Cleaning Verification / Validation of

Pharmaceutical Manufacturing
Equipment From a Laboratory
Perspective
Adam W. Grobin
Southern California
Pharmaceutical Discussion Group
Sept. 19, 2013

Disclaimer
Any views or opinions expressed or presented are
solely those of the author and do not necessarily
represent those of any employer past or present.

The
Manufacturing
Floor

Macro Scale
Team Activity
Highly Proceduralized
Specific Roles / Compartmentalization

The Laboratory

Micro / Molecular Scale

Individual Activity
Highly Proceduralized
Roles highly flexible

1. clean
a : free from dirt or pollution <changed
to clean clothes><clean solar energy>
b : free from contamination or disease <a clean wound>
c : free or RELATIVELY FREE from
radioactivity <a clean atomic explosion>

2. clean
a : UNADULTERATED, PURE <the clean thrill of one's first flight>
b of a precious stone : having no interior flaws visible
c : free from growth that hinders tillage <clean farmland>

Good Manufacturing Practices

cGMPs include the prevention of possible
contamination and cross-contamination of
pharmaceutical starting materials and products.

Dietary Supplements / Drugs / Devices

PART 111--CURRENT GOOD MANUFACTURING PRACTICE IN
MANUFACTURING, PACKAGING, LABELING, OR HOLDING
OPERATIONS FOR DIETARY SUPPLEMENTS
111.27(d) You must maintain, clean, and sanitize, as necessary, all equipment,

utensils, and any other contact surfaces used to manufacture, package, label, or hold
components or dietary supplements

PART 211 -- CURRENT GOOD MANUFACTURING PRACTICE

FOR FINISHED PHARMACEUTICALS
211.67 Equipment cleaning and maintenance
PART 820QUALITY SYSTEM REGULATION
820.70(e) Contamination control. Each manufacturer shall establish and
maintain procedures to prevent contamination of equipment or product by
substances that could reasonably be expected to have an adverse effect on product
quality.

Seems Simple, so why

1988, major experience with cross contamination traceable
to inadequate cleaning and cleaning validation.
An API supplier of Cholestyramine Resin recall the product,
due to contamination with low levels of intermediates and
degradants from the production of agricultural pesticides.
This cross-contamination attributed to drums used to recover
solvent from agricultural pesticides manufacture at another
location. The drums were not properly cleaned leading to
agricultural pesticides entering the API manufacturing
process.

ROHM & HAAS CHARGED WITH COVERUP PESTICIDES WERE FOUND

IN PRODUCTS
By Richard Burke, Inquirer Staff Writer, Philli.com (The Inquirer, Daily News)
POSTED: March 23, 1989

It (Warner- Lambert) was one of two

pharmaceutical companies using the Rohm & Haas
chemical as an ingredient in its anti-cholesterol
drug. Introduction of Warner- Lambert's drug was
delayed six months last year when the company
learned of the contamination

http://articles.philly.com/1989-03-23/business/26126982_1_rohm-haas-bristol-myers-warner-lambert

A recent example
Europe wide recall of HIV drug due to cleaning
related contamination. Reports indicate a MSA
storage tank cleaned with ethanol was not free of
ethanol prior to charging with MSA.
API produced soon after had elevated levels of a
potential GTI (10 x > TTC). Batches made months
later exhibited values as high as 2,300ppm (EMs
TTC = 0.6ppm)

ROCHE RECALLS VIRACEPT DUE TO CHEMICAL IMPURITY

Patients are requested to contact their doctors to discuss alternative
therapies
Media Release
Basel, 06. June 2007

Roche, in agreement and cooperation with Health Authorities (EMEA

and Swissmedic), recalls in Europe and some other world regions all
batches of Viracept powder and tablets. The US, Canada and Japan are
not affected by this recall.
Roche has received several reports that some batches of Viracept 250
mg tablets have a strange odour. A detailed chemical analysis of the
affected tablets showed they contain higher than normal levels of
methane sulfonic acid ethylester. In the interest of patients safety
Roche has decided to recall all batches of Viracept tablets and powder.
Patients are requested to contact their doctors to discuss alternative
therapies.

http://www.roche.com/media/media_releases/med-cor-2007-06-06b.htm

What does it mean to be clean?

