Project Work DQAC 31 OCT 2021

INTERNAL AUDIT REPORT
FOR
VALIDATION OF ASEPTIC OPERATION OF STERILE OPHTHALMIC SUSPENSIONS ON
THREE PIECE FILLING LINE BY PROCESS SIMULATION/ MEDIA FILL
PROJECT WORK (PART III)

ALTERNATIVE - 1
SUBMITTED AS PARTIAL FULFILMENT OF THE REQUIREMENT

FOR
DIPLOMA IN GMP AUDITORS CERTIFICATION

COURSE
VERSION 3, JULY 2021
OF
INSIGHTS PROFESSIONAL MANAGEMENT ACADEMY,
PUNE, MAHARASHTRA, INDIA.
MUKESH SHARMA
REGISTRATION No. DAQC/3/21-09
SENTISS PHARMA PRIVATE LIMITED
VILLAGE: KHERA NIHLA, TEHSIL: NALAGARH, DISTRICT: SOLAN,
HIMACHAL PRADESH, INDIA.
This document is proprietary & confidential. It may not be disclosed or reproduced, in whole or in part, without written consent of COMPANY NAME.
COMPANY LOGO INTERNAL QUALITY AUDIT REPORT
Audit Report No.: 2021/QA/007 Audit Date: 21 and 22 SEP 2021

Audited Department: Validation, Production, Microbiology and Quality Assurance
1.0 EXECUTIVE SUMMARY

1.1 Audit Objective:
To ensure that the recent two validation of aseptic operation of sterile
ophthalmic suspensions on three piece filling line by process simulation/ media
fill (pre and post shutdown) conforms to the corresponding Standard Operating
Procedures and eventually complies with the established requirements of
cGMP.
1.2 Audit Scope:

 Process simulation/ media fill of sterile ophthalmic suspension process.
 Three piece manufacturing and filling line.
 Microbiology laboratory.
 Moist heat steriliser/ autoclave (ID: PR1).
 Moist heat steriliser/ autoclave (ID: MI1).
1.3 Overall Assessment:

The internal audit of the recent two validation of aseptic operation of sterile
ophthalmic suspensions on three piece filling line by process simulation/ media
fill (pre and post shutdown) does not comply with the requirements of 21 CFR
Part 211 and Guidance for Industry: Sterile Drug Products Produced by Aseptic
Processing – Current Good Manufacturing Practice.
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2.0 AUDIT PLANNING

2.1 Audit Criteria:
 SOP titled Process simulation of ophthalmic suspension on three piece line
(SOP No. MF001-00).
 SOP titled Operation of moist heat sterilizer (ID: PR1) (SOP No. PR001-00).
 SOP titled Operation of moist heat sterilizer (ID: MI1) (SOP No. MI001-00).
 Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing
– Current Good Manufacturing Practice.
 21 CFR Part 211: Current Good Manufacturing Practice for Finished
Pharmaceuticals.
 Internal Audit Checklist of Process Simulation.
2.2 Audit Schedule:

 21 SEP and 22 SEP 2021.
2.3 Audit Agenda:

 21 SEP 2021: Areas covered along with tentative timelines;
Time Activity
09:00 to 09:15 Opening meeting with representatives of Validation,
Production, Microbiology and Quality Assurance.
09:15 to 10:00 Inspection of moist heat steriliser/ autoclave (ID: PR1 and
MI1).
10:10 to 11:30 Review of sterilization record of machine parts and media.
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Time Activity
11:30 to 13:30 Review of environmental monitoring by active air sampling
and passive air sampling.
13:30 to 14:00 Lunch Break
14:00 to 15:00 Review of environmental monitoring programme by active air
sampling and passive air sampling.
15:00 to 17:00 Review of personnel monitoring programme.
17:00 to 17:15 Discussion between auditors on observations and findings.
17:15 to 17:30 Closing meeting with representatives of Validation,
 22 SEP 2021: Areas covered along with tentative timelines;
Time Activity
09:00 to 09:15 Opening meeting with representatives of Validation,
09:15 to 10:30 Review of sterilization record of sterile gowning.
10:30 to 11:30 Review of gowning qualification and personnel qualification
of participants in process simulation.
11:30 to 13:30 Review of process simulation/ media fill batch record (Batch
No. 2021MF1 and 2021MF2) against sterile ophthalmic
suspensions processes of Briti and Texa (Batch No. B101 and
T102).
13:30 to 14:00 Lunch Break
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Time Activity
14:00 to 16:00 Review of process simulation/ media fill batch record (Batch
No. 2021MF1 and 2021MF2) against sterile ophthalmic
suspensions processes of Briti and Texa (Batch No. B101 and
T102).
16:00 to 17:00 Effectiveness Check of previous internal audit.
17:00 to 17:15 Discussion between auditors on observations and findings.
17:15 to 17:30 Closing meeting with representatives of Validation,
2.4 Notification to the Auditee:

 Notification for internal audit was sent to Senior Manager – Validation,
Senior Manager – Production, Senior Manager – Microbiology and Senior
Manager – Quality Assurance on 15 SEP 2021.
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3.0 THE AUDIT

3.1 Opening Meeting:
 The audit approach is risk based citing recent failure in process simulation. It
was described that audit shall be a mix of horizontal audit and vertical audit
comprising of the Validation, the Production, the Microbiology and the
Quality Assurance department.
 Attendance was marked at the end of opening meeting.
3.2 Facility Tour:

3.2.1 Moist heat steriliser/ autoclave (ID: PR1)
 The sterilisation area was maintained neat and tidy.
 Label for Qualification Status was tagged to the steriliser.
 The steriliser was within its qualification period.
 Calibration labels were affixed to the gauges.
 The Equipment Usage Logbook was maintained neat and tidy.
3.2.2 Moist heat steriliser/ autoclave (ID: MI1)

 The sterilisation area was maintained neat and tidy.
 Label for Qualification Status was tagged to the steriliser.
 The steriliser was within its qualification period.
 Calibration labels were affixed to the gauges.
 The Equipment Usage Logbook was maintained neat and tidy.
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3.2.3 Three piece filling room – entry and exit.

