Pharma forum 2018(1)
11.
What do you mean by re-validation?
A repeat of the process
validation to provide an assurance that changes in the
process/equipments
introduced in accordance with change control procedures do not
adversely affect process
characteristics & product quality.
22.
What do you mean by “worst case”?
A condition or set of
conditions encompassing upper and lower processing limit and
circumstances, within
standard operating procedures, which poses the greatest chance of
product or process
failure when compared to ideal conditions. Such conditions do not
necessarily induce
product or process failure.
33.
What do you mean by “performance qualification”?
The performance
qualification documents describes the procedures for demonstrating that a
system / piece of
equipment can consistently perform & meet required specifications
under
routine operation and
where appropriate, under worst case situations.
44.
What is the abbreviation of CAS Number?
CAS Number : Chemical
Abstract Service Number.
55.
How do we know that the gauges are ok?
Gauges are periodically
calibrated and they bear the calibration status tag.
66.
What is the limit for “Individual unknown Impurity” in API as per
ICH Q2A?
The limit of the “Any
individual unknown Impurity” is not more than 0.1%
77.
What is mean by designated area?
By designated area we
mean:
- Specific area for a
specific operation: e.g. packing operation shall be carried out only in
packing room and not
elsewhere.
88.
What are cGMP requirements for building and facilities?
Following are the cGMP
requirements:
- Suitable size,
construction and location
- Facilitate cleaning,
maintenance and proper operation
- Adequate space
- Defined areas of
adequate size
- Water supply:
continuous and of good quality
- Power supply:
continuous
- Adequate lighting,
ventilations, air filtration, plumbing sewage, toilet facilities
99.
What is personal hygiene?
Each personal
should:
- Wear clean
uniform
- Take bath daily
- Report illness or
injury
- Be medically fit
- Develop good hygiene
habits.
110.
Why do we conduct trainings?
It brings awareness and
helps us in becoming competent.
111.
For which areas do we have SOPs?
We have SOPs for the
following areas:
- Quality
Assurance
- Quality Control
- Production
Personnel
- Warehouse
- Safety &
Environment
- Engineering
- Estate
Management
- Info tech
112.
Why cGMP should be followed?
This is a regulation
that each one of us is trained in cGMP and practices cGMP
- It minimizes the
possibilities of any errors caused by subjectivity.
- It makes you do your
job right the first time and every time.
113.
Is cGMP requirement only for personnel in the manufacturing?
No, this requirement is
for each and every employee of the organization who must know the
relevant cGMP
requirements in his/her area.
114.
What is
the name of the instrument, which is used for measuring of vacuum (in Tars)
during high vacuum distillation?
Mcleod gauge
115.
Write the classification of contaminants in clean rooms?
Substance: Physical
: Dust, Dirt, Grit, Fiber, Lint & Fly ash.
Chemical : Organic
compound, Inorganic salts, vapor, mist, fume & smoke.
Biologic : Bacteria,
Fungus, Spore, Pollen, Virus, Human skin & cells.
Energy : Thermal, Light,
Electromagnetic (EMI), Electrostatic (ESD), Radiation & Electrical.
116.
What is mean by “Clean-in-Place” and “Clean-out-Place”?
Clean-in-Place: The
cleaning of large pieces of equipment may be performed in the
equipments permanent
location. Generally, in a configuration very similar to that in which it
is
utilized for production.
This procedure widely known as Clean-in-Place (CIP)
Clean-out-Place: The
smaller items are frequently transported to a designated cleaning or
washing area where the
cleaning procedures is performed. This practice is known as clean-out
-place (COP)
117.
What precautions do we take during storage of API?
All APIs are stored
under controlled conditions of temperature and humidity in their
designated
area.Records of temperature
and humidity are maintained on daily basis.
House keeping is done on
daily basis and records are kept for the same.
Insects, pests and
rodent control procedures are follows.
118.
What is the abbreviation of “TDP” and its contents?
