1.
21 CFR 211.192
pharmauptoday@gmail.comConsult Yourself.... “Know Regulation - No Observation”

2.
- 2014 inspectional observations
- List of Top observations in 2014
- Sec. 21 CFR 211.192
- 483 observations
- Warning Letters
- Other Guidance
- How to avoid observations
- Batch Record Review
- Investigations
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Contents

3.
Total Inspectional Observations
Center Name 483s Issued
Foods 2476
Devices 972
Drugs 645
Veterinary Medicine 337
Bioresearch Monitoring 297
Biologics 146
Human Tissue for Transplantation 115
Parts 1240 and 1250 70
Radiological Health 16
Sum Product Area 483s from System* 5074
Actual Total in System 483s** 4943
Number of 483s Issued from the System*
Inspections ending between 10/1/2013 12:00:00 AM and 9/30/2014 12:00:00 AM

4.
Inspectional Observations - Drugs
Summary Count (Number)
Total 483’s issued for Drugs center in 2014 645
Total number of observations issued for Drugs center in 2014 2997
Total number of observations related to cGMP (21 CFR part 211) violations 2835
Total number of top 10 CFR part 211 violation 1653 (58%)
Total number of top 15 CFR part 211 violation 2110 (74%)
Total number of top 20 CFR part 211 violation 2398 (85%)
Number of CFR part 211 parts violated 54

5.
S.No. CFR Frequency % S.No. CFR Frequency % S.No. CFR Frequency %
1 21 CFR 211.160 235 8.3 19 21 CFR 211.186 48 1.7 37 21 CFR 211.204 10 0.4
2 21 CFR 211.22 218 7.7 20 21 CFR 211.63 41 1.4 38 21 CFR 211.101 9 0.3
3 21 CFR 211.192 209 7.4 21 21 CFR 211.80 41 1.4 39 21 CFR 211.105 6 0.2
4 21 CFR 211.67 184 6.5 22 21 CFR 211.142 32 1.1 40 21 CFR 211.115 6 0.2
5 21 CFR 211.100 167 5.9 23 21 CFR 211.167 32 1.1 41 21 CFR 211.134 6 0.2
6 21 CFR 211.165 143 5.0 24 21 CFR 211.170 31 1.1 42 21 CFR 211.82 6 0.2
7 21 CFR 211.42 143 5.0 25 21 CFR 211.125 29 1.0 43 21 CFR 211.196 5 0.2
8 21 CFR 211.113 128 4.5 26 21 CFR 211.56 28 1.0 44 21 CFR 211.44 5 0.2
9 21 CFR 211.166 115 4.1 27 21 CFR 211.150 23 0.8 45 21 CFR 211.48 4 0.1
10 21 CFR 211.25 111 3.9 28 21 CFR 211.46 20 0.7 46 21 CFR 211.52 4 0.1
11 21 CFR 211.68 99 3.5 29 21 CFR 211.122 19 0.7 47 21 CFR 211.184 3 0.1
12 21 CFR 211.198 95 3.4 30 21 CFR 211.130 19 0.7 48 21 CFR 211.86 3 0.1
13 21 CFR 211.84 91 3.2 31 21 CFR 211.58 18 0.6 49 21 CFR 211.87 3 0.1
14 21 CFR 211.110 89 3.1 32 21 CFR 211.182 17 0.6 50 21 CFR 211.34 2 0.1
15 21 CFR 211.194 83 2.9 33 21 CFR 211.103 14 0.5 51 21 CFR 211.65 2 0.1
16 21 CFR 211.188 74 2.6 34 21 CFR 211.137 13 0.5 52 21 CFR 211.89 2 0.1
17 21 CFR 211.180 72 2.5 35 21 CFR 211.111 12 0.4 53 21 CFR 211.176 1 0.0
18 21 CFR 211.28 53 1.9 36 21 CFR 211.94 11 0.4 54 21 CFR 211.208 1 0.0
21 CFR 211 Observations - Drugs

6.
21 CFR 211 Observations - Drugs
0
50
100
150
200
250
21CFR211.22
21CFR211.25
21CFR211.28
21CFR211.34
21CFR211.42
21CFR211.44
21CFR211.46
21CFR211.48
21CFR211.52
21CFR211.56
21CFR211.58
21CFR211.63
21CFR211.65
21CFR211.67
21CFR211.68
21CFR211.80
21CFR211.82
21CFR211.84
21CFR211.86
21CFR211.87
21CFR211.89
21CFR211.94
21CFR211.100
21CFR211.101
21CFR211.103
21CFR211.105
21CFR211.110
21CFR211.111
21CFR211.113
21CFR211.115
21CFR211.122
21CFR211.125
21CFR211.130
21CFR211.134
21CFR211.137
21CFR211.142
21CFR211.150
21CFR211.160
21CFR211.165
21CFR211.166
21CFR211.167
21CFR211.170
21CFR211.176
21CFR211.180
21CFR211.182
21CFR211.184
21CFR211.186
21CFR211.188
21CFR211.192
21CFR211.194
21CFR211.196
21CFR211.198
21CFR211.204
21CFR211.208

