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WorksheetsFinal Exam BTEC 4320 Quiz 6
Total questions: 96
Worksheet time: 53mins
What is not a main job responsibility of the QC group?
Analytical testing of raw materials against specifications before use by the production group
Provide analytical support for process validation
Checking accuracy of process operators entries in batch records
Environmental monitoring for viables and non-viables
Testing of drug products against specifications before release
What is not always a requirement for cGMP-compliant sampling?
Sampling plans must be based on appropriate statistical criteria
Samples must be an accurate representation of the material or drug product batch
Sample containers should be properly identified and labelled.
Samples must be obtained where they are within easy reach by the process technician
Sampling plans and methods must be written, defined, and pre-approved
What is not a source of information on acceptable sampling sizes, like the table shown on slide 35?
International Organization for Standardization
American Standards Congress
American Society for Quality
Military standard
American National Standards Institute
What does not apply to specifications for release of finish drug products?
Specifications consist of test procedures
Product release specifications are not required by the FDA for evaluation of marketing applications
Many analytical procedures that are part of specifications are found in the US Pharmacopoeia
Quality and safety of the drug product is ensured by conformance to specifications
Specifications include rejection criteria for certain attributes
What does not apply to specifications for release of finish drug products?
Acceptable reference chemicals used in tests should be purchased from USP only
Quality and safety of the drug product is ensured by conformance to specifications
What is considered as a contaminant in the manufacturing of small molecule drugs?
host cell DNA and proteins
residual solvents
incompletely synthesized API
Leachates from equipment
degradation products
A single identity test, based on the CofA, is all that is required for most excipient lots received by the drug manufacturer
FALSE
TRUE
45 drums of bulk raw material were delivered to your manufacturing company. As the QC analyst assigned to handle the delivered material, what is the minimum number of drums that you should sample and test for attributes like impurities or water content?
8 drums (sqrt of 45 is 6.7+1=7.7)
15 drums
7 drums
9 drums
6 drums
In the sampling table shown in slide 35, for a lot size of 658, ______________ units should be obtained and tested for conformance to specifications.
50 units
200 units
32 units (sqrt of 658 is 25.65+1=26.65)
125 units
315 units
In the Genzyme video on producing biotherapeutics using mammalian cells, what is the correct sequence of manufacturing activities in the 90-day production flow?
Which is not an in-process control test used to monitor the progress of protein production during fermentation?
Presence of misfolded proteins
Presence of chemicals used to clean the bioreactor
Concentration of biologic
Gene copy number
Endotoxin levels
What is not a process control variable in the downstream cell harvesting processes that could impact product quality and yield?
Bioreactor cleaning reagents
pH of chromatography mobile phase
Centrifugation speed
Filtration temperature
Filtration backpressure
Procedures and Acceptance Criteria for release testing of drug tablets are found in ICHQ4, while that for biotechnological or biological products are found in ICH _________.
ICHQ6B
ICHQ7
ICHQ3C
ICHQ5A
Dissolution tests are performed on tablets or capsules to predict:
Resistance to chipping, crumbling or breaking when shaken in containers
API release profile inside the patient's blood stream
There's no correct answer choice (dissolution predicts how fast and how much API dissolves out of the dosage form in the GI tract)
Uniformity of API concentration in the average tablet
Breaking of the drug product into smaller pieces inside the GI tract
What is not true about RSD?
RSD is a statistical measure of process variability
A low RSD value is desirable
RSD stands for relative standard deviation
Reflects deviation of individual samples from the lowest sample value
RSD is often expressed as a percentage
What is an acceptable quantity of each sample that should be obtained when sampling in-process material for blend uniformity using a sample thief, if the final drug product is a 300 mg tablet containing 30 mg API?
30 mg
3000 mg
500 mg
250 mg
1000 mg
What is not considered as in-process tests for typical coated tablets?
