AAPS

Academy of Applied
Pharmaceutical Sciences

CLV-3001
CLEANING VALIDATION IN THE
PHARMACEUTICAL INDUSTRY

SESSION 1

Instructor: Kevin Mueller

ASSESSMENTS
Experiment #1 (Week 1) 10%
Experiment #2 (Week 2) 10%
Experiment #3 (Week 3) 10%
Experiment #4 (Week 4) 10%
Experiment #5 (Week 5) 10%
Final Exam 50%
 Course Agenda
➢ Experiments Start Today !!!

Class 1: SOP for Swabbing Coupons for Laboratory Analysis

Class 2: Method Validation - LOD/LOQ Calculation by Linearity
Class 3: Method Validation - LOQ Analysis and Coupon Blank
Class 4: Method Validation - Coupon Blank and Accuracy
Class 5: Investigation of Accuracy Results
Class 6: Final Exam – 50%, Lab book Submission – 50%
 Agenda

1. Introduction
1.1 What is Cleaning Validation in the Pharma Industry?
1.2 Cleaning Validation Program
1.3 Cleaning Validation Evaluation
EXPERIMENT 1 SOP for Swabbing Coupons for Laboratory
Analysis
Introduction
What is Cleaning Validation in the
Pharmaceutical Industry?
What is Cleaning Validation in the
Pharmaceutical Industry?

1. What exactly are we Cleaning?

 What are we Cleaning?

1. Manufacturing Equipment
➢ Surfaces with direct contact to product

2. Non-contact surfaces where product can migrate

➢ Mixing shafts
➢ Seals
➢ Fans
➢ Walls
➢ etc.
 Manufacturing Equipment
a) Granulation

i. “Wet” - granulator ii. “Dry” – roller compactor

Manufacturing Equipment
b) Drying

“Fluid Bed” Dryer

 Manufacturing Equipment
c) Blenders

i. “Bin” blender ii. “V” blender

 Manufacturing Equipment
c) Tableting/Encapsulation

i. “Rotary” Tablet Press ii. Capsule Filling Machine

Manufacturing Equipment
c) Coating

Film Coating Machine

 What is Cleaning Validation in the
Pharmaceutical Industry?

2. What is Validation?

The process used to confirm that the cleaning is suitable for the
intended use of the equipment.
 History of Cleaning Validation in the
Pharmaceutical Industry?
June 1992 – Feb. 1993: The United States vs. Barr Laboratories

➢ Decision: Cleaning Validation is now required

1993: The Fourman and Mullen Article

➢ Criteria for determining acceptance limits

 History of Cleaning Validation in the
Pharmaceutical Industry?

November 2000: International Conference On Harmonisation Of

Technical Requirements For Registration Of Pharmaceuticals For
Human Use

➢ “ICH Harmonised Tripartite Guideline Good Manufacturing

Practice Guide For Active Pharmaceutical Ingredients Q7”
➢ Guidance for GMPs
 History of Cleaning Validation in the
Pharmaceutical Industry?

Sept. 2007: Pharmaceutical Inspection Convention Pharmaceutical

Inspection Co-operation Scheme (PIC/S)

➢ Recommendations on Validation Master Plan Installation And

Operational Qualification Non-sterile Process Validation
Cleaning Validation (PI 006-3), 25 September 2007
➢ Guidance for GMP inspectors
 History of Cleaning Validation in the
Pharmaceutical Industry?
Jan. 2008: Health Products and Food Branch Inspectorate

➢ Guidance Document - Cleaning Validation Guidelines

GUIDE-0028
➢ “This document on Cleaning Validation is intended to address special
considerations and issues pertaining to validation of cleaning procedures for
equipment used in the manufacture of pharmaceutical products,
radiopharmaceuticals, and biological drugs. The document is also intended to
establish inspection consistency and uniformity with respect to equipment
cleaning procedures. Principles incorporated in international guidance have been
taken into account in the preparation of this document. The document is
intended to cover validation of equipment cleaning for the removal of
contaminants associated with previous products, residues of cleaning agents as
well as the control of potential microbial contaminants.”
 What does “Clean” mean?
After cleaning, the manufacturing equipment should be free of:

Typically:
➢ Product (API, excipients, coating)
➢ Product Degradants
➢ Detergent (Cleaning Agents)

Other material that must be considered:

➢ Lubricants, anything else used in the process
➢ Airborne matter
➢ Bacteria, mold
 Purpose of Cleaning Validation

➢ Verification of an effective and consistent cleaning

procedure to acceptable and predetermined limits …
so that regular monitoring is not required or reduced to a
minimum.
 Purpose of Cleaning Validation

➢ In reality …
➢ It is impossible to prove that the equipment is 100%
clean !!!
➢ But it should be practical, achievable, and verifiable

➢ It is possible to:
➢ Prove that the traces of residue left over after
cleaning (mainly API) that are carried over:
➢ Can be detected and quantitated
➢ Are below an acceptable limit
 Why is Cleaning Validation important
in the Pharmaceutical Industry?
1. SISPQ
➢ Avoid cross-contamination residue (API, degradants,
excipients, cleaning agents)
➢ Recalls

2. Required by regulations
➢ GMPs: GUI-0028 (Cleaning Validation Guide)
➢ cGMPs: 211.67 (Equipment Cleaning and Maintenance)
 Why is Cleaning Validation important
in the Pharmaceutical Industry?
3. Equipment is reused
➢ Used for multiple products
Note: this course will NOT focus on
biopharmaceuticals !!!
➢ Biopharmaceuticals pose unique concerns
➢ e.g. cellular debris, bacterial contamination
 Cleaning Validation Program

The overall program (from development to ongoing monitoring,

after product approval) to prove that the cleaning procedure is
effective and reproducible.
 Cleaning Validation Program
Corporate (Marketing, Senior Management)
➢ New Product

R&D Lab R&D Manufacturing

➢ Method Development ➢ Product Development
➢ Method Validation ➢ Compounding, Tableting

QC Lab Manufacturing
➢ Approved products ➢ Approved products
➢ Routine testing ➢ Compounding, Tableting

Any Changes?
 Cleaning Validation Program
R&D Manufacturing

1. Cleaning Process development

➢ Develop cleaning procedure for new product
➢ GUI-0028 “Phase 1”
 Cleaning Validation Program
R&D Manufacturing

2. Cleaning process Qualification

➢ Conduct cleaning procedure verifications according to a
protocol to prove the procedure is effective and
reproducible
➢ Pilot scale equipment then full-scale equipment
➢ Verifications: using data from a validated analytical
method
➢ GUI-0028 “Phase 2”
 Cleaning Validation Program
R&D Lab

1. Develop and validate method for cleaning process

Qualification and Ongoing Monitoring
➢ Must be capable of quantitating low levels of API,
detergent, degradants
➢ GUI-0028 “Phase 2”
 Cleaning Validation Program
R&D Lab

2. Perform cleaning process Qualification (verification) testing

➢ Provides the data to prove that the cleaning procedure
is effective and reproducible
➢ GUI-0028 “Phase 2”
 Cleaning Validation Program
Manufacturing

1. Perform ongoing monitoring

➢ Proves that the cleaning procedure is under control
➢ Cleaning verifications, rinse sample analysis
➢ Review of quality indicators (complaints, deviations,
lab OOS)
➢ Trending
➢ GUI-0028 “Phase 3”
 Cleaning Validation Program
QC Lab

1. Perform testing for ongoing monitoring

➢ Generates data that proves that the cleaning procedure
is under control
➢ GUI-0028 “Phase 3”
 Cleaning Validation Program
Any Changes?

If any changes to:

➢ Raw material suppliers
➢ Different physical properties and impurities
➢ Formulation
➢ Lot size, campaign size
➢ Equipment, processes
➢ Detergent, cleaning SOP

➢ Possible causes: deviation, OOS, complaint, continuous

improvement
 Cleaning Validation Program
Any Changes?