“TDP” means Technical
Data Package and shall contain the following contents, but not limited:
Brief manufacturing process·
Solvents used in the manufacture·
Impurity profile·
Working standard profile (If any)·
Characterization data (if any)·
Specifications and test procedures of the
supplier·
TSE / BSE free Certificate·
Stability studies/ Hold time data·
Storage conditions·
Packing details·
MSDS·
Certificate Of Analysis (COA)·
DMF Number (if any)·
119.
What are the types of non-compliances in the internal audit?
Non-compliances shall be
categorized as follows:
Critical: Those findings
that warrant stoppage of any further operations in the facility until the
corrective actions have
been completed.
Major: Those findings
that require immediate corrective action plan and compliance although
operations can be
continued.
Minor: Those findings
that require corrective action plan as agreed between the Auditee
department Head and
Quality Assurance.
220.
Describe the categories of the market complaints?
Market complaints are
categorized into three types and are as follows:
Critical: Complaints
related to suspected contamination, adulteration and mislabeling.
Major: Complaints
related to the product not meeting its pre-determined critical
specifications
and damage to primary
packaging.
Minor: Complaints
related to the product not meeting non-critical quality attributes, or
damage
to secondary packaging
or shortages etc.
221.
What do you mean by market complaint?
Any communication,
written or verbal, received regarding the quality, packing directly from
any
traders or product
manufacturer and marketing staff or any other such complaints shall be
considered as a Market
Complaint.
222.
What is maximum time period for the sending of the final
response to concerned customer regarding the market complaint?
Within 30 days or
as specified in the Market compliant SOP
223.
Write the different types of stability study conditions as per ICH
guidelines?
General storage
conditions:
Name Temperature (°C)
Relative humidity (%)
Long term 25±2
60±5
Intermediate 30±2
65±5
Accelerate 40±2
75±5
Storage in a
Refrigerators:
Long term 5±3 NA
Accelerate 25±2
60±5
Storage in a
Freezer:
Long term -20±5 NA
224.
Define stability study and its necessity?
Stability study is
defined as “stability testing is to provide evidence how quality varies with
time
under influence as:
temperature, humidity & light”
- Establish re-test
period for drug substance
- Establish shelf life
for drug product
- Recommended storage
conditions
225.
What do you mean by “Reference standard” and “Working
standard”?
Reference Standard: A
substance that has been shown by an extensive set of analytical tests to be
authentic material that should be of high purity. This standard may be obtained
from an
officially recognized
source or may be prepared by independent synthesis or by further
purification of existing
production material.
Working Standard: A
substance of established quality and purity, as shown by comparison to a
primary reference
standard, used as a reference standard for routine laboratory analysis
226.
Inspection can be of three types, what are those?
Inspections are three
types:
- Study /test based
inspection
- Facility based
inspection
- Process based
inspection
227.
What is critical process parameter?
A process parameter
whose variability has an impact on a critical quality attribute and
therefore should be
monitored or controlled to ensure the process produces the desired
quality.
Or
A process condition or
material or a test when it is essential to maintain a predetermined rage
in order to reproducibly
meet the specification is called critical parameter. Critical parameters
have direct impact on
the quality of a product.
228.
What precautions are to be observed while working in the powder processing
room?
Following precautions
should be observed while working in the powder processing rooms:
- Absolute discipline
w.r.t complete uniform
- Bunny suit, clean shoe
covers, hand loves, snoot mask etc. and SOPs compliance
- Positive
pressure
- House keeping
- Avoid foreign objects
(pens, pencils, tools etc.)
- Identification /
status card on materials
- Stage slips on
equipments
- Temperature (less than
25°C)
- Avoid extraneous
contamination from dust, insects, micro-organism, foreign particles etc.
- Check the condition of
sieves used in multi mill and sifter
- Cleaning and
calibration of weighing balances
- Usage of fresh, clean
drums and poly bags for final packing.
229.
What is inprocess control?
Monitoring the
manufacturing process at different stages is called in-process control.
In-process control of
the process provides an acceptable and achievable level of built in
quality
assurance for the
product. This is possible through appropriate GMP during all
manufacturing
steps.
