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Cleaning Qualification

of Tablet Compression
Tools and Press
PARTHIBAN ANBALAGAN

PHARMACEUTICAL MANUFACTURING
CONSULTANT

NATOLI ENGINEERING COMPANY


www.natoli.com
Importance
q  To ensure purity and safety of the product
Residues of APIs and excipients are an
issue in inspections and audits.
Particularly when highly potent APIs are involved

q  Regulatory requirement for the manufacture of


API products
Compliance with GMP regulations

q  Assures the quality of the process through


internal controls and compliance

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GMP guidelines

Cleaning procedures have to be validated to satisfy the following agency


requirements:

q FDA published Guide to Inspections of Validation of Cleaning


Processes – 1993

q PIC/S Guideline to Validation – PI -006-3 (2007)

q ICH Guideline Q7

However, specific guidelines for acceptance criteria or method for


determining the cleanliness of a particular process are not available.

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Cleaning validation program

Cleaning Cleaning Cleaning Continued


VMP process process cleaning
design qualification process
verification

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Validation plan
(Risk-based approach)

q  How clean is clean? q  Sampling location based on


-  Setting limits should have a sound equipment design
scientific rational

q  In-depth risk assessment of the q  Define CPP’s and CQA’s


cleaning process

q  List products manufactured using q  Sampling / monitoring strategy


the same equipment

q  Clearly define product contact q  Dirty Hold Time / Clean Hold Time
surfaces

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A clean tableting press…..or is it?

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Contaminants

q API/Excipient contaminants

q Lubricants

q Cleaning agents

q Microbial contaminants

q Others (e.g. rust)

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Contact and non-contact surfaces

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Critical areas
Punches Dies

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Sophisticated tooling configurations

Source: https://natoli.com/products/punches-and-dies/multi-tip-punches/

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Critical areas
Hopper

Tablet chute

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Critical areas
Feed frame

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Critical areas
Lower punch retainers Upper punch retainers

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Critical areas
Turret surfaces

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Critical areas
Cam tracks

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Sampling/monitoring strategy
ICH Q7

Sampling should include swabbing, rinsing, or alternative methods (e.g.,


direct extraction), as appropriate, to detect both insoluble and soluble
residues. The sampling methods used should be capable of quantitatively
measuring levels of residues remaining on the equipment surfaces after
cleaning.

Equipment cleanliness can be monitored by analytical testing and visual


examination, where feasible. Visual inspection can allow detection of gross
contamination concentrated in small areas that could otherwise go
undetected by sampling and/or analysis.
q  Visual inspection q  Direct surface

q  Swab sampling q  Placebo

q  Rinse sampling

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Visual inspection
Goal: Ensure equipment is clean and in an acceptable condition for
manufacturing

First line of defense against surface non-uniformities

What to look out for?

q  Solid residues

q  Metal discoloration

q  Worn out parts (e.g. corrosion, cracks)

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Visual inspection

Source: http://www.intertest.com/borescopes/-hawkeye-v2

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Analytical methods
Analytical methods should be validated before use in cleaning validation

Suitability of testing methods used should be verified under actual


conditions of use and documented.

Requirements available from USP and IC references

q  ICH Q2A: Text on Validation of Analytical Procedures

q  ICH Q2B: Validation of Analytical methods: Methodology

q  Chapter 1225: “Validation of Compendial Methods; US Pharmacopeia

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Sampling locations

q Functional locations
- Contact surfaces

q Difficult-to-clean
locations

q Sites of product
migration

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Rinse sampling

Using a solvent to contact surfaces of sampled item to


quantitatively remove target residue

Residue measured in collected sample

Useful for sampling inaccessible locations and large areas

Sampling conditions have to be defined:

q  Volume
q  Time
q  Sampling solution

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Swab sampling

Physically swabbing a specified area


of a piece of equipment with a swab
with the intent to extract any collected
residue from that swab for analysis

Ideal for residues not easily removed


with water rinsing

Often used for sampling surfaces of


the tableting press

Source: http://www.biocontrolsys.com/products/view/MVPS
Source: http://www.pharmaceutical-technology.com/contractors/cleanroom

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Swab sampling
Swabbing pattern is critical to ensure
accurate and reproducible collection of
residues

Flip swap over, swab in


perpendicular direction

Swab deposited into the


collection vial

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Communicate with us
Cleaning process design
begins with a tableting
system that minimizes
contamination and facilitates
cleaning

Tableting press / tools can


be designed to reduce
migration of contaminants

Source: https://natoli.com/products/tablet-presses/np-500/

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Questions

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Thank You!

Natoli Engineering Company Inc.


28 Research Park Circle • St. Charles, MO 63304 • 636-926-8900
www.natoli.com • sales@natoli.com

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