Subject Name: Quality Assurance Module -IV

Subject Code: BP 606T

Objectives of the course



 Appreciate the importance of documentation, complaints, quality audit and quality

review according to regulatory agencies.

Learning outcomes

 Students learnt about the documentation, quality of product, various records, and
complaints in pharmaceutical industry.
 Structure of Module -4BP 606T
Learning Material

Complaints- Complaints and evaluation of complaints, Handling of return good, recalling

and waste disposal.

Document Maintenance in Pharmaceutical Industry- Batch Formula Record, Master

Formula Record, SOP, Quality audit, Quality Review and Quality documentation, Reports
and documents, distribution records.
 Complaint

COMPLAINT
• Reasons
• Types of Complaint
• Steps involved in Handling of complaints
• Product Complaint Data Sheet
• Complaint Record
• Regulatory Guidelines
• SOP on Complaint Handling
Complaint
Statement that is something wrong or not good enough, which shows
customer dissatisfaction about the company and the product
Example: Complaint about packaging materials, Concerning about the product
etc.
Reasons
 It gives the company an opportunity to improve the quality of the product
 It is helpful to maintain cGMP
 It maintains committed relationship between the customer and company
 It is the regulatory obligation.
 Aid in implementing solutions to these quality problems
 Reduce costs and improve production schedules
 Reduce employee confusion
 Improve the safety and performance of devices
 Identify poor performance in the overall quality system, particularly
faulty design of devices, and faulty manufacturing processes
 Verify confidence in, and improve the performance of the quality system
 Reduce medical device reporting
 Improve customer relations by reducing the frequency of problems,
complaints, and recalls; and,
 Assure compliance with device regulations and consensus standards.

Types of Complaint

Quality complaints: Originate at consumer level and concern with

physical, chemical and biological properties or condition of labeling and /or
 packaging of the product.
Adverse reaction complaints: Due to allergic reactions of any other untoward
reaction or fatal reaction or near fatal reaction.
Other medically related complaints: Include complaints such as lack of
efficacy or clinical response
PROCEDURE:
1. Market complaint may be received from any of the following sources:
Physicians , Pharmacist , Warehouse, Patients, Regional Offices, Hospitals
Regulatory affairs, Wholesale Traders, Actual users
2. Complaints shall be classified in following categories to facilitate
investigation:
- Product quality complaints (non therapeutic).
- Packaging complaints (shortages and packaging error).
- Medical complaints (therapeutic problems).
3. As a company policy even verbal complaints shall be formalized and
investigated.
4. All written and oral complaints to be forwarded to Head,
QA/QC/Regulatory or his nominee for investigation
5. All the Product Quality Complaints shall be investigated jointly with
QA/F and D/Manufacturing within 5 days of the receipt of the complaint.
6. Medical complaint investigations shall be carried out jointly by
Medical department, QA, Production, F and D and Marketing Department
within 3 days of receipt of complaint
7. Packaging complaints and Quality complaints shall be jointly
investigated by QA, F and D and Manufacturing department within 10 days
of receipt of complaint.
8. The investigator shall investigate the complaint by referring to the
Batch Manufacturing Record, SOP, machine log tables, retain samples,
reconciliation of materials, storage conditions used and prepare the
Product Complaint Report (PCR)
9. The PCR shall include the product details, details of the complainant,
quantity involved, enclosed complaint sample (if any), details of
investigation actions taken and recommended corrective actions to prevent such
recurrences in future. Each PCR shall be approved by
Head/QA/QC/Regulatory or his nominee
10. Incase of the Head/QA/QC/Regulatory finds that investigation is not
necessary, such written records shall be maintained including reasons for not
conducting the investigation.
11. Each report shall be assigned a specific PCR number, which will be a 3 digit
number starting with “001”in continuous sequence prefixed with “PCR” and
suffixed with the last two digits of the year. For example, the first market
complaint for 2006 shall have the number PCR/001/006
12. If product defect is established or suspended in a batch,
Head/QA/QC/Regulatory will decide for checking other batches in order to
determine weather they are also affected.
13. Incase of medical complaints, if Head, /QA /QC /Regulatory and
Medical Advisor feels that the product will put the public at risk, he shall advise
immediate recall of the batch. The depth of recall is dependent on the
seriousness of the complaint.
14. Complaint Record shall be maintained at least one year after
expiration date of medicine.
15. Complaint Record shall be reviewed and a monthly summary shall be
prepared for the management.
16. A Register is maintained having the complete details of complaint for future
reference.
 DOCUMENTATION IN PHARMACEUTICAL INDUSTRY
Method of preparing a written material, which describes the process in terms of
specifications and instructions etc. The D & C Act under conditions of granting
license and schedule M require manufacturer of drugs to maintain various
records.
Importance of documentation
Provides necessary working details
Reduces the risk of mistake
Helps in decreasing batch to batch variation
Considered as the history of batch operations
Types of documentation
 Commitment document: Relationship between industry and the regulatory
authorities.
 Directive document: Relationship between management and employee.
 Record document : Relationship between the employee and the work they
perform

