 Review of Risk Assessment Concepts for FMEA and HACCP

› Initiating a QRM process

 RM activities should be performed using systematic processes designed to
coordinate, facilitate and improve science-based decision-making with respect to
risk. Possible steps used
1. Risk assessment :to initiate and plan a QRM process might include the following
(Ref. ICH Q9):
1. Risk identification( define the problem and/or risk question, including
pertinent assumptions identifying the potential for risk)
2. Risk analysis( different technique FMEA,HACCP,..)
3. Risk evaluation assemble background information and/or data on the
potential hazard, harm or human health impact relevant to the Risk control

2. Risk control: Identify a leader and necessary resources; and specify a timeline,
deliverables and appropriate level of decision-making for the risk
 Risk reduction
 Risk acceptance;
 Review of Risk Assessment Concepts for FMEA and HACCP
› Risk control: The following questions need to be asked
 What can be done to reduce or eliminate risks?
 What is the appropriate balance among benefits, risks and resources?
 Are new risks introduced as a result of the identified risks being controlled?

3. Risk communication and review appropriate systems should be in place, Examples

of such changes include changes to control systems, changes to equipment and
processes, changes in suppliers or contractors and organizational restructuring
 Figure_Risk Management Process.pdf
 Principles of quality risk management:
› The two primary principles of QRM are:
 a) evaluation of the risk to quality should be based on scientific knowledge and
ultimately linked to the protection of the patient; and
 b) the level of effort, formality and documentation of the QRM process should be
commensurate with the level of risk.
 Normally, potential risks in relation to the following should be considered:
 – materials and ingredients;
 – physical characteristics and composition of the product;
 – processing procedures;
 – microbial limits, where applicable;
 – premises;
 – equipment;
 – packaging;
 – sanitation and hygiene;
 – personnel – human error;
 – utilities;
 – supply chain.
 FMEA: Failure mode and effect analysis
› a) Potential Application: Evaluate equipment and facilities analyze a
manufacturing process to identify high risk steps and/or critical Parameters.

› b) Description/attributes
 Assumes comprehensive understanding of the process and that critical process
parameters (CPPs) have been defined prior to initiating the assessment tool
ensures that CPPs will be met.
 Assesses potential failure modes for processes, and the probable effect on
Outcomes and/or product performance
 Once failure modes are known, risk reduction actions can be applied to eliminate,
reduce or control potential failures
 Highly dependent upon strong understanding of product, process and/or facility
under evaluation
 Output is a relative “risk score” for each failure mode
 Module 03 Attachment No. 2.doc,
 Module 03 Attachment No. 3.doc
 Risk_Analysis.pdf
 HACCP: Hazards analysis and critical control
points
› Potential applications
 Better for preventative applications rather than reactive
 Great precursor or complement to process validation
 Assessment of the efficacy of CPPs and the ability to consistently execute
them for any process

› Description/attributes
 Identify and implement process controls that consistently and effectively
prevent hazard conditions from occurring
 Bottom-up approach that considers how to prevent hazards from occurring
and/or propagating
 Emphasizes strength of preventative controls rather than ability to detect
 QRM application during validation and qualification
› QRM principles can be used to narrow the scope of IQ, OQ and PQ to cover only the
essential elements that can affect product quality. It can also be used to determine the
optimal schedule for maintenance, monitoring, calibration and requalification.

