Wita adds. 

PAI tracks its quarterly error or exception rate based on type of cause. “We then compare it to the same rate for
those causes in previous years, and finally to the quantity of product produced,” Wita says. “We look for a number of
repeat occurrences that is above the norm for that cause. 

“We also track what shift the errors occurred on,” he continues. “So if you see that the second shift had more errors,
then you want to ask what is different — for instance, is there new management on that shift?”
Problems also can be caused or related to time of year, he says, because some types of problems are more
sensitive to cold or hot weather. 

A useful feature of the CAPA system is its ability to track the level of risk according to the type of incident. “When
you are entering an exception into the Pilgrim system, you assign it a risk of high, medium or low. This enables us to
subdivide CAPA events by risk level and by cause.”

PAI’s new plant will, by design, push the company’s quality levels still higher, Wita believes. “The new plant will do in
two shifts what we currently do in two shifts and a weekend shift, and in four manufacturing tanks it will produce
what we currently require 30 tanks to produce,” he says. “The new equipment will be computer-controlled to
continuously monitor various aspects of each batch, ensuring a more safe, uniform product,” Wita adds.

Published in the May 2013 issue of Pharmaceutical Manufacturing magazine

Related Content

Perfecting CAPA
“Flawless” may not exist on the plant floor, but reviewing your quality process can save…

Most Popular
Past 7 Days Past 30 Days Past 6 Months

01 The most — and least — expensive places to run a pharma plant

02 Pfizer banks on restructuring plan for new growth

With sales for several key drugs plummeting, Pfizer is moving ahead with a…

03 AbbVie to donate HIV drug to combat coronavirus

AbbVie said it will donate more than $1 million worth of its drug, Aluvia,…

04 Pharma companies race to develop coronavirus vax

Atlanta-based GeoVax has announced a partnership with a Chinese company to…

05 One dose of psychedelic compound has ‘mind-boggling’ success at easing anxiety

Nearly five years after cancer patients received a single dose of a…
About

General Information

Contact Us

Subscription Services

Media Kit

Editorial Calendar

Editorial Submissions Guidelines

Editorial Advisory Board

Content

Resource Libraries

OpEd

Fundamentals

News

Articles

White Papers

Products

All Star Innovators

Funny Pharm

Magazine

Subscribe (print)

Current Issue

Issue Archive
 Site Tools

Site Map

Resource Directory

Stay Connected

My Account

Events Calendar

E-Newsletters

Human Interest

Facebook

Twitter

LinkedIn

YouTube

RSS Feed

Contact Us | Advertise | Privacy Policy | Legal Disclaimers, Terms & Conditions

Copyright © 2004 - 2020 Pharma Manufacturing. All rights reserved.
P: 630-467-1300 | 1501 E. Woodfield Road, Suite 400N, Schaumburg, IL 60173

Chemical Processing | Control | Control Design | Food Processing | Pharma Manufacturing | Plant Services | Smart Industry