BPR review and batch release

1. BPR review and Batch
Release
Dr. A. Amsavel

2. Introduction

3. Content
• Introductions
• Definition
– Deviation, Critical Process Parameters and Critical Quality Attributes
• Regulatory requirement Q7 and CFR Specific to Batch Review an
Release
• Quality Unit Requirements
• Batch Record Defined in the Regulations
• Regulatory Consequences & FDA Citations
• Batch Record Review and Release
• SOP & Checklist
• Records to be Reviewed
• Cleaning & Line Clearance
• ALCOA

4. If it isn’t documented, it is not done or
It isn’t happened
If it isn’t documented, it doesn’t exist.
“If it is not documented, it is a rumour!”
This is the FDA approach
The product considered as “Adulterated” if the
procedure not followed/ not documented properly.
Importance of Documentation

5. What is BPR
• Batch Production Record (BPR) / Batch Record/
Production Control Record, Production Batch Record, etc….
Ref 21 CFR Part 211.188:
• BPR is step-wise procedure that production operators follow to
manufacture of API or a drug product or Intermediate for sale
– “Batch Production and Control Records shall be prepared for
each batch of drug product produced and shall include complete
information relating to the production and control of each
Batch.”
• Each BPR is a controlled document from the time it is issued
until it can eventually be destroyed.

6. Objective of BPR Review
Purpose
To confirm that there is sufficient evidence to demonstrate
the batch is of acceptable quality and is produced within a
state of control.
Significance
This confirmation is required to release product for
distribution.
It Is a permanent record in the event documented evidence
of conformance to specifications & cGMPs followed.
It is needed until the life of the product.

7. Definition
Deviation
Departure from an approved instruction / procedure or established
standard or specification
Quality Impacting Incident:
• Quality impacting incidents are errors or occurrences during execution
of an activity which will affect the Quality, Purity, Strength of the drug
product.
Quality Non-impacting Incident:
• Quality Non-impacting incidents are errors or occurrences during
execution of an activity which may have no impact on the quality,
purity and strength of a drug product
In-Process Control (or Process Control)
• Checks performed during production in order to monitor and, if
appropriate, to adjust the process and/or to ensure that the
intermediate or API conforms to its specifications.

8. Definition
• Critical Process Parameters (CPPs)
A process parameter which has impact on a CQA, hence those
parameter should be monitored or controlled to ensure the
process produces the desired quality.
• Critical Quality Attributes (CQA’s)A physical, chemical, or
microbiological property or characteristic that should be
within an appropriate limit, range to ensure the desired
product quality. CQAs are the aspects that affecting product
purity, strength, drug release, and stability.
• Process Parameter (PP)
Generally, they involve temperature, time, flow rates,
pressures, and numerous other discreet input settings or
output readings on the process equipment that are employed
in a manufacturing process.

9. GMP requirement
ICH Q7 - same as WHO-GMP
2.2 Responsibilities of the Quality Unit(s)
The main responsibilities of the independent quality
unit(s) should not be delegated
1. Releasing or rejecting all APIs. Releasing or rejecting
intermediates for use outside the control of the
manufacturing company;
2. Establishing a system to release or reject raw materials,
intermediates, packaging and labelling materials;
3. Reviewing completed batch production and laboratory
control records of critical process steps before release of
the API for distribution;

10. GMP requirement
ICH Q7 - same as WHO-GMP
2.3 Responsibility for Production Activities
• Reviewing all production batch records and ensuring that
these are completed and signed;
• Making sure that all production deviations are reported
and evaluated and that critical deviations are investigated
and the conclusions are recorded;

11. Requirement (ICH Q7)
Batch Record, Batch Production Record, Batch Production
Control Record, Production Batch Record, or other term,
6.5 Batch Production Records (Batch Production and Control
Records)
6.5.1 Batch production records should be prepared for each
intermediate and API and should include complete
information relating to the production and control of each
batch.
Batch production record should be current and reference to
the current master production
6.5.2 These records should be numbered with a unique batch or
identification number, dated and signed when issued