 QRM application during commercial manufacturing

› risk assessment and risk control of product quality risks;
 adverse impact to patient health based on product quality defects;
 product supply interruption to patients;
 GMP and regulatory compliance risks;
 multisite risks;
 multiproduct risks;
 new facility and changes to existing facility, e.g. start-ups, new commercial
 manufacturing processes, technology transfers and product discontinuation
 View the design of an aseptic facility, including the
material and personnel flow
› Aseptic Design Criteria
 Aseptic facility layout must be an integrated design that satisfies
process and equipment layout requirements while catering for good
levels of access for operability, maintenance, personnel, product,
component and raw material movements.
 Architectural design should provide a contained environment, with
selected room finishes to enhance hygiene, environment and safety
level and the design must comply with relevant fire codes and building
regulations.
 Fundamental aspects of building location and block layout should be
considered. Careful attention should be given to the location of air
intakes and exhausts in relation to the prevailing wind direction,
neighboring facilities exhausts and the risk of cross-contamination.
 02. Unidirectional Air Flow.pdf
Material/Personnel Flow, in order to produce an acceptable
sterile product, the design of personnel and material flows
should minimize or prevent the introduction of contamination to the
clean area. 04. Aseptic Processing Area.pdf
 One-way personnel flow is preferred, providing physically separate entry
and exit routes or the separation can be achieved by ? ISO 14644-4.
 Process or operation waste should be removed from the aseptic area
without contaminating the product either by direct contact or passing
through areas. How used machine parts and canisters can be removed
from the area if there is no physical separation available between entry/exit
?
 Due to the problems in maintaining the Differential pressure , the airlock to
be used between rooms or areas of different air quality classification.
 03. Disturbance in Unidirectional Air Flow.pdf
• View the process from preparation and
formulation to container closure
• Integrated Facility Design:
 Integrated facility design includes everything from the weighing
of components through the storing, packaging and labeling of
the finished product. Steps includes, mixing, formulating,
filtering, lyophilizing, filling, encapsulating and sterilizing.
 The design of each element of the aseptic manufacturing facility
should contribute minimizing the contamination risk.
 Important that integrated facility technology can be supported
by local personnel, such that maintenance and repair costs can
be minimized and facility up time be optimized.
 01. Sterile Movement.pdf
 View the process from preparation and formulation to
container closure
› Filling / Stoppering process:
 U shaped filling and stoppering line has the advantage of returning the container to the pharmaceutical area
for capping 06. Filling Stoppering Process.pdf

 Fill accuracy-Sampling technique-fill inhibited if no container detected-Online and offline checking

 Fill reproducibility – rejection( with lock) for no fill and no stopper- fill container &stopper container counter

 Pre and post gassing rate

 Moving part above the filling table should be minimize

 Change parts design for fitting and removing with minimum use of tooling

› Capping / labelling process:

- Crimping force checking and reproducibility

- Rejection if there no container/stopper missing

- Design of ease of cleaning and removing of metallic fragments generated by the crimping process

- Unit counter & label reconciliation

 Determine “the Criticals” that need to be focused on
› Media fill program should include worst case activities
 Factors associated with longest permitted run (e.g. operator fatigue).
 Representative number, type, and complexity of normal interventions, non-routine
interventions and events (e.g maintenance, stoppages, etc)
 Aseptic equipment assembly
 No of personnel and their activities, shift changes, breaks,
 gown changes
 Representative number of aseptic additions (e.g. charging
 containers, closures, sterile ingredients) or transfers
 Aseptic equipment connections/disconnections
 Aseptic sample collections
 Line speed and configuration
 Regulatory Media Fill Requirements
› Useful reference from regulatuion/guidance
› FDA Guidance for Industry- Sterile Drug Products Produced by Aseptic
Processing - Current Good Manufacturing Process
› United state pharmacopeias USP 35
› PIC/S Recommendation on the Validation of Aseptic Processes
› ISO 13408 Aseptic Processing of Health Care Products
› Part 1: General Requirements
› Part 2: Filtration
› Part 3: Lyophilization
› Part 4: Clean-In-Place Technologies
› Part 5: Sterilization-In-Place
› Part 6: Isolator Systems
› Media Fill (6)
 Frequency and Number
 Three initial, consecutive per shift
 Subsequently semi-annual per shift and process
 All personnel should participate at least annually,
 consistent with routine duties
 Changes should be assessed and revalidation carried out
 as required
 Contamination Rates:
› Terminally sterilized drugs should provide a sterility assurance level (SAL) of at
least 10-6.
› Aseptically filled drugs should be an SAL of at least 10-3.
› When filling fewer than 5,000 units, no contaminated units should be detected.
 One (1) contaminated unit is considered cause for revalidation, following an
investigation.
› When filling from 5,000 to 10,000 units
 One (1) contaminated unit should result in an investigation, including consideration of a
repeat media fill.
 Two (2) contaminated units are considered cause for revalidation, following
investigation.
› When filling more than 10,000 units
 One (1) contaminated unit should result in an investigation.
 Two (2) contaminated units are considered cause for revalidation, following
investigation.
 Weight checks
 Container closure systems
 Specific provisions in processing instructions
› Written batch record documenting conditions and activities
› Should not be used to justify risky practices
› Environmental conditions
 Representative of actual production conditions (no. of personnel, activity
levels etc) – no special precautions (not including adjustment of HVAC)
 if nitrogen used for overlaying/purging need to substitute with air
 Media
› Anaerobic media should be considered under certain circumstances
› Should be tested for growth promoting properties (including factory isolates)
 Incubation, Examination
 In the range 20-35ºC.
 If two temperatures are used, lower temperature first
 Inspection by qualified personnel.
 All integral units should be incubated. Should be justification for any units not
incubated.
 Units removed (and not incubated) should be consistent with routine
practices (although incubation would give information regarding risk of
intervention)
 Batch reconciliation
 Sterility Test:
› Perform sterility test for:
 Empty Sealed Vials
 Sterile Lactose
 Media-filled vials
 Lactose-media filled vials
 › Growth promotion tests must demonstrate that the medium supports
recovery and growth of low numbers of microorganisms, i.e. 10-100
CFU/unit.
 Perform the growth promotion test at the end of incubation period to ensure
that the media could keep its growth promotion capability during the
incubation period
 Growth should be demonstrated within 5 days at the same incubation
temperature as used during the simulation test performance.
› Worst-case conditions are often thought to be the largest container with
the widest mouth as it is exposed longer to the environment.
› The fill volume of the containers must be sufficient to enable contact of
all the container-closure seal surfaces when the container is inverted
and also sufficient to allow the detection of microbial growth.
Intervention Maximum Permitted Number of Containers (All
Routine Intervention
Code Time sizes) to be Rejected

