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UNIVERSITY OF CHEMICAL TECHNOLOGY,
CHHATRAPATI SAMBHAJINAGAR.
PHARMACEUTICAL QUALITY ASSURANCE DEPARTMENT
~ POOJA HARKAL
Documentation in Pharmaceutical Industry
Technical Documentation
Documentation is the Essential and crucial part in any of the company. In pharma we
can say “If it is not documented, it has not done”. Documentation is an evidence to
show or to prove that the things have done accordingly. Quality assurance documents
are the heart of the company.
Technical documents are
 Master Formula Record (MFR).
 Batch Manufacturing Record (BMR).
 Drug Master File (DMF)
While registering the Indian product in overseas market RA team should be carefully
check, verify all the documents for the genuinity, quality and uniformity from batch
to batch and to avoid delay in the approval process.
Documentation flow chart
Batch Manufacturing Record
Scale up batch
Master Formula Record
Formulation and development
Master Formula Record (MFR):
 MFR is a master document which contains detailed
information about the product, process etc. MFR is
prepared by the Formulation and Development team
which is called technology transfer. By this master
document BMR and BPR prepared.
MASTER BATCH RECORD
1. Master Batch Record also known as MFR (Master Formula/Mfg Record).
2. It should be available for each product, batch and pack size.
3. It is a master document for any pharmaceutical product.
4. It contains all information about the manufacturing process for the product.
5. It is prepared by the research and development team of the company.
6. It is used as reference standard for preparing batch manufacturing record
(BMR) by manufacturing units.
7. It plays an important in consistency for each batch manufacturing.
 Responsible Department :
Primary Responsibility : Formulation Research and Production Department
Secondary Responsibility : QA Department
Content
of Master
Batch
Record
1. Product details:
Name, address, logo of the manufacturing
company.
Product name.
Dosage form.
Brand name.
Generic name.
Product code.
Product description.
Label claim of all ingredients used. Batch size.
Pack size.
Shelf life.
Storage conditions
2. Flow chart:
• Steps involved in the manufacturing process and flow chart representing the
material movement from dispensing to the finished product to packaging and to
the store.
3. Equipment:
• List of equipment required for the manufacture of the product with the capacity
4. Special instructions:
• Warnings and precautions related to manufacturing process should be clearly
mentioned.
• Quantity to be added should be mentioned.
• Time interval and overages to be added to be mentioned clearly.
• Name of the ingredient with tests and specification limit as per IP, BP and USP.
5. Calculations:
• Quantity to be added to get 100% final product.
• It can be done by using water content or LOD to get 100% potency.
6. Manufacturing process:
 It should include all the steps involved the manufacturing
process like sifting, milling, granulation, mixing, blending,
lubricating, compression, coating, filling, if necessary filtration
with environmental conditions such as temperature, humidity,
storage to be maintained with time.
7. Packaging process:
 Details of packaging materials used.
 Line clearance, batch reconciliation of the packing
material.
8. Yield:
 It includes theoretical yield, Practical yield and acceptance
limit of the batch
 Master Batch Record Packaging details :
• There have to be authorized packaging instructions
• Name.
• Description of dosage form.
• Pack sizes- Number, dose volume.
• A total list of all Packaging materials required for standard
batch size with reference to the specifications of the packaging
material
• Specimens of all packaging material.
• Line clearance instructions.
• Description of packaging operations.
• In process controls.
BATCH MANUFACTURING RECORD
Once the Master formula is prepared, pilot batch will be started to
validation and BA/BE studies, upon getting the report from the pilot batch
BMR will be prepared which will be used for commercial batch
manufacturing.
a. The "Batch Manufacturing Record" is the necessary quality and GMP documentation for
tracing the complete cycle of manufacturing batch or lot.
b. The batch manufacturing record should be checked before issuance to assure that it is the
correct version and a legible accurate reproduction of the appropriate master production
instruction.
c. Before any processing begins, a check should be performed and recorded to ensure that the
equipment and workstation are clear of previous products, documents, or materials not
required for the planned equipment is clean and suitable for use.
d. These records should be numbered with a unique batch or identification number and dated
and signed when issued.
Batch Manufacturing Record Content :
1. Name of the product, Batch number, revision number, effective
date.
2. Product details like Type of the product, dosage, shape of the drug.
3. Batch size and Total number of tablets or capsules.
4. Pack size and packaging Instructions.
5. Storage instructions.
6. Production batch record issuance.
7. Signed & issued by QA
8. Signed for completion by production
9. Bill of materials: It is a list of all raw material ingredients that are
required involving more materials appear in the final product.
10.Reference documents i.e., SOP’s such as Dispensing of the product,
temperature and humidity monitoring, material weighing, cleaning procedure,
use, operation and cleaning of the equipment.
11.List of raw material along with quantity required.
12.Equipment description, calibration certificate etc.
13.Area clearance- step by step cleaning of the equipment and area.
14.Production procedure- Instruction for each step of the production from
dispensing to dispatch.
