MERCK CITED - FDA INSPECTION

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FWD: from PROVE

Dawn

PROVE(Parents Requesting Open Vaccine Education)

<A HREF= " mailto:prove@... " >prove@...</A> (email)

<A HREF= " http://vaccineinfo.net/ " >http://vaccineinfo.net/</A> (web site)

Merck, one of the larger vaccine manufacturers, shut down one of their

vaccine manufacturing locations after the FDA inspected the plant and found

numerous problems. Here is an article about it. Some concerned parents

requested the full FDA report and made excerpts available for all to see

through the Illinois Vaccine Awareness Coalition. Those excerpts appear

below this article. The findings speak for themselves. And just think,

vaccine manufacturers who get away with producing vaccines under these types

of conditions are still immune from liability if they kill or injure your

child. Vaccines made at this plant include those for chicken pox, MMR,

hepatitis A and Hepatitis B - all forced by law for children in one place or

another. Dawn

<A

HREF= " http://www.nj.com/business/ledger/index.ssf?/business/ledger/1580e88.htm

l " >http://www.nj.com/business/ledger/index.ssf?/business/ledger/1580e88.html

</A>

Merck hit for plant problems

FDA cites the drug maker after Pa. plant inspections

01/08/02

BY ED SILVERMAN

STAR-LEDGER STAFF

Merck & Co. has been cited by federal regulators for numerous

quality-control problems at a manufacturing plant where several important

vaccines are made.

The Food and Drug Administration issued two enforcement reports -- extensive

reviews of manufacturing practices -- following inspections of a Merck plant

in Pennsylvania this past summer and fall, according to documents obtained

by The Star-Ledger.

After the second report was compiled in November, the Merck executive in

charge of vaccine operations at the West Point, Pa., plant took early

retirement, according to a company memo.

The FDA found Merck improperly performed procedures for sterility, testing

and documentation, among other things. They were noticed by regulators at

the same time Merck bid on -- and lost -- a $428 million contract to make

smallpox vaccine for the federal government.

Such inspections are routine in the pharmaceutical industry, but lengthy

enforcement reports aren't -- the second report was 22 pages. Ultimately,

Merck could face stiff fines if enough serious violations are found over a

prolonged period.

Meanwhile, people familiar with the situation say production at the plant

has been halted while new supervisors are trained. Between 300 and 400

people work there.

This is only the latest reversal of fortunes for the Whitehouse Station drug

maker, which makes some of the best-known medicines. Recently, patents

expired on some big-selling drugs, its Vioxx painkiller missed sales targets

and was linked to cardiovascular problems, and company officials scaled back

their earnings outlook.

" Merck's had a particularly tough year. And they've got a way to go to get

back on track, " said Mark Ravera, an analyst at Mehta Partners, a

health-care investment firm. " Something like this would not be a welcome

addition to their burdens. They certainly don't need any more bad press. But

the FDA has been really cracking down on everybody. "

Indeed, the FDA review is another example of how regulators, who have been

widely criticized for the way they approve new drugs, have become stricter

about enforcing manufacturing problems. In 2000, the FDA levied a large fine

on American Home Products Corp. and has recently cited plants run by

Schering-Plough Corp. and Eli Lilly & Co.

A Merck spokesman, Greg Reaves, declined to comment on dealings with the FDA

or the departure of the vaccines executive, Laser. Reached at home,

Laser, 55, declined to comment. " I don't think there are a whole lot of dots

to connect. "

Reaves also insisted any supply shortages are due to " voluntary "

interruptions in production, which he attributed to maintenance upgrades and

changes in manufacturing practices. But he stressed that shipments are

proceeding.

Among the problems the FDA found at Merck:

Timely inspections weren't performed after noticing sterility failures.

Discrepancies in the number of rejected batches weren't documented.

Spreadsheets used to determine questionable results weren't verified.

Sufficient air pressure in the building wasn't maintained properly.

The FDA typically doesn't comment on inspections that haven't yet been

resolved, but an FDA source said the Merck case remains open.

Products made at Merck's Building 29, part of a huge research and

manufacturing facility in West Point, include Varivax, a chicken pox

vaccine; a vaccine for MMR, or measles, mumps and rubella; and vaccines for

Hepatitis A and B, the spokesman confirmed.

Vaccines generated only about $1 billion in sales for Merck last year out of

total revenue of $21 billion. But Merck has repeatedly identified vaccines

as a growth engine. For instance, the company is working on an AIDS vaccine.

" Vaccines aren't as big as Zocor, " the cholesterol medication, said Hemant

Shah, an independent analyst who tracks drug makers. " But it's still an

important business. "

Ed Silverman can be reached at esilverman@... or at (973)

392-1542.