R-1 Assembly of Powder Filling Machine 45 Min. Zero

R-2 Initial Powder Introduction 10 Min. 24 Empty

R-3 Initial Rubber Closures Introduction 05 Min. Zero

R-4 Initial Powder Fill Weight Adjustment 05 Min. 24 Filled

R-5 Initial Rubber Closures Adjustment 05 Min. Zero

R-6 Periodic Powder Replenishment 10 Min. 24 Filled

Periodic Rubber Closures
R-7 03 Min. Zero
Replenishment
In-process Powder Fill Weight
R-8 05 Min. 24 Empty+24 Filled
Adjustment
R-9 Environmental Monitoring 40 Min. 24 Empty

R-10 Medicinal Gas Replenishment 15 Min. 24 Filled

R-11 Operator breaks and meals 60 Min. Zero

R-12 Change of operator 15 Min. Zero

Intervention Maximum Permitted Number of Containers (All
Code Non-Routine Intervention Time sizes) to be Rejected

NR-1 Stopper misfeeds or clumping 10 Min. 24 Filled Vials

NR-2 Fallen, broken or Jammed containers 15 Min. 24 Filled Vials

NR-3 Product Spillage 10 Min. 24 Empty

NR-4 Sensor adjustments or Replacement 10 Min. 24 Filled Vials

NR-5 Powder Dosing Disk replacement 20 Min. 24 Filled Vials

NR-6 Change of needle/pump 20Min. 24 Empty

NR-7 Conveyor Speed Adjustments 10 Min. 24 Empty

Increasing/Decreasing filling room
NR-8 temperature 60 Min. Zero
Increasing/Decreasing Filling room
NR-9 relative humidity 30 Min. Zero
Increasing/Decreasing Filling room
NR-10 differential pressure 15 Min. Zero
R-11 Operator breaks and meals 60 Min. Zero
R-12 Change of operator 15 Min. Zero
 FDA Warning Letters
› Your disinfectant qualification for (b)(4) and (b)(4) bi-spore disinfectants documented
that the log reduction criteria (Bacteria = 4, Fungi = 3) was not met when challenged
with multiple organisms in a variety of surfaces. After disinfection, you recovered
Micrococcus luteus on vinyl, (b)(4), stainless steel, glass, and wall laminate and
Enterobacter cloacae, Rhodococcus sp, Burkholderia cepacia, Pseudomonas
aeruginosa, Methylobacterium mesophilicum and, Acinetobacter lwoffi on glass.
However, your procedures for routine cleaning of the aseptic manufacturing area
continue to require the use of unqualified disinfectants during days (b)(4) through
(b)(4) of your disinfectant program.
› media fill conducted during January 2011 resulted in two contaminated units. Your
firm attributed the failures to stopper bags left inside the class 100 area for a long
period of time (throughout a shutdown that took place prior to the media fill in January
2011 shutdown). There is inadequate information available to support your
conclusion, including information regarding the microorganisms recovered from the
stopper bags and the sterility test conducted, along with an evaluation of your
sampling procedure and environmental monitoring program
 FDA Warning Letters