7.
List of “Top 20 – CFR parts to know”
S.No. CFR Frequency %
1 21 CFR 211.160 235 8.3
2 21 CFR 211.22 218 7.7
3 21 CFR 211.192 209 7.4
4 21 CFR 211.67 184 6.5
5 21 CFR 211.100 167 5.9
6 21 CFR 211.165 143 5.0
7 21 CFR 211.42 143 5.0
8 21 CFR 211.113 128 4.5
9 21 CFR 211.166 115 4.1
10 21 CFR 211.25 111 3.9
11 21 CFR 211.68 99 3.5
12 21 CFR 211.198 95 3.4
13 21 CFR 211.84 91 3.2
14 21 CFR 211.110 89 3.1
15 21 CFR 211.194 83 2.9
16 21 CFR 211.188 74 2.6
17 21 CFR 211.180 72 2.5
18 21 CFR 211.28 53 1.9
19 21 CFR 211.186 48 1.7
20 21 CFR 211.63 41 1.4
Total 2398 85
• The top 10 cGMP violations (21
CFR part 211 observations)
comprises a huge percentage
(58% i.e. 1653 number of
observations).
• The top 20 cGMP violations (21
CFR part 211 observations)
comprises a huge percentage
(85% i.e. 2398 number of
observations).
• If the top 20 violations are
eliminated, 85 % of the
observations can be reduced.

8.
Subpart I--Laboratory Controls
Sec. 211.160 General requirements.
21 CFR 211.160 (a)
21 CFR 211.160 (b)
21 CFR 211.160 can be accessed from the link:
http://www.slideshare.net/skvemula/top-20-observation-
series-1-21-cfr-211160
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21 CFR 211.160

9.
Subpart B--Organization and Personnel
Sec. 211.22 Responsibilities of quality control unit.
21 CFR 211.22 (a)
21 CFR 211.22 (b)
21 CFR 211.22 (c)
21 CFR 211.22 (d)
http://www.slideshare.net/skvemula/top-20-observation-
series-2-21-cfr-21122
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21 CFR 211.22

10.
Subpart J--Records and Reports
Sec. 211.192 Production record review.
21 CFR 211.192
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21 CFR 211.192

11.
483 citations related to 21 CFR 211.192
Year Number
2006 176
2007 163
2008 131
2009 165
2010 182
2011 229
2012 179
2013 239
2014 209
0
50
100
150
200
250
300
2006 2007 2008 2009 2010 2011 2012 2013 2014
483 Observations

12.
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Regulation

13.
CFR part 211 Regulation - 21 CFR 211.192
Sec. 211.192 Production record review.
All drug product production and control records, including those for packaging and
labeling, shall be reviewed and approved by the quality control unit to determine
compliance with all established, approved written procedures before a batch is released or
distributed.
Any unexplained discrepancy (including a percentage of theoretical yield exceeding the
maximum or minimum percentages established in master production and control records)
or the failure of a batch or any of its components to meet any of its specifications shall be
thoroughly investigated, whether or not the batch has already been distributed.
The investigation shall extend to other batches of the same drug product and other drug
products that may have been associated with the specific failure or discrepancy.
A written record of the investigation shall be made and shall include the conclusions and
follow-up.

14.
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Previous observations

15.
483 citations related to 21 CFR 211.192
Cite Id Reference Number Short Description Long Description
Frequency
2014 2013
2027 21 CFR 211.192
Investigations of
discrepancies, failures
There is a failure to thoroughly review [any unexplained discrepancy]
[the failure of a batch or any of its components to meet any of its
specifications] whether or not the batch has been already distributed.
Specifically, ***
94 131
4402 21 CFR 211.192
Written record of
investigation incomplete
Written records of investigations into [unexplained discrepancies] [the
failure of a batch or any of its components to meet specifications] do
not [always] include the conclusions and follow-up. Specifically, ***
38 32
2028 21 CFR 211.192
Extent of discrepancy,
failure investigations
Investigations of [an unexplained discrepancy] [a failure of a batch or
any of its components to meet any of its specifications] did not
extend to [other batches of the same drug product] [other drug
products that may have been associated with the specific failure or
discrepancy]. Specifically, ***
32 26
4576 21 CFR 211.192
No written record of
investigation
Written records are not [always] made of investigations into
[unexplained discrepancies] [the failure of a batch or any of its
components to meet specifications]. Specifically, ***
24 22
2026 21 CFR 211.192
Quality control unit review
of records
Drug product production and control records, are not [reviewed]
[approved] by the quality control unit to determine compliance with
all established, approved written procedures before a batch is
released or distributed. Specifically, ***
21 28

16.
483 citations related to 21 CFR 211.192
Ref: 483 of Teva Parenteral Medicines Inc (07/2009)

17.
483 citations related to 21 CFR 211.192
Ref: 483 of Ameridose LLC (10/2012)

18.
Warning letter observations -2015 - 21 CFR 211.192
Your quality control unit failed to review and approve all drug product production
and control records to determine compliance with all established, approved written
procedures before a batch is released or distributed (21 CFR 211.192).
b. Your firm’s implementation of the audit program described in the Global Policy "Audit
Program" document #GPOL-015 dated September 7, 2013 is inadequate in that it failed to
prevent the recurrence of testing unofficial samples of drug product prior to testing the
official sample and generating only those results to be reported.
c. In addition the inspection revealed that failing or otherwise atypical results were not
investigated, nor included in the official laboratory control records as required by 21 CFR
211.192. We reiterate that an investigation is necessary for any out-of-specification (OOS)
event. Refer to the FDA's guidance on OOS investigations.
Ref: WL: Apotex Research Private Limited 1/30/15 (WL: 320-15-06)

19.
Warning letter observations -2014 - 21 CFR 211.192
Your firm did not properly document or investigate out-of-specifications (OOS) and
other discrepancies(21 CFR 211.192).
For example, the inspection documented that OOS Investigation #1203, related to the
presence of metal particles in (b)(4), failed to determine the root cause of the
contamination or explain why the (b)(4) step was unable to prevent the contamination
Ref: WL: Novacyl Wuxi Pharmaceutical Co., Ltd. 12/19/14 (WL: 320-15-04)

