International

Pharmaceutical
Quality ™

www.IPQpubs.coM MARCH/APRIL 2009 | Vol. 3, No. 2 | $400 per year

DRUG MANUFACTURERS ARE REASSESSING HOW THEY MANAGE Co n te n ts

REGULATORY INSPECTIONS as they shift focus onto the challenge of
conveying the strength of their quality systems to find and address 2 Communication Is The Challenge
problems and risks. The diversity of inspectors and regulatory
2 Firms Can Trip On Their Own Hurdles
agencies that manufacturers routinely face also is prompting them
to clarify and refine their approach to managing inspections. The 4 Investigators Want Operator Input
consensus from both sides of the Atlantic is that opening the com-
munication channels is key to a positive inspection outcome and 5 Honesty Is The Best Policy
that putting up barriers to this interchange is counterproductive. The
experts agree that the following are good inspection facilitators: 5 When In Doubt, Ask
• operator receptivity to dialogue • asking investigators to clarify
6 Have Records Available, Site Active
requests and findings as needed • having records/applications
available • being truthful • volunteering information that can help
8 Meetings: With Whom and When?
mitigate investigator concerns • understanding and addressing
rather than arguing with concerns raised, and • supporting dis- 9 What If You Disagree?
agreements with data. Regulators want to see a sense of urgency
from firms about their CAPA commitments in responding to 11 Give Action Timelines In 483 Responses
inspection findings.
Bill Paulson, Editor-In-Chief 13 OOS Investigations Indicate the Culture

VOICES FROM THE DIALOGUE: • Industry consultant Richard Davis on OOS investigations and inspection
preparation (Appendix I, pp. 14) • Paraxel consultant Peter Smith on interacting during inspections (Appendix II,
pp. 19)• Richard Davis on responding to 483s (Appendix III, pp. 26)

The increasing diversity of inspectors and regulatory agen-
cies with which drug manufacturers must deal and the shift
to a more quality systems-oriented compliance paradigm are
forces prompting firms to clarify and refine their practices
for inspection handling.
Regulators, in turn, are seeking to streamline the inspection
process and are actively speaking out at public forums on
how firms can help.
The advice from European and U.S. inspection experts
on what companies should and should not be doing is
markedly similar. The basic advice from both sides of the
Atlantic is to clarify what investigators are asking for and
what they are finding and to openly volunteer information
that mitigates the concerns raised.
Firms are also being advised that investigators want to talk
directly to those involved in the operations under review
and that putting up barriers to this open communication is
generally counterproductive to a good inspection outcome.
Likewise viewed as counterproductive are company efforts
to direct or redirect the inspection process.

