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 820—QUALITY 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 (EM’s
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 isn’t 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 • Short / no development
• Total organic carbon (TOC) • Typically faster
• Visual • My be sensitive to other
• pH considerations (excipients,
cleaning agents)
• Greater likelihood of false
positives
• May require a specific method
to investigate OOS
Specific Methods
Methodology
• 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)
Considerations
• 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