Validation of A Consumer

Healthcare Facility
A Case Study in Time & Cost Reduction
By R.J. Noy, Ph.D.
SmithKline Beecham Consumer Healthcare

A
s national health ser- dation requirements between
vices throughout the A recent upgrade sterile injectables and a med-
world have become icated mouthwash. As a result,
starved of cash and more reliant at SmithKline the full force of a validation
on patient self-medication, OTC exercise was required. Certain
healthcare products have Beecham’s facility standards, which clearly could
become increasingly important in the UK raised the not be compromised, had to be
to the healthcare and pharma- the same as they are for pharma-
ceutical industries. SmithKline age-old validation ceuticals. Still, both internal and
Beecham’s Maidenhead facility external sources advised us that
specializes in consumer health- battle of approved while validation documentation
care products, particularly oral methodologies is a prerequisite for compliance,
care medications. Since 1994, certain facets of the validation
the site has undergone a major versus their cost. process need not be as rigorous.
refurbishment to upgrade its This paper sets out the scope,
facilities. At the same time, it philosophy, schedule, time and
was necessary to continue production to meet the cost savings for the validation of an oral healthcare
demands of the marketplace. manufacturing facility in the light of these recommen-
In conjunction with this major renovation, valida- dations. At no time during the validation investigation
tion was included in the remit and steps were taken to did SmithKline’s standards fall below the legal base-
validate the process equipment and facilities for all line of critical pharmaceutical quality requirements.
licensed products manufactured on-site. However,
since the Maidenhead site manufactures mostly unli- SCOPE AND STRATEGY
censed consumer healthcare products, no validation in
the true pharmaceutical sense was required. Table 1 indicates the scope of the validation pro-
While the site was undergoing its upgrade, it was ject required to obtain an ML from the UK MCA.
decided to introduce a dedicated facility to produce Because the full validation team was not organized
medicated mouthwash. Consequently, true valida- until late in the project, the study was partly retro-
tion was needed for the process equipment and asso- spective on new equipment and facilities. Given that
ciated infrastructure. the manufacturers of the systems were unfamiliar
The EC-GMP guidelines do not distinguish vali- with validation requirements, the validation team

12 Special Edition: Facility Qualification


was able to assemble documents and ensure the
careful installation and commissioning of the facili-
ties according to the requirements of the SmithKline
validation team.
One of the most important aspects of this fast-track
validation exercise was setting up an implementation
team that met at regular intervals (weekly) or on a
rapid-response basis. If problems became critical dur-
ing the project, they were discussed quickly, and solu-
tions were sought and responded to in minutes or
hours. This proved to be an excellent strategy as
major difficulties were overcome and the validation
project continued unabated. Table 2 outlines the
members of the validation implementation team.
The second most important element was the for-
mation of a validation team, which was created over
the course of six weeks. One of the members was an
experienced validation manager familiar with the
R.J. Noy, Ph.D.
preparation of SOPs, protocols and test sheets. The
validation manager was required to direct the valida-
tion effort and have the depth of background to set
standards for testing and develop the technical phi-
losophy for the exercise. Shortly after this appoint-
ment, a validation engineer was recruited to act as a
deputy to the validation manager. The technicians
who actually performed the testing were chosen
soon after the validation manager had been appoint-
ed. Table 3 shows the type of personnel sought for
these vital responsibilities.
We adopted the systems and subsystems method
of approach, and the validation master plan submit-
ted to the MCA reflected this philosophy.
Budget constraints and the overall resources
required to complete the exercise were other major
considerations. Senior management continually asked
the same question: Why does a mouthwash facility
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R.J. Noy, Ph.D.

Table 2: Validation Implementation Team

Table 3

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 R.J. Noy, Ph.D.

need to be validated to ethical manufacturing stan- plan was chosen because we had all of the O/M
dards? In a way, this question was justified, since the manuals from the suppliers, as well as SAT and
product was a medication for oral use only. However, installation documentation, such as weld details,
the active ingredient was a very effective biocide in passivation data and other information.
large concentrations. Poor manufacturing practices The next system to be validated was the bulk man-
could have resulted in disastrous consequences. ufacturing plant. (As luck would have it, obtaining
The underlying culture of the site was a consumer the vendor documentation followed according to
goods manufacturing plant. Site development included plan.) By October or November 1995, we started on
a major upgrade in cGMPs and the transition to a the filling and packaging hall, which was dedicated
healthcare culture. These goals called for a massive for all mouthwash products and used mostly for unli-
change in culture and the creation of validation proce- censed products. The licensed mouthwash was sec-
dures to satisfy an inspection from the MCA. ondarily packed on this line, but it was not labeled
there. Dedicated equipment was used for this job.
DOCUMENTATION Test sheets were largely devised from the ven-
dor’s O/M manuals, though SmithKline’s own in-
Documentation was the starting point of the pro- house expertise in packaging technology was of ben-
ject. Without validation SOPs to drive the validation efit. PLC validation of all equipment was compared
protocols, it was impossible to begin the study. against the URS and FDS (information supplied
Most of the project team had to agree to, approve from the user and the vendor respectively). By the
and sign all SOPs and protocols, which was a major end of January 1996, we were in position to request
achievement in itself. Table 4 gives a summary of an inspection from the MCA.
the major levels of documentation used to define,
initiate and record validation data. DEPTH OF VALIDATION
The next major decision regarding the reduction
of time and expense involved determining which In order to complete the schedule by the end of
tests to perform and to what depth and detail. January 1996, a certain amount of fast-tracking
(Table 6 provides examples of some of the savings was required. As indicated earlier, the biggest
adopted during this
study.) Table 4: Amount of Documentation Used During Project
The validation master
plan was written first and TITLE PURPOSE
submitted to the MCA for Validation Master Plan (1) Overall Plan
overall “approval” of the Validation SOPs (35) Drives Generic Methodology
methodology and ap- Validation Protocols (54 Specific Methodology
Test Sheets (Many) Data Gathering
proach. This document
O/M Manuals (12) Data From Vendors
was submitted in July Technical Files (10) Additional Data
1995 and approved short- Work Instructions (102) Site and Facility Instructions
ly after. Validation work (Equivalent to SOPs used at the plant)
began in August 1995 Validation Reports (15) Reporting to the Validation Work
with the preparation of Remedial Action Reports (1) Description of Remedial Action Required
SOPs and protocols. System Error/Failure Sheets (26) Identifying Errors
The water plant and Master Index (1) Ease of Documentation Location
ring main were the first Certificates (3) Final Approval
Review Protocols (3) Annual Review
systems to be validated
Change Control Dossier (3) Recording Technical Changes
using the documents and Training Records (1) Training of Staff
test sheets described in Maintenance Records (3) Maintenance and Asset Register
this paper. The water (The figures in parentheses indicate the number of versions of each document.)

15 Special Edition: Facility Qualification 15

R.J. Noy, Ph.D.
Table 5: Depth of Requirements
questions were how far to carry out the validation,
particularly in terms of testing, and how to keep
the cost and time at a minimum. The use of a mas-
ter index, which cross-referenced all of the SOPs
and protocols, was very advantageous in keeping
track of the work. It also provided a quick refer-
ence while an inspector was on-site. Table 5 offers
a summary of the depth of requirements required
for this exercise.
The URS was not officially written at the kick-
off of the project, as the validation team arrived
fairly late in the proceedings. However, upon
arrival, the validation team worked according to
the following URS:
• Materials of construction philosophy
• Cleanability
• Maintenance
• Performance of equipment and processes
• Critical parameters identified
• Operating ranges of critical parameters
defined
• Essential design criteria defined
• Requirements of the PLC, PC and C/I
• Training requirements identified
• Documentation unambiguous
16 Special Edition: Facility Qualification
TEST SHEETS AND FORMS
Design Qualification (DQ) - Minimal DQ was
undertaken as the project was well into the construction
phase when the validation team arrived. Still, a DQ ret-
rospective validation review was performed quickly,
and the following record forms were completed:
• Design safety form
• Layout review record form
• GMP review record form
• PLC, PC, C/I review record form
• Commissioning and start-up review record form
Installation Qualification - The IQ test sheets
and forms were reduced to the list shown below by
combining common parameters, such as materials of
construction, lubricants and elastomers. Similarly,
the utilities and services test sheets and forms were
combined to include electrics, water, gases, drains,
etc. IQ also incorporated the following:
• Associated items form
• Critical information form
• Consumable information form
• Drawing information and verification form
• Specification information form
16

