Introduction to Medicines

Inspections Technical Updates:GMP inspections of Active Pharmaceutical Ingrédients and Finished

Pharmaceutical Products (including Reproductive Health Products)

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Vimal Sachdeva, Technical Officer (Inspector)

WHO Prequalification Team (PQT), WHO/HIS/EMP/RHT

20 Avenue Appia, CH - 1211, Geneva 27, Switzerland

Tel.: +41-22-791 13615

Fax: +41-22-791 4730

e-mail: sachdevav@who.int

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This Presentation Includes:

� International Norms, Standards and Guidelines

� WHO Prequalification GMP Inspection Process

� API and FPP manufacturing sites inspected

� Compliance status and inspection outcome

� Top ten observations (including reproductive health product)

� Discussion on commonly found top three observations

� Recommendations

� Concluding remarks

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http://apps.who.int/prequal/assessment_inspect/info_inspection.htm#2

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Prequalification Programme: International norms, standards and guidelines used in inspection activities to ensure wide

applicability

Prequalification Programme: International norms, standards and guidelines used in inspection activities to ensure wide

applicability

USPBP

Ph. Eur.Ph. Int.

Other guidelines e.g. ICH, ISO

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� Manufactures are inspected by WHO-PQT on a routine basis

using an SOP, and based upon a risk based approach;

� As part of pre-approval activity

� Post approval surveillance

� For special cause e.g. serious complaints

� Before inspection, inspector is required to verify objective of

inspection to be carried out;

� Inspector determines what the scope and depth of the

inspection will be based on product dossier assessment

report(s) and findings of previous inspection, if applicable and

other intelligence;

WHO Prequalification Medicines Inspections Process-1

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� WHO-PQT inspections may be conducted purely as WHO-PQT inspections, and may be joint inspection with other authorities (e.g. API cooperation scheme);

� WHO PQ conducts system based inspection but also covers product specific elements (e.g. dossier integrity);

� It is possible to prequalify a product which was not specifically covered during an inspection (e.g. same site, same QMS, same production facilities, based on more recent inspection, and depending on specific product risk);

� Up-to-date Site Master File (SMF);

� Review of variation list, complaint register;

� Preparation of tentative inspection plan;

WHO Prequalification Medicines Inspections Process-2

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� Opening meeting covering introduction and brief

presentation of site

� Inspection to cover an on-site verification of dossier

accuracy and data verification

� Assessment of robustness of Quality System and GMP

compliance, what the company is good at and where

there are gaps and weaknesses

� Observations are based on ‘RED’

� Requirement

� Evidence

� Deficiency

• Review of the company CAPA, and

• Final compliance decision and recommended inspection

re-interval.

WHO Prequalification Medicines Inspections Process-3

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WHO-PQT Medicines Inspections-1:

0

5

10

15

20

25

30

35

40

API FPP

39

32

Number of GMP Inspections in

2014

Number of Inspections

0

5

10

15

20

25

API FPP

21

14

Number of GMP Inspections in 2015

(Jan-Jun)

Number of Inspections

9

WHO-PQT Medicines Inspections:

0

5

10

15

20

25

30

New Routine Requires

Follow-up

Special

5

30

4

0

Break-up of API sites

API sites

0

2

4

6

8

10

12

14

16

18

New Routine Requires

Follow-up

Special

11

18

3

0

Break-up of FPP Sites

FPP Sites

10

WHO-PQT Medicines Inspections (API):

28

11

Inspection Outcome for API

sites inspected in 2014

Immediate

Compliant

After 1st

round of

CAPA

After 2nd or

more round

26

8

5

Final Compliance Status of

API Sites in 2014

Compliant

Non-

compliant

Requires

Follow-up

11

WHO-PQT Medicines Inspections (FPP):

3

27

1

Inspection Outcome for FPP

sites inspected in 2014

Immediate

Compliant

After 1st

round of

CAPA

After 2nd

or more

round

25

5 1

Final Compliance Status of

FPP Sites in 2014

Compliant

Non-

compliant

Requires

Follow-up

12

WHO-PQT Medicines Inspections:

10

2

8

1

Compliance Status of API

sites during Jan-Jun 2015

Compliant

Non-

compliant

Awaits

CAPA

7

2

5

Compliance Status of FPP

sites during Jan-Jun 2015

Compliant

Non-

compliant

Awaits

CAPA

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API Sites: Top 10 Areas for Improvements

1. Design, Maintenance and Cleaning of Equipment

2. Product Quality Review (PQR)

3. Process Validation

4. Computerised Systems – data integrity

5. Change Controls

6. Production and Packaging Operations

7. Design, Maintenance & Cleaning of Production Premises

8. Documentation Control

9. Investigation of out of specification (OOS), Deviations

10.Quality Risk Management

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FPP Sites: Top 10 Areas for Improvements

1. Product Quality Review (PQR)

2. Design, Maintenance and Cleaning of Equipment

3. Computerised Systems – data Integrity

4. Contamination & Cross Contamination (physical/chemical)

5. Investigations of Deviations, out of specification (OOS)

6. Contamination & Cross Contamination (microbial)

7. Change Controls

8. Design & Maintenance of HVAC system

9. Design, Maintenance & Cleaning of Production Premises

10.Documentation Control

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RH (API & FPP sites): Top 10 Areas for Improvements