20.
Warning letter observations -2014 - 21 CFR 211.192
Your firm failed to thoroughly investigate any unexplained discrepancy or failure of
a batch or any of its components to meet any of its specifications, whether or not
the batch has already been distributed (21 CFR 211.192). For example,
Your firm failed to conduct thorough investigations of your environmental monitoring (EM)
excursions (i.e., exceeds action levels) found in your Class 100 areas. During the
inspection, the review of the available data for the period of January 2012 to December
2013 revealed that your firm identified 23 EM samples that exceeded action levels in the
Class 100 aseptic area on Line (b)(4) in your building identified as Hikma (b)(4). Our review
of the investigations collected during the inspection noted that all investigation reports
identified “possible root causes” of the EM excursions as mishandling and/or poor aseptic
technique during sampling. In all of these investigations you were unable to determine an
actual root cause; yet, you disregarded the EM excursions without justification. In
addition, your firm failed to evaluate the potential impact of these EM excursions on the
quality of the product manufactured.
Ref: WL: Hikma Farmaceutica, (Portugal) S.A. 10/21/14 (WL: 320-15-003)

21.
Warning letter observations -2014 - 21 CFR 211.192
Your firm failed to thoroughly investigate unexplained discrepancies or failures of a
batch or its components to meet its specifications, whether or not the batch has
already been distributed (21 CFR 211.192). For example,
a. Several out-of-specification (OOS) results for the impurity (b)(4) ((b)(4)) from the
stability studies of multiples batches of (b)(4) Injection were inadequately investigated.
In April 2013, testing at the (b)(4) stability interval for batch (b)(4) resulted in OOS values
for (b)(4). The results obtained for one of the three vials tested in duplicate were
OOS, with values of (b)(4)% and (b)(4)% (specification: avg. of 3 vials NMT (b)(4)%). Your
firm’s investigation PRID 128835, initiated on April 29, 2013, concluded that the(b)(4) in
the (b)(4) of the vials was the cause for the OOS, but no action was taken with respect to
the affected batch. This investigation also referenced an earlier OOS result of (b)(4)% for
the same impurity for batch (b)(4) at the 12-month stability interval. You concluded that the
OOS for batch (b)(4) was an isolated event and no action was taken with respect to the
affected batch.
Ref: WL: Hospira Australia Pty Ltd. 9/26/14 (WL: 320-14-15)

22.
Warning letter observations -2013 - 21 CFR 211.192
• Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch
or any of its components to meet any of its specifications, whether or not the batch has
already been distributed (21 CFR 211.192).
• For example, on multiple occasions, you failed to perform failure investigations for rejected batches
or implement any preventive actions.
The inspection found that your firm failed to perform an investigation for the failure of (b)(4) Injection
(b)(4) mg/ml lot (b)(4) to meet in-process pH requirements. This failing pH result was confirmed by
your QC laboratory. Additionally, you rejected filled (b)(4) Injection lot (b)(4) when sub-lots failed to
meet the particle in-process acceptance criteria, but did not conduct an adequate investigation into
that failure. In your response, you stated that the “…process is known to generate occasional out of
limit in-process (b)(4) aggregate particle density results…” However, you did not provide your
determination of actual root cause for this failure to meet in-process limits. Additionally, you noted
that the sponsor of this product is planning (b)(4) activities for this process and will target consistent
particle results as part of the validation of the new process. Please note that your firm is expected to
conduct thorough investigations for each failure to meet specifications, regardless of future plans for
validation.
Ref: WL: Jubilant Hollister Stier General Partnership 2/20/13 (WL: 320-13-08)

23.
Warning letter observations -2013 - 21 CFR 211.192
Your firm failed to thoroughly investigate any unexplained discrepancy or failure of
a batch or any of its components to meet any of its specifications, whether or not
the batch has already been distributed (21 CFR 211.192).
Two examples of this violation include:
• Lot #JU83 of Infant Gripe Mix failed the pH specification. The range was (b)(4) to (b)(4), whereas
the result recorded in the batch record was (b)(4).
• Lot # KM40 of Diphenhydramine Expectorant failed specific gravity and (b)(4). The results for
specific gravity and (b)(4) were (b)(4) and (b)(4), whereas the acceptable ranges were (b)(4)-
(b)(4) and (b)(4)-(b)(4), respectively.
Ref: WL: P.A. Benjamin Manufacturing Co., Ltd. 1/29/13 (WL: 320-13-07)

24.
Warning letter observations -2013 - 21 CFR 211.192
Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its
components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR
211.192).
Our investigator found that your firm released partial batches to the U.S. market without specific criteria for the partial
release decision and without appropriate investigations. You have been cited for the same practice in previous
warning letters. Indeed, your firm released at least 76 sublots from January 2011 to August 2012 without adequate
investigations.
• For example, on April 13, 2011, while (b)(4) the (b)(4) during the (b)(4) step for (b)(4) tablets, batch (b)(4), your
operator noticed five tablets with breached (b)(4) in (b)(4), a critical defect. The documentation available indicates that
the (b)(4) used for (b)(4) of the tablets was (b)(4) prior to the start of (b)(4), and your firm re-sampled (b)(4) and found
that (b)(4) had one critical defect. Your firm permits zero critical defects at the (b)(4) step. Your firm rejected
(b)(4). On May 4, 2011, your firm released the tablets from (b)(4) to market as batch #(b)(4). Your investigation and
your response indicate that the breached (b)(4) was attributed to the use of a (b)(4) with rough edges and variation of
the (b)(4) technique.
• In addition, on May 25, 2011, during the compression of (b)(4) tablets batch #(b)(4), your Quality Control Unit rejected
a portion of the batch due to black specks observed on the tablets. However, your firm failed to identify the
contaminant(s) found in this lot, and according to your investigation report, you were not able to determine a definitive
root cause. In your September 14, 2012 response you indicated that the specks may have been linked to punches
and punch seals, and that you released for distribution the remaining sublot, as #(b)(4).
Ref: WL: Apotex Inc. 2/21/13 (WL: 320-13-09)

