14 BioPharm International Quality and Regulatory Sourcebook eBook March 2022 www.biopharminternational.com
acceptable to the regulatory auditors.
An agenda was provided, and the com-
pany paid for translators to participate
in the videoconferences and translate
the requested documents into English.
Case number three
The management of an aseptic man-
ufacturing facility in Asia submitted
a biological license application (BLA)
to FDA for a combination product
with the drug substance (DS) manu-
factured on site, but the drug product
produced by a contract manufactur-
ing organization (CMO). The com-
pany received a Form F DA 4 0 03,
Inspect ion Records Request. T he
company asked if this would serve in
lieu of, or in addition to, an on-site
inspection and needed to translate
the documents. The Form FDA 4003
records request included a request
to con f ir m t he specif ic roles a nd
responsibilities of the various compa-
nies involved in this application and
focused on the DS production at the
applicant site.
After a few weeks, the company
received a second Form FDA 4003
requesting additional, focused doc-
uments relating to the new product
application. The second request asked
for complete translations of some doc-
uments that had only been summa-
rized in the first request. In between
the two records requests, FDA issued
guidance on how it intended to con-
t inue inspec t ing du r ing t he pa n-
demic. The guidance says that FDA
may make use of the information in
inspection reports issued by other reg-
ulatory authorities, for which mutual
re c og n it ion a g re ement s ( M R A s)
exist. Furthermore, the new Form
FDA 4003 was updated to clarify if
the request is an Inspection Records
Request with or without an interactive
assessment or in lieu of or in addition
to an (on-site) inspection. As of the
writing of this article, FDA had not
informed the company if they intend
to either conduct an interactive assess-
ment or an (on-site) inspection, leav-
ing the company in limbo.
Case number four
A company in Western Europe was
remotely inspected by the Japanese
Pharmaceuticals and Medical Devices
Agency (PMDA). Over three months,
the agency requested nearly 600 doc-
uments in several installments. Every
document had to be translated in its
entirety and annotated. The annota-
tions are necessary to provide context,
which would normally be provided
by company staff when handing the
documents to inspectors on site (e.g.,
specific pieces of information may be
difficult to find within a document and
attaching pointers is sensible). PMDA
insisted on email communication and
would not agree to video conferences or
phone calls with the site.
LESSONS LEARNED
Though regulators have published var-
ious guidance documents on remote
inspections, much of the actual details,
such as structure, length, etc. remain
unclear. Even though the inspectors
have every intention to resume on-site
inspect ions, t his w i l l not happen
quickly, especially when it comes to
overseas inspections. Thus, industry
must be prepared for remote inspec-
tions for some time to come. Being
prepared means having the procedures
and processes in place to respond to
documentation requests and to host
virtual inspections.
T he COV I D -19 pa ndem ic ha s
c h a n g e d t h e w o r l d w e l i v e i n .
Regulatory authorities responded to
the challenge by implementing alter-
native means of evaluating company
compliance. Challenges for the regu-
lated industry remain, such as:
• Acc u rate t ra nslat ion of t he
requested documents with a short
time frame for response
• Not knowing if the records request
will be followed by an interactive
assessment or inspection
• More thorough review of docu-
ments as many more documents
are requested and reviewed
• MRAs have not been utilized as
envisaged by industry (i.e., there
has not been a significant reduc-
tion in inspection requests)
• Regulator y authorities do not
have an inspection trip time-
frame limiting them
• Technical challenges of setting
up the SME inter views using
v ideo conferencing soft ware,
conducting virtual site tours
• Potential delay in approval of
new products due to delayed
pre-approval inspections.
As noted from the case studies pro-
vided, learning from the experience
of others is one of the best ways of
understanding and preparing for the
challenges of remote inspections.
REFERENCES
1. EC, Directive 2011/62/EU of
The European Parliament And
Of The Council of 8 June 2011
amending Directive 2001/83/EC
on the Community code relating
to medicinal products for human
use, as regards the prevention of
the entry into the legal supply
chain of falsified medicinal
product.
2. PDA, Points to Consider in Remote
and Hybrid GMP/GDP
Inspections, May 2021.
3. MHRA Inspectorate blog,
Inspectors Grounded–A Year of
Innovation, March 26, 2021.
4. J. S. Eglovitch, "FDA's
Document-based Inspections
Prompt Warning Letters for
GMP Violations," R APS.org,
April 13, 2021.
5. FDA, Staff Manual Guides, Volume
IV - Agency Program Directives,
General Or Multidiscipline, Policy
And Procedures For Requesting
Records In Advance Of Or In Lieu
Of A Drug Inspection, Staff Manual
Guide 9004.1, FDA.gov.
6. FDA, Inspection Records Request
Form 4003.
BP
Quality and Regulatory Sourcebook Regulations: Inspections