Top 20 observation series 2: 21 CFR 211.22

21 CFR 211.22
pharmauptoday@gmail.comConsult Yourself.... “Know Regulation - No Observation”

- 2014 inspectional observations
- List of Top observations in 2014
- Sec. 21 CFR 211.22 (a)
21 CFR 211.22 (b)
21 CFR 211.22 (c)
21 CFR 211.22 (d)
- 483 observations
- Warning Letters
- Other Guidance
- How to avoid observations
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Contents

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

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%)
Number of CFR part 211 parts violated 54

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

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

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.

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
21 CFR 211.160

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)
21 CFR 211.22

483 citations related to 21 CFR 211.22
Year Number
2006 150
2007 190
2008 119
2009 191
2010 223
2011 243
2012 232
2013 237
2014 218 0
50
100
150
200
250
300
2006 2007 2008 2009 2010 2011 2012 2013 2014
483 Observations

Regulation

CFR part 211 Regulation - 21 CFR 211.22 (a)
• There shall be a quality control unit that shall have the responsibility and authority to
approve or reject all components, drug product containers, closures, in-process
materials, packaging material, labeling, and drug products, and the authority to review
production records to assure that no errors have occurred or, if errors have
occurred, that they have been fully investigated.
• The quality control unit shall be responsible for approving or rejecting drug products
manufactured, processed, packed, or held under contract by another company.

Previous observations

483 citations related to 21 CFR 211.22(a)
Cite Id
Reference
Number
Short Description Long Description
Frequency
2014 2013
9001 21 CFR 211.22(a) Lack of quality control unit There is no quality control unit. Specifically, *** 24 26
1033 21 CFR 211.22(a)
Authority lacking to
review records, investigate
errors
The quality control unit lacks authority to [review
production records to assure that no errors have
occurred] [fully investigate errors that have
occurred]. Specifically, ***
11 17
1079 21 CFR 211.22(a)
Contract drug products--
lack of responsibility
The quality control unit lacks responsibility for
approving or rejecting drug products
[manufactured] [processed] [packed] [held] under
contract by another company. Specifically, ***
9 2
1049 21 CFR 211.22(a)
Approve or reject
components, products
The quality control unit lacks the responsibility and
authority to [approve] [reject] all [components]
[drug product containers] [closures] [in process
materials] [packaging material] [labeling] [drug
products]. Specifically, ***
7 9

CFR part 211 Regulation - 21 CFR 211.22 (b)
Adequate laboratory facilities for the testing and approval (or rejection) of
components, drug product containers, closures, packaging materials, in-process
materials, and drug products shall be available to the quality control unit.

483 citations related to 21 CFR 211.22(b)
Cite Id
Reference
Number
Frequency
2014 2013
1086 21 CFR 211.22(b)
Adequate lab facilities not
available
Adequate lab facilities for testing and approval or
rejection of [components] [drug product
containers] [closures] [packaging materials] [in-
process materials] [drug products] are not available
to the quality control unit. Specifically, ***
7 12

Warning letter observations -2013 - 21 CFR 211.22(b)
Your firm failed to have an adequate laboratory facility available for the testing and
approval (or rejection) of components, drug product containers, closures, packaging
materials, in-process materials, and drug products (21 CFR 211.22(b)).
For example, assay methods used by your contract testing laboratory to test your finished
products (e.g. Instaclean and PeriShield) for release have not been validated.
Ref: WL: 14-NWJ-02 (Ameriderm Laboratories, Ltd. 12/2/13)

CFR part 211 Regulation - 21 CFR 211.22(c)
• The quality control unit shall have the responsibility for approving or rejecting all
procedures or specifications impacting on the identity, strength, quality, and purity of the
drug product.

483 citations related to 21 CFR 211.22(c)
Cite Id
Reference
Number
Frequency
2014 2013
1098 21 CFR 211.22(c)
Approve or reject
procedures or specs
The quality control unit lacks responsibility to
[approve] [reject] all procedures or specifications
impacting on the [identity] [strength] [quality]
[purity] of drug products. Specifically, ***
15 16

CFR part 211 Regulation - 21 CFR 211.22(d)
• The responsibilities and procedures applicable to the quality control unit shall be in writing;
such written procedures shall be followed.

