A for-cause quality audit of a fictional pharmaceutical company.

1. Quality Audit Exercise
Moshe Ben Yitzhak

2. Situation
• Goliath Pharmaceuticals, Inc. (a fictional company) is a
global pharmaceutical company with manufacturing
operations in 21 countries.
• Goliath’s manufacturing site in Florida recently reported a
rise in the number of customer complaints regarding three
different sterile products (one lyophilized product and its
accompanying sterile diluent, and a sterile vaccine).
• All of these are high volume products and very profitable
to the company.
• The Director of Corporate QA in London has initiated a
“For-cause” audit and ordered you to lead the audit team.

3. Pareto Chart of Complaints
Customer Complaints
0
5
10
15
20
25
30
35
40
M
issing
CapsDam
aged
Seals
M
issing
Seals
&
C
aps
Film
/Foreign
Substance
Cracked
VialsScratched
Vials
Discolored
stoppers
Description
Number

4. Situation,
continued
The Complaints Department has done a very good job
and obtained samples from the customers in every
instance. Pareto Analysis over the last three months
reveals:
– Thirty-six complaints for missing caps
– Twenty-four complaints for damaged seals
– Twenty-two complaints for missing seals and caps
– Eighteen complaints for a “film-like substance” in the neck
of the vial, between the vial wall and the rubber stopper.
– Ten complaints for cracked vials
– Six scratched vials
– Two discolored stoppers

5. Who are your auditors?

6. Select your Audit Team
• The team will consist of you, plus two other auditors.
• Pick any two of these five:
– Jennifer: a GCP specialist used to traveling.
– David: a Part 11 specialist with broad industry experience.
– Simon: who recently joined the company after working seven
years at a small biotech firm.
– Bella: worked in Packaging (3 yrs.) and Planning (3 yrs.) at the
Florida site, before joining corporate QA two years ago.
– Rachel: a former microbiology lab supervisor at the Florida site.
She won’t be back from a supplier audit she is currently doing
until next week.
• Who did you pick and why?

7. The Planning Phase
Your team now needs to do the following in rapid
succession:
• Send a Notification Letter to the departments that will be
audited at the Florida site.
• Prepare an Audit Plan
– Decide on a strategy
– Determine which tools will be used in support of that strategy
– Prepare the necessary checklists, questionnaires and sampling
plans.
– Obtain and review the relevant Policies, SOPs and standards
– Obtain approval from the Audit Authority.
• Make your travel plans

8. What documents & records would you
like to use to plan the audit?

9. Some Assumptions
Your team may make the following assumptions:
• Corporate QA in London has a track record of being
very progressive regarding the use of draft
standards/guidance from the FDA.
• The Florida site produces both sterile and non-sterile
products.
– One QA unit services both sterile and non-sterile products.
• The last FDA-483 was received thirteen months ago.
– The site’s response promised actions within six months.
• Inventory cycle time for components is 95 days.

10. The Opening Meeting
• The Opening Meeting was held as planned, on May 28th
.
• The Lead Auditor reviewed the reasons for the audit.
• Site QA offered a presentation about the Florida site, but
the Lead Auditor asked to defer it.
Is skipping the site presentation good
time management or a missed
opportunity?

11. The Opening Meeting
• Who’s at the Opening Meeting?
– Your entire audit team
– The site’s QA Director and a senior QA associate.
– The site’s QC Director.
– The site’s General Manager, plus two of his direct
subordinates:
• Warehouse Sr. Supervisor
• Component Prep Sr. Supervisor
• The manager of Sterile Filling was at a meeting.
• The Packaging Manager is on maternity leave.

12. The Audit: Material Controls
• Specification PC-011.
– The specification states that a Durometer Hardness
test should be performed on incoming rubber
stoppers in accordance with MIL STD 105E.
– You are not familiar with the Durometer Hardness test
and ask to see the durometer itself and the
procedures for it.
• The QA Inspector informs you that there is no such piece of
equipment or procedure.
• You are told that it is “no big deal,” since PC-011 is used in a
veterinary product and “GMPs don’t apply to animals.”

13. The Audit: Material Controls, continued
• There seems to be no consistent storage of the
Certificates of Quality (COQ) for components, as required
by the procedure.
– COQs are found in batch records, receiving records maintained in
the warehouse, testing records maintained in QC and batch
records maintained in QA.
– In ten instances, COQs were missing entirely.
• By tracing forward the usage of individual batches of
packaging components, it was revealed that packaging
components are routinely released prior to the completion
of incoming inspection.
– Samples are drawn from the lot and given to the Supplies
Inspection Department, while the remainder of the lot is forwarded
to a inspection area.