Modern analytical technology presented a
challenge to conventional notions of what is
clean (a variation of none detected).
Trace analysis
Sports / performance enhance substances
Food / pesticide residue, 1996 repeal the 1958
Delaney Clause.

Practical Definitions
Cleaning: Removal of residues and contaminants to a
controlled level. The residues and contaminants can be
by cross-contamination from previously
manufactured products in the equipment or from the
cleaning procedure (detergents / sanitizers) or
degradation products resulting from the cleaning
process itself, as well as microorganism*.
Cleaning verification: A quality control process for
determining the effectiveness of a cleaning process
for a specific cleaning event.
Cleaning validation: A methodology used to assure
the effectiveness and consistency of a cleaning
process to remove residues and contaminants

Establishing Scientifically Sound

Residue Limits (1993)
No quantity of residue will be visible on the
equipment after cleaning procedures are
performed.
No more than 10 ppm of a product will appear in
another product.
No more than0.001 dose of any product will
appear in the maximum daily dose of another
product.
Fourman, G., and Mullin, M., Determining Cleaning Validation Acceptance Limits for
Pharmaceutical Manufacturing Operations, Pharmaceutical Technology, April 1993

Establishing Scientifically Sound

Residue Limits (2012)
PDA Technical Report No. 29, Revised 2012:
Points to Consider for Cleaning Validation
The underlying assumptions are unchanged from
basic approach is unchanged from the 1993
Fourman and Mullin publication.

The Approach
For the purpose of calculation, equipment
contamination is assumed to be evenly
distributed throughout the equipment surface
and any contamination quantified will be
considered completely dispersed in the
subsequent product.

Practical Considerations
Assuming a Safety Factor of 0.1% (1/1,000)
No more than 0.1% of the minimum therapeutic
dose of Drug A will be found in the largest daily
dose of Drug B
This is a good start, but how is the limit
calculated?

Maximum Allowable Carryover

MAC = Lowest Dose Product A

Max Daily Dose Product B

----------------------------- X -------------------------Safety Factor

Smallest Batch Prod B

Surface Acceptance Limit

MAC
SAL = ---------------------------- = micrograms/in2
Equipment Surface Area

Swab Acceptance Limit

Swab Acceptance Limit
SwAL = SAL X Area Swabbed X Rf
Rf = Recovery Factor (assume 50%)

Test Solution Concentration Limit

SwAL
Sample Conc. Limit = ---------------------------------Extraction & Dilution Volume

Method LOQ/LOD
Limit Test vs. Quantitative Assay
50% to 150% ?
80%, 100%, 120% ?

Setting Limits
Product Specific
Bracketing / Cleaning Matrix
Product families: Similar solubility, cleaning
procedure, safety profile. Selecting worst case

Special Consideration:
Allergenic and highly potent materials
e.g. penicillins and cephalosporins
e.g. anovulent steroids, potent steroids and
cytotoxic compounds

Microbiology
Limits for Aseptic Manufacturing equipment can
be justified using a similar carry over argument,
with recognition that the components of the next
product also contribute to the total bioburden
Bioburden NMT 25 cfu per 25 cm2 This level is
readily dealt with by typical SIP processes.
Endotoxin less than 0.25 EU/mL
(surface EU x contact surface area = transferred EU)

Useful Assumptions
Minimum batch size set to minimum capacity
of compounding / mixer for agitation to operate.
Maximum Dose of Next Product 4g/day
(based on some antibiotics). Phase 1 does
escalation protocol
Equipment surface area a few pieces will
provide the majority of the area
Safety Factor: 1/1000 by Phase 3, 1/10000 NCEs

Organizational Interdependencies
The process of developing a suitably sensitive
analytical method, validating, and establishing a
surface recovery factor is time consuming.
Without the required inputs such as equipment
surface area, area to sample swab / rinse, largest
daily dose of next product, smallest batch size of
next product etc., a residue limit isnt established.
A fit for purpose method is not developed without
a target limit / LOQ, LOD in mind.