› The investigators noticed during the inspection one of the operators sanitizing his hands
with (b)(4) immediately prior to conducting his own personnel monitoring sampling. Your
personnel monitoring program should include appropriate sampling and practices to
reflect whether personnel maintain asepsis during sterile drug manufacture.
› In addition, the (b)(4) “Dynamic Airflow Visualization” video provided in your firm’s
response shows an operator spraying his hands with (b)(4)(b)(4)(b)(4)% directly over
the air viable microbial plate. This practice is unacceptable because the environmental
monitoring results from plates sprayed with (b)(4) may be inaccurate and may not reflect
the actual microbiological environment of the Class 100 (ISO 5) room.
› Your firm has not thoroughly investigated the failure of a batch or any of its components
to meet its specifications whether or not the batch has already been distributed [21
C.F.R. 211.192]. For example,
› The inspection documented that (b)(4) Injection, batch # (b)(4), failed the sterility test.
Your quality control unit repeated the test on a new sample to confirm the original result
prior to initiating an investigation. The quality control unit’s decision to perform a retest
without conclusive assignable laboratory cause is not in accord with USP <71> and is
an unacceptable practice
 FDA Warning Letters
› FDA response
› Please include in the response to this letter a copy of your final sterility failure
investigation report for (b)(4) Injection, batch # (b)(4). Your response should include a
detailed explanation of your root cause analysis and the corrective actions implemented to
prevent recurrence of the event(s) that lead to the contamination of the lot. Your firm
should also indicate if a media fill was conducted as part of your sterility failure evaluation.
If so, provide a copy of the media fill protocol and report as part of your response to this
letter. Also include a list of all lots of sterile drug products manufactured at your facility that
initially failed the sterility test, and that were released based on a passing re-sample or re-
test result. Provide the product name, original test and re-test date, microorganism
isolated and product destination.
 FDA Warning Letters
› Your firm has not established appropriate written procedures designed to prevent
microbiological contamination of drug products purporting to be sterile [21 C.F.R.
211.113(b)]. For example,
› a. During the aseptic filling of two injection batches on filling line (b)(4), where (b)(4)
injection for the U.S. is filled, employees
› were observed following poor aseptic techniques. Specifically, movements inside the
class A area were not slow and deliberate; operators and an engineer were observed
with exposed facial skin during the filling operation; and a force was observed in a class
B (ISO 6) area and was then used to remove fallen ampoules from the aseptic
processing line in the class A (ISO 5) area.
› b. Employees who perform critical duties in your aseptic filling line (b)(4) did not
participate in an (b)(4) line qualification (process simulation) during 2010, 2009, and
2008.
› c. The tubing ends used to connect the solution tanks to the filling line (b)(4) are not
protected prior to sterilization to reduce the potential of contamination after sterilization,
and prior to the aseptic connection.
› d. The disinfectant efficacy studies have not been completed for three of the (b)(4)
disinfectants used to sanitize surfaces in the sterility testing suite and production aseptic
core filling line (b)(4).
› Your response indicates corrective action through training employees, equipment
purchase, and procedural improvements. However, your response fails to specifically
address the observed deficiencies and whether the products already distributed have
been evaluated.
 FDA Warning Letters
› Your firm used dried/desiccated media agar plates for environmental monitoring
testing used to support the release of batches. On November 15, 2011, you
documented that 155 of a total of 247 media plates evaluated (more than 50%)
were dried. The use of dried agar plates, which do not reliably support microbial
growth, to recover microbial contamination is inadequate.
›
b) On November 14, 2011, the FDA investigator observed desiccated
environmental monitoring plates in your incubators. However, your analysts only
recorded the results as dried media but not the counts from the plates (if any). On
this same day, the FDA investigator observed plate “(b)(4),” sampled on November
9, 2011, to have growth of 1 Colony Forming Unit (CFU). However, your firm
documented the result of this plate’s reading as "SAUSEN MEDIUM", dry medium,
and failed to report the microbial growth.
›
c) Your environmental monitoring data for January 2009 through October 2011
contains documentation of only two action limit excursions in the Grade A
manufacturing areas. In apparent contradiction, during an FDA visit to your
microbiology laboratory on November 14, 2011, nine plates, collected as part of the
environmental monitoring program from the Grade A manufacturing area were
found inside an incubator in the microbiology laboratory with visible growth of
microorganisms.
FDA Warning Letters