Container closure integrity
Water content
Blend uniformity
Particle size distribution
Tablet capping
What is not a product release test for biologics?
mg antibody per vial of drug product
identity test for the cell substrate
amino acid sequencing of biologic
tests for potency
PCR for viral contaminants
What is not used as a potency assay for antibodies?
ELISA
Western blot
Flow cytometry
Blood pressure measurement
Which test is not acceptable for identity testing of biotherapeutic proteins?
Western Blot
Ion-exchange chromatography
Amino acid sequencing
Peptide map
Absorbance at 280 nm
In the production of biotherapeutic protein using Chinese Hamster Ovary cells as expression hosts, which of these impurities is a product-related impurity, that is, not considered a process-related impurity?
Lysozyme used to break cell open
Media components
Ligands used for affinity purification
Detergents used to clean bioreactors
Recombinant product missing the first 10 amino acids
Stability testing of biologics with shelf life 1 year or less is performed on at least 3 lots ____________ .
at 0, 3, 6, 9, 12th month
at 0, 1, 2, 3, 12th month
at 0, 1, 2, 3, 6, 12th month
Every month until month 12
at 0, 1, 2, 3, 6, 9, 12th month
Stability tests look at the change in quality attributes over time. For biologics, what quality tests are not performed as part of stability studies because the results are not expected to change much from time zero?
Percent purity
Product potency
Amount of host cell protein
Quantity
Peptide mapping
To confirm a bioreactor SIP SOP, what are placed inside the bioreactors to demonstrate the effectiveness of the sterilization process?
TSA contact strips
Biological indicator strips
LB Agar plates
RODAC plates
Sabouraud agar plates
In the video on test to confirm sterility of the biosafety cabinet (BSC), for how long were the settling agar plates left open in the BSC?
30 min
2 hours
10 min
one day
one hour
Environmental monitoring in an aseptic manufacturing facility by the quality control group does not include:
Measuring the levels of fungi on equipment surfaces
Measuring the levels of dust that could be from equipment
Measuring the levels of dust that could be generated from growth media
Measuring the levels of nitrogen in the air
Measuring the levels of bacterial spores in the air
What instrument is used to actively sample the air in a biomanufacturing suite for viables?
High Efficiency Particulate Air (HEPA) sampler
Hamster wheel
Laser particle counter
Biological indicator strips
Centrifugal Air sampler
Of the locations given, which one is supposed to be a Class A area?
For cellular drug products with short shelf life, the BACT-ALERT 3D system provides a quick way to detect microbes by detecting increasing levels of ________________ in the culture bottles.
Carbon dioxide
Acetate
Carbon monoxide
Adenosine triphosphate
Oxygen
The drug filling area is a specially vulnerable area to contamination by microbes and dust thus requiring Class 100 air quality. How many microbes are allowable per cubic meter of air in an area which is class 100?
Less than 10 CFU per cu. m
Less than 100 CFU per cu. M
Less than 200 CFU CFU per cu. m
None
1 or less CFU per cu. m
What is not true about endotoxins?
The upper limit for endotoxins in water used in injectable drug products is 2.5 endotoxin units per ml
In mammalian cell production hosts, endotoxins are considered contaminants rather than process impurities
Endotoxins are molecules found on the surface of the outer membrane of Gram negative, but not in Gram positive bacteria
Endotoxins are chemical substances that cause fever in humans in drugs that are administered intravenously
Endotoxins belong to a class of molecules called lipopolysaccharides
Endotoxins are lipopolysaccharides found on the outer membrane of Gram negative, but not in Gram positive bacteria. What is not used to test for the presence of endotoxins in drug products?
Rabbit Pyrogen Test
Gram staining
Pyrogene
Recombinant Factor C assay
Chromogenic LAL Assay
Mycoplasma is a common contaminant of cell cultures and can adversely affect virus propagation for vaccines and recombinant protein quality. What is not used as a test for Mycoplasma?
Polymerase chain reaction
Bradford assay
Fried egg-shaped colonies on plates
Microscopy
Hoechst fluorescent stain
The cGMP-compliant flow of air in a sterile manufacturing suite is demonstrated using smoke studies and best described as:
Turbulent
Unidirectional
Indirect
Monodirectional
Bidirectional
What does not apply to specifications?
