Top 20 observation series # 6 21 CFR 211.165 - Testing and release for distribution

21 CFR 211.165
pharmauptoday@gmail.comConsult Yourself.... “Know Regulation - No Observation”

- 2014 inspectional observations
- List of Top observations in 2014
- Sec. 21 CFR 211.165
- 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 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) can be accessed from the link:
21 CFR 211.67

Subpart F- Production and Process Controls
Sec. 211.100 Written procedures; deviations.
21 CFR 211.100(a)
21 CFR 211.100(b) can be accessed from the link:
21 CFR 211.100

Sec. 211.165 Testing and release for distribution.
21 CFR 211.165(a)
21 CFR 211.165(b)
21 CFR 211.165(c)
21 CFR 211.165(d)
21 CFR 211.165(e)
21 CFR 211.165(f)
21 CFR 211.165

483 citations related to 21 CFR 211.165
Year Number
2006 143
2007 127
2008 100
2009 108
2010 140
2011 156
2012 139
2013 179
2014 143
0
20
40
60
80
100
120
140
160
180
200
2006 2007 2008 2009 2010 2011 2012 2013 2014
483 Observations

Regulation

CFR part 211 Regulation - 21 CFR 211.165(a)
• Subpart I--Laboratory Controls
• Sec. 211.165 Testing and release for distribution.
(a) For each batch of drug product, there shall be appropriate laboratory determination of
satisfactory conformance to final specifications for the drug product, including the identity and
strength of each active ingredient, prior to release. Where sterility and/or pyrogen testing are
conducted on specific batches of shortlived radiopharmaceuticals, such batches may be
released prior to completion of sterility and/or pyrogen testing, provided such testing is
completed as soon as possible.

483 citations related to 21 CFR 211.165(a)
Cite Id
Reference
Number
Short Description Long Description
Frequency
2014 2013
1883
21 CFR
211.165(a)
Testing and release for
distribution
Testing and release of drug product for distribution do not include
appropriate laboratory determination of satisfactory conformance to
the [final specifications] [identity and strength of each active
ingredient] prior to release. Specifically, ***
64 66

Ref: 483 of Sandoz Inc (06/2011)

Ref: 483 of Zions RX Formulations Services LLC (01/2014)

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

Ref: 483 of Ohm Laboratories Inc (08/2009)

Ref: 483 of Pyramid Laboratories, Inc (01/2015)

Ref: 483 of Hospira Inc (03/2013)
Continued …

Ref: 483 of Hospira Inc (03/2013)

Ref: 483 of Formulation Technology Inc (07/2013)

Ref: 483 of Downing labs, LLC (07/2014)

Warning letter observations
Ref: WL: Peking Medicine Manufactory 3/25/13 (320-13-12)
Testing and release of drug product for distribution do not include appropriate laboratory determination of
satisfactory conformance to the final specifications and identity and strength of each active ingredient
prior to release. [21 C.F.R. § 211.165(a)]
a. Your finished product, STRONG WOO LOK GAO (lot#II18A) was not tested for conformance to the labeled
amount of active ingredients.
Your firm contracted out the STRONG WOO LOK GAO product.
Your firm accepted and relied on the Certificate of Analysis (COA) from your contract manufacturer (CMO) and
failed to verify the accuracy and completeness of testing results in the COA. For example, STRONG WOO LOK
GAO contains six active ingredients. The COA for this lot showed that only identity testing for two of the six active
ingredients was conducted. No assay testing was conducted.

Ref: WL: Kanebo Cosmetics Inc. 4/1/13 (320-13-14)
Your firm does not have, for each batch of drug product, appropriate laboratory determination of
satisfactory conformance to final specifications for the drug product, including the identity and strength
of each active ingredient, prior to release (21 CFR 211.165(a)).
For example, your firm did not determine the purity and strength of the active ingredient(s) in any batch of
your(b)(4) over-the-counter (OTC) drug products manufacturedprior to June 2012. These products are currently in
the U.S. market. In response to this letter, provide scientifically sound and appropriate written test
procedures, sampling plans, and specifications for your (b)(4) drug products, including documentation of validation
for allnon-compendial analytical methods. Provide test results of all your drug product batches within expiry that
have been distributed to the U.S. to demonstrate conformance to final specifications, and to support your product
label claims as to the amount of active ingredient(s). Describe and provide supportive documentation for any
corrective action and/or market action you will take for product batches that are non-conforming or lack
appropriate product release testing. In addition, explain how you will assure adequate finished product testing for
all future drug product batches prior to release.

