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ACTIVE PHARMACEUTICAL INGREDIENTS COMMITTEE

9.1. Production Systems and Process Risk Assessment

1) Scenario:

The MES system is an IT platform, having several modules for serving end to end manufacturing purposes. For this example, the focus is on the production
execution module, in particular the ‘Synthesis’ process module. Material GxP data is available and approved. Equipment is calibrated, configured under
change control and in a clean status. Raw materials are available and approved. Users are trained and assigned the correct role. The recipes have lifecycle
management guaranteeing change control and are in an approved status.

Sample labels are all created from a prepopulated template.

Remark:

The analytical instruments are not taking into account for this example as this is already covered under the lab system example.
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2) Business process mapping

The business process mapping utilizes the 6 FDA systems and their subsystems

➔ FDA Process: Production control system

3. Proccess
1. Vendor 4. Material 5. Weigh & 6. Material
2. Raw Material Manufacturing A
Qualification Picking / Staging Dispense Charging
Order

8. Material 11. Batch Record 12. Batch

A 7. Processing 9. Packing 13. Logistics
Discharge Review Releases

10. Inprocess 14. QC Laboratory

Controls Analysis
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➔ Sub Process: Processing (Synthesis)

6. Charge Material 7.3/ Heating & 7.4/ Sampling/ 7.5/ Cooling

7.1/ Dissolution 7.2/ Mixing B
Process Steering Testing (Stop reaction)

7.6/ 7.7/ Sampling/ 7.9/ Washing & 8. Material Discharge

B 7.8/ Isolation
Crystallization Testing Drying Process

3) Data (paper/electronic) and system identification

a. System identification: (see section 3 step A)

7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 7.9

Start Dissolution Mixing Heating Sampling/ Cooling Crystallization Sampling/ Isolation Washing &
& Steering Testing (Stop reaction) Testing Drying
GxP electronic electronic electronic paper/ electronic electronic paper/ electronic electronic
Data electronic electronic
System MES MES MES MES MES MES MES MES MES
PCS/DCS PCS/DCS PCS/DCS Analytical PCS/DCS PCS/DCS Sample label PCS/DCS PCS/DCS
Data Historian Data Historian Data Historian Instrument1 Data Historian Data Historian LIMS Data Historian Data Historian
Sample label
LIMS

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Instrument with DI requirements is not further discussed in this example as this is already covered in the lab system example.
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b. Data Identification: (see section 3 step B)

Step 7.1 Dissolution 7.2 Mixing 7.3 Heating 7.4 Sampling/
7.5 Cooling 7.6 7.7 Sampling/ 7.8 Isolation 7.9 Washing &
& Steering Testing(Stop reaction) Crystallization Testing Drying
System 1: PCS/DCS → Transferring and controlling GxP data from the equipment towards the Data historian and MES systems
Speed of addition Agitation speed Temperature* Temperature* Agitation speed Temperature* Temperature
elements
GxP Data

Steering Speed Steering Speed Pressure Pressure Temperature Pressure

Vessel Temp Temperature* Speed Speed Quantity added
Sludge Temp
Pressure
System 2: Data Historian → Recording of the continuous pressure/temperature/speed (trend) data, for permanent storage
Speed of addition Agitation speed Temperature Temperature Agitation speed Temperature Temperature
elements
GxP Data

Steering Speed Steering Speed Pressure Pressure Temperature Pressure

Vessel Temp Temperature Speed Speed Quantity added
Sludge Temp
Pressure
System 3: MES
User ID User ID User ID User ID User ID User ID User ID User ID User ID
Start Date & Time Start Date & Time Start Date & Time Start Date & Time Start Date & Time Start Date & Time Start Date & Time Start Date & Time Start Date & Time
End Date & Time End Date & Time End Date & Time End Date & Time End Date & Time End Date & Time End Date & Time End Date & Time End Date & Time
Equipment ID Equipment ID Equipment ID Equipment ID Equipment ID Equipment ID Equipment ID Equipment ID Loss Equipment ID
Ph Duration* Temperature* Batch Duration Ph Batch on drying Quantity*
Dissolution confr. Agitation speed Pressure Material ID Material ID Visual check result Duration
Speed of addition Steering Speed Speed Storage Condition Storage Condition Duration
elements
GxP Data

Steering Speed Temperature*

Vessel Temp
Sludge Temp
Pressure
System 4: LIMS
Sample ID Sample ID
User ID User ID
elements
GxP Data

Date/Time Date/Time
Quantity / Batch Quantity / Batch
Material ID Material ID
Sample result* Sample result*
System 5: Sample Label
Sample ID Sample ID
User ID User ID
elements
GxP Data

Date/Time Date/Time
Quantity / Batch Quantity / Batch
Material ID Material ID
Storage Condition Storage Condition

c. Highlight electronic GxP data that can be modified/deleted or re-processed after creation. (as indicated by an asterix in above table) (see section
3 step C)
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4) Data and System categorisation

a. Data severity assessment (see section 4.1)

This example will focus on the MES system only. The PCS/DCS, Data Historian, Sample label and LIMS should be handled in a separate assessment.

The MES is used for intermediates and APIs manufacturing.

According to the severity definitions, the API categorisation results in very high severity data.

b. System profiling (see section 4.2, decision tree figure 3)

System 1: PCS/DCS -> cat 6

System 2: Data Historian -> cat 5
System 3: MES -> cat 6
System 4: LIMS -> cat 6
System 5: Sample label -> cat 1
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c. System assessment: (according to checklist 4.3 table 2)

Only the gaps are in below overview.
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5) Risk Assessment (FMEA to calculate the gaps and their current individual Risk Priority Numbers (RPN)) (see section 5)

6) Risk management (see section 6)

The above table shows that 4 of the 5 gaps have a high RPN (Red). Actions have been defined to address these issues immediately.
Additional actions have also been defined to mitigate the other gaps
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In the next table the RPNs are recalculated after implementation of the defined actions.
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To close out the risk in a documented and formal way, an additional column can describe the objective evidence that has been implemented to remediate
the gaps.
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Long term
Checklist ID Step Potential Failure Mode Effect Severity Occurrence Detectability RPN References
Recommended Action

Update the software 1) Change control document

It is possible that data is not saved at the end of the to go to the version upgrade UV software
8 Data capture/entry measurement. The system is asking if data need to be Data can be lost. which is storing 5 1 1 5 2) Qualification report of UV
saved or not. automatically all of the software NameX, version xx
runs. 3)Training records analists 1, 2, x

1) Change control document

Install a full automated
There is no system in place for back-up and storage of connecting UV to network
back-up system with a
14 Backup/restore stand alone systems. (not connected to a network) Data can be lost. 5 1 1 5 2) Qualification report of back-
There is no fixed schedule. defined customized
up/restore sotware NameY, version
interval
xx
NA since short term
1) Change control procedure
17 Backup/restore see question 14 see question 14 inmplementation is 0
version xx
sufficient
Even the new software 1) logbook reference xxx
User levels can be changed. (e.g. an analist doesn't have the audit
23 Functionality No user management audit trail available 5 2 2 20
can receive admin rights) trail function for user
management
1) Change control document
Implement automatic
upgrade UV software
The UV systems doesn't require periodic pasword password rules in
34 Authentication
change.
Possible misabuse of someones password 5 0 1 0 2) Qualification report of UV
system. (or update
software NameX, version xx
software)

Update the software 1) Change control document

to include user level upgrade UV software
Date and time settings (including time zones) are
44 Access security
accessable by all users.
Time of creating data can be adulterated. access on date and 5 0 1 0 2) Qualification report of UV
time settings (including software NameX, version xx
time zone)