25.
Warning letter observations -2013 - 21 CFR 211.192
Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any
of its components to meet any of its specifications, whether or not the batch has already been
distributed (21 CFR 211.192).
• Your firm failed to conduct an adequate investigation that should have resulted in your implementation of
corrective actions to prevent recurrence of the problem and evaluate other potentially affected
lots. Specifically, on April 17, 2012, your (b)(4) site reported that out-of-specification (OOS) endotoxin
results were at or above the (b)(4) EU/ml limit in Torisel Diluent batch AGMV/1. We note that a portion of
batch AGMV/1 was shipped to a contractor, (b)(4), for distribution to the U.S. market, on January 5, 2012.
• Your investigation into the (b)(4) Torisel Diluent batch AGMV/1 failures began on April 17, 2012, and you
continued to test and re-test samples from this lot through August 14, 2012. In an attempt to find the root
cause of the OOS results, your firm used different endotoxin testing platforms, tested at three different
laboratories, wiped external vials with (b)(4), and used (b)(4) to try to mitigate endotoxin failed
results. Subsequently, your firm tested nine Catania AGMV/1 retain samples and six (b)(4) AGMV/1
samples on multiple dates with several failures. In addition, your firm sent one Catania AGMV/1 retention
sample and one (b)(4) AGMV/1 sample to an external testing laboratory. The extensive repeat testing of
(b)(4) Torisel Diluent batch AGMV/1 samples resulted in inconsistent passing and failing results. At no
point did you conduct quantitative endotoxin testing to determine the extent of the endotoxin specification
failure.
Ref: WL: Wyeth Lederle S.p.A 3/27/13 (WL: 320-13-10)

26.
Warning letter observations -2013 - 21 CFR 211.192
• Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch
or any of its components to meet any of its specifications, whether or not the batch has
already been distributed (21 CFR 211.192).
• For example, your firm failed to determine the cause of the OOS for Spiriva
HandiHaler lot 908679 that failed the uniformity of delivered dose test specification with a
reported value of (b)(4)% during the 9-month stability interval. This same lot also failed the
uniformity of delivered dose attribute during the 12-month stability interval. It was only after
the 12-month OOS result that your firm decided to initiate a product recall for this Spiriva
lot. We are concerned about the management decision to allow adulterated product to
remain in the market between the 9 and 12 month stability stations.
Ref: WL: Boehringer Ingelheim Pharma GMBH & Co 5/6/13 (WL: 320-13-15)

27.
Warning letter observations -2013 - 21 CFR 211.192
Your firm failed to thoroughly investigate any unexplained discrepancy or failure of
a batch or any of its components to meet any of its specifications, whether or not
the batch has already been distributed (21 CFR 211.192).
Specifically, your firm did not initiate an investigation to determine the root cause of a
humidity excursion during the packaging of (b)(4) lots # (b)(4) (Master No. (b)(4)), # (b)(4)
(Master No. (b)(4)), and # (b)(4) (Master No. (b)(4)). The humidity conditions in blister
rooms (b)(4) fell below the lower RH limit ((b)(4)-(b)(4)% RH) specified in your master
packaging record.
Ref: WL: Contract Pharmaceutical Services of Australia Pty Ltd 5/17/13 (WL: 320-13-16)

28.
Warning letter observations -2013 - 21 CFR 211.192
Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its
components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR
211.192).
For example, your firm did not identify, report, or investigate the following out-of-specification (OOS) results.
a. On May 06, 2012, the 12-month stability interval assay test for (b)(4) mg tablet batch (b)(4) failed to meet the
established specifications with a result of (b)(4) (specifications: (b)(4)-(b)(4)).
b. On July 16, 2011, the assay for (b)(4) API batch (b)(4) failed to meet the established specification with a result of
(b)(4) (specifications: (b)(4)- (b)(4)). This API batch was used in the manufacture of (b)(4) finished drug product
batches.
c. On January 26, 2011, the related substance assays for three (b)(4) API raw material batches (b)(4), (b)(4), and
(b)(4) exceeded the (b)(4) and (b)(4) impurity specifications ((b)(4)%). These API batches were used in the
manufacture of (b)(4) finished drug product batches.
d. On October 10, 2012, the two-month stability assays for the (b)(4) USP batch (b)(4)-tablet presentation showed a
significant unknown peak at approximately (b)(4) on the chromatograms.
Ref: WL: RPG Life Sciences Limited 5/28/13 (WL: 320-13-17)