Inside The Global Regulatory Dialogue™

 International Pharmaceutical Quality
Operating under a more quality system/risk management-
oriented framework, regulators are making it clear that com-
pliance is not about the absence of manufacturing deviations
and risks, but how firms are addressing them (IPQ, July/Aug.
2008). The new regulatory framework is prompting manu-
facturers to rethink how they are managing inspections and
to enhance their communication skills to ensure that the
strength of their quality system is conveyed to the inspector.
Communication Is The Challenge
The importance of good communication during the inspection
process has been a recurrent theme in the dialogue between
regulators and industry at recent public conferences.
FDA and EU inspection officials joined with expert industry
consultants in exploring the theme at drug GMP-oriented
conferences in March sponsored by the University of Georgia
(UGA) and University of Rhode Island (URI), respectively.
The give and take at these meetings resulted in a lot of practi-
cal advice on why the communication is important and how
to expedite it.
In her concluding remarks to a presentation on “What I am
Looking for During a GMP Inspection” at the URI confer-
ence, Minneapolis District Drug Expert Investigator Sharon
Thoma gave voice to the new compliance paradigm and the
communication challenges involved.
Ultimately, she asserted, “the intensity of FDA oversight
is related to a firm’s ability to manage risk associated with
product quality.” At issue in assessing this ability is “a firm’s
degree of product and process understanding and the robust-
ness of the quality system controlling that manufacturing
process.”
Avoiding compliance entanglements thus becomes a factor
of how effectively firms can convey this understanding and
robustness. In this context, firms being audited need to pay
close attention to what investigators are focusing on, what
they are asking for, and what knowledge they need to be
reassured that the company understands their concerns and
has a system in place that addresses them.
At the URI conference, British Medicines Health
Agency (MHRA) Senior GMP Inspector Andrew
Hopkins joined with Thoma and a handful of former
FDA field office veterans now consulting – David
Chesney, Richard Davis and Debra Pagano – in explor-
ing the theme and offering advice on what firms should
and should not do to accomplish the communication
goal. The advice was notably congruent.
ww w.ipqpubs.com
2 MARCH/APRIL 2009
MHRA inspectors, Hopkins affirmed, encourage discussion
on the issues at hand during inspections and become wary
when firms are too reticient or place hurdles to this informa-
tion exchange.
“We will tell you straight away what we think is a deficiency”
to provide the opening for this discussion, he explained. “That
gives you the chance to say, ‘yes, you have understood that
bit right. But there is actually this entire side process that goes
on that supports that and mitigates this risk you are talking
about.’ So make sure you do have those discussions.”
The EU regulations, in turn, which are not very prescrip-
tive and give “a lot of leeway,” provide a foundation for this
knowledge exchange, Hopkins said. “We want you to under-
stand what you are doing. We don’t want to have to tell you
what you are going to do.”
If the firm has done the appropriate work and doesn’t bother
to volunteer it, a deficiency results. Reporting on this work in
the follow-up response to the agency, in turn, suggests that
“you don’t know what you are up to,” Hopkins cautioned.
The communication becomes particularly important when
the inspector views a deficiency as potentially “critical,” he
stressed. MHRA investigators won’t delineate the level of the
deficiency unless it reaches the critical level. At that point,
Hopkins advises that firms should inform their senior man-
agement and “start pulling your whole story together in this
one area, so that we can work on mitigating that deficiency.”
“It is a whole lot of work for us to actually take home a criti-
cal deficiency, so we would like to work with you to prove
that what we are looking at isn’t a critical deficiency,” he
explained. “We also would like to prove that there is noth-
ing out on the market that is likely to kill somebody. So that
is why we will tell you straight away” when the deficiency as
viewed as potentially critical.
PAREXEL Consulting Strategic Compliance Services VP
David Chesney, a former FDA field manager, offered the same
advice on volunteering information that can help assuage
investigator concerns. “Certainly, if you have information
that would be helpful to ensuring the regulator understands
the correct situation, then you want to consider giving that
up” even if it was not asked for.
Firms Can Trip On Their Own Hurdles
The experts likewise cautioned that trying to place hurdles
in the way of the investigators or to hide problems can be
counterproductive in proving the strength of the quality
 International Pharmaceutical Quality
system, and particularly costly where application approval
is at stake.
Hopkins cited the example of his experience in the U.S.
where there may be legal advisors “sitting in the back room
going ‘no they can’t look at that. Nope they are not having
that. Draw a line through that. Blank that out.’ If you have
legal advisors telling you not to show us things, let us know.
Because although we have no legal remit in the U.S., if I can’t
see everything I want to see on site, I will just say I haven’t
got enough evidence to support your application … and you
won’t get your license. So let’s have that discussion up front.
I can tell you why I am looking at things. You can understand
where I am coming from.”
The MHRA inspector recalled a site visit during which he
asked to see the deviation list for the last two years and the
firm refused to give it to him, claiming it was part of their
self-inspection process. “Luckily the site was already at a
critical [deficiency level], so I didn’t really worry about it too
much. However, had that been sort of a borderline discus-
sion, I would have just gone off site. I would not have contin-
ued the inspection.”
At issue is conveying to the investigator the capability
of the quality system, obviating the need for more reg-
ulator oversight. If the company is finding and address-
ing its own problems, the investigator can move on.
“If I am asking for a deviation list,” Hopkins clarified, “it
