Top 20 observation series # 4 : 21 CFR 211.67

21 CFR 211.67
pharmauptoday@gmail.comConsult Yourself.... “Know Regulation - No Observation”

- 2014 inspectional observations
- List of Top observations in 2014
- Sec. 21 CFR 211.67
- 483 observations
- Warning Letters
- Other Guidance
- How to avoid observations
pharmauptoday@gmail.com
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 high 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) can be accessed from the link:
21 CFR 211.22

Subpart J--Records and Reports
Sec. 211.192 Production record review.
21 CFR 211.192 can be accessed from the link:
21 CFR 211.192

Subpart D--Equipment
Sec. 211.67 Equipment cleaning and maintenance.
21 CFR 211.67(a)
21 CFR 211.67(b)
21 CFR 211.67(c)
21 CFR 211.67

483 citations related to 21 CFR 211.67
Year Number
2006 137
2007 142
2008 111
2009 143
2010 171
2011 190
2012 175
2013 192
2014 184
0
50
100
150
200
250
2006 2007 2008 2009 2010 2011 2012 2013 2014
483 Observations

Regulation

CFR part 211 Regulation - 21 CFR 211.67(a)
(a) Equipment and utensils shall be cleaned, maintained, and, as appropriate for the
nature of the drug, sanitized and/or sterilized at appropriate intervals to prevent
malfunctions or contamination that would alter the safety, identity, strength, quality, or
purity of the drug product beyond the official or other established requirements.

Previous observations

483 citations related to 21 CFR 211.67(a)
Cite Id
Reference
Number
Short Description Long Description
Frequency
2014 2013
1213 21 CFR 211.67(a)
Cleaning / Sanitizing /
Maintenance
Equipment and utensils are not [cleaned] [maintained]
[sanitized] at appropriate intervals to prevent
[malfunctions] [contamination] that would alter the
safety, identity, strength, quality or purity of the drug
product. Specifically, ***
63 71

CFR part 211 Regulation - 21 CFR 211.67(b)
(b) Written procedures shall be established and followed for cleaning and maintenance of
equipment, including utensils, used in the manufacture, processing, packing, or holding of a drug
product. These procedures shall include, but are not necessarily limited to, the following:
(1) Assignment of responsibility for cleaning and maintaining equipment;
(2) Maintenance and cleaning schedules, including, where appropriate, sanitizing schedules;
(3) A description in sufficient detail of the methods, equipment, and materials used in cleaning and maintenance
operations, and the methods of disassembling and reassembling equipment as necessary to assure proper
cleaning and maintenance;
(4) Removal or obliteration of previous batch identification;
(5) Protection of clean equipment from contamination prior to use;
(6) Inspection of equipment for cleanliness immediately before use.

483 citations related to 21 CFR 211.67(b)
Cite Id Reference Number Short Description Long Description
Frequency
2014 2013
1215 21 CFR 211.67(b)
Written procedures not
established/followed
Written procedures are not [established] [followed] for the cleaning and maintenance of equipment,
including utensils, used in the manufacture, processing, packing or holding of a drug product.
Specifically, ***
72 77
4303 21 CFR 211.67 b)
Written procedures fail to
include
Written procedures for cleaning and maintenance fail to include [assignment of responsibility]
[maintenance and cleaning schedules] [description in sufficient detail of methods, equipment and
materials used] [description in sufficient detail of the methods of disassembling and reassembling
equipment as necessary to assure proper cleaning and maintenance] [instructions for removal or
obliteration of previous batch identification] [instructions for protection of clean equipment from
contamination prior to use] [parameters relevant to the operation]. Specifically, ***
23 26
1219
21 CFR
211.67(b)(2)
Cleaning SOPs/schedules
Procedures for the cleaning and maintenance of equipment are deficient regarding maintenance and
cleaning schedules, including, where appropriate, sanitizing schedules. Specifically, ***
1 1
1220
21 CFR
211.67(b)(3)
Cleaning
SOPs/instructions
Procedures for the cleaning and maintenance of equipment are deficient regarding sufficient detail of
the methods, equipment, and materials used in the cleaning and maintenance operation, and the
methods of disassembly and reassembling equipment as necessary to assure proper cleaning and
maintenance. Specifically, ***
3 1
1222
21 CFR
211.67(b)(4)
Cleaning SOPs/equipment
identification
Procedures for the cleaning and maintenance of equipment are deficient regarding the removal or
obliteration of the previous batch identification. Specifically, ***
1 1
1223
21 CFR
211.67(b)(5)
Cleaning SOPs/equipment
protection
Procedures for the cleaning and maintenance of equipment are deficient regarding the protection of
clean equipment from contamination prior to use. Specifically, ***
2 0
1224
21 CFR
211.67(b)(6)
Cleaning SOP/inspection
Procedures for the cleaning and maintenance of equipment are deficient regarding inspection of the
equipment for cleanliness immediately before use. Specifically, ***
1 1

Ref: 483 of Andrx Pharmaceuticals Inc (04/2006)

Ref: 483 of Teva Parenteral Medicines Inc (07/2009)

483 citations related to 21 CFR 211.67
Ref: 483 of Hospira Inc (02/2013)

Warning letter observations -2014 - 21 CFR 211.67(b)
Failure to adequately complete and follow written procedures for cleaning equipment and its
release for use in API manufacture, and to maintain adequate records of major equipment
usage.
• Your firm failed to ensure that employees adequately cleaned (b)(4) after
use. Your (b)(4) equipment cleaning standard operating procedures (SOP-HE 063-02 - instruction
4.2.2.1, SOP-HE 064-02 – instruction 4.3.4.3, and SOP-HE 055-02 – instruction 4.2.1.1), require
that employees visually inspect equipment after the cleaning process. Our inspection found (b)(4) in
the manufacturing workshop for (b)(4) with various levels of contamination and foreign objects
inside, including what looked like the remains of a pen in one of the (b)(4). Your employees had
labeled this equipment as clean. These (b)(4) are used for the manufacture of multiple APIs.
• In addition, your firm’s production system did not maintain equipment logs or other documents that
adequately record manufacturing operations performed on individual pieces of equipment.
• We note that your production operation supervisors and Quality Unit (QU) failed to detect and
correct these deficient cleaning practices.
Ref: WL: Tianjin Zhongan Pharmaceutical Co., Ltd. 6/10/14 (320-14-09)

Ref: WL: Ameriderm Laboratories, Ltd. 12/2/13 (14-NWJ-02)
Your firm failed to establish and follow adequate written procedures for
cleaning and maintenance of equipment (21 CFR 211.67(b)).
For example, the cleaning procedures described in Chapter 2-SOP-5 Cleaning of
Batching Vessels lack detailed instructions for the cleaning and sanitization of non-
dedicated equipment, including mixing kettles and tanks, used to manufacture your
OTC drug products. There is no assurance that the cleaning and sanitization
methods described in your cleaning validation documents are adequate.
In addition, your firm does not maintain individual equipment logs for non-dedicated
equipment, including mixing kettles and tanks, in order to document equipment
cleaning, maintenance, and use.

Ref: WL: P.A. Benjamin Manufacturing Co., Ltd. 1/29/13 (WL: 320-13-07)
For example, your firm failed to validate a cleaning method used for the multi-
product manufacturing equipment and utensils. Your firm has no assurance that your
current, manual cleaning methods are effective in removing residues of drug
products and detergents from the manufacturing equipment and utensils.
Additionally, your firm failed to validate the “(b)(4)” device used to
detect (b)(4) traces on the equipment surfaces after cleaning. Finally, your firm failed
to implement procedures on the proper use of the device.

Ref: WL: CMI Cosmetic Manufacturers Inc. 4/25/13 (WL: 320-13-13)
For example, your firm has failed to evaluate the effectiveness of your cleaning
procedures. You do not have data to show that your equipment cleaning procedure
is adequate to prevent cross-contamination.
Specifically, your firm has not conducted cleaning validation, cleaning verification, or
swab recovery studies for multi-use equipment used in the production of your OTC
drug products.

CFR part 211 Regulation - 21 CFR 211.67(c)
(c) Records shall be kept of maintenance, cleaning, sanitizing, and inspection as specified
in 211.180 and 211.182.

483 citations related to 21 CFR 211.67(c)
Cite Id
Reference
Number
Short Description Long Description
Frequency
2014 2013
1227
21 CFR
211.67(c)
Cleaning/maintenance
records not kept
Records are not kept for the [maintenance] [cleaning]
[sanitizing] [inspection] of equipment. Specifically, ***
18 12

483 citations related to 21 CFR 211.67(c)
Ref: 483 of Amylin Pharmaceutical Inc (12/2009)

Warning letter observations -2014 - 21 CFR 211.67
Failure to document manufacturing operations at the time they are performed.
• When reviewing the entries in your (b)(4) use, cleaning, and maintenance logbook for the
days immediately prior to the inspection, our investigator found missing entries. Your
operators stated that lines were left blank to later add information about cleaning events
that may have occurred during a previous shift.
• During the inspection, our investigator found other similar instances of missing data or
belated data entry in your manufacturing records. These practices are not consistent with
CGMP. Operators acknowledged that there is no system in place to report these lapses in
the documentation system; documentation errors of this type did not require deviation
investigations or notification to the Quality Unit.
Ref: WL: Zhejiang Jiuzhou Pharmaceutical Co., Ltd. 7/9/14 (320-14-12)

Summary of Observations
• Inadequate equipment cleaning and validation protocols
• Cleaning methods for common equipment not validated
• Inadequate sampling and testing of equipment surfaces
• No record to document alarms with the cleaning equipment
• CIP record sheets that document the CIP of the manufacturing equipment are not reviewed by Production
or Quality Assurance Staff.
• Residue limits for potential contaminants not established
• Specificity and sensitivity of analytical methods not established
• No testing for residues of solvents used in API production
• The CIP validation didn’t include studies to determine or evaluate what are the most difficult (“Hot Spot”)
locations to clean.

Other Guidance …

Validation of Cleaning Processes (7/93)

Questions and Answers on Current Good Manufacturing
Practices, Good Guidance Practices, Level 2 Guidance - Laboratory
Controls

USP General Chapter <1072> DISINFECTANTS AND ANTISEPTICS

Comparison between US and EC GMP

EU Non-Compliance Reports
Firm Name Nature of non-compliance
Wockhardt Limited,
Aurangabad; Jan 2015
A major deficiency was cited with regards to equipment and facility, maintenance, design
and qualification. Examples included, inappropriate pressure differentials that were not in
line with the original design but had not been changed using change control, cleaning
validation that was not sufficiently robust to confirm cleaning practices and maintenance
issues, such as the failure to spark test glass lined reactor vessels for integrity especially
following maintenance.
MANUEL RIESGO S.A.,
Spain; Nov 2014
Utensils are not cleaned and stored to prevent contamination.
Taishan City Chemical
Pharmaceutical Co.
Ltd., China; Nov 2014
Multiple risks of contamination identified in the production areas of Ciclosporin (e.g. no
protection of clean equipment outlets, equipment under status “to be used for production”
stored dirty for several months, open parts of the final steps exposed in dirty
surroundings);
VETPROM AD,
Bulgaria; Aug 2014
The procedure for cleaning validation is ineffective and does not include all medicines
(human and animal medicinal use);

Health Canada – GMP
• Examples of observations from frequently cited sections of the Food and Drug
Regulations - Good Manufacturing Practices Inspections

pharmauptoday@gmail.comHow to avoid 21 CFR 211.67 observations ?

Basics
Clean(liness) (adj.)
• visually clean - absence of materials which would
adulterate a product when inspected with the eyes
• detectably clean - absence of materials which would
adulterate a product down to the level of detection
• chemically clean - absence of all chemicals which would
adulterate a product.
Cleaning validation
• Documented evidence to establish that cleaning
procedures are removing residues to predetermined levels
of acceptability, taking into consideration factors such as
batch size, dosing, toxicology and equipment size.

Cleaning Documentation
• The cleaning validation must document the efficiency of a cleaning procedure
• The cleaning procedure must be reliable with regard to removal of contamination (e.g.
products, cleaning agents, microorganisms) to a predetermined acceptable level
• Procedures for cleaning of areas in product contact must be validated (with consideration to areas out
of product contact).
• The intervals between use and cleaning of equipment as well as between cleaning and reuse must be
validated.

Recordings
• Preceding product
• ”Batch to batch” cleaning or ”product to product” cleaning
• The cleaning documentation for equipment which is considered to be critical for the
product
• Sampling of equipment which is considered critical for the product
• Applied cleaning agents and concentrations (batch no.)
• Time of cleaning – date of performance and signature
• Observations during inspection of equipment prior to production

Equipment Cleaning
• Preparation and storage of cleaning solutions, maintenance of cleaning equipment, such as
mops, buck, etc., and procedures used for cleaning.
• review the regulatory requirements for establishing a cleaning program.
• Discuss personnel qualifications, written procedures, selection of cleaning agents, and
recordkeeping.
• Determine if the procedures are being followed, and if they specify the cleaning agents and the
preparation of those cleaning agents.
• Ensure that the cleaning agents, their concentration, and the procedure for use are consistent with
those that have been used in the cleaning validation.
• Review the written procedures for equipment cleaning. Ensure that the purpose of the cleaning is
consistent with the agent chosen for use. For example, if the objective of the cleaning is to sanitize
a piece of equipment, ensure that the cleaning agent chosen is designed to accomplish the desired
sanitization by reviewing the technical literature available from the supplier.

Approach
The following considerations are proposed as part of a systematic approach to determine the most difficult-to-
clean sampling locations in manufacturing equipment:
• Equipment technical analysis. The type of surface, interfacial effects, and shadowed areas should be
considered. Materials of construction (MOC) and geometrical configurations, type of processing (wet or
dry), and problematic hard-to-clean areas of the equipment are noted. For example, stainless steel is
generally harder to clean than glass or Teflon. Additionally, for a specific MOC, the smoothness of the surface
can significantly affect its cleanability.
• Observation of equipment after processing. The equipment is observed after processing typical
pharmaceutical products. Areas of excessive process residue accumulation are noted.
• Equipment disassembly review. The equipment is observed after disassembly. Product contact areas that
are the most difficult to clean are noted. Equipment components that are disassembled for cleaning and
subsequent evaluation pose a much lower risk than components that are part of the fixed equipment assembly
and are cleaned in place. Accessibility of components on the fixed equipment assembly is noted.
• Cleaning procedure review. The cleaning procedure for the equipment is reviewed. Ability to visually
observe equipment and components is noted. Parts and equipment locations previously identified as difficult
to clean may not be difficult to clean after equipment disassembly.
• Operator interviews. Discussions with operators experienced with cleaning the equipment of interest are
utilized to determine difficult-to-clean locations. Their recommendations of difficult-to-clean areas of the
equipment based on actual experience are noted.

Considerations ….
• Cleaning procedures should be sufficiently detailed to remove the possibility of any inconsistencies during
the cleaning process. Following parameters are to be considered during cleaning procedures.
A. Equipment
Parameters to be
evaluated
• Identification of the
equipment to be
cleaned
• 'Difficult to clean' areas
• Property of materials
• Ease of disassembly
• Mobility
B. Residues to be
cleaned
• Cleaning limits
• Solubility of the
residues
• Length of campaigns
C. Cleaning agent
parameters to be
evaluated
• Preferable materials
that are normally used
in the process
• Detergents available
(as a general
guide, minimal use of
detergents
recommended unless
absolutely required)
• Solubility properties
• Environmental
considerations
• Health and safety
considerations
D. Cleaning techniques
to be evaluated
• Manual cleaning
• CIP (Clean-in-place)
• COP (Clean-out-of-
place)
• Semi automatic
procedures
• Automatic procedures
• Time considerations
• Number of cleaning
cycles

Considerations ….
• Automated Cleaning
Vs Manual Cleaning
• Clean-In-Place (CIP)
Vs Clean-Out-of-
Place (COP)
Cleaning
Program
Criteria
• Dedicated Vs Non-
Dedicated Manufacturing
Equipment
• Dedicated Vs Non-
Dedicated Cleaning
Equipment
• Non-Product Contact Vs
Product Contact
Surfaces
• Non-Critical Site Vs
Critical Site
• Minor Equipment Vs
Major Equipment
Equipment
Characteristics /
Materials of
Construction
• Low Risk Vs High
Risk Drugs
• Highly Characterized
Vs Poorly
Characterized
• Non-Sterile Vs
Sterile
Product
Attributes
• Solids Vs Liquids
• Soluble (Active or
Excipient) Vs
Insoluble (Active or
Excipient)
Formulation
Attributes
• Single Product
Facility Vs Multiple
Product Facility
• Campaign
Production Vs
Batch Production
• Simple Equipment
Train Vs Complex
Equipment Train
Operational
Issues

Training
Training practices will vary from one company to another but operator training may be enhanced by
some of the following suggestions:
- Clearly written, understandable and sufficiently detailed SOPs.
- Use of checklists to determine that all operations are carried out in the proper sequence and are
documented.
- Periodic monitoring of cleaning processes to ensure proper training of operators and continued
compliance with SOPs.
- Dedicated or assigned cleaning personnel.
- Feedback from operators to modify procedures.
- Use of video to demonstrate proper cleaning operations and techniques.
• Overall the operators should understand the process of cleaning and the operation of the
equipment they are cleaning. In addition the operators should be aware of the cleaning process
impact on the quality of the next product manufactured in the same equipment.

Major Sampling Techniques - Attributes

Typical Cleaning Validation Assay Methods

cGMPCleaningCompliance
Source:
5 Tactics for Cleaning Validation
Compliance (IVT Network)

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 # 5 21 CFR 211.100
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Top 20 observation series # 4 : 21 CFR 211.67

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