Product Cleaning Campaign was exceeded during the packaging process of Lyrica 100mg x 90's at Line 11 Event: On 09/16/10

during the first shift, it was observed that the Product Cleaning Campaign was exceeded during the packaging process of Lyrica 100mg x 90's at Packaging Line 11 as per SOP. Lot V101360 was the six consecutive lot packaged of Lyrica 100mg Cap 90's presentation. SOP VB-PKG-002 "Limpieza de las Lneas de Empaque" establish that a major cleaning of the product contact parts is to be performed after the packaging of five (5) consecutive lots or no more than 104 hours for this presentation. At the time the event was observed, packaging lot V101360 was already completed.

Se utilizo el comil U-20 (P00862) con una limpieza parcial luego de 7 dias cuando lo que aplicaba era una limpieza mayor On 09/06/07 the Comil U-20 was used for the manufacturing of Neurontin 600mg lot 16567V with an interval cleaning after 7 days of use, instead of the required major cleaning. As per SOP PRO-207 a major cleaning is required after processing 15 consecutive lots of Neurontin/ Greenstone Gabapentin Tablets or a maximum of seven (7) days, whichever occurs first. The Comil U-20, asset # P00862 was major clean on 08/27/07, and the seventh lot of the campaign, 16567G, was milled on 09/04/07, eight days after the major cleaning was performed. Defining a campaign for the purpose of cleaning validation it is a series of consecutive batches and/or days of the same product manufactured in a piece or train of equipment. When considering campaigns, the main thing to be evaluated is the buildup of microbial residues. Taking this into consideration the Neurontin 600mg Score tablets lot 16567V was tested for microbiological load to demonstrate that microbial residues were maintained with specification. Microbial count Specification Results: Bacteria Max 1000 cfu/g < 100 cfu/g Mold + Yeast Max 200 cfu/g < 100 cfu/g Indicator Organism Escherichia coli None Negative The data demonstrates that the deviation did not adversely affect the microbial load of the product. Technical Services concludes that the deviation did not adversely affect Neurontin 600mg Score Tablets lot # 16567V.

Precisa 18 (052177) and capsule polisher 053377 both exceeded major cleaning time while encapsulating lot 15967C. Precisa 052177 in room #1007 exceeded the 34 days allowed before a major clean up due to start problems with the machine's control panel. Lyrica 75mg lot 15967 was being inspected at the time but was not impacted by the event according to microbiologycal sample results.

El uso de la Korsch ( K-3 ) excedi el largo de campaa establecido de 20 lotes o 16 das. Se excedi uso por 7 das Description of Event : Equipment cleaning holding time exceeded for compress machine T00339, metal detectors 050006, 053800 and dedusterT01906 for 7days. Assignable Cause : The manufacturing operators keep focus in the total lots of the campaing instead of the days establised for the cleaning holding time. It was a deviaton to SOP VB-PRO-0188 Impact of event : Based on the information presented above Technical Services does not foresee any unfavorable impact from a technical standpoint on Lipitor lots. Corrective & Preventive Actions : SOP VB-PRO-185 will be revised . The event will be discussed with all the operators.

Line Cleaning Limit Exceeded for Azithromycin 250mg in Line 8, SOP VB-PKG-002 Event: The cleaning validation expiration limit for Azithromycin 250mg Tab was exceeded during the packaging of Lot V090755 in Blister Line 8. Assignable Cause: The cleaning validation expiration limit of the presentation in SOP VB-PKG-002 was not verified by the operators on 05/11/09. Each operator claimed it was an oversight on their behalf. The event was detected on on 05/12/09. Corrective action: 1) A discussion of the event, the investigation process and the impact was held with the packaging personnel. Evidence of the discussion is attached for reference. 2) In order to reduce the probability of re-occurence of the event, a visual aid in the form of a label, was placed on the front cover of the Cleaning Logbooks of all blister and bottle packaging lines making reference to the verification of the cleaning validation expiration limit of SOP VB-PKG 002 at the start of each shift. An example of the Cleaning Logbook with the verification label is attached for reference.