Ref: WL: Jabones Pardo S.A. 8/22/13 (320-13-25)
Your firm does not have, for each batch of drug product, appropriate laboratory determination of
satisfactory conformance to final specifications for the drug product, including the identity and strength
of each active ingredient, prior to release (21 CFR 211.165(a)).
For example, your firm failed to test its products for the identity and strength of each active ingredient prior to
release. The investigator obtained certificates of analyses (COAs) for your drug products showing your firm did not
perform identity and strength testing for the release of these over-the-counter (OTC) drug
products: (b)(4),Le’dermis Skin Solutions Anti-Acne Medicated Cream, and (b)(4) distributed to the US market. For
those drug products, your firm failed to test for the active ingredients (b)(4)%, (b)(4)%, Salicylic Acid 1%, and
Octinoxale 1%.
Additionally, you failed to perform antimicrobial effectiveness testing on your drug products, in accord with United
States Pharmacopeia <51>.

Ref: WL: Jubilant Hollister Stier General Partnership 2/20/13 (320-13-08)
Your firm does not have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to
final specification for the drug product, including identity and strength of each active ingredient, prior to release (21 CFR
211.165 (a)).
Your firm also failed to establish acceptance criteria for the sampling and testing conducted by the quality control unit that are
adequate to assure that batches of drug products meet each appropriate specification and appropriate statistical quality
control criteria as a condition for their approval and release (21 CFR 211.165(d)).
For example, your firm released multiple lots of finished (b)(4) products despite the failure of these lots to meet acceptance criteria during
100% visual inspection.
The inspection revealed that (b)(4) Injection lots #(b)(4), #(b)(4), and #(b)(4), and (b)(4) lots #(b)(4), #(b)(4), and #(b)(4) failed to meet
the visual inspection specification of ≤ (b)(4)% and ≤ (b)(4)%, respectively, for major defects. Nonetheless, you released these batches
for distribution without re-evaluating them to ensure that none of the vials you released contained (b)(4) defects, glass particles, or other
foreign material which could impact product performance (e.g., reconstitution, stability) or pose a hazard to its consumers. Regarding lot
#(b)(4), your firm had a compressor failure (due to a power outage) during the (b)(4) operation that resulted in a 34oC increase above the
target temperature at that stage of the cycle.
This excessive deviation was measured on at least two shelves and resulted in unacceptable (b)(4) appearance. During final visual
inspection, more than 2500 vials were inspected out of the batch due to the temperature deviation. On the basis of this visual
inspection, you allowed the remainder of the batch (over (b)(4) vials) to be released. Please explain this decision in your response, and
include a discussion of whether it is feasible for your operators to visually detect and sort out all affected units of a batch following such a
significant temperature deviation in the (b)(4) cycle.

CFR part 211 Regulation - 21 CFR 211.165(b)
(b) There shall be appropriate laboratory testing, as necessary, of each batch of drug product
required to be free of objectionable microorganisms.

483 citations related to 21 CFR 211.165(b)
Cite Id
Reference
Number
Frequency
2014 2013
1885
21 CFR
211.165(b)
Microbiological testing
Each batch of drug product required to be free of objectionable
microorganisms is not tested through appropriate laboratory testing.
Specifically, ***
17 26

