soft gelatin &wets audit report

Level 2 Audit Report

GMS Quality - Audit Report

03/09

for

GSK QMS Audit of

Soft Gelatin& Wets Value stream

Date of Inspection:23-26 March 2009

Auditee Details Lead Auditor Details

Site

Location

GlaxoSmithKline Egypt

P.O. Box 3001-El Salam

City 11491 Cairo – Egypt

Lead

Auditor

Helmy Ismail

Compliance auditor

E-mail: [email protected]

Tel : +2 02 22777126

Main

Contact

Dr:Elhamy Kamal

Report Distribution

Complete Report

Eng.Adel Darwish Site director

Dr:Hanan Lamei Head of Quality

Dr: Eman Hegazy Compliance manager

Dr:Elhamy KamalWets &Cephs SLT

Eng. Khaled Gheith Engineering SLT

Dr.Sahar Awwad Technical senior manager & OE Champion

Mrs.Aya Dwidar Head of HR &Security

Dr. Abdelmoneim A

AbuYoussef

Solid SLT

1

Executive Audit Report Summary

Conclusion

1.1 Summary and Comments

The QMS implementation system in Soft gelatin department is in place and in use, the manufacturing

and packaging areas look tidy with good housekeeping. Three risks identified in the risk log {(SG04)

Liability of cross contamination in SG area, (SG 05) Medicine contamination and (SG08) Failure of the

pressure difference in SG area were disclosed and managed.

-The L4 CAPAs for Ukraine and MOH were closed effectively on time. The previous L2 audit findings

related to the above mentioned departments were reviewed and closed effectively.

During this audit there were 7 finding 3 of them were considered to be major.

The major findings related to The Facility operation, Air quality and Calibration.

The risk associated with the major findings as follows:

1-Deterioration in utilities maintenance that increases the possibilities of particulate cross contamination.

Inadequate physical contamination control due to presence of particulate shedding material in the

manufacturing area. Incomplete check of the cleaning record to ensure the effectiveness of the

cleaning procedure.

2- Lack of assurance that air of correct particulate quality is supplied to SG manufacturing area to

protect product from environmental contamination.

3- There is no document highlighting the product quality impact in case of instrument calibration failure

or instrument defect.

In conclusion:

According to the L2 local procedure and the criticality of area:

-The overall risk of soft Gelatin department is a moderate risk and it is recommended to keep the audit

frequency to be every 9 months.

-The overall risk of wets area is a high risk and it is recommended keeping the audit frequency to be

every 6 months to ensure the complete and effective closure of the raised risk.

1.2 Recommendation of Audit Frequency

Current Audit Frequency:

6 months

Decrease to

Remain

Audit Frequency:

9 months for SG

6 months for wets

Background information

2.1 Pharmaceutical Product Dosage Forms

2

Sterile Products Inhaled Products Other Dosage Form √

2.2 Markets Supplied

US √ EU JP AU CN Other:

2.3 Date of Last Audit

August 2008

* * * * * End of Executive Summary * * * * *

3

Audit Background

Introduction:

GSK Cairo is aiming to implement Quality Management System as

standard for internal audit level 2 for all systems.

The previous L2 audit conducted on August 08 , Based on the overall

risk assessment of the auditee profile . The Soft gelatin was considered

as a moderate risk and the Wets department was considered as a high

risk ,according to the number of rejected batches ,rework due to quality

issues ,numbers of complaints received during 2008 and the number of

major findings of the previous audit levels.

Objective:

The audit was to evaluate the level of compliance of systems compliance against QMS policies in respect to risk assessments, identified gaps and areas for improvement highlighted through the last GQA as well as the last L2 audit .

Scope:

The audit primarily focused on the activities and systems involved in the Soft gelatin, wets and semisolid including manufacturing and packaging at Cairo site facility. The audit also assessed the identification and management of risk and the effectiveness of total disclosure of the previous audit findings.