 Name of the participants was mentioned in authorised personnel list
issued by QA.
 Biometrics was enabled for every participant.
 The participants were there in the filling room for less than 4 hours at a
stretch.
 All the participants in current process simulation were involved in earlier
process simulations.
3.3 Documents Reviewed:

 SOP on process simulation/ media fill of ophthalmic suspension on three
piece line (SOP No. MF001-00).
 SOP on operation of moist heat sterilizer (ID: PR1) (SOP No. PR001-00).
 SOP on operation of moist heat sterilizer (ID: MI1) (SOP No. MI001-00).
 Sterilisation records of three piece filling machine parts.
 Sterilisation records of media.
 Process simulation/ media fill Batch Record (Batch No. 2021MF1).
 Process simulation/ media fill Batch Record (Batch No. 2021MF2).
 Batch record of sterile ophthalmic suspension Briti (Batch No. B101).
 Batch record of sterile ophthalmic suspension Texa (Batch No. T102).
 Entry and exit logbook of three piece filling room.
 Qualification of operators.
 Usage logbook of PR1, MI1 and Mobile LAF.
 Preventive maintenance logbook of PR1 and MI1.
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 Calibration planner of production (Year 2021).

 Calibration records of thermocouples and gauges of moist heat sterilisers/
autoclaves.
 Certificate of Analysis of Compressed Air.
 Certificate of Analysis of SCDM.
 Certificate of Analysis of sterilisation of bottle, nozzle and cap.
 Effectiveness checks for previous internal audit.
3.4 Personnel Interacted during Audit:

 Validation: Mr. Rajneesh (Subject Matter Expert).
 Production: Mr. Atul (Primary Operator), Mr. Narender (Secondary
Operator) and Mr. Abhishek (Secondary Operator).
 Microbiology: Mr. Manoj, Mr. Ankit (Active Air Sampling), Ms. Pallavi, Ms.
Aakanksha (Passive Air Sampling (by Settling Plate) and Mr. Naveen, Mr. Amit
(Personnel Monitoring (Contact Plate)).
 Quality Assurance: Mr. Naresh.
 Engineering: Mr. Gopal and Mr. Sanjay.
3.5 Positive Audit Observations:

3.5.1 Steriliser (ID: PR1): The sterilisation records of three piece filling machine
parts and sterile gowning were reviewed and following was observed;
 Load pattern for sterilising the machine parts was defined in the SOP No.
PR001-00.
 Overkill approach was used for sterilisation.
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 Bowie Dick test was pass.

 Steam quality test report was reviewed. The amount of non-condensable
gas was less than 3.5 ml of gas per 100 ml of condensate as required by
EN 285.
 The printout of sterilisation cycles was reviewed and all the 12
thermocouples had logged temperature above 121.1°C.
 The cycle time of minimum 30 minutes was met.
 F0 value achieved was 40 minutes.
3.5.2 Steriliser (ID: MI1): The sterilisation records of media were reviewed and
following was observed;
 Load pattern for sterilising the machine parts was defined in the SOP No.
MI001-00.
 Overkill approach was used for sterilisation.
 Bowie Dick test was pass.
 Steam quality test report was reviewed. The amount of non-condensable
gas was less than 3.5 ml of gas per 100 ml of condensate as required by
EN 285.
 The printout of sterilisation cycles was reviewed and all the 10
thermocouples had logged temperature above 121.1°C.
 The cycle time of minimum 30 minutes was met.
 F0 value achieved was 37 minutes.
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3.5.3 Process Simulation/ Media Fill Batch Record of Batch No. 2021MF1 was
reviewed against products Briti and Texa (Batch No. B101 and T102
respectively) and following was observed;
 The batch record was developed from the SOP No. MF001-00.
 The temperature was maintained between 25±2°C.
 SCDM was the media of choice for process simulation.
 Only 2 operators were there in the manufacturing room.
 Audit Observation: Filtration was performed using the 10μ filter.
Whereas, Briti (Batch No. B101) used 10μ filter, Texa (Batch No. T102)
used 20μ filter for API and excipient solution filtration.
 The filling machine setup was accomplished with 2 primary operators and
1 secondary operator.
 6 personnel were there in the filling room. The filling room is qualified
occupancy of 5.
 10,000 vials of 15 ml were filled.
 Fill volume was adjusted to not less than 13.5 ml.
 Routine speed was 30 to 80 vials per minute. The worst case being 30 vials
per minute.
 The duration of process simulation was 5 shifts. During regular production
the suspension process lasts 4 shifts.
 Each of the 5 personnel were in filling room for up to 6 hours as non-
routine corrective intervention during process simulation.
 The air handling unit was switched off in filling room and adjacent rooms
for 4 minutes to simulate power failure.
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 All the filled vials were visually inspected for any defects.
 The vials were incubated in upright position for 7 days at 20-25°C and next
7 days in inverted position for 30-35°C.
 No growth was observed at the end of incubation period.
3.5.4 Process Simulation/ Media Fill Batch Record of Batch No. 2021MF2 was
reviewed against products Briti and Texa (Batch No. B101 and T102
respectively) and following was observed;
 The batch record was developed from the SOP No. MF001-00.
 The temperature was maintained between 25±2°C.
 SCDM was the media of choice for process simulation.
 Only 2 operators were there in the manufacturing room.
 Audit Observation: Filtration was performed using the 10μ filter.
Whereas, Briti (Batch No. B101) used 10μ filter, Texa (Batch No. T102)
used 20μ filter for API and excipient solution filtration.
 The filling machine setup was accomplished with 2 primary operators and
1 secondary operator.
 5 personnel were there in the filling room. The filling room had qualified
occupancy of 5.
 10,000 vials of 10 ml were filled.
 Fill volume was adjusted to not less than 8 ml.
 Routine speed was 30 to 80 vials per minute. The worst case being 30 vials
per minute.
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 The duration of process simulation was 5 shifts. During regular production

