Strategies on how
to meet PIC/S
GMP Requirements
Overview
How to Improve compliance with the PIC/S GMP
Guide:
● Regular internal audits against PIC/S GMP.
● Regular training of all staff.
● Ensure compliance with the 10 Principles of GMP.
● Being aware of and adapt to:
● PIC/S operations (covered in morning session).
● PIC/S inspection procedures (covered in morning session).
● Recent & upcoming changes to the PIC/S GMP Guide
(covered in morning session).
● Recent areas of focus by PIC/S GMP inspectors.
● Common GMP deficiencies noted by PIC/S.
● Changes to PIC/S inspection procedures. 2
Internal Audits
Audit for compliance with PIC/S GMP Guide:
- Use experienced internal auditors.
- If necessary, use external consultants familiar with PIC/S
GMP Guide requirements.
Utilize aide-memoires from the PIC/S web site.
Prioritize corrective actions using a risk based
approach.
Use CAPA system to correct and close out
deficiencies noted during internal audits.
Establish a budget to enable corrective actions to be
implemented.
3
Staff training
Educate all relevant staff about:
- General requirements of PIC/S GMP Guide.
- Job related requirements for specific employees.
- Regular on-going GMP training.
Include contractors such as contract
cleaners.
Include purchasing staff.
Document staff training in such a manner
that training history for each employee is
readily available.
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The Ten Principles of GMP (www.gmp1st.com)
Principle #1
Writing detailed step-by-step procedures that provide a roadmap for
controlled and consistent performance.
Principle #2
Carefully following written procedures to prevent contamination, mix-
ups and errors.
Principle #3
Promptly and accurately documenting work for compliance and
traceability.
Principle #4
Proving that systems do what they are designed to do by
validation work.
Principle #5
Integrating productivity, product quality, and employee safety into the
design and construction of facilities and equipment. 5
The Ten Principles of GMP (www.gmp1st.com)
Principle #6
Properly maintain facilities and equipment.
Principle #7
Clearly defining, developing and demonstrating job competence.
Principle #8
Protecting products against contamination by making cleanliness a daily
habit.
Principle #9
Building quality into products by systematically controlling our components
and product related processes such as manufacturing, packaging and
labelling, testing, distribution and marketing.
Principle #10
Conducting planned and periodic audits for compliance and performanc6e.
Recent Changes to PIC/S GMP
Product Quality Review (new clause 1.5)
Commenced on 1 January 2006.
Requires annual quality reviews of all products to verify the
consistency of the existing process to highlight trends & to
identify the need for product/process improvements.
Requires reviews of:
- Starting & packing materials, especially from new sources.
- Critical in-process controls and finished product results.
- All batches that failed to meet specifications.
- All significant deviations.
- All changes to processes and analytical methods.
- Marketing Authorisation variations.
- Stability monitoring and any trends.
- Recalls, complaints and returns.
- Qualification status of equipment & utilities.
- Technical agreements.
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Upcoming Changes to PIC/S GMP
On-going stability (new clauses 6.23 – 6.33)
Expected to commence on 1 June 2006 or soon after.
Requires monitoring of stability after marketing, against a
written protocol.
Stability program should be extended to the end of the shelf
life of the product.
One batch per year of each product strength & each primary
packaging type.
Maintain a written summary of the data generated.
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Upcoming Changes to PIC/S GMP
Reference Samples & Retention Samples (new Annex 19)
Expected to commence on 1 June 2006 or soon after.
Purpose and definitions.
Duration of storage.
Size of samples.
Storage conditions.
Written agreements.
What to do in the event of the closure of a manufacturer.
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Upcoming Changes to PIC/S GMP
Sterile Products (changes to Annex 1)
Expected to commence on 1 June 2006 or soon after.
Changes to some particle size limits for clean-room classification
purposes.
Media fill limits specified for the validation of aseptic
processing.
Pre-sterilization bioburden assays required for aseptic processing
and terminal sterilization.
Grade A environment required for:
- Partially stoppered freeze drying vials.
- Area where aluminium caps on aseptically filled vials are crimped.
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Areas of Focus by PIC/S
Recent areas of focus by PIC/S inspectors
Sampling of raw materials (cl. 5.30 & Annex 8, cl. 2):
- 100% sampling of every starting material for ID testing.
Separate, secure storage of printed packaging materials (cl. 3.25, 5.41).
Control of labels (cl. 5.40 to 5.57).
Qualification and validation (Annex 15).