29.
Warning letter observations -2013 - 21 CFR 211.192
Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch
or any of its components to meet any of its specifications, whether or not the batch has
already been distributed (21 CFR 211.192).
Your firm did not determine a root cause for the clogging of the (b)(4) experienced during the
transfer of product from the (b)(4) tank to the (b)(4) tank for batches (b)(4), and (b)(4) of (b)(4)
((b)(4)) (b)(4) between (b)(4) and March 2012. The (b)(4) clogging was not observed prior to these
batches and your corrective action was to permit an in-process change of the (b)(4) if it becomes
clogged. We note that you continued to manufacture and release these (b)(4) products without
determining the most probable root cause of the (b)(4) clogging.
The investigations for two media fill (process simulation) failures between September and December
2011 were not adequate Specifically, the investigation report for the “Process Simulation Failure of
the (b)(4) Process” concluded that the probable root causes were inadequate cleaning of the
pressure gauge and inadequate sampling technique. However, your firm did not provide sufficient
basis or perform any studies to confirm these conclusions. Similarly, the investigation for the
“Process Simulation failure of (b)(4) Process” concluded that the probable root cause was the
handling and use of returned sterile primary packaging material, but the investigation had insufficient
basis or studies to support the conclusion.
Ref: WL: Promed Exports Private Limited 8/9/13 (WL: 320-13-24)

30.
Warning letter observations -2013 - 21 CFR 211.192
Your firm’s quality control unit failed to review and approve all drug product
production and control records to determine compliance with all
established, approved written procedures before a batch is released or distributed
(21 CFR 211.192).
For example, your firm’s quality unit failed to adequately review and approve your firm’s
production and control records. There is no assurance that the quality unit fully reviewed
and approved all batch-related documentation prior to release of finished product to the
U.S. market. Specifically, your firm distributed the following lots to the U.S. market without
adequate review: (b)(4) lot (b)(4), (b)(4) lot (b)(4), (b)(4) lot (b)(4) and (b)(4) and Le’dermis
Skin Solutions Anti-Acne Medicated Cream lot 130058.
Ref: WL: Jabones Pardo S.A. 8/22/13 (WL: 320-13-25)

31.
Warning letter observations -2013 - 21 CFR 211.192
You failed to thoroughly investigate any unexplained discrepancy or the failure of a
batch or any of its components to meet any of its specifications whether or not the
batch has already been distributed. In addition, you failed to extend the
investigation to other batches of the same product and other products that might
have been associated with the discrepancy [21 C.F.R. § 211.192].
Our inspection in 2012, and the current inspection, found that you have received multiple
consumer complaints related to mislabeled bags, inadequate bag size, defective product
components, and product mix-ups in your blood collection and component preparation
units. You have confirmed most of these quality issues. Your investigations have failed to
identify the deficiencies in need of correction to avoid the distribution of blood products
which are not in full compliance with regulatory specifications. In addition, the scope of
your investigations was not expanded to other lots and products potentially affected by
these deviations.
Ref: WL: Fenwal, a Fresenius-Kaby Company 8/16/13 (WL: 13-SJN-WL-05)

32.
Warning letter observations -2013 - 21 CFR 211.192
Your firm failed to thoroughly investigate any unexplained discrepancy or failure of
a batch or any of its components to meet any of its specifications, whether or not
the batch has already has already been distributed (21 CFR 211.192).
You failed to initiate investigations following the identification of discrepancies potentially
affecting the safety of sterile finished drug products. You have failed to conduct an
investigation of the non-integral gloves found during FDA inspection and continued to
manufacture (b)(4) batches of drug product using the same lot of defective gloves.
Ref: WL: Agila Specialties Private Limited 9/9/13 (WL: 320-13-26)

33.
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Other Guidance …

34.
Questions & Answers on Current Good Manufacturing Practices, Good
Guidance Practices, Level 2 Guidance - Records and Reports
Some products, such as transdermal patches, are made using manufacturing processes with
higher in-process material reject rates than for other products and processes. Is this okay?
• Maybe. It depends on the cause and consistency of the reject rate. Many transdermal patch
manufacturing processes produce more waste (i.e., lower yield from theoretical) than other
pharmaceutical processes. This should not of itself be a concern. The waste is usually due to the
cumulative effect of roll splicing, line start-ups and stoppages, roll-stock changes, and perhaps
higher rates of in-process sampling. This is most pronounced for processes involving lamination of
rolls of various component layers. Roll-stock defects detected during adhesive coating of the roll, for
example, can often only be rejected from the roll after final fabrication/lamination of the entire
patch, which contributes to the final process waste stream.
• We expect that validated and well-controlled processes will achieve fairly consistent waste amounts
batch-to-batch. Waste in excess of the normal operating rates may need (see 211.192) to be
evaluated to determine cause (e.g., due to increase in sampling or higher than normal component
defects... or both) and the consequences on product quality assessed. We've seen a small number
of cases where unusually high intra-batch rejects/losses were due to excessive component quality
variability and poorly developed processes.

35.
Do the CGMP regulations permit the destruction of an internal quality assurance audit report once the
corrective action has been completed?
The CGMP regulations (21 CFR 210 and 211) for finished pharmaceutical manufacturing do not specifically
address the requirement to conduct, or to keep records of, internal quality assurance audits. If the report in
question were from a routine audit to verify that the firm's quality system is operating as intended, then it would
be acceptable if the firm elected to discard the report once all corrections have been verified.
• However, any documentation of corrective action as a result of such an audit would have to be retained (see
211.180 and 211.188). For example, if a routine internal audit finds a problem with a mixing step and the
outcome is a change in mixing time, all affected procedures, including the master production record, are to
reflect the necessary changes, and such records are subject to FDA inspection as usual. Any investigation into
the impact this problem had on related batches is to be retained and also made available for inspection by FDA
(see 211.192).
• In addition, any reports of investigations or evaluations prepared in response to, for example, a product
complaint (211.198), vendor qualification (211.84), periodic review of records and data (211.180(e)), and a
failure investigation (211.192) are not internal audits as discussed above. Such records are subject to FDA
inspection and must be retained for at least the time specified in the CGMP regulations (see 211.180).
Questions & Answers on Current Good Manufacturing Practices, Good
Guidance Practices, Level 2 Guidance - Records and Reports