the suspension process lasted 3 shifts.
 Each of the 5 personnel were in filling room for up to 6 hours as non-
routine corrective intervention during process simulation.
 The air handling unit was switched off in filling room and adjacent rooms
for 4 minutes to simulate power failure.
 All the filled vials were visually inspected for any defects.
 The vials were incubated in upright position for 7 days at 20-25°C and next
7 days in inverted position for 30-35°C.
 No growth was observed at the end of incubation period.
3.5.5 Training records of operators was reviewed and following was observed;
 The participants were trained on aseptic techniques, aseptic behaviour,
basics of microbiology and interventions they were assigned to perform
during process simulation.
 The primary operator was trained in machine part assembly, addition of
primary packaging material, interventions inside the ORABS, aseptic
connection in filtration, sterile product filter installation, purging of
solution and environmental monitoring viz. active, passive and non-viable
particle monitoring inside the ORABS.
 The secondary operator was trained in machine/ area/ equipment
cleaning and sanitisation, material transfer in filling room, machine parts
unloading from moist heat steriliser/ autoclave, documentation in ISO 6/
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Grade B, environmental monitoring viz. active, passive and non-viable

particle monitoring, maintenance and purging of solution.
3.5.6 Few discrepancies with respect to good documentation practices were

noticed during document review, which were described to the auditees. The
discrepancies were acknowledged and corrected immediately.
3.6 Recommendations for Improvement:

During documentation review it was noticed that personnel had scribbled at
times, which rendered the original entries unreadable. Training on Good
Documentation Practices is sought for personnel involved in process simulation/
media fill under the scope of current internal audit.
3.7 Effectiveness Check of Previous Internal Audit:

 The previous internal audit was conducted on 16 and 17 MAR 2021.
 There were 2 major and 2 other findings in previous internal audit.
 The CAPA Plan for previous internal audit was reviewed.
 The identified CAPA was implemented for all 7 previous internal audit
findings.
3.8 Compliance Status of Previous Internal Audit:

 The system was under state of control as revealed by effectiveness check of
previous internal audit findings.
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3.9 Closing Meeting:

 Discrepancies noticed during the course of audit were presented to the
auditee during closing meeting.
 The concerns of the auditee were addressed with respect worst case in
context with filtration and thereby the bioburden.
 Filtration during process simulation was done using 10μ filter.
 Filtration of the mixture of API and excipients of the sterile product Briti
(Batch No. B101) ophthalmic suspension used 10μ filter.
 Filtration of the mixture of API and excipients of the sterile product Texa
(Batch No. T102) ophthalmic suspension used 20μ filter.
 Thus, 20μ filter is the worst case in context with bioburden.
 The above incidence does not comply with the requirements of 21 CFR Part
211.113(b) and a) IX. Validation of aseptic processing and sterilization; A.
Process Simulation.
 The audit finding was accepted by the auditee.
 CAPA Plan was discussed and laid down as below.
 Attendance was marked at the end of closing meeting.
3.10 Recommended CAPA Plan

3.10.1 Corrective Action:
 Next process simulation/ media fill for ophthalmic suspension process
shall incorporate 20μ filter for filtration of the mixture of API and
excipients.
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 Impact assessment to study the adverse effect of the audit finding on

batches since the start of manufacturing of Texa ophthalmic suspension.
3.10.2 Preventive Action:

 Process simulation/ media fill of last 2 years shall be revisited to discover
any such or similar gaps in the actual process and process simulation/
media fill
3.11 Classification of audit findings:

 Critical: Describes a situation that is likely to result in a product that may
result in an immediate or latent health risk, or that involves fraud,
misrepresentation or falsification of processes, products or data.
 Major: Describes a situation that may result in the production of a drug not
consistently meeting its marketing authorization.
 Other: Describes a situation that is neither critical nor major, but is a
departure from the cGMP.
3.12 Glossary:
 Audit: Systematic, independent and documented process for obtaining
objective evidence and evaluating it objectively to determine the extent to
which the audit criteria are fulfilled.
 Audit Conclusion: Outcome of an audit, after consideration of the audit
objectives and all audit findings.
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 Audit Criteria: Set of policies, procedures or requirements used as a

reference against which objective evidence is compared.
 Audit Finding: Results of the evaluation of the collected audit evidence
against audit criteria.
 Audit Observation: A deficient condition that an auditor sees during an audit.
 Correction: Action to eliminate a detected non-conformity.
 Corrective Action: Action to eliminate the cause of a non-conformity and to
prevent recurrence.
 Non-conformance: A gap or a difference between actual performance and
stated requirements or standards.
 Non-conformity: Non-fulfilment of a requirement.
 Non-compliance: Non-adherence to a set of rules and regulations of GMP,
which may include requirements and standards. Non-compliance occurs
when a law, a regulation or a code is violated.
 Preventive Action: Action to eliminate the cause of a potential non-
conformity or other potential undesirable situation.
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Audit Report No.: 2021/QA/007
Audited Department: Validation
Audit Date: 21 and 22 SEP 2021 Auditor: Akhilesh Srivastava, Mukesh Auditee: Yogesh Sharma, Jaswinder Rana,
Sharma Manmit Khale
4.0 AUDIT OUTCOME