12. Requirement (ICH Q7)
6.5 Batch Production Records (Batch Production and Control Records)
• 6.52 Documentation of completion of each significant step in the batch
production records (batch production and control records) should
include:
– Dates and, when appropriate, times;
– Identity of major equipment (e.g., reactors, driers, mills, etc.) used;
– Specific identification of each batch, including weights, measures,
and batch numbers of raw materials, intermediates, or any
reprocessed materials used during manufacturing;
– Actual results recorded for critical process parameters;
– Any sampling performed;
– Signatures of the persons performing and directly supervising or
checking each critical step in the operation;

13. Requirement (ICH Q7)
• 6.5.2 Batch Production Records ...
– In-process and laboratory test results;
– Actual yield at appropriate phases or times;
– Description of packaging and label for intermediate or API;
– Representative label of API or intermediate if made commercially
available;
– Any deviation noted, its evaluation, investigation conducted (if
appropriate) or reference to that investigation and
– Results of release testing.
• 6.53 Investigating critical deviations or the failure of a batch of
intermediate or API to meet specifications. The investigation
should extend to other batches that may have been associated
with the specific failure or deviation.

14. GMP requirement Q7
6.7 Batch Production Record Review
1. Written procedures should be established and followed for the review and
approval of batch production and laboratory control records, including
packaging and labelling, to determine compliance of the intermediate or
API with established specifications before a batch is released or distributed.
2. Batch production and laboratory control records of critical process steps
should be reviewed and approved by the quality unit(s) before an API batch
is released or distributed. Production and laboratory control records of
non-critical process steps can be reviewed by qualified production
personnel or other units following procedures approved by the quality
unit(s).
3. All deviation, investigation, and OOS reports should be reviewed as part of
the batch record review before the batch is released.
4. The quality unit(s) can delegate to the production unit the responsibility
and authority for release of intermediates, except for those shipped outside
the control of the manufacturing company.

15. Production Record Review (21 CFR 211.192)
“All drug product production and control records, including
those for packaging and labeling, shall be reviewed and
approved by the quality control unit to determine
compliance with all established, approved written
procedures before a batch is released or distributed.
Any unexplained discrepancy (including theoretical yield or
the failure of a batch or any of its components to meet any of
its specifications shall be thoroughly investigated whether or
not the batch has already been distributed.
The investigation shall extend to other batches and other
products that may have been associated with the specific
failure or discrepancy and recorded

16. Responsibilities of Quality Control Unit
21 CFR 211.22:
The Quality Control Unit has the authority for the following:
• QC shall have Responsibility and authority to approve or reject
all components, drug products, containers, in-process
material, packaging material and Labels.
• Authority to Review Production Records to assure that no
errors have occurred.
• If errors have occurred, that they have been fully investigated.
• Responsibility for approving or rejecting all procedures or
specifications impacting the identity, strength, quality and
purity of the drug product.
• Responsibilities and Procedure shall be made available

17. Regulatory Consequences
21 CFR Part 210 cGMP in Manufacturing, Processing,
Packaging, or Holding of Drugs;
General
The failure to comply with any regulation set forth in
this part and in parts 211 through 216 of this chapter in
the manufacture, processing, packing, or holding of a
drug shall render such drug to be adulterated under
section 501(a)(2)(B) of the Act and such drug, as well as
the person who is responsible for the failure to comply,
shall be subject to regulatory action.

18. Regulatory Overview
Federal Food, Drug, and Cosmetic Act (the Act)[21 U.S.C
§ 331(a)(2)(B)]
 Methods, Facilities, and Controls must comply with
cGMP or the drug product is deemed adulterated!
 Need to provide the evidence that review of the
Batch Record including all critical step.
 The above confirms that the product meets cGMPs
with the Batch Record documentation.

19. Regulatory Overview
What is stand for Adulterated?
“A drug or device shall be deemed adulterated…if it (the
product) is a drug and the methods used in, or the
facilities or controls used for, it’s manufacture,
processing, packing or holding do not conform to or are
not operated or administered in conformity with current
good manufacturing practice to assure that such drug
meets the requirements of this Act as to safety and has
the identify and strength, and meets the quality and purity
characteristics, which it purports or is represented to
possess.”