483 citations related to 21 CFR 211.22(d)
Cite Id
Reference
Number
Frequency
2014 2013
1105
21 CFR
211.22(d)
Procedures not in
writing, fully followed
The responsibilities and procedures applicable
to the quality control unit are not [in writing]
[fully followed]. Specifically, ***
145 155

• The responsibilities and procedures applicable to the quality control unit are not fully followed.
Ref: 483 of Novartis Consumer Health (Feb-2013)

Ref: 483 of Hospira Inc. (Mar-2013)

Ref: 483 issued to Pfizer Inc. (Jun-2012)

Ref: Sandoz Inc., Date Issued: 06/22/2011

• The “Quality Manual”, document #030-SOP-OP-01340, dated 28 Feb 2011, “describes the
pharmaceutical quality system (PQS) as implemented at BVL. The Quality Manual identifies the
elements of the PQS and the sequences, linkages, and interdependencies of related processes, and
the responsibilities of Management to ensure effective implementation.”The “Quality Manual
includes the principles and responsibilities for implementation of BVL’s PQS and pertains to all BVL
departments involved in performing and/or supporting the
development, manufacturing, testing, holding, distribution, and marketing of pharmaceutical
products.” However, the following observations document a lack of adequate oversight by the
Quality Unit to approve or reject the products manufactured and processed, as well as, approve or
reject the established procedures and/or specifications impacting the quality of the drug product.
a. The Quality Unit is not following the established procedures in that senior management is not
notified within [REDACTION] hours of [REDACTION] initiated with an initial assessment of critical
per procedure. For example, [REDACTION] 115576 (failing vial washer re-qualification),discovered
on 3/17/11, was opened on 4/14/11 with an initial critical designation and senior management was
not notified. On 4/18/11, this [REDACTION] was downgraded from critical to major with no evidence
to show management was notified. Furthermore, there is no documented justification to show why
this[REDACTION] was downgraded.
Ref: Ben Venue Laboratories, Inc., Date Issued: 12/02/2011

b. The Quality Unit is not initiating investigations and documentation of those investigations
in a timely manner. For example [REDACTION] 115576 was discovered on 3/17/11 (failing
vial washer re-qualification) and the [REDACTION] was not opened until 4/14/11.
c. Routine preventative maintenance activities are not performed at their scheduled
intervals. As of 11/11/11, there were approximately 107 required preventative maintenance
activities for GMP equipment past their scheduled due date. To be considered past
due, the event must be greater than [REDACTION] days past due date. There is no
evidence to show the Quality Unit took action on these overdue preventative maintenance
issues concerning equipment qualifications and validations of the respective processes.
Ref: Ben Venue Laboratories, Inc., Date Issued: 12/02/2011

• The responsibilities and procedures applicable to the quality control unit are not fully
followed.
QA and Compliance Department overall responsibilities per the firm’s [REDACTION] is
deficient as follows:
it does not maintain adequate laboratory facilities for the testing and approval (or rejection) of
components and drug products;
in neglects review and approval of validation protocols regarding changes in product processes and
equipment to determine when revalidation is or should be warranted;
it is default in investigations, tracking, trending and maintenance of consumer complaint follow-up;
and it lacks trending of products, components (i.e., water), and complaints to demonstrate a
broad perspective to assure plant conformance with CGMPs.
Ref: McNeil Consumer Healthcare, Div of McNeil-PPC, Inc., Date Issued: 04/30/2010

• The Responsibilities and procedures applicable to the quality control unit are not in writing and fully
followed. Specifically:
a. Recognizing that an Out-of-Specification Test Result was obtained in [REDACTION] specification
of [REDACTION] as per requirement of your Quality Control/Quality Assurance Standard Operating
Procedure for OOS Investigation, SOP Number 2802, Reporting, Investigation and Disposition of
Out of Specification (OOS) Laboratory Results, effective 02/05/09 and previous revisions, it appears
that you avoided to perform an Investigation for the assay test result of [REDACTION]. In
addition, you failed to perform a complete assessment for the failure of the microbiology laboratory
autoclave qualification that took place in February 2009. These incidents were never informed to the
respective head of departments (QA/QC) which are not stationed here at your Gloversville, NY
facility.
b. Procedures are not established which are designed to assure that the responsible officials of the
firm, if they are not personally involved in or immediately aware of, are notified in writing of
investigations conducted or any unexplained discrepancy.
Ref: Ohm Laboratories, Inc., Date Issued: 08/12/2009