Tentative Date for Receiving
Internal Audit Report shared on: 29 SEP 2021 Compliance Report: 28 OCT 2021
Audit Audit Finding Classification Reference of Audit Criteria CAPA Plan with Target
Finding Completion Date
No.
1. The validation of aseptic Critical. 1. Guidance for Industry: Correction: Not applicable.
operation of sterile ophthalmic Sterile Drug Products
suspensions on three piece Produced by Aseptic Corrective Action:
filling line by process Processing – Current Good a) The next semi-annual
simulation/ media fill does not Manufacturing Practice validation of aseptic
closely simulate aseptic a) IX. Validation of aseptic operation of sterile
manufacturing operations processing and sterilization ophthalmic suspensions on
incorporating the worst-case A. Process Simulation three piece filling line by
activity and conditions at least at process simulation/ media fill
F22_SOP-018-10 P a g e | 17
Sharma Manmit Khale
No.
one incidence wherein the An aseptic processing planned in FEB 2022 shall use
ophthalmic suspension operation should be 20μ filter for mixing of API and
manufacturing process of validated using a Excipients considering it as a
product Briti (Batch No. B101) microbiological growth worst-case. (TCD: FEB 2022)
sterile product uses the 10μ medium in place of the
filter for filtering the mixture of product. This process b) Production, Validation and
API and excipients, and product simulation, also known as a Quality Assurance shall
Texa (Batch No. T102) media fill, normally includes prepare an Impact
ophthalmic suspension process exposing the microbiological Assessment to assess adverse
uses the 20μ filter for API and growth medium to product effect of this non-conformity
excipient solution filtration. contact surfaces of on safety, identity, strength,
Whereas the process simulation equipment, container quality, purity and efficacy of
F22_SOP-018-10 P a g e | 18
Sharma Manmit Khale
No.
for the suspension process is closure systems, critical batches of finished
performed using the 10μ filter environments, and process pharmaceutical products
with no documented rationale. manipulations to closely manufactured on three piece
In the above filtration schemes simulate the same exposure line since the start of
the process using the 20μ filter that the product itself will manufacturing of Texa
in Briti (Batch No. B101) for undergo. ophthalmic suspension
mixing of API and Excipients is process. (TCD: NOV 2021)
worst case considering the bio- b) 1. Study Design
burden point of view. Media fill studies should Preventive Action:
closely simulate aseptic Process simulation/ media fill of
manufacturing operations sterile ophthalmic suspension
incorporating, as process and sterile ophthalmic
F22_SOP-018-10 P a g e | 19
Sharma Manmit Khale
No.
appropriate, worst-case solution process on all
activities and conditions that manufacturing lines for last 2
provide a challenge to years shall be revisited to
aseptic operations. determine;
a) There is no gap in the
2. 21 CFR Part 211: Current validated manufacturing
Good Manufacturing process and process
Practice for Finished simulation/ media fill. (TCD:
Pharmaceuticals DEC 2021)
Sec. 211.113 Control of
microbiological b) Process simulation/ media fill
contamination. simulates by incorporating
F22_SOP-018-10 P a g e | 20
Sharma Manmit Khale
No.
(b) Appropriate written the worst-case activity and
procedures, designed to conditions. (TCD: DEC 2021)
prevent microbiological
contamination of drug
products purporting to be
sterile, shall be established
and followed. Such
procedures shall include
validation of all aseptic and
sterilization processes.
4.1 Notification to Management: Quality Assurance department shall apprise the top management of this critical audit finding
as defined in the SOP on Notification to Management.
F22_SOP-018-10 P a g e | 21
Sharma Manmit Khale
4.2 Follow up Action:

The Quality Assurance department in connivance with the Production and the Validation department shall update President
Office on;
 Impact Assessment and its progress every Friday till finalised Impact Assessment is signed, submitted to President Office
and necessary actions e.g. Product Recall arising out of Impact Assessment are implemented. (TCD: NOV 2021)
 Review of process simulation/ media fill records of sterile ophthalmic suspension process and sterile ophthalmic solution
process on all the filling lines for previous 2 years. Its progress shall be updated to President Office every Friday to ensure
there is no gap in the process and that process simulation/ media fill simulates incorporating the worst-case activity and
conditions. (TCD: DEC 2021)
 Next process simulation/ media fill for sterile ophthalmic suspension shall use 20μ filter for mixing of API and Excipients
considering it as a worst-case. (TCD: FEB 2022)
4.3 Tracking and Trending:

 Quality Assurance department shall now onwards track such non-compliances in context with process simulation/ media
fill.
F22_SOP-018-10 P a g e | 22
Sharma Manmit Khale
 Biennially the Quality Assurance department shall trend non-compliances/ non-conformities in process simulation/
media fill and present it to the top management during Quality Metrics presentation.
AUDIT REPORT PREPARED BY AUDITOR AUDIT REPORT ACCEPTED BY AUDITEE

Auditor-1 Auditor-2 Head – Validation Head – Production Head – Quality
Assurance
AKHILESH MUKESH SHARMA MANMIT KHALE JASWINDER RANA YOGESH SHARMA
Name and
SRIVASTAVA ASSISTANT SENIOR MANAGER
Designation
SENIOR MANAGER MANAGER SENIOR MANAGER SENIOR MANAGER
Signature Akhilesh Srivastava Mukesh Sharma Manmit Khale Jaswinder Rana Yogesh Sharma
with Date 29 SEP 2021 28 SEP 2021 03 OCT 2021 04 OCT 2021 03 OCT 2021
F22_SOP-018-10 P a g e | 23
INTERNAL QUALITY AUDIT CHECKLIST FOR
COMPANY LOGO
PROCESS SIMULATION
The checklist can be used as a guidance for auditing process simulation/ media fill on
the basis of 21 CFR Part 211.
Checkpoint Complies (Yes or No)
Buildings and Facilities Not applicable (NA)
1. 21 CFR 211.42(b) The flow of components, drug Yes.
product containers, closures, labeling, in-process
materials, and drug products through the
building or buildings shall be designed to prevent
contamination.
2. 21 CFR 211.42(c) Operations shall be performed Yes.
within specifically defined areas of adequate size.
There shall be separate or defined areas or such
other control systems for the firm’s operations as
are necessary to prevent contamination or
mixups during the course of the following
procedures:
3. (10) Aseptic processing, which includes as
appropriate:
4. (i) Floors, walls, and ceilings of smooth, hard
surfaces that are easily cleanable;
5. (ii) Temperature and humidity controls;
6. (iii) An air supply filtered through high-efficiency
particulate air filters under positive pressure,
regardless of whether flow is laminar or
nonlaminar;
7. (iv) A system for monitoring environmental
conditions;
8. (v) A system for cleaning and disinfecting the
room and equipment to produce aseptic
conditions;
9. (vi) A system for maintaining any equipment used
to control the aseptic conditions.
10. 21 CFR 211.46(b) Equipment for adequate Yes.
control over air pressure, micro-organisms, dust,
F22_SOP-018-10 P a g e | 24
COMPANY LOGO
PROCESS SIMULATION

