TEAM BIOLOGICS

INSPECTION APPROACH
Ann Marie Montemurro, Supervisory CSO
FDA / ORA / ORO Team Biologics Core Team
 Objective

 Provide a brief overview of the Team

Biologics program
 Outline the Team Biologics inspection
approach under Compliance Program
7345.848
Team Biologics - Who Are We?
 Team Biologics is a partnership between ORA and
CBER
 Established in 1997
 Focus on ensuring the quality and safety of biologic products
 Assure consistent comprehensive inspections of biologics
manufacturers

 Core Team Includes specially trained field investigators:

Rose Ashley Omotunde Osunsanmi
Jacqueline Diaz-Albertini Prabhu Raju
Cynthia Jim Helen Ricalde
Mihaly Ligmond Paula Trost
Christian Lynch Supervisor: Ann Marie Montemurro

 Also includes: CBER product specialists, ORA and

CBER compliance officers, and respective management
 What Do We Do?
 Responsible for conducting post-market inspections of
licensed biologic drugs and devices including:
 Vaccines
 Allergenic extracts products
 Antitoxins, antivenins, and venoms
 Plasma derived products, including their recombinant analogues
 Licensed IVD products
 Gene / Cellular Therapy Products
Note: In 10/2007 the inspection responsibility for CDER regulated
licensed therapeutic products was transferred from Team
Biologics to the District Offices
 Inventory of Firms
 28 Vaccines and Related Products
 42 Plasma derived products and their
recombinant analogues
 15 Allergenic Extracts
 26 IVD
 1 Cell Therapy
Includes both domestic and foreign sites
 Team Biologics Inspections
 TB post-approval inspections led by ORA
 biennial GMP
 Directed / Compliance Follow-up inspections – may
be more frequent

 Inspection Team
 ORA CT Investigator(s)
 Center Product Specialists
• Participation on-site or via telephone
 May Include district participation
 Can be conducted jointly with CBER/DMPQ pre-
approval inspection
 Systems Based Inspections
 Utilize a risk-based approach to conducting
inspections which identifies six key systems
and three critical elements within each system
that are common to establishments that produce
biological drug products.
 This approach is outlined in Compliance
Program Guidance Manual (CPGM) 7345.848,
Inspection of Biologic Drug Products.

Note: Licensed IVD inspections are not conducted using the system
based approach.
 Systems Approach
 Six Key Systems  Three Critical
Elements
 Quality System
 Production System  Standard Operating
 Facilities and Procedures (SOPs)
Equipment System
 Materials System
 Training
 Packaging and  Records
Labeling System
 Laboratory Control
System
 Quality Product

Quality System
Directed by Quality Unit

Laboratory Control
System Production
Packaging and Labeling
System
System
Facilities and Equipment
System Materials
System
 Quality System
This system assures overall compliance with CGMPs,
internal procedures, and specifications which includes,
but is not limited to the quality control unit (QC)
responsibilities such as:
 release of components and in-process materials
 change control
 reprocessing
 batch release
 annual record review
 validation protocols and reports
 product defect evaluations
 complaint handling
 evaluation of returned and salvaged products
 Assessment of the
Quality System
 Phase I – evaluate whether the QC unit has
fulfilled its responsibility to review and approve
all procedures related to production, quality
control and quality assurance and to ensure the
procedures are adequate for their intended use.
This assessment should also include review of
the associated record keeping systems.

 Phase II – assess data collected in order to

identify quality problems that might be linked to
other systems
 Quality System – 483 / Warning
Letter Examples
 Failures were not fully investigated and documented, nor were
they extended to other batches as appropriate. For example:
a. You failed to quarantine numerous process intermediates
associated with the use of [redacted] filter membranes that
were identified to cause foaming during filtration. This foaming
was found to be associated with leaching of [redacted] into
process intermediates. These process intermediates were used
to further manufacture finished vaccine product lots.

 Failure to report any event and relevant information associated

with the manufacturing of a licensed biological product that
represents a deviation from current good manufacturing practice,
applicable regulation, applicable standards, or established
specifications that may affect the safety, purity, or potency of a
distributed biological product as required by 21 CFR
600.14(b). For example, you failed to report to FDA that:
a. product complaints were received concerning glass in the
product, which your investigation concluded were missed
during the 100% inspection of the product;
 Quality System – 483 / Warning
Letter Examples
 You failed to establish adequate written procedures
describing the handling of all written and oral complaints
regarding a drug product [21 CFR 211.198]. For
example, Standard Operating Procedure (SOP) 123-456,
[redacted] directs that a lot history be performed. This
lot history is performed for the final finish lot number,
which is the packaging/labeling lot number. However,
complaints such as leaking vials/syringes and various
container/closure defects would be associated with a fill
lot number, and a fill lot number may be associated with
several final finish lot numbers.
 Facilities and Equipment System
 This system includes the measures and activities that
provide an appropriate physical environment, along with
the equipment and resources that are used in the
production of the biological drug product.