==================================================

We've been able to get a copy of the FDA's report on the inspections at

Merck that led to the closing of the PA facility last fall. MMR and Hep B

(among others) are produced there. It's a 23 page report, we've pulled the

highlights and posted at <A HREF= " http://www.vaccineawareness.org " >

www.vaccineawareness.org</A>.

It is truly scarey reading.

Sherry,

's Mom

<A HREF= " http://www.vaccineawareness.org/information/MerckInspection.htm " >

http://www.vaccineawareness.org/information/MerckInspection.htm</A>

Illinois Vaccine Awareness Coalition 1/2002

*Please note - '===' has been used to replace words/numerals that the FDA

has blacked out.

Food and Drug Administration Inspection/Observation Report of Merck &

Company on 8/6/01 and 10/29/01, released 1/4/2002;

Sent to Allan Shaw, Executive Director Virus/Cell Biology and R.

Laser, Vice President, Vaccine & Sterile Operation, 7700 Sumneytown Pike,

West Point, Pennsylvania, 19486

(23 pages total)

Quotes regarding improperly performed procedures-sterility, testing,

documentation:

" Raw data is being changed with no justification. "

" There is no procedure in place to determine when a Research Lab is assessed

to assure suitability for clinical testing prior to start up. "

" Spread sheets used to determine questionable results and retesting of

clinical samples for ===* has not been validated. "

" Notebooks do not identify each technician performing each task. "

" .during the aseptic filling of Recombivax, lot ===we observed foreign

material on the filler grates in the class 100 filling core of line ===

including an approximate 3 " diameter patch hanging down.The firm stated that

the materials was=== grease/caulk that was used to repair HEPA filters

during the recent recertification. "

" .ongoing supervisory oversight of personnel and housekeeping activities

failed to note the material and assure that the room was maintained in an

acceptable state of cleanliness. "

" The firm's investigation in to this deviation, as documented on ,=== is

deficient, in that concluded that there is no product impact for this and

other lots, solely because the adhered material did not impact air

laminarity and the material is an FDA-approved sealant, c) failed to discuss

the detection of===the material used for HEPA challenges during the

shutdown) on the filter grates.consequently, there is no documented

evaluation of the impact on product of this observation, and there are no

documented corrective and preventive actions to prevent the reoccurrence of

liquid=== on the downstream side of the HEPA filters. "

" .we observed deviations from the gowning requirements.involving 3 of the 4

employees engaged in aseptic filling operations on the two operating lines

(line === illing Recombivax, lot === line === filling Pneumovax, lot ===. "

" .they fail to document the root-cause for the systemic human errors.there

is no explanation of root cause for the failure to follow good aseptic

technique and line clearance procedures. "

" .we observed the following on the ceiling above partially stoppered

vials;=== a) droplets of an unknown substance suspended from the ceiling,

a missing light cover, and c) foreign material adhering to the ceiling. "

" .we observed: a) dust accumulated on the HEPA pre-filters.c) a cracked

light cover within the core. "

" we observed several black particles on the top horizontal surface of an

equipment cabinet in the . area of filling line. "

" .we observed a wood pallet which had an unidentified white powder

accumulated on it in use in room=== which is the sealing and inspection room

for department. "

" an audit conducted in 9/1998 noted that the aging infrastructure in Bldg.

29 has operational deficiencies including insufficient airflow. "

" .while the room pressure in the filling room dropped below the adjacent

inspection room.which is an unclassified environment. The two rooms are

connected by a mouse hole used to convey filled vials out of the filling

room. The batches were released by Sterile Product Release, despite numerous

alarms recorded in the === database signaling the out of control condition

and === data available at the time which showed the potential reversal of

unclassified air into the filling room. "

" The Standard Operating Procedures requires technician to be dispatched when

alarms exceed 30 seconds, yet there are multiple instances where this has

not occurred with regard to pressure differential alarms in Building 29. "

" Unsealed.vials of Varivax lyophilized powder are routinely held.and are

then sealed in an uncontrolled room.yet the container/closure study for the

unsealed.vial/stopper combination for this product.failed the microbial

ingress challenge.this container closure study was not submitted as part of

the supplement to the === for the process upgrade for this product . the

cover letter for this supplement also fails to note the new stopper as one

of the changes in the process upgrade. "

" There is no assurance that Varivax vials can maintain intended vacuum

levels. "

" The firm's investigation into the sterility failure of lot ===Varivax fails

to note, and therefore address, all potential causes for the failure,

including the container closure study which documented microbial ingress

into crimped containers. "