humidity, and temperature shall be provided
when appropriate for the manufacture,
processing, packing, or holding of a drug product.
11. 21 CFR 211.46(c) Air filtration systems, including Yes.
prefilters and particulate matter air filters, shall
be used when appropriate on air supplies to
production areas.
12. 21 CFR 211.63 Equipment used in the Yes.
manufacture, processing, packing, or holding of a
drug product shall be of appropriate design,
adequate size, and suitably located to facilitate
operations for its intended use and for its
cleaning and maintenance.
13. 21 CFR 211.65(a) Equipment shall be constructed Yes.
so that surfaces that contact components, in-
process materials, or drug products shall not be
reactive, additive, or absorptive so as to alter the
safety, identity, strength, quality, or purity of the
drug product beyond the official or other
established requirements.
14. 21 CFR 211.67(a) Equipment and utensils shall be Yes.
cleaned, maintained, and sanitized at
appropriate intervals to prevent malfunctions or
contamination that would alter the safety,
identity, strength, quality, or purity of the drug
product beyond the official or other established
requirements.
15. 21 CFR 211.113(b) Appropriate written Yes.
procedures, designed to prevent microbiological
contamination of drug products purporting to be
sterile, shall be established and followed. Such
procedures shall include validation of any
sterilization process.
Personnel Training, Qualification, & Monitoring Yes.
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COMPANY LOGO
PROCESS SIMULATION

16. 21 CFR 211.22(a) There shall be a quality control Yes.
unit that shall have the responsibility and
authority to approve or reject all components,
drug product containers, closures, in-process
materials, packaging material, labeling, and drug
products, and the authority to review production
records to assure that no errors have occurred or,
if errors have occurred, that they have been fully
investigated. The quality control unit shall be
responsible for approving or rejecting drug
products manufactured, processed, packed, or
held under contract by another company.
17. 21 CFR 211.22(c) The quality control unit shall Yes.
have the responsibility for approving or rejecting
all procedures or specifications impacting on the
identity, strength, quality, and purity of the drug
product.
18. 21 CFR 211.25(a) Each person engaged in the Yes.
drug product shall have education, training, and
experience, or any combination thereof, to
enable that person to perform the assigned
functions. Training shall be in the particular
operations that the employee performs and in
current good manufacturing practice (including
the current good manufacturing practice
regulations in this chapter and written
procedures required by these regulations) as
they relate to the employee's functions. Training
in current good manufacturing practice shall be
conducted by qualified individuals on a
continuing basis and with sufficient frequency to
assure that employees remain familiar with
CGMP requirements applicable to them.
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COMPANY LOGO
PROCESS SIMULATION

