BATCH MANUFACTURING RECORDS,

COMPLAINTS RECALLS AND

CONTRACT LICENSES
SUB: VALIDATION AND REGULATORY
AFFAIRS IN PHARMACEUTICAL INDUSTRIES
Prepared and submitted by
T.RAGAVENDRAN
FIRST YEAR M.PHARM
BATCH MANUFACTURING
RECORDS
INTRODUCTION
 BMR is the necessary quality and GMP
documentation for tracing the complete cycle of
manufacture of a batch or lot.
 BMR should be prepared for each intermediate
and API and should include complete
information relating to the production and
control of each batch.
 BMR should be checked before issuance to
ensure that it is the correct version
BATCH NUMBERING SYSTEM
 BMR should be numbered with a unique batch
or identification number, dated and signed
when issued.
 The BMR shall be numbered as BMR:XXX:00
followed by a one digit numeral for a specific
batch size starting with 1 for the first batch
size and 2,3,..etc for the subsequent batch
sizes.
CONTENTS OF BMR
 BATCH FORMULA WORK SHEET
 FORMS
 ADDITIONAL FORMS
 API COA
 FINISHED GOODS COA
 DEVIATION (if applicable)
 CHANGE CONTROL (if applicable)
BATCH FORMULA WORK SHEET
 Formula worksheet shall start with the
manufacturing formula for the standard batch
size.
 Followed by the expression for calculating the
theoretical quantity of the API.
 The theoretical quantity of the API shall be
calculated based on minimum assay and
maximum water content/LOD/ Maximum
Solvent Content.
 The actual quantity shall be written in the
indent sheet based on the theoretical quantity
CREATION & IDENTIFICATION OF
FORMS
 The individual forms of the BMR shall have
titles and identification numbers.
 The form “BMR Cover Sheet” shall be
numbered as F: 004: BCS
 Right hand bottom corner.
 If form is of more than one page the form
shall be written as page X of Y.
 If the form undergoes a revision, the form
number shall be revised to include a slash
followed by a suffix A for the first
amendment.
ADDITIONAL FORMS
 Additional forms shall be included for
recording information required for
demonstrating compliance to Good
Manufacturing Practices (GMP).
 Forms with a provision to affix
 ‘cleaned’ status labels of equipments.
 ‘Dispensed material’ labels.
 Labels of blend containers.
 Labels of bulk products.
COMPLETE BMR 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.
COMPLETE BMR SHOULD
INCLUDE
 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 if stored
separately.
 Results of release testing.
BMR REVIEW
 Written procedures should be established
and followed for the review and approval of
BMR.
 Batch production and laboratory control
records of critical process steps should be
reviewed and approved by the quality unit(s)
before an batch is released.
 All deviation, investigation, and OOS reports
should be reviewed as part of the batch
record review before the batch is released.
COMPLAINTS RECALLS
INTRODUCTION
 A Product Recall is the act of requesting the
return of a batch or entire production run of a
commercial product, usually because of a
defect, safety concern, or efficiency problem.
 The guidance includes a checklist of
documentation and information that FDA
utilizes to evaluate, classify, monitor and audit
product recalls.
 This guidance provides more specific
recommendations and applies to both
mandatory and voluntary recalls of all FDA-
regulated products.
INTRODUCTION
 This is a level 2 guidance document
published for immediate implementation in
accordance with FDA's good guidance
practices (21 CFR 10.115).
 This guidance sets forth the agency's existing
practices in the handling of recalls.
 Recalling firms are urged to notify the local
FDA District Recall Coordinator as soon as a
decision is made that a recall is appropriate
and prior to the issuance of press or written
notification to customers.
CLASSES OF RECALL
Category-I (Class-I) :
 Reasonable likelihood that the use of, or
exposure to a product will cause serious
adverse health consequences or death.
 Recall shall be initiated within 24hrs.
CATEGORY-I (CLASS-I)
Examples:
 Wrong product (label and contents are different
products).
 Correct product but wrong strength, with serious
medical consequences.
 Microbial contamination of sterile injectable or
ophthalmic product.
 Chemical contamination with serious medical
consequences.
 Mix up of some products (“rogues”) with more than
one container involved.
 Wrong active ingredient in a multi-component product
with serious medical consequences.
CLASSES OF RECALL
Category-II (Class-II) :
 A situation in which use of, or exposure to a
product may cause temporary or medically
reversible adverse health consequences or
where the probability of serious adverse
health consequences is remote.
 Recall shall be initiated within 48hrs.
CATEGORY-II (CLASS-II)
Examples:
 Mislabelling: e.g. wrong or missing text or figures.
 Missing or incorrect information - leaflets or inserts.
 Microbial contamination of non-injectable, non-
ophthalmic sterile product with medical consequences.
 Chemical/physical contamination (significant
impurities, cross-contamination,particulates).
 Mix up of products in containers (“rogues”).
 Non-compliance with specification (e.g. assay,
stability, fill/weight).
 Insecure closure with serious medical consequences
(e.g. cytotoxics, child-resistant containers, potent
products)
CLASSES OF RECALL
Category-III (Class-III) :
 Defect in quality of the product with respect to
physiochemical characteristics, purity, and efficacy.
Situation in which use of, or exposure to, a violative
product is not likely to cause adverse health
consequences.
 Recall shall be initiated Not More Than 10 days.
 Examples:
 Faulty packaging: e.g. wrong or missing batch number
or expiry date.
 Faulty closure.
 Contamination (Microbial spoilage, Dirt or detritus,
Particulate matter)
VOLUNTARY RECALL
 Material and product integrity failure.
 Formulation problems, product mix-ups and
other contaminants.
 Label mix-ups and errors.
 Physical and visual deterioration like significant
discoloration, sedimentation, crystallization etc.
 Drop in assay or Related Substance of active
ingredients below the statutory limits.
 Results of ongoing stability studies shows
significant changes in purity, microbial quality
as prescribed in the specification.
RECALL SUBMISSION TO FDA
1) PRODUCT INFORMATION.
 Additional information for Drug recalls.
 Additional information for Medical Device
recalls.
 Additional information for Biological recalls.

