ANSM - Compliance To Preliminary Inspection Report With Annexure

ENCUBE ETHICALS PVT LTD
MADKAIM PONDA GOA

RESPONSE TO ANSM PRELIMINARY INSPECTION REPORT
(Ref. 17IPP148, dated 25/06/2018)
(French National Agency for Medicines and Health Products Safety)
INSPECTION DONE BY: Ms. Catherine LEFEBVRE and Mr. Thomas ERLICH
DATES OF INSPECTION : 8th to 10th November 2017
Observation #D1: (Other)
The quality manual and the SOP dealing with the quality review meetings do not defined the quality indicators
which are supposed to assess the performance of the company’s quality system. The minutes of the
management review concludes “there is no need to change any aspect of the quality system" but the indicators
monitored to arrive to this conclusion are not discussed and continuous improvement and assessment of
suppliers/externals contractor’s performances are not addressed as well. (GMP 1.3, 1.4 viii, 1.6, 1.7).
Response to #D1:
1. Investigation:
1.1 The Quality Manual, Doc#EE/QAM (effective date 22nd June 2017) was reviewed and it was observed that
although there was a clause (3.9.3) for performing management review, the details related to scope of
the review, agenda items and conclusion were not included.
1.2 Similarly, a review of the SOP on “Management review meetings”, SOP No. QA/016, revealed that the SOP
includes the points (quality indicators) to be discussed during the Management Review Meetings. Some
of the important points are listed below,
 Quality Audit (Self Inspection) reports
 Customer complaints and investigations
 Corrective and Preventive Actions
 Customer Feedbacks
 Resource requirements including training needs
 Development activities pertaining to new product and modifications in the existing products
 Objectives of the quality management or need to change any aspects of quality system as a result of
change in market ,legal or technical requirements
 Effectiveness of Quality Management System
 Surveillance Reports e.g. any product, process or system non-conformities ,details of in-house QC checks
 Results of external audit
 Process Performance And Product Conformity
 New or revised regulatory requirements
 Critical Change Controls
However, it was observed that the SOP did not have detailed instructions on how to perform the assessment for
determining the effectiveness of Quality Management System. A discussion with the team revealed that the
conclusion of the effectiveness of QMS as satisfactory with no need to change any aspect of the Quality System
was arrived at after considering the outcome of the review of quality indicators of various quality system elements
covered under the existing SOP such as, self-inspection reports, customer complaints, CAPAs, process performance
and product quality, non-conformity investigations, review of change controls etc. However, the discussion of all
these points was not summarised in the minutes of the meeting.
Besides, it was observed that the following indicators were not included in the current SOP that are required to be
considered to assess the effectiveness of the quality system:
 Tracking the deviations and failure investigations
Page 1 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
 Feedback on Outsourced Activities ( Suppliers / External Contractors)

 Discussion on Continuous improvement initiatives and use of Risk Assessment Tools for prioritizing items
for continuous improvement
1.3 Minutes of the Meeting:

A review of the MOMs of the Management Review Meeting (August 2017 and October 2017) confirmed
that the MOM included the quality indicators specified in the SOP Management Review Meetings, SOP
No. QA/016 and updates and actions required against each item were recorded. As stated earlier, the
MOM did not elaborate on the conclusion drawn on assessment of effectiveness of QMS since SOP did
not have specific instructions.
2. Corrective and Preventive Action:

2.1 Quality Manual
The existing quality manual reviewed during the inspection was common for Quality management system,
Environment and medical device. This manual was later reviewed and new manual was prepared
separately as “Quality and Environment management system Manual”, document #EE/QEMS dated
26.06.18.
 This Quality Manual EE/QEMS dated 26.06.18 ,will be revised to include a section on Quality System
providing high-level details of quality system elements to be implemented and reviewed for continual
improvement of products, processes and the system itself.
 The requirement of conducting Periodic Management Review of the Pharmaceutical Quality System
through a formal process will be included. The scope of the review shall include quality indicators of
processes within the pharmaceutical quality system, such as Complaints, Change management processes,
deviation, self-inspection, external inspection, supplier and external contractors’ performance, process
performance and product quality monitoring, CAPAs and continual improvement initiatives that can be
used to monitor the Pharmaceutical Quality System effectiveness.
2.2 SOP and Minutes of the Meeting:
The SOP Management Review Meetings, SOP No. QA/016 will be revised to expand the existing list of quality
indicators to be reviewed (Refer to para 1.2) during the meeting to include indicators related to handling of
deviations, assessment of performance of suppliers and external contractors and continual improvement. The
SOP will also include an instruction to take into account the outcome of the review of all the quality indicators
in assessing the effectiveness of the quality system and to record the details of the discussion in the minutes
of the meeting.
Training of the concerned employees will be conducted to ensure effective implementation of the revised SOP.
Timeline for Completion: 30.08.18
Page 2 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
The QRM process described in the SOP raised the following comments (GMP 1.12, 1.13, 2.11,4.2) :
A. The SOP mentioned mainly the use of 2 methodologies to perform risk management, One of these is
the failure Mode Effects Analysis (FMEA). The scoring for severity, probability, detection and the risk
ranking system are anticipated in the SOP despite this is a general approach and despite the risks to
handle are not identified. The scoring is not established on a case by case for each risk to manage
Response to #D2.a:
The SOP “Quality Risk Management” QA/062 reviewed during the time of inspection explains the scale for
evaluating and arriving at a Risk Priority Number (RPN) based on ranking of Severity, Probability and
Detectability. The SOP provides instructions to assign risk scores to each parameter based on the general
description provided for each level of risk. This description was given as a general guidance and was not
very specific in the context of patient safety for better ranking of the risk.
We have now revised the risk ranking levels with detailed specific description of risk at each level for each
of the parameters i.e. Probability, Severity and Detectability. Also the risk numbers that were randomly
assigned for each level such as 1, 2 to 3, 4 to 6 etc. have been revised to sequential numbers starting from
1, 2, 3, 4 and 5 as specified in the table provided in CAPA section below. Further this guidance will be used
for ranking the risk on a case by case for each risk to manage and the justification for assigning individual
scores will be documented along with the risk score as a part of the each risk assessment process.
Consequently, the Risk Assessment format will be modified to include a specific column for providing
justification for assigning the risk scores for each parameter.
Corrective and Preventive Actions:
The SOP “Quality Risk Management”, QA/062 will be revised to include the following table describing the
details of risk levels of each parameter and to rate the risk score from 1 to 5. Additionally, the format ‘Risk
Assessment Template’ #F-QA-114 will be revised to include provision for documenting the justification for
assigning the specific risk scores.
Probability Risk Score
Risk Level Description
Score
1 Remote Failure impact is not expected to occur during the life cycle under specified operating conditions. Improbable to
occur. Rare event. (Example: Once in 20 batches, Once per 3 years, More than 1% within a batch etc.)
2 Low It has occurred once and/or rarely occur during the life cycle under specified operating conditions.
(Example: Once in 10 batches, Once in a year, More than 3% within a batch etc.)
3 Moderate It has occurred and/or likely to occur infrequently during the life cycle under specified operating conditions.
Probable to occur. May happen. (Example: Once in 5 batches, Once per 6 months, More than 5% within a batch
etc.)
4 High It has occurred and/or likely to occur several times during the life cycle under specified operating conditions.
(Example: Once per batch, Once per 3 months, More than 8% within a batch etc.)
5 Very High It has occurred and/or likely to occur regularly or many times during the life cycle under specified operating
conditions. Realistic chance / expected to happen. (Example: More than one batch, More than once in a month,
More than 10% within a batch etc.)
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MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
Severity Risk Score

Score
1 Minor No patient harm (i.e. functional failure) or perceived quality discourages patient from using. Minor GMP non-
compliance; no possible impact on patient, yield, product quality or on production capability.
2 Low Results in temporary injury or impairment not requiring medical intervention.
Nature of the failure causes only slight issues in the product quality or patient safety.
3 Moderate Medical Intervention required, but permanent injury is unlikely. Significant GMP non-compliance; possible
impact on patient; moderate impact on yield or production capability.
4 High Serious deterioration of health which could possibly be permanent
Could cause product non-compliance or patient’s safety.
5 Very High Life threatening illness or injury – irreversible. Serious GMP non-compliance; Probable serious harm or death;
critical impact on yield or production capability.
Detectability Risk Score

Score
1 Very High 100 % confidence in testing, controls will almost certainly detect a failure
Control system in place has a high probability of detecting the defect or its effects.
The process/system in which failures are detected obviously and have alarm system.
2 High Controls may have a good chance to detect a failure mode (95 to 99% confidence)
The process/system which are with 100% inspection along with verification by second person
3 Moderate Controls may detect a failure mode (50% confidence). Control system in place could detect the defect or its
effects. The process/system which are with statistical sample check through an automatic system or with
verification check by second person.
4 Low Controls will not detect a failure mode (25% confidence). The process/system wherein complete manual
inspection is done. Without verification check by second person.
5 Very Low No control. There is no control system to detect the defect
The process/system wherein failures are not detectable by current methods
Target Completion Date:

Revision of SOP “Quality Risk Management”, QA/062 – 30.08.18
Implementation of revised Risk assessment template #F-QA-114 – 30.08.18
B. All the scores for severity, probability and the detection are not quantitative. They are qualitative and
that means they are related to a human based approach with inherent subjectivity.
Response to #D2.b:
As per SOP “Quality Risk Management” QA/062 the ranking of Severity, Probability and Detectability is
determined quantitatively at the scale of 1 to 10. This SOP provides a range to be referred to assign each
risk score as summarized below:
Rank Probability Severity Detectability
1 Remote Minor Very High
2-3 Low Low High
4-6 Moderate Moderate Moderate
7-8 High High Low
9-10 Very High Very High Very Low
Page 4 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
Although the ranking is defined as a range in the SOP, the final ranking is assigned collectively after mutual
agreement within the team. However, to avoid the variability due to inherent subjectivity the SOP “Quality
Risk Management”, QA/062 will be revised to provide a scale of 1 to 5 for the parameters severity,
probability and detection as specified in Response to Observation No. D2.a above.
Corrective and Preventive Actions: Refer to CAPA section of Response to Observation No. D2.a.
Target Completion Date: Implementation of revised SOP QA/062 – 30/08/18
C. The rational for setting the Risk Priority Number (RPN) is 125 based on the product of the mid score of
each parameters (Severity, Probability, and Detectability) and this in not appropriately justified.
Response to #D2.c:
As stated in Response to Observation # D2.b the risk score for severity, detectability and probability is
defined at a scale of 1 to 10.
Rank Probability Severity Detectability
1 Remote Minor Very High
2-3 Low Low High
4-6 Moderate Moderate Moderate
7-8 High High Low
9-10 Very High Very High Very Low
The acceptable RPN was fixed as 125 by applying the ranking as 5 (moderate) of each parameters (Severity,
Probability, and Detectability). The number 5 was selected as the mid score between 4 and 6.
Now as stated in Response to D2.a to bring more clarity in performing Quantitative Assessment we have
initiated revision of this SOP to fix the risk score as 1 to 5 for each parameter. Based on this risk score the
RPN will be calculated to decide the mitigation plan as given below.
Rating Mitigation Actions

RPN Below 20 No actions required
RPN Above 20 to Below 60 Actions required for mitigation
RPN Above 60 to Below 100 Immediate Actions required for mitigation
RPN Above 100 to Below 125 Not acceptable and process should be ceased

We have now initiated revision of the SOP “Quality Risk Management” QA/062 to include instructions to
provide specific criteria to initiate mitigation actions based on the RPNs arrived.
Implementation of revised SOP “Quality Risk Management” QA/062 – 30/08/18
Page 5 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
D. Though the SOP appropriately outlines that the risk assessment is performed by an interdisciplinary
team, the risk assessments are often performed by 2 or 3 managers but there is no operator and all the
appropriate departments are not always involved (e.g. RA/15/004 where no representative from the QC
laboratory has contributed. There were only 3 people from engineering, QA and manufacturing;
RA/15/011 where only the QA manager and the manufacturing Senior Manager was involved).
Response to #D2.d:
Based on the SOP “Quality Risk Management” QA/062 the Risk Assessment process is performed with an
interdisciplinary team. During this assessment process various stake holders including Executives and
Operators from different departments are interviewed. Similarly in the case of Risk Assessment RA/15/011
the assessment was performed by interviewing and interacting with the concerned personnel at user level.
The name of the personnel involved at the user-level were not included in the Risk assessment report as
the SOP did not have clear instructions to identify and document the team members interacted for
contributing in the assessment process.