19. 21 CFR 211.25(b) Each person responsible for Yes.
supervising the manufacture, processing,
packing, or holding of a drug product shall have
the education, training, and experience, or any
combination thereof, to perform assigned
functions in such a manner as to provide
assurance that the drug product has the safety,
identity, strength, quality, and purity that it
purports or is represented to possess.
20. 21 CFR 211.25(c) There shall be an adequate Yes.
number of qualified personnel to perform and
supervise the manufacture, processing, packing,
or holding of each drug product.
21. 21 CFR 211.28(a) Personnel engaged in the Yes.
drug product shall wear clean clothing
appropriate for the duties they perform.
Protective apparel, such as head, face, hand, and
arm coverings, shall be worn as necessary to
protect drug products from contamination.
22. 21 CFR 211.28(b) Personnel shall practice good Yes.
sanitation and health habits.
23. 21 CFR 211.28(c) Only personnel authorized by Yes.
supervisory personnel shall enter those areas of
the buildings and facilities designated as limited-
access areas.
24. 21 CFR 211.28(d) Any person shown at any time Yes.
(either by medical examination or supervisory
observation) to have an apparent illness or open
lesions that may adversely affect the safety or
quality of drug products shall be excluded from
direct contact with components, drug product
containers, closures, in-process materials, and
drug products until the condition is corrected or
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determined by competent medical personnel not
to jeopardize the safety or quality of drug
products. All personnel shall be instructed to
report to supervisory personnel any health
conditions that may have an adverse effect on
drug products.
procedures:
appropriate:
conditions.
Components and Container/Closures Yes.
29. 21 CFR 210.3(b)(3) Component means any Yes.
ingredient intended for use in the manufacture
of a drug product, including those that may not
appear in such drug product.
30. 21 CFR 211.80(a) There shall be written Yes.
procedures describing in sufficient detail the
receipt, identification, storage, handling,
sampling, testing, and approval or rejection of
components and drug product containers and
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closures; such written procedures shall be
followed.
31. 21 CFR 211.80(b) Components and drug product Yes.
containers and closures shall at all times be
handled and stored in a manner to prevent
contamination.
32. 21 CFR 211.84(d) Samples shall be examined and Yes.
tested as follows: (6) Each lot of a component,
drug product container, or closure that is liable to
microbiological contamination that is
objectionable in view of its intended use shall be
subjected to microbiological tests before use.
33. 21 CFR 211.94(c) Drug product containers and Yes.
closures shall be clean and, where indicated by
the nature of the drug, sterilized and processed
to remove pyrogenic properties to assure that
they are suitable for their intended use.
34. 21 CFR 211.94(d) Standards or specifications, Yes.
methods of testing, and, where indicated,
methods of cleaning, sterilizing, and processing
to remove pyrogenic properties shall be written
and followed for drug product containers and
closures.
Endotoxin Control Yes.
36. 21 CFR 211.63 Equipment used in the Yes.
drug product shall be of appropriate design,
adequate size, and suitably located to facilitate
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operations for its intended use and for its
cleaning and maintenance.
37. 21 CFR 211.65(a) Equipment shall be constructed Yes.
so that surfaces that contact components, in-
process materials, or drug products shall not be
reactive, additive, or absorptive so as to alter the
safety, identity, strength, quality, or purity of the
drug product beyond the official or other
established requirements.
38. 21 CFR 211.67(a) Equipment and utensils shall be Yes.
cleaned, maintained, and sanitized at
appropriate intervals to prevent malfunctions or
contamination that would alter the safety,
identify, strength, quality, or purity of the drug
product beyond the official or other established
requirements.
39. 21 CFR 211.94(c) Drug product containers and Yes.
closures shall be clean and, where indicated by
the nature of the drug, sterilized and processed
to remove pyrogenic properties to assure that
they are suitable for their intended use.
40. 21 CFR 211.167(a) For each batch of drug product Yes.
purporting to be sterile and/or pyrogen-free,
there shall be appropriate laboratory testing to
determine conformance to such requirements.
The test procedures shall be in writing and shall
be followed.
Time Limitations Yes.
41. 21 CFR 211.111 When appropriate, time limits for Yes.
the completion of each phase of production shall
be established to assure the quality of the drug
product. Deviation from established time limits
may be acceptable if such deviation does not
compromise the quality of the drug product.
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Such deviation shall be justified and
documented.
Validation of Aseptic Processing and Sterilization Yes.
42. 21 CFR 211.63 Equipment design, size, and Yes.
location.
43. 21 CFR 211.65 Equipment construction. Yes.
44. 21 CFR 211.67 Equipment cleaning and Yes.
maintenance.
45. 21 CFR 211.84(c) Samples shall be collected in Yes.
accordance with the following procedures:
46. (3) Sterile equipment and aseptic sampling
techniques shall be used when necessary.
procedures for production and process control
designed to assure that the drug products have
the identity, strength, quality, and purity they
purport or are represented to possess. Such
procedures shall include all requirements in this
subpart.
Laboratory Controls Yes.
49. 21 CFR 211.22(b) Adequate laboratory facilities Yes.
for the testing and approval (or rejection) of
components, drug product containers, closures,
packaging materials, in-process materials, and
drug products shall be available to the quality
control unit.
50. 21 CFR 211.22(c) The quality control unit shall Yes.
have the responsibility for approving or rejecting
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all procedures or specifications impacting on the
identity, strength, quality, and purity of the drug
product.
procedures:
appropriate:
conditions.
54. 21 CFR 211.56(b) There shall be written Yes.
procedures assigning responsibility for sanitation
and describing in sufficient detail the cleaning
schedules, methods, equipment, and materials
to be used in cleaning the buildings and facilities;
such written procedures shall be followed.
55. 21 CFR 211.56(c) There shall be written Yes.
procedures for use of suitable rodenticides,
insecticides, fungicides, fumigating agents, and
cleaning and sanitizing agents. Such written
procedures shall be designed to prevent the
contamination of equipment, components, drug
product containers, closures, packaging, labeling
materials, or drug products and shall be followed.
56. 21 CFR 211.110(a) To assure batch uniformity Yes.
and integrity of drug products, written
procedures shall be established and followed
that describe the in-process controls, and tests,
or examinations to be conducted on appropriate
samples of in-process materials of each batch.
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Such control procedures shall be established to
monitor the output and to validate the
performance of those manufacturing processes
that may be responsible for causing variability in
the characteristics of in-process material and the
drug product.
57. 21 CFR 211.113(b) Appropriate written No.
58. 21 CFR 211.160(b) Laboratory controls shall Yes.
include the establishment of scientifically sound
and appropriate specifications, standards,
sampling plans, and test procedures designed to
assure that components, drug product
containers, closures, in-process materials,
labeling, and drug products conform to
appropriate standards of identity, strength,
quality, and purity. Laboratory controls shall
include:
59. (1) Determination of conformance to
appropriate written specifications for the
acceptance of each lot within each shipment of
and labeling used in the manufacture,
processing, packing, or holding of drug products.
The specifications shall include a description of
the sampling and testing procedures used.
Samples shall be representative and adequately
identified. Such procedures shall also require
appropriate retesting of any component, drug
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product container, or closure that is subject to
deterioration.
60. (2) Determination of conformance to written
specifications and a description of sampling and
testing procedures for in-process materials. Such
samples shall be representative and properly
identified.
descriptions of sampling procedures and
appropriate specifications for drug products.
Such samples shall be representative and
properly identified.
62. (4) The calibration of instruments, apparatus,
gauges, and recording devices at suitable
intervals in accordance with an established
written program containing specific directions,
schedules, limits for accuracy and precision, and
provisions for remedial action in the event
accuracy and/or precision limits are not met.
Instruments, apparatus, gauges, and recording
devices not meeting established specifications
shall not be used.
63. 21 CFR 211.165(e) The accuracy, sensitivity, Yes.
specificity, and reproducibility of test methods
employed by the firm shall be established and
documented. Such validation and
documentation may be accomplished in
accordance with § 211.194(a)(2).
64. 21 CFR 211.192 All drug product production and Yes.
control records, including those for packaging
and labeling, shall be reviewed and approved by
the quality control unit to determine compliance
with all established, approved written
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procedures before a batch is released or
distributed.
65. 21 CFR 211.194(a)(2) Laboratory records shall Yes.
include complete data derived from all tests
necessary to assure compliance with established
specifications and standards, including
examinations and assays, as follows:
66. A statement of each method used in the testing
of the sample. The statement shall indicate the
location of data that establish that the methods
used in the testing of the sample meet proper
standards of accuracy and reliability as applied to
the product tested. (If the method employed is in
the current revision of the United States
Pharmacopeia, National Formulary, AOAC
INTERNATIONAL, Book of Methods, 1 or in other
recognized standard references, or is detailed in
an approved new drug application and the
referenced method is not modified, a statement