Audit team:

Salwa Tolba Compliance auditor

Auditee:

Dr:Mohab Elmasry Soft gelatin section head

Dr: Ahmed Samir Wets departmental head

Dr: Dalia Samy Senior validation coordinator

Dr:Ahmed Abdel Raouf Validation section head

4

Classification of Audit Findings

5

Audit Findings Classifications

Dependent on the nature of the findings and the risk associated with any non-

compliance the following classifications should be used:

Classification Description of Classification Action to be Taken

Critical Deficiencies which have a high

probability of causing adverse

consequences to the patient or

consumer; may result in

significant deviations in the safety,

identity, strength or purity of the

product; or are a combination of

major deficiencies which indicates

a critical system failure.

The auditor is to define which

operations, or supply to GSK,

must stop until corrective and

preventive actions (CAPAs) are

implemented.

Major Deficiencies which could

potentially cause adverse

consequences to the patient or

consumer if left un-addressed,

could be considered indicative of

poor control, could be considered

major deviations by regulatory

authorities, or a combination of

minor deficiencies which indicate

a major systems failure, or a

number of repetitive minor

deficiencies.

CAPAs are to be agreed although

operations can proceed.

Minor A deficiency which cannot be

classified as critical or major.

CAPAs are to be agreed although

operations can proceed.

Note A deficiency, which is not related

to GMP or regulatory

conformance requirements e.g.

Environmental Health and Safety,

but does warrant attention by the

auditee.

CAPAs do not need to be agreed

with the lead auditor.

6

Good

Practice

Demonstration of exemplary

achievement of compliance, or

setting a precedent within the

current industry standard.

7

Categorisation of Audit Findings

Audit Findings Classifications

Dependent on the nature of the findings and the risk associated with any non-

compliance the following categorisations should be used:

Disclosed and

Managed

• The scope of the risk has been defined.

• The root cause(s) have been identified.

• A solution specification is in place.

• Remedial, corrective and preventive actions have been

identified.

• The actions are assessed as effective to address the root

cause i.e. the auditor believes that the plans will reduce the

risk.

• Actions have owners and target dates.

• The status of the plan is monitored routinely.

• Actions will reduce the risk in an acceptable timeframe and

are progressing to schedule.

• There is a process to assess the impact of any changes to

the plan (including date extensions) and approve those

changes.

Disclosed and

Incompletely

Managed

• The scope of the risk has not been defined.

• The root cause(s) have not been identified.

• A solution specification is not in place.

• Remedial, corrective and preventive actions have not been

identified.

• The actions are not assessed as effective to address the root

cause i.e. the auditor believes that the plans will reduce the

risk.

• Actions do not have owners and target dates.

• The status of the plan is not monitored routinely.

• Actions will not reduce the risk in an acceptable timeframe

and are not progressing to schedule.

• There is no process to assess the impact of any changes to

the plan (including date extensions) and approve those

changes.

8

Audit Identified Issues identified during the audit.

9

Findings

Audited System: Management

The self inspection GQP No. (1211) was reviewed. During this audit the self

inspection reports dated on 11/2/2009 &25/1/2009 for SG and wets were

reviewed.

FindingClassification: Audit identified-

Note

Reference:

[ GQP1202]

Risk management :

-During 2008 there were 13 complaints related to oily and leaked capsules and one rework for re-

insertion of Supravit capsule B.N 080858A due to capsule leakage. The risk log of S.G department

has a green risk No.SG 02 dated on 8 July 2007,it has been described as (Leakage of S.G

capsules after quality release) with risk index value 4.

By discussion with the area owner it was noticed that those complaints related to batches were

manufactured during 2006 and many CCRs were raised to solve this problem .

-There is no document for risk revaluation and monitoring of the after action review to ensure that

the previously taken corrective actions are effectively implemented and they are sufficient to

prevent the recurrence of this deviation in the future and reassess the likelihood value of this risk .

Response of Auditee

CAPA Details Due Date: [Date for latest completion of all actions required by this CAPA]

[Enter key aspects of CAPA with sufficient detail to establish that all aspects of the observations

will be addressed sufficiently to achieve compliance].

