Sterile GMP UpdateAugust 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/OfficeofGlobalRegulatoryOperationsandPolicy/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 duringthe inspection of your facility. They are inspectional observations; and donot represent a final Agency determination regarding your compliance. Ifyou have an objection regarding an observations, or have implemented orplan to implement corrective action in response to an observation, youmay discuss the objection or action with FDA representative(s) during theinspection or submit this information to FDA at the address above. If youhave any questions, please contact FDA at the phone number and addressabove.
• In other words, the results of the inspection are going to bereviewed by higher levels in the FDA, and the FDA 483 is notnecessarily 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 aresummarized from:– Akorn Pharmaceuticals
– Cantrell Drug Company
– Delta Pharma
– Fusion IV Pharmaceuticals
– KRS Global Biotechnology
– RAM Pharma
• All of these are relatively small companies. The havetheir own products (mostly generic), provide contractmanufacturing for larger firms, and also manufactureclinical supplies on contract.
Inspectional Observations
• The following series of tables identify the inspectional observations.
Observation FDA 483
Obs. No.GMP Akorn Cantrell Delta
Fusion
IV
KRS
Global
RAM
Pharma
Aseptic processing areas are
deficient regarding the system for
cleaning and disinfecting the room
and equipment to produce aseptic
conditions.
5-Delta
4-RAM
§211.42(a)
§211.42(c)X X
Inspectional Observation
Obs. No. in FDA 483
GMP Reference
Companies
Summary of Observations – Equipment & Facilities
Observation FDA 483
Obs. No.GMP Akorn Cantrell Delta
Fusion
IV
KRS
Global
RAM
Pharma
Aseptic processing areas are
deficient regarding the system for
cleaning and disinfecting the room
and equipment to produce aseptic
conditions.
5-Delta
4-RAM
§211.42(a)
§211.42(c)X X
Aseptic processing areas are
deficient in that walls are not
smooth and/or hard surfaces that
are easily cleanable.
6-Delta
3-RAM
§211.42(a)
§211.42(c)X X
Routine calibration of equipment is
not performed according to a
written program designed to assure
proper performance.
8-Delta
11-RAM§211.67(a),(b) X X
Control procedures are not
established which validate the
performance of those
manufacturing processes that may
be responsible for causing variability
in the characteristics of in-process
material and the drug product.
6-Akorn §211.100(a) X
Summary of Observations – Equipment & Facilities
Observation FDA 483
Obs. No.GMP Akorn Cantrell Delta
Fusion
IV
KRS
Global
RAM
PharmaAseptic processing areas are deficient
regarding the system for cleaning and
disinfecting the room and equipment to
produce aseptic conditions.
1-Cantrell §211.113(b) X
Aseptic processing areas are deficient
regarding air supply that is filtered
through HEPA filters under positive
pressure.
8-Cantrell
3-KRS
Global
§211.46(b) X X
The building lacks adequate space for
the orderly placement of equipment
and materials to prevent mix-ups
between different components, drug
product containers, labeling, in-process
materials and drug products to prevent
contamination.
9-Cantrell §211.42(a),(b) X
Separate or defined areas to prevent
contamination or mix-ups are deficient
regarding operations related to aseptic
processing of drug products.
3-Cantrell §211.113(b) X
Summary of Observations – QC LabObservation FDA 483
Obs. No.GMP Akorn Cantrell Delta
Fusion
IV
KRS
Global
RAM
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
conform to appropriate
standards of identity,
strength, quality and
purity. The suitability of
all testing methods is
not verified under actual
conditions of use.
5-Akorn §211.160(a) X
Test procedures relative
to appropriate
laboratory testing for
sterility and pyrogens
are not written and
followed.
4-Cantrell §211.160(a) X
Summary of Observations – QC LabObservation FDA 483
Obs. No.GMP Akorn Cantrell Delta
Fusion
IV
KRS
Global
RAM
Pharma
There is no written testing
program designed to
assess the stability
characteristics of drug
products.