Adequacy of premises (cl. 3.1 to 3.33):
- HVAC and quality of air supplied to processing environments.
- Air-locks.
- Surface finishes.
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Common GMP
Deficiencies
Facilities
Mould evident on roof above mixing tank used to make creams.
Rapid roller door separating the raw material warehouse and the
outside environment was left open for extended periods of time.
Company’s reluctance to produce specifications for air handling
system.
Insufficient lighting in label storage area.
Inadequate segregation of manufacturing of high risk products
(such as penicillins, cephalosporins, antineoplastics, steroids,
hormones) resulting in high risk of cross contamination.
The storage area for rejected materials & products was not
segregated from other storage areas in the warehouse
12
Common GMP
Deficiencies
Facilities
Company’s reluctance to allow auditor to enter locked room.
Layout of facility did not match drawings/plans of facility,
revealing hidden rooms.
Physical address of premises did not match address given to
regulatory authority.
No instructions (such as photos or diagrams) in airlock change
areas advising staff of the procedures to follow (gowning/hand-
washing, etc) prior to entering controlled environments.
Factory located alongside a manufacturer of carbon black.
Annual microbial monitoring of production areas is too
to detect emerging contamination trends.
infrequent
13
Common GMP
Deficiencies
HVAC
Diagrammatic plan of layout of clean areas did not show airflow
patterns or pressure differentials.
- Pressure differential limits not established
The components in the AHU were not specified in a controlled
document, especially for purchasing.
The pressure differential across terminal air filters not monitored
to establish when they needed changing.
- Pressure differential limits not established
Air entry and exhaust both at ceiling level in production rooms.
Microbial monitoring not part of the OQ for HVAC.
HEPA filters for Class A and B rooms not terminally mounted in
the ceiling. 14
Common GMP
Deficiencies
Sampling
There was no procedure how to take QC samples.
Not every container of active starting material sampled for
identification testing.
Raw materials sampled in an open warehouse.
Containers from which samples had been taken for QC testing
were not labelled with a “sampled” label.
Production personnel taking raw material samples had not been
trained or authorised by QC.
Samples of products for QC testing were taken from the middle
of a production run (not representative of entire run).
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Common of GMP Deficiencies
Sampling
Tablets for in-process QC were taken outside the tablet
compression room to carry out the QC checks, with the remaining
tablets returned to the room.
Bulk containers of tablets coming from another supplier are not
sampled for identification testing.
No procedure for cleaning the area used for sampling.
HEPA filters in the sampling area not checked for efficiency.
Sampling of purified water for QC testing did not imitate the
procedure used in production for its use.
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Common GMP
Deficiencies
Manufacturing
Rubber gaskets on manufacturing equipment were perished and
shedding particles of rubber.
Manufacturing services & product transfer lines, including purified
water, were not fully identified with their contents and direction
flow.
Stored equipment not properly protected from contamination.
Mixing tanks and filtration equipment were exposed to the outside
environment during and after their cleaning.
Cleaning status labels not used on equipment of areas to indicate
“uncleaned” and “clean” status.
Plastic transfer hoses were stored coiled up on pegs, with water
residues still present at the lowest part of the coils.
17
Common GMP
Deficiencies
Manufacturing
Labels on empty containers of raw materials not removed or
defaced before the container was discarded or reused.
Containers of materials and bulk products labelled on the removal
lid only.
Lubricant for tablet punches not controlled as a raw material.
There was no list of equipment used in production areas and the
QC laboratory together with their identification numbers.
The actual procedure used to clean a tablet machine was different
to that specified in the cleaning SOP for that machine.
There were several written instructions attached to the walls in
the tablet manufacturing area that had not been authorised or
dated.
Manufacturing equipment not labeled to indicate the name and
batch number of the product being processed. 18
Common GMP
Deficiencies
Packaging
The use of cut labels in packaging of final products creates a significant
risk of labelling mix-ups.
- Poor controls for label design, contract printer (no audit), printing plates, QC
checking on receipt, storage, issue, verification, reconciliation.
Cotton wool dispensers in tablet packaging area not covered.
Packaging line clearance checks cover the packaging line only and not
also the surrounding areas.
Correct operation of the label verifier and label counter not checked
for each operation.
Labels on either side of a splice on roll feed labels on formally
checked.
Poor maintenance of King Tablet Counter:
- Cardboard & adhesive tape used to make temporary modifications & repairs.
- Although labelled as “clean”, foreign tablets were found within the tablet counting
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machine.