Justification for specifications are based on lots manufactured for pre-clinical and clinical testing
Specifications includes acceptance criteria for drug product release prior to distribution
Specifications include series of tests and instructions on performing the tests
Drug product release specifications are not included in the common technical document submitted for marketing approval
Distributed products that are later found to fail specifications may be withdrawn or recalled from the market
Out-of-specification results can arise from:
missteps by manufacturing personnel
All the other answers are correct
errors in QC analytical test SOPs
errors in the master batch record instructions
mistakes by QC analysts
In what instance might a drug product be considered out of specifications?
The tablet is greenish when acceptance criteria specifies white tablets
The obtained test results are in the middle of the range of passing values
Which drug product quality attribute is expected to be higher in stability samples than in the release test results (time=0)?
Dissolution rates
Degradation products
Content uniformity
Assay
Appearance
For tablets, in which of these activities will an OOS apply to in some but not all cases?
Results of blend uniformity tests are below the acceptance criteria for API levels
Results of development work which are out of pre-specified criteria
Results of method validation which are out of pre-specified criteria
Results of instrument validation which are out of pre-specified criteria
Results of method transfers which are out of pre-specified criteria
For tablets, in which of these activities will test results outside of the specified criteria be considered OOS?
Results of method validation which are out of pre-specified criteria
Results of method transfers which are out of pre-specified criteria
Results of instrument validation which are out of pre-specified criteria
Results of development work which are out of pre-specified criteria
Results of API content testing of stability samples which are out of the pre-specified criteria
What is not considered an assignable cause for an OOS event?
The analyst plugged in the wrong value in the formula for calculating the %API
There were undissolved crystals found in one of the unused solutions
The analyst has been trained 3 times on the SOP
A retired method for quantifying the API was used
There was an error found in the volume of a reagent specified in a method for quantifying an impurity
In the event of non-assignable cause for OOS, what would be part of the Phase II of the OOS investigation?
Re-sampling if the original samples were not representative of the batch.
The original analyst redoes the test using the original prepared solutions
A second analyst redoes the test using the solutions originally used by the first analyst
Field Alert Report should be filed with the FDA within 3 days, once a first analyst performs retests and still obtains OOS results for a stability sample of an already marketed drug.
TRUE
FALSE
What does the phrase “testing into compliance” mean?
A non-conforming material is tested using a different SOP to see if it passes specs
A non-conforming batch is reprocessed and retested until it passes specs
A non-conforming batch is rejected after non-conforming test results
Test results from a non-conforming batch is manipulated by a second analyst until the numbers are within specs
A non-conforming batch is resampled and retested until passing results are obtained
The Ishikawa diagram is a useful tool for root cause investigation of an OOS. The root cause of OOS results can be traced to any one of the 5M inputs in the drug manufacturing process. Which is not one of the 5Ms?
Man
Machine
Environment
Mischief
Methods
What is not an acceptable practice with regards to OOS?
A Field Alert Report should be filed with the FDA for marketed drug products that got OOS stability results
Only data that conform with specifications should be recorded in lab notebooks
Non-conforming drug product should not be released for distribution
Retest other batches that were analyzed by the same analyst who generated OOS results in another batch
OOS should be investigated whether or not the batch has been distributed
Which ICH document has guidelines for method and process validation in API manufacturing?
ICHQ6
ICHQ9
ICHQ8
ICHQ7
ICHQ4
Which of the steps in bioreactor qualification will focus on the availability of utilities, like uninterruptible power supply and readily accessible oxygen tanks, to support the growth of cells in the bioreactor?
Installation qualification
Process qualifications
Performance qualification
Operational qualification
Design qualification
In a validated analytical method, which method attribute pertains to the ability of the method to detect very low levels of an impurity in a drug product?
Reproducibility
Accuracy
Sensitivity
Specificity
Consistency
In method validation, say for a PCR, which method attribute pertains to the lowest amount of DNA in a given sample that can be measured accurately?