Based on the above investigation the SOP “Quality Risk Management” QA/062 is already revised with
following instructions:
a) Instruction to assign concerned members from all levels by the Head of the Department for
participation in the respective Risk assessment process.
b) Instruction to verify and approve the selection of the interdisciplinary team by QA based on the topic
of Assessment.
Format F-QA-115 “Format for Quality risk management report” is revised accordingly.
Annexure - # D2.d:
(i) Relevant pages of the revised SOP “Quality Risk Management” QA/062
(ii) Copy of the revised Format F-QA-115 “Format for Quality risk management report”
E. The persons who are leading the risk assessment processes have been trained to the SOP on risk
management but they have never been trained on the QRM methodologies.
Response to #D2.e:
The Risk Assessment process was performed by personnel trained on the SOP “Quality Risk Management”
QA/062. This SOP has brief instructions on the two QRM methodologies adopted for Risk Management.
However, there were no separate trainings conducted on the application of Risk Management tools.
Page 6 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)

a. We have conducted an onsite training by external trainer Ms. Stephanie Wilkins from M/S
Pharmaconsult US (Refer Attached Curriculum Vitae) on the risk management process. The
training was emphasized on identification of risk, risk ratings, mitigation plans and application of
different tools for assessment.
b. In addition to this two personnel are certified on Advanced Program in Pharmaceutical Quality
Management of 20 days on various aspects of pharmaceutical Quality System including Risk
Assessment conducted by NSF Healthcare US in association with Indian Drug Manufacturer
Association (IDMA). Refer Attached certificates.
c. We have listed out the personnel trained under the program and they will be certified as approved
trainer for Quality Risk Management topic.
Target Completion Date : 14.08.18
Annexure # D2.e
CV of Ms. Stephanie Wilkins from M/S Pharmaconsult US
Certificates on Advanced Program in Pharmaceutical Quality Management
F. The risk assessment for the additional user loop in Phase II Purified Water System II (RA/15/004)
addressed the risk of an adverse passivation in the purified water loop by testing the water quality on 3
consecutive days at all point. This mitigation measure was appropriate for the management of the
immediate impact on water quality but the long term impact has not been managed. The review of the
purified waters quality on a longer term in the context of this passivation has not been mentioned. The
associated change control number of the water loop (CC5/03/052) is not reported in the risk assessment
form.
Response to #D2.f:
We have reviewed the Risk Assessment (RA/15/004) performed with respect to the installation of
additional purified water user point. This assessment was initiated as a part of the Change control #
CC5/03/052.
During the assessment the actions required to mitigate the risk during the installation were identified and
implemented. As a part of the assessment the monitoring of water for quality for chemical and microbial
was performed for three consecutive days before releasing for routine usage. Further the water chemical
and microbial quality of the additional user point was done for a period of one week which showed
complying results.
Page 7 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
As per the Risk Assessment Summary, long-term impact due to this change was planned to be monitored
through the online monitoring of conductivity, TOC, Velocity and temperature which will give indication of
any failures. There were no failures reported after this installation.
Based on the review three days trend of all purified water user points, 7 days trend of the new purified
water user point and the online monitoring of conductivity, TOC, Velocity and temperature the review of
long-term trend was not included in the Risk Assessment Report. However, to verify the impact, the trend
of purified water for a period of three months is reviewed including the newly installed user point and the
results were found to be complying with no significant variation with respect to chemical and microbial
quality.
Further, a review of the SOP “Quality Risk Management” QA/062 confirmed that the Format for Risk
Management Report F-QA-115 did not have provision to record the associated document number. Hence
the Change control number was not mentioned in the Risk Assessment Report.

The format for Risk management report F-QA-115 is already revised (effective from 07.05.18) to include
recording the relevant document number such as Change Control or Deviations.
As stated in Response to Observation D2.e, training is imparted to the concerned personnel by an External
Trainer on identification of risk, risk ratings, mitigation plans and application of different tools for
assessment.
Annexure #D2.f:
Relevant pages of the revised format for Risk management report F-QA-115
Fusidic Acid Eur. Ph. Micronized was exposed during transport from the supplier to Encube to a temperature
excursion (up to 16, 7 °C) during 2 days while the requirement of for the transport of the material the time of
acceptance but the impact on the quality of the finished products where this batch was introduced was not
considered (e.g. by including in the ongoing stability programme one of the 9 batches of finished product where
this batch of active substance has been incorporated) (GMP 1.8. vii, 6.33) – DV6/04/015
Response to # D3:
The Deviation DV6/04/015 was raised on 21.04.2016 for observation of out of limit temperature in the data
downloaded from data logger transported with material Fusidic acid Ph. Eur, A. R. No. R160001167 which was
received on 18.04.2016. Total excursion was observed for 1 day 23 hours 30 minutes and a Maximum temperature
of 18.3°C was observed. However mean kinetic temperature was found to be 8.6°C.
Page 8 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
In the meantime the supplier was contacted who shared the stability study data to confirm the impact on stability
of the material in case of excursions. Following is the summary data available for performance during higher
temperature.
Stability Condition Number of Days Compliance with specification

25˚C/60% RH 30 days Complies
40˚C/75% RH 37 days Complies
The data shows that the material is stable and complying with the specification for a period of 30 days at long-
term and accelerated conditions that is substantially more than the period of excursion.
Further the material was tested and found to be complying with specification. Based on the Mean Kinetic
Temperature, Stability data from the supplier and the results of analysis the consignment was released for usage.
The following batches were manufactured using the API of this batch number.
Product details Impacted Batch Numbers. Number of batches

Fusidic Acid Cream 6F13, 6F12, 6F11, 6F10, 6F09, 6F08 and 6F07 7
Fusidic Acid and Betamethasone Cream 632UK ,631TA 2
The bulk and finished product results of all these batches were reviewed and found to be complying with the
specification.
Based on the Mean Kinetic Temperature, satisfactorily stability data from the supplier, and based on the results of
analysis of the API and the results of analysis of all the batches of finished product the batches were released
without charging a representative batch of finished product for stability.
A review of the instances of similar excursion in the previous period confirmed that in two such events the finished
product batches were in fact charged for stability study and the results were found to be complying with the
specification. The details are provided in the table below:
Deviation Analytical Impacted Batch Numbers. Max. Mean No. of days Batch charged
No. Reference Fusidic acid Fusidic acid temper kinetic of for stability (If
Number Cream and ature temper excursion any) (25˚C/60%
Betamethason observ ature RH)
e Valerate ed
Cream
DV5/04/ R150000826 5F02,5F03 Nil 16.8°C 7.8°C 3 days 5F01
009 R150000819 5F01,5F02
DV6/01/ R160000016 6D01 617E, 618E, 30.2°C 8.0°C 2 days 16 6D01
015 619E, 620E, hours
621E, 622E,
623E, 624E,
625E, 626E,
627E, 628E,
629E, 630E,
Page 9 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
 Based on the findings of the above two investigations, it is evident that excursion of temperature for a
duration of 3 days did not have any significant impact on the stability of the finished product. Hence not
charging the finished product batch manufactured using the API under investigation that had excursion
of less than 2 days did not have an impact on the product quality. However, we have implemented
following corrective and preventive actions.
Corrective Action and Preventive Action:
 SOP “Deviations/Incidents Handling” QA/004 will be amended to include an instruction for handling the
investigations of such excursions observed during the transportation. The instructions will include a need
to review the stability study of the finished product if conducted earlier and the highest duration of the
excursion of the API used for the manufacturing of the product while taking a decision to approve the
material.
 Additionally the following instructions will be included in the SOP.
If the excursion period of the supply of API under investigation is within the duration of the excursion of
the earlier supply for which finished product stability data is available, the material can be accepted
without a need to initiate stability study of the finished product to be manufactured, provided stability
report of the raw material is made available by the supplier and the API complies with the specification. If
either the stability data of the product is not available or if the excursion period of the API in transit exceeds
the earlier excursion period, 1 batch made out of current lot will be charged for stability.
 Training will be given to all the concerned personnel involved to evaluate the need of conducting stability
study by following the revised instruction in the SOP.
 Addendum to the deviation DV6/04/015 is prepared addressing the justification for not charging the
batches affected for stability study. (Completed)
Annexure #D3:
Communication received from the Supplier on stability data
Target Date for completion: 14.08.18
The reporting mechanism of deviations or adverse events is not designed to be contemporaneous and
independent of management hierarchy. Operators in production have to inform the quality assurance
supervisor or an engineering manager when they are facing an adverse event or a deviation. It has been declared
that in case of non-conformity result during the quarterly balance calibration the engineering personnel will be
informed for corrective action but the failure calibration will not be recorded in the respective log book. They
would not make the recording by their own. Additionally, the space is not large enough in logbooks and batch
Page 10 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
records for the recording of any remark by operators. These do not guarantee that all deviations are recorded
(GMP 1.8. vii, 4.8, 4.6; www.ema.europa.eu/questions& answers on data integrity)
Response to #D4:
As per SOP on “Deviation/Incident Handling”, SOP# QA/004, any deviation identified is to be reported immediately.
However, non-conformity result during the quarterly balance calibration are being informed to Engineering and
subsequently to Quality Assurance. This procedure followed was in line with SOP "Calibration & verification of
Electronic balances”, SOP#GEN/060. This SOP states that during the daily balance verification/quarterly calibration
activity if any weight readings is found out of specified limit, then immediately balance usage is stopped and
intimation is given to engineering department as well as to QA department through format “Intimation to
Engineering /QA Department” #F-EG-100 (format Attached). This format is used as an intimation to QA for
assessment for initiating the Deviation. Until clearance a label “Out of Calibration” is affixed on the balance to
prevent further usage of the balance.
The Engineering Department performs an investigation and action plan for rectification. The proposed action plan
is further evaluated by Quality Assurance for the impact of the calibration/verification failure and finally concludes
on initiation of deviation.
A review of the SOP “General Guidelines for Calibration”, SOP# QA/030 also confirmed that Calibration failure shall
be reported to Engineering and QA through format “Intimation to Engineering /QA Department” # F-EG-100. The
SOP don’t have clear instructions to initiate a deviation to investigate a situation of out of calibration.
Further we have reviewed the log book and confirmed that the space in the equipment log book also is not
sufficient to document calibration failures. In case of BMR and BPR there is a section provided “Process Deviations”
to report any deviations occurred during the time of batch processing.
Based on the above investigation following corrective and preventive actions are initiated:
1. The SOP on “General Guidelines for Calibration”, SOP# QA/030 will be revised to include the procedure to report
any calibration failure through deviation and reporting of calibration failures in the log book.
2. The SOP on "Calibration & Verification of Electronic balances”, SOP#GEN/060, will be revised to include the
procedure to report any calibration failure through deviation and reporting of calibration failures in the log book.
3. Format#F-PR-156 “Daily Balance Verification” and F-PR-157 “Quarterly Balance Calibration Record” will be
revised to include additional column as “Remark” in the log book for recording by operators so that sufficient space
is available for documentation.
Timeline for Implementation: 14.08.18
Page 11 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
In the fusidic acid cream BP, results on stability data on finished product are presented in table but there is no
graphic representation to highlight trends and to identify any adverse trend which might need to be correlated
with release specifications and to strengthen if appropriate the internal specifications (GMP 1.10. VII, 1.11, 6.35)
Response to #D5:
The stability data is attached to the (Annual Product Quality Review) APQR in the form of stability grids which
contains the stability results of various time intervals as per the approved stability protocol. The stability grid is
prepared, reviewed and approved by QC. Further final approval is done by QA after reviewing the data and
verifying the trend of stability performance. During compilation the stability grids are reviewed to draw a
conclusion in the APQR and the stability grid is attached to the APQR. However there is no graphical representation
of the data done as this was not specified in the existing SOP “Annual Product Quality Review” SOP QA/036. Further
the SOP “Stability studies” QC/043 also does not have instructions to prepare the trend.
1. SOP “Annual Product Quality Review” SOP QA/036 will be revised for including graphical representation
of stability data during APQR preparation and accordingly training shall be imparted to all the concerned
personnel on the same.
2. The SOP “Stability studies” QC/043 will be revised to include instructions to prepare the trend during
compilation of the stability data. This trend will be reviewed to identify any adverse trend to be correlated
with release specifications and to strengthen the internal specifications (if required).
Timeline for Implementation:
Revision of SOP “Annual Product Quality Review” SOP QA/036 - 14.08.18

Revision of SOP “Stability studies” QC/043 – 14.08.18
Observation #D6: (Major)
The company fails in the management of the PQR process and the key personnel who approves the PQR has not
fully adopted a quality culture for transparency in failures in these documents. In particular, the PQR for fusidic
acid and betamethasone valerate cream raises the following deficiencies (GMP 1.0,1.11, 4. principle;
www.ema.europa.eu/questions & answers on data integrity.
a. Results on total microbial count and total yeast and mould count are all reported as being conform to
the specification though 10 out of the 50 batches were contaminated.
b. Though the complaint number 208/2015 and failure investigation FI/15/021 are discussed in Section 9,
the rejection of 10 out of the 50 batches is not mentioned.
Page 12 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
Response to # D6 a. & b.:

The results on total microbial count and total yeast and mould count were reported in APQR (APQR/16/112)
based on the data generated during batch release at site. These results were complying with the specification
and therefore captured as such in Section 3, Review of Critical Finished Product Results.
The complaint received (No. 208/2015) with respect to microbial contamination from customer during their
analysis at Kymos Pharma Services, in its Quality of EU batch testing site for 10 batches was reported in Section
9, Review of Quality Related Returns/Complaints/Recalls of the APQR. This section provided details about the
failure investigation FI/15/021 and rejection of 10 batches for microbial quality.
On discussion with the APQR team, it was observed that the need for linking the failure reported in Section 9
in the other part of APQR particularly in Section 3 wasn’t realized, since APQR was prepared in a modular
format separately. Besides, there was no specific instruction in the SOP or in the format to consider rejection
of the batches after initial clearance from the site that would have helped the preparatory and the reviewer
of the APQR to link the information of failure and capture it in Section 3.
Root cause: It was thus confirmed that the, omission to capture the failure of batches in Section 3, which was
reported in Section 9, appeared to be a case of poor understanding of the personnel rather than an attempt
to withhold the information of failure of batches.
We agree that the APQR has to be prepared holistically and the conclusions of individual sections have to be
drawn on the basis of information available/provided in other sections of the APQR and also on the basis of
feedbacks from customers. This fact has been explained and emphasized on the team members during the
investigation and the following CAPAs are proposed.
CAPA:
1. The SOP Annual Product Quality Review #QA/036 will be revised to include specific instructions to review
the information of individual sections where any failure is reported based on investigations and customer
feedback and link it with other sections as necessary to arrive at correct conclusion about the product
quality review.
2. The APQR format used for reporting the finished product results will be revised to include an instruction
for review of other sections for any failure reported and reflect them in the finished product result sheet
of the APQR.
3. Additionally, we would like to assure you that we are committed to ensuring quality and reliability of the
data and reporting of failures of quality systems transparently. We have SOPs related to Data integrity
and ALCOA principles in place and training on these SOPs is imparted during induction as well as
periodically thereafter. Refresher training shall be conducted of all the key employees of all the
departments to reinforce the need for transparent reporting of failures and implementation of ALCOA
principles in handling of manual and electronic data.
Target date of completion:
1. Implementation of revised SOP – 14.08.2018
2. Revision of format F-QA-150 – 14.08.2018
3. Refresher training – 14.08.2018
Page 13 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
c. The PQR include only batches marketed for the European Market. It does not clearly state where there are
batches for the local or the third country markets.
d. In section 13, there is only one technical agreement mentioned though 3 importers are releasing the
product for the European Market (Ecopharm group AD, Mylan (Hungary), Polpharma (Poland).
e. In Section 7, the review of variations is limited to Mylans Marketing Authorization (MA) and do not address
those for Polpharma and Ecopharm.
Response to D6 c., d. & e.