36.
EC GMP Guide
Chapter 1 Pharmaceutical Quality System
Product Quality Review:
1.10 Regular periodic or rolling quality reviews of
all authorised medicinal products, including
export only products, should be conducted with
the objective of verifying the consistency of the
existing process, the appropriateness of current
specifications for both starting materials and
finished product, to highlight any trends and to
identify product and process improvements.
Such reviews should normally be conducted
and documented annually, taking into account
previous reviews, and should include at least:

37.
EC GMP Guide
(i) A review of starting materials including packaging materials used in the product, especially those from new sources and in
particular the review of supply chain traceability of active substances.
(ii) A review of critical in-process controls and finished product results.
(iii) A review of all batches that failed to meet established specification(s) and their investigation. A review of all significant
deviations or non-conformances, their related investigations, and the effectiveness of resultant corrective and preventive
actions taken.
(iv) A review of all changes carried out to the processes or analytical methods.
(v) A review of Marketing Authorisation variations submitted, granted or refused, including those for third country (export only)
dossiers.
(vi) A review of the results of the stability monitoring programme and any adverse trends.
(vii) A review of all quality-related returns, complaints and recalls and the investigations performed at the time.
(viii) A review of adequacy of any other previous product process or equipment corrective actions.
(ix) For new marketing authorisations and variations to marketing authorisations, a review of post-marketing commitments.
(x) The qualification status of relevant equipment and utilities, e.g. HVAC, water, compressed gases, etc.
(xi) A review of any contractual arrangements as defined in Chapter 7 to ensure that they are up to date.

38.
EC GMP Guide
Chapter 4 Documentation
Generation and Control of Documentation:
4.3 Documents containing instructions should be approved, signed and dated by appropriate
and authorised persons. Documents should have unambiguous contents and be uniquely
identifiable. The effective date should be defined.
4.24 There should be written procedures for the internal labeling, quarantine and storage of
starting materials, packaging materials and other materials, as appropriate.

39.
EC GMP Guide
Chapter 5 Production
General:
5.8 Checks on yields, and reconciliation of quantities, should be carried out as necessary to
ensure that there are no discrepancies outside acceptable limits.
Processing operations: intermediate and bulk products:
5.44 Any significant deviation from the expected yield should be recorded and investigated.

40.
EC GMP Guide
Chapter 9 Self Inspection
9.3 All self inspections should be recorded.
Reports should contain all the observations made during the inspections and, where
applicable, proposals for corrective measures.
Statements on the actions subsequently taken should also be recorded.

41.
EU Non-Compliance Reports
Firm Name Nature of non-compliance
Sri Krishna
Pharmaceuticals Ltd.,
Hyderabad, India; Dec
2014
Written production and process control procedures are not documented at the time of
performance.
Specifically, Too Numerous to Count (TNTC) torn and discarded controlled
manufacturing batch records for a variety of different products issued by the Quality
Unit were found during a walk-through inspection of the facility.
Five batch records were compared with the archived manufacturing one and it was
ascertained that no records had been made for duplicate issuance of these five batches
chosen for review, as required per SOP QA/SOP/DOC/001.
Notably, after subsequent investigation it was found that the Master Batch Record
(version 0) had been back-dated by the most responsible persons within your firm’s
Quality and Manufacturing departments, which was confirmed by these persons during
our inspection.

42.
EU Non-Compliance Reports
Firm Name Nature of non-compliance
IND-SWIFT LIMITED,
Punjab; Mar 2014
Established processes to verify data accuracy and integrity had failed and there had
been no formal investigation raised by the company.
Medreich Limited –
Unit V; Dec 2014
5 were related to poor level of quality management (inadequate deviations
management system with no exhaustive record, no classification and no thorough
investigation)
Renown
Pharmaceuticals Pvt.
Ltd., Gujarat, India;
Aug 2014
Record integrity and veracity: some records were made up or altered.
Defects on deviation recording and investigation.

43.
Health Canada – GMP
7.3 Reviewing completed batch production and laboratory control records of critical process steps before
release of the API for distribution;
7.8 Batch production and laboratory control records of critical process steps should be reviewed and
approved by the quality unit(s) before an API batch is released or distributed. Production and laboratory
control records of non-critical process steps can be reviewed by qualified production personnel or other
units following procedures approved by the quality unit(s).
8.1 Written procedures followed for the review and approval of batch production and laboratory control
records, including packaging and labelling, to determine compliance of the API with established
specifications before a batch is released or distributed.
18. Where critical data are entered into a computerized system manually, there should be an additional
check on the accuracy of the entry. This can be done by a second operator or by the system itself.
19. Incidents related to computerized systems that could affect the quality of APIs or the reliability of records
or test results should be recorded and investigated.
21. All deviation, investigation, and OOS reports should be reviewed as part of the batch record review
before the batch is released.

44.
ICH

45.
ICH
6.7 Batch Production Record Review
6.70 Written procedures should be established and followed for the review and approval of batch
production and laboratory control records, including packaging and labelling, to determine
compliance of the intermediate or API with established specifications before a batch is released or
distributed.
6.71 Batch production and laboratory control records of critical process steps should be reviewed and
approved by the quality unit(s) before an API batch is released or distributed. Production and
laboratory control records of non-critical process steps can be reviewed by qualified production
personnel or other units following procedures approved by the quality unit(s).
6.72 All deviation, investigation, and OOS reports should be reviewed as part of the batch record
review before the batch is released.
6.73 The quality unit(s) can delegate to the production unit the responsibility and authority for release
of intermediates, except for those shipped outside the control of the manufacturing company.