Specificity
Limit of quantitation
Accuracy
Consistency
Reproducibility
In method validation, which method attribute pertains to the ability to obtain instrument readings, say absorbance, which are directly proportional to the concentration (amount) of analyte in the sample?
Specificity
Consistency
Sensitivity
Reproducibility
Linearity
What will not need to be established in the process validation for production of a biologic drug?
Holding time for the culture supernatant or filtrate
Endotoxin control
Cell transformation efficiency
Virus removal
Removal of host cell proteins
Validation is expensive. What is not a way by which validation saves the company money in the long run?
Better product quality can translate to enhanced customer preference and market share
Improved process consistency eliminates the need for raw material testing
Increased throughput or productivity due to a reduction in rejects and reworks
Fewer product complaints that need to be addressed or investigated and less product returns or recalls
Improved process efficiency means lower utility and raw material costs
When manufacturing of the anti-inflammatory drug, Remicade, was transferred from the Netherlands site to Pennsylvania and scaled up, what was the unanticipated consequence of processing the resulting increased product yield which led to a need to revalidate processes?
The product binds tightly to the chromatography column and are not washed out of the column
A great portion of the product produces protein aggregates in the column
The column gets clogged more easily and need constant cleaning and replacement
A significant portion of the product do not bind to the chromatography column and just goes through the column
There is increased clogging of the bioreactor spin filters in the continuous cultures
What is not a performance aspect that needs to be validated for holding tanks for biologics?
Need to validate holding time effects on aseptic conditions
Need to validate pumps for feeding nutrients to the growing cells
Need to assure that tanks are connected to a working back-up generator
Need to validate the ability of the holding tank to maintain low temperatures
Need to validate effectiveness of cleaning process in getting rid of detergents
A valve used to transfer material from a holding tank to the purification suite is malfunctioning and you'll need a replacement. Which internal document might not provide information concerning the make and model of the valve currently in use?
Validation master file
Equipment master file
Sterility qualification file
User's manual
Being a zealous manufacturing supervisor, you noticed that your autoclave loading plan leaves room for additional material which can be loaded. Realizing that increasing that amount of material in the autoclave will shorten the turn around time for the production line you considered increasing the amount of material loaded into the autoclave than specified by the loading plan. Despite the change in loading amount, design and installation qualification will not need to be redone.
TRUE
FALSE
A different kind of baffle was installed in the bioreactor to improve gas and nutrient exchange. Which test may not need to be performed to check the effect of the change on product quality attributes?
Testing for product degradation
Testing for adventitious viruses
Examining 3D structure by NMR
Immunological tests including Western blots
Testing for activity of the protein product
FDA audits are data-based, periodic assessments to verify companys compliance with regulations and guidances. What is not typically included in FDA audits of drug manufacturers?
Observation of personnel behavior in the cafeteria
observation of personnel while engaged in everyday routine manufacturing activities
observation of facility conditions
Interviews with personnel while performing tasks
observation of data collection activities
Audits are data-based periodic assessments to verify companys compliance with regulations and guidances. Which type of audit should be the broadest and most in depth?
Internal audit by the companys own QA group
Regulatory audit by the FDA or EMEA
Safety audit by OSHA
Manufacturers audit by a customer
QAs audit of a supplier
In the FDAs quality system inspection technique, for a company that already had several products rejected for marketing approval because of chemistry, manufacturing and control issues, the FDA would likely inspect:
The management and production system
The quality system alone is sufficient
The quality system + at least 1 other system
The quality system + 5 other systems
The quality system + at least 3 other systems
Why are results of internal audits performed by QA not routinely inspected by FDA investigators?
Company management forbids regulators from asking
Recalled lots may not get documented
Those kinds of documents are not relevant to the inspection
QA will be tempted not to record quality failures
It is against the law for FDA to ask for them
What would not be a characteristic of an effective audit?