1. Quality Management – Product Quality Review

2. Contamination & Cross Contamination

3. Computerised Systems – data integrity

4. Duties of key personnel

5. Hygiene and Clothing

6. Supplier and Contractor selection/monitoring/audit

7. Warehousing and Distribution activities (temp. control & monitoring)

8. Documentation Control (general, manufacturing & procedures)

9. Quality Risk Management

10. Management Review

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� The quantity of data being collected was not adequately

and critically reviewed;

� The selection of those criteria to be trended was not well

explained and linked to product and process risk. There

was no risk assessment documented to justify critical in

process parameters

o There was no appropriate review and trending of

the API quality attributes, excipients, and packaging

components;

o No robust tool used to assess any trend and or

variation e.g. Trends were not adequately evaluated

using appropriate statistical means.

Product Quality Reviews (PQR)-1

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o Stability data were not trended for any adverse

trends;

o No mentioning of media simulation studies;

o No mentioning of use of contractual services

(calibration, qualification, requalification);

o No comment was made on post/marketing;

commitments for new dossiers and variation to the

dossiers;

o Environmental monitoring of production areas and

purified water were not included as part of PQR

review for all products inspected.

Product Quality Reviews (PQR)-2

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� The SOP should include clear objectives of PQR or regular

reviews. The objective is not to look into whether batches

manufactured during a year were within specification or not,

but to verify consistency of the process and identify where

there is a need for improvement;

� Wisely use data collected for review. It is not for the

inspectors, but for you and your company to improve the

processes;

� It is important to identify trends, interpret data and draw

conclusions from the data.

What makes a Good PQR-1

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� Control Charts (Shewhart control charts enables

manufacturers to determine upper and lower control limits,

and identify trend & shift in mean etc) and,

� Process Capability Study (to determine whether a process

is stable and capable, Cp is used to evaluate variation of

the process whereas CpK is used to evaluate centering of

process) are recommended to verify process variability,

where applicable;

� Conclusion should be based on the critical review of data,

and should propose recommendations for further

improvements.

What makes a Good PQR-2

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� Inadequate number of software licences for the number of

workstations;

� Sharing of common password – not attributable

� Trial system suitability was not included in the sample set,

not mentioning in analytical report and chromatogram not

filed;

� Procedure not in place giving details of how manual

integration be performed and control over such events;

� Audit trail on HPLC systems were disabled without

justification;

� Audit trials were not reviewed as part of CDS data.

Computerised Systems – Data Integrity-1

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� It was noted that during testing of related substances that

there was shift in the retention time which necessitated re-

designation of integration events. Whilst in this case the

correction was scientifically justified and could be tracked

in the software audit trial, the changes were not discussed

and reported in the relevant test record;

� Allocation of access rights presented potential conflict of

interest. Laboratory supervisor had system administrator

rights to the CDS software;

� No procedure and practice in place for scientifically sound,

timely back-up and archive of the e-data generated by

Empower software;

Computerised Systems – Data Integrity-2

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� Understand and learn our expectations

� WHO draft Guidance on Good Data and Record Management

Practices, and other guidelines (e.g. MHRA);

� Set realistic and achievable expectations

� Monitor process capabilities

� Provide necessary resources

� Reduce pressure and possible source of error

� Adoption of Quality Culture within the company;

� Design a system to improve detection of errors/changes;

� Training of personnel on computerised systems and review of

electronic data.

How to establish and run Good Data Management Practices

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� There was no de-duster and metal detector for compression machines;� The scoops for transferring granule to the vibratory sieve were in a very

poor condition and had uncleanable recesses in the welding;� The blender seal was in a poor condition and staff had been using

sealing tape to contain leakage;� Some punches were stored unprotected in a drawer due to inadequate

locations in frame. There was therefore a risk that tips could crash and it was noted that some punches appeared to have attrition damage;

� Not all dust collector extracts could be properly adjusted. There was a build-up of residues and the some of the flaps were jammed.

� There was no enough water to perform cleaning of equipment� No non-return valves were installed in nitrogen supply pipelines to

prevent backflow.� There was no integrity test (such as spark test) performed for glass-

lined reactors as part of the initial equipment qualification and preventive maintenance program.

Design, Maintenance and Cleaning of Equipment

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� Aim to have closed processes & equipment whenever appropriate.

� Always aim to have equipment which minimizes risk of errors, permit effective cleaning and maintenance.

� Always ensure parts of the production equipment that come into contact with product are not reactive, additive or absorptive.

� Equipment, especially if non-dedicated should be cleaned according to validated cleaning procedures.

� Remember, one of the most important processes in a pharmaceutical plant is often assigned to the lowest paid staff…. CLEANING

Reduce Risks of Cross-contamination by better Design of Processes, Maintenance & Cleaning of Equipment

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� Understand requirements and expectations

� Have good quality metrics and monitoring processes

� Keep systems up to date, and perform robust investigations

� Financial incentives don’t reduce errors. Employees must be passionate about eliminating mistakes

� Have pride in whatever work assigned - small or big

� Celebrate success of not doing things twice

Concluding Remarks

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