Reprinted from

PHARMACEUTICAL ENGINEERING
THE OFFICIAL TECHNICAL MAGAZINE OF ISPE

NOVEMBER/DECEMBER 2013, VOL 33, NO 6

regulatory compliance
©Copyright ISPE 2013
Risk-MaPP
www.PharmaceuticalEngineering.org

Risk Assessment for Cross-

Contamination in Solid Dosage
Form Manufacturing Facilities
by Mock FMEA Special Interest Group (SIG), Containment COP, and
ISPE Japan Affiliate

This article presents a risk evaluation method and case studies using Failure
Mode and Effects Analysis (FMEA) introduced in ICH Q9 to establish
cost-effective countermeasures for cross-contamination in solid dosage
form manufacturing facilities.

I 
SPE developed a Baseline® Guide, Risk-Based Manufac- When executing a risk assessment, it may be reasonable to
ture of Pharmaceutical Products (Risk-MaPP),1 using a leave issues related to mix-up and retention to the existing
scientific risk-based approach to maintain product qual- GMP and cleaning validation activities since GMP guidelines
ity and worker safety in order to reflect the importance provide recommendations for prevention of cross-contam-
of quality risk management as defined by ICH Q9.2 Pro- ination. In most existing manufacturing, countermeasures
fessionals with varied experience representing a number for cross-contamination attributed to mechanical and
of pharmaceutical companies in the US, EU and Japan airborne transfers have been based on visual inspection on
collaborated on the development of the Risk-MaPP non-product contact surfaces, such as containers, floors,
Guide. The content of the Guide was reviewed by the US walls, corridors and fittings. When highly potent products
Food and Drug Administration (FDA) and acknowledged in (as opposed to general products) are manufactured, judg-
the forward section of the guide. ing by visual inspection is inappropriate because visible
The Containment Community of Practice (COP) of ISPE amounts that are transferable by mechanical and airborne
Japan Affiliate has been committed to the development and pathways would exceed acceptable limits for non-product
the implementation of Risk-MaPP from the beginning. surfaces. Accordingly, a risk assessment here is conducted
In this article, some examples of the risk assessment focusing mainly on mechanical transfer and airborne trans-
based on Risk-MaPP are provided for the prevention of fer on non-product contact surfaces for highly potent prod-
cross-contamination in solid dosage form manufacturing ucts on the assumption that there are plausible pathways by
facilities and summarized in the Appendices. which this material could be transferred to a product being
The four routes of cross-contamination indicated in Risk- manufactured in the same area.
MaPP are listed below in order of importance:
Risk Management Tools
• Mix-Up: mix-up of API, process, potency, labeling, etc. Among the tools introduced in ICH Q9, Failure Mode and
• Retention: carry over on product contact parts, failure to Effect Analysis (FMEA) is employed herein. As introduced in
clean to limits of product to another product on gowning ICH Q9, FMEA enables one to establish cost-effective coun-
and equipment termeasures against risks by prioritizing risks and counter-
• Airborne Transfer3: sedimentation of aerosols from one measures by relative scores.
product into another

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4. Severity: scoring for the degree of the impact of exposure