Or
Checks performed during
production in order to monitor and, if necessary to adjust the
process and / or to
ensure that the intermediate or API conforms to its specifications.
330.
What is the difference between specification and Limit?
Specification: A document
giving a description of a starting material, packaging material,
intermediate, bulk or
finished product in terms of its chemical, physical & possibly
biological
characteristics. A
specification normally includes description clauses & numerical clauses,
the
latter stating standards
& permitted tolerances.
Or
It is the type of
standard which is often referenced by a contract or procurement document.
It
provides the necessary
details about the specific requirements.
Or
Lists of detailed
requirements with which the products/ materials used or obtained during
manufacture have to
conform. They serve as a basis for quality evaluation.
Limit: The point, edge
or line beyond which something cannot or may not be proceed. The
boundary surrounding a
specific area, bounds.
331.
Describe about swab and rinse sampling?
Swab: Areas which are
reasonably accessible & hardest to clean can be evaluated, leading to
level of contamination
or residue per given surface area.
Take the clean swab having surface area of
10mmX10mm·
Put the swab in the test tube containing 10 ml
suitable solvent and squeeze the swab·
along the sides of the
test tube to remove the excess of water from it.
Identify the locations for swab sampling·
Take out the wet swab from the test tube
without touching the tip of swab.·
Place the one side of swab over the identified
location and apply it on the 10 X 10 sq.·
cm area first in
vertical fashion without changing face of the swab
Turn the swab to other side and apply it on
the area in horizontal fashion covering all·
the areas
Place the swab stick in to the test tube
having 10 ml suitable solvent without touching·
the tip.
Lave the test tube with the location·
Rinse: Large area or
parts of equipments which could not be swabbed should be rinse sampled or
directly extracted by solvent. The areas which are not reasonably accessible
for
direct surface sampling
have to be rinsed with suitable solvent.
Use specified volume of suitable solvent for
rinsing·
Rinse the identified locations using the
following procedure·
Take specified quantity of suitable solvent in
a graduated bucket·
Use a clean mug to splash the solvent in the
reactor·
Close the bottom valve of the reactor·
Take solvent in the mug splash at all side of
the reactor·
Attention to be applied particularly on the
blind sides in the inside top of the reactor·
Splash the solvent at the agitator shaft and
blades·
Open the bottom valve and collect the washed
solvent in a clean bucket. Collect about·
100 ml (specified
quantity in the protocol) in a sample bottle from the bucket. Close the
lid and label it
properly.
When more than one equipment is involved
(equipment chain) for rinsing, suitable·
quantity of solvent
shall be used and the rinse volume shall be measured.
332.
What do you mean by “performance qualification”?
The performance
qualification documents describes the procedures for demonstrating that a
system / piece of
equipment can consistently perform & meet required specifications
under
routine operation and
where appropriate, under worst case situations.
33. How will you close a market complaint?
(a) If satisfactory
response obtained from complainant against our written reply
(b) If the material is
recalled
(c) If no response
obtained from the complainant after 90 days (or specified in SOP) from
date of our written
reply.
333.
What do you mean by “worst case”?
A condition or set of
conditions encompassing upper and lower processing limit and
circumstances, within
standard operating procedures, which poses the greatest chance of
product or process
failure when compared to ideal conditions. Such conditions do not
necessarily induce
product or process failure.
334.
What do you mean by re-validation?
A repeat of the process
validation to provide an assurance that changes in the
process/equipments
introduced in accordance with change control procedures do not
adversely affect process
characteristics & product quality.
335.
Why is data integrity most important issue in regulator?
The decision of the
regulator is based on the eexpectation that data and information are
*Complete
*Accurate
*Truthful
When records are
inaccurate, incomplete or untruthful.
*Quality processes fail
to stand up to scrutiny.
*Safety and efficacy of
the products becomes questionable.
*Company values come
under a scanner.
*Company’s brand and
reputation can be tarnished.
It also raises questions
about data and information in other records.
336.
How sharing password is very serious issue in data integrity?