Formal audit report should link an observation to a relevant regulation or guidance
Audits should be effective in guiding the company with its regulatory compliance
Auditor limits his or her questioning to members of QA
The audit should assess how well SOPs are followed
Auditor should ask open-ended questions, not simple yes or no questions
In internal audit companies, some companies classify deficiencies as critical, major, and minor. What is a disadvantage of such ranking system?
Rankings don't help the auditee in prioritizing the areas to correct
Theres no industry standardization on how to rank deficiencies
Auditors are not able to point out areas of concern that may not have caught management's attention
FDA inspectors don't really care about the rankings
There is no disadvantage to the rankings
Representatives of the company being audited should:
Have a bunch of Post-It-Notes in their work station to give the impression that they are keeping busy
Refuse to hand over OOS records
Not volunteer to answer questions from inspectors if they're not sure of the answer.
Volunteer information that is not being asked by the FDA inspectors
Never admit to a recording error
What normally won't FDA auditors look at during a manufacturing facility inspection?
Employee time cards and vacation records
Signatures and signature logs of manufacturing personnel
Reasons for personnel turnover
Organizational charts and personnel responsibilities
QC analytical equipment computers
What might FDA inspectors find about personnel and not lead to concerns regarding compliance?
There's a large number of temporary workers
QA head is the signing authority for release of finished drug product
High staff turnover and high number of unfilled positions
There's lack of enough personnel to conduct certain activities
There's lack of trained personnel
Select the correct ranking of FDA communications with a company after inspection, from less to most serious.
Form 483, Warning Letter, Consent Decree, Seizure
Warning Letter, Form 483, Seizure, Consent Decree
Form 483, Warning Letter, Seizure, Consent Decree
Consent Decree, Seizure, Form 483, Warning Letter
In 2004, what was the leading reason for receiving warning letters from the FDA?
Deviations from SOPs
Filing of Field Alert Reports more than 3 days after a confirmed OOS
Lack of personnel training
Inadequate control of microbial contamination
Inadequate stability program
What is not found under the Testing section of the Biotechnology Inspection guide document found in the link: https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/inspection-guides/biotechnology-inspection-guide-1191
Quality testing for physical appearance including color and clarity
Potency testing using animal cells
Identity tests to confirm amino acid sequence
Equipment maintenance and calibration
Purity testing for endotoxins or Mycoplasma
Which of these viruses is not used for therapeutic gene delivery in humans?
adeno-associated virus (AAV)
All the other choices are being used for therapeutic gene delivery in humans
adenovirus (AdV)
lentivirus
Newcastle virus
In the Johnson and Johnson vaccines for COVID, FDA requires that replication-competent adenovirus (RCA) be less than:
1 RCA in 3 billion viral particles
1 RCA in 3,000,000 viral particles
1 RCA in 30 billion viral particles
1 RCA in 3,000 viral particles
1 RCA in 10,000,000 viral particles
In FDA documents, the cell substrate normally refers to the:
the substrate to which cells adhere to in culture
the cell which is the source of template for PCR
the host cell which is propagated
the cell culture media
the virus which carries the functional gene
Which drug product quality attribute is measured by freezing point determination?
identity
Osmolality
What technique is used to separate T-cells that have the Chimeric Antigen Receptor (CAR) displayed on their cell surface from other cells not expressing CAR?
high performance liquid chromatography
quantitative real time PCR
time of flight mass spectrometry
liquid chromatography - mass spectrometry
Fluorescence Activated Cell Sorting
Which technique is not used to quantify viral genomes in a given solution?
enzyme linked immunosorbent assay
high performance liquid chromatography
quantitative PCR
gene transfer assay
liquid chromatography - mass spectrometry
For the ex vivo gene therapy product Abecma, the strength of the drug product is expressed as:
percent of T cells per dose
total number of CAR+ T cells per dose
international units per IV bag
total number of T cells per dose
percent of CAR+ T cells per dose
For ex vivo gene therapy, it is acceptable to perform sterility release testing on in-process materials instead of the final drug product
True
False
An intravenous drug product can have detectable endotoxins and still be accepted and released for marketing by QA
True
False
In both ex vivo and in vivo gene therapy, the viral vector is found only in the in-process materials, but not in the final drug product.