indicating the method and reference will suffice).
The suitability of all testing methods used shall
be verified under actual conditions of use.
Sterility Testing Yes.
67. 21 CFR 210.3(b)(21) Representative sample Yes.
means a sample that consists of a number of
units that are drawn based on rational criteria
such as random sampling and intended to assure
that the sample accurately portrays the material
being sampled.
68. 21 CFR 211.110(a) To assure batch uniformity Yes.
and integrity of drug products, written
procedures shall be established and followed
that describe the in-process controls, and tests,
or examinations to be conducted on appropriate
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samples of in-process materials of each batch.
Such control procedures shall be established to
monitor the output and to validate the
performance of those manufacturing processes
that may be responsible for causing variability in
the characteristics of in-process material and the
drug product.
69. 21 CFR 211.160(b) Laboratory controls shall Yes.
include the establishment of scientifically sound
and appropriate specifications, standards,
sampling plans, and test procedures designed to
assure that components, drug product
containers, closures, in-process materials,
labeling, and drug products conform to
appropriate standards of identity, strength,
quality, and purity. Laboratory controls shall
include:
70. (1) Determination of conformance to
appropriate written specifications for the
acceptance of each lot within each shipment of
and labeling used in the manufacture,
processing, packing, or holding of drug products.
The specifications shall include a description of
the sampling and testing procedures used.
Samples shall be representative and adequately
identified. Such procedures shall also require
appropriate retesting of any component, drug
product container, or closure that is subject to
deterioration.
specifications and a description of sampling and
testing procedures for in-process materials. Such
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samples shall be representative and properly
identified.
descriptions of sampling procedures and
appropriate specifications for drug products.
Such samples shall be representative and
properly identified.
73. (4) The calibration of instruments, apparatus,
gauges, and recording devices at suitable
intervals in accordance with an established
written program containing specific directions,
schedules, limits for accuracy and precision, and
provisions for remedial action in the event
accuracy and/or precision limits are not met.
Instruments, apparatus, gauges, and recording
devices not meeting established specifications
shall not be used.”
74. 21 CFR 211.165(a) For each batch of drug Yes.
product, there shall be appropriate laboratory
determination of satisfactory conformance to
final specifications for the drug product,
including the identity and strength of each active
ingredient, prior to release.
75. 21 CFR 211.165(e) The accuracy, sensitivity, Yes.
specificity, and reproducibility of test methods
employed by the firm shall be established and
documented. Such validation and
documentation may be accomplished in
accordance with § 211.194(a)(2).
76. 21 CFR 211.167(a) For each batch of drug product Yes.
purporting to be sterile and/or pyrogen-free,
there shall be appropriate laboratory testing to
determine conformance to such requirements.
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The test procedures shall be in writing and shall
be followed.
77. 21 CFR 211.180(e) Written records required by Yes.
this part shall be maintained so that data therein
can be used for evaluating, at least annually, the
quality standards of each drug product to
determine the need for changes in drug product
specifications or manufacturing or control
procedures.
distributed. Any unexplained discrepancy
(including a percentage of theoretical yield
exceeding the maximum or minimum
percentages established in master production
and control records) or the failure of a batch or
any of its components to meet any of its
specifications shall be thoroughly investigated,
whether or not the batch has already been
distributed. The investigation shall extend to
other batches of the same drug product and
other drug products that may have been
associated with the specific failure or
discrepancy. A written record of the investigation
shall be made and shall include the conclusions
and followup.
79. 21 CFR 211.194(a)(2) Laboratory records shall Yes.
include complete data derived from all tests
necessary to assure compliance with established
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specifications and standards, including
examinations and assays, as follows:
80. A statement of each method used in the testing
of the sample. The statement shall indicate the
location of data that establish that the methods
used in the testing of the sample meet proper
standards of accuracy and reliability as applied to
the product tested. (If the method employed is in
the current revision of the United States
Pharmacopeia, National Formulary, AOAC
INTERNATIONAL, Book of Methods, 1 or in other
recognized standard references, or is detailed in
an approved new drug application and the
referenced method is not modified, a statement
indicating the method and reference will suffice).
The suitability of all testing methods used shall
be verified under actual conditions of use.
Batch Record Review: Process Control Yes.
Documentation
procedures for production and process control
designed to assure that the drug products have
the identity, strength, quality, and purity they
purport or are represented to possess. Such
procedures shall include all requirements in this
subpart. These written procedures, including any
changes, shall be drafted, reviewed, and
approved by the appropriate organizational units
and reviewed and approved by the quality
control unit.
82. 21 CFR 211.100(b) Written production and Yes.
process control procedures shall be followed in
the execution of the various production and
process control functions and shall be
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documented at the time of performance. Any
deviation from the written procedures shall be
recorded and justified.
83. 21 CFR 211.186 Master production and control Yes.
records.
84. (a) To assure uniformity from batch to batch,
master production and control records for each
drug product, including each batch size thereof,
shall be prepared, dated, and signed (full
signature, handwritten) by one person and
independently checked, dated, and signed by a
second person. The preparation of master
production and control records shall be
described in a written procedure and such
written procedure shall be followed.
85. (b) Master production and control records shall
include:
86. (1) The name and strength of the product and a
description of the dosage form;
87. (2) The name and weight or measure of each
active ingredient per dosage unit or per unit of
weight or measure of the drug product, and a
statement of the total weight or measure of any
dosage unit;
88. (3) A complete list of components designated by
names or codes sufficiently specific to indicate
any special quality characteristic;
89. (4) An accurate statement of the weight or
measure of each component, using the same
weight system (metric, avoirdupois, or
apothecary) for each component. Reasonable
variations may be permitted, however, in the
amount of components necessary for the
preparation in the dosage form, provided they
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are justified in the master production and control
records;
90. (5) A statement concerning any calculated excess
of component;
91. (6) A statement of theoretical weight or measure
at appropriate phases of processing;
92. (7) A statement of theoretical yield, including the
maximum and minimum percentages of
theoretical yield beyond which investigation
according to § 211.192 is required;
93. (8) A description of the drug product containers,
closures, and packaging materials, including a
specimen or copy of each label and all other
labeling signed and dated by the person or
persons responsible for approval of such
labeling;
94. (9) Complete manufacturing and control
instructions, sampling and testing procedures,
specifications, special notations, and precautions
to be followed.
95. 21 CFR 211.188 Batch production and control Yes.
records.
96. Batch production and control records shall be
prepared for each batch of drug product
produced and shall include complete information
relating to the production and control of each
batch. These records shall include:
97. (a) An accurate reproduction of the appropriate
master production or control record, checked for
accuracy, dated, and signed;
98. (b) Documentation that each significant step in
the manufacture, processing, packing, or holding
of the batch was accomplished, including:
99. (1) Dates;
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100. (2) Identity of individual major equipment and
lines used;
101. (3) Specific identification of each batch of
component or in-process material used;
102. (4) Weights and measures of components used in
the course of processing;
103. (5) In-process and laboratory control results;
104. (6) Inspection of the packaging and labeling area
before and after use;
105. (7) A statement of the actual yield and a
statement of the percentage of theoretical yield
at appropriate phases of processing;
106. (8) Complete labeling control records, including
specimens or copies of all labeling used;
107. (9) Description of drug product containers and
closures;
108. (10) Any sampling performed;
109. (11) Identification of the persons performing and
directly supervising or checking each significant
step in the operation, or if a significant step in the
operation is performed by automated equipment
under § 211.68, the identification of the person
checking the significant step performed by the
automated equipment.
110. (12) Any investigation made according to §
211.192.
111. (13) Results of examinations made in accordance
with § 211.134.
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distributed. Any unexplained discrepancy
(including a percentage of theoretical yield
exceeding the maximum or minimum
percentages established in master production
and control records) or the failure of a batch or
any of its components to meet any of its
specifications shall be thoroughly investigated,
whether or not the batch has already been
distributed. The investigation shall extend to
other batches of the same drug product and
other drug products that may have been
associated with the specific failure or
discrepancy. A written record of the investigation
shall be made and shall include the conclusions
and followup.
Filled by: Auditor