5-Cantrell
10-Delta
8-RAM
§211.166(a) X X X
Testing and release of drug
product for distribution do
not include appropriate
laboratory determination
of satisfactory
conformance to the
identity and strength of
each active ingredient
prior to release.
6-Cantrell
5-Fusion IV
7-RAM
§211.165(a) X X X
Testing and release of drug
product for distribution do
not include appropriate
laboratory determination
of satisfactory
conformance to the final
specifications prior to use.
9-Delta
6-RAM§211.165(d) X X
Summary of Observations – Packaging & Labeling
Observation FDA 483
Obs. No.GMP Akorn Cantrell Delta
Fusion
IV
KRS
Global
RAM
Pharma
The labeling of your
outsourcing facility's drug
products are deficient.
11-Cantrell
12-Delta
6-Fusion IV
6-KRS Global
12-RAM
FDCA,
§503B(b)X X X X X
Strict control is not exercised
over labeling issued for use
in drug product labeling
operations.
7-Fusion IV§211.137(a),
(b)X
Your outsourcing facility did
not submit an initial report
to FDA identifying products
compounded during the
previous six months as
required by section
503B(b)(2)(A).
8-Fusion IV
13-RAM
FDCA,
§503B(b)X X
Summary of Observations - ProductionObservation FDA 483
Obs. No.GMP Akorn Cantrell Delta
Fusion
IV
KRS
Global
RAM
Pharma
Deviations from written
production and process
control procedures are not
recorded and justified.
1-Akorn §211.101(a) X X
Aseptic areas are deficient
regarding the system for
monitoring environmental
conditions.
7-Cantrell
4-KRS Global
2-RAM
§211.110(a)(6) X X X
Procedures designed to
prevent microbiological
contamination of sterile
drug products are not
established.
2-Cantrell
1-Fusion IV
1-KRS Global
1-RAM
§211.110(a) X X X X
Procedures designed to
prevent microbiological
contamination of sterile
drug product do not
include validation of
sterilization process.
1-Delta
2-Fusion IV
2-KRS Global
5-RAM
§211.113(b) X X X X
Summary of Observations - ProductionObservation FDA 483
Obs. No.GMP Akorn Cantrell Delta
Fusion
IV
KRS
Global
RAM
Pharma
Drug product containers are
clean, sterilize and processed to
remove pyrogenic properties to
assure that they are suitable for
their intended use.
2-Delta
3-Fusion IV
§211.94(c)
§211.94(d)X X
Clothing of personnel engaged
in the processing of injectable
drug products is not
appropriate for the duties they
perform.
3-Delta
5-KRS Global
9-RAM
§211.28(a) X X X
Aseptic processing areas are
deficient regarding the system
for monitoring environmental
conditions.
4-Delta
4-Fusion IV§211.110(a)(6) X X
Time limits are not established
when appropriate for the
completion of each production
phase to assure the quality of
the drug product.
11-Delta §211.111 X
Summary of Observations - Quality
Observation FDA 483
Obs. No.GMP Akorn Cantrell Delta
Fusion
IV
KRS
Global
RAM
Pharma
There is no quality
control unit with the
responsibility and
authority to approve or
reject all components,
drug product containers,
closures, in-process
materials, packaging
materials, labeling and
drug products.
10-RAM §211.22(a) X
The responsibilities and
procedures applicable to
the quality control unit
are not fully followed.
2-Akorn §211.22(a) X
Summary of Observations - Quality
Observation FDA 483
Obs. No.GMP Akorn Cantrell Delta
Fusion
IV
KRS
Global
RAM
Pharma
There is a failure to review
thoroughly any unexplained
discrepancy, whether or not
the batch has already been
distributed.
10-Cantrell
7-Delta
§211.101(a)
§211.192X X
Investigations of a failure of a
batch or any of its
components to meet any of its
specifications did not extend
to other drug products that
may have been associated
with the specific failure or
discrepancy.
12-Cantrell
3-Akorn§211.192 X X
Quality controls do not include
a determination of
conformance to written
descriptions of sampling
procedures for drug products.
4-Akorn§211.22(d)
§211.84(a)X
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?
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