A product container (T02927) was used verification.

for commercial lot without

cleaning

Description of Event: Container T02927 was originally used for Fesoterodine 8 mg tablets lot T0069T. This lot required visual inspection due to coating defects. In order to inspect the lot, the container was emptied and the tablets were transferred into drums. Container T02927 was kept in the area with the intention of reusing it after completing the inspection. Therefore, the equipment was not identified in any special way nor a cleaning verification was requested. The inspection took longer than planned and another colleague saw the empty container, took the container and sent it for cleaning. After the equipment was cleaned and dried, since the equipment was not identified, the compressing operator understood that the cleaning validation was completed and that the equipment could be used for different products and used the container to store Neurontin tablets lot 09VNT047. Lot 09VNRT047 was bulk packaged as lots 01039V and 01209V. A cleaning verification swab sampling was required for the equipment since this product is new on the facility. The operator that used the container is trained in Standard Operating Procedure (SOP) VB-PRO-060 "Utilizacin de equipos de manufactura". SOP VB-PRO-060 establishes that every equipment may be used for multiple products if the cleaning validation for the last product processed is approved. It then requires to verify if the product for which the equipment will be used has cleaning validation. If the cleaning validation is not approved, a cleaning verification is required and the equipment and logbook must be identified with a label indicating that cleaning verification is required. The container was intended to be used for the same product and lot for which it had been previously used; therefore, it was not identified. Thecleaning validation verification should be done using the Equipment Cleaning Validation List and the list is not currently available. The last product processed, Fesoterodine, does not have approved cleaning validation studies. The product for which the container was going to be used, Neurontin, has approved cleaning validation studies. Based on the current requirements a single run is required if a new product is included in the validated product matrix to confirm the adequacy of the cleaning procedure in the removal of the product residues to an acceptable level. Therefore, a cleaning verification run was performed after the Major Cleaning of PC 053030 used during the compression process of Fesoterodine 8mg lot V0069V2. Based on the fact that the Bin Washer is a validated automated system, results obtained during the cleaning verification process of PC 053030 will be applicable to PC T02927. The Residue Acceptability Limit (RALT) calculation for a product combination considering Fesoterodine 8mg as Product A and Neurontin 600mg as Product B was conducted to determine the acceptable limit during the cleaning verification process of the PC. The Residue Acceptability Limit calculated for a product combination considering Fesoterodine 8mg as Product A and Neurontin 600mg as Product B is 38.68 g A / in2. Results reported for PC 053030 cleaning verification were ND = non detected (Limit of Quantitation = 0.11 g/in2). Results obtained for PC 053030 demonstrate that the cleaning performed for the PC was effective in reducing the residues of active ingredient below the pre-determined acceptance criteria of 38.68 g A / in2 calculated for the product combination Fesoterodine 8mg Neurontin 600mg Tablets.

Dilantin 100 mg empty capsules were found in the sorter air filter canister previously Lyrica lot were processed. Description of Event On July 06, 2009, the manufacturing operator found three (3) Dilantin 100 mg empty capsules during the IMATIC (C-10) machine empty capsule sorter setup jog in process. The capsules fell from the empty capsules sorter filtered air line. The manufacturing operator and the mechanic opened the utilities cabinet of the empty capsules sorter and found approximately 350 empty Dilantin 100 mg capsules inside the filter canister. The filtered air is used for the pneumatic transfer system to deliver empty capsules from the capsule sorter to the capsule filler. The empty capsules sorter set up was performed after a major cleaning process when a Lyrica 50 mg Capsules lot 09VLYE104 encapsulation was completed. A total of 16 Lyrica 50 and 100 mg capsule bulk lots were manufactured after the last Dilantin 100 mg capsule lot was encapsulated on 04/28/2009. Scope of Impact A total of 12 out of the 16 Lyrica bulk lots produced after the Dilantin campaign were already packed into 13 finished product lots. The four bulk lots still at the plant were placed on hold status. A stop distribution notice was issued on July 06, 2009 for the 13 lots at the distribution center. Two lots were already marketed. This incident could be considered as an isolated event and exclusively related to Dilantin capsule filling process based on investigation results. Based on the investigation finding the immediate and further action performed and the inspection performed to manufacturing lots and waste we can conclude the probability to have Dilantin empty capsules in Lyrica lots is negligible.

Product Cleaning Campaign was exceeded during the packaging process of Lyrica 100mg x 90's at Line 11 Event: On 09/16/10 during the first shift, it was observed that the Product Cleaning Campaign was exceeded during the packaging process of Lyrica 100mg x 90's at Packaging Line 11 as per SOP. Lot V101360 was the six consecutive lot packaged of Lyrica 100mg Cap 90's presentation. SOP VB-PKG-002 "Limpieza de las Lneas de Empaque" establish that a major cleaning of the product contact parts is to be performed after the packaging of five (5) consecutive lots or no more than 104 hours for this presentation. At the time the event was observed, packaging lot V101360 was already completed.