Illinois Vaccine Awareness Coalition 1/2002

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 James 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 b) 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, b) 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: b) 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. b) 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, b) 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, b) === 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, b) 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, b) 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."

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

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