In a simple sense, it
violates the principle of who records the data and who approves it.
The very basic tenet of
Data integrity is that the person performing an activity or observing a process
is the one who records the data. Only he is authorized to record the data and
make changes as per protocol. When password is shared the second person mis
represents as the first person and this is NOT ACCEPTABLE.
337.
Why is FDA concerned with the use of shared log in accounts for
computer systems?
You must exercise
appropriate controls to assure, that only authorized personnel make changes to
computerized MPCRs or other records or input laboratory data into computerized
records and you must implement documentation controls that ensures actions are
attributable to a specific individual.
When login credentials
are shared, a unique individual cannot be identified through the login and the
system would not confirm to the cGMP requirements in parts 211 & 212.
FDA requires that
systems controls, including documentation controls be designed to follow cGMP
to assure product quality.
338.
What is Tailgating?
Tailgating is one of the
most common and incorrect security, breaches. Tailgating means allowing other
person to enter in the area along with you without registering his credentials
in a biometric or electronic access control system. Tailgating leads to un
authorized access to process area and contribute to compromise with
attributability of activity performed and data generated.
Or
Example:
Tailgating is the act of driving on a road too close
to the vehicle in front, such that the distance between the two vehicles does
not guarantee that stopping to avoid collision is possible.
339.
What is an audit trial?
Now
that you have understood the attributes of data, you should also know that
regulators expect changes to data is traceable and original data related GXP should
also be retained. This is possible through AUDIT TRIAL.
Audit
trial is a form of meta data.
*Creation
*Modification
*Deletion
History
of events
Creation---What
is happened?
Addition---Who
did it?
Deletion---When
was it happened?
Alteration---Why
was it done?
440.
How does FDA use the terms “static”
and “dynamic” as they relate to record formats?
Static
is used to indicate a fixed-data document such as a paper record or an
electronic image, and dynamic means that the record format allows interaction
between the user and the record content.
For
example, a dynamic chromatographic record may allow the user to change the
baseline and reprocess chromatographic data so that the resulting peaks may
appear smaller or larger. It also may allow the user to modify formulas or
entries in a spreadsheet used to compute test results or other information such
as calculated yield.
441.
How Data integrity issues unintentional?
Till now we understood
data integrity concepts, now let us discuss issues in handling the data. Data
handling issues can be un intentional or intentional.
Unintentional data
errors include transcription errors and failure to record activities
contemporaneously (at the time they are performed).
Transcription errors are
the errors that are committed while noting the data either on paper or
electronically also called “Fat Finger” error.
442.
What are the standards to be followed for integrity in maintaining
records?
*Data should be recorded
promptly as it happens.
*Entries should be in
indelible ink, so that records cannot be altered or damaged.
*There should be no
usage of “ditto” marks(-“-) while recording entries.
*Entries must be dated
and signed.
*Any changes should not
obscure original entry.
*If data needs to be
changed or amended, strike, through the entry with one solid line.
*Reason for changing the
data must be indicated, signed and dated.
*It is also important to
not errors. Use a consistent system for noting errors.
*For computer based
records, audit trial has to be enabled.
*Every person accessing
the electronic record should be uniquely identifiable. No sharing of passwords.
*Appropriate back up of
electronic records have to be taken.
Regulating Authority:
Utilities, offices, warehouses,
production units, laboratories.
443.
Can electronic signatures be used instead of handwritten
signatures for master production and control records?
Yes, electronic signatures with the
appropriate controls can be used instead of handwritten signatures or initials
in any CGMP required record. While
211.186(a) specifies a “full signature, handwritten,” as explained in
the Federal Register on September 29, 1978 (43 FR 45069), part of the intent of
the full signature requirement is to be able to clearly identify the individual
responsible for signing the record.
An
electronic signature with the appropriate controls to securely link the
signature with the associated record fulfills this requirement. This comports
with part 11, which establishes criteria for when electronic signatures are considered
the legally binding equivalent of handwritten signatures. Firms using
electronic signatures should document the controls used to ensure that they are
able to identify the specific person who signed the records electronically.