.
 Master formula record (MFR):
Written procedure that give the complete description of all aspects of manufacture, packing
and control with an inspection to ensure purity, identity, quality and strength of each dosage
unit through its shelf life. Includes all the materials used in any batch manufacturing
and step by step process of manufacturing.
The master formula must include:
a) The name of the product together with product reference code relating to
its specifications.
b) The patent or proprietary name of the product along with the generic name,
a description of dosage form, strength, composition of the product and batch size
c) A statement of the processing location and the principal equipment to be
used.
d) Name , quantity and reference number of all starting materials to be used.
e) A statement of expected final yield with the acceptable limits and of relevant
intermediate yields, where applicable.
f) The methods or reference of the methods to be used for preparing the critical
equipment including cleaning, assembling, calibrating, sterilizing.
g) Detailed stepwise processing instructions and the time taken for each step.
Master production and control record
Detailed written instructions including all operations starting from dispensing of
raw materials till finishing of bulk products and packaging operation of the
particular product.
It includes batch size, date of manufacture and full signature by 1st person and
further independently checked, dated and signed by 2nd person.
Preparation of master formula
 Master formula can be prepared by competent technical staff.
 It should be reviewed by the head of production, QC department and R &
D department.

Drug master file Drug Master File (DMF):

Document prepared by a pharmaceutical manufacturer and submitted solely at its
description to the appropriate regulatory authority in the intended drug market.
There is no regulatory requirement to file a DMF.
The DMF provides confidential, detailed information about facilities, process or articles
used in the manufacturing, packaging, storing etc. to the regulatory authority.
DMF is filed when two or more firms work in a partnership or developing or
manufacturing a drug product.
Drug master file include ncludes:
A) General information
1. General properties.
2. Structure.
3. Nomenclature.
B) Manufacture
1. Manufactures.
2. Description of manufacturing process and process control.
a) Flow chart of manufacturing process,
b) Synthetic route of manufacturing process,
c) Manufacturing method,
Drug Master
3. Control of Material
1. List of materials
2. Specification and routine test of the raw material
4. Control of critical steps and intermediates
1. Critical steps,
2. Process validation,
5. Specifications and test method for the intermediates, 6.Manufacturing process
development
…..
C) Characterization
1.Elucidation of structure and other characteristics-
a) Elemental analysis
b) IR spectrum of drug substance
c) NMR spectrum of drug substance
d) Mass spectrum of drug substance
e) UV spectrum of drug substance
f) X-ray diffraction
g) Thermal analysis
h) Comprehensive illustration
Drug Master: Cont …..
2) Impurities
a) Sources of potential impurities
b) Types of impurities
c) Test procedure for determining impurities
D) Control of drug substances
a) Specifications
b) Analytical procedure
c) Validation of analytical procedure
d) Batch analysis
e) Justification of specification
Drug Master File (DMF) Includes: cont …..
E) Reference standards of material
F) Container closure system
G) Stability
H) Material data safety sheet

TYPES OF DRUG MASTER FILE e (

Type 1: Manufacturing site, facilities, operating procedures and personnel.
Type 2: Drug substance, drug substance intermediate and material used in their
production or drug product.
Type 3: Packaging material.
Type 4: Excipient, colorant, flavor.
Type 5: FDA accepted reference information.
Types of Drug Master File (DMFCont…
Type 1:
 Manufacturing site, facilities ,operating procedures and personnel
 No longer used, once used to describe facilities
 Recommended for a person outside of the United states to assist FDA in conducting
on site inspections of their manufacturing facilities
 Should describe manufacturing site, operational layout, equipment capabilities,
processing layout.
Type 2:
Drug substance ,drug substance intermediate and material used in their preparation or
drug product required for drug substance – active ingredient.
A separate DMF is filed for each active ingredient.
Brief description of the manufacturing facilities, the address, a contact, phone number
and fax number.
Manufacturing procedures and control for finished dosage forms submitted in an IND,
NDA, ANDA or export application.
Type 3:
Packaging material,
Its components and composition,
Packaging material intended for use,
Name of the suppliers or fabrications of the components used in preparing the
packaging material.
Acceptance specifications,
Eg: - Products that would be classified as type 3 DMFs include bottles, seals,
dispensers etc.
Type 4:
Excipient, colorant, flavor, essence used in their preparation.
Each additive should be identified by this method of manufacture, release
specification and testing methods.
Toxicological data would be included.
The official compendia and FDA regulation for color additives, direct food additives
and food substances may be used as sources for release tests and safety.
Type 5:
FDA accepted reference information.
FDA discourages the use of type 5 DMFs for miscellaneous information, duplicate
information.
 To submit the data which is not covered in type 1 to type 4 DMF
A holder must first submit a letter of intent to the drug master file staff.
FDA will contact the holder to discuss the proposed submission.
Distribution record
Written procedures shall be established and followed, describing the distribution of drug
products
Include:
1. A procedure where by the oldest approved stock of a drug product is distributed first
2. A system by which the distribution of each lot of drug product can be readily
determined to facilitate its recall if necessary.
3. Distribution records must be constructed and procedures established to facilitate
recall of defective product.
4. All records should be indexed by either the manufacturing batch-lot number of the
packaging control number as a means of accountability. It shall contains:
1. Description of dosage form
2. Name and address of the consigner
3. Date and qty shipped
4. Lot and control number of the drug
5. Name of drug and strength
WHO guidelines of Distribution records
Written instruments and records should be available.
Procedure should be established and maintained.
The title, name and purpose of each document should be clearly stated.
All documents should be completed, approved,signed ad dated by an appropriate
authorized persons.
In the case of temperature-sensitivity pharmaceutical products, records of
investigations and actions should be retained for at least one year after the expiry
date of the product.