GMP REMEDIATION
Case Study
GMP REMEDIATION: ASEPTICALLY PRODUCED “STERILE DRUG PRODUCTS” MANUFACTURING FACILITY
by Manish Bhatkar
Founder & CEO – RedLotus Pharmtech Pvt. Ltd.
Client engaged in manufacturing of sterile drug substance and drug products was
asked to engage a third-party consultant to resolve critical observations/ gaps
identified in an US-FDA inspection. The client hired RedLotus (RPPL) + Jeff Yuen
Associates Inc. (JYA) to make necessary quality system improvements and to
ensure sterility assurance of finished drug products manufactured to date since
the last US-FDA inspection.
RPPL worked diligently to complete comprehensive quality systems and cGMP
assessments of the client manufacturing facility(s) and existing GMP systems,
processes and procedures according to a formal QA pre-approved protocol. The
protocol defined the key objectives of the assessment, outlined scope &
approach, and provided guidance for evaluation and categorization of each
observation or improvement opportunity. Important highlights that were
integral to the comprehensive quality systems and cGMP assessments and the
approach used are summarized below:
• Each of the key six (6) GMP systems elements, specifically Quality
Systems, Equipment & Facility, Production Controls, Laboratory Controls,
Materials Management, and Packaging & Labeling was reviewed in detail
through first hand, on-site assessments that included direct interviews
with key personnel at various levels and a formal document / records
review. A senior associate that is expert in US-FDA remediation and
familiar with the Indian culture was selected for this assessment. The
assessments provided the site leadership team objective feedback and
specific areas that should be strengthened prior to the next US-FDA re-
inspection. It is important to note that the Board and executive leadership
team remain fully committed to working with JYA to ensure that a proper
level of sustained compliance is achieved. Remediation plans have been
initiated with defined deliverables and time frames for completion. This
commitment is continuously being re-emphasized to key site leadership
team and staff members at management meetings.
• In addition to the six (6) quality systems consistent with US-FDA’s QSIT
approach to inspections, a special emphasis was directed towards sterility
assurance and contamination control. A detailed holistic review of key
sterility assurance elements such as equipment & facility design;
qualification & validation; component preparation processes including vial
and stopper wash, sterilization and Depyrogenation; and most importantly
Case Study 3
IN THIS CASE STUDY
a review of aseptic practices and aseptic process validation or media
simulation studies (media fills) were extensively reviewed. In addition, as
noted earlier categorically, the microbiology laboratory and a review of
sterility and endotoxin test methods were included in the review.
• Each applicable system, procedure and/ or process was reviewed against
the corresponding regulation, guideline and where applicable according to
a custom checklist.
• Each observation or area for improvement was scored with respect to the
potential risk to patient, product quality AND cGMP/ regulatory
compliance to allow for proper prioritization to allow for optimal focus and
attention on remediation efforts.
• A detailed self-inspection or internal audit report describing specific
observations or areas for improvement needed and pertinent
recommendations including a well-organized proposal for the structure of
an appropriate remediation plan with defined tasks and sub-tasks and
projected time frames for completion.
Some important areas where RPPL was engaged to make a systemic and
sustainable improvement are described below under points (A) to (E), below
these points actual action(s) taken and the current status is also explained:
(A) Aseptic operator behaviors and aseptic practices training require
enhancements to increase awareness and to ensure that movements were
slow and deliberate and aseptic practices were optimized to minimize
potential contamination risks during critical interventions.
Activities Completed
1) Playbooks prepared for all activities that normally occur in the aseptic
processing areas in normal course of actions, which includes 22 aseptic
interventions and 7 aseptic transactions
2) Teams under the leadership of identified staff member were
established to focus on improvement of the aseptic practices
3) Aseptic processing area operators trained on operator behavior and
aseptic practices
CASE STUDY | 3
This includes the general SOP on; “Aseptic Practices and Aseptic
Behaviour” as well as the applicable SOP #(s) as defined in the
playbook(s) corresponding to their area/ responsibility of the work
4) Aseptic practices inspectors were trained for observing the operator
aseptic behavior and aseptic practices
Area/ function in-charge/ line supervisor/ officers generally were made
responsible for aseptic practices inspection.
Conduct, behavior and aseptic practices of the operators is monitored
and observed by a trained team on the shop-floor and/ or on the video
footage
5) Each operator was given feedback and (re)training in case of
undesirable behavior/ observation by the aseptic practice’s inspectors
In the initial phase of implementation of this program, RPPL + JYA also
conducted inspections and provided inputs at 3 instances/ visits.
Additionally, off-line review performed on recorded video footage
(more than 1100 minutes) for each identified aseptic intervention/
transaction until a satisfactory improvement was noted in the aseptic
operator behavior and practices
Current Status
A team under the leadership of plant head continues to monitor the aseptic
practices on a daily basis and (re)train the aseptic processing area
operators on good aseptic practices if and when needed.
(B) Aseptic process validation or media simulation studies require clarification
and better definition and classification of planned vs. unplanned
interventions, proper audit trail and documentation with respect to
reconciliation of units and documented evidence of units eliminated from
the media fill study once units are placed in incubation, assurance that all
critical interventions were covered to be representative of set up, aseptic
filling and support operations such as EM monitoring in the critical Grade
A zones. The comprehensive cGMP assessment included a review of all
past media fill studies performed.
