Annexure - III
Investigation Report Format I/QA/18/034
Purpose of this incident investigation to identify the probable root cause for observed lubricated granules yield i.e. 101.53 % more than the specified limit in BMR i.e. 96 to 100 % for product Common blend for fenofibrate capsules USP (Micronized) 67, 134 and 200 mg.
This incident investigation is applicable to following;
Product name: Common blend for fenofibrate Capsules USP (Micronized)
Generic name: Common blend for fenofibrate Capsules USP (Micronized)
Batch number: 12818003
Batch Size: 177.84 Kg
Client: Amerigen pharmaceuticals, USA market.
Common blend for Fenofibrate Capsules USP (Micronized) 67 mg, 134 mg and 200 mg is one of the product manufactured in Inventia Healthcare Ltd. at Ambernath plant for client: Amerigen Pharmaceuticals (USA market).
Manufacturing process are involved sifting, dry mix, wet granulation, drying, sifting, milling, blending & lubrication. After lubrication stage, Standard yield was calculated and it was found more than specified limit. Standard yield: 100.53% (Limit: 96%-100%).This observation was noted during batch record review at client end.
Hence this incident management is raised to investigate the probable root cause for getting less yield and to suggest suitable corrective and preventive action.
Brain storming was carried out and identified following probable reason for getting higher yield.
- Quantity of milled granules transferred to lubrication
- Batches run in campaign and probably may be during granulation and drying previous batch material in small quantities may carry forward in next batch.
- Lower loss on drying and more holding time before lubrication
- Difference in specified yield limit for milled granules limit is 95 to 101 % and lubricated granules limit is 96 to 100 %.
To identify the probable cause batch manufacturing record review was carried out.
➢ Input material for each stage i.e. wet granulation, drying, sizing and lubrication is carried .Weight recorded at each stage for each material verified.
➢ Loss on drying of granulation lot was checked against the mentioned specification i.e. NMT 1.0 % w/w and observed loss on drying in batch under investigation was 0.76 % w/w. Loss on drying was observed well within specification.
➢ Quantity of milled granules transferred for lubrication was verified. Yield of milled granules was observed 100.7 % (limit is 95% to 101%) which was within specified range. But yield of milled granules comparatively more than previous two batches (For B. no. 12818001-97.02% and for B.no.12818002- 97.13%). B.Nos.12818001,
SOP Ref. No. : CQ/003 Page 2 of 4
Format No.: CQ/003/F-03
12818002, 12818003 were manufactured in campaign and batch under investigation was the last batch in campaign.
➢ Previous product/batches manufactured and its yield was checked and observed that in one campaign after product changeover yield of milled granules of first batch observed lower comparatively to the last batch in the same campaign.
Data of input material, loss on drying of dried granules, milled granules output is compared and tabulated on next page.
- Holding period of dried granules to lubrication stage checked and found that activity was in continuous and holding of material was not observed till lubrication activity. Hence yield because of intermittent storage/holding of granules. Lower loss on drying and more holding time before lubrication and may be in between, weight gain by granules is ruled out.
➢ At milling stage handling waste was 0.42 kg is less as compared to previous two batches (For B. no. 12818001-1.50kg and for B.no.12818002- 1.20 kg). At milling stage less losses observed as compared with earlier batches. This may be one of probable cause for getting more yield at milled granules stage.
➢ Batches run in campaign and on preliminary investigation it was observed before first batch in campaign product changeover was taken and later on batch to batch changeover was taken. At the time of line clearance it was ensured that no remnant of previous batch present. Procedure is in place hence possibility of small quantities carry forward in next batch is minimum or less. It doesn’t have significant impact on yield.
➢ Another probable reason may be variation in specified yield limit for milled granules limit is 95 to 101 %) and lubricated granules limit is 96 to 100 %. After milling, yield of milled granules of batch under investigation was 100.7 % which was well within the milled granules yield specification.
➢ As mentioned in BMR, if yield of milled granules observed less than 98 % then further lubricant quantity calculation shall be done. In this case yield was more than 100 % hence no further calculation was required and mentioned quantities of excipient in bill of material were dispensed as it was. Hence with addition of lubricant quantities, chance of yield more than 100 % is obvious. Which is more than the mentioned BMR limit
➢ Yield limit for sized granules and lubrication stage were made stringent in the batch under investigation against the change control number C/QA/18/025. 12817001to 12817006 are the validation batches. 12818001 to 12818003 are the normal batches.
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Format No.: CQ/003/F-03
Comparison data of granulation and lubrication activity:
Lot No. ( LOD in % w/w)
NMT 1.0 % w/w at 60 °C
Sized Granules Wt. (Kg.)
Handling Waste (Kg.)
Total sized granules Wt. in Kg ( Std. Qty.: 159.69 Kg)
( % yield)
Limit 95 to 103 %
Lubricated Granules wt. ( Kg)
( % yield)
Limit 94 to 103 %
Rejection during Lubrication
Limit 95 to 101 %
Limit 96 to 100 %
SOP Ref. No. : CQ/003 Page 4 of 4
Format No.: CQ/003/F-03
During sizing of dried granules less handling waste observed in comparison with earlier batches. This leads to more yield at sizing stage but within the limit i.e. 100.7 % (limit was 95 to 101 %) however on further addition of lubricant it was observed to 100.53 % which is out of limit of yield at lubrication stage (limit 96 to 100%).
Yield observed at milled granules stage was 100.7 % which was within its specification limit. After addition of lubricants it observed 100.53 %. This was out of specification.
Yield at sizing stage observed higher may be because of less handling waste in comparison with earlier batches trend. No losses observed during lubrication activity.
- Reference incident number shall be mentioned on BMR.
- Finished product analysis results with respect to assay and related substance of capsules checked and found complying and in line with trend.
Yield observed marginally higher at lubrication stage, analysis of lubricated granules and finished product found complying. No risk identified to granules quality.
Based on next 10 batches data, yield limit to be revisited