20. Regulatory Observations (483)
• Batch production and laboratory control records of critical process
steps are not reviewed and approved by the Quality Unit before an
intermediate or API batch is released or distributed.
– Specifically, your firm failed to review complete batch records to include
all stages of manufacturing prior to batch release for all marketed
products.
• Failure to ensure Batch Production Records are prepared for each
of your APIs and include complete information relating to the
production and control of each Batch..
• Failure to extend the investigation to other batches and other
products that may have been associated with the specific failure

21. Regulatory Observations (483)
• Batch Production and Control Records fail to document the
completion of each significant manufacturing step, the signature of
the persons performing manufacturing steps, equipment used, and
sampling information.
• There is a failure to throughuly investigate unexplained
discrepancy and failure of a batch or any of its components to meet
any of its specifications shall be thoroughly investigated whether or
not the batch has already been distributed
• Quality control Unit 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. Your
Production Records for bulk Batch document the size of this Batch
as….

22. Batch Record Review & Release
How To Conduct Effective BPR Review:
The following documents are needed for an effective,
consistent, and systematic review:
• SOP for Batch Record Review shall cover Production,
Packaging, Labeling, Laboratory Testing etc…
• BPR Review Checklist - to ensure completeness and
evidence of BPR review.
• Also can use Corrections Sheet

23. SOP for Batch Record Review
SOP for the Batch Record Review ;
 Describes the purpose / scope of BPR Review
 It is not just to identify exceptions (e.g., mistakes, oversights, illegible
entries, etc.) and action to be taken
• Responsibility / authority to release :QA head, or Authorised person or
any other person suitably Authorised
 Describes the significance of an accurate & complete review of BPR.
 It is to confirm that the records are clear, accurate, and include
evidence to support that the batch was manufactured and
controlled as per internal procedures and cGMPs.
 Refer the SOP of review of BPR by production
 Defines a time for completion of the review


24. SOP for Batch Record Review
SOP for the Batch Record Review shall have the following;
 Details of Production and QA Reviewer feedback and correction.
 Reviewer identifies the mistakes, missing entries, or failures to follow
GDP observed during review
• Describe the elements of a “Corrections Sheet”, that can be used by
the QA reviewer to record corrections , that are identified during a
review.
• Verification of source data where possible, to verify the contents of
the Record.
– Example, weighing print of materials, temperature record, dispensing
record, etc.
• If critical information is missing, SOP shall describe how and when a
QA reviewer should inform to initiate and investigate deviations

25. SOP for Batch Record Review
• Review elements that should be included in the respective Checklist.
Common check list or product specific if required. Eg. API /
Intermediate
• Verify the presence of a signature page that includes the name,
initials, and signature for each person, who performed the process.
• Verify that all pages of the BPR and supporting documentation are
attached and cross referenced;
– examples include, but are not limited to, Reaction monitoring data, in-
process data, packing list, Environmental Data (sterile) etc..
• Verify that significant steps were verified by a second person (i.e.,
weighing of materials and charge of components).
• Verification that the sequence of events is clear and complete.
• Verify all calculations in the Record as accurate.

26. SOP for Batch Record Review
• Review / verify the following to ensure that product meets the
quality and consistent.
– This is ensured by controlling the critical steps and other variable in
affects the quality
• Process Parameter (PP)
…temperature, time, flow rates, pressures, and other discreet input
settings or output readings on the process equipment
• Critical Process Parameters (CPPs)
A process parameter which has impact on a quality attributes;
• Critical Quality Attributes (CQA’s)
In process control / quality parameters- A physical, chemical, or
microbiological results are within the limit

27. SOP for Batch Record Review
• Investigating critical deviations or the failure of a batch of
intermediate or API to meet specifications.
• The investigation should extend to other batches that may have
been associated with the specific failure or deviation.
• All deviation, investigation, and OOS reports should be reviewed
as part of the batch record review before the batch is released.

28. SOP for Batch Record Review
BPR Review Checklist:
• Checklist can be prepared to address;
– Review details/ standard elements, observation and action taken
– Cover manufacture, packaging, and labeling section
– Reporting deviations observed during review

29. Records
Examples of Records to be Reviewed:
• Production and Process Control Records
• Material used are traceable and quantity is as per standard (KSM,
RM, reagents, Solvents, Catallyst, seed etc….
• Calculation & verification of Yield
• Reconciliation of intermediate if used from multiple lots /batches
• Equipment Identification & log book
• Sampling and Testing of in-process materials
• Critical Quality Attributes- test results are meeting the specification
• Time Limits of Production as applicable
• Critical Process Parameters are as per standard limit
• Room / Area Cleaning & Clearing – Line Clearance
• Calibration of instruments

30. Records
• Packaging and Labeling Control Records
• Label issuance and reconciliation
• Laboratory Control Records
– Specifications & test Method followed
– Test report / Certificate of Analysis
– Test Records / Raw Data
• Deviations and investigations related to the production,
packaging, labeling, and testing operations for the batch.
• OOS and investigations
• Changes that occurred during the production, packaging,
labeling, and testing operations for the batch.