46.
APIC

47.
APIC
6.7 Batch Production Record Review
6.71 During a batch record review check for
• missing records and out-prints
• incomplete entries
• illegible corrections
• equipment maintenance, breakdown and replacement
• valid calibrations and service intervals of test equipment (as a useful cross check to routine control of test
equipment)
• reports on OOS-results
• completeness of deviation reports
• impact of reported deviations on product quality
• compliance with specifications, parameter ranges or acceptance criteria including tighter customer
specifications
• usage decision

48.
pharmauptoday@gmail.comHow to avoid 21 CFR 211.192 observations ?

49.
pharmauptoday@gmail.comBatch Record Review

50.
Purpose of Batch Record Review
In general, all components of the batch record are assembled, records
are reviewed, questions and issues are resolved, and the batch is
released by QA. This review has several purposes:
• Assure compliance with all procedures
• Assure GMP compliance
• Assure product quality

51.
Purpose of Batch Record Review
• Assure compliance with all procedures:
GMP regulations require that all written procedures for manufacturing and testing pharmaceutical products be
followed.
The batch record review assures that the required materials procedures are used in manufacturing
product, and that all requirements for manufacturing and testing were met.
QA should only focus on critical parameters and review each parameter once.
Capturing errors and omissions on the same shift reduces risk and improves quality of resolution.
Batch Records, therefore, should be reviewed and corrected immediately, and with the people who are
executing the production task.
Setting a rule that the personnel do not leave until the batch is cleared is a good approach.

52.
Purpose of Batch Record Review
• Assure GMP compliance:
GMP also require that any deviation from requirements be documented and investigated.
Deviations could include problems in manufacturing, OOS results, or any other issue that could potentially
impact product quality. One purpose of the batch record review is to determine if overall GMP requirements
have been met.
There are a range of well-known tools and techniques for optimizing the deviation-management process so that
it runs quickly and effectively.
Rapid root-cause investigations teams trained to use Define, Measure, Analyze, Improve, Control (DMAIC)
approaches, are armed with standard ways of categorizing deviations supported by black-belt facilitators.
Appropriate tools and a well-trained team should be brought into play as soon as any critical deviation is
identified. Such an approach is now considered best practice across the industry.

53.
Purpose of Batch Record Review
• Assure product quality:
The batch record review is also important to assure the quality of the product produced.
It is essential to provide an independent review of all documentation and results to assure that requirements
were achieved, and that the final product meets release specification.

54.
Approach for Batch Record Review
• One key element necessary to assure a complete and thorough batch record
review is providing the reviewer with a means to know what should be present in
the record. There are several approaches to this:
 Design batch records
 Develop a batch record checklist
 Organize and number batch record pages
 Right-First-Time Approach

55.
Approach for Batch Record Review
Design batch records:
• Poor Batch Record design can also lead to overly lengthy review and approval. For some
companies, compliance and completeness are the only concerns in the design of the Batch Record.
• There is little or no consistency in the way requirements are stated in the document, and the entry format and
location are not clear to the operator.
• The document and work sequence differ, confusing the operator. The operator must regularly interpret
tolerances in the BR and make many transcriptions. These procedures are a recipe for error and delay.
• In addition, the Batch Record should mirror the operator work sequence.
• No mental calculations and few transcriptions should be needed to complete the Batch Record.
• Only the required information should be entered.
• Crucial or license-related parameters need to be highlighted so they are clear to the operator.
• There should be an obvious distinction for parameter outputs between target and required.
• In addition, there needs to be a statement of policy and principle that protects Batch Record simplicity and
effectiveness from being eroded over time with additional statements, checks, and signatures from poorly-
constructed corrective action and preventive action changes.

56.
Approach for Batch Record Review
Develop a batch record checklist:
A product specific checklist that includes all required elements of the batch record can be an excellent tool for
the record reviewer to assure that all components of the record are present.
This checklist must be QA controlled and current.
The use of this checklist also provides documentation that each element of the record was present and
reviewed.

57.
Approach for Batch Record Review
Organize and number batch record pages:
• Some firms develop batch records to include all possible elements into the numbered batch record.
• Thus, assuring completeness involves only verifying that all pages are present. For example, if the record has
43 pages, each labeled with “page 21 of 43,” etc., the reviewer needs only to assure that all pages are present
to conclude that the record is complete.
• This is often not completely possible because batch records often include chart recordings, temperature
strips, and other miscellaneous documents.
• The review must be aware of which of these are required to assure that the review is complete.

58.
Approach for Batch Record Review
Right-First-Time Approach:
• To achieve a one-day Batch Record review and approval, a right-first-time (RFT) culture must pervade the
organization. This means that 95% of batch records should be RFT.
• Best practice dictates that the Batch Record be error-proofed, based on a clear methodology to make the
person and document interface error-free.
• There should be an obvious pattern to the way requirements are stated and laid out that helps the user.