There
is no requirement for a handwritten signature for the MPCR.
444.
Is transcription of data from notepads/port it notes a Data
integrity violation? Please explain how?
Raw data should be
captured in the legitimate GxP records, If the data is in adventently captured
on post it notes/notepads etc.,then that becomes the raw data and should be
attached along with the legistative GxP records.
Transcribibg from raw
notes into GxP records is a Data Integrity violation as it defects the very
purpose of Raw data and negates contemporaneous data recording.
Errors can also creep in
while transcribing.
445.
How should black form be controlled?
There must be document
controls in place to assure product quality.
FDA recommends that, if
used blank forms(including but not limited to worksheets, laboratory notebooks
and MPCRs) be controlled by the quality unit or by another document control
method.
For example, numbered
sets of blank forms, may be issued as appropriate and should be reconciled
upon, completion of all issued forms. Incomplete or errorneous form should
replacement.
Similarly, bound
paginated notebooks, stamped for official use by a document control group,
allow, detection of unofficial notebooks as well as of any gaps in notebook
pages.
446.
Is it acceptable to retain paper printouts or static records
instead of original electronic records from stand-alone computerized laboratory
instruments such as an FT-IR instrument?
A paper
printout or static record may satisfy retention requirements if it is a
complete copy of the original record.
For
example, pH meters and balances may create a paper printout or static image
during data acquisition as the original
record. In this case, the paper printout or static image created 268 during
acquisition, or a true copy, should be retained.
However,
electronic records from certain types of laboratory instruments are dynamic
records, and a printout or a static record does not preserve the dynamic format
which is part of the complete original record. For example, the spectral file
created by FT-IR 273 (Fourier transform infrared spectroscopy) can be
reprocessed, but a static record or printout is fixed, which would not satisfy
CGMP requirements to retain original records or true copies. Also, if the full spectrum is
not displayed, contaminants may be excluded.
Control
strategies must ensure that original laboratory records, including paper and
electronic records, are subject to second-person review to make certain that all test results are appropriately
reported.
For PET
drugs, see the guidance for industry PET Drugs — Current Good Manufacturing
Practice (CGMP) for discussion of equipment and laboratory controls, including
regulatory requirements for records.
447.
When does electronic data become a cGMP record?
When
generated to satisfy a CGMP requirement, all data become a CGMP record.
You must document, or save, the data at
the time of performance to create a record in
compliance with CGMP requirements.
FDA
expects processes to be designed so that quality data required to be created and maintained cannot be modified.
For example, chromatograms should be sent
to long-term storage (archiving or a permanent record) upon run
completion instead of at the end of a
day’s runs.
It is
not acceptable to record data on pieces of paper that will be discarded after
the data are transcribed to a permanent
laboratory notebook. Similarly, it is not acceptable to store data
electronically in temporary memory, in a
manner that allows for manipulation, before creating a permanent record. Electronic data that are automatically saved
into temporary memory do not meet CGMP
documentation or retention requirements.
You may
employ a combination of technical and procedural controls to meet CGMP documentation practices for electronic
systems. For example, a computer system, such as a Laboratory Information Management System
(LIMS) or an Electronic Batch Record
(EBR) system, can be designed to automatically save after each separate
entry. This would be similar to
recording each entry contemporaneously on a paper batch record to satisfy CGMP requirements. The computer
system could be combined with a procedure
requiring data be entered immediately when generated.
448.
Is it acceptable to only sae the final results from reprocessed
laboratory chromatography?
No, Analytical methods should be capable
and stable. For most lab analyses, reprocessing
data should not be regularly needed. If chromatography is reprocessed,
written procedures must be established
and followed and each result retained for review.
FDA requires complete data in laboratory records, which
includes raw data, graphs, charts, and spectra
from laboratory instruments
449.
Can electronic copies be used as
accurate reproductions of paper or electronic records?
Yes.
Electronic copies can be used as true copies of paper or electronic records,
provided the copies preserve the content and meaning of the original data,
which includes associated metadata and
the static or dynamic nature of the original records.