31. Check list
Sr.
No. Check point
Observ
ation
Corrective
action
taken
1 Yield ( %/ Kg) is complying with the standard limits.
2 Calibration & Cleaning is verified as per BPR manufacturing
equipment.
3 Procedure followed for each operation is as per BPR/ECR.
4 All entries in BPR/ECR is complete, signed and dated.
5 Over writing if any, have been corrected as per SOP.
6
Equipments used for manufacturing are as per the BPR.
7 Input UIN & quantities recorded in BPR / ECR is complying
with raw/packing material issue slip.
`
8 Entries on raw / packing material issue slip are complete.

32. Check list
Sr.
No. Check point
Observ
ation
Corrective
action
taken
9 Entries of In process weights & results are done
10
In process test results are complying with the standard
specification.
11 Critical process parameters are meeting the requirement.
12
Supporting data like raw / packing material issue slip, in
process test reports and equipment cleaning sample reports
are attached.
13 Packing list with seal umber is correct
14 Specimen product label of the batch is attached.
15
Finished product results are complying with the standard
specification
16 Any other information

33. Check list
Sr. No Deviations / OOS / OOC
Observati
on
(Minor/
Major)
Corrective
action
taken
1 Deviations if any reported and status
2 OOS if any reported and status
3 OOC if any reported and status
Remark: (Justification if any open issues):
Status: The Batch is Released / Not Released
Reviewed by (QA): Approved by QA:
Date:
Date:

34. Correction Sheet
Sr.
No
Page / Section
No
Observation
Action taken
Reason /
Justification
if required
1
2
3
Reviewed by QA: Approved by QA:
Date:
Date:

35. Batch Release
Consider all aspects before important decision is made.
• “Do I release, reject or what?”
• RELEASE OF PRODUCT IS NOT JUST BASED ON THE BPR
• Endure that the
Quality system Supporting
Manufacture is ‘in control’.
• Ensure GDP is followed
• Ensure there is no DATA INTEGRITY

36. Batch Cleaning Record Review
21 CFR 211.182 Equipment Cleaning and Use Log
• Verify equipment and usage log & Cleaning log are correct
• Verify the Cleaning of equipment & area are cleaned appropriately.
• All cleaning related logbooks are reviewed to indicate Date, Time,
Product & Lot Number of previous batch processed
• Before Batch Release, verify cleaning, room clearance and line
clearance via Line Clearance Checklist(s) filed with the Batch Record.
• Equipment Cleaning Record should be reviewed
– Verifies the PCO / Line Clearance Checklist. Residual content is within
the limit, physical verification –Equipment is clean, Area is cleared of all
previous batch materials, utensils, labels, etc.)

37. Let us learn
DATA INTEGIRITY

38. ALCOA ACRONYM (Data verification)
ALCOA Explanation
A Attributable Who performed and when?
L Legible Can it be read? Permanent
Record
C Contemporaneous Recorded at the time the
activity was performed
O Original` Original record or
certified true copy
A Accurate Error free

39. ALCOA (Data verification)
ALCOA Description/Explanation
A Attributable Who performed an action and when?
If a record is amended / changed, who did it and
why?
Why- reason & explain in detail
Traceable to the source data.
L Legible Data shall be recorded permanently
Record shall be durable & readable.
C Contemporane
ous
The data shall be recorded at the time the work
is performed. Signature / initial with date
O Original Is the information the original record or a
certified true copy?
A Accurate No errors or if editing shall be amended
properly

40. ALCOA Plus (Data verification)
ALCOA + Description/Explanation
1 Complete All data including repeat or reanalysis
performed on the sample.
2 Consistent Consistent application of data time
stamps in the expected sequence
3 Enduring Recorded on controlled worksheets,
laboratory notebooks, or electronic
media.
4 Available Available/accessible for review/audit for
the lifetime of the record.

41. Thank You