2) CODES (Production Identification

Numbers).
3) RECALLING FIRM.
CONTACTS for Recalling Firm.
4) MANUFACTURER.
RECALL SUBMISSION TO FDA
5) IDENTIFY FIRM RESPONSIBLE FOR
THE VIOLATION/PROBLEM.
6) REASON FOR THE RECALL.
7) HEALTH HAZARD ASSESSMENT.
8) VOLUME OF RECALLED PRODUCT.
9) DISTRIBUTION PATTERN.
10) RECALL STRATEGY.
MOCK RECALL
The purpose of effectiveness checks is to verify that all
consignees at the recall depth specified by the strategy have
received notifications about the recall have taken
appropriate action.
 Level A – 100% of the total number of consignees to be
contacted.
 Level B – some % of the total number of consignees to be
contacted, which % is to be determined on a case by case
basis, but is greater than 10% and less than 100% of the total
number of consignees.
 Level C – 10% of the total number of consignees to be
contacted.
 Level D – 2% of the total number of consignees to be
contacted.
 Level E – No effectiveness checks.
GUIDANCE FOR WRITTEN RECALL
NOTIFICATION LETTERS
Recall Notifications should be flagged in large bold print
"URGENT: [insert "FOOD", "DRUG", "MEDICAL DEVICE",
etc.] RECALL or CORRECTION”.
A. Product Identification
B. Description Of The Problem
C. Depth Of The Recall
D. Instructions To Customers
E. Evaluation Of The Recall
 Effectiveness of the recall.
 Recall status reports.
 Root cause of the problem that resulted in the recall.
 Corrective actions to prevent future occurrences of the
problem.
 Termination Of The Recall.
CONTRACT LICENSES
INTRODUCTION
 Contract manufacturing refers to a situation in
which a license manufacturer establishes a
contract with another entity(ies) to perform some
or all of the manufacture of a product as a
service to the license manufacturer.
 CONTRACT: An order placed to one party upon
another may constitute a legally binding contract.
The contract could be constructed as having a
legal meaning in terms of a legally binding
document. Rather than contract the phrase
technical agreement may be more acceptable to
each party.
CONTRACT MANUFACTURE
 It is the process where one company or
organization gets manufacturing done in
premises of other manufacture who is called as
principal manufacturer.
 Manufacturing may be complete or may be
partial to a given standard specification.
 Person or organization who gives the contract
may emphasize the GMP facilities and legal
requirements.
 The principal manufacturer may be required to
manufacture only, to assemble only or to
perform both functions.
SELECTION OF CONTRACT
MANUFACTURER
 Statutory clearance / licenses.
 Adequate and appropriate facilities for storage,
handling, manufacturing and testing of
raw/packaging material and finished product.
 Experience and competence of employees directly /
indirectly responsible for the manufacturer.
 Experience and competence of employees entrusted
with the job of quality assurance / quality control.
 Manufacturers experience in manufacturing similar
products.
 Documentation system and cGMP requirements.
RESPONSIBILITIES OF LICENSE
MANUFACTURER
 The safety, purity, and potency of the product (PHS
Act; 21 CFR Parts 600 through 680);
 Ensuring that manufacture of the product complies
with the provisions of the BLA and the applicable
regulations, including, but not limited to, 21 CFR
Parts 210, 211, 600 through 680, and 820; and