• The QC Director and QA Associate Director which are stationed in a different State, as well
as your Plant Manager and QA Supervisor were not notified of the failure of the
Microbiology Autoclave Validation as well as the [REDACTION] OOS test result that was
treated as an out-of-trend results (OOT), among others. According to your statements, they
were not informed of the events, therefore, no assessment was ever performed to
determine the magnitude, impact and significance of such failures.
• On 08/06/09, the Vice-President QA and QC [REDACTION] stated that the information of
the delay stability samples with the difference (in days) from pull out to testing were not
informed by the local employees to upper management.
Ref: Ohm Laboratories, Inc., Date Issued: 08/12/2009

• The quality control unit lacks responsibility to approve and reject all procedures or specifications
impacting on the identity, strength, quality, and purity of drug products. Specifically,
a. The ANDA submits for the “Validation of Aseptic Operations (Sterile Media Fills) are performed “To
minimize the bioburden levels during the manufacturing process, strict aseptic manufacturing procedures
are followed.” “Aseptic media fill runs are performed in order to confirm the established aseptic
manufacturing procedures used by the company.” “Process simulation runs (media fill runs) are
performed[REDACTION] at a minimum) to requalify the total aseptic manufacturing operations for the
filling process” to support of the Sterility Assurance Validation” for the “Validation of Aseptic Fill and
Terminal Sterilization Processes for Small Volume Parenteral Products”. However, the company has not
performed media fills since the original 1998 ANDA submission.
b. The company has not submitted, for example a Post Approval Change or a Change
Being[REDACTION] for the ANDA that addresses the cessation of aseptic media fills and/or provides the
scientific rationale with respect to the cessation and impact on the “Sterility Assurance Validation” for the
finished product.
c. The company has not submitted, for example, a Post Approval Change or a Change
Being [REDACTION] for the ANDA regarding the use of a BI challenge for the[REDACTION] steam
sterilization process with less than a [REDACTION] spore population.
Ref: Teva Parenteral Medicines Inc., Date Issued: 07/24/2009

• The responsibilities and procedures applicable to the quality control unit are not in writing
and fully followed. Specifically,
1. The written procedure, AA204 Media Fill Process Simulation, does not adequately
describe the instructions for the aborting and invalidating of media fill batches. For
example,
a. Media Fill Batch [REDACTION] Code 7002, 100mL vials, performed in filling area AH
and lyophilisation in room AJ on 7-28-08 when it was invalidated after growth promotion
acceptance criteria were not met. The instructions in the written procedure do not describe
when a media fill batch is invalidated.
b. Media Fill Batch [REDACTION] Code 7002, 100mL vials, performed in filling Area AH
and lyophilisation in room AJ on 9/30/08 when it was aborted because of a malfunction of
the surge vessel. The instructions in the written procedure do not describe when a media
fill batch is aborted.
Ref: Akorn, Inc., Date Issued: 06/30/2009

• 2. There is no written procedure that describes the storage conditions and storage location of
integral rejects (intervention rejects) after the media fill is completed at one facility before they are
transferred to another facility for incubation. For example,
a. Media Fill Batch [REDACTION] for Code 7002, 100mL vials, performed in filling Area AH and
lyphilization in room AJ on 1/23-24/08 had 75 integral rejects (intervention integral rejects).The
integral rejects were accidently disposed of by a production employee along with non-integral rejects
while awaiting transfer to the incubator at another facility.
3. There is no written procedure that describes for the requirement for Quality Assurance to approve
handwritten changes (pen amendment changes) to the batch records by production personnel
before they are done. For example a production employee was allowed to cross out the non-braided
tubing, part number [REDACTION] listed in the media fill batch record and to make handwritten
changes using a pen for the purpose of using a similar tubing, part number ASTP-16F, without
Quality Assurance approval at the time it was actually used in the media fills Pen amendment
changes were made to the the Media Fill Batches 61268, 61278, 61188, 61178, 61378, and 61058.