› d) Your environmental sampling and testing program procedure is inadequate because

it fails to adequately identify (e.g., with diagrams) the locations from which the surface
samples are collected. In addition, you do not collect sufficient active viable air samples
and dynamic non-viable particulate air samples from the critical area during
manufacturing.
› e) The agar level on surface contact plates (used for surface environmental and
personnel monitoring sample testing) was below the rim of the plates creating the
possibility that the agar would not have contact with the surface intended to be
sampled.
› The operator of filling line F200 was observed leaning over the top of (b)(4) containing
filled opened sterile vials during the loading of the (b)(4), thereby blocking the
unidirectional airflow over the open vials.
› b) The operator was observed compromising the connection’s sterility of the filling line
by exposing the (b)(4) to the Grade B area during this aseptic connection with no
further (b)(4) of the line after its installation.
› c) During the set-up for the filling line, water sprayed from the filling line directly onto an
operator, which wet his gown. The operator continued line setup activities without re-
gowning until instructed to stop by firm management after an FDA investigator pointed
out the concern.
 FDA Warning Letters

› The operator of filling line F200 was observed leaning over the top of (b)(4) containing filled
opened sterile vials during the loading of the (b)(4), thereby blocking the unidirectional airflow
over the open vials.

› b) The operator was observed compromising the connection’s sterility of the filling line by
exposing the (b)(4) to the Grade B area during this aseptic connection with no further (b)(4) of
the line after its installation.

› c) During the set-up for the filling line, water sprayed from the filling line directly onto an
operator, which wet his gown. The operator continued line setup activities without re-gowning
until instructed to stop by firm management after an FDA investigator pointed out the concern.

› d) Uncovered (b)(4) are not maintained under Grade A conditions during their movement from
the (b)(4) located in Room (b)(4) to their Grade A staging area near the F200 filling line in
Room (b)(4). The (b)(4) are transported through a Grade B area to their staging
area. Additionally, during the filling operation, the operator was observed removing the (b)(4)
and (b)(4) from their Grade A staging area through a Grade B area to the Grade A area, where
the (b)(4) and (b)(4) are loaded with vials, and placed on a (b)(4). These (b)(4)
 FDA Warning Letters
› Your firm failed to conduct adequate investigations of three media fill failures in the
aseptic filling line used to produce sterile products. Your firm uses (b)(4) vials to fill
(b)(4), which is shipped to the US market. Your firm performed the last successful
media fill using the (b)(4) vials on November 28, 2010, Lot (b)(4), and the last
successful media fill lot for (b)(4) vials on February 26, 2011.
› Significantly, the three media fill failures on filling line F200 occurred from May to
September 2011. While the last successful (b)(4) media fill on this line (F200) was
conducted on November 28, 2010, your firm released batches manufactured on this
same filling line between November 28, 2010 and February 26, 2011. Your firm failed
to adequately evaluate the impact of the contamination hazards revealed by these
media fill failures on commercial batches (e.g., (b)(4)).
› b) Your investigation concluded that the probable root cause for the media failure was
the contamination of Media Fill Lot (b)(4) by an earlier media fill Lot (b)(4) that had
failed. In your response, you attribute these two media fill failures to the testing of your
(b)(4) Vessel (b)(4) procedure, and proposed changing the (b)(4) and revising your
procedures. Your firm’s investigation found that both of these media fills were
contaminated with Burkholderia cepacia. Your investigation was not extended to other
areas of the aseptic operation. For example, deficient design or control of rooms,
equipment, or the Water for Injection (WFI) system, may also have caused the
introduction of these water-borne microbes to the aseptically processed vials.
 Environmental Monitoring
› Physical
› Particulate matter
› Differential pressures
› Air changes, airflow patterns
› Clean up time/recovery
› Temperature and relative humidity
› Airflow velocity