• Lubricant, materials of construction, and elas-
tomer form
• Weld information form
• Vessel and tank information form
• Controls, instrumentation, indicators and safety
devices check sheet
• Utilities and services information and test sheet
• Error/failure log form
Operational Qualification - The OQ test and infor-
mation sheets were rationalized and made easier to
complete by the test engineer. These sheets, which were
very similar to those for IQ, were composed of objec-
tive, method, acceptance criteria, results and pass/fail
blocks. OQ included in the following documents:
• Prerequisites form (all IQ errors must be closed
out before continuation to OQ)
• FDS comparison form
• SOP information form
• Noise level test form
• Speed and rotation test form
• Flow rate test form
• Critical devices and interlocks test form
• Screen identification form
• Leak and tank capacity test form
• Stirrer efficiency test form
• Error/failure log form
The error/failure forms were generated for both
IQ and OQ because errors and failures inevitably are
found during testing. In all cases remedial action
was taken to rectify the faults. This activity was a
prerequisite for both OQ and PQ investigations, as
well as for PLC validation.
Performance Qualification - The PQ test sheets
were similar to the OQ test sheets. They largely
referred to the technical report prepared by R&D on
the three consecutive batches of two different vari-
ants of the formulation which had been prepared
during the experimental work batch phase of the
project. The following documents were included:
• Prerequisites form (All OQ errors and failures
must be closed out before PQ starts)
• Measurement devices form
• Raw materials requirements form
• Instrumentation and devices form
17
R.J. Noy, Ph.D.
• Cleaning verification form
• Critical process steps form
• Critical operating parameters form
• Controls form
• Product composition form
• Quality of product produced form
• Disaster recovery form
• Integrated line testing form
Finally, a validation report was written summa-
rizing these results in about two pages.
Cleaning Qualification - The test and informa-
tion sheet approach was undertaken. The definition
of cleaning at SmithKline is taken in the broadest of
terms, ranging from chemical sanitization of the
purified water plant storage tank, feed tank and ring
main to CIP of the bulk manufacturing tanks and
manual cleaning of the line items. Due to this diver-
sity, the decision was made to use detailed validation
reports, which took the form of technical reports that
included acceptance criteria.
PLC Qualification and Validation - The protocol
was called the “Validation Qualification Protocol” and
comprised the following test and information sheets:
• Specification test sheet for URS and FDS
comparison
• Control system data form
• Input test form
• Timer, counter and data register test form
• Output test form
• PLC module test form
• Blackout/disaster recovery test form
• Critical device calibration test form
• PLC incident form
• Error/failure form
Not all of the test and information sheets were
applicable. A summary sheet was added to the front
of the documents to indicate which forms were used
and the number of pages of each.
HVAC and Room Environment Qualification -
Test and information sheets similar to those for the
process systems were used for HVAC and room envi-
ronmental qualification. However, extra test sheets,
along with a specialized OQ sheet, were added for room
data. The PQ of the bulk manufacturing area was a daily
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R.J. Noy, Ph.D.
logging of environmental parameters, such as tempera-
ture, particles, RH, oxygen and air flow characteristics.
General Qualification - This area is defined as the
daily, weekly or monthly logging of equipment, utili-
ties, production processes and other data. Daily logs
of pressures, UV lamp intensities, temperatures, air
flow, etc., were recorded manually to ensure the facil-
ity remained in control. For its part, the QA/QC
Department prepared daily logs of raw materials, such
as water, actives, excipients, packaging components,
batch records and out-of-spec results. However, it
proved to be difficult to fully educate the Engineering
and Production Departments, as they were not fully
conversant with the daily logging of data. The educa-
tion and training of this personnel is an ongoing exer-
cise by both the QA/QC and Validation Departments.
CHANGE CONTROL
Change control often frightens many of the estab-
lished and older personnel on the production floor.
To them, it means slowing production schedules,
more paperwork, etc. For an FMCG factory, this is
even more pronounced and obvious. However, the
need for change control in a cGMP facility is essen-
tial to keep compliant with required standards. The
change control procedures again were rationalized
to make the system user-friendly.
VALIDATION REPORTS
These reports were written at the end of the full
validation of process equipment or utilities. They
proved to be an excellent way of summarizing the
exercise, describing what went wrong and how it
was remedied. The inspectorate also found this an
excellent way of understanding the project and its
faults. It was in no way detrimental to our applica-
tion for a license. In fact, it helped us a great deal.
VALIDATION REVIEWS
This will occur in October 1996 at the anniversary
of the OQ sign-off. The check list approach will be
used to complete the following major categories:
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• Validation master plan review
• Validation reports, protocols and SOPs review
• Trend and daily log analysis
• Change control dossier review
• SOPs and work instructions review
• Batch records review
• Customer complaint review
• Reject materials review
• Process changes and deviations review
• Maintenance and calibration record review
• Audit and self-inspection review
• Retained sample and stability record review
• Out-of-spec results review
• Training records review
CERTIFICATION AND HAND-OVER
At the end of the validation project, the facility
was “handed over” to the new owners of the facility,
namely the Production Department. This involved
the acknowledgement and transfer of a formal cer-
tificate verifying that validation had met cGMP and
GEP standards. Time will tell if the new owners of
the facility are able to run a cGMP facility to the
level required by the inspectorate.
OVERALL COST AND TIME
REDUCTION
Table 6 summarizes how much time and money
were saved using the fast-track validation methodol-
ogy described in this paper. Although subjective in
its content, this table gives an accurate picture of the
validation project and the ways expenditures of time
and money were kept in check.
The overall costs were probably half to two-
thirds the costs normally associated with an ethical
pharmaceutical product (prescription-only medi-
cine). The total time taken to obtain the license, up
to and including PQ, was 17 weeks at a cost of 3%
of the book value of the facility.
CONCLUSION
The result of the exercise was a good one for the
SmithKline Validation Department. The company
 R.J. Noy, Ph.D.

Table 6: Estimated Time & Cost Reductions

received its first license for the new site. The team JOURNAL OF VALIDATION TECHNOLOGY
involved in the inspection requirements was truly a
“dream team,” the dynamics of which will be diffi-
RELATED ARTICLES
cult to assemble again. The team’s meeting and May 1996
planning strategy was excellent, as was the commu- 1. Wayne T. Flaherty, “Facility Validation: Management Issues.”
February 1995
nication between members. The project was within 2. Patricia Stewart, “New vs. Existing Facilities: Two
budget due to the rational and targeted validation Approaches for Developing IQs.”
strategy that was adopted.
The URS was in compliance, and although a
formal DQ was not written, cGMP compliance
was achieved, specifications were attained, docu-
ments from vendors were forthcoming and cGMP
boundaries were well defined. Additionally, in
most cases, design changes were recorded and
vendors audited. Finally, SmithKline proved to a
high degree of assurance that the oral healthcare
facility was in control. All that remains is that the
company continue to operate accordingly over the
lifetime of the facility. ❏

Special Edition: Facility Qualification 19