Multifunctional Endeavor
Toxicology NOAEL, LD50
Clinical / Med Affairs - Posology
Engineering Equipment surface area & material of
construction
Manufacturing Scheduled based on business needs,
execute cleaning, perhaps swabbing
Chemistry Swab preparation, residue analysis, timely
results
Microbiology Sampling, bioburden, endotoxin, advise
on cleaning procedures and equipment storage
Validation Project coordination, protocols
Quality Assurance Quality system oversight

What Residue to Analyze

Assuming compendial / GRAS components are
used in the formulation, the API is the most
likely analyte.
- However easily degraded drugs (thermal
instability, air oxidation, easily hydrolyzed,
reactive to cleaning agents.
- Conduct an exhaustive study of the possibilities?
- Establish 1st and 2nd choice cleaning approaches, and
test to those conditions.

Cleaning Agents

A common problem associated with detergent use

is its composition. suppliers will not provide
specific composition. As with product residues,
it is expected evaluate the efficiency of the
cleaning process for the removal of residues.
However, unlike product residues, it is expected
that no (or for ultra sensitive analytical test
methods - very low) detergent levels remain after
cleaning. Detergents are not part of the
manufacturing process only added to facilitate
cleaning... Thus, they should be easily removable.
Otherwise, a different detergent should be selected.
FDA GUIDE TO INSPECTIONS VALIDATION OF CLEANING PROCESSES July 1993

 A formulated cleaning agent may contain (in

addition to water) a surfactant, an alkalinity
source (e.g. KOH), and a chelant
It is reasonable to target one component of the
cleaning agent provided there is some rational
basis to expect the components will remain in the
same ratio, or the selected analyte is an effective
reporter for the maximum level of any component.
Using compendial and/or GRAS materials as
cleaning agents greatly reduces safety concerns.

Sampling Methods
Direct Surface Sampling

Swabbing
Viewed as more reliable
Insoluble or dried residues
may be removed by physical
action
When accessible, hardest to
clean areas can be sampled,
indicating a likely maximum
level of the residue
Swab selection
Technique dependent

Rinsing

Larger surface area may be

sampled
Inaccessible areas can be
sampled
Demonstrating recovery &
establishing an acceptable
recovery factor

Swab Sampling Technique

Technical Resource Library from Cole-Parmer

Non-Specific Methods

Methodology

Considerations

Conductivity
Total organic carbon (TOC)
Visual
pH

Short / no development
Typically faster
My be sensitive to other
considerations (excipients,
cleaning agents)
Greater likelihood of false
positives
May require a specific method
to investigate OOS

Specific Methods
Methodology

Considerations

Chromatography (LC, GC, IC,

TLC)
Specific detection modes
(LC-UV, Flour, ELSD, CAD,
CLND, MS, MS/MS)
Atomic Spectroscopy (AA,
ICP-OES, ICP-MS)
ELISA
Ion-mobility
spectrometry (IMS)

Time consuming to develop

Typically longer analysis
times
Low likelihood of false
positives
Typically insensitive to other
considerations
Cost / training

Time Limits
End of manufacture to start of cleaning ? calendar
days
Start of cleaning to completion of cleaning
Verification sampling
Completion of sampling to initiation of analysis
Unextracted vs extracts & storage (stability/recovery)

Completion of testing to delivery of results of

analysis from Labs to X
Receipt of results of analysis to completion of
protocol and submission for post-approval

The Challenges
Communication, communication, and
communication
Lack of appreciation for necessary prerequisite
information

Push vs. Pull manufacturing technology transfer

Schedule pressure
Who owns the process

Useful Tools
Cleaning Validation Master Plan
RACI Chart (Responsible, Accountable, Consulted, Informed)
Overview of the process for involved parties
Clear / executable SOPs

Acknowledgments
My many colleagues in Pharma manufacturing
and R&D
The work of the PDA Technical Committees and
National Regulatory Authorities

Discussion

Setting Cleaning Validation Acceptance Limits for

Topical Formulations
M. Ovais, Lai Yeo Lian, Pharmaceutical Technology,
Volume 32, Issue 1, Jan. 2, 2008

Single Use Systems