 Assessment of this system may include:

 Verification of the appropriateness and maintenance of buildings
and facilities
 Equipment qualification, calibration, maintenance and cleaning
(validation and routine)
 Facility utilities (HVAC, water, steam, and compressed air)
qualification, routine monitoring and maintenance
Facilities and Equipment System –
483 / Warning Letter issues
 Your disinfectant effectiveness study # FR000-01 dated 01/01/2008,
is incomplete.
The study did not evaluate the effectiveness of the disinfectants in
use on fungi and spore forming microorganisms. Spore forming
microorganisms have been routinely isolated in your manufacturing
facility and accounted for 17% of total isolates identified in 2008 and
2009; 14% in 2007 and 7% in 2006.

 Your firm failed to establish an adequate system for cleaning and

disinfecting the room and equipment to produce aseptic conditions.
For example your firm's cleaning validation studies demonstrate the
selected cleaning agent is not effective on spore forming
microorganisms. However, spore forming microorganisms have
been detected in the environmental monitoring samples, personnel
monitoring samples, and sterility test samples of final product.
Facilities and Equipment System –
483 / Warning Letter issues
 Failure to keep equipment and supplies used in work on or otherwise
exposed to any potentially pathogenic agent separated from equipment and
supplies used in the manufacture of products to the extent necessary to
prevent cross-contamination [21 CFR 600.11(e)(5)]. Hallway 111 in building
H, which connects directly to the sterile gowning suite used for sterile
processing and to the equipment airlock for passing equipment in and out of
the sterile filtration room, does not provide for adequate segregation of early
production materials from materials used in sterile processing. During
sterile filtration of vaccine A concentrate lot 00000, this common hallway
was utilized to transport already-sterilized equipment into the equipment
airlock as well as to transport soiled equipment and carts containing
inoculated eggs, for personnel traffic, and to transfer reagents between
rooms.

 You failed to assure that equipment used in the manufacture, processing,

packing and holding of a drug product is calibrated, inspected, or checked
according to a written program designed to assure proper performance
[21CFR 211.68(a)]. Specifically, a set of control samples representing
defect types are examined by the automated inspection equipment prior to
beginning each inspection process. The reject set testing allows high rates
of known rejects to be accepted by the equipment. In addition, the first time
non-accepts are sent back through the equipment and only those rejected a
second time are discarded.
 Materials System
 This system includes the measures and activities to
control finished products, such as components, source
materials, water or gases that are incorporated into the
product, and container and closures.

 Assessment of this system may include:

 Validation of computerized inventory control processes
 Product storage
 Distribution controls
 Records for detection of counterfeiting
 Control of facilities used for storage (warehouse, cold rooms,
freezers, etc)
 Materials System – 483 / Warning
Letter issues
 Written procedures are not followed for the storage and
handling of drug product containers.
Specifically, SAP inventory for Glass syringe lot 999999 did not
match the physical inventory in the warehouse reject cage on
7/3/07. One box from this sprayer lot was found damaged on
6/18/07, and was placed in the reject cage. However, this
transaction was not entered into SAP as required by written
procedures.

 The segregation of products to prevent products mix-up is

deficient, for example:
1) Staging areas for receiving and shipping of products are
conducted from the same location and there are no identifications
of the areas for the storage of incoming and outgoing products.
2) Freezer #371B (-40ºC) for the storage of received products and
Freezer (Cold Room #371) for the storage of work in progress
(WIP) were not identified.
3) Caged area for Controlled Drug Substances is not identified.
 Materials System – 483 / Warning
Letter issues
 You failed to assure that container closure systems provide
adequate protection against foreseeable external factors in storage
and use that can cause deterioration or contamination of bulk drug
substances and sterile solutions used in production. For example:
a. Study FR #99-000, [redacted] did not include an assessment of the
effect of storage conditions. This container/closure is used for bulk drug
substances.
b. [Redacted] sterile filtered solutions used in the manufacture of vaccines
are stored in containers for [redacted]. Validation studies have not
been conducted to assure container/closure integrity.

 There is no assurance that the 1000 mL bottles with screw cap

closures used to store frozen bulk product are non-reactive, additive
or adsorptive.
 Production System
 This system includes the measures and activities to
control the manufacture of biological drug products
including following and documenting performance of
approved manufacturing procedures.