FindingClassification: Audit identified-

Minor

Reference:

GQP1211

10

Self inspection :

In complete CAPA management system of Level one audit .There are many overdue CAPA s

and delay in the target completion dates

-The CAPA identified in the level 1 audit doesn’t perform in its due date. There was a delay in

IQ&OQ of balance of soft gelatine department. Many work orders were initiated related to epoxy

work, fixation of backstop in soft gelatin but no further progress has been done.

-The self inspection of soft gelatin& wets department mentioned that the calibration of equipment

were reviewed and confirmed while there were many defected devices have no label indicated its

status ( out of use and not calibrated) as recommended inQD574/08.the defected device such as

(the defected temperature indicator of the Diessel tank , the dial thermometer of Diessel holding

tank 3000 l in wets area )& (Stirrer RPM indicator and rotational speed indicator in S.G

department)without label (not calibrated ) .

-In self inspection report of wets area there was an observation related to creation of Arabic

version of SOP without mentioning the SOP number and the target completion date which

required for effective follow up and CAPA closure.

Response of Auditee




Audited System: Personnel

This clause was not covered during this audit.

Audited System: Documentation

GQP3201 Was reviewed

11

Finding Classification: Audit identified- Minor Reference:

[ GQP321

Documents and Data :life –cycle management.

-The log book of IWKA drops packaging machine ( ), had detached papers of APP II of SOP No.

GP 002/01.the log book was not identified by page numerical numbers. Some records missed the

machine name.

-This machine used in packaging of Amproxol drops that exported to EU market. The Machine

data and documentations must comply with the packaging process requirements and provide the

correct information that could be used during problem investigation.

- Incomplete distribution system of electronic SOP was noticed for engineering procedures. The

SOPs hard copies are distributed and controlled by quality department while the electronic

versions were archived in connectware named GMS sops that had an obsolete version of SOP

Number EP 317/07.

Recommendation :

-Effective documentation system must be implemented for drops packaging machine.

-The electronic versions of SOP s must be reviewed and ensure that the current procedures are

available to be used by all authorized users

Response of Auditee




Audited System: Facilities

The following systems were reviewed during this audit.

Facility design (GQP 4201), Air quality (GQP 4204), Compressed gas systems (GQP4206),

Vacuum system (GQP 4210), Facility operation (GQP4301), Calibration (GQP 4304) and

Monitoring and review of environmental controls and utilities environmental (GQP 4401).

-The L4 CAPA for MOH and Ukraine audits were reviewed and closed on time. The air lock

alarms have been installed in soft gelatine and wets area. The status of manufacturing

processes was identified & all rooms had their unique identification numbers.

-The CAPA related to finding number FND-L3-0096034 of L3 GQA audit 2008 was reviewed

and it is ongoing and planned to complete on time to dedicate a storage area for bulk soft

gelatine capsules.

-The CAPA for the previous level two audit were reviewed

12

Finding Classification: Audit identified- Minor Reference:

[ GQP321

Documents and Data :life –cycle management.

-The log book of IWKA drops packaging machine ( ), had detached papers of APP II of SOP No.

GP 002/01.the log book was not identified by page numerical numbers. Some records missed the

machine name.

-This machine used in packaging of Amproxol drops that exported to EU market. The Machine

data and documentations must comply with the packaging process requirements and provide the

correct information that could be used during problem investigation.

- Incomplete distribution system of electronic SOP was noticed for engineering procedures. The

SOPs hard copies are distributed and controlled by quality department while the electronic

versions were archived in connectware named GMS sops that had an obsolete version of SOP

Number EP 317/07.

Recommendation :

-Effective documentation system must be implemented for drops packaging machine.

-The electronic versions of SOP s must be reviewed and ensure that the current procedures are

available to be used by all authorized users

Response of Auditee




Audited System: Facilities


Facility design (GQP 4201), Air quality (GQP 4204), Compressed gas systems (GQP4206),

Vacuum system (GQP 4210), Facility operation (GQP4301), Calibration (GQP 4304) and

Monitoring and review of environmental controls and utilities environmental (GQP 4401).

-The L4 CAPA for MOH and Ukraine audits were reviewed and closed on time. The air lock

alarms have been installed in soft gelatine and wets area. The status of manufacturing

processes was identified & all rooms had their unique identification numbers.