The product is manufactured for Marketing Authorization holder Mylan, Ecopharm Group AD and Polpharma SA
and is being marketed to European countries only. The details of countries along with Technical agreements are
as mentioned below.
Customer Name Types of Agreement Dated Countries

MYLAN Quality Technical 21.08.2015 Portugal, Denmark, Italy, Ireland, UK,
Germany, Spain, Greece
ECOPHARMA Quality Technical 07.07.2015 Bulgaria
POLPHARMA Quality Technical 23.10.2017 Latvia, Lithuania and Poland
The review period for APQR/16/112 was January 2015 to June 2016 in which the details of the countries and
market was not specified. Also the batches considered in the review period were produced and dispatched only
for Mylan. Review also confirms that there were no batches manufactured for Ecopharm and Polpharma in the
review period. Moreover the Technical agreement for Polpharma was verified and found to be effective after the
review period of APQR/16/112.
Since the batches for Ecopharm and Polpharma were not manufactured during the review period, the Technical
Agreements were not included in the APQR. Besides, there was no specific instructions in the SOP for APQR or in
the format to consider the requirement of review and inclusion of all Technical agreements specific to the product
under review even if the batches were not produced.
We agree that the APQR has to be prepared to include all Technical agreements during the review period
irrespective of the batches produced or not for the respective customers. Hence following CAPAs are proposed.
CAPA:
I. Addendum to APQR/16/112 has been prepared for inclusion of review of all Technical agreements
irrespective of batches manufactured or launched during the review period.
II. SOP Annual Product Quality Review, #QA/36 will be revised for inclusion of review of all Technical
agreements irrespective of batches manufactured or launched during the review period.
Target completion date:
I. Addendum to APQR/16/112 – completed
Page 14 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
II. SOP Annual Product Quality Review, #QA/36 implementation – 14.08.2018
Response to D6 e.
During the review period of APQR/16/112 (January 2015 to June 2016) the variations were filed only for Mylan
and products for Ecopharm and Polpharma were not yet launched. Hence the variations only pertaining to Mylan
have been included in the PQR. However, there is no statement which clarifies that no variations were granted for
other two customers.
CAPA: Based on the above investigation, following CAPAs are identified.
I. Addendum to APQR/16/112 has been prepared for inclusion of review of variations for Polpharma and
Ecopharm MA holder and also for inclusion of market and countries for the batches.
II. All concerned personnel are trained on review of variation of all customers and to ensure that in case
if no variations are granted in review period, it should be stated clearly in the review section.
III. SOP Annual Product Quality Review, #QA/36 will be revised to include instructions to specify the
country and market of batches supplied and also include comments on the variations of the Marketing
Authorizations. In addition, the format F-QA-0150 will be modified accordingly.
Target Completion Date:
I. Addendum to APQR/16/112 – completed

II. SOP Annual Product Quality Review, #QA/36 implementation – 14.08.2018
f.The qualification status of the equipment and utilities are claimed as qualified though the pre-filtered water
cannot be considered qualified any longer as the FI/15/021 revealed that the QC lab has always monitored the
microbial quality of water without neutralizing the inhibiting effects of residual chlorine.
Response to D6 f.
Based on the review of the APQR, it was observed that the Section 12 “Qualification Status of Equipment and
Utilities” of the APQR was compiled and documented based on the review of the qualification status of equipment
& utilities. The results of microbial trend of purified water were reviewed and the results were within the specified
standard limits. The conclusion in the APQR on Qualification of water system was drawn based on the trend of
Purified water that was found to be satisfactory.
The filtered water is used for preliminary washing of manufacturing accessories and CIP of manufacturing vessels.
SOP “Microbiological Water Quality” QC/013 did not specifically instruct on preparation of trend for both Filtered
and Purified water and thus the trends were not prepared and also not reviewed as a part of the APQR. Thus you
will appreciate that the conclusion in the APQR section was not based on filtered water but purified water.
An investigation was initiated to find out the reasons for not neutralizing filtered water samples and the impact on
the quality of the filtered water. The findings are as follows:
Page 15 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
The SOP “Sampling of water for Microbiological Analysis” QC/067 effective during the APQR review period had
two types of Water samples included in it; Raw Water Sample and Purified Water Sample. The Raw water is
chlorinated online and is used after filtration for preliminary washing stage.
The Raw Water sampling points TW007 to TW010 located in the pump house in the generation system were
identified as Chlorinated Raw Water since the sampling points were located immediately after chlorination and
before de-chlorination stage. The samples drawn from these points were instructed for neutralization before
testing in SOP “Microbiological Analysis of Water” QC/013 and were neutralized using Sodium Thiosulphate. The
results of these points were always found to be satisfactory with respect to Microbial Quality.
However all other chlorinated water points used for preliminary washing in CIP cycle (CIP user points) were
referred to as Filtered Water points and the water collected was considered as filtered de-chlorinated water.
Consequently, the SOP “Microbiological Analysis of Water” QC/013 did not include instruction for neutralization
of water collected from these points.
Further, as a part of the failure investigation an impact analysis was done to assess the impact on the results of
samples that were not neutralized. The samples from the CIP user points were tested after neutralization and
results were complying with the specification. Also the SOP “Microbiological Analysis of Water”, QC/013 was
revised on 23.12.15 to include instructions for neutralizing the samples of chlorinated water collected from all the
sampling points (Refer to CAPA Section).
Thus you will appreciate that the Raw water from the four sampling points from the generation system was always
neutralized before testing and was found to be satisfactory with respect to microbial quality. Although the samples
from filtered water were not de-chlorinated before analysis, the impact analysis confirmed that the samples
passed after de-chlorination.
The SOP “Microbiological Analysis of Water”, QC/013 is already revised (Effective Date: 23.12.15) to include
instructions for neutralizing the samples of chlorinated water collected from all the sampling points.
Additionally, as a part of continuous improvement plan filtered water pipeline was completely replaced with UPVC
and dosing with Virosil was introduced from 28.08.16. Further, the trend of filtered water after implementation of
this CAPA was reviewed and the results were found to be satisfactory as on date. Thus confirming that filtered
water is in qualified state.
CAPA: Based on the above investigation, following CAPAs are identified.
I. Addendum to APQR/16/112 has been prepared for inclusion of update on the testing of filtered water.
II. The SOP “Microbiological Water Quality” QC/013 will be further revised to include clear instructions
for preparation of trend for both Raw water and Purified water.
III. The SOP “Annual Product Quality Review”, #QA/36 will be revised to include instructions to review the
trend of Raw water and Purified water during preparation of APQR.
Target Date of Completion:
I. Implementation of revised SOP “Annual Product Quality Review” QA/036 – 14.08.2018
Page 16 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
II. Implementation of revised SOP “Microbiological Water Quality” QC/013 – 14.08.2018
g.There is no discussion on the issue on the microbial limit test on the Finished Product (performance of the
filtration method versus the pour-plate method) nor on the non-suitability of the method to test the specified
micro-organisms Staphylococcus aureus and Pseudomonas aeruginosa.
Response to D6 g.
In context to method suitability of microbial test, following are the experimental validation done for suitability of
the method to be used for testing of product:
 Pour plate method was previously validated through protocol No. # PRO/EM/MMV/019, where the
recovery for all specified organism (Pseudomonas aerugoinosa and Staphylococcus aureus) was obtained.
However for total Aerobic microbial recovery obtained was less than factor of 2 for Pseudomonas
Aeruginosa and Staphylococcus aureus. Recovery of all other organism was found to be satisfactory.
 Further experimentation was carried out to neutralise the inhibiting effect of the product by using
neutralising medium and membrane filtration through protocol #PRO/EE/ST/058. The outcome of study
revealed that even after using neutralising medium, the recovery obtained were less than the factor of 2
and even lesser than the initial validation carried out as per protocol No. PRO/EM/MMV/019. The
membrane filtration method showed no recovery for added microorganisms except for Candida albicans
and Aspergillus niger. Hence it was recommended to use the pour plate method validated as per
procedure given in protocol no. PRO/EM/MMV/019.
Refer to the Summary of Suitability Test for Microbial Test Method:
Name of Recovery %
organisms Exp.1 Exp.1 Exp.2 Exp.3 Exp.4 Exp.5 Exp.6
Reference Protocol No. Reference Protocol No. PRO/EE/ST/058
PRO/EM/MMV/019
10 g of the Fusidic acid and Using Fluid BSPS with BSPS with BSPS with (C) (C)
Betamethasone Valerate casein 5% 5% 5% Filtration Filtration
cream B. No. FBV/P/039 in 5 digest soya polysorbate polysorbate polysorbate method method
g sterile polysorbate 80. Heat lecithin 80 containing 80 80 containing (Dilutions) (Dilutions
to not more than 45°. Mix polysorbate 1 ml of 5% containing 1 ml of 10% 1:10 ) 1:100
and add 85 ml of pre warmed 20 medium potassium 1 ml of 7% potassium 10g sample 10g
buffered sodium chloride permanganate potassium permanganate +5g tween sample
peptone solution pH 7.0 and solution. permangan solution. 80 + 85 ml +5g tween
mix. ate BSPS 80 + 85
solution. ml BSPS
Dilution 1:10 1:10 1:10 1:10 1:10 1:10 1:100
Bacillus 85 78 78 0 0 0 0 0 0
subtilis
ATCC 6633
Pseudomonas 24.2 8.5 5.4 4.44 0 0 0 0 0
aeruginosa
ATCC 9027
Staphylococcu 10 10.8 3.29 0 0 0 0 0 0
s aureus
ATCC 6538
Candida 87 81 93.9 92.9 0 0 0 77.9 100
albicans
ATCC 10231
Aspergillus 72 74 68.9 98 0 0 0 78.7 63
niger
ATCC 16404
Page 17 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
 Method validated at Kymos also did not give recovery of added microorganisms by membrane filtration
for Total aerobic microbial count and for Total combined yeast and mould count. (Reference Microbiology
Suitability Test Report, S15/154-EE received from Kymos).
 Based on the above experimentation the pour-plate method was used as most appropriate method
After comparing both methods pour plate method was selected for analysis due to better recoveries of all
organisms. However, the above evaluation was not documented by the APQR team separately as this was a part
of the complaint investigation.
Please also refer to response to Observation no. D21.c & d for additional discussion on differences between the
method and proposed CAPA.

Based on the above investigation following CAPAs are identified:
I. Addendum is prepared to APQR/16/112 by including the discussion on Microbial limit test and its
suitability of testing.
II. The SOP Annual Product Quality Review QA/036 will be revised to include detailed instructions to
review the updates and discussions with Client with respect to failures or investigations and document
as a part of the APQR to draw a valid conclusion.
Target Date for Completion:
I. Addendum to the APQR /16/112 with summary of discussions on suitability of microbiological