A Change Control is required to:

➢ Document the changes
➢ Assess potential impact to cleaning process
➢ Re-development?
➢ Re-qualification?
 Cleaning Validation Evaluation
➢ “Sample” the equipment to prove the effectiveness of the
cleaning

1. Sampling Techniques:
a) Swabbing/Wiping the Equipment
➢ Sample the surface directly after cleaning and drying
➢ A “swab” (or wipe) is dipped in solvent then a fixed
area of surface is rubbed in order to remove any residue
➢ The residue is then extracted into a known volume of
solvent
 Cleaning Validation Evaluation
What is a swab?
Cleaning Validation Evaluation
Cleaning Validation Evaluation
 Cleaning Validation Evaluation
1. Sampling
Techniques:
b) Coupons

The lab will then swab the coupon to create the sample for analysis.
Cleaning Validation Evaluation
 Cleaning Validation Evaluation
General Swabbing Procedure:

1. Dip swab #1 into solvent.

2. Squeeze out excess solvent.

3. Swab the coupon in a 4. Flip swab over and swab in a

horizontal direction. vertical direction.

https://www.gerbig.com/how-to-swab-cleanroom-surfaces-in-a-reproducible-manner/
 Cleaning Validation Evaluation
General Swabbing Procedure (Continued):

4. Snap the head of the swab off into a vial.

 Cleaning Validation Evaluation
General Swabbing Procedure (Continued):

5. Dip swab #2 into solvent.

6. Squeeze out excess solvent.

7. Swab the coupon in a 8. Flip swab over and swab in a

diagonally upward direction. diagonally downward direction.

https://www.gerbig.com/how-to-swab-cleanroom-surfaces-in-a-reproducible-manner/
 Cleaning Validation Evaluation
General Swabbing Procedure (Continued):

9. Snap the head of swab #2 off into the same vial.

 Cleaning Validation Evaluation
General Swabbing Procedure (Continued):

10. Pipet 10.0 mL of mobile phase into the test tube.

11. Sonicate the solution containing the swabs for 5 minutes.

 Experiment #1
Background:

Nivek Pharmaceuticals plans to develop and manufacture a new

product: Acetaminophen 325 mg Tablets

➢ You have been hired as the first Cleaning Validation Specialist

for the R&D lab
 Experiment #1

➢ Your first job is to write a new SOP (SOP #8.8) for swabbing
coupons for laboratory analysis
 Experiment #1
Main elements of an SOP:

➢ Purpose
➢ Scope – activities (who, what, where, when, why, how) that use
this SOP
➢ Procedure (step-by-step)
➢ Who is responsible for each step
 Experiment #1
Suggested elements of an SOP:

➢ Pictures
➢ Definitions
➢ Attachments
➢ References
➢ Where to go for help
➢ Written by the people doing the work
 Experiment #1
From TWR:

SOPs (per company SOP for SOPs) should include the following:
1. Company Logo
2. Header information on each page which includes:
a) “Standard Operating Procedure”
b) The SOP name
c) Unique SOP identifier number
d) Revision number
e) Department that owns SOP
f) Effective date g) Approval Date
3. Sign off + date by the author (initiator/originator), their manager, and QA
4. Scope (what is covered)
 Experiment #1
SOPs should include the following (Cont’d):
5. Purpose
6. History of changes
7. Definitions
8. Responsibilities
9. List of equipment and materials needed
10. The procedure (using numbered steps, e.g. 1.1, 1.2, 1.3, 2.1, 2.2)
11. References
12. Flow Chart
13. Appendices
14. Copy Number
15. Pagination on each page (page 1 of 5, page 2 of 5, etc.)
Refer to the SOP provided for more information, but remember this is just an
example; SOPs differ between companies!
 Experiment #1
Example of an SOP:

SOP #1.1 – Studying for the CLV3011 Final Exam

Purpose:
This document describes how to study for the Cleaning Validation
(CLV3011) final exam.

Scope:
All students enrolled in the Cleaning Validation course at AAPS
college who want to maximize their final mark.
 Experiment #1
Responsibility:
All CLV3011 students.
 Experiment #1
Procedure:
1. After a maximum of two days after each class, review the
slides and experiment.

2. If any questions arise, e-mail the instructor.

3. After class #5, study all slides and experiments for ½ hour each
day until the final exam.

4. If any questions arise, e-mail the instructor.

 Experiment #1

➢ In your teams, take the next 15 minutes to write a new SOP

(SOP #8.8) for swabbing coupons for laboratory analysis

GOOD LUCK !!!