Hazard Level Exposure Route
to patients and/or workers that is determined by the
Acceptable Daily Exposure Mechanical Airborne matrix of Acceptable Daily Exposure (ADE) and exposure
(ADE) Transfer Transfer
route (Table A).
>10 mg/day 1 1
5. Potential Cause(s) of Failure: lack of control, ineffective
1 - 10 mg/day 3 1 control technique, human error and equipment malfunc-
tion are considered as the major factors among major
0.01 - 1 mg/day 5 3
causes.
< 10 μg/day 7 5
6. Occurrence for Process: scoring for the degree of con-
The values of severity are defined: tamination occurrence which is attributable to process
10: Injury to a patient or employee unit operations. That is defined by the matrix of amount
7: Cause extreme customer dissatisfaction
5: Something likely to result in a complaint of airborne/residue and degree of process. The example
3: Minor nuisance resulting in no loss of scoring of occurrence is shown in Table B.
1: Unnoticed and does not affect performance
7. Current Controls (Detection): scoring is based on char-
Table A. Scoring of severity (example). acters of failures (e.g., carry over, upset, and leakage)
and its detection devise as shown in Table C. Failures are
classified into 1. failure that is foreseeable and avoided
Risk Evaluation using FMEA for Process beforehand by detecting its root cause, 2. failure that can
A rule for scoring needs to be established prior to the risk
be detected when it happens, and 3. failure that cannot be
assessment using FMEA and for this example as follows:
detected when it happens. Detection devices (automatic
vs. manual) provide easiness and reliability on detections
1. Unit of Evaluation: a typical part of a manufacturing sys-
of failure and its root cause.
tem including process equipment, a building and HVAC
system. 8. Risk Priority Number (RPN): RPN is a number obtained
by multiplying scores of severity, occurrence and detec-
2. Potential Failure Mode: mechanical transfer and airborne
tion. Limits or zones need to be established for RPN by
transfer are taken as potential failure mode herein that
which acceptability and correction priority can be as-
could lead to exposure among the four routes of cross-
sessed.
contamination. (The others are mix-up and retention as
discussed above).
FMEA Evaluation (Examples)
3. Potential Effect(s) of Failure: patients exposure and pre- In this article, the following two case studies for risk assess-
sumed adverse effects. ment based upon Risk-MaPP are discussed:

Case Study 1: Weighing Process

Property of Open Process Closed
Operation Process Weighing of materials for an anti-neoplastic agent is con-
Amount of Long Short ducted in a weighing isolator as seen in Figure 1. The inside
Airborne/Residue Term Term1 of the isolator is kept under negative pressure. Air is sup-
Product Contact Parts MT 10 7 1 plied to the isolator from the process room through HEPA
(More Than) ADE or Cleaning filters and double HEPA filters are located at the exhaust
Limit port. All of the necessary equipment and sealed material
Product Contact Parts 1 1 1 containers are transported into the isolator through the Pass
NMT ADE or Cleaning Limit

Non-product Contact Parts2 1 1 1 Failure Classification Automatic Manual

NMT ADE or Cleaning Limit Detection Detection

Notes: Foreseeable failure with its detectable 1 3

1. Short term means less than a few seconds. The scoring table root cause
is based on the risk assessment table proposed in Baseline®
Guide “Bulk Pharmaceutical Chemicals (Second Edition)”. Detectable failure 5 7
2. In Table B, the scoring in case of MT cleaning limit at non- (Not foreseeable)
product contact parts is not defined. When containment system
do function well, the above case could not be considered. Undetectable failure 10 10

Table B. Scoring of occurrence for process (example). Table C. Scoring of detection (sample).

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Valves (SBV). Containers with leftover

materials are put into a container via the
Rapid Transfer Port (RTP) and kept in
storage. Any wastes in the isolator are
contained in a plastic bag through the
bag-out port, removed using a safe-
change system, and incinerated. When a
series of process operations is completed,
the inside of the isolator is manually
cleaned with water by glove operation
using spray guns.