-The CAPA related to finding number FND-L3-0096034 of L3 GQA audit 2008 was reviewed

and it is ongoing and planned to complete on time to dedicate a storage area for bulk soft

gelatine capsules.

-The CAPA for the previous level two audit were reviewed

13

• The risk of finding was described as (lack of assurance that product

quality is not compromised due to the required arrangement for

facilities) ,the CAPA was effectively closed . The batch records of Haemoton

& Supravit capsules have been updated to include the microscope for the

IPC test that has the plant No.1268.

• The risk of finding has been described as (Risk of possibility of product

contamination due to unsuitability of level of control on operations )In

the Soft Gelatin department all the cleaning equipment, holding containers

were labeled and had its identification label.

• The risk of finding has been described as (Risk of lack of assurance that

existing controls establish a base line of local environmental isolate )

the CAPA was closed ,the identification reports of non sterile areas and one

identification report for atypical result of iron oxide raw material were

reviewed and found satisfactory & comply with the GQP 4401 and CAP 044.

-The cleaning records of soft gelatine department were revised refer to SOPs No SG

103/04,SG 112/04,SG 104/08 and SG 105/04 and were found satisfactory , during this audit

the soft gelatin department had a good house keeping and looked clean and tidy .

-During this audit the compressed gases monitoring results for soft gelatine and wets

departments were reviewed refer to SOP EP350/01&QD 583/05and found comply with the

GQP 4206.

-The microbiological environmental monitoring of wets and soft gelatine results were reviewed

.refer to SOP QD 583/05 and found satisfactory.

-The vacuum system for soft gelatine and wets area are dedicated and not shared.The risk

number SG05 in the risk log (Medicine contamination in case of electricity cut off was

disclosed and managed by installing double non return valve and water trap for the medicine

mixing vessel.

The previous L2 audit finding related to the air quality of wets area was closed and the

particulate air count for 0.5 micron were taken and the records dated on 7/5/2008 were

reviewed and found comply with the GQP4204.by reviewing the Sop EP 317/08 the

particulate count for 0.5 micron or greater was performed .

FindingClassification: Audit identified-Major Reference: GQP4301

14

Facility Operation :

I-Wets manufacturing area :

Deterioration in utilities maintenance that increases the possibilities of particulate cross

contamination.

The following observations were detected due to delay in implementation of the planned maintenance

shout down.

-The wall covings of syrup & topical preparation rooms had cracks and need repairing. The

ceiling and partitions of syrup preparation room need repainting

-The stopbacks bars in the topical preparation room were damaged.

-The exit HVAC grill of syrup preparation room wasn’t clean and had a red stain dust.

- Water leakage from the sanitary valve of the topical wash bay purified water loop.

-Damage of temperature control unit in the topical wash bay.

- Water leakage from TE3 steam line jacket.

-The Syrup purified water loop has an attached long welded hose.

Inadequate physical contamination control due to presence of particulate shedding material in the

manufacturing area.

-In topical preparation room there were carton boxes (Secondary pack of Supocire item No. W

01600.00 B.No. 2008251004 )that used in preparation of Abimol suppositories

-Inside the Sarong suppositories filling machine there was a sheet of paper used as lighting lab

cover to reduce the light reflection.

15

Incomplete check of the cleaning record to ensure the effectiveness of the cleaning

procedure.

- The cleaning record of holding tank was not including the cleaning after the previous

manufactured product ( Septrin suspension B.N 091050 ) prepared on 23 March 2009 as

recommended in SOP WP 101/08 cleaning is carried out after each prepration.

-The APP I of SOP (WP 101/08) does not include the batch number of the last manufactured

product to enhance checking of the cleaning procedure and follow up.

Recording of product batch number will help in checking of cleaning record to know if the

manufactured product is the last batch of campaign so the cleaning method mentioned in SOP

(WP101/08) must be applied after completion of campaign.

- In the topical preparation room, the Melter hadn’t label indicate that was under cleaning after

preparation of Dermovate cream B.N. 091100. And the cleaning records of TE3 were not checked

since 2/3/2009.The plastic baskets of manufactured bulk topical tubes were un- cleaned.