testing method - Completed
II. Implementation of SOP “Annual Product Quality Review” QA/036 : 14.08.18
h.The Validation Status of the manufacturing process is not discussed nor the holding time and the total
duration of manufacturing and filling though the qualified person from Mylan Hungary raised questions at the
end of September 2015 at the launch of the product on EU market.
Response to D6 h.
Currently during review of PQR, any changes in the validation status of the product are summarised as a part of
change control process in the APQR. The existing format for APQR has no specific provision for evaluation of the
process validation and total hold time from manufacturing to filling.
CAPA:
I. Addendum to APQR/16/112 has been prepared for inclusion of review Validation status and Hold-time.
II. SOP Annual Product Quality Review, #QA/36 will be revised for inclusion of review of validation status of the
product including hold time studies.
III. The APQR format will be revised to include provision to review Validation details.
Page 18 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
Target completion date: For SOP and Format implementation – 14.08.2018
i. The conclusion does not outline all the follow up preventive and corrective actions that have to be
addressed and discussed in the following PQR
Response to D6 i.
The APQR format has the provision for mentioning recommendation from the review and then raising any CAPA
from the APQR and mentioning the CAPA Number of the same in the APQR under section 16. However there was
no separate CAPA initiated as an outcome of APQR as there was a CAPA initiated and tracked as a part of failure
investigation FI/15/021.
CAPA:
Training shall be imparted to concerned personnel to review the relevant CAPAs and mention the follow-up actions
to be discussed in following APQR.
In the first part of the Ladies staff changing room (at the basement) there is no notification promoting the use
of the hand washing facilities before entering into second part of the changing room. The procedure displayed
in the second part of this changing room is references with hand-written notes dated 2011. Moreover, it is stated
that personnel should disinfect their hands before taking their production garment but it was observed that the
people were disinfecting their hands at the far end of the dressing rather than before holding their garment.
(GMP 2.15, 2.21, 4.5)
Response to D7:
SOP “Entry of Employees into the Factory Premises”, GEN/002 was reviewed and it was observed that the
procedure defines the usage of hand washing facility with soap solution and water before entering the change
room, but there were no pictorial representation placed in the respective area which indicated or instructed the
employees to use the hand washing facility before entering the change room.
In addition, SOP states disinfecting the hands with IPA solution before holding the garments but the practice was
not followed occasionally which indicates the need of training of personnel to follow the instructions as per the
SOP.
Based on the above investigation following corrective and preventive actions are implemented:
 Pictorial instructions on hand washing and disinfection are displayed in the respective locations in the
Ladies Change Room (at basement).
 This CAPA is also extended to all other change rooms at site.
Page 19 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
 Training has been imparted on the SOP “Entry of Employees into the Factory Premises”, GEN/002 to the
concerned personnel to re-emphasise the practice of disinfection before holding the garments.
Timeline for Implementation: Completed on 23.12.17
The computerized system used to assign location of materials in the “Storage Cabinet" is not operational because
the barcode reader cannot connect by Wi-Fi to the software. The recording of materials is therefore manually
performed. A drum of fusidic acid drug substance (item code: 101941, batch number R170002151) was stored at
the location of SC3B in the storage cabinet" (at 2°C-8°C) and was not found in the Warehouse Management
System (SAP). At location SC3B, the material item code was 10149. The manual assignment of locations in
Storage areas where there are disinfections from the SAP system is not managed appropriately to GMP
requirements (GMP 3.21, 3.24, Annex 11.6, Annex 11.6)
Response to #D8:
The discrepancy was investigated as per deviation # DEV-E1-17-0373 and as an immediate action location of the
Fusidic Acid Ph.Eur. of AR No.R170002151 was updated at its physically stored rack no. SC3B in storage cabinet
bearing ID no 29/SC/02.
As per the current system once the Goods Receipt Note is generated in the System Application and Products
Data Processing System (SAP) system, barcode labels are generated for individual containers. Barcode Label
displays the following information pertaining to the material :
 Item Code,
 A.R. Number,
 Batch Number,
 Manufacturing Date,
 Expiry Date,
 Supplier Name,
 Manufacturer Name,
 Number of Containers Received
 Quantity Received.
Once the labels are affixed to the individual container, the palletisation activity is initiated where in the barcode
label and Rack ID is scanned together using a Barcode Scanner/ HHT (Hand Held Terminal) which helps to link the
material to the rack ID and the location of the material physically present in the storage cabinet that is updated in
the SAP system.
In the case of incident reported above for location mismatch, the scanner used for barcode scanning was not able
to scan the material bar code since the Wi-Fi connectivity in the storage cabinet was weak. Hence, the details were
updated manually in SAP by the concerned stores personnel. As per the investigation, it was identified that the
Page 20 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
material code was incorrectly entered in the handheld terminal as 10149 instead of 101491 which further lead to
location being untraceable and was not matching with the container stored at location #SC3B. The WIFI
connectivity was poor as the person has to enter the cold storage cabinet which is air tight with a capacity of 1 ton
to scan each material location.
The root cause is attributed to the store personnel entering the material code manually in the handheld terminal
to update the location in the SAP System, since the scanner was not able to read the barcode in the storage cabinet
due to weak connectivity.
The review of process confirmed that before usage of the materials the SAP system verifies the picking list of the
material with respect to approval status & FEFO and compares with the BOM of the batch under dispensing. The
material is further verified by the IPQA and Stores personnel before initiating for dispensing. This eliminates any
possibility of dispensing any wrong material due to this error. Further all the materials in the storage area were
verified for correct location and found to be correct.
Corrective and Preventive Action:
Based on the investigation following Corrective and Preventive Actions are implemented:
 Position of WI-FI device is relocated near storage cabinet and the connectivity was checked for both
storage cabinet and found satisfactory.
 As the cold storage cabinet is very small in size the location bar code has been affixed at the entrance of
the storage cabinet bearing I.D.No.29/SC/02 for traceability of material location stored inside the storage
cabinet. This will ensure that the location can be scanned outside the storage cabinet itself with improved
WIFI connectivity.
 The effectiveness of traceability of material location in system and physical location is verified for a period
of 1 month to ensure the correct management of location is being followed and same is found to be
effective.
The 5 µm filter located on the purified water loop is monitored with the differential pressure measurement. The
specification for identifying the need of the filter change is set based on the filter supplier but record of this
differential pressure shows that this specification is much higher than the trend data. The specification has not
been tightened in the light of trend data and experience to optimize the monitoring of filters. (GMP 3.40, 3.
Principle 1.8.i)
Response to #D9:
5 Micron filters are located at in-feed of DM feed tank and in-feed of DM storage tank which is used to remove the
suspended particles in incoming water. The filter at the in-feed of DM storage tank is installed to prevent clogging
of ultrafiltration unit due to sediment accumulation. Replacement criteria for this 5 Micron filters are set as
Page 21 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
pressure drop more than 2kg/cm² based on the vendor’s recommendation. Based on this the below SOPs for
Purified Water Generation and Storage System was finalized initially with instruction to replace the cartridge filter
if the differential pressure drop is more than 2kg/cm² or when brownish colouration or sediment layer is observed
over the filter surface during periodic disinfection procedure.
 SOP "Purified Water Generation and Storage System (Phase- I) ENG/080

 SOP "Purified water generation and storage system (Phase II)" ENG/081
 SOP " Purified Water Generation and Storage System 2 (Phase 2)” ENG/102
Based on the observation made during the time of inspection we have reviewed the data of filter replacement of
past 3 years for all the three water systems. Review of the data revealed that the maximum pressure drop observed
was 0.8kg/cm² and the replacement frequency due to brown coloration was observed to be four to five weeks.
Based on this maximum pressure drop observed, the limit for replacement of filters is fixed as NMT 0.8kg/cm².
On the basis of trend data available and to optimise the filter monitoring activity the differential pressure limit has
been revised from NMT 2kg/cm² to NMT 0.8kg/cm² and the filter replacement frequency is defined as monthly.
Filters will be replaced if pressure drop exceeds 0.8kg/cm² or for a month whichever is early.
The limits for the other two systems (phase II purified water system I and purified water system II) are also revised
accordingly.
Based on the above observation we have implemented following corrective and preventive actions:
1. SOP "Purified Water Generation and Storage System (Phase- I)" ENG/080 has been revised on 03.01.2018,
ENG/081 "Purified water generation and storage system (Phase II)" has been revised on 03.01.2018 and
ENG/102 " Purified Water Generation and Storage System 2 (Phase 2) has been revised on 03.01.2018 to
include the pressure differential limit as 0.8 Kg/cm² and replacement frequency as One Month.
2. Format no. F-EG-171 "Pressure Difference across Filter" has been revised on 21.12.2017, F-EG-172 "Pressure
Difference across Filters of Phase One Purified Water Systems" has been revised on 30.12.2017 and F-EG-
218 "Pressure Difference across Filters of Purified water System" has been revised on 21.12.2017, F-EG-163
"Disinfection and Replacement of 5µ Absolute Filter" has been revised 30.12.2017.
Timeline for Implementation: The above action item has been implemented.
Annexure # D9:
 Recommendation from Vendor for replacement criteria of 5 Micron filters
 Relevant page of SOP #ENG/080
 Relevant Page of Format#F-EG-171
Page 22 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
3 " Spares weighing balances" (Identification numbers: EE/BL/010, EE/BL/07 and E108/BL/105) are stored in
room 29A to replace those in the dispensing area in the case of failure. Their logbooks are used to record their
calibration but their chronological uses, maintenance, repairing are not recorded in these logbooks (GMP 3.41)
Response #D10:
We have reviewed the “Daily Balance verification “ log book of spare balance and found that log book was updated
as “No Activity” in place of daily weight verification and in same log book it was found that daily weight verification
has been done as required. The daily verification is performed before the balance is used for any activity. Hence
daily verification was not performed on all days as the balance was used only when required.
Balances used are verified daily and calibrated quarterly as per the approved procedure “Calibration and
Verification of Electronic Balances”, SOP#GEN/060. All the calibration and verification records are documented in
Format “Daily Balance Verification” # F-PR-156. As per the procedure, if the balance in the area is out of order
during the activity, then the defective balance is labelled as “Out of Calibration” and is removed from the user
point to prevent further usage. Another spare/idle balance with the same capacity is used for further activity. The
Balance will be only used after verification of calibration and daily verification status during line clearance by
Quality Assurance.
Log book for Daily Balance Verification currently does not have the provision to document the area where the
balances are used neither the activity for which the balance is used such as weighing, maintenance or if the balance
is not in use. Hence the required details were not updated in the log book. However, the format "Daily balance
verification record F-PR-156 is used to record the details if there is not activity. Moreover, the Balance ID is always
mentioned in the batch records of the product batch were it is used.
The observation was further extrapolated to all other critical equipment's in manufacturing and filling area and it
was observed that the equipment log already covers the details of the usage of the equipment and provision to
record any deviation.
 The Format F-PR-156 "Daily balance verification record” is revised on 16.01.2018 as "Daily Balance
Verification & Usage record” with additional column as "Area of usage /Activity performed". This will ensure
that the area and the activity performed is always recorded in the log book. This log book is applicable for all
the balances in the manufacturing area.
 The format "Daily Balance Verification & Usage record”, F-PR-156 shall be further revised to include
additional column as “Remark” as stated to document any activity such as maintenance, repairs and
deviations if any.
Timeline for Implementation: Revision of format F-PR-156 – 14.08.18
Page 23 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
The microbiological testing on purified water (produced by ultrafiltration) is only performed on 100 ml though
the very low contamination level of this water. The testing volume is not assessed to the expected level of
contamination. (EU GMP 6.12, Annex 8 Principle, Eur. Ph 0008 and 0169)
Investigation:
As per current practice, 100 ml of sample is used for testing of hot purified water (80 degree Celsius) based on
Limits given in European pharmacopoeia. However the count observed using 100 ml of sample is low. To
investigate the suitability of the sample quantity of using 100 ml samples, a protocol based study (Study protocol
& Report no: PRO/EE/ST/785 “Evaluation of sample volume of purified water on analysis”, effective date:
30.12.2017) was initiated using 200 ml of sample by membrane filtration method for total count for a week.
Wherein samples were collected as per schedule (F-QC-452 – Schedule Monitoring for Water Sampling) and tested
as per the procedure “Microbiological Analysis of Water” SOP QC/013.
The study confirmed that the results of 100 ml purified water sample and 200 ml purified water are comparable
to each other. Moreover the water system is designed to generate hot purified water with a temperature of 80
degree celsius which is less prone for microbial contamination. Hence it is concluded that the current practice of
analysing water sample using 100 ml quantity is sufficient to determine the quality of water.
It was expected that during the tour of the manufacturing premises that pressure differences (ΔP) between
production and adjacent rooms were not designed and/or suited to the intended purpose (GMP 3.34, 3.33,
5.19, 5.21.x):
• The pressure gauge 52A/DPT/01 was increasing from 0.8,, to 1.0 mm H20 during the opening of the door.
• The pressure differences between 2 adjacent rooms were out of the target limit (e.g. between room 32A and
room 36 between 10C and 15 between room 15 and room 17, etc...) where the ΔP was less or equal to 0.3 mm
H20 (door closed) though the specification was "more than 0.5mm H20".
• Several pressure differences did not changed significantly during the opening of the doors (e.g. pressure
gauge 39/DPT/01 for which the pressure difference was at 2.7 mm h20/door closed and at 2.8 mm H20/ door
opened.
• The specification for the pressure differences between the corridor 34 and the drying area 42A was not
indicated on the pressure gauge 34/DPT/01.
Response to #D12:
Page 24 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
Brief Overview of HVAC System:
The manufacturing facility is provided with Air handling systems for the following different areas:
 Manufacturing areas along with corridor

 Filling areas along with corridor
 De-cartoning areas
 Packing Halls
 Dispensing (Steroid and Non-steroid)
 Sampling areas
 Stores
The core areas (Manufacturing, Filling, Main corridor, Dry area, Microbiology, Change rooms to
Manufacturing and Filling) are designed as ISO Class 7 (Class 10 000/Grade C) at rest and adjacent areas
(Wash area, De-cartoning area, background to the RLAF in Sampling and Dispensing areas) are designed
as ISO Class 8 (Class 100 000 /Grade D) at rest.
A differential pressure (DP) range of 0.5 to 1.0 mm wc is maintained between the corridor and the rooms
(corridor being positive) to prevent risk of cross-contamination between the rooms.
Investigation:
On 08.11.2017 after acknowledgement of discrepancies related to differential pressure, a Deviation