 Equipment/container preparation and sterilization

› All equipment (including lyophilizers) and product containers/closures should be
sterilized using validated cycles same requirements apply for equipment sterilization
that apply to terminally sterilized product particular attention to stoppers - should not be
tightly packed as may clump together and affect air removal during vacuum stage of
sterilization process equipment wrapped and loaded to facilitate air removal particular
attention to filters housings and tubing.
› Equipment should be appropriately cleaned - O-rings and
› Gaskets should be removed to prevent build up of dirt or
› Residues
 rinse water should be WFI grade

 equipment should be left dry unless sterilized immediately after

 cleaning (to prevent build up of pyrogens)

 washing of glass containers and rubber stoppers should be validated for endotoxin

removal/NACl removal
 In clean rooms:
› Position plates directly under HEPA filters
› Position plates well away from human activity
› Use “old” plates that are dehydrated
› Do not monitor filling machine set-up
› Do not use Sabouraud Dextrose media when fungal spores are likely to be present
 In water testing:
› Run water at the test point for 5 min. (Production won’t do that)
› Store the water sample as long as possible before testing (cells attach to container
walls)
› Use the pour plate method
› Use the incorrect medium
 In the sterility test:
› Allow the membrane filter to dry out under vacuum
› Place filter in the oxidised layer of Thioglycollate medium
› Use old Thioglycollate that is fully oxidised
 Contamination sources
› Raw material suppliers
› Inadequate cleaning
› Personnel
› Inadequate procedures
› Inadequate processe Environment

 Thin glass flakes

› Stainless steel particulates
› Small white particles (polyethylene terephthalate polyester) or
from the active ingredient
› Cracked glass
› brown and Black particles
› Fibers
 Contamination Sources
› Internal Sources: Contamination sources that arise within a sterile manufacturing facility
generally are from:
› The HVAC system
› Process or Operations
› Number of particles generated. 09. Number of Particles Generated Per Second Per
Person.pdf
› Human Particle Generation 08. Human Particle Generation.pdf
› The Operations (normally the highest source of contamination), capping and crimping
process generate large number of particles, so room pressure reversals is critical and
need to be avoided
› The introduction of components and equipments.
› The introduction for raw materials
› Adjacent, less controlled areas.

 External Sources:
› Use of re-circulated air from the manufacturing area, provided no cross contamination
risk.
› Careful selection of filters to match particular application
› Careful location of fresh air intakes.
› Location of the facility.
 Container preparation
› Four forms of contamination
 Bioburden: Viable microbiological count CFU
 Endotoxins:Pyrogenic cell wall materials resulting from growth
and degradation of microorganism
 Extraneous particulates: Solid particulate matter resulting from
container manufacturing, packaging and staging processes
glass fragment)
 Extraneous chemicals: e.g: excess quantities of surface
treatment chemicals

› Sinks and drains avoided, and excluded in Grade A and B areas

 Where installed, design, location, maintenance
 Effective cleanable traps
 Air breaks preventing backflow
 Floor channels open and easily cleanable
 Investigation
› If Appearance of turbidity in the vials indicates contamination. Isolate such vials for
determination of compliance with acceptance criteria for rate of contamination.

› If some microbial growth shows up as a faint haze, which is difficult to detect,

conform the bacterial growth by streaking on SCDA Medium.