Name and Designation Signature with Date
MUKESH SHARMA Mukesh Sharma

ASSISTANT MANAGER 22 SEP 2021
F22_SOP-018-10 P a g e | 43

Project Work DQAC 31 OCT 2021

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Project Work DQAC 31 OCT 2021

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INTERNAL AUDIT REPORT

PROJECT WORK (PART III)

SUBMITTED AS PARTIAL FULFILMENT OF THE REQUIREMENT

DIPLOMA IN GMP AUDITORS CERTIFICATION

Audit Report No.: 2021/QA/007 Audit Date: 21 and 22 SEP 2021

1.0 EXECUTIVE SUMMARY

1.2 Audit Scope:

1.3 Overall Assessment:

Audit Report No.: 2021/QA/007 Audit Date: 21 and 22 SEP 2021

2.0 AUDIT PLANNING

2.2 Audit Schedule:

2.3 Audit Agenda:

Audit Report No.: 2021/QA/007 Audit Date: 21 and 22 SEP 2021

 22 SEP 2021: Areas covered along with tentative timelines;

Audit Report No.: 2021/QA/007 Audit Date: 21 and 22 SEP 2021

2.4 Notification to the Auditee:

Audit Report No.: 2021/QA/007 Audit Date: 21 and 22 SEP 2021

3.0 THE AUDIT

3.2 Facility Tour:

3.2.2 Moist heat steriliser/ autoclave (ID: MI1)

Audit Report No.: 2021/QA/007 Audit Date: 21 and 22 SEP 2021

3.2.3 Three piece filling room – entry and exit.

3.3 Documents Reviewed:

Audit Report No.: 2021/QA/007 Audit Date: 21 and 22 SEP 2021

 Calibration planner of production (Year 2021).

3.4 Personnel Interacted during Audit:

3.5 Positive Audit Observations:

Audit Report No.: 2021/QA/007 Audit Date: 21 and 22 SEP 2021

 Bowie Dick test was pass.

Audit Report No.: 2021/QA/007 Audit Date: 21 and 22 SEP 2021

Audit Report No.: 2021/QA/007 Audit Date: 21 and 22 SEP 2021

Audit Report No.: 2021/QA/007 Audit Date: 21 and 22 SEP 2021

 The duration of process simulation was 5 shifts. During regular production

Audit Report No.: 2021/QA/007 Audit Date: 21 and 22 SEP 2021

Grade B, environmental monitoring viz. active, passive and non-viable

3.5.6 Few discrepancies with respect to good documentation practices were

3.6 Recommendations for Improvement:

3.7 Effectiveness Check of Previous Internal Audit:

3.8 Compliance Status of Previous Internal Audit:

Audit Report No.: 2021/QA/007 Audit Date: 21 and 22 SEP 2021

3.9 Closing Meeting:

3.10 Recommended CAPA Plan

Audit Report No.: 2021/QA/007 Audit Date: 21 and 22 SEP 2021

 Impact assessment to study the adverse effect of the audit finding on

3.10.2 Preventive Action:

3.11 Classification of audit findings:

Audit Report No.: 2021/QA/007 Audit Date: 21 and 22 SEP 2021

 Audit Criteria: Set of policies, procedures or requirements used as a

4.0 AUDIT OUTCOME

4.2 Follow up Action:

4.3 Tracking and Trending:

AUDIT REPORT PREPARED BY AUDITOR AUDIT REPORT ACCEPTED BY AUDITEE

Checkpoint Complies (Yes or No)

Checkpoint Complies (Yes or No)

Checkpoint Complies (Yes or No)

Checkpoint Complies (Yes or No)

Checkpoint Complies (Yes or No)

Checkpoint Complies (Yes or No)

Checkpoint Complies (Yes or No)

Checkpoint Complies (Yes or No)

Checkpoint Complies (Yes or No)

Checkpoint Complies (Yes or No)

Checkpoint Complies (Yes or No)

Checkpoint Complies (Yes or No)