II-Soft Gelatin Department :

-The colouring room wall had a crack and need repainting .There are many cracks in the gelatin

stirrer protective D -shaped wall.

-The Floor epoxy of CAM 2 room had a crack and need repairing.

-The hopper plastic cover of CAM 2 (1050) was broken.

-Deterioration of the MK5 gelatin lines thermal isolation.

-Due to the extension project of the soft gelatine department. In the inspection room there was a

wooden partition placed to separate this room from the working area .

Most of the above observations in soft gelatin department were identified in the L1 audit but there

is no further action has been taken.

Response of Auditee




16

FindingClassification: Audit identified-Major Reference:

[GQP4204]

Air quality :

Lack of assurance that air of the correct particulate quality is supplied to areas to

protect product from environmental contamination).

The particle count of 0.5 micron or greater wasn’t performed in soft gelatin manufacturing area as

recommended in GQP4204. the SOP EP 317/08 mentioned monitoring of particle size 5 micron

only.

Recommendation :

-Perform the non viable particulate count of 0.5 micron in soft gelatine manufacturing department

refer to the GQP 4204 to ensure the correct air quality is supplied to the manufacturing areas

where the material and products are handled.

Response of Auditee




17

Finding Classification: Audit identified-Minor Reference:

[ GQP4401]

Environmental controls and utilities.

Incomplete check of temperature &Relative humidity in the encapsulation room .There is no

accurate device for environmental monitoring in the encapsulation room for continuous

checking.

a -The batch record of Supravit capsule bulk page No.22/32 has an instruction to check the

Temperature and Relative humidity (RH) of the drying tunnels: (the limit for RH is 20% ± 5 and

{15-25} for temperature).

-During the encapsulation of Haemoton B.No. 0090917 the Batch record signed checked while the

reading of temperature /RH monitoring device was 18.18 c &96.47% accordingly) .The Temp.RH

reader had an inaccurate reading while it has a valid calibration date till 23/4/2009.

-The operators signed the batch records based on the control and monitoring of Soft gealtin

manufacturing area that is carried out by Building manufacturing system (BMS ) using Stiva

monitoring device placed in the second floor which is not accessibleto the operators .By printing

the actual temp.&RH for the encapsulation room from the (BMS )it was for RH: 17% and Temp :

23.5

b-The SOP EP 317/08 does not include the environmental air condition limit of the drying tunnels.

It has the air condition limit for the encapsulation room NMT 24 C and NMT 50% relative humidity.

The air condition monitoring and control of drying tunnels is essential and had a direct impact on

product quality and affects on the capsules drying process .

Recommendation :

-Continuous accurate monitoring system must be placed at the manufacturing area to be

accessible to the operator .The signature on the batch record must be based on actual

temperature checking.

Response of Auditee




18

Finding Classification: Audit identified-Major Reference:

[ GQP4304]

Calibration :

There is no document highlighting the product quality impact in case of an instruments

calibration failure or instrument defect. The Notification of SOP No. GP 321/08 does not assess

the risk associated with instrument defect.

Absence of documented risk assessment of defected machines represents a risk from lack of assurance that the

equipment used in the manufacturing area are not source of significant risk to product.

By reviewing the Calibration list of Soft gelatin and wets area ,there were many examples of defected

spare parts as follows:

- The dial thermometer of Diessel suspension tank Ref.No. 154/T1 & Product temperature

indicator of Dissel preparation tank Reference Number 1166/T1& 183/T1 were defected and

need to be replaced since August 2006 and no further action has been taken to repair the

defected device or remove from the calibration list .the above devices are classified in SOP

GP 231/06 as’’ Quality critical devices’’.

- Rotational speed indicator Of MK5 Reference No.268/RPM1 & Stirrer RPM indicators of mixing

vessel Ref No. 260/RPM1 were defected since 6/4/2007. those devices are classified as ( EHS

& Business )

- Refer to the SOP GP 231/06 both quality critical and EHS/Business critical need planned and

regular calibration while their related notification reports were not include the target

replacement date or its impact on the product quality.