59.
pharmauptoday@gmail.comInvestigations

60.
Investigation - Definition
• A formal, organized, and documented study conducted to identify the cause in order to correct
and prevent deviations and unexplained events in the manufacturing or testing of pharmaceutical
products.
• Formal: an investigation must occur in a prescribed and planned manner, not occur randomly – an SOP
describing the investigation approach is required
• Organized: an investigation must be organized, preferably following a specific predetermined pattern of
data gathering and assessment
• Documented: as with all GMP activities, investigations must be documented, including the study
rationale, data, decisions, actions, and follow-up
• Cause: an extensive effort must occur to determine the single root cause, when possible
• Correct and Prevent: the ultimate goal of an investigation is to correct the problem and prevent a
recurrence

61.
What must be investigated ?
• Deviation From Requirements:
A deviation from an established or published requirement requires that an investigation occur. The
key to this or any investigation is to learn what happened, and what can prevent a recurrence.
Examples:
• Required drying temperature not maintained
• SOP requirements could not be followed
• Time limits for conducting stability tests were not met
• Incorrect analytical method used
• Room differential pressure below limits

62.
What must be investigated ?
• Failure to Achieve Required Results:
Failure to obtain expected results should result in an investigation. The inability to achieve an
expected result is a sign that some facet of the process is not operating normally. Thus, an
investigation should be conducted to determine what is happening, and what can stop or prevent
failures.
Examples:
• Product final assay specification not attained
• In-process tablet hardness results not achieved
• Stability test failure
• Sterility failure
• Blend homogeneity fails
• Black specks in solution
• Environmental monitoring results fail

63.
What must be investigated ?
• Any Failure in Product, Process, Equipment, or Personnel:
Any real or possible product, process, equipment, or personnel failure should result in an
investigation. In many cases, though a product failure has not yet occurred, a solid investigation can
prevent a future failure.
Examples:
• Weighing error
• Failure to blend for required time
• Failure to use the proper cleaning procedure
• Excessive capping for compressed tablets
• Documentation for required process steps was incomplete
• Equipment failure causing extended line downtime
• Equipment visually dirty after cleaning completed
• Foreign tablet found on-line during packaging

64.
7 Elements of Investigation

65.
7 Elements of Investigation
1. Discovery/Problem Description:
• The initial step in any investigation is the problem discovery and description.
• Systems and procedures must exist that allow early detection and communication of problems.
• It is not sufficient to rely upon final batch record review to detect deviations and unexplained events.
• A culture that encourages and allows operators, technicians, and associates to raise concerns and issues as
they arise, is imperative to early detection and correction of problems.
• Once a problem is discovered, it is important that all known details be described in as much detail as
possible.
• The investigation system, SOP, or form must include a listing of the types and kinds of details that should be
gathered and recorded early in the stages of an investigation.

66.
7 Elements of Investigation
2. Containment:
• Another key early step in the investigation process is to contain or limit the problem.
• Unless containment occurs, the problem can extend beyond its original scope, or become more
difficult to assess. For example, if an equipment malfunction occurs on-line during filling, early
containment can assure that affected product is isolated to limit involvement to minimal pallets of
product.
• Proper containment usually involves the following actions:
• Stop – halt production, testing, or other actions that could extend the problem until it is properly described
• Establish limits – define the start and stop points of the problem, and
• Establish control – isolate affected product or processes

67.
7 Elements of Investigation
3. Corrective Action:
• Once the problem is described and contained, the next step is to determine the immediate actions
needed to correct the specific problem and restart operations.
• In other words, you must now answer the question, “What do I need to do to assure that product
manufactured (or tested, etc.) after restart will not be affected by this same problem?”
• Corrective action can be as simple as correcting the equipment problem, re-sanitizing the
equipment, shifting to a new lot of material, or other similar actions.
• However, you must assure that the problem is sufficiently described and a likely cause
identified, or the problem may still extend to other products or batches.

68.
7 Elements of Investigation
4. Cause and Analysis:
• Possibly the most important phase of an investigation is to thoroughly analyze the problem, and
determine the likely “root cause.”
• A root cause is that single action or event that created the problem or deviation studied.
• It is important to determine the root cause to provide a sense of confidence that once corrective
and preventative action has occurred, the problem will not reoccur.
• When the potential exists that the problem could reoccur, or if you do not know the root cause of
the incident, you cannot have confidence that the problem is solved. So, extensive effort is needed
to identify the root cause.
• There are several successfully used systems that identify root cause. Several commercially
available systems exist, and other “classical” systems are in use.

69.
7 Elements of Investigation
5. Preventive Actions:
• For any verified or unknown cause, the investigation must eventually include an action to eliminate
that cause from contributing to future similar concerns.
• The investigation should include a listing of these causes, and specific actions with individuals
responsible, and target dates for completion.
• By conducting a thorough identification of possible causes and eliminating these causes from
future involvement, you have a high likelihood that recurring investigational issues will not occur or
be significantly reduced.
• Preventive actions must be both specific and definitive. In other words, preventive action must
result in change in order to be effective.
• It is not usually adequate for preventive actions to involve only communication or notification.

70.
7 Elements of Investigation
6. Conclusions/Product Disposition:
• A final step in conducting an effective investigation is to recommend and document the final
conclusions and disposition of all products, materials, or systems affected.
• It is critical to clearly state what will occur with segregated materials, why that action was
taken, and the justification for this final disposition.
• Unless these decisions are clearly listed, the possibility for miscommunication or unintended
actions exists.

71.
7 Elements of Investigation
7. Follow-up and Tracking:
• Once an investigation is closed, a system is needed to track promised actions to assure that, they
were implemented as promised and, they were effective in eliminating the cause.
• Investigations with open action items must be visible in a database or other tool to allow routine
review.
• Failure to assure that investigation action items are complete is a GMP violation often cited on FDA
483s.

72.
pharmauptoday@gmail.com
Thank You
The module Consult Yourself.... “Know Regulation - No Observation” deals with most common (top 20)
basic CFR regulations having frequent violations and previous observations for better understanding.
The module will be continued with # 4 21 CFR 211.67
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