Report (DEV-E1-17-0371) was initiated to investigate the root cause and to perform an impact assessment.
Based on the investigation, it was confirmed that all the AHUs were in operation and there was no changes
in its settings for controlling DP. The conditions of the motor & belt were reviewed and found to be
satisfactory, there was no filter chocking observed. The controlling system of AHU is manual & unchanged
and was working satisfactorily. We have investigated the discrepancy and the details are summarized
below for each specific type of discrepancy.
a. The pressure gauge 52A/DPT/01 was increasing from 0.8 to 1.0 mm H20 during the opening of the
door.
This discrepancy was observed for differential pressure monitoring of Air lock (positive) with respect to
storage cabinet area/change room. We have reviewed this observation and confirmed that the digital
pressure gauge was used in all areas for monitoring of the differential pressure. This gauge placed on the
wall is provided with silicon tube on higher and lower pressure sides. These tubes are connected to the
ports provided in the gauge. As a part of the investigation the gauge was opened and it was observed that
one of the silicon tube connected to the port was slightly squeezed leading to blockage of air from the area
to the gauge resulting in faulty reading.
It was confirmed that the tube could have got squeezed during the last calibration done on 08.10.17.
Further, there was no instruction in the SOP “Calibration Procedure for Magnahelic Gauge and Differential
Pressure Transmitter” SPC/09 to check the zero reading after completion of calibration activity.
Page 25 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
All other areas were verified for similar defects of silicon tube and found to be satisfactory.
This discrepancy was immediately addressed and calibration was performed with zero correction. After
calibration the reading was checked and found to be 1.4mm WC (NLT 0.5mm WC). Further, on opening
the door the gauge showed zero reading.
As a part of the corrective and preventive action following actions are implemented:
 The SOP “Calibration Procedure for Magnahelic Gauge and Differential Pressure Transmitter” is
revised to include instructions for verification of zero reading after each calibration.
 The Format “Calibration Record for Magnahelic Gauge and Differential Pressure Transmitter” F-EG-
189 is revised to include provision to check and record the zero display (on disconnection of tubes
and on opening doors), functioning of magnahelic gauge and verification of proper connection of
silicon tubing’s.
b. The pressure differences between 2 adjacent rooms were out of the target limit (e.g. between room
32A and room 36 between 10C and 15 between room 15 and room 17, etc...) where the ΔP was less or
equal to 0.3 mm H20 (door closed) though the specification was "more than 0.5mm H20".
This observation was made for the differential pressure between following areas
i. 32A (Alcoholic Area Change Room) with respect to (wrt) 35 (Change Room)
ii. 10C (Air lock) wrt 15 (Change Room)
iii. 15 (Change Room) wrt 17 (Filling Area-1)
As stated above to investigate the discrepancy reported for differential pressure readings, a deviation was
initiated. Based on the investigation the reading of the above rooms were checked on the same day again
and was found to be as given below.
i. 32A (Alcoholic Area Change Room) wrt 35 (Change Room) : 0.5 (Limit: NLT 0.5mm WC)
ii. 10C (Air lock) wrt 15 (Change Room) : 1.2 (Limit: NLT 0.5mm WC)
iii. 15 (Change Room) wrt 17 (Filling Area-1) : 3.2 (Limit: NLT 0.5mm WC)
Except in the case of serial no. I which was found to be on the border limit, the other two areas were found
to be within the limit. It was confirmed that the out of limit readings observed during the inspection was
momentary due to man and material movement in the area. During the review of other areas few more
instances (11 out of 197 area) were found where the differential pressure was below the limit
momentarily. The trend of differential pressure for every 30 minutes were reviewed and it was confirmed
that in no case the pressure was out of the limit above 30 minutes except in case of filling (E53) with
respect to wash area (E51).
Page 26 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
In the case of differential pressure failure of filling (E53) with respect to wash area (E51) a detailed
investigation was initiated and it was confirmed that the differential pressure was out of limit for a period
of one hour. The root-cause was attributed as simultaneous opening of the interlock of pass box located
in filling to de-cartoning area due to malfunctioning of the interlock system. However, the interlock system
was rectified and the DP was achieved within the limit.
A study was previously conducted through Protocol No. PRO/EE/PQ/781 to assess the impact of Air flow
pattern on door opening and it was concluded that the Air flow pattern remains unchanged until
30minutes of door opening. This confirms that the momentary fluctuation of differential pressure in the
above areas does not have impact on the air flow direction.
Moreover there is an alarm system in place if such fluctuations exceeds more than 10 minutes to initiate
necessary actions. In order to monitor and control any out of limit situations for differential pressure, the
alarm system is in place. Based on the alarm appropriate actions will be initiated by the user and the
engineering team.
c. Several pressure differences did not changed significantly during the opening of the doors (e.g.
pressure gauge 39/DPT/01 for which the pressure difference was at 2.7 mm h20/door closed and at 2.8
mm H20/ door opened.
We have performed an investigation for this discrepancy and confirmed that this observation was made
for the Change room (39) with respect to Manufacturing-1 (37). It was confirmed that during the
investigation the zero calibration of magnahelic gauge was disturbed. This error was not noticed during
the calibration as zero reading verification after calibration was not a part of the calibration SOP.
The calibration of the gauge was done and zero calibration was verified. After this calibration the DP results
of this area were found to be 1.7mm WC limit of NLT 0.5mm WC. The investigation was extended to all
other areas and zero calibration was confirmed.
For CAPA kindly refer to section of D12.a for details.
d. The specification for the pressure differences between the corridor 34 and the drying area 42A was not
indicated on the pressure gauge 34/DPT/01.
We have verified the specification for the differential pressure for the area and confirmed that the sticker
label affixed on the gauge was removed accidentally. This gauge is affixed with the specification limit now.
All other areas were verified for similar observation and found to be with specification limits affixed on
the gauge.
Based on the above investigation It was concluded that the required air Pressure was maintained in the
areas and DP between areas was proper with only difference in the readings on the display.
Page 27 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
Samples from production are stored at receipt in the quality control laboratory in two rooms. There are no
logbooks in these rooms to track all samples received for testing, with the registration number allocated for each
sample, date of receipt, number of containers and quantity per container. (GMP 4.31,4. required GMP
documentation - Records GMP documentation - Records 6.11, 6.12)
Response to #D13:
All samples received in QC are stored in the sample storage room (Sample storage Room no: 213 and 214). The
status of the samples was monitored through SAP system, wherein the report is tracked for status which includes,
Material code, Material Name, AR Number, Sample Qty and Status. In addition to this each sample is labelled with
status label with Material name and Batch No.
For assigning the samples to respective analysts, Sample Allocation Register is available in QC, wherein details of
the allocation with respect to each sample and analyst is available with the status of the completion. However,
complete traceability of all samples were not available in a separate register at the point of storage of samples
before assigning to individual analysts.

Based on the above investigation following corrective and preventive actions are initiated:
 SOP, "Inspection and testing of Raw Materials, Packing Materials, Bulk Products, Finished Products, Stability
Testing and Non Routine Samples ", QC/034 is revised to include detailed procedure for sample management
and a new format F-QC-564 "Sample Management Register" is introduced to update the details of all samples
received at the Sample Storage Room.
 Training is provided to all concerned personnel on 20.06.2018 for implementation of changes in the
procedure.
Annexure # D13:
 Relevant pages of SOP "Inspection and testing of Raw Materials, Packing Materials, Bulk Products, Finished
Products, Stability Testing and Non Routine Samples "QC/ 034,
 Format "Sample Management Register" F-QC-564
Though the company is manufacturing the fusidic acid and betamethasone cream since more than 10 years, the
batch processing instruction is still providing the pH adjustment with either acid or base without any targeted
quantity. Though pH is a quality attribute which impact which impact the cream viscosity, there has been no
trend performed over the years on all the batches produced to established in the processing instruction whether
the operators should add the acid or base and if the quantity required could be set or not. The manufacturing
process is not reviewed in the light of experience (GMP 5.23, 1.2, 1.4, 1.4viii, 1.4.ix, 1.4.xi, 1.8.i, Annex 15.5.2.1,
Annex 15.5.7).
Page 28 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
Response # D14:
During inspection of the manufacturing facility, product under processing in manufacturing line-I was Betnovate N
skin cream (Betamethasone Valerate and Neomycin sulphate cream) and not Fusidic acid and Betamethasone
Valerate as stated in the observation. This product is manufactured at the site since July 2015 while Betnovate N
skin cream is manufactured since last 10 years.
The product Betnovate N skin cream has step of pH adjustment by using acid or base.
Based on the observation, we have reviewed the data of pH adjustment of 188 batches and it is noted that pH
adjustment was done only with acid (Phosphoric acid) and no base was used for pH adjustment. The quantity of
acid added varies from batch to batch depending on lot of the active ingredient Neomycin Sulphate used in the
batch. However, based on the trend the minimum quantity required for pH adjustment was determined as 1400ml.
The BMR will be revised to include the instructions to add the pre-determined quantity, check the pH and further
small quantity if required to achieve the target pH to be indicated in the BMR. (Refer to CAPA Section below)
The observation was further extended to all other products and 6 more products were identified where similar
instructions are required to be included in the BMR.
1. BMR for the product Betnovate N cream will be revised to include only Acid addition for pH adjustment
and the minimum quantity will be fixed as 1400ml.
2. The BMRs of the following 6 products identified will be revised to include the minimum quantity and usage
of Acid or Base specifically for pH adjustment.
I. Desowen Lotion 0.05%

II. Photoban -30 Lotion
III. Zoray Aqua Gel
IV. Cetaphil Dam Lotion
V. Photoban 30 Aqua Gel
VI. Elovera Baby Moisturising Lotion

Revision of BMR of Betnovate N cream - 30.08.12018
Revision of 7 Batch Records - 30.09.2018
Page 29 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
Though there is no independently check of the materials weights in the dispensing area, there is no check as
well of the empty containers after the incorporation of the materials after the compounding step. The weighing
process of materials is not designed to be independently checked (GMP 5.38).
Response #D15:
We have done a review of the dispensing and material verification process and confirmed that during dispensing
the tare weight, net weight and gross weight of each pack is verified and documented by stores. This weighing
activity is cross verified by QA. These weights are documented in the Dispensing Record and the Dispensed
Material label.
Further, after taking the dispensed raw materials to the manufacturing area the gross weight of all raw materials
are checked by the production officer on weighing balance and recorded in the Batch Record.
During this verification of gross weight as defined in SOP GEN/018 “General Procedure for Manufacturing of
Ointments, Creams and Gels” if any discrepancy is observed the same is handled through deviation as per SOP
QA/004 “Deviation and Incident handling”.
This confirms that the tare weight of the bags/containers are verified independently along with the net weight &
gross weight during dispensing and the gross weight is again verified before addition of the material into the batch.
However, in order to confirm correct addition of the dispensed quantity into the batch we have already initiated
the practice of verification of gross weight in manufacturing area independently by Operator and Executives.
Additionally, tare weight and net weights recorded in the dispensing record by Stores officer and verified by QA
Officer will be checked by the Operator and Executive after weighing the gross weight to confirm correctness of
the weight added to the batch.
Processing methods used for High Performance liquid chromatography (HPLC) testing can be changed by any
personnel from the QC laboratory without any preapproval authorisation by his supervisor (GMP 6.16, 6.17,
Annex 11.12; www.ema.europa.eu Q&A on data integrity).
Response #D16:
The current SOP #QC/117 “Administrative Policies and controls of Empower software” has been reviewed for the
system policies, user types and their privileges, routine review of analytical data and audit trail to understand the
existing systems in place for ensuring reliability of data and to identify the additional controls required.
As per the SOP #QC/117, total 22 privileges out of 131 are allotted to Analyst Role which allows analysts to select
or modify the processing parameters as per the chromatogram pattern for adequate integration. However
following instructions given in the SOP “Operation and calibration of High Performance Liquid Chromatography
system- with UV-Detector" IOP/190 ensures additional controls while processing the method.
 Use minimum integration parameters for peak integration (marking)
Page 30 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
 All peaks should be auto integrated (marked) by using default integration parameters through software.
 Except related substances test use same processing method for standard and sample chromatogram
integration.
 Peak should be integrated (marked) base to base by using integration parameters.
In addition to this Empower 3 chromatogram template is designed to print in dual window wherein one window
of chromatograms are displayed in zoomed condition for clear visual display of the noise level peaks and all peaks
are marked at base by triangular marking system which ensures peak marking is clearly visible. The peak tables are
also designed to identify the Peak integration type as given below and peak altered, peak faults, manual and
number of results.
Sr.no Integration type Peak Integration mode

1 BB Auto integrated
2 bB Manual integrated at fronting side of peak
3 Bb Manual integrated at tailing side of peak
4 bb Manual integrated at both side of peak
Any integration performed outside the instructions will be printed in the chromatographic peak table and these
chromatograms are reviewed by the Reviewer as per the instructions given in the SOP “Review of Analytical
reports" #QC/107 to ensure the correctness of integration and reliability of data.
In addition to the current controls following additional controls will be introduced:

 The privileges assigned to analysts for creation and modification processing method will be disabled and
will be assigned to Supervisor.
 Further if any modification to processing method is required a form will be introduced to make a request
to the QC Head. On approval by the QC Head, Supervisor will carry out necessary changes as approved.