Ref: WL: VUAB Pharma a.s. 5/27/15 (320-15-10)
Your quality unit released API with objectionable microbial contamination into distribution. For example,
a. In January 2014, your firm received a customer complaint regarding microbial contamination of (b)(4), API
lot (b)(4). Your customer tested samples of this lot produced by your firm and identified Clostridium sphenoides.
During your customer complaint investigation, you were unable to detect the contamination in the samples your
customer returned. Your customer’s May, 2014, on-site audit of your firm revealed differences in microbiological
test methods: your test method was inadequate to detect Clostridium sphenoides growth. Once you modified the
test method per your customer’s recommendation, your firm confirmed Clostridium sphenoides contamination in
your retain sample. However, you failed to identify the source of the contamination or to implement meaningful
corrective actions to prevent future microbial contamination.
Test results exhibiting objectionable microbial contamination represent a significant deficiency in the safety and
quality of your APIs. Since microbial contamination is typically non-uniform, the risk of patient exposure to a
contaminated drug is exacerbated by low detectability of a test of limited sample size. In addition, your customers
may not perform any additional microbiological testing upon receipt of your API. Furthermore, objectionable
microbiological contamination in your API, which is intended for (b)(4) and (b)(4)suspensions, indicates a
significant failure in your capability to prevent microbiological contamination in your operation.

CFR part 211 Regulation - 21 CFR 211.165(c)
(c) Any sampling and testing plans shall be described in written procedures that shall include the
method of sampling and the number of units per batch to be tested; such written procedure shall
be followed.

483 citations related to 21 CFR 211.165(c)
Cite Id
Reference
Number
Frequency
2014 2013
1886
21 CFR
211.165(c)
Sampling and testing
plans not described
Sampling and testing plans for drug products are not
described in written procedures which include the [method of
sampling] [number of units per batch to be tested].
Specifically, ***
5 5
4355
21 CFR
211.165(c)
Sampling and testing
plans not followed
Written procedures for sampling and testing plans are not
followed for each drug product. Specifically, ***
2 2

Ref: 483 of Hospira Inc (03/2013) Continued …

CFR part 211 Regulation - 21 CFR 211.165(d)
(d) Acceptance criteria for the sampling and testing conducted by the quality control unit shall be
adequate to assure that batches of drug products meet each appropriate specification and
appropriate statistical quality control criteria as a condition for their approval and release. The
statistical quality control criteria shall include appropriate acceptance levels and/or appropriate
rejection levels.

483 citations related to 21 CFR 211.165(d)
Cite Id
Reference
Number
Frequency
2014 2013
3616
21 CFR
211.165(d)
Acceptance criteria for
sampling & testing
Acceptance criteria for the sampling and testing conducted by the
quality control unit is not adequate to assure that batches of drug
products meet [each appropriate specification] [appropriate
statistical quality control criteria] as a condition for their approval
and release. Specifically, ***
8 13
4354
21 CFR
211.165(d)
Acceptance/Rejection Levels
The statistical quality control criteria fail to include appropriate
[acceptance levels] [rejection levels]. Specifically, ***
2 1

CFR part 211 Regulation - 21 CFR 211.165(e)
(e) The accuracy, sensitivity, specificity, and reproducibility of test methods employed by the firm
shall be established and documented. Such validation and documentation may be accomplished
in accordance with 211.194(a)(2).

483 citations related to 21 CFR 211.165(e)
Cite Id
Reference
Number
Frequency
2014 2013
1890
21 CFR
211.165(e)
Test methods
The [accuracy] [sensitivity] [specificity] [reproducibility] of
test methods have not been [established] [documented].
Specifically, ***
27 39

Ref: 483 of Ameridose LLC (11/2012)

Ref: 483 of Impax Laboratories Inc (07/2014)
Continued …

Ref: 483 of Impax Laboratories Inc (07/2014)

CFR part 211 Regulation - 21 CFR 211.165(f)
(f) Drug products failing to meet established standards or specifications and any other relevant
quality control criteria shall be rejected. Reprocessing may be performed. Prior to acceptance
and use, reprocessed material must meet appropriate standards, specifications, and any other
relevant criteria.

483 citations related to 21 CFR 211.165(f)
Cite Id
Reference
Number
Frequency
2014 2013
1891
21 CFR
211.165(f)
Failing drug products not
rejected
Drug products failing to meet established [standards]
[specifications] [quality control criteria] are not rejected.
Specifically, ***
18 27

Ref: 483 of Ipca Laboratories Ltd (10/2014)

Ref: 483 of Akorn Inc (05/2011)

Ref: WL: Boehringer Ingelheim Pharma GMBH & Co 5/6/13 (320-13-015)
Your firm failed to reject drug products that did not meet established standards or specifications and any
other relevant quality control criteria (21 CFR 211.165(f)).
Your firm failed to reject multiple batches of (b)(4) Capsules (b)(4) µg batches that were contaminated with foreign
particles. During 2010 and 2012, several lots of (b)(4) API batches (lots (b)(4)) were contaminated with extrinsic
foreign particles found during (b)(4), weighing or by visual inspection and were used for finished drug
manufacturing. The size and weight of the particles ranged from approximately 200 microns to approximately 5
mm, from 0.4 micrograms to approximately 9 mg, respectively.
We disagree with your decision to use the (b)(4) API because the contaminated batches met the final
specifications. Use of appropriate manufacturing, controls, quality standards, and systems for investigations of
atypical events (e.g., contamination) are all essential parts of a robust quality system. Additionally, quality cannot
be added into a product after it has been manufactured. We are therefore concerned about your decision to use
contaminated (b)(4) API to manufacture your (b)(4) capsules, as this drug is approved for patients diagnosed
with (b)(4).

Other Guidance …

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

Questions and Answers on cGMP, Good Guidance Practices,
Level 2 Guidance - Production and Process Controls

Comparison between US and EC GMP

EC GMP Guide
Chapter 4 Documentation
Specifications for intermediate and bulk products
4.15 Specifications for intermediate and bulk products should be available for critical steps or if these are purchased or dispatched. The
specifications should be similar to specifications for starting materials or for finished products, as appropriate.
Specifications for finished products
4.16 Specifications for finished products should include or provide reference to:
a) The designated name of the product and the code reference where applicable;
b) The formula;
c) A description of the pharmaceutical form and package details;
d) Directions for sampling and testing
e) The qualitative and quantitative requirements, with the acceptance limits;
f) The storage conditions and any special handling precautions, where applicable;
g) The shelf-life.

EC GMP Guide
Chapter 6 Quality Control
Principle
• Quality Control is concerned with sampling, specifications and testing as well as the
organisation, documentation and release procedures which ensure that the necessary and
relevant tests are carried out, and that materials are not released for use, nor products
released for sale or supply, until their quality has been judged satisfactory.
Testing
6.15 Testing methods should be validated. A laboratory that is using a testing method and
which did not perform the original validation, should verify the appropriateness of the
testing method. All testing operations described in the marketing authorisation or technical
dossier should be carried out according to the approved methods.

EC GMP Guide
Documentation
• 6.7 Laboratory documentation should follow the principles given in Chapter 4. An important part of
this documentation deals with Quality Control and the following details should be readily available to
the Quality Control Department:
i. Specifications;
ii. Procedures describing sampling, testing, records (including test worksheets and/or laboratory
notebooks), recording and verifying;
iii. Procedures for and records of the calibration/qualification of instruments and maintenance of
equipment;
iv. A procedure for the investigation of Out of Specification and Out Of Trend results;
v. Testing reports and/or certificates of analysis;
vi. Data from environmental (air, water and other utilities) monitoring, where required;
vii. Validation records of test methods, where applicable.

EC GMP Guide
Sampling
6.11 The sample taking should be done and recorded in accordance with approved written procedures that
describe:
i. The method of sampling;
ii. The equipment to be used;
iii. The amount of the sample to be taken;
iv. Instructions for any required sub-division of the sample;
v. The type and condition of the sample container to be used;
vi. The identification of containers sampled;
vii. Any special precautions to be observed, especially with regard to the sampling of sterile or noxious materials;
viii. The storage conditions;
ix. Instructions for the cleaning and storage of sampling equipment.

EC GMP Guide
Testing
6.15 Testing methods should be validated. A laboratory that is using a testing method and
which did not perform the original validation, should verify the appropriateness of the
testing method. All testing operations described in the marketing authorisation or technical
dossier should be carried out according to the approved methods.
6.16 The results obtained should be recorded. Results of parameters identified as quality
attribute or as critical should be trended and checked to make sure that they are consistent
with each other. Any calculations should be critically examined.

EC GMP Guide
Rejected, recovered and returned materials
5.67 The reprocessing of rejected products should be exceptional. It is only permitted if the quality of
the final product is not affected, if the specifications are met and if it is done in accordance with a
defined and authorised procedure after evaluation of the risks involved. Record should be kept of
the reprocessing.
5.69 The need for additional testing of any finished product which has been reprocessed, or into
which a recovered product has been incorporated, should be considered by the Quality Control
Department.

Health Canada – GMP
Drugs and Health Products, Good Manufacturing Practices (GMP) Guidelines - 2009 Edition, Version 2 (GUI-0001)
4.2.3 Quality Control
• 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 products 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 product. 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, intermediate bulk and finished products, and, where appropriate monitoring environmental
conditions for GMP purposes;
1.1 Samples of raw materials, packaging materials, and intermediate, bulk, and finished products 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
investigated;
1.4 Records are made of the results of the inspection and testing of materials and finished products against specifications;
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 drug is released for sale or supply prior to approval by the quality control department;
1.7 Sufficient samples of raw material and finished product are retained to permit future examination if necessary.

Drugs and Health Products, Good Manufacturing Practices (GMP) Guidelines - 2009
Edition, Version 2 (GUI-0001)
7. The reprocessing of any lot or batch of drug is given prior approval by the quality control department.
Approval of a reprocessed lot or batch of a drug by the quality control department is based on
documented scientific data, which may include validation. The reprocessing of products that fail to meet
their specifications is undertaken only in exceptional cases. Reprocessing is permitted only when the
following conditions are met:
7.1 The quality of the finished product is not affected;
7.2 The reprocessed lot meets specifications;
7.3 The reprocessing is done in accordance with a defined procedure approved by the quality control department;
7.4 All risks have been evaluated;
7.5 Complete records of the reprocessing are kept;
7.6 A new batch number is assigned; and
7.7 Validation demonstrates that the quality of the finished product is not affected.

Drugs and Health Products
Good Manufacturing Practices (GMP) Questions and Answers
• Q.7 Can the sampling for the microbial monitoring of air in non-sterile areas where susceptible products are
produced be conducted when there are no manufacturing packaging activities?
A.7 The sampling should occur during actual manufacturing or packaging in order to reflect the conditions to which the
products being produced are really exposed. Monitoring between production runs is also advisable in order to detect potential
problems before they arise.
• Q.8 Must written procedures be available to prevent objectionable microorganisms in drug products not required to
be sterile?
A.8 Yes. Appropriate written procedures, designed to prevent objectionable microorganisms in drug products not required to
be sterile, should be established and followed. This means that even though a drug product is not sterile, a firm must follow
written procedures that pro-actively prevent contamination and proliferation of microorganisms that are objectionable.

pharmauptoday@gmail.comHow to avoid 21 CFR 211.165 observations ?

7 Steps to avoid observations
1. Know the Regulation / Guidance
2. Perform a review / GAP Analysis
3. Identify the gaps in the system / practices
4. Change control process
5. Develop, Train & implement
6. Evaluate the implications
7. Recommendations (if any)
Know /
Update
Review
Identify
gap
Change
control
process
Develop,
Train &
implement
Implicati
ons
Recomm
endations

Specifications
• A specification is defined as a list of tests, references to analytical procedures, and
appropriate acceptance criteria, which are numerical limits, ranges, or other criteria for
the tests described.
• It establishes the set of criteria to which a drug substance or drug product should
conform to be considered acceptable for its intended use.
• "Conformance to specifications" means that the drug substance and / or drug
product, when tested according to the listed analytical procedures, will meet the listed
acceptance criteria.
• Specifications are critical quality standards that are proposed and justified by the
manufacturer and approved by regulatory authorities as conditions of approval.
• For each batch of drug product, there shall be appropriate laboratory determination of
satisfactory conformance to final specifications for the drug product, including the
identity and strength of each active ingredient, prior to release.

Periodic or skip testing
• Periodic or skip testing is the performance of specified tests at release on pre-
selected batches and / or at predetermined intervals, rather than on a batch-to-
batch basis with the understanding that those batches not being tested still must
meet all acceptance criteria established for that product.
• This represents a less than full schedule of testing and should therefore be
justified and presented to and approved by the regulatory authority prior to
implementation.
• This concept may be applicable to, for example, residual solvents and
microbiological testing, for solid oral dosage forms.

Objectionable Organism
The definition of an “objectionable organism” has been under intense scrutiny
recently. The critical nature of the issue is reflected by its presence in three
separate citations in the current GMP :
• 21 CFR 211.84(d)(6) “Each lot of a component, drug product container, or closure with potential
for microbiological contamination that is objectionable in view of its intended use shall be
subjected to microbiological tests before use.”
• 21 CFR 211.113(a) “Appropriate written procedures, designed to prevent objectionable
microorganisms in drug products not required to be sterile, shall be established and followed.”
• 21 CFR 211.165(b) “There shall be appropriate laboratory testing, as necessary, of each batch
of drug product required to be free of objectionable microorganisms.”

Objectionable Organism
Factors that can cause a microorganism to be Objectionable:
1. Cause illness or injury or cause harm with the anticipated use of the product
2. Affect product stability
3. Affect container/ closure system
4. Affect analytical testing
5. Affect active ingredient
6. Produce off odors, flavors or undesirable metabolites
7. Have the potential to grow and exceed the total aerobic count specification
8. High virulence, low infective dose
9. Resistance to antimicrobial therapy

Sampling and Testing
Sampling and Testing of Incoming production materials:
• Perform the identity test on each batch of raw material received.
• If a reduced testing program is used, ensure that a complete analysis is performed at
appropriate intervals?
• Sampling methods must specify the number of containers to be sampled
• Sampling to be conducted at defined locations, and define procedures shall be designed
to prevent contamination of the material being sampled
• Sampled containers should be marked to indicate that sampling has occurred.

Sampling and Testing
In-Process Sampling and Controls:
• Written procedures that define in-process controls and their acceptance criteria should
be available.
• Critical in-process controls should be stated in writing and approved by the quality unit?
• Written procedures that describe the sampling methods for in-process
materials, intermediates, and APIs should be available.
• In-process sampling should be performed according to a sampling plan
• Design procedures to prevent contamination of the sampled material.

Validation of analytical methods
Types of Analytical Procedures to be Validated
Four most common types of analytical procedures:
- Identification tests;
- Quantitative tests for impurities' content;
- Limit tests for the control of impurities;
- Quantitative tests of the active moiety in samples of drug substance or drug product or other
selected component(s) in the drug product.
• The tests like dissolution for drug products or particle size determination for drug
substance, is equally important.

Validation of analytical methods
• The accuracy (trueness) of an analytical procedure
expresses the closeness of agreement between the
value which is accepted either as a conventional true
value or an accepted reference value and the value
found.
• Specificity is the ability to assess unequivocally the
analyte in the presence of components which may be
expected to be present. Typically these might include
impurities, degradants, matrix, etc.
• Reproducibility expresses the precision between
laboratories (collaborative studies, usually applied to
standardization of methodology).
• The precision of an analytical procedure expresses
the closeness of agreement (degree of scatter)
between a series of measurements obtained from
multiple sampling of the same homogeneous sample
under the prescribed conditions.

Rejection & Reprocessing
Rejection and Requalification of Material:
• The final disposition of rejected material always should be recorded
• The controls should be in place to prevent formation of by-products and overreacted materials in
reprocessing operations.
• An investigation shall be performed into the reason for nonconformance prior to reworking batches.
• Reworked batches, subject to testing and evaluation requirements, demonstrate that the reworked
product is of equivalent quality to that produced by the original process.
• Approved procedures for the recovery of reactants, intermediates, or the API shall be available.
• The recovered materials shall meet specifications suitable for their intended use.
• Reworks/reprocessing procedures should be approved by the quality unit.
• Reprocess procedures should be validated.

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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 211.42
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Top 20 observation series # 6 21 CFR 211.165 - Testing and release for distribution

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