P. R.

Pote Patil College of Pharmacy,

Amravati

SPECIFICATIONS AND
SUBMISSION OF DOCUMENT

Presented by Guided by
Manohar Sakharam Kasdekar Dr. Dipti Ruikar mam
 INDEX

• Specification and test procedures, Protocols and reports.

• Distribution records.
• Electronic data handling.
• Concepts of controlled and uncontrolled documents.
• Submission documents for regulators DMFs, as Common
Technical Document and Electronic Common Technical
Documentation (CTD, eCTD).
• Concept of regulated and non regulated markets
 SPECIFICATIONS

Specification may be defined as a set of parameters along with

their acceptance limits. Expected to be met by a particular
material, piece of equipment or any such object. In case of
pharmaceutical products, we need specification for active and
inactive starting material.
 TYPES OF SPECIFICATION

1) Specification for active and inactive starting material

2) Specification for packing material

3) Specification for Intermediate and Bulk product

4) Specification for Finished Product

 1. SPECIFICATION FOR ACTIVE AND
INACTIVE STARTING MATERIAL

Name of the material

Code number reference
approved supplier and original manufacturer
• Name of Direction for sampling and testing or reference to
the procedure
• Storage condition and safety precaution if any
 2)SPECIFICATION FOR PACKING
MATERIAL

Name of material
Code number reference
Sampling instruction
Storage condition
• Frequency of re-examination of stored components
 3. SPECIFICATION FOR FINISHED
PRODUCT

Name of the product

Code number reference
Names of the active ingredient
The formula or reference to the formula
Shelf life
• The qualitative and quantitative requirements with
acceptances limits
 TEST PROCEDURE

Test procedure must be described in a sufficiently detailed manner

to enable any official laboratory to verify compliance of the
medicinal product up to the end of shelf life. Control method must
be validated in accordance with the note for guidance.
The test procedure may use either an official reference substance
(European pharmacopeia national pharmacopeia ,WHO).
Accept for those official included in the European pharmacopeia
eg. sterility test.
 UNIVERSAL TESTS

1. New drug substance

2. New drug product

1. New drug substance

The following tests and acceptance criteria are considered generally
applicable to new drug substances.
Description: a qualitative statement about
the state (e.g. Solid, liquid) and colour of the new drug substance. If
any of these characteristics change during storage, this change should
be investigated and appropriate action taken.
Identification: identification testing should optimally be able to discriminate
between compounds of closely related structure which are likely to be present.
Identification tests should be specific for the new drug substance eg. Infrared
spectroscopy.

Assay: A specific, stability indicating procedure should be included to determine

the content of new drug substance. In many cases it is possible to employ the
same procedure (e. G., HPLC) for both assay of the new drug substance and
quantitation of impurities.

Impurities: Organic and inorganic impurities and residual solvents are included
in this category. (Refer to the ICH Guidelines Impurities in new drug substances
and Residual solvents in pharmaceuticals for detailed information.)
as per the ICH guideline Q3 A
2) New Drug Product
Description: A qualitative description of the dosage form should be
provided (e.g., size, shape and colour).
Identification
Assay
Impurities
 SPECIFIC TESTS/ CRITERIA

when the tests have an impact on the quality of drug

substance and drug product.
Tests other than this may be needed in particular situations or
as new information become available.
 PROTOCOL

Protocols are written records clearly defining the objectives

and methods that will be used for the validation programs.
An important part of the protocol is the description of the
testing method including who will test the system, how they
will test it and what data is to be collected and reported
Computerized system protocols often include the three
distinct stages as described in PMA reports:
Installation Qualification (IQ)
Operational Qualification (OQ)
Performance Qualification (PQ)..
INSTALLATION QUALIFICATION
OPERATIONAL QUALIFICATION
PERFORMANCE QUALIFICATION
 PROTOCOL CHANGES

Document requirements specifies that who and how changes

can be done to parameters, thresholds, and acceptance
criteria.
It is not impossible to make changes after or during testing,
but these changes must be properly implemented and
approved to be validated.
 PROTOCOL FOR DOCUMENTATIONS

1.Serial number of the Batch Manufacturing Record.