The SOP QC/117 "Administrative policies and controls of Empower software" will be revised to include following:
 Introduction of format “Authorization for modification of processing method, wherein if any modification
in processing method is required it should be supported with justification and duly authorised by QC-Head.
 To disable the privilege for creation and modification of processing methods to ‘Analysts’.
 To include instruction to create and modify the processing method by ‘Supervisor’, ‘System Owner’ and
‘Administrator’.
Page 31 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
The design of the sampling plan of the finished product is not compliant with the European Pharmacopoeia
where it is required for such products containing 1 mg/g of betamethasone and 20 mg/g of Fusidic acid to take
a minimum of 10 containers per batch. Based:
• On the time required from compounding to final filling (up to 8 days),
• On the different successive holding times (compounding on 18 January 2017/ filling into 5 packaging types run
from 21 January at 8h40 to 25 January 17h00),
• On the occurrence of major microbiological OOS (complaints 208/2015 and PCC-E1-17-0052)
• On the “passed results” of microbial testing immediately performed after the batch manufacturing at Encube
while there are “failed results” detected later at Kymos (mentioned in failure investigation report FI/15/021
page 13).
Each pack sized should be considered as a separate batch and the sampling strategy should be designed taking
in consideration the above mentioned points (GMP 6.12; Ph. Eur. 2.6.12, 2.6.13).
Response #D17:
Based on your observation we have verified the European Pharmacopeia and as per the Ph. Eur. Section 2.6.12,
Point No. 5.1, “Amount used for the test”, it is specified to use 10 g of the product to be examined unless otherwise
prescribed.
The second Para under the Ph. Eur. 2.6.12, Point No. 5.1, indicates that the sample quantity used for the test may
be reduced to less than 10 g. The point states that the amount to be tested may be reduced for active substances
that will be formulated in following conditions. The amount for dosage units (tablet capsule and injection) is less
than or equal to 1 mg or the amount per g or mL (for preparation not presented in dosage units) is less than 1 mg
in this cases the amount to be tested is not less than the amount present in 10 dosage units or 10g or 10 ml of the
product.
Since semi-solid preparations are preparations not presented in dosage units the 10 dosage criteria will not be
applicable but 10g or 10ml criteria will apply as explained in Second para of the Ph. Eur. 2.6.12, Point No. 5.1.
Therefore for our product containing 1 mg/g of betamethasone and 20 mg/g of Fusidic acid reduced sampling plan
of 10g as specified in Second para will apply.
Our existing sampling plan is based on risk management approach and in order to ensure the samples are
representative of the entire filling run, 3 tubes are collected from initial, middle and end of filling run except for
the products where specific sampling requirements are provided by the customer. Additionally, the samples are
drawn separately for each pack size (SKU) of a batch and analysed separately.
Further, as explained in the Response to Observation # D21.a additional samples were withdrawn and tested based
on risk based approach to increase the probability of detection of any contamination.
Page 32 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
We will revise the SOP “Sampling of FP” QA/028 will be revised to include instructions for selection of sample
quantity based on risk based approach covering the process runs, holding time, any interruptions etc.
Timeline for Implementation: Implementation of- 30.08.18
Working standards are stored in large quantity in multi-use container without consideration of the risk of
decomposition, contamination or water uptake. This practice does not guarantee that these standards will
maintain the same property as the primary standard to which they are traceable. (GMP 6.19, 6.22; Eur. Ph.
5.12).
Investigation:
The SOP “Handling of analytical standard” QC/014 was reviewed for handling and maintenance of Laboratory
analytical standards. As per this SOP the qualified standard is being filled in minimum 12 amber coloured vials
considering usage of one vial per month and sealed properly. These vials are stored in refrigerated conditions
under lock and key along with silica gel pouch.
One vial is issued per month that is placed in SS container (In-use container) along with silica gel pouch and stored
in refrigerator. This container is issued as per requirement to analyst.
Before using the vial is allowed to attain room temperature and the outer surface is wiped with tissue paper to
remove adhered moisture. During usage the moisture and light sensitive materials are handled as quickly as
possible. The excess quantity of dispensed standard is never put back into the working standard vials. The issued
vial after usage is closed properly and stored in refrigerator.
The multiple usage of same vial of working standard is validated as per Protocol no: PRO/EE/ST/639, "Study
protocol for Verification of Assigned validity period of one month for In-Use working standard vial”. This study was
performed to simulate the routine conditions for usage of vial with a worst case approach. The material with worst
case characteristics (hygroscopic, light sensitive and viscous liquid) were selected for the study and was performed
for 15, 30 and 40 day’s interval by opening the vial twice a day for 2 minutes. This study confirmed that the
standards are stable for 40 days.
However, to mitigate the potential risk of any decomposition, contamination or water intake we are in
agreement for usage of working standards with single use vial.
The SOP# QC/014 “Handling of analytical standard” will be revised to include instructions for usage of single use
vial.
Page 33 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
The level of controls of reference standards is not commensurate to their intended use (GMP 6.19, 6.20; Eur.
Ph. 5.12).
• a. The European Pharmacopoeia reference standards are authorised to be used once the vial has been
already sampled. This practice is not appropriate,
Response to D19.a:
The SOP “Handling of analytical standard” QC/014 was reviewed and as per this SOP, any reference standard
received from respective pharmacopeia commission are stored as per the specified storage conditions in self-
sealing polythene bag and stored in individual stainless steel container.
In addition to this the SOP also provides precautionary measures to be followed during usage of reference standard
like purging with nitrogen, appropriate sealing and restriction to place the excess dispensed quantity back to the
vial to maintain the pack integrity.
The issued vial is closed properly and stored in refrigerator. During usage the moisture and light sensitive materials
are handled as quickly as possible. The excess quantity of dispensed standard is never put back into the working
standard vials. Before using the vial is allowed to attain room temperature and the outer surface is wiped with
tissue paper to remove adhered moisture.
However the SOP will be revised to include instructions to use reference standard as per the instructions given in
respective pharmacopeia. With regards to reference substances of European Pharmacopeia used for quantitative
testing the reference substance will not be used subsequently.
The SOP# QC/014 “Handling of analytical standard” will be revised to use reference standard as per the
instructions given in respective pharmacopeia.
• b. The working standards for betamethasone-17-valerate and betamethasone-21-valerate (provided from the
active substance manufacturer) which are used against the European Pharmacopoeia monograph are not
qualified against this monograph but against the United States Pharmacopoeia (USP) monograph which has
different testing methods.
Response to D19.b:
Page 34 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
The Working standard Betamethasone 17-Valerate, WS No: WS/061 (WS A. R no: WS170122) was reviewed and
found that this working standard was qualified against USP reference standard (Lot no: L0K350) and received on
19.06.2017 from customer GSK with validity period up-to 23.08.2019.
The review of the SOP confirmed that working standards have to be qualified against the reference standards of
the pharmacopeia specified in the specification of the material/product. The label of the working standard
provides the potency of the standard qualified against the respective reference standard and a reference to the
Pharmacopoeial standards used for qualification (such as USP, Ph. Eur.)
In the present case the working standard that was received from the customer did not have the reference of the
primary standard as USP claimed on the label. This vial was accepted without confirming the details claimed on
the label and was used in the testing of product of European Pharmacopoeia monograph.
However, to meet the requirement of respective pharmacopeia following corrective and preventive actions will
be initiated.

1. The SOP QC/014 “Handling of analytical standard” will be revised to include instruction that in case working
standard is received from customers and did not claim any pharmacopeia status, the working standard
pharmacopeia status shall be verified from the COA and mentioned along with the name on the working
standard vial.
2. Training will be imparted to all the concerned analysts to verify the standards on the label of the working
standard correctly before using.
Timeline for Implementation: For implementation of revised SOP: 30.08.18
The table of responsibilities is defined between Encube Ethicals and Mylan. The responsibilities endorsed by
Mylan Ireland and those endorsed by Mylan Hungary are not clear to Encube Ethicals. Moreover, this contract
raises additional comments (GMP 7.1, 7.14):
• The recalls are under the responsibility of Mylan though Encube Ethicals has also the responsibility to initiate
a recall in case of a GMP failure which could compromise the quality of the products that are manufactured by
the site,
• The API manufacturer approval, qualification and assessment program is under the responsibility of Encube
Ethicals without any consideration of the responsibility of the EU Qualified person who releases the finished
product on the market,
• Mylan responsibilities for the submission to Encube Ethicals of any falsified products or of any complaints
(quality/efficacy/security) received from a customer/ patient for a product manufactured by Encube Ethicals
are not mentioned
Page 35 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
Response to #D20:
Encube Ethicals Pvt Limited (Contract Acceptor) has signed the Quality Technical Agreement (QTA) with MA holder
Mylan Ireland Limited dated 21st August 2015. This agreement has a clause (Refer to Page 2 of 35, 3rd Para) which
states that Mylan Ireland has designated Mylan Hungary to assume all GMP responsibilities and Quality contacts
for batch release. However, the responsibility between Mylan Hungary and Mylan Ireland is not clearly
differentiated under Section “Compliance Responsibilities” checklist Section 8.0.
Response to each sub points are provided below:
a) As per the Quality Technical Agreement (QTA) clause # 8.1.11 Mylan is responsible to initiate, manage and
control market withdrawal and product recall. This agreement was agreed and signed between both the parties
on 21.08.2015. However, the need to initiate recalls by Encube in case of a GMP failure which could compromise
the quality of the products was not addresses in the QTA. It was considered that in case of such failures the
intimation will be given to Mylan and Mylan will initiate the Recall.
b) We have reviewed the QTA and the clause # 8.2.8 states that Encube is responsible for API manufacturer
qualification / assessment program, therefore as per the agreement all the APIs manufacturers used for Mylan
products were qualified by Encube Ethicals. However, all the APIs qualified by Encube are reviewed and a
Declaration letter of API Supplier acceptability is issued by the Qualified Person of Mylan. This is explained in clause
8.2.17, which states that Mylan shall maintain the Qualified person declaration of API acceptability.
c) As per the current procedure, all the Complaints/falsified product or of any complaints (quality/efficacy/security)
received from a customer/patient for a product manufactured by Encube Ethicals are informed by Mylan to the
site i.e. Encube Ethicals and the same is investigated as per the procedure and replied to Mylan as per the agreed
timeline defined in the Quality Agreement. However agreement is deficient in stating clearly the responsibility of
Mylan for submission of any such notification of falsified medicines/complaint to Encube Ethicals.
Based on the above review and discussion with Mylan Team the Quality Technical Agreement will be revised in co-
ordination with Mylan Ireland with following requirements.
 To define the responsibilities between Mylan Ireland, Mylan Hungary and Encube Ethicals clearly under
section 8.0 “Compliance Responsibilities” checklist Section.
 To state that, Encube Ethicals shall be responsible to intimate Mylan to initiate a recall in case of a GMP failure
which could compromise the quality of the products that are manufactured by the site.
 To include Mylan’s responsibilities for intimation to Encube Ethicals of any falsified products or of any
complaints (quality/efficacy/security) received from a customer/ patient
Timeline for Implementation of QTA: 30.12.2018
Annexure #D20: Relevant page of Technical/Quality Agreement. (Section 8 “Compliance Responsibilities”)
Page 36 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
The Company does not assess appropriately the impact of quality defects and does not implement all the
appropriate related corrective and preventive actions (GMP 1.4.xiv, 1.4.ix, 1.9.iv):
a. There is no investigation carried out on batches previously manufactured to the batch 501TA (e.g.; from
September 2014 when the pipeline was implemented). The assessment of the starting date of risk of
contamination due to failure in filtered water quality combined with the corrosion of the 4 meter pipeline
was not performed. Additionally, the increase of the sampling plan on the retested batches was not
considered to optimise the probability of detection of a contamination,
Response to D21.a
Encube has extended the investigation to conduct a comprehensive evaluation and impact assessment pertaining
to the microbiological contamination observed during release testing at Kymos and the disparity with the Encube’s
testing results generated through pour plate technique.
1. Retrospective Product Assessment: A review of all the 609 batches manufactured since Sept 2014 (The date
since CIP system was implemented) till November 2015 was carried out for Manufacturing-I area. The review
concluded the following:
 There were no failures reported for any of these batches in this period during initial testing.
 Out of 609 batches, 43 batches were charged on stability and found complying with the specification and
found without any significant change. All these batches are now expired however stability results of these
batches were complying up-to shelf life of product.
Further a review of the last six months microbial quality of the environment was performed as a part of the Failure
investigation FI/15/021 and there were no abnormal trends or failures observed.
Based on this review it is ascertained that there is no impact on the previous batches manufactured on this
manufacturing area due to cleaning of equipment using the impacted CIP line.
Therefore from the outcome of the retrospective review coupled with the microbiological risk assessment
(Performed as a part of Failure Investigation) of the manufacturing process it is confirmed that the marketed
product are not impacted. Additionally the controls imposed by the actions identified as part of failure
investigation were found effective in addressing the root cause of contamination.
2. Assessment from starting date of risk of cross contamination:
Page 37 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
As stated above the assessment of batches manufactured since Sept 2014 (The date since CIP system was
implemented) till November 2015 was carried out retrospectively to ascertain the impact on the previous batches
manufactured. In addition to this a review of microbial data of water and air is performed for the period of
September 2014 to December 2017 and there were no abnormal results observed.
3. Assessment of Sampling Plan of the product
In order to optimize the probability of detection, based on the findings of the investigation the sample quantity
for analysis of Control sample was increased from one sample to multiple samples based on the process run of the
batch.
 Initial 3 batches after implementation of CAPA were tested individually by collecting 10 samples
throughout the filling process along with one composite sample
 These three batches were subjected for stability monitoring. (Reference Batch Nos. 601UK, 602TA and
603UK)
 Further, 15 batches after implementation of CAPA were tested individually at start, middle and end sample
and one composite sample.
 After monitoring of 15 batches this sampling plan LIST-QA-019AI of the product “Fusidic acid and
Betamethasone Valerate’ was revised to include this sample quantity of three tubes as a part of the routine
testing.
 Later this sampling plan was extended to all other products except for the products for which specific plan
of sampling was identified by customer and SOP #QA/028 was revised dated 31.12.2015.
4. Summary of Implemented Corrective and Preventive actions :
As a corrective and preventive action a CAPA was initiated CAPA5/12/015 to implement the actions identified
including the below.
 The impacted pipeline was removed and the cleaning agent for CIP cycle was changed to SU561K. (Potassium
Hydroxide and Tetra sodium ethylene-diamine-tetra-acetate (EDTA))
 CIP cycle was enhanced to ensure that surface temperature of 80 deg is maintained during sanitisation
 SOP for “Qualification” was revised to include verification of material of construction (MOC) of every piece of
pipeline before painting.
 All sampling points of chlorinated water (which includes filtered water) - frequency of testing was increased
from 3 monthly to monthly for monitoring purpose for the period of 6 months.
 Filtered water from all sampling points was tested by both membrane filtration method and pour plate
method for a period of 3 months.
 SOP on Microbiological Testing procedure # QC/027 was revised to include preparation of composite sample
from samples collected at different intervals of the batch for final testing purpose so that it is representative
of the entire batch. Sampling plan for the product was revised to capture the same.
 CIP program is modified to maintain the Sanitisation temperature and also Sanitisation time was increased
in the recipe.
Further as a part of continuous improvement following additional actions were initiated:
Page 38 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
 Filtered water pipeline was completely replaced with UPVC (Un-plasticized Polyvinyl chloride) through change
control CC6/03/029.
 Treated water was dosed with Virosil (10% hydrogen peroxide with and 0.01% Diluted Silver Nitrate) as an
additional sanitising and disinfecting agent. This is an additional sanitising agent in addition of water being
chlorinated. This activity was performed later and hence was not summarised in the failure investigation
report.
Following SOPs will be revised as a part of the corrective and preventive actions:
 SOP “Handling of Market Complaints” QA/013 will be revised to include instructions to assess the impact
of the complaint comprehensively including impact on other batches manufactured concurrently, batches
manufactured in the previous period, other products / systems etc. as relevant and appropriate global
CAPAs shall be implemented. Also, in the case of microbiological testing the need for increase in sample
quantity for ensuring the probability of detection in case of any investigation shall be ascertained.
 SOP “Failure Investigation” QA/052 will be revised to include instructions to assess the impact and modify
the sample quantity to increase the probability of detection in case of any investigation.
 SOP “Corrective and Preventive Action” QA/054 will be revised to include instructions to extrapolate the
corrective and preventive actions to potentially impacted areas/batches/items.
Target Completion Date: 30.08.2018
b. The use of purified water instead of filtered water for pre-washing of equipment has been questioned as a
temporary measure but not as a long term corrective measure though the company cannot consider that
microbial trend on the filtered water is monitored and under control (the microbial quality has always been
hidden by the inhibiting effect of the residual chlorine),
Response to D21.b
This observation was made with respect to the complaint investigation report (PC-E1-17-0052) received in
March 2017.
We have reviewed the Failure Investigation Report FI-EI-17-0018 prepared for investigation of the complaint
received in March 2017 and confirmed that filtered water was used for cleaning by mixing with steam at the
mixing station to generate hot water for removal of waxy residue of the product. This filtered hot water was
used for cleaning of small vessels and accessories in the wash area.
The usage of mixing station and filtered water was stopped since the hose-pipes with rough surfaces in the
mixing station contributed to contamination of filtered water due to bio-film formation. Consequently usage of
Page 39 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
purified water was proposed as a part of the immediate action identified during the investigation since the
purified water was available at 80 Degree Celsius.
The cleaning procedure used for cleaning of manufacturing tanks was not impacted since filtered water that
was heated using mixing station was never used for removing the waxy residue from the surface of the tanks.
Instead the CIP cycle uses hot filtered water heated using the steam jacketed vessel to remove the wax residue
followed by detergent cycle, purified water rinsing and sanitisation. This confirms that the hot filtered water
from the mixing station was only used for cleaning of ancillary items and small vessels which was stopped and
replaced with hot purified water.
As stated in Response to observation D6.f. the Raw Water (chlorinated water) sampling points TW007, TW008,
TW009 and TW010 located in the pump house in the generation system were tested after neutralization. The
results of these four points were always found to be satisfactory with respect to Microbial Quality.
Further, as a part of the failure investigation an impact analysis was done to assess the impact on the results of
samples that were not neutralized. The samples from the CIP user points were tested after neutralization and
results were found to be complying with the specification.
Thus it is confirmed that the Raw water from the four sampling points from the generation system was always
neutralized before testing and was found to be satisfactory with respect to microbial quality. Although the
samples from filtered water were not de-chlorinated before analysis, the impact analysis confirmed that the
samples passed after de-chlorination.
The SOP “Microbiological Analysis of Water”, QC/013 is already revised (Effective Date: 23.12.15) to include
instructions for neutralizing the samples of chlorinated water collected from all the sampling points.
Additionally, as a part of continuous improvement filtered water pipeline was completely replaced with UPVC
and dosing with Virosil was introduced from 28.08.16. Further, the trend of filtered water after implementation
of this CAPA was reviewed and the results were found to be satisfactory as on date.
Based on the above impact assessment, corrective & preventive actions and review of trend of filtered water it
is confirmed that the filtered water was always qualified and continued to be in qualified state.
c. Microbial method performed by Kymos was a membrane filtration method while the Encube method is a
pour-plate method. The FI report mentions the decision to ask Kymos to perform the pour-plate method
though all the OOS were detected by Kymos and not by Encube. Even if Encube’s rational is based on the
fact that the recovery is better with the pour-plate method than the membrane filtration, the decision to
ask Kymos to switch on the pour-plate method is not based with appropriate experiments,
d. Kymos uses membrane filtration method for the microbial testing and Encube uses Pour-plate method
because there was no recovery at all by membrane filtration. The decision was taken to ask Kymos to
Page 40 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
perform the Pour-plate method though the membrane filtration permitted detection of a contamination
which was not detected by Encube.
Response to D21.c and D21.d
These complaint batches were initially tested as per the pour-plate method by Encube and the batches were
tested by Kymos using Membrane filtration method. Later as a part of the complaint investigation the batches
were tested by Encube using pour-plate method and similar growth was observed which confirms that the
pour-plate method is capable of detecting the microbial contamination.
Following section outlines the background for selection of pour plate method for routine analysis by Encube.
Experimental Data for Migration of Method from Membrane Filtration Method (MFM) to Pour Plate
Method at Kymos: As outlined in the failure investigation, the selection of Pour Plate Method was based on
the following experimental and development data.
 Pour plate method was validated through protocol# PRO/EM/MMV/019, where the recovery for all
specified organism (Pseudomonas aerugoinosa and Staphylococcus aureus) was obtained. However
for total Aerobic microbial recovery obtained was less than factor of 2 for Pseudomonas Aeruginosa
and Staphylococcus aureus. Recovery of all other organism was found to be satisfactory.
 Further experimentation was carried out to neutralise the inhibiting effect of the product by using
neutralising medium and membrane filtration through protocol #PRO/EE/ST/058. The outcome of
study revealed that even after using neutralising medium, the recovery obtained were less than the
factor of 2 and even lesser than the initial validation carried out as per protocol No.
PRO/EM/MMV/019. The membrane filtration method showed no recovery for added microorganisms
except for Candida albicans and Aspergillus niger. Hence it was recommended to use the pour plate
method validated as per procedure given in Protocol no. PRO/EM/MMV/019.
To finalise the diluents, dilution factors and method of analysis experiments were evaluated and the details are
summarized below:
Summary of Suitability Test for Microbial Test Method:
Recovery %
Page 41 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
Name of Exp.1 Exp.1 Exp.2 Exp.3 Exp.4 Exp.5 Exp.6