Common GMP
Deficiencies
Water Treatment Systems
Purified water was used in the final purification steps of a sterile
API, without any studies to show this water was endotoxin free.
PVC pipes used for Purified Water treatment system.
Microbiological test method for purified water not validated
(consistent zero counts for micro-organisms gave suspicion of no validation)
Direct transfer method, using 1ml sample, used for microbial
testing.
Purified water storage tank not fitted with microbial filter.
UV lamps not monitored for degradation of UV intensity.
The water treatment system contained many dead-legs as well as
PVC pipe-work with crevices at joins.
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Common GMP
Deficiencies
Documentation
No documented procedure for the control of documentation.
Pencil used to record signatures on batch manufacturing records.
No register of signatures and initials.
Deviations from instructions not approved.
No staff organisation chart & no job descriptions.
Product was released by QC despite yield exceeding specified
limit, without further investigation.
No records kept for calibration of measuring equipment, eg.
balances, thermometers, manometers, etc.
Product formulation different to that lodged with regulatory
authority for product approval.
The company had manufactured a product which was outside
scope
the of its manufacturing licence. 21
Common GMP
Deficiencies
Documentation
Instructions/SOPs attached to walls in processing areas had not
been authorised or dated.
No authorised list of approved suppliers, particularly for
purchasing staff.
SOPs held on computer (no hard copies available to staff) which
were slow to retrieve, resulted in SOPs not being used by staff.
No SOP on the procedure to follow in the event of power failure or
other emergency situations.
No SOP on the control of keys used to access restricted areas
such as label store, reject store, narcotics store, etc.
No SOP for the release for supply procedure
No SOP to describe how cleaning mops are to be cleaned,
decontaminated and stored. 22
Common GMP
Deficiencies
Quality Assurance
The supplier qualification program did not include audits of
suppliers of pre-printed packaging materials (labels, cartons, etc)
or companies carrying out the laundering of protective garments.
There was no formal review of batch production records, yields &
reconciliations and all QC test results prior to release for supply
of each batch of product.
Test methods not validated.
Analytical equipment not calibrated for accuracy.
The HPLC method validation for determining potency of various
products did not address all necessary elements, ie. specificity,
accuracy, reproducibility, robustness.
23
Common GMP
Deficiencies
Quality Control
Passwords to access computers in the QC laboratory were not
changed on a regular basis.
No SOP on updating analytical specifications to reflect changes in
Pharmacopoeial requirements.
Retention samples of raw materials were kept for one year past
the expiry date of the product in which they are used.
Retention samples of final products did not comprise the final
batch numbered sales pack.
Only 1mL samples of purified water were tested for microbial
content 24
No procedure for OOS
Common GMP
Deficiencies
Staff & Training
QA Manager reported to Production Manager.
Operator not using method of manufacture lodged with regulatory
authority for product approval.
No authorised plan for ongoing GMP training.
The training did not include an assessment of its effectiveness.
No job descriptions for operators and no training records to
demonstrate that personnel allocated with key responsibilities
have been trained and assessed as competent in their roles and
responsibilities.
Some staff smoking in warehouse (cigarette buds noted).
25
Common GMP
Deficiencies
Staff & Training
Operators in manufacturing areas with hair-covers not properly
covering their hair. Beard covers not worn.
Staff wore jewellery and make up in production & packaging
areas.
Discussion with machine operator revealed questionable
competence.
Contract cleaning staff or purchasing staff were not subjected to
GMP training.
Staff wore cleanroom garments outside the cleanroom and
returned to the same cleanroom without changing in to fresh
garments.
Staff were permitted (& encouraged) to wear their protective
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garments home, and to launder them at home.
PIC/S Inspection Procedures
Recent changes to PIC/S inspection procedures
More unannounced inspections.
More use of specialist inspectors, eg. Microbiologist,
analyst, etc.
Detailed checks of Marketing Authorisations against
product formula and method of manufacture used by
company.
Targeted samples of products taken during
inspections for testing by regulator.
Longer time spent on site.
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Summary
Use regular internal audits to identify those areas
that require attention to comply with the PIC/S GMP
Guide.
- Utilise external consultant(s) if necessary.
Prioritise implementation of corrective actions using a
risk based approach.
Establish a budget to enable appropriate corrective
actions to be implemented.
Keep watch on PIC/S and EMEA web sites for changes
in GMP coming up in the future.
Establish industry networking system to monitor and
report on inspection trends by GMP regulators.
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And Finally…
Thank You
Any Questions?
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