2. Name of the product.
3. Reference to Master Formula Record.
4. Batch/Lot number.
5. Batch/Lot size.
6.Date of commencement of manufacture and date of completion of manufacture.
7. Date of manufacture and assigned date of expiry.
8. Date of each step in manufacturing.
9. Names of all ingredients with the grade given by the quality control department.
10. Quality of all ingredients.
11. Control reference numbers for all ingredients.
12. Time and duration of blending, mixing, etc. Whenever applicable.
13. pH of solution whenever applicable.
14. Filter integrity testing records.
15. Temperature and humidity records whenever applicable.
16. Records of plate-counts whenever applicable.
17. Results of pyrogenic and/or bacterial endotoxin & toxicity.
18. Results of weight or volume of drug filled in containers.
19. Bulk sterility in case of aseptically filled products.
20. Leak test records.
 REPORT

Documentation and records used throughout the manufacturing process, as well

as supporting processes (e. G. Quality Control or Quality Assurance)
It includes,
• Batch Record Forms
• Bill of materials (BOM
• Specification
• Policies
• Protocols
• Standard Operation Procedure (SOPs)
• Work Instructions
• Check lists
• Forms/ long sheets
• Certificates of Analyses or Certificates of Compliance
• Technical transfer reports
• Test Methods
• Training Assessments
• Records
• Worksheet, notebooks and long books
• Manufacturing and packaging instructions
• Confidentiality agreements
• Change control
 DISTRIBUTION RECORDS

Distribution records shall contain the name and strength of

the product and description of the dosage form, name and
address of the consignee, date and quality shipped, and lot or
control number of the drug product. For compressed medical
gas products, distribution records are not required to contain
lot or control numbers.
Distribution records include a wide range of documentation
such as invoices, bills of lading, customers’ receipts, internal
warehouse storage and inventory records.
 ELECTRONIC DATA HANDLING

It is a software based laboratory and

information management system that offers a
set of key features that helps supporting
modern laboratory’s operations. Electronic
data handling is replace the traditional paper-
based data collection methodology to
streamline data collection
 ADVANTAGES ELECTRONIC DATA
CONTROL

1. Faster data transfer

2. Instant data access by the staff
3. Reduced queries
4. Data can be categorized and indexing is possible
5. Decision point can be reached more quickly, this will save both
time and money
 DISADVANTAGES OF EDC

1. Installation of software in each PC which is costlier

2. Availability of Internet connections in remote areas where
trial is being conducted
3. Data security is a major problem if public internet is being
used
4. Regular validation of electronic devices
5. Regulatory compliance
 CONCEPTS OF CONTROLLED AND
UNCONTROLLED DOCUMENTS

CONTROL DOCUMENT
Each manufacturer shall establish and maintain procedure to
control all document that are required by this part. The
procedure shall provide for the following.
a) Document approval and distribution
b) Document changes
 A. DOCUMENT APPROVAL AND
DISTRIBUTION

- Each manufacturer shall designate an individual to review

for adequacy and approve prior to issuance all document
established to meet the requirement of this part.

The approval, including the data and signature of the

individual approving the document, shall be documented.
 B. DOCUMENT CHANGES

Changes to document shall be reviewed and approved by an

individual in the same function or organization that
performed the original review and approval.
Approved changes shall be communicated to the appropriate
personnel in a timely manner.
 UNCONTROLLED DOCUMENT

Uncontrolled copy shall be prepared by photocopy of master

copy with stamping of “UNCOTROLLED COPY” in red
colour and signed/ dated by QA on each page of the
document at centre on the matter.
Uncontrolled copy shall be distributed on need as a reference
copy for external regulators and concerns.
 CTD

CTD (Common Technical Document):- is a harmonized

format for submission of detailed information on medicines
to regulatory authorities and agencies for the purposes of
obtaining approval to market a product.
GUIDELINES FOR THE INDUSTRY
M4(R4)
Organisation Including the Granularity document that provides guidance on
document location and paginations
M4 Q&As (R3)
Organisation of the Common Technical Document for the Registration of
Pharmaceuticals for Human Use
M4S: Safety
M4S(R2) CTD on Safety
M4S Q&As (R2) CTD on Safety
M4E: Efficacy
M4E(R2)
CTD on Efficacy
 CTD MODULES