organisms Reference Protocol No. Reference Protocol No. PRO/EE/ST/058
PRO/EM/MMV/019
10 g of the Fusidic acid and Using Fluid BSPS with 5% BSPS with BSPS with 5% (C) Filtration (C)
Betamethasone Valerate casein digest polysorbate 80 5% polysorbate 80 method Filtration
cream B. No. FBV/P/039 in 5 soya lecithin containing 1 ml polysorbate containing 1 ml (Dilutions) method
g sterile polysorbate 80. Heat polysorbate of 5% 80 containing of 10% 1:10 (Dilutions)
to not more than 45°. Mix and 20 medium potassium 1 ml of 7% potassium 10g sample 1:100
add 85 ml of pre warmed permanganate potassium permanganate +5g tween 10g sample
buffered sodium chloride solution. permanganat solution. 80 + 85 ml +5g tween
peptone solution pH 7.0 and e solution. BSPS 80 + 85 ml
mix. BSPS
Dilution 1:10 Dilution 1:10 Dilution 1:10 Dilution 1:10 Dilution 1:10 Dilution 1:10 Dilution
1:100
Bacillus subtilis 85 78 78 0 0 0 0 0 0
ATCC 6633
Pseudomonas 24.2 8.5 5.4 4.44 0 0 0 0 0
aeruginosa
ATCC 9027
Staphylococcus 10 10.8 3.29 0 0 0 0 0 0
aureus
ATCC 6538
Candida 87 81 93.9 92.9 0 0 0 77.9 100
albicans
ATCC 10231
Aspergillus niger 72 74 68.9 98 0 0 0 78.7 63
ATCC 16404
Based on the above experimental study it was observed that by Membrane filtration method the recovery was not
obtained. Whereas for Pour-plate method recovery was observed but not within factor of 2 for Staphylococcus
aureus and Pseudomonas aeruginosa only. Recovery for all other organisms by pour-plate method was within the
factor of 2 (50 to 200% from standard inoculated organism). Hence, pour plate method was considered suitable
for the routine analysis.
We have evaluated the reason behind low recovery of Staphylococcus aureus and Pseudomonas aeruginosa and
concluded that this could be due to antimicrobial property of the API Fusidic acid present in the product. Fusidic
acid is generally effective against Staphylococcus aureus and a gram negative organism Propionibacterium acne.
However, we have initiated experimental studies to develop a most suitable method by validating different
dilutions and neutralizing agents. Refer to CAPA section below.
Further, during review of the Method validation data (Reference Microbiology Suitability Test Report, S15/154-EE)
of Kymos it was confirmed that recovery of added microorganisms by membrane filtration for Total aerobic
microbial count were not within the factor of 2. Refer to enclosed report Annexure.
Summary of comparison between method suitability using Pour-plate method and Membrane filtration method
performed by Encube and Kymos.
Page 42 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
Method Lab Bacillus Pseudomonas Staphylococc Candida Aspergillus

subtilis aeruginosa us aureus albicans niger
ATCC 6633 ATCC 9027 ATCC 6538 ATCC 10231 ATCC 16404
Pour-plate Encube 78 to 85 5 to 24 3 to 10 81 to 94 69 to 74
Kymos 0 83 to 106 0 78 to 100 100 to 131
Membrane Encube 0 0 0 78 78
Filtration
Kymos 0 Not available 0 Not available Not available
Based on the Failure investigation, the conclusion on suitability to use the pour-plate method was informed to
Kymos. After intimating this, Kymos has adopted the pour-plate method. Later in the month of March 2017 a
similar complaint was received for Batch no. 704GE which also has shown failing results which was analysed as per
pour plate method.
Although the membrane filtration method is universally accepted for microbial analysis for all dosage forms, for
topical formulations membrane filtration method is not preferred due to the oily and viscous nature of the dosage
form which can clog the membrane filter. However, in order to further evaluate suitability of both the methods
we have initiated a comparative assessment.
Comparative Assessment of Microbiological Method of Kymos Lab and Encube: In order to identify the causes
that led to failure of in house method for detecting the contamination, a detailed assessment of the Kymos lab
testing procedure will be performed to develop the suitable method to recover the isolates identified at Kymos
laboratory and to recover the compendia organisms. The outcome of this assessment will be used for development
of enhanced method for recovery studies and optimized recovery of strains identified at Kymos. The following
factors will be considered for the comparative assessment of Kymos and in-house method.
1. Testing Technique
2. Testing Methodology (Pour Plate/Filtration)
3. Neutralizers
4. Dilution factor
Development of Optimized Method: Although the existing validation demonstrated suitability for optimum
recovery in comparison to Membrane Filtration Method (MFM), further developmental trials will be performed to
evaluate both the methods by discussion with Vendor, Millipore using various neutralizers. Based on the outcome
Page 43 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
of the developmental study, an enhanced method will be validated for Microbial Limit Testing of Fusidic acid and
Betamethasone valerate cream.
As part of this method development, the recovery trials will be carried out until the remaining inhibiting effect for
the specified micro-organisms (Pseudomonas & Staphylococcus) are neutralised.
Target Date of Completion for Development of Optimized Method: 30.10.18
CAPA Effectiveness Check:
We will perform a protocol based assessment of all CAPAs implemented/initiated with respect to FI No. FI/15-021
and FI-E1-17-0018 to evaluate the effectiveness of the actions initiated to prevent the recurrence. This will include
verification of previously implemented and currently proposed CAPAs.
Target Completion Date for Verification of CAPAs: 30.08.18
D21 For the microbial contamination of the finished product in 2017 (complaint PC-E1-17-0052):
e. Though the contamination of the finished product was again detected by the importer when Encube Ethicals
had passed the microbial test before release for shipment, there was no deep investigation to explain the
discrepancy in the results between Encube and Kymos and no discussion on the most appropriate method,
Response to D21.e
This complaint was received in the month of March 2017 for the batches manufactured in January 2017. The
Failure Investigation Report (FI-EI-17-0018) was reviewed and confirmed that the complaint batches were
tested by Encube and Kymos using same method (Pour-plate method). Hence the details on comparison of
the appropriate method was not included in the investigation report. Further the testing performed
consequent to the complaint at Encube confirmed the failure.
Kindly refer to Response to observation D21.c and D21.d for investigation and explanation on selection of
pour-plate method.
On investigating the reason for initial passing results at Encube it was observed that out of 5 SKUs of Batch No.
704E, only three were found to be contaminated. Rest two batches were passing at both the labs indicating
that the batch had a chance contamination. Thus it was likely that the contamination was not picked up in the
samples used for initial testing at Encube.
However as explained in response to Observation 21D.c and 21D.d As part of this method development, the
recovery trials will be carried out until the remaining inhibiting effect for the specified micro-organisms
(Pseudomonas & Staphylococcus) are neutralised.
Page 44 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
f. The failure investigation (page 33) indicate that the Pour-plate microbiological method is validated though
validation reports shows that there is a remaining inhibiting effect for the specified micro-organisms
(Pseudomonas & Staphylococcus).
Response to D21.f
Kindly refer to Response to observation D21.c and D21.d. As stated in the response, although the existing
validation demonstrated suitability for optimum recovery in comparison to Membrane Filtration Method
(MFM), further developmental trials will be performed to evaluate both the methods by discussion with
Vendor, Millipore using various neutralizers. Based on the outcome of the developmental study, an enhanced
method will be validated for Microbial Limit Testing of Fusidic acid and Betamethasone valerate cream.
As part of this method development, the recovery trials will be carried out until the remaining inhibiting effect
for the specified micro-organisms (Pseudomonas & Staphylococcus) are neutralised.
g. The FI report indicate that the filtered water will be replaced by purified water but this is not described in
the final list of CAPA.
Response to D21.g
We have reviewed the Failure Investigation Report FI-EI-17-0018 prepared for investigation of the complaint
received in March 2017 and confirmed that filtered water was used for cleaning by mixing with steam at the
mixing station to generate hot water for removal of waxy residue of the product. This filtered hot water was
used for cleaning of small vessels and accessories in the wash area.
The usage of mixing station and filtered water was stopped since the hose-pipes with rough surfaces in the
mixing station contributed to contamination of filtered water due to bio-film formation. Consequently usage of
purified water was proposed as a part of the immediate action identified during the investigation since the
purified water was available at 80 Degree Celsius.
Further, a detailed investigation was extended to assess all possible probabilities for the failure and to identify
additional corrective and preventive actions which can control and monitor the quality of filtered water. These
corrective and preventive actions identified were documented as final list of CAPA in the Failure Investigation
Report. However, the stoppage of filtered water and usage of purified water was not documented under the
final list as it was initiated as a part of immediate action during the investigation.
We have initiated revision of the SOP “Corrective and Preventive Action” QA/054 to provide instructions to list
down all identified corrective and preventive actions irrespective of the initial or final identified actions under
one final list of CAPAs.
Timeline for implementation: 30.08.18
Page 45 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
h. The corrective actions are limited to manufacturing – 1 though the risk of biofilm in manufacturing 2-3
common washing area is similar.
Based on the review of the Failure Investigation Report it was observed that the extrapolation of this
complaint investigation was done in Manufacturing-2, Manufacturing-3 (common wash area) and Filling-1
wash areas. As a part of this investigation to identify any possible contamination in these areas swab samples
were collected for microbial assessment. The sampling points included:
 Pendent pipes of filtered water, steam and purified water