 Inspection of this system may include evaluation of:

 Batch formulation
 Dosage form production
 Sterile filtration
 Aseptic processing
 In-process testing
 Lot release
 Process validation
Production System – 483 / Warning
Letter issues
 Your firm failed to establish an adequate system for monitoring
environmental conditions of aseptic processing areas [21 CFR
211.42(c)(10)(iv)]. For example:
a. There is no documentation that monitoring covers all production shifts and is
performed during active operations.
b. There is no assurance that monitoring is at the locations where critical
operations are performed.

 Failure to follow appropriate written procedures designed to

prevent microbial contamination of drug products purporting to be
sterile [21 CFR 211.113(b)]. For example, during aseptic filling
operations for vaccine X, an operator was observed with head
and torso over partially stoppered vials while loading vials onto
lyophilization trays.
Production System – 483 / Warning
Letter issues
 At least three [redacted] manufactured in 2006 exceeded your endotoxin
action limit of [redacted] EU/ml. Three [redacted] that exceeded the
endotoxin action limit were blended with [redacted] that did not exceed
your action limit and were used in the formulation of final product lots T3
and T4 that were shipped to and distributed in the United States.

 Your firm failed to assure that there are written procedures for production
and process controls designed to assure that the drug products have the
identity, strength, quality, and purity they purport or are represented to
possess [21 CFR 211.100(a)]. For example:
a. The validation performed in December 2006 for [redacted] machines 2, 3, and 4 is not
representative of the actual automated inspection process for detection of [redacted]
defects, in that there was no assessment of acceptably filled vials. This equipment is
used to inspect multiple vaccine products from filling lines 131 and 138.
b. Process control limits were not evaluated and re-established for filling line defects for
vaccine final product as required by SOP 321X. The SOP states that the Process
Control Limits (PCL) should be evaluated after the first [redacted] lots and again after
[redacted] lots or sooner if changes were made to the process. [Redacted] lots were
inspected by the [redacted] from February 2006 to September 2007, yet the limits have
not been evaluated.
Production System – 483 / Warning
Letter issues
 Visual inspection operators and QC personnel lack the necessary training
or qualifications to perform their assigned functions. Specifically:
a. Operator 2 passed the filled syringe screening certification on 9/2/08; however,
failed to pass the 10/13/08 medical surveillance for visual acuity. There is no
documented medical rationale as to why the failing visual acuity results would
not interfere with job performance.
b. Visual inspection procedures for QC inspectors are not reflective of
qualification. Specifically, QC inspectors are qualified using white/black
background and magnifying glass; however, routine procedures are not
specific and QC Inspectors do not inspect vials under these conditions.
 You failed to ensure that operators performing setup, sterile filtration
and/or aseptic dispensing use proper aseptic techniques to prevent
microbial contamination of monovalent lots. Specifically:
a) Operators were observed wearing safety glasses allowing for skin to be
exposed and, therefore, increasing the opportunity for contamination.
b) On March 28, 2007, an operator was observed removing his/her safety
glasses, then removing and cleaning his/her prescription type glasses, thus
allowing for skin to be exposed.
c) Also, an operator was observed sampling his/her fingers onto an agar touch
plate and without sanitizing or changing his/her gloves, mixing the sterile
filtered monovalent.
 Packaging and Labeling System

 This system encompasses the measures and

activities that control packaging of biological
drug product.

 Inspection of this system may include evaluation

of:
 procedures and documentation of label control to
prevent mix ups
 facilities, equipment, and support systems to maintain
proper environmental and processing controls during
operations
 Packaging & Labeling System –
483 / Warning Letter issues
 Examination of labeled product for suitability and
correctness is not documented in the batch
record. Specifically, during labeling & packaging
operations, final product syringes can be
rejected by the automated equipment at several
stations. The syringes rejected by the
automated equipment are manually inspected by
production operators and reintroduced to the
packaging operations if deemed acceptable.
However, this visual inspection and
reintroduction into the line is not documented in
the batch record.
 Laboratory Control System
 This system measures the activities related to laboratory
procedures, analytical methods development, validation
or verification, and the product stability program

 Inspection of this system includes the evaluation of:

 SOPs for control of microbiological contamination and
environmental monitoring
 Records for source materials
 In-process and finished process testing
 Methods for sampling and testing
 Validation of test methods
Laboratory Control System – 483 /
Warning Letter issues
 Failure to establish the accuracy, sensitivity, specificity, and
reproducibility of test methods, in that analytical methods have not
been validated [21 CFR 211.165(e)]. For example:
a) Sterility test method STR-MTM-0006 has not been validated for
sterility testing of [redacted] liquid bulk.
b) bioburden test method S004 has not been validated for
bioburden testing of [redacted] pre-filtration bulk.
 Laboratory raw data is recorded onto data sheets. These
sheets may be printed at will by analysts from a
computerized document management system without
tracking as to the number of data sheets printed or used.
 Data was not available to support expiration dates assigned to in-
house prepared reagent solutions used in the testing of final bulk
product.
Level I and Level II Inspections
The inspection will be conducted under
either a Level I or Level II inspection
option.
 Level I

 In-depth audit of the three critical elements

in each of the six systems and provides a
comprehensive evaluation of the
establishment's compliance with CGMPs
 Always apply in the following conditions:
 Level I
 Initial inspection of a firm
 Firms that have a history of fluctuating compliance
problems
 Compliance follow-up inspections (ex. Inspection
following warning letter)
 Firms under a Consent Decree of Permanent
Injunction
 Firms under NOIR and/or other administrative
actions
 Significant changes since last inspection
 After two previous inspections conducted have been
at Level II
 Level II
Streamlined evaluation of an
establishment's compliance with CGMPs,
and provides coverage of the three
critical elements in two mandatory
systems (Quality and Production), plus
at least one additional system on a
rotating basis during successive biennial
inspections. Level II is used for the
following options:
 Level II
 The establishment has a satisfactory history of
compliance.
 One of the two previous Biennial inspections
was a Level I inspection.
 The inspection preparation revealed no specific
trends that may have significant impact on
product safety or quality (review of BPDRs,
product recalls, etc)

Note: If significant objectionable conditions are noted

during a Level II inspection, the inspection could
change to a Level I while in progress.
 Additionally
 Since 2005, TB has been conducting “off-year”
inspections of manufacturers of Influenza Virus
Vaccine
 Flu vaccine manufactures are scheduled every
year with the off-year inspection occurring in-
between routine biennial inspections
 Off-year inspections include coverage of flu
vaccines only (Quality, Production and other
systems as needed)
Top 10 Drug Observations Cited in
Turbo EIR
 21 CFR 211.22(d)The responsibilities and procedures applicable to the
quality control unit are not [in writing] [fully followed]. Specifically, ***
 21 CFR 211.100(b)Written production and process control procedures are
not [followed in the execution of production and process control functions]
[documented at the time of performance]. Specifically, ***
 21 CFR 211.110(a)Control procedures are not established which [monitor
the output] [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. Specifically, ***
 21 CFR 211.160(b)Laboratory controls do not include the establishment of
scientifically sound and appropriate [specifications] [standards] [sampling
plans] [test procedures] designed to assure that [components] [drug product
containers] [closures] [in-process materials] [labeling] [drug products]
conform to appropriate standards of identity, strength, quality and purity.
Specifically, ***
 21 CFR 211.100(a)There are no written procedures for production and
process controls designed to assure that the drug products have the
identity, strength, quality, and purity they purport or are represented to
possess. Specifically, ***
Top 10 Drug Observations Cited in
Turbo EIR continued
 21 CFR 211.192There is a failure to thoroughly review [any unexplained
discrepancy] [the failure of a batch or any of its components to meet any of
its specifications] whether or not the batch has been already distributed.
Specifically, ***
 21 CFR 211.165(a)Testing and release of drug product for distribution do
not include appropriate laboratory determination of satisfactory
conformance to the [final specifications] [identity and strength of each active
ingredient] prior to release. Specifically, ***
 21 CFR 211.25(a)Employees are not given training in [the particular
operations they perform as part of their function] [current good
manufacturing practices] [written procedures required by current good
manufacturing practice regulations]. Specifically, ***
 21 CFR 211.188Batch production and control records [are not prepared for
each batch of drug product produced] [do not include complete information
relating to the production and control of each batch]. Specifically, ***
 21 CFR 211.67(b)Written procedures are not [established] [followed] for the
cleaning and maintenance of equipment, including utensils, used in the
manufacture, processing, packing or holding of a drug product. Specifically,
***
 Summary
 Team Biologics is a partnership between
ORA and CBER
 TB is responsible for conducting post-market
inspections of licensed biologic drugs and
devices
 Utilize a systems-based approach to conducting
inspections as outlined in Compliance Program
Guidance Manual (CPGM) 7345.848, Inspection
of Biologic Drug Products.
 Six systems
 3 critical elements
 ?? QUESTIONS ??

Ann Marie Montemurro, Supervisory CSO

ORA HQ / ORO / Team Biologics
Phone: (856) 783-1398
E-mail: [email protected]
 Special Thanks To:
 Paula Trost
 Laurie Norwood