Module 1 – Administrative Information (Region Specific)

Module 2 – CTD Summaries (QOS)

Module 3 – Quality (CMC)

Module 4 – Non-Clinical Study Reports

Module 5 – Clinical Study Reports

 MODULE 1

Administrative Information (Region Specific)

Should contain documents specific to each region
For USA For EU
Application form
Application form 356h
Summary of product
Proposed label characteristics
Patent certification / information Labelling text and mockups
Information about the experts
Debarment certificate
Environmental risk assessment
Letter of Authorization (LOA)/ DMF letter Description of the
Labelling text pharmacovigilance system
Risk management plan
 MODULE 2

CTD Summaries (QOS)

It contain 7 sections in the following order:
2.1 CTD TOC (Module 2-5)
2.2 CTD Introduction
2.3 Quality Overall Summary
2.4 Non-clinical Overview
2.5 Clinical Overview
2.6 Non-Clinical Summary
2.7 Clinical Summary
 MODULE 3

Quality (CMC)
3.1 TOC of Module 3
3.2 Body of Data
3.2.S – Drug substance
3.2.P – Drug product
3.2.A – Appendices
3.2.R Regional Information
3.3 Literature references
 MODULE 4

Non-Clinical Study Reports

4.1 TOC of Module 4

4.2 Study reports

4.2.1 Pharmacology
4.2.2 Pharmacokinetics
4.2.3 Toxicology

4.3 Literature References

 MODULE 5
Clinical Study Reports
5.1 TOC of Module 5
5.2 Tabular listing of Clinical Studies
5.3 Clinical study reports
■5.3.1 Reports of Biopharmaceutical (BA-BE) Study
■5.3.2 Reports of Pharmacokinetic (biomaterial) study
5.3.3 Reports of Pharmacokinetic (PK) Studies
5.3.4 Reports of Pharmacodynamics (PD) Studies
5.3.5 Reports of Efficacy and Safety studies
■5.3.6 Reports of Post-Marketing experience
■ 5.3.7 Case Report Forms & Individual patient listings
 BENEFITS OF CTD

Easy “Reviewable” applications.

Complete, well-organized submission.
More predictable format.
More consistent reviews.
Easier analysis across application.
Easier Exchange of information.
• Facilitates electronic submission.
 ECTD

eCTD (Electronic Common Technical Document): is the electronic version of

CTD.
An eCTD is simply a standard electronic format for sending data from the applicant
to the regulatory authority.
The electronic Common Technical Document (eCTD) is the electronic equivalent
of the Common technical document, which is standard format for submissions to
the authorities and agencies responsible for regulation of pharmaceutical of
products in US, Europe and Japan.

Why Electronic?
- Improve the submission and review process.
- Increase accuracy of the Submission.
 BENEFIT OF ECTD

Improve handling and archiving of submission.

Support Life cycle Management.
Immediate access to complete and Up to date information.
Search functionally for assessors and increased tracking
ability.
Reduced Workload.
• Better communication with industry.
 REGULATED MARKET

These countries have well-defined procedures for marketing and

distribution of pharmaceuticals both for human and veterinary use.
MAHs should file applications to market their drugs with all the
supportive and required data.
Eg: Major big countries with specific authorities / monitoring bodies to
look after health of its citizens – US, JAPAN, AUSTRALIA, CANADA,
INDIA, Etc.
Regulated pharma markets require submission of dossier in CTD format
which has to provide clinical trial and bioequivalence studies.
 NON-REGULATED MARKET

Non-regulated: Small to very countries which do not have

any specific authorities which controls the supply of
medicine. One can consider newly formed countries, small
population countries and under developed countries.
AFRICAN countries, Asian countries. Being said since these
countries do not have specific monitoring authorities, they
depend on other regulated countries.
 REFERENCE

Raviteja, M.N. And Gupta, N.V., 2013. A review on electronic data management
in pharmaceutical industry. Asian Journal of Pharmaceutical and Clinical
Research, 6(2), pp.38-42.
1. Pharmaceutical Quality Assurance and Management by KP Bhusari, UD
Shihari and D C Goupale published Nirali prakashan 2 ndedition 2014
2. Shah, D.H., 2002. QA manual. Business Horizons.
THANK YOU