is not so I can say ‘you had something go wrong with your
autoclave last week. I am giving you a deficiency because
there is something going wrong with your autoclave.’ Things
go wrong – we appreciate that. It is how you deal with them
afterwards that we are looking for. So that is why we are look-
ing for deviation lists. If you can actually demonstrate that
you found the issues before we got there, you are unlikely to
get a deficiency about it. So it actually works in your favor.”
In this vein, the inspector will want to see whether a firm’s
quality system has digested deficiencies uncovered during
previous inspections and made the necessary course
corrections.
Hopkins reported that MHRA had returned to a site for a fol-
low-up visit a year after several high-level deficiencies were
identified. His inspection team asked if the firm’s self-inspec-
tion process had been tailored to the deficiencies found pre-
viously. “What we found was that the self-inspection group
hadn’t actually been told of any of our findings, and their first
two inspections for the year were pest control and security –
interesting choices.”
Inside The Global Regulatory Dialogue™
The moral of the tale, Hopkins suggested: “Use your self-
inspection process to work for you. Modify it. Don’t just
[view it as] ‘a tick in the box – we have a procedure for self
inspection now.’ Make it work for you.”
Self-auditing reports have been an area where inspec-
tor access has been an issue.
The usual policy in the U.S. and EU has been not to review
the internal reports in detail during inspections, in view of
the self-incrimination concern and the desire for the self-audit
process to be as meaningful as possible (IPQ, Jan/Feb 2008).
While “rare,” EU investigators may look at the audit reports
if a lot of deficiencies have already been found, raising the
issue of why the company didn’t find the problems them-
selves if the area was audited, Hopkins explained.
Similarly for vendor assessments: “If you are using a vendor
and we don’t think your assessment is very good, especially
in IMPs [investigational medicinal products] and APIs, that
actually may be a for-cause reason of why we need to go to
that vendor. Again, it is rare.”
Debra Pagano, who began consulting in 2002 after a
17-year career with FDA that included service as a drug
expert investigator, trainer and field office pre-approval
program manager, summed up the way investigators
view deviations from a quality systems perspective at
the URI conference.
As an investigator or an auditor, she stated emphatically, “if
I go into a company and they have zero problems, I am more
concerned about them not having systems in place to find
their problems.”
The concern around deviations for the investigator is rather:
“How are you capturing them? How are you prioritizing
them? Do you understand why your CAPAs are open? How
are you trending them? Do you have a lot in one particular
area? How are you looking at the deviations and non-confor-
mances? Are they being looked at collectively?”
Product complaints need to be tied in as well as change con-
trol. Similarly to deviations, investigators will want to see
that firms know how many complaints are open and if there
are trends. “Do we see a big jump in our product lines? Why?
Did we make a change? How often has this happened? Is that
being captured? And how are we handling them?”
She noted that companies have different names for these sys-
tems that identify weaknesses and problem areas. FDA may
MARCH/APRIL 2009 3
 International Pharmaceutical Quality
say, ‘show me everything,’ so you need to understand what
identifies your problems,” she affirmed.
The linkage between manufacturing and quality is also at
issue. Pagano espoused the benefit of “looking at all the dif-
ferent variables with the process” and giving manufacturing
some responsibility “right there on the shop floor” for having
relevant process capability knowledge.
One firm she was working with had “started this practice a
couple of years ago and it was amazing. Quality said they
have manufacturing calling them up now on lines going out
of trend based on how the process has been running.”
FDA investigators were being trained in this quality
systems perspective well before ICH Q10, she noted.
“When we had an area of concern,” the question to be
asked was “what system or lack of system allowed this
incident to occur?”
In turn, companies should ask the same question in respond-
ing to FD-483 observations. In cases where application with-
holding was at issue, the pre-approval inspection manager
was “always very impressed” if the 483 response was proac-
tive and said, “FDA gave us these three observations but we
took it a step further and we looked to see that this was not
something that was an out of control situation.”
So when doing audits or looking at deviations, Pagano
advised, “ask what allowed this to happen – why did this
happen?”
Investigators Want Operator Input
Hopkins joined Chesney and Thoma in stressing that investi-
gators will want to talk to the actual operators and that allow-
ing this open interchange will make for a smoother inspection
process.
“QA managers are lovely people. Production managers are
lovely people. But I don’t what to spend five days talking to
them,” Hopkins quipped. “I want to talk to your operators”
and ask them directly “‘what are you doing? How do you do
that? Why are you doing that?’”
Companies should prepare their operators accordingly, so
that some of “the mystique” and the intimidation factor has
been removed. In turn, inspectors “don’t think there is any
benefit in scaring people to death,” Hopkins maintained. “We
will do our best not to unnerve people when we are discuss-
ing things with them. But we will want to speak to people.”
ww w.ipqpubs.com
4 MARCH/APRIL 2009
In considering the access issue, he advised, “ask yourselves
this: If you are not willing to let an operator talk to us, what
does that say for your confidence in your operator? And we
will ask ourselves the same question.”
Thoma offered similar advice on preparing employees
for this kind of interchange.
“Tell them it is okay to talk to FDA,” she affirmed. “I look
more highly at firms that train their people on how to speak
to an FDA investigator and how to answer the questions.”
She added that “if you don’t know the answers, say I don’t
know.”
Investigators view companies that allow this open inter-