15. Calculation of yield.
Yield =Weight of tablets × 100
Weight of raw materials
Finished product Yield = No. of goods produced in process+Rejects+Samples+Returned × 100
No. of goods received at the start of procedure
16. Post production review- Complete batch has been reviewed for
the completeness and accuracy in the entries for Good
Documentation Practices.
17. Product release- the product should comply with the finished
goods specifications and released to market
Responsibility :
• Primary Responsibility : QA/ QC/ Production Officer
• Secondary Responsibility : QA/ QC/ Production Manager
BMR format should contain following parts:
1. Batch record : First page of the BMR has all records about the batch as batch no.,
batch size, composition MFR, weight of drug, shelf life, storage condition,
manufacturing date, expiry date.
2. General instruction for mfg. : Health and safety instruction to the operation and
be followed during the mfg. process regarding the material and equipment used
during mfg.
3. Equipment cleaning record : Check list of the cleaning of all equipment is
prepared. Those are used in manufacturing of the batch including the previous
product batch and date of cleaning.
4. Bills of materials : list of the raw materials should have the quantity of the material
with that AR number. Weight of the material should be verified by QA.
5. Manufacturing Process : Should be written step by step in easy language.
Milling, Shifting, Drying, Compression, Coating and Packing having all
instruction with process time should be written.
6. Yield : Yield of batch should be calculated at the end of every stage to
calculate the process loss. Final yield should be calculated at the end of
manufacturing that should not be less than 99%.
7. Abbreviations : list of used in document should be made to understand the
BMR easily.
8. History of changes : At the end of document should have a list of the
changes in the document including the revision no. and date of change.
Documentation of Completion of each Significant step in
the BMR should include:
• Specific identification of each batch, including weights, measures,
and batch numbers of raw materials, intermediates, or any
reprocessed materials used during manufacturing.
• Signatures of the persons performing and directly supervising or
checking each critical step in the operation.
• In-process and laboratory test results.
• Actual yield at appropriate phases or times.
• Any deviation noted, its evaluation, and investigation conducted (if
appropriate) or reference to that investigation (if stored separately).
• Results of release testing.
• Production and quality control records should be reviewed as part of
the approval process of batch release.
• Any divergence or failure of a batch to meet its specifications should be
thoroughly investigated.
Following Attachments Required To Be Attached To BMR Before
Submitting The Completed BMR To Quality Assurance :
Equipment clean record status label.
Equipment clean record.
Raw materials dispensed weighing slip.
Intermediate raw material sealed.
Transfer note for finished goods to F.G. store.
Raw material issue order (P.R).
IPQC-In Process Test Request Cum Report.
Excess material requisition (S.R.).
Deviation note if any.
Certificate of Analysis (COA).
Finish product dispatched data.
CONCLUSION
• Master batch records provide the product's overall description
and detailed manufacturing and testing instructions.
• Batch manufacturing record (BMR) is an important document for
chemical and process manufacturers.
• It tells users how to produce a batch of a given product, then
records the entire production process, from start to finish.
• It is a complete specification for manufacturing a specific batch
size in a specific plant at a specific time.
Introduction Of Quality Audit :
Quality audit Is defined as a
“Systematic and independent
examination of manufacturer
quality system to determine
whether activities and related
results comply with planned
arrangement are implemented
effectively and we suitable to
achieve objective.”
Quality audit means a
systematic examination
of a quality system.
Quality audits are
typically performed at
defined intervals.
Any failure in their proper
implementation may be
published publicly and may
lead to a revocation of
quality certification.
• To check out the compliances of activities and results of
quality systems; with the procedures of quality systems.
• To investigate that whether the working procedures are
implemented effectively or not.
• Also to evaluate that implemented procedures are suitable or
not, in order to achieve the objectives of quality systems.
• Basically this quality audit is carried out by internal / external
quality auditors or audit team.
• This quality audit programs are effective means of evaluating
the compliance with the objectives of quality system.
• Also it provides the feedback to the management, as a part of
continuous improvement program.
• We can also evaluate the particular process or activity,
whether it is going as per plan or not. And if any deviation is
occurring then corrective action can be taken to bring the
process on normal.
Objectives
Of Quality
Audit
Planning:
Aims
of
quality
audit
plan:
To access the company's performance on the fact.
To obtained unbiased information about company.
To know factually if company is at risk.
To evaluate manufacturers compliance with GMP.
To identify the deficiency and faults to make improvements in quality.
To investigate the root cause of any quality related problem.
To educate and trained the people within organization.
To make the supplier aware of any quality related problem in their supplies.
Internal
Audit
External
Audit
Regulatory
Audit
Types
of
Audit :
 The other names of this type of audit are first party audit or self audit.
 The auditors and the process or product being audited belongs to same company.
 Self audit helps to achieve goals of pharmaceutical industry in a professional
way by advising them in improvement of any procedure related to the
quality of the product.
1.Internal audit
BENEFITS OF INTