Sterile GMP Update

August 2017
Moshe Ben Yitzhak, MSc., MBA
CGMP Solutions, Ltd.
 Objective
• This presentation provides a high-level review
of some recent (2016-2017) inspections of
manufacturers of sterile drugs produced by
aseptic processing.
• It covers seven firms inspected – some of
them multiple times – over this period.
• Results are presented in a tabular form; the
recent Consent Decree agreed to by Isomeric
is covered separately.
 What is a FDA 483?
• An FDA 483 is a standardized form that inspectors use to
report violations of cGMPs.
• It is typically the first step that the FDA takes when a firm is
found to be in violation.
• The Agency may issue a Warning Letter (which is more severe)
if the violations were:
– Observed on previous inspections, or
– Too numerous (there is no hard rule as to how many observations are
too many), or
– The company that was inspected was non-cooperative during the
inspection.
• FDA 483s may be found at:
https://www.fda.gov/AboutFDA/CentersOffices/OfficeofGlobalR
egulatoryOperationsandPolicy/ORA/ORAElectronicReadingRoom
/default.htm
 Disclaimer
• FDA 483s always start with a disclaimer that reads as
follows:
– This document lists observations made by the FDA representatives during
the inspection of your facility. They are inspectional observations; and do
not represent a final Agency determination regarding your compliance. If
you have an objection regarding an observations, or have implemented or
plan to implement corrective action in response to an observation, you
may discuss the objection or action with FDA representative(s) during the
inspection or submit this information to FDA at the address above. If you
have any questions, please contact FDA at the phone number and address
above.
• In other words, the results of the inspection are going to be
reviewed by higher levels in the FDA, and the FDA 483 is not
necessarily the last word on the subject.
 General Format of the FDA 483
• Header section with contact information
• Disclaimer
• Inspectional observations
– Quality System element (note: some inspectors do not identify this)
• Observation
– Supporting evidence.
– Inspectors usually provide multiple examples of violations.
– If a particular violation was noted in the previous inspection,
they may provide just one example.
 Example
Production System
Observation 1: Deviations from written production and process
control procedures are not recorded and justified. Specifically:
Investigation 14-14-01453 was initiated 26NOV2014 for a Media Fill failure.
The most probable root causes of contamination were attributed to the
following:
Slower than routine production) leading to issues in stoppering; a larger than
usual media fill, leading to operator fatigue where commercial fills are limited
to a maximum of [vials – exact number redacted].
A broken bolt on the table and frame required personnel to lift and secure the
vial mechanism.
This led to operators leaning over filled, partially-stoppered vials to clear jams,
which would have led to the full clearance and reject of units during a
commercial production run.
Inspectors then quoted from the company’s SOPs relevant to
this activity.
 Example
• Based on the contents of the FDA 483:
– There was a failure; and
– The company investigated; and
– It came to conclusions regarding the root causes.
• However:
– According to the firm’s own SOPs, media fills are supposed to be
treated exactly like commercial batches, including the decision
when to abort a batch.
– According to interviews with management, batches are aborted
before filling and stoppering, so this media batch should not have
been filled.
– Management also stated that the inoperability of downstream
equipment should have triggered the aborting of the batch – that
did not happen either.
– Finally, operators failed to complete logbook entries regarding this
media fill, as required by SOP.
 Example
From this one observation we can draw several conclusions about
how the FDA conducted this inspection:
1. Although the inspection was conducted in June 2016, the
inspectors reviewed records of media line failures at least as
far back as November 2014.
2. This indicates that the inspectors asked for and received:
a) A list of media batches produced, and/or
b) A list of media batch failures, and/or
c) A list of deviation investigations.

3. The inspectors thoroughly review records.

4. The inspectors thoroughly review a company’s procedures.
 Recent Inspections
• The inspectional observations in this presentation are
summarized from:
– Akorn Pharmaceuticals
– Cantrell Drug Company
– Delta Pharma
– Fusion IV Pharmaceuticals
– KRS Global Biotechnology
– RAM Pharma
• All of these are relatively small companies. The have
their own products (mostly generic), provide contract
manufacturing for larger firms, and also manufacture
clinical supplies on contract.
 Inspectional Observations
• The following series of tables identify the inspectional
observations.

Inspectional Obs. No. in GMP

Companies
Observation FDA 483 Reference

Observation FDA 483 Fusion KRS RAM

GMP Akorn Cantrell Delta
Obs. No. IV Global Pharma
Aseptic processing areas are
deficient regarding the system for
5-Delta §211.42(a)
cleaning and disinfecting the room
4-RAM §211.42(c)
X X
and equipment to produce aseptic
conditions.
 Summary of Observations – Equipment & Facilities
Observation FDA 483 Fusion KRS RAM
GMP Akorn Cantrell Delta
Obs. No. IV Global Pharma
Aseptic processing areas are
deficient regarding the system for
5-Delta §211.42(a)
cleaning and disinfecting the room
4-RAM §211.42(c)
X X
and equipment to produce aseptic
conditions.
Aseptic processing areas are
deficient in that walls are not 6-Delta §211.42(a)
smooth and/or hard surfaces that 3-RAM §211.42(c)
X X
are easily cleanable.
Routine calibration of equipment is
not performed according to a 8-Delta
written program designed to assure 11-RAM
§211.67(a),(b) X X
proper performance.
Control procedures are not
established which validate the
performance of those
manufacturing processes that may 6-Akorn §211.100(a) X
be responsible for causing variability
in the characteristics of in-process
material and the drug product.
 Summary of Observations – Equipment & Facilities

Observation FDA 483 Fusion KRS RAM

GMP Akorn Cantrell Delta
Obs. No. IV Global Pharma
Aseptic processing areas are deficient
regarding the system for cleaning and
disinfecting the room and equipment to
1-Cantrell §211.113(b) X
produce aseptic conditions.
Aseptic processing areas are deficient
8-Cantrell
regarding air supply that is filtered
through HEPA filters under positive
3-KRS §211.46(b) X X
pressure. Global
The building lacks adequate space for
the orderly placement of equipment
and materials to prevent mix-ups
between different components, drug 9-Cantrell §211.42(a),(b) X
product containers, labeling, in-process
materials and drug products to prevent
contamination.
Separate or defined areas to prevent
contamination or mix-ups are deficient
regarding operations related to aseptic
3-Cantrell §211.113(b) X
processing of drug products.
 Summary of Observations – QC Lab
Observation FDA 483 Fusion KRS RAM
GMP Akorn Cantrell Delta
Obs. No. IV Global Pharma
Laboratory controls do
not include the
establishment of
scientifically sound and
appropriate sampling
plans designed to assure
that in-process materials
and drug products 5-Akorn §211.160(a) X
conform to appropriate
standards of identity,
strength, quality and
purity. The suitability of
all testing methods is
not verified under actual
conditions of use.
Test procedures relative
to appropriate
laboratory testing for
sterility and pyrogens
4-Cantrell §211.160(a) X
are not written and
followed.
 Summary of Observations – QC Lab
Observation FDA 483 Fusion KRS RAM
GMP Akorn Cantrell Delta
Obs. No. IV Global Pharma
There is no written testing
program designed to 5-Cantrell
assess the stability 10-Delta §211.166(a) X X X
characteristics of drug 8-RAM
products.
Testing and release of drug
product for distribution do
not include appropriate
laboratory determination 6-Cantrell
of satisfactory 5-Fusion IV §211.165(a) X X X
conformance to the 7-RAM
identity and strength of
each active ingredient
prior to release.
Testing and release of drug
product for distribution do
not include appropriate
9-Delta
laboratory determination
6-RAM
§211.165(d) X X
of satisfactory
conformance to the final
specifications prior to use.
 Summary of Observations – Packaging & Labeling

Observation FDA 483 Fusion KRS RAM

GMP Akorn Cantrell Delta
Obs. No. IV Global Pharma
The labeling of your 11-Cantrell
outsourcing facility's drug 12-Delta
FDCA,
6-Fusion IV X X X X X
products are deficient. §503B(b)
6-KRS Global
12-RAM
Strict control is not exercised
over labeling issued for use §211.137(a),
7-Fusion IV X
in drug product labeling (b)
operations.
Your outsourcing facility did
not submit an initial report
to FDA identifying products
8-Fusion IV FDCA,
compounded during the X X
13-RAM §503B(b)
previous six months as
required by section
503B(b)(2)(A).
 Summary of Observations - Production
Observation FDA 483 Fusion KRS RAM
GMP Akorn Cantrell Delta
Obs. No. IV Global Pharma
Deviations from written
production and process
1-Akorn §211.101(a) X X
control procedures are not
recorded and justified.
Aseptic areas are deficient
7-Cantrell
regarding the system for
4-KRS Global §211.110(a)(6) X X X
monitoring environmental 2-RAM
conditions.
Procedures designed to
2-Cantrell
prevent microbiological
1-Fusion IV
contamination of sterile §211.110(a) X X X X
1-KRS Global
drug products are not 1-RAM
established.
Procedures designed to
prevent microbiological 1-Delta
contamination of sterile 2-Fusion IV
§211.113(b) X X X X
drug product do not 2-KRS Global
include validation of 5-RAM
sterilization process.
 Summary of Observations - Production
Observation FDA 483 Fusion KRS RAM
GMP Akorn Cantrell Delta
Obs. No. IV Global Pharma
Drug product containers are
clean, sterilize and processed to
2-Delta §211.94(c)
remove pyrogenic properties to X X
3-Fusion IV §211.94(d)
assure that they are suitable for
their intended use.
Clothing of personnel engaged
in the processing of injectable 3-Delta
drug products is not 5-KRS Global §211.28(a) X X X
appropriate for the duties they 9-RAM
perform.
Aseptic processing areas are
deficient regarding the system 4-Delta
§211.110(a)(6) X X
for monitoring environmental 4-Fusion IV
conditions.
Time limits are not established
when appropriate for the
completion of each production 11-Delta §211.111 X
phase to assure the quality of
the drug product.
 Summary of Observations - Quality

Observation FDA 483 Fusion KRS RAM

GMP Akorn Cantrell Delta
Obs. No. IV Global Pharma
There is no quality
control unit with the
responsibility and
authority to approve or
reject all components,
10-RAM §211.22(a) X
drug product containers,
closures, in-process
materials, packaging
materials, labeling and
drug products.
The responsibilities and
procedures applicable to
2-Akorn §211.22(a) X
the quality control unit
are not fully followed.
 Summary of Observations - Quality
Observation FDA 483 Fusion KRS RAM
GMP Akorn Cantrell Delta
Obs. No. IV Global Pharma
There is a failure to review
thoroughly any unexplained
10-Cantrell §211.101(a)
discrepancy, whether or not X X
7-Delta §211.192
the batch has already been
distributed.
Investigations of a failure of a
batch or any of its
components to meet any of its
specifications did not extend 12-Cantrell
§211.192 X X
to other drug products that 3-Akorn
may have been associated
with the specific failure or
discrepancy.
Quality controls do not include
a determination of
§211.22(d)
conformance to written 4-Akorn X
§211.84(a)
descriptions of sampling
procedures for drug products.
 Isomeric Pharmacy Solutions, LLC
• This is the worst-case scenario!
• Isomeric was inspected in 2015 and received a FDA 483
that had five multi-part observations.
• Isomeric was inspected in 2016 and received a FDA 483
that had eleven multi-part observations.
– FDA was not satisfied with Isomeric’s response at the time, and a
Warning Letter was issued in December 2016.
• Isomeric was inspected again 22/02/17 through 24/03/17
and the inspectors recorded fourteen multi-part
observations.
• The same inspectors performed all three
inspections.
• FDA turned to the U.S. Department of Justice to
obtain relief.
 Isomeric Pharmacy Solutions, LLC
• U.S. District Judge Robert J. Shelby entered a consent decree of
permanent injunction yesterday against Isomeric Pharmacy Solutions
on 4 August 2017.
– In it’s complaint, FDA alleged that Isomeric manufactured and distributed
purportedly sterile drug products that were adulterated because the drugs
were made under insanitary conditions and in violation of current good
manufacturing practice requirements under the FD&C Act.
– The consent decree prohibits Isomeric from manufacturing, processing,
packing, holding, or distributing drugs until they comply with the Federal
Food, Drug, and Cosmetic Act (FD&C Act) and its regulations.
– FDA’s complaint also alleged that Isomeric manufactured and distributed
unapproved drugs and drugs that were misbranded because their labeling
did not bear adequate directions for use.
• Isomeric agreed to a voluntary nationwide recall of all lots of
unexpired drug products produced for sterile use and distributed to
patients, providers, hospitals, or clinics nationwide between Oct. 4,
2016 and Feb. 7, 2017.
 Conclusions
• In aseptic processes, the drug product, container, and closure
are subjected to sterilization methods separately, as
appropriate, and then combined.
• Because there is no process to sterilize the product in its final
container, it is critical that containers be filled and sealed in an
extremely high-quality environment.
• Aseptic processing involves more variables than terminal
sterilization, and as such, presents a higher risk to the patient.
• Thus, inspections will focus on:
– Systems and processes with the highest risk factors.
– Systems and processes that have been proved inadequate in past
inspections.
 Conclusions
• FDA, as explained in Guidance - Sterile Drug Products Produced
by Aseptic Processing (2004), places emphasis on (this is the
order in which they appear in the guidance):
– Facilities and Equipment
– Personnel training and Monitoring
– Components and Containers/Closures
– Endotoxin Control
– Validation of Aseptic Processing and Sterilization
– Laboratory Controls
– Sterility Testing
– Batch Record Review
• Quality Assurance cuts across all these systems and processes,
and therefore should be evident in all of them.
 Conclusions
• Management – regardless of specific departmental
responsibility – needs to ask itself the following questions:
– Do I understand the concept of the Quality System approach?
– Do I understand the processes that are part of the specific Quality
System for which I am responsible?
– Do I understand the documentation requirements (batch records,
change control, SOPs, logbooks)?
– Do I understand the records that should be generated as a result
of each process?
– Do I understand the results, and long-term trends these data
indicate?
– Am I taking the appropriate actions based on the CGMP
requirements?