Case Study 2: Compression

Process
A typical rotary tablet press machine is
used as an example in the second case
study - Figure 2. The reason for this is be-
Figure 1. Diagram of a weighing isolator. cause such tablet press machine is suitable
for mass-production and can be easily
Box (PB) prior to weighing. After conducting predetermined automated. Also, the weight variation of each product manu-
weighing procedures in the isolator, the weighed materials factured by this machine tends to be small. Moreover, this
are charged into a weighing container via the Split Butterfly machine contains generated dust and is easy to handle. These
are many benefits for using this machine.
A tablet press machine with rotary system
is formed by several metallic punches and
dies (upper punch, lower punch, and die)
attached to a horizontal turntable. The
turntable is rotated by a motor and while
it rotates through 360 degrees, the fol-
lowing series of procedures is conducted
continuously: 1. powder filling – a raw
material powder is filled quantitatively
into a cavity, 2. compression molding -
compression and molding are conducted
as the upper punches and lower punches
rotate through the compression roll, and
3. product discharge.
Materials are charged from the top of
a device using supply containers and the
tablet product is contained in a product
container. Prior to implementation of any
risk reduction measures, these contain-
ers had a split butterfly valve installed to
enable containment. In this scenario, the
tablet press machine itself has no device
to predict risks, such as device to monitor
the pressure inside a machine.
For the manufacturing of the anti-
neoplastic products, the risk reduction
measures for cross-contamination from
a GMP standpoint was considered to
ensure the safety of patients who take the
Figure 2. Diagram of a tablet press machine. pharmaceuticals.

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Table D. FMEA (weighing process, in case of ADE < 10 μg/day).

The FMEA evaluation examples in the risk tables could introduced. Its mock-application refers to the “application
occur in the pharmaceutical manufacturing process (Tables example” in Risk-MaPP, Appendix 14.
D and E). While this risk assessment using FMEA method was
executed, some issues were identified. For instance:
Recommendations
In this article, the risk assessment methodology for GMP • In an FMEA, the results are represented by Risk Priority
(quality) concerns regarding cross-contamination, especially Number (RPN) that locates and prioritizes areas where
airborne and mechanical transfer mode exclusively, was failure is likely caused.

Table E. FMEA (compression process, in case of ADE <10 μg/day).

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• RPN is calculated by multiplying three scores: Sever- This article only covers the risk assessment using FMEA
ity, Occurrence, and Detection. When unsatisfactory limited to GMP concerns. Those for IH concerns also can
RPN numbers are obtained, the area of risk reduction be conducted. These case studies demonstrated very clearly
measures needs to be studied by examining these three that FEMA was very useful to conduct risk assessment for
scores, i.e., the factors of the RPN. process and premises in alignment with Risk-MaPP. Thus,
• The ADE is an important parameter in the assessment, the project which applies FMEA to the actual situation was
particularly in determining Scores of Severity in our established and now has been studied. The results from this
definition. Due to the fact that ADEs are scientifically study will be released in a report in near future.
developed values, Scoring of Severity helps to add quanti-
tative meanings. The ADE values established by differ- References
ent toxicologists should be sufficiently close so as not to 1. ISPE Baseline® Pharmaceutical Engineering Guide:
lead to different severity scores or control measures that Volume 7 – Risk-Based Manufacture of Pharmaceutical
might be needed or implemented. Products (Risk-MaPP), International Society for Phar-
• Verification data using the ADE applied over a standard maceutical Engineering (ISPE), First Edition, Septem-
surface area (e.g., 100 cm2) consistent with the exposure ber, 2010, www.ispe.org.
pathways used in the risk assessment need to be collected
to assess whether the risk reduction measures imple- 2. ICH Harmonised Tripartite Guideline, Quality Risk
mented as a result of the FMEA are adequate to control Management, Q9, Step 4 version, 9 November 2005,
risks to the patient. www.ich.org.

To judge, in FMEA, to find if the status is satisfactory, it 3. Takahashi, H., and Nakamura, S., “Case Study: Risk-
refers to the predetermined RPN score or zone for satisfac- Based Approach to Containment and Control for Potent/
tion. The score of satisfaction shall be established by Senior Hazardous Compounds,” Pharmaceutical Engineering,
Management and shall not be changed unless it becomes November/December 2009, Online Exclusive, www.
inappropriate and needs to be adjusted to reflect the results PharmaceuticalEngineering.org.
for a certain number of projects.

PHARMACEUTICAL ENGINEERING NOVEMBER/DECEMBER 2013 5