True
copies of dynamic electronic records may be made and maintained in the format
of the original records or in a
compatible format, provided that the content and meaning of the original records are preserved and that a
suitable reader and copying equipment (for example, software and hardware, including
media readers) are readily available.
550.
Who should review audit trials?
Audit
trails are considered part of the associated records. Personnel responsible for
record review under CGMP should review the audit trails that capture changes to
critical data associated with the record as they review the rest of the record.
For
example, all production and control records, which includes audit trails, must
be reviewed and approved by the quality unit. This is similar to the
expectation that cross-outs on paper be
assessed when reviewing data.
551. How
often should audit trails be reviewed?
FDA recommends that
audit trails that capture changes to critical data be reviewed with each record
and before final approval of the record. Audit trails subject to regular review should include, but are not limited to, the
following: the change history of finished
product test results, changes to sample run sequences, changes to sample
identification, and changes to critical
process parameters.
FDA
recommends routine scheduled audit trail review based on the complexity of
the system and its intended use.
552. Why
has the FDA cited use of actual samples during “system suitability” or 333
test, prep, or equilibration runs in warning letters?
FDA prohibits sampling and testing
with the goal of achieving a specific result or to overcome an unacceptable result (e.g.,
testing different samples until the desired passing result is obtained). This practice, also
referred to as testing into compliance, is not
consistent with CGMP (see the guidance for industry Investigating
Out-of-Specification (OOS) Test Results for Pharmaceutical Production). In some
situations, use of actual samples to perform system suitability testing has
been used as a means of testing into
compliance. We would consider it a violative practice to use an actual
sample in test, prep, or equilibration
runs as a means of disguising testing into compliance.
According to the United States
Pharmacopeia (USP), system suitability tests should include replicate
injections of a standard preparation or other standard solutions to determine if requirements for precision are
satisfied (see USP General Chapter
Chromatography). System suitability tests, including the identity of the
preparation to be injected and the
rationale for its selection, should be performed according to the firm’s established written procedures and the
approved application or applicable compendial monograph
If an actual sample is to be used for
system suitability testing, it should be a properly characterized secondary
standard, written procedures should be established and followed, and the sample
should be from a different batch than the sample(s) being.
All data should be included in the
record that is retained and subject to
review unless there is documented scientific justification for its exclusion.
553. Can
an internal tip regarding a quality issue, such as potential data falsification, be handled informally outside
of the documented CGMP quality system?
No. Suspected or known
falsification or alteration of records required under parts 210, 376 211, and
212 must be fully investigated under the CGMP quality system to determine the
377 effect of the event on patient safety, product quality, and data
reliability; to determine the root cause; and to ensure the necessary
corrective actions are taken.
FDA invites individuals
to report suspected data integrity issues that may affect the 382 safety,
identity, strength, quality, or purity of drug products at “CGMP data
integrity” should be included in the subject line of the email.
554. Should
personnel be trained in detecting data integrity issues as part of a routine CGMP training program?
Yes. Training personnel
to detect data integrity issues is consistent with the personnel requirements
under 211.25 and 212.10, which state that personnel must have the education,
training, and experience, or any combination thereof, to perform their assigned
duties.
555. Is
the FDA investigator allowed to look at my lectronic records?
Yes. All records required
under CGMP are subject to FDA inspection. You must allow authorized inspection,
review, and copying of records, which includes copying of electronic data.
See also section 704 of
the FD&C 401 Act.
5
FDA encourages you to
demonstrate that you have effectively remedied your problems by: hiring a third
party auditor, determining the scope of the problem, implementing a corrective action plan (globally), and
removing at all levels individuals responsible for problems from CGMP
positions. FDA may conduct an inspection to decide whether CGMP violations
involving data integrity have been remedied.
These expectations
mirror those developed for the Application Integrity Policy.
For more detailed guidance, see the “Points to
Consider for Internal Reviews and Corrective Action Operating Plans” public
document available on the FDA Web site.
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