 Compliance with both product and establishment
standards.
 The contract manufacturer should share with the
license manufacturer all important proposed changes
to production and facilities (including introduction of
new products or at inspection). The license holder is
responsible for reporting these changes to FDA
RESPONSIBILITIES OF THE
CONTRACT MANUFACTURER
 The product specifications used by the
principal manufacturer comply with the
relevant legal requirements such as the
marketing authorization and label declarations.
 The product as manufacturing, meets the
specification.
 Quality is maintained during transport,
distribution and storage.
 All operations are carried out according to
good manufacturing practices with the
requirements of the marketing authorization.
CONTRACT SHOULD COVER
 Providing technical know and safeguards for security.
 Supply of material.
 Quality specifications for input and finished products.
 Quality assurance systems including documentation and
audits by either or both parties, individually or jointly.
 Responsibilities for batch release.
 Responsibilities, accountability, and redressal, should a
failure occur.
 Compliance with cGMP and other statutory requirements
including retention of manufacturing record and control
samples.
 Commercial terms.
 Provision for reviewing the agreement in aprt or whole,
including technical aspects.
ANALYTICAL WORK CONTRACT
 When analytical work contracted to a third party
following points should be addressed.
 Requirements and fulfillment of good laboratory
practice.
 The specifications methods authorized in the
marketing authorization.
 Validation of instruments and method of
analysis.
 Reporting of spurious results and their
relationship to the samples being analyzed, the
other results obtained and the bulk which has
been sampled.
MASTER FILES
 Manufacturing document shall be fully
documented in the form of a master formula card.
 Materials and product specifications including
testing procedures shall be drawn.
 In process controls, including limits as applicable
shall be in place.
 Responsibilities, individual as well as joint, shall
be assigned.
 A list of all products manufactured in a contract
facility .
 Non compendia test procedures (standard
operating procedures)
LABELING
 The contract facilities are considered to be
under the control of the license holder,
specific identification of the contractor in
the product labeling is not required.
 The labeling for an intermediate product
intended for shipment to or from a contract
facility include a statement that it is
intended for further manufacture.
 The licensed intermediate products include
“for further manufacture” as part of the
proper name.
REFERENCE
 “Guidance for Industry : Q7A Good Manufacturing
Practice Guidance for Active Pharmaceutical
Ingredients” http://www.fda.gov/cber/guidelines.htm .
 http://
whoguideline.blogspot.com/2010/03/batch-manufacturi
ng-record-review.html
 “The Pharmaceuticals Sciences Pharma Pathway” pure
and applied pharmacy, D.A. Savant, Fourth revised and
enlarged edition, Pragati books Pvt Ltd, Pg no: 1.58-
1.60.
 http://www.fda.gov/Safety/Recalls/IndustryGuidance/
ucm129259.htm
DT:15.02.2011.
  
http://www.fda.gov/BiologicsBloodVaccines/GuidanceC
omplianceRegulatoryInformation/Guidances/General/uc