 Identify the microorganisms present in the every contaminated vial of the

simulation test/ & determination of the possible sources of the contamination

 After identification of root cause, an effective corrective action can be

implemented before repeating the media fill study.PDA technical reports provide
some indications; Documentation of results/CAPA through deviation control
system SOP
 Checklist examples
› Identification of organism in the contaminated units/environment/surface/personnel
› Check the environmental monitoring records/plates/results.
› Check the gowning qualification of all personnel enter the clean area/plates,
surface sampling from the hand/head/and body of the operators.
› Check the media fill process, documentation(batch records/deviations/filter integrity
testing before and after filling/cleaning and sanitization/autoclave and tunnel
sterilization charts and phases/disinfectant preparations/UV pass box/any presence
of stagnant waters.
› Check the differential pressure gauges/records& pressure cascade/HEPA
filters/WFI units/Purified water/steam generator/calibration and preventive
maintenance records.
 Check the previous media fill reports/qualification document for machine/change
control documents/process holding time example
 Storage period of sterilized vials/rubbers/flip of seal/machine parts/disinfectants
 Time between loading of sterile materials and start of filling/start and end of filling
period
 Time between complete the mixing process and start filtration process/duration of
filtration
 Freeze dryer cycle duration /unloading to capping
 Tunnel sterilization duration/unloading to filling
› maximum permitted holding time of bulk if held after filtration prior to filling
› product exposure on processing line
› total time for product filtration to prevent organisms from penetrating filter
› maximum time for upstream filters used for clarification or particle removal (can
support microbial attachment)
 Check the video tape, its very important to obtain trending by the distribution of the
contaminated units and cause of failure. Each tray should be identified with tractability in
order to identify the root cause if any)
 Filling of solution may be followed by lyophilization (freeze drying)
› Stoppers partially seated, product transferred to lyophilize (Grade A/B conditions)
› Release of air/nitrogen into lyophilizer chamber at completion of process should be
through sterilizing filter
 Possible cause of failure in the beginning of filling: contamination during line setup
(needels, dosing disk, dosing pump, stoppers bowl).
 Possible cause of failure in the middle of filling: Could caused by incorrect performing
critical intervention during filling/sudden DOP of flow/DP of LAF
 Possible cause of failure in the end of filling ( area cleanless failure/ contamination from the
operators( fatigue), gowning integrity failure, wrong aseptic connection to the media tank,
containatuion in the recirculation loop, filter integrity failure for HVAC/WFI ,refill the hopper
with unsealed container.
 The inspectors will look to find

› Critical deficiencies on Day 1, Major on Day 2 and Other on Day 3.

› Inadequate environmental monitoring programmes.
› Inadequate control over equipment autoclave sterilisation cycles.
› Inappropriate behaviour in clean rooms.
› Changing rooms being too small with inadequate segregation.
› Inappropriate process and personnel flow.
› Single door autoclaves instead of double door.
› At one site, management could not find the media preparation area.
› No quantitative limits for fertility test. Qualitative limit (growth/no growth is not
acceptable)
› Expiry date of media not validated.
› Growth promotion capability decreases rapidly in first week after preparation.
› It is very easy to obtain zero results in all microbiological monitoring, including sterility &
bioburden testing.
› If there are find pages & pages of zero results this should ALERT you NOT satisfy you.
 Case Study
› Media Fill Failure:
 Approx. 60% contaminated
 Considered spurious. Corrections made to firm’s satisfaction.
› FDA Guideline (and PDA #22): 3 Lots for Revalidation
 First Media Fill Batch = No contamination
 Second Media Fill Batch = Over 95% contaminated (over 5000 vials)
 Third Media Fill Batch = No contamination
› If one batch was run, a firm would return to production/release of commercial lots
without knowledge non-sterility problem still existed.
› Root Cause:
 Personnel / Aseptic Connection
 Isolates in both failures were common skin-borne microbes
 Only Partially Gowned, Skin Exposed, Aseptic Technique questionable.
 Corrections to resolve these issues: Full sterile gown donned and enhanced
personnel/environmental monitoring performed in near term. Equipment later
modified to allow for SIP.
 The microenvironment inside an equipment load cannot be guaranteed because it
relies upon:
› adequate air removal
› adequate steam penetration
› lack of leaks in the autoclave (door seal, valves, pipework)
› prevention of introduction of non- condensable gases from the steam supply.
› prevention of condensate accumulating in equipment
 Equilibration time, that is, the time for the penetration thermocouples to show the
same temperature as the chamber.
 Equilibration time should be less than 15 seconds for chambers less than 800l and 30
seconds for larger chambers
 If the equilibration time is exceeded it diagnoses:
› Inadequate air removal OR
› Inadequate steam penetration OR
› Excessive non-condensable gases
The End

Amjad Ganma, M.Sc (London)

Quality Unit Manager
Tabuk Pharmaceutical Manufacturing Co.,
Tabuk, Saudi Arabia
Per. Email: amjad_ganma@yahoo.com
Off. Email : amjad@tpmc.com.sa
Mobile num: 00966509522269