14. The Audit: Material Controls, continued
• Corporate QA performs a pre-award survey audit
of suppliers, but sites are responsible for
maintaining an appropriate supplier management
program after that.
• The Florida site has no records of supplier audits
for containers, components, closures or labels.
• There is no written procedure for conducting
supplier audits.

15. The Audit: Component Prep
• Component Prep Department:
– An auditor observes the washing and siliconization of rubber
stoppers.
– Technicians state that the boxes of rubber stoppers do not
always have a green release sticker on them when they arrive in
the department.
– While observing the washing and siliconization the auditor notes:
• The washing vessel is connected to the WFI port via a rubber
hose; the hose is left on the port after the vessel has been
filled with WFI. The hose is looped around the port.
• The silicone oil is stored on the shelf above the vessel. It
does not have a release sticker.
• There is no logbook for the vessel. Operators inform you
that it is cleaned when the room is cleaned, at the end of the
day.

16. The Audit: Lyophilization Process
• Operators explain that a “double sampling plan” is
employed in the inspection of lyophilized units for
“cake elegance” and “proper stopper placement”
after the conclusion of the lyophilization process,
however the auditor noted:
– There is no objective standard or description of what
constitutes “cake elegance” and “proper stopper
placement.”
– The standard cited for inspection is MIL STD 105E, but no
particular sampling scheme or plan is detailed; the
Operators know that the plan itself is in SOP GOL 494-004
and have access to the procedure.
– Inspection reports are signed-off by the Lyophilization
Department supervisor and are submitted as part of the
batch record.

18. The Audit: Cap & Seal Process
• The Supervisor explains that whenever a major
defect/nonconformity is found on the Cap and Seal line, he
orders an sample be taken of all the units produced since
the last check.
• This is part of the “self audit” the department has been
performing since the inspection process was transferred
from QA to Cap and Seal six months ago.
• The supervisor informs the operators what constitutes the
sample size and accept/reject level for this particular
inspection.
• The supervisor transferred into Cap and Seal from QA, six
months ago. He is still officially “in training,” but has been
supervising by himself for three months.

20. The Audit: Site QA
One of the auditors notes the following:
•A failure to complete investigations within an appropriate
time frame.
– Four lots that failed assay at the six month time point were still
under investigation at the time of the FDA inspection.
– These investigations have been in-progress for 34, 65, 81 and
104 days respectively.
•Also, five separate batches were released despite the fact
that there were extra inspections performed in the Cap &
Seal Department.
•A failure to have the appropriate quantity of reserve
samples necessary to perform the required tests, and to
examine the reserve samples visually at least once a year
for evidence of deterioration.

21. Audit Team Daily Caucus
• One team member reports that nothing seems
out of the ordinary in the QC Microbiology Lab,
where all sterile products are tested.
– One of the microbiologists (the auditor’s roommate
from college) is working on the company’s first
veterinary drug and that he thinks it is worthwhile to
buy some more stock through the company’s ESOP.
– The only thing the auditor notes is that the agar
plates, used for plating technicians to determine if
they have gowned properly, seem to be stored every
where in the lab. A lab worker told him they are
ordering a large cabinet in the future.

22. Daily Briefing
• You tell your team to consider the next day’s
activities, while you go speak with the acting QA
Manager and the escort. You make a mental note
to yourself to remind them that you need to see:
– The training metrics and deviation trending for the last
six months.
– The PQ for the siliconization vessel and its cleaning
validation.
– You requested these at the Opening Meeting in the
morning, but were never provided these records.

23. Information Collected on the Last
Scheduled Day of the Audit
• The site produced four batches in a row, of a veterinary
product that is in development in January-February of this
year using the same formulation and filling lines as are
used for approved products.
• The matrix used for cleaning validation does not consider clinical
materials; the supervisor directed operators to use a standard
solution of bleach, followed by an IPA wipe-down.
• No media simulations were performed between the production of
the Phase I products and the approved products.
• Batch IND-POR-02 was rejected for failing sterility; sterility testing
identified a Porcine Parvovirus and a T4 bacteriophage.

24. Close-out Meeting
• Who is going to give the report to the site’s General
Manager and QA Director?
– Just the Lead Auditor?
– Or will each team member present his observations?
• Are observations reported individually or within a
system framework?
• Has your team identified the root cause of any of the
complaints recorded in the Pareto Diagram?
• Is it the Audit team’s responsibility to find the root
cause?