• 4. The written procedure, “Batch Record Review: Product Release/Closeout & Media
Review/Closeout”, No. QA101, does not adequately describe the instructions for the
aborting manufacturing batches. For example,
a. Lot 21039, Product Code 5010, 100mg/mL, 5mL vials, performed in filling area K on
04/27/2009 was aborted. The batch record does not include any information for aborting
the lot. NO investigation was included with the bath record.
b. Lot 91208, Product Code 5010, 100mg/mL 5mL, vials, performed in filling area K on
09/09/2008. The batch record does not include a thorough investigation detailing abortion
of the lot.

• The Quality control unit lacks authority to review production records to assure that no
errors have occurred and fully investigate errors that have occurred Specifically,
Ref:Andrx Pharmaceutical, Inc., Date Issued: 04/18/2006

Ref: 483 of Teva Parenteral Medicines Inc (Jul-2009)

Ref: 483 of Able Labs (2005)

Warning letter observations -2015 - 21 CFR 211.22
Your firm failed to follow written procedures applicable to the quality control unit (21
CFR 211.22(d))
Your procedure titled “Quality Unit Responsibility” (#GPOL-004 dated 07/09/2013) states that
“any deviation shall be investigated to discover possible causes and prevent possible
reoccurrence.” Although your written procedure clearly describes the protocols for
handling deviations, your quality unit management indicated to our investigator that there
were no deviation reports, no OOS investigations, nor any evaluations to address the
possible root cause(s) of the deviations/OOSs. Among other failures, your quality unit did
not follow your procedures for conducting investigations into the examples listed in citation
#1 of this letter.
Ref: WL: 320-15-06 (Apotex Research Private Limited 1/30/15)

Your quality control unit failed to approve procedures and specifications impacting the
identity, strength, quality and purity of the drug product. Secondly, your quality control unit
failed to exercise its authority to approve or reject drug product
components, containers, closures, in-process materials, packaging material, labeling and
finished products.
This responsibility includes the requirement to review production records to assure that no
errors have occurred or, if errors have occurred, that they have been fully investigated, and
approving or rejecting drug products manufactured, processed, packed, or held under
contract by another company.
Finally, there are no written procedures describing the responsibilities and procedures
applicable to the quality unit. [21 C.F.R. § 211.22].
Ref: WL: 320-13-12 (Peking Medicine Manufactory 3/25/13)

• Your firm failed to have a functioning quality control unit (QCU). Several examples of the violation
are as follows:
a) Your quality unit has not approved procedures and specifications impacting the quality of
finished drug products imported to the U.S. market.
(i) During the inspection, our investigator found that your current procedures have not been
reviewed and approved by the QCU. Examples of these unapproved procedures include: Finished
Product Release, Storage, and Distribution (SOP-01-05); Stability Testing of Finished Product (SMP-
QC-016-00); Change Control and Validation (PS-10); Material Receipt Management Procedure (RM-
02); Product Recall Management (SMP-11-02); and Complaint and Adverse reactions (SMP-12-01).
(ii) Additionally, our investigator also found that your QCU failed to establish and approve standard
operating procedures (SOPs) as follows: cleaning validation; finished product release and control;
change control; labeling and packaging operations; annual product review; and procedure for
writing, reviewing, and approving standard operating procedures.

b) Your finished drug products have been released by your warehouse manager, not signed off by your
QCU. In addition, your unapproved procedure, SOP-01-05 “Finished Product Release, Storage and
Distribution” addresses how your warehouse releases materials for shipping, not how your finished
product is examined, and approved by your QCU.
c) Your QCU failed to establish SOPs to examine and ensure the suitability of incoming raw
materials, components, container, closures, or labels.
d) Your firm contracted out the manufacturer of STRONG WOO LOK GAO to an external party. Your
firm is the owner of this drug product, but did not adequately evaluate whether the CMO (contract
manufacturing organization), which is an extension of your operations, can consistently produce product
that is suitable for distribution. For example, your quality unit did not evaluate the quality of each batch of
drug product produced by the CMO in order to make an appropriate disposition decision (approval or
rejection).
e) There is no written procedure or program to address the validation of processes used to produce any
of the finished drug products manufactured by your firm.
f) Your firm has not established an SOP describing the specific responsibilities of the QCU.

• Your quality control unit failed to exercise its authority to approve or reject drug product
components, containers, closures, in-process materials, packaging material, labeling and finished
products. Secondly, the quality control unit failed to approve procedures and specifications impacting
the identity, strength, quality and purity of the drug product. Finally, there are no written procedures
describing the responsibilities and procedures applicable to the quality unit [21 C.F.R. § 211.22].
• Three examples of violations of § 211.22 are as follows:
a. The raw materials and components used in the production of the drug product were not approved
by the quality unit.
b. The quality unit failed to approve procedures and specifications impacting the quality of the (b)(4).
c. There are no written procedures describing the Quality Unit responsibilities.
Additionally, records pertaining to the production and release of your drug products were not
provided to the investigator for review. The only documentation available on site for the batches of
drug products manufactured by your firm was two pages from a notebook listing the ingredients
used.
Ref: WL: 320-12-023 (Fercy Personal Care Products Co., Ltd 9/7/12)

• Your quality control unit (QCU) has not approved or rejected all procedures or specifications
impacting the identity, strength, quality, and purity of the drug product. Secondly, the QCU lacked
the responsibility and authority to approve or reject all components, drug product
containers, closures, in-process materials, packaging material, labeling, and drug
products. Finally, the QCU failed to exercise its authority to review production records to assure that
no errors occur or, if errors occur, that they are fully investigated. [21 C.F.R. § 211.22].
• Four examples of this violation include:
a. Your firm has not established standard operating procedures (SOPs) describing the
responsibilities of the QCU.
b. There is no QCU oversight for the review of finished products before release and distribution.
c. Your firm has not established specifications for the release of drug product components.
d. Your firm has not followed the procedure for testing (b)(4) used in the manufacture of drug
products.
Ref: WL: 320-13-01 (International Laboratories (Canada) Ltd. 10/23/12)

• Your firm failed to establish an adequate quality control unit with the responsibility and authority to
approve or reject all components, drug product containers, closures, in-process materials, packaging
material, labeling, and drug products, and the authority to review production records to assure that
no errors have occurred or, if errors have occurred, that they have been fully investigated. [21
C.F.R. § 211.22(a)]
• Four examples of violations of § 211.22(a) are as follows:
a. Your quality control unit (QCU) failed to adequately review the batch production record for your
product (b)(4) Skin Protectant Cream, bulk batch # (b)(4). Our inspection documented
discrepancies between your batch production and cleaning records. For example, your batch
product record indicated that on August 31, 2011, your firm began processing bulk batch
#(b)(4) in (b)(4) at 7:20 A.M., and that the production ended at (b)(4)A.M. of the same
day. However, your cleaning record showed that the same (b)(4) #3 had been cleaned between
8:00 to (b)(4) A.M. on the same day of August 31, 2011. The information collected indicates that two
different operations were being performed during the same period of time.
Ref: WL: 320-13-02 (Shanghai Huhui Daily Use Chemical Products Co., Ltd. 11/14/12)

b. Your QCU did not notice the contradictory yields obtained between your batch production record and
raw data record sheet for the same batch of the drug product (b)(4) Skin Protectant Cream. Your
production records for bulk batch (b)(4) document the size of this batch as (b)(4). Your raw data record
sheets for finished product batch #(b)(4) showed that a total of (b)(4) of final product were packed from
the bulk batch lot #(b)(4). Your firm’s management could not explain and justify the origins of the
extra (b)(4) of finished product. Similarly, the investigator found that the quantity of bulk batch
# (b)(4) produced was (b)(4), whereas your raw data records show that the quantity of finished product
(batch #(b)(4)) produced from this bulk batch was (b)(4).
c. Your QCU failed to ensure the traceability of the batch lot number used in the production
of (b)(4) Skin Protectant Cream. Your firm’s QCU was unable to determine the final finished product lot
produced from the two bulk lots #(b)(4) (batch size: (b)(4)) and #(b)(4) (batch size: (b)(4)).
d. The investigator also observed the presence of opaque correction fluid in many of your production
records of (b)(4) Skin Protectant Cream. For instance, your firm used opaque correction fluid to change
lot numbers of two raw materials in the bulk batch lot #(b)(4), signatures in bulk lot #(b)(4), and process
temperature and viscosity readings in lot #(b)(4). In each instance, there was no notation of who made
the change or when and why the change was made. Please note that batch records are to document
accurately the production and control activities associated with each lot. A QCU cannot reasonably rely
on records containing unexplained corrections to make batch release decisions.
Ref: WL: 320-13-02 (Shanghai Huhui Daily Use Chemical Products Co., Ltd. 11/14/12)

• Failure to establish and follow written responsibilities and procedures applicable to the
quality control unit [21 CFR 211.22(d)]. For example: ...
• Written procedure 1-013, "Validation Policy," dated 12/29/05, was not followed when a
change was made to the manufacturing process used for PyrantelPamoate Suspension
Canine-2X (4.54 mg / mL), Lot [redacted] in April 2006. A planned deviation changed the
compounding tank, mixer speeds and mixing times used to make this [redacted]batch of
suspension product. The Validation Department did not determine if the modification was
major or minor as defined in Section 7.2 of SOP 1-013. In addition the Validation
Department did not address the need to do additional testing to assure the product was
equivalent to that made by the validated process.
Ref: WL: First Priority, Inc., Date Issued: July 9, 2007

• The quality control unit does not adequately exercise its responsibilities to approve procedures or
specifications that may impact the identity, strength, quality, and purity of the drug product [21 C.F.R.
§ 211.22(c)]. For example,
• There was inadequate oversight of the media fill process conducted for batch
#(b)(4). Furthermore, the "responsibility" section of procedure JZ-V/JK-053, Validation of Aseptic
Manufacturing and Filling Process Using the PST (media fill), makes no mention of the quality
control unit having an active role in the oversight of media fill studies.
• Your response indicates that procedural corrections will be implemented. Please provide more
information in your response regarding how the quality control unit’s role has evolved including
describing its function relating to observation and approval of media fills (e.g., recent March 2011
media fills).
• We remind you that it is your responsibility to implement sustainable corrective actions to ensure
that you firm’s drug manufacturing operations are in compliance with the applicable
requirements, including the CGMP regulations. FDA expects Pharmaceutical Company Jelfa SA to
undertake a comprehensive assessment of the manufacturing operations to ensure that drug
products conform to FDA requirements.
Ref: WL: Pharmaceutical Company Jelfa SA, Date Issued: July 14, 2011

• We are particularly concerned with your firm’s failure to implement a robust Quality
System. Repeat citations from prior inspections indicate that your quality control unit is not
exercising its responsibilities, and may not have the appropriate authority to carry out its
responsibilities. Due to continuing CGMP issues at your firm, we recommend you engage a
third party consultant having appropriate CGMP expertise to assess your firm’s
facility, procedures, processes, and systems to ensure that your drug products consistently
meet standards for identity, strength, quality, and purity.
• In addition to the items listed above, this inspection identified other worrisome
deficiencies. These deficiencies include, but are not limited, to: inadequate vendor
qualification of your API suppliers and inadequate smoke study results for aseptic filling
line (b)(4).
Ref: WL: Pharmaceutical Company Jelfa SA, Date Issued: July 14, 2011

• Failure of your quality control unit to ensure cleaning procedures are validated.
For example, your firm has no cleaning validation (cleaning and drying for reuse) for the large
flexible bags you use to hold the (b)(4) of the (b)(4) after the (b)(4) step, and before the (b)(4) step.
Although you use these bags to hold material from the different (b)(4) manufacturing processes
executed at your site, you have not performed a validation of the current cleaning procedure. These
bags are also not dedicated to a specific process or (b)(4). In addition, you do not follow the current
cleaning procedure as written. Examples of inconsistencies between the procedure itself, HES-III-
SEI-514, “SOP for Cleaning of the Flexible Large Bags and what your employees actually perform
include, the (b)(4) of the bags in (b)(4) for (b)(4) minutes and “Hand washing” is not define as
using (b)(4) on the (b)(4) of the bag.
Your response indicates that you will revise HES-III-SEI-514, “SOP for Cleaning of the Flexible
Large Bags,” and you will validate the cleaning procedure. Include in your response to this letter an
English translation copy of the revised procedure, the training documentation for this procedure, and
an English translation copy of the validation protocol for this cleaning procedure. Also, if you plan to
validate the cleaning of these bags using a matrix approach based on the worst case (e.g. hardest to
clean) (b)(4) include a justification for the choice of the selected worst case (b)(4).
Ref: WL: Yamaguchi Production Center, Date Issued: September 29, 2010

• Failure of your quality unit to provide confidence that API manufacturing processes will consistently yield a product
meeting its intended specifications. Your firm manufactures USP products at your facility without applying the
appropriate controls and GMPs. For example,
a) Our inspection of your facility revealed that your firm failed to perform process validation for three USP
products: (b)(4). This is a repeat observation. The June 2001 FDA inspection reported that your firm failed to
conduct process validation studies for (b)(4) , a USP product manufactured at your facility.
b) Your firm failed to perform stability studies for (b)(4) to support the (b)(4) year expiration date currently
assigned. This is a repeat observation. The June 2001 FDA inspection documented your failure to perform stability
studies on (b)(4), a USP product manufactured at your facility.
c) Your firm failed to perform cleaning validation studies to support the use of "city water" to clean all your
equipment. Your firm lacks data to support the use of city water for the cleaning operation. Also, the inspection
documented that (b)(4) #2 and (b)(4) #4 are non-dedicated pieces of equipment, and that they can be used for
various USP products. The potential for product carry-over between batches or manufacturing campaigns
underscores the importance of a robust cleaning procedure.
Your response lacks the appropriate documentation corrections to these deviations regarding process
validation, stability studies, and cleaning validation for all drug products manufactured at your facility, intended for the
U.S. market.
Ref: WL: Macco Organiques, Inc., Date Issued: December 10, 2010

• The responsibilities and procedures applicable to the quality control unit are not fully
followed. [21CFR 211.22(d)]
• During upgrading your (b)(4) system in July 2007, your distribution loop and (b)(4) pump were
accordingly modified for purportedly eliminating dead legs and allowing continuous recirculation for
both distribution line (b)(4) and (b)(4). However, your Quality Control Unit failed to follow your
change control procedure (SOP-3141, dated on December 15, 1998) to document and also assess
the impact of these changes on the new (b)(4) system prior to commissioning of this new equipment.
• Your firm's response indicated that your firm modified the distribution loop after updating the system
in July 2007 and again after inspection. Please provide details, including a scientific rationale, of the
two modifications implemented, especially for the post-inspection modifications.
• Meanwhile, your response provided only one training record to showing that one person from the
production department has received training. Your response did not demonstrate that other people
who have been involved with the change control procedure have been trained, as well. Please
clarify and provide any supportive documentation if applicable.
Ref: WL: Laboratoire Atlas, Inc., Date Issued: June 25, 2009

• ... The response to the second example does not address the issue of the failure to follow the
validation policy SOP when a change was made in the compounding tank, mixer speeds and mixer
times for the production of a lot of suspension product (PyrantelPamoate Canine (4.54 mg / mL).
The response says, in the future, your firm will only make this suspension product in kettles with dual
motion sweep agitation.
However, your firm made one lot in Tank #8 for the purpose of process validation. We do not
understand why, if First Priority determined a new mixing tank should be used for suspension
products, was a lot manufactured in Tank #8? The validation consisted of collecting 3 samples, one
from the top, one from the middle and one from the bottle of the tank. The three values ranged
from [redacted] mg / mL [redacted] %) to [redacted] %).
There is no discussion or explanation of the relatively low results provided with the response. If this
lot was formulated for 100% as required by cGMPs, we question what happened to almost 5% of the
active ingredient in the middle sample and we wonder why this lot was made using Tank #8 when
your firm identified the need to change the mixing process using a kettle which has dual motion
sweep agitation
Ref: WL: First Priority, Inc., Date Issued: July 9, 2007

Other Guidance …

EC GMP Guide
Chapter 2 Personnel
2.6 The head of the Quality Control Department generally has the following responsibilities:
i. to approve or reject, as he sees fit, starting materials, packaging materials, and intermediate, bulk and finished
products;
ii. to evaluate batch records;
iii. to ensure that all necessary testing is carried out;
iv. to approve specifications, sampling instructions, test methods and other Quality Control procedures;
v. to approve and monitor any contract analysts;
vi. to check the maintenance of his department, premises and equipment;
vii. to ensure that the appropriate validations are done;
viii. to ensure that the required initial and continuing training of his department personnel is carried out and adapted
according to need.