Activities Completed
1) Existing practices, procedures and documentation thoroughly
reviewed and compared with current industry trend, regulatory
expectations, applicable regulations and guidelines to identify all gaps
and/ or non-compliances
2) All aseptic interventions identified and evaluated in accordance with a
protocol-based study to classify according to the possible risk to the
product contamination and/ or sterility assurance
3) A new SOP for lifecycle management and trending of the intervention
in routine product batch(s) manufacturing prepared
4) SOP for planning and conducting media fill revised, primarily to; [a]
align the practices with current trends and regulatory expectations, [b]
incorporate principles of continuous process verification, [c]
integration with the media fill study planning and verification of key
check points (like – intervention trend review, aseptic practices and
behavior, personnel qualification status etc.) before initiating a regular
media fill batch
5) Media fill BMR revised to capture all improvements (as mentioned
above), as well as improving clarity on handling of rejects by; [a]
identification of rejects at each manufacturing step, [b] incorporating
unambiguous instructions for handling each type of the reject, and [c]
their reconciliation
6) A focused and documented on-job training and class room training/
workshop conducted for the staff on all above topics. Similarly, a
training was also conducted on revised and improved media fill
program before executing the media fill study
Current Status
All actions completed on media fill topic.
2
Subsequent to making all these improvements/ changes/ revisions, three
Process Simulation Studies comprising of 6 media fill batches have been
manufactured successfully and satisfactorily, results documented and
reviewed by JYA.
(C) A documented scientific rationale and risk assessment to support the
environmental monitoring performed in the aseptic core required
supplemental information to include with their scope personnel, material,
product and waste flows and a review of air flow patterns to ensure that
there is unidirectional airflow or non-turbulent airflow pattern at the critical
height and at key locations where sterile components are staged inside the
aseptic core.
This is the most challenging topic due to the reason that, complete and
comprehensive historic EM results are not available for evaluation and to
strengthen unsupported and unrealistic corrections communicated to the
US-FDA in past responses
Activities Completed
1) Existing practices, procedures and documentation are thoroughly
reviewed and compared with current industry trend, regulatory
expectations, applicable regulations and guidelines to identify all gaps
and/ or non-compliances
2) EMP reviewed in accordance with the aseptic practices, activities, air-
flow pattern, and traffic of material/ personnel in the aseptic
processing area
3) Each EM location being studied as per the current SOP evaluated in
accordance with a protocol-based study to classify according to the
possible risk to the product contamination and/ or sterility assurance
4) Preliminary review of the historic EM result indicates, misalignment
and in sharp contrast with the results expected from a kind of EM
control and management system design installed and being used. This
is a cause of concern as explained in the opening remarks on this topic
Current Status
The data in as-is basis has been reviewed RPPL. The review findings were
used to formulate the remediation strategy.
Activities Completed
1) Existing practices, procedures and documentation thoroughly
reviewed and compared with current industry trend, regulatory
expectations, applicable regulations and guidelines to identify all gaps
and/ or non-compliances
2) EMP reviewed in accordance with the aseptic practices, activities, air-
flow pattern, and traffic of material/ personnel in the aseptic
processing area
3) Each EM location being studied as per the current SOP evaluated in
accordance with a protocol-based study to classify according to the
possible risk to the product contamination and/ or sterility assurance
4) Preliminary review of the historic EM result indicated, misalignment
and in sharp contrast with the results expected from a kind of EM
control and management system design installed and being used.
These findings led to identifying equipment, practices (particularly
aseptic practices), processes (particularly sanitization)
5) EM results subsequent to implementation of all the identified
corrections have yielded excellent results and the aseptic processing
area results are now compliant with the expectations with high degree
of confidence. Results are being compiled to report and present to US-
FDA
(D) Supplemental smoke studies were also required to verify and document
the adequacy of proper dynamic (i.e., “in operation”) representative airflow
patterns during additional simulated critical interventions.
Activities Completed
1) Existing practices, procedures and documentation are thoroughly
reviewed and compared with current industry trend, regulatory
CASE STUDY | 3
expectations, applicable regulations and guidelines to identify all gaps
and/ or non-compliances
2) Protocol for planning and conducting smoke study is revised, primarily
to; [a] align the practices with current trend and regulatory
expectations, [b] incorporate principles of continuous process
verification, [c] integration with the intervention risk assessment and
EM location risk assessment study findings
3) A focused and documented on-job training and class room training/
workshop conducted for the staff and the photographer on planning,
conducting and reporting the smoke study before actually executing it
4) Subsequent to making all these improvements/ changes/ revisions, a
smoke study has been completed. Videos of the air flow visualization
study have been reviewed by RedLotus for review – while there had
been no critical observations/ discrepancies all observations have been
received and already been evaluated for the consideration during the
next air-flow visualization study.
Current Status
Smoke study completed according to the revised protocol. Results
reviewed and found acceptable.
Systems, process(s) and staff related to and responsible for facility &
equipment control and management required enhanced training and
awareness with respect to cGMP’s and US-FDA compliance expectations.
Completed through more than 10 meetings/ workshops/ visits and
discussions by RPPL + JYA experts
3
(E) Quality systems require further integration and streamlining to ensure
basic cGMP elements such as incident or deviation and OOS investigations,
root cause analysis, CAPA, change control and GMP risk assessments are
properly linked and better understood at across departments.
Process flow charts for each key element of QMS have been worked out
along with the client team and provided to be used as a base for revision/
improvement of the corresponding system.
Reviews done subsequent to the implementation of upgraded/ improved
quality systems/ processes indicates improvement with respect to the
improvement in the quality of reporting, investigation, analysis of the
trends and integration with the management reviews.
Additionally, training on following specialized topics was given to the client staff:
• Risk Assessment (with a particular focus on “Sterility Assurance”)
• Aseptic Practices & Behavior in Cleanrooms
• Data Continuity/ Integrity
• Quality Metrics & Management Reviews
• Effective Investigations
• Trend Analysis and Statistical Techniques
Documentation of the studies indicated above have been reviewed and sent to
the US-FDA, indicating completion of the GMP remediation and that the site is
ready for inspection. US-FDA inspection awaited…