 Hose Pipe inlets of filtered water and steam
 Hose Pipe outlets of filtered water and steam
 Inlet of mixing station of filtered water and steam
 Mixing cone
The results of swab testing were found to be within acceptance range.
Later, the filtered water hose pipe of Manufacturing-2 and Manufacturing-3 wash area were cut open and
swab samples were collected from the tube. The results of this microbial analysis was found satisfactory.
This confirmed that there were no contaminations observed in Manufacturing-2, Manufacturing-3 (common
wash area) and Filling-1 wash areas. However the corrective and preventive actions identified for
Manufacturing-1 wash area was implemented for other areas also as detailed below:
 The mixing units were removed from all the areas (Mfg.1 , Mfg.2, Mfg.3 and Filling-1 wash areas)
 The evaluation of hose pipe in all wash areas were done and all hose pipes were replaced with smooth
silicon hose pipes.
 After the replacement all hosepipes were cleaned and sanitized with hot purified water and swab
sample testing was performed. The results showed microbial count within the specified limit.
 A log book is implemented for monitoring of cleaning, disinfection, and sanitization of all hose pipes.
 SOP QC/067 is revised (May 2017) to include the procedure to collect filtered water from the end of
the all hosepipes instead of sampling after removal of hosepipe. This will ensure that the water quality
used for cleaning is known.
 A Protocol based (Reference # PRO/EE/ST/608) study is performed for a period of 6 months where
swab samples were collected from all the hose pipes of the filtered water to establish the frequency
of disinfection and sanitization. Based on this study performed the SOP PRD/220 is revised to include
weekly frequency for disinfection of hose pipes for all the areas.
In order to emphasize the need extrapolating the corrective and preventive actions to other impacted
areas/products/items of following SOP “Corrective and Preventive Action” QA/054 will be revised.
Timeline for implementation: 30.08.18
Page 46 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
i. The FI report mentions a failure of the Air Handling Unit (AHU) during 24 hours but the data on
excursions of temperature, pressure and relative humidity during the failure are not addressed.
We have reviewed the FI Report (FI-E1-17-0018) and confirmed that the air handling unit was switched off for
24 hours on 22.01.17 which was due to weekly off on Sunday. The activity was resumed back on Monday
23.01.17. During this period bulk of Batch No. 704E was stored in the storage tank with remaining quantity in
hopper. The Storage tank holding the bulk connected to the filling machine was stored on the upper floor.
This area is always maintained under specified environmental conditions and the temperature, RH & DP was
satisfactory. This assessment was not included in the FI report as the Bulk was in controlled environment and
AHU of the filling area (lower floor) was OFF.
The hopper was closed and stretch wrapped without exposure of the bulk to the environment. The bulk
product was waiting for filling of 30g pack to proceed on Monday (23.01.17). It was confirmed that this batch
filled after the holiday was passing for microbial quality at both labs. Later this batch was also rejected as a
part of the Complaint Investigation Report since the bulk was same.
However, the SOP “Filling and Packing of Ointment, Cream, Gel and Lotion”, GEN/019 was revised dated
13.05.17 to include the following instructions
a) In case of holidays ensure that the filling machine hopper is emptied out and wrapped with stretch film
along with filling nozzles.
b) If the bulk is remained in the filling machine hopper then maintain the environmental condition in the
area and wrap with stretch film along with filling nozzles.
In addition we have initiated below additional CAPA to ensure all actions out of the investigation are
documented and extrapolated to other systems/areas. .
 SOP “Corrective and Preventive Action” QA/054 will be revised to include instructions for extrapolating
the corrective and preventive actions to other impacted areas/products/items of following.
Target Completion Date: 30.08.18
The quality issue on the contaminated filtered water which could have had an impact on recall of products
has not been reported to concerned Competent Authorities and to ANSM as Supervisory Authority for the
E.U. Moreover, Encube Ethicals was not able to provide the risk assessment performed by the EU Qualified
person justifying that batch 502TA was not recalled when all the other batches from the same campaign
were rejected. It was declared that there were teleconferences and e-mails with Mylan’s QP but the
company has not managed the archiving of this kind of documentation to support the rational for not
Page 47 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
informing the Competent Authorities. A risk assessment was provided (see annex 4) by Mylan Hungary Ltd
just after the inspection (10 Nov 2017) but it was not performed by the EU QP in place currently (GMP 8.15).
Response to #D22:
1. We have reviewed the Failure Investigation Report (FI/15/021) and observed that for the following reasons
the Batch No. 502TA was released.
1.1 As a part of investigation of Batch No. 501TA all batches manufactured were retested including Batch No.
502TA. Batch 502TA passed at both at Encube and Release lab.
1.2 This Batch No. 502TA was the only batch manufactured in the campaign on 25.07.15 and was not
manufactured in campaign with Batch No. 501TA that was reported to be failing. Prior to manufacturing
of Batch No. 502TA full cleaning cycle was employed which could remove any chance contamination
introduced in the first cycle of wash with filtered water by subsequent sanitization with hot purified water
followed by rinsing with hot purified water.
1.3 This Batch No. 502TA was charged for stability for 24 Months for long-term (30/75 & 25/60) and
accelerated conditions (40/75) (Reference Protocol No. PRO/EE/STB/933). During this study the microbial
quality was tested and all time points, at all conditions and was found to be satisfactory.
These findings were also confirmed by Mylan in their justification report dated 10.11.17.
1. The Technical agreement between Mylan and Encube will be revised to include responsibility assigned to
document the decision making with respect to marketed product during investigations and rationale for
notifying, or not notifying Competent Authorities.
2. The SOP “Market Complaints”, SOP#QA/013 will be revised to include that any critical quality complaints
which has direct impact on product quality as confirmed by the investigation shall be communicated to
concerned MA Holder, who in-turn will inform to the concerned Competent Regulatory Authorities.
Similarly SOP “Out of Specifications (OOS) results in Laboratory”, SOP#QC/029 will be revised to provide
similar instructions for confirmed OOS results related to marketed batches.
3. The Market Complaint SOP will be further revised to include instructions to archive all communications
and supporting documents with/from the Contract Giver/MA Holder/QP along with the Complaint
Investigation report.
Page 48 of 50
MADKAIM PONDA GOA
(Ref. 17IPP148, dated 25/06/2018)
1. Revision of Technical Agreement - 31.12.18

2. Revision of SOP “Market Complaints”, SOP#QA/013 - 14.08.18
3. Revision of SOP “Out of Specifications (OOS) results in Laboratory”, SOP#QC/029 – 30.08.18
Observation #R1: (Remarks)
The validation of the holding time of the bulk product Fusidic acid and betamethasone cream was performed on a
pilot batch size of 3 kg in stainless steel containers. The industrial size is 600 kg and is stored in a 1000 kg storage
tank. As the bulk product is stored under nitrogen gas flushing, the absence of impact of the batch size on this 15
days bulk holding time, it is recommended to integrate in the on-going stability program.
We have made note of this remark and accordingly the SOP “Bulk hold time study” will be revised to include
instructions to charge samples from bulk under hold time study for long term storage condition.
Target Completion Date: Revision of SOP “Bulk Hold Time Study” – 30.08.18
Recommendations #R4: (Remarks)
Points to be considered for Improvement of Site Master File
a) The company declared that there were 8 Bulk Manufacturing Lines and 16 filling and Packing Lines
implemented but the drawings are presenting 7 Manufacturing areas and 9 filling areas. The areas
where there are several manufacturing lines or several filling lines should be pointed out in the next
SMF. The manufacturing lines and filling lines where corticoids are processed should be clearly
mentioned.
b) The gowning/de-gowning procedure to allow personnel flow from production, Storage areas to the
staff canteens (E21 and 93) and Workers Canteen (E23 AND 100 and 108) should be written
c) Some items (e.g. description of the QMS, training, planned preventive maintenance programme for
premises and equipment, recording system and computerized system, handling of complaints and
distribution and interaction with importers in the particular context of the products marketed in Europe
with different contract givers and exporters) are addressed mainly by making reference to SOPs in
place but the brief description should allow the inspector to have an idea of how the particular
processes are implemented by the company.
d) Filtered Water producing and distribution systems are not described though they are used in the pre-
washing operations. Furthermore, changes since the last inspection in the purified water loops and in
the QC facility are not discussed. Updated drawings of all the water systems (filtered, demineralised and
purified) should be provided.
Page 49 of 50

ANSM - Compliance To Preliminary Inspection Report With Annexure

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ENCUBE ETHICALS PVT LTD

MADKAIM PONDA GOA

Observation #D1: (Other)

 Tracking the deviations and failure investigations

 Feedback on Outsourced Activities ( Suppliers / External Contractors)

1.3 Minutes of the Meeting:

2. Corrective and Preventive Action:

Timeline for Completion: 30.08.18

Observation #D2: (Other)

Corrective and Preventive Actions:

Severity Risk Score

Detectability Risk Score

Target Completion Date:

Target Completion Date: Implementation of revised SOP QA/062 – 30/08/18

Rating Mitigation Actions

Corrective and Preventive Actions:

Implementation of revised SOP “Quality Risk Management” QA/062 – 30/08/18

Corrective and Preventive Actions:

Corrective and Preventive Actions:

Target Completion Date : 14.08.18

Corrective and Preventive Actions:

Observation #D3: (Other)

Stability Condition Number of Days Compliance with specification

Product details Impacted Batch Numbers. Number of batches

Corrective Action and Preventive Action:

Communication received from the Supplier on stability data

Target Date for completion: 14.08.18

Observation #D4: (Other)

Corrective Action and Preventive Action:

Timeline for Implementation: 14.08.18

Observation #D5: (Other)

Corrective Action and Preventive Action:

Timeline for Implementation:

Revision of SOP “Annual Product Quality Review” SOP QA/036 - 14.08.18

Observation #D6: (Major)

Response to # D6 a. & b.:

Response to D6 c., d. & e.

Customer Name Types of Agreement Dated Countries

Target completion date:

I. Addendum to APQR/16/112 – completed

II. SOP Annual Product Quality Review, #QA/36 implementation – 14.08.2018

CAPA: Based on the above investigation, following CAPAs are identified.

Target Completion Date:

I. Addendum to APQR/16/112 – completed

CAPA: Based on the above investigation, following CAPAs are identified.

Target Date of Completion:

I. Implementation of revised SOP “Annual Product Quality Review” QA/036 – 14.08.2018

II. Implementation of revised SOP “Microbiological Water Quality” QC/013 – 14.08.2018

Corrective and Preventive Actions:

Target Date for Completion:

I. Addendum to the APQR /16/112 with summary of discussions on suitability of microbiological

Target completion date: For SOP and Format implementation – 14.08.2018

Observation #D7: (Other)

Corrective Action and Preventive Action:

Timeline for Implementation: Completed on 23.12.17

Observation #D8: (Other)

Corrective and Preventive Action:

Observation #D9: (Other)

 SOP "Purified Water Generation and Storage System (Phase- I) ENG/080

Corrective and Preventive Actions:

Corrective Action and Preventive Action:

Observation #D10: (Other)