" The firm's investigation and corrective action with regard to the sterility

failure of Varivax lot === were inadequate, in that: they failed to

document the rationale for their determination of potentially associated

lots, and they continued to manufacture and release the product without

determining the root cause for the failure.c) they failed to enter the

suspect lot and the associated 'sister' lots into the quarantine system.e)

the (Standard Operating Procedures) only requires manufacturing

investigation to be initiated after the sterility failure is validated by a

laboratory investigation. This precludes a prompt determination of the root

cause for the failure, yet the firm will continue to ship potentially

associated product until a root-cause determination implicates additional

lots. "

" There is no objective definition . of the defect " dirt/debris/lubricant " as

it applies to incoming.acceptance inspection for rubber stoppers. In at

least one instance the change in the number of defects has resulted in the

acceptance of a lot that otherwise would have been rejected due to excessive

major defects. "

" .incoming . statistical inspection of the glass lot by Merck found ===

cracks out of ===

samples. This met the firm's release criteria for major defect.and the lot

was accepted for use.a portion of this glass was used in === product fills

and === vials were noted with manufacturing defect . initial manual

inspection of lot === of Comvax . found === cracks and the automated ===

inspection found === rejects. The lot was deemed acceptable and released. To

date, there have been three complaints on this lot ===for broken vials. "

" the qualification of the === Pin Hole Inspector is inadequate. The 1997

retrospective qualification failed to include an objective historical

evaluation of the performance of the machine. The evaluation of the ability

to detect unacceptable vials was only limited to a challenge with 10 vials

damaged in excess of the crack detection capabilities of the pin-hole

detector. The unquantified damage to the challenge vials was described as

'Cracked tips, sides, bottoms, underfilled.'

" On multiple occasions the firm has discovered leaking product pathways and

relied upon additional double sterility testing of the lot, or portions of

the lot, to determine the stability for release of the product manufactured

under this unvalidated condition:.Comvax.Recombivax. "

" we observed a silicon tube extending from the . drop into a sink in room. "

" An error in the . text and the failure to verify the accuracy with raw data

documentation caused the inadvertent release of product that the firm deemed

to be manufactured out of control conditions with regard to the air

differentials between the filling room ===and the uncontrolled inspection

room.and the uncontrolled, connected inspection room === Subsequent

investigation into this systemic deficiency by the firm resulted in the

identification of at least two other lots where incorrect situations:

Comvax, lots===. "

" The following six products had microorganisms on product contact surfaces

which should have initiated an action level response however they were

handled as an alert level response: a) Comvax===CFU (colony forming units)

on inside stopper bowl===this product was released. c) VAQTA===cfu on inside

stopper bowl===this product was released. e) MMR II¨¨¨cfu on fill

needles===This product is under quarantine. f) Comvax===cfu on fill

needles=== This product is under quarantine.

" an employee . had === CFU's on her gloves during sterile fill MMR II

production . Employee's retraining efforts included counseling on the

importance of proper aseptic technique as well as a gowning evaluation by a

production supervisor, however, the retraining did not include an evaluation

of her operations during an aseptic fill and there are no procedures to

direct such an observation.No corrective action is taken procedurally when

the same observation is made during the review of aseptic gowning. "

" The results of environmental monitoring samples designated 'routine' are

not captured in any system, so that the sterile products release groups is

aware of the finding when making a batch release decision; there are no

procedures to direct this information to be captured for quality release. "

" .===overhead circulation fans were not operating and there was a presence

of particles near the anchor bolts where the Cold Vault walls fasted to the

floor. The report did not mention the storage of Pepcid bulk lots === during

the time the sample was taken. "

" The rationale and justification of environmental monitoring samples for all

locations is not documented. "

" Control Monitoring requires only a gram stain to be performed for positive

growth on sites that result in alert levels. "

" The form has not conducted any recovery studies to qualify the swab method

and material utilized for swabbing product contact surfaces at the

conclusion of an aseptic fill. "

" .'Environmental Monitoring Plan for Classified Areas and Systems,'.is

unclear regarding the frequency of testing critical gown and fingertips of

all personnel involved in aseptic manipulations during product fills. The

inspection revealed that Sterile Product Release was making decisions on

products to be released to the market under the premise that all personnel

involved in aseptic manipulations were tested per fill; however, Control

Monitoring samples critical gown and fingertips of personnel involved in

aseptic fills of only those employees who are present at the time of

testing. "

" The air returns . are in the floor just below the doors for Lyophilizers

cabinet === The area under the grates of the air returns is not a part of a

routine scheduled cleaning procedure, but employees are directed to inspect

the area and clean when needed. For calendar year 2001, the area was cleaned

=== in February === in March ¨¨¨ in April and then === in September. "

" 'In-Line statistical secondary inspections of product filled in Lyophilized

operations. allows for reinspection without investigation of lyophilized

products when foreign product, incorrect stoppers or incorrect containers

are discovered during product inspection. "

" Process capability limits for sterile pharmaceutical and biological liquid

and lyophilized products were not calculated properly in accordance with .