- There is an SOP No. QD 574/08 (action to be taken in case of exceeding calibration due date

or failed calibration requirement) effective on October 2008 in place but it is not for the device

has been defected before .the in use of this sop will be reviewed in next audit.

- The RH &Temp chart recorder (plant number 001266) had a valid calibration date till 23/4/2009

while its reading had an inaccurate values (RH: 96.47) & (Temp.:18.8 C). So the instrument is

in use while it exceeds its permitted limits.

Recommendation :

-Comply with the GQMP 4002 requirement in respect to perform a quality impact assessment for all

items on the maintenance list to determine its impact on the product quality.

- Perform a detailed risk assessment in case of machine or equipment calibration failure to ensure

the risk is fully understand and appropriate mitigation plan is implemented.

-Any equipment not performing as its permitted limit must be identified as out of use.

Response of Auditee


19

[Enter key aspects of CAPA with sufficient detail to establish that all aspects of the observations will be

addressed sufficiently to achieve compliance].

20

Audited System: Material and Product Control

The following systems were reviewed during this audit. Material and product labelling (GQP

5203), Storage and handling of materials and products (GQP5209) and Rejects and disposals

(GQP 5211)

-The CAPA related to L4 of Ukraine was closed and the batch record of (Vitamin capsule two

colours) has an effective date 25/3/09 (item code AM 310 /01)has been updated to include the

total sample size for work samples in IPC. And the Kg of manufactured bulk capsule to be

translated into number of finished product packs in the batch record of packaging.

Finding Classification: Audit identified -MinorReference:

[ GQP5211]

Reject and disposals:

-In soft gelatine department :

-In batch reviewing room. There were collection bags having blisters of capsules eg. Vitamax plus

capsule 090709 A. Those blisters having label of operator name who perform the leakage test for

rechecking .Those blistered were place in collection bags without labelling until rejection.

During the audit the remedial action has been taken and the blisters placed in plastic basket

labelled by rejected red label.

-The rejected product must be stored in secured controlled place with label to ensure it will not

enter in the manufacturing operation or misused.

Recommendation :

Comply with GQP 5211 for identification and segregation of rejected materials

Response of Auditee




Audited System: Process Assurance


21

Printed packaging components verification and control (GQP 6103), Area line clearance (GQP

4204) and Deviation and investigation handling (6302).

The CAPA related the previous audit l2 finding (possibility of product contamination due to

improper implementation of Area line clearance), The line clearance system was reviewed

during packaging of Haemoton capsules No.090910A and Septrin suspension B.N. 091050 A

and the batch records found satisfactory. the CAPA related to the evaluation of cleaning agent

impacts ,it was included in the cleaning validation master plan document No. COCLEAN /08.

The CAPA related to the yield calculation was reviewed, and there was a visual yield trend for

wets products. This trend should be considered in the periodic product review.

During this audit the mitigation plan for risk has been described as (Product mix up due to

mix up within received printed packaging materials or during packaging operations

that led to single product/single market recall) was reviewed the CAM 2 (1050) barcode

reader was checked and found satisfactory for Haemoton capsule box (50GX AB6001/16 )and Leaflet

(40AB6001/06) .Visiotec Camera for missing capsules was checked and found effectively working.

While the carton box Barcode reader is not working for Vitamax carton box due to the quality of material

or supplier performance issue. Kaizen was conducted to follow the action plan, the progress in the

action plan will be revised in the next audit.

Audited System: Laboratories Controls


Audited System: Incident Management


22

Next Steps

• Auditee to submit to lead auditor within 20 working days of

receipt of the audit report details of proposed corrective actions,

including timeframes for the full implementation of each of the

corrective actions. Electronic communication is preferred; hard copy

is not necessary if an electronic copy can be sent.

• Lead auditor to review corrective and preventive action (CAPA)

proposals and send comments to the auditee.

• Auditee (only if agreed with the auditor) to prepare a report of

progress made with actions, at agreed time intervals.

If you have any questions regarding this report or require

clarification on any issues, please feel free to contact me.

We look forward to receiving your CAPA in due course.

Thank you for your co-operation.

Signed and approved……………………….…….Dated:

…………………………

23