change more favorably than those that try and prevent it,
Thoma explained. The ability of employees to address the
questions shows that “they know why they are doing a cer-
tain job function. They know the criticality of that and how it
relates to the end product that you are manufacturing.”
Chesney affirmed that “good inspectors want to talk to the
people that really know the answer. If that means the tablet
press operator, the filling machine operator, the lab techni-
cian on the bench, so be it. You are not going to be able to con-
fine them to just the top tier.”
Thoma echoed Hopkins’ recognition that the process
is not helped by investigators intimidating employees,
and she also works to lessen the tension accordingly.
Nor is it helped by the company trying to overmanage
the interchange.
In one recent international inspection, Thoma interacted with
an employee who “was so nervous and so flustered, he was
not going to be able to give me a good response. So I said,
‘why don’t you go and review the SOPs, get what you need
and come back to me with the answer.’ And you know what,
he did really well right after lunch when he did that.”
The nervousness, she noted, did not stem from the FDA ques-
tioning as much as the presence of his boss, who was “sitting
right across the table watching every move he made. He was
more worried about his boss and his job, then he was about
me, for fear that he might answer my question wrong or not
the way the boss wanted him to answer it.” Thoma recog-
nized that the employee was in an unfamiliar and stressful
situation and made allowances accordingly.
Managers can also create problems by attempting to be
the all-knowledgeable source for inspector inquiries.
 International Pharmaceutical Quality
At a URI conference on vaccines in late March, PAREXEL con-
sultant Peter Smith examined the role of management during
the inspection process, cautioning about managers assuming
a role better played by the actual hands-on operators.
“They think, because they are most responsible, they should
know everything and that is usually wrong,” Smith said.
“Managers can not know everything that goes on to the detail
that FDA would like to get to during the inspection.”
As an FDA investigator, Smith experienced “many instances”
where the manager answered questions incorrectly. “The best
role for the manager here,” he maintained, “is to direct FDA
to the right person and to facilitate things, but perhaps not
answer all the questions.”
[EDITOR’s NOTE: Smith’s advice at the URI conference on
interacting with FDA investigators during the inspection
process and the common mistakes firms make is provided as
Appendix II. Along with management’s role, the PARAXEL
consultant discusses first impressions, the opening meeting,
and interviewing with inspectors. Smith’s advice reflects his
lengthy service with FDA as an expert drug investigator and
foreign inspection program manager.]
Honesty Is The Best Policy
Honesty, the presenters stressed, is the best policy.
In responding to questions, Thoma commented, “don’t make
me think you are withholding information unnecessarily.
Because I go into a whole different mode of the investigation
that will come about if I feel that people are lying to me.”
FDA inspectors go through investigative interview training
that sensitizes them. “I usually can tell when people are lying
to me,” Thoma said, adding that “it is getting an admission
which is the difficult part.”
Nobody likes a confrontational inspection, she commented.
“But I have been in them, and I know how to handle them
quite well.” Companies, she warned, “don’t want to spiral
down to where we think you are withholding information,”
and she will be blunt with firms when she perceives this hap-
pening. On the other hand, she said, “I also am very consider-
ate of the people that I am dealing with, because I know that I
am asking for a lot of documentation. And I know your people
at the firm are running around frantically to get that.”
Not being completely truthful, Chesney cautioned, is the
“biggest pitfall” in the inspection process. “Once you take
Inside The Global Regulatory Dialogue™
even a tiny step down that path, it is an extremely slippery
slope. I urge you not to go there.”
Not being forthcoming in applications, for example
about failed batches, can also come back to haunt com-
panies, the presenters pointed out.
Thoma cited an example she uncovered where only the lot
which passed specifications was filed in the application, while
all other lots at that strength failed and were not mentioned.
“You just don’t do that,” the FDA investigator stated. “You
need to let us know when you have issues like that.” If you
withhold that information, “it is going to be looked at very
poorly. I go into a different mode when I see stuff like that
and I start digging. And when you start digging into different
records it is amazing what you find sometimes.”
In the case mentioned, Thoma said, “it opened up the firm to
a lot of scrutiny, and then when we found a second and third
instance of application integrity problems, that firm was on
the AIG [application integrity policy list] for years.”
Davis made a similar point in his presentation at the confer-
ence on responding to 483s (see Appendix III). He advised
firms not to “omit bad data from requested documents or try
to hide it or not send it in, because once the agency finds bad
data that you haven’t submitted” it will take a long time to
gain back its trust.
When In Doubt, Ask
The experts on the panel were in agreement on the impor-
tance of asking for clarification if there is uncertainty about
what an investigator is asking for or about an issue that has
come up as a concern.
It is important not to panic, Thoma stressed. “Investigators
are real people. If you do not understand what they are
asking for, ask for clarification. You are going to save yourself
time, you are going to save us time.”
When she is not getting the answers she needs, Thoma recog-
nizes that “it may be that when I provided you information
up front at the start of the inspection, whoever was taking the
notes didn’t properly relay what I was looking for. Or maybe it
was a misunderstanding. So I always tell firms, ‘anytime you
have questions about what I ask for or what I plan to look at,
ask me and get clarification.’ Because you don’t need people
in that back room running around unnecessarily trying to get
documents that weren’t even what I requested.”
MARCH/APRIL 2009 5