'Establishing Product Specific Process Capability Limits (PCL),' . When a

PCL is exceeded, the firm's procedures required the completion of an

atypical report. "

" For example: a) Varivax === was operating at a PCL of === effective 7/7/01

and === effective 8/9/01, the result according to the current approved

procedure should have been === On 8/13/01, Fill Lot === had an PCL of ===

which should have triggered the initiation of an Atypical Progress Report

(APR). The APR was not initiated until October 20001. MMR II === was

operating at a PCL of === effective 4/21/01, the result according to the

current approved procedure should have been === on 4/29/01, Fill Lot === had

a PCL of === which would have triggered the initiation of an Atypical

Process Report (APR). The APR was not initiated until October 2001. "

" An Atypical Process Report === dated 2/22/01 reported finding particulates

in lyophilized vials of

MMR II lot === Investigation tied in Varivax as also having this issue. The

investigation determined the defect to be a fine dispersion of smaller

particles rather than a particulate: a) The source of stainless steel

elements found in vials of MMR and Varivax has not been determined, The

classification of the issue has resulted in reducing the level of defect to

minor from critical. Per procedure, 'In-Line Statistical Secondary

Inspections of Products Filled in Lyo Operations, ¨¨¨ effective 4/27/01 and

current version 10/05/01 a minor defect will allow up to === vials of

stainless steel particles out of === vials manually inspected whereas the

critical defect rejected on === vial, c) The vials with visible particulates

have not been placed on stability, and a safety assessment has not been

conducted, d) The automated inspection equipment . is not qualified to

detect and reject the lyo cake with visible stainless steel particles. There

are no procedures to direct 1000% Manual inspection of lots of MMR or

Varivax, even though the automated inspection process is not capable of

rejecting vials with the visible aggiomerated Stainless Steel particles. "

" Since 2/22/01, there have been a total of === lots of these three products

associated with this stainless steel particle issue a) ===lots of MMR II ===

lots were released, === lots are pending release, ===lots are quarantined,

and === lot was rejected, === lot of Meruvax (MMR family) was released,

c) === lots of Varivax Process Upgrade === lots quarantined === lots pending

release. "

" Available documentation shows that new employees participated in aseptic

operations in the sterile core prior to completing prerequisite training and

qualification. "

" Media fills conducted in Building 29 routinely fail to provide adequate

assurance in the ability to set up and operate the filling lines

aseptically, in that: a) Media fills are performed by setting up the

apparatus, filling diluent for === then switching to the media and filling

to a target of === vials. This practice fails to capture aseptic breaches

during setup because the system has been flushed for ¨===prior to collecting

media, Media fill procedure allows unlimited production rejects . Rejects

have reached as high as === in a batch with an actual yield of ===

Furthermore, the reason for the rejects is not documented, c) Vials are

rejected for non-container closure integrity issues such as cosmetic flaws. "

" The media fill challenge program is inadequate, in that a) Not all lines

are challenged twice per year per shift. "

" HEPA filtration systems over some . filling areas had a record of

repeatedly failing. For example, HEPA certification reports for Line === for

the period 12/98 to 7/01 show: Winter 1998, Summer 1999, Winter 1999 ===

filters failed and replaced, Summer 2000 === filters failed and replaced .

filters resealed, Summer 2001=== filters failed and replaced===. "

" The firm lacks corrective/preventive actions given that the filters are

documented to fail repeatedly. Quality Assurance and Product Release were

not advised on the pattern of failing filters out of the magnitude of the

failures to assess product impact. "

" Firm uses " Aseptic Manipulations Testing' to qualify personnel to

participate in sterile operations. Aseptic Manipulations Testing is an

inadequate surrogate for media challenges in the : a) The test fails to

simulate personnel interaction, movement, equipment failure, and time

pressure of the production line, Employees pass this test without

training . c) The test permits the operator to reject any number of vials

for any reason. These rejects are not documented, d) There is no opportunity

to violate === air because the operation is performed in a sitting position,

e) The testing is of short duration and fails to simulate operator fatigue. "

" Employees that participate in failed media fill challenges are allowed to

continue to work in the sterile core conducting aseptic operations prior to

being requalified for aseptic operations. "

" Errors in calculating the results of moisture determinations were not

documented for over one year by the Sterile Products Laboratory. Neither the

data analysts nor the supervisors noticed these errors upon second review . "

" There was no second review signature, and therefore no verification of raw

data, observed on many Sterile Pharmaceutical Testing Laboratory notebook

pages as required . "

" Sample transfers from manufacturing were not always done properly. "

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