Health Canada – GMP
Regulatory Sections Cited most Frequently
• A total of 2,933 observations were noted during the 428 inspections conducted in FY 2013-
2014. The majority of observations were cited against requirements for the quality control
department C.02.013-15

Health Canada – GMP
• Quality control is the part of GMP that is concerned with sampling, specifications, testing, documentation, and release
procedures. Quality control ensures that the necessary and relevant tests are carried out and that raw materials, packaging
materials, and APIs are released for use or sale, only if their quality is satisfactory. Quality control is not confined to laboratory
operations but must be incorporated into all activities and decisions concerning the quality of the API.
• The basic requirements of quality control are as follows:
• Adequate facilities, trained personnel, and approved procedures are available for sampling, inspecting and testing of raw
materials, packaging materials, APIs, and, where appropriate monitoring environmental conditions for GMP purposes;
1.1 Samples of raw materials, packaging materials, and APIs are taken according to procedures approved by the quality control department;
1.2 Test methods are validated;
1.3 Records demonstrate that all the required sampling, inspecting, and testing procedures were carried out, and any deviations are recorded
and critical deviations investigated;
1.4 Records are made of the results of the self-inspection program;
1.5 The procedures for product release include a review and evaluation of relevant production documentation and an assessment of deviations
from specified procedures;
1.6 No API is released for sale or for further use prior to approval by the quality control department;
1.7 Sufficient samples of raw material and final API forms are retained to permit future examination if necessary.

pharmauptoday@gmail.comHow to avoid 21 CFR 211.22 observations ?

Review of data
• There is a distinct difference between a technical review of data and a release review. A technical
review is that final review of all raw data, worksheets, chromatograms, calculations, etc. associated
with testing to assure data integrity prior to release of the data. The release review is the review that
assures results meet specifications prior to release of the product.
• Each review should be well-defined in SOPs.

Investigations
• To assure that the “quality unit” has proper authority to approve or reject raw materials, an FDA
investigator will often closely scrutinize investigations relating to raw materials released. If evidence is
found that a non-conforming lot of material was given additional review, additional testing, or other
opportunities to pass specifications, it might indicate that the quality unit lacks the autonomy to make
the final lot disposition.
• To avoid the appearance of impropriety, assure that all decisions to overturn an original failing
result, or to conduct additional testing is without interference from those outside the quality unit with a
vested interest in using the material.

Review and Approval of laboratory data
• The reviewer must be qualified – the individual that provides a technical review of data must be
qualified by a combination of “education, training, and experience” and the fact that an individual is
qualified must be documented
• All data, including raw data, must be available and reviewed by the reviewer – a proper technical
review should include a detailed review of the method used, and all results (including raw
data, charts, spectra, reagent preparation records, calculations, etc.), and the final result, must be
repeatable by calculation by the reviewer
• The technical reviewer must be provided the time and authority to conduct a thorough
review, e.g., the technical review must not be a secondary activity performed between analyses. This
activity must be taken seriously, and the reviewer must have authority to reject any data not
appropriately derived, documented, or defendable

Contract laboratory
• Whether or not you routinely use a contract laboratory, it is a good practice to have one or more
contract laboratories qualified and approved for use in the event of an emergency or unexpected
project deadline. Because it can take several months to identify, audit, and qualify an alternate
laboratory, much time can be saved if this is accomplished beforehand.
• There are several good reasons why a contract laboratory may make sense:
- The contract laboratory offers testing capabilities you do not have
- To conduct easy, routine tests allowing the focus of your laboratory to remain with more challenging testing
- To meet a temporary project need
- To provide flexibility

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 # 3 : 21 CFR 211.192
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Top 20 observation series 2: 21 CFR 211.22

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Top 20 observation series 2: 21 CFR 211.22