True
False
For testing of Master Cell Banks, the presence of retroviruses is indicated by the presence of?
Mycoplasma
Bacteriophage
Endotoxin
Prion
From FDA's device classification database, which device is least likely to be required to comply with quality systems regulations during its development stage?
Oxygen mask
artificial heart
Insulin pump
HIV test
Implantable pacemaker
Failure to comply with any applicable provisions of FDA's Quality Systems Regulation in CFR21 Part 820 will render a device adulterated and ________________ is (are) subject to regulatory action.
The person responsible
The device and person responsible
The device and the legislator
The code and person responsible
The device and the code
cGMPs for pharmaceuticals are found in CFR21 part ___, while the equivalent quality systems regulations for devices are in CFR21 part ____.
211:80
211:820
210:600
210:800
211:620
A ______ filing is required if a new device is not substantially equivalent to other devices that have been cleared through a ________ process.
510k:520k
510k:pre-market approval
pre-market approval:510k
pre-market notification:510k
pre-market notification:pre-market approval
Which document is not one that management might normally review at defined time intervals to assess the effectiveness of the quality system that had been put in place for device manufacturing?
Units sold annually
QC test results
Service records
Customer complaints
Audit results
Which of these information will be found in the device history record but not in the device master record?
Records of maintenance and service performed
Procedures and specifications
Production flow diagram
Packaging and label designs
SOPs for installation, maintenance, and servicing
Which of the 8 components of design control involves demonstrating the ability to translate manufacturing design from small pilot scale to larger manufacturing scale?
Design transfer
Design Validation
Design and Development Planning
Design Output
Design Changes
Design Input primarily involves:
ensuring that the device conforms to its intended use by testing the performance of initial production units under actual or simulated use conditions
setting performance characteristics and passing specifications for the device
Tracking, verifying, validating, and approving changes before implementation
demonstrating the ability to translate manufacturing from small scale to larger manufacturing scale
assigning personnel and responsibilities and setting timelines and product deliverables
For a PCR-based medical device, the sensitivity performance characteristic is best described as:
the lack of significant variability in results obtained when the tests are done by different analysts or operators
the lack of effect of substances, like toothpaste, mouthwash or tobacco, on inhibiting or enhancing diagnostic test results
a measure of the lowest amount of templates that the device could detect per sample tested
the ability of the device to give the correct quantification of the number of target molecules present in a given test sample
the ability of the device to give accurate results even when there are differences in the composition of patient samples being tested
Which of the performance characteristics of a diagnostic medical device that involves the use of a PCR is demonstrated by lack of significant variability in results obtained when the tests are done using different instruments situated in different test sites and executed by different operators?
Robustness
Sensitivity
Linearity
Detectability
What is not part of acceptance activities under medical device quality system regulations?
receiving and acceptance of in-process materials during different stages of the manufacturing process
receiving of recalled and returned products from customers
receiving and acceptance of raw materials from suppliers
receiving and acceptance of device parts from suppliers
acceptance activities for the finished device
Medical device records, including complaint files, should be retained:
two years beyond the expected life of the device
one year beyond the expected life of the device
for the expected life of the device
three years beyond the expected life of the device
for one year after approval of the device
Which of the following is NOT typically monitored during environmental monitoring in an aseptic manufacturing facility?
Levels of viable microorganisms in the air
Levels of non-viable particles on surfaces
Levels of carbon dioxide in the air
Levels of fungi on growth media
Levels of bacterial spores on equipment
Which method attribute is most relevant when determining the ability of an analytical method to consistently produce the same results under unchanged conditions?
Sensitivity
Reproducibility
Specificity
Accuracy
Limit of detection
During stability testing of biologics, which time point is commonly included for products with a shelf life of 1 year or less?
15th month
24th month
36th month
0 month
18th month
