Introduction to Medicines

Inspections Technical Updates:

GMP inspections of Active Pharmaceutical Ingrdients and Finished
Pharmaceutical Products (including Reproductive Health Products)

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

USP
BP
Ph. Eur.
Ph. Int.
Other guidelines e.g.
ICH, ISO

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 WHO Prequalification Medicines Inspections Process-1

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;

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 WHO Prequalification Medicines Inspections Process-2

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;

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 WHO Prequalification Medicines Inspections Process-3

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.
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 WHO-PQT Medicines Inspections-1:
Number of GMP Inspections in
2014

39
40
32
35
30 Number of GMP Inspections in 2015
25 (Jan-Jun)
20 Number of Inspections

15
25
10 21
5 20
0 14
API FPP 15
Number of Inspections
10

0
API FPP

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 WHO-PQT Medicines Inspections:

Break-up of API sites Break-up of FPP Sites

18
30 30 18

16
25
14

20 12 11
10
15 FPP Sites
API sites 8

6
10
4 3
5 0
5 4 2
0
0
0 New Routine Requires Special
New Routine Requires Special Follow-up
Follow-up

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 WHO-PQT Medicines Inspections (API):

Final Compliance Status of Inspection Outcome for API

API Sites in 2014 sites inspected in 2014

Immediate
5 11 Compliant
Compliant
8
After 1st
Non-
round of
compliant
CAPA
26 Requires
After 2nd or
Follow-up 28
more round

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 WHO-PQT Medicines Inspections (FPP):

Final Compliance Status of Inspection Outcome for FPP

FPP Sites in 2014 sites inspected in 2014
1 Immediate
3 Compliant
5 1 Compliant

After 1st
Non-
round of
compliant
CAPA
25 Requires
After 2nd
Follow-up
or more
27 round

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 WHO-PQT Medicines Inspections:

Compliance Status of API Compliance Status of FPP

sites during Jan-Jun 2015 sites during Jan-Jun 2015

1
Compliant 5 Compliant
8 10
Non- Non-
compliant compliant
7
Awaits Awaits
2 CAPA CAPA
2

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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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 Product Quality Reviews (PQR)-1

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.

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 Product Quality Reviews (PQR)-2
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.

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 What makes a Good PQR-1

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.

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 What makes a Good PQR-2

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.

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 Computerised Systems Data Integrity-1

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.

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 Computerised Systems Data Integrity-2

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;

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How to establish and run Good Data Management Practices

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.

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Design, Maintenance and Cleaning of Equipment

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.

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

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

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 Concluding Remarks

Understand requirements and expectations

Have good quality metrics and monitoring processes

Keep systems up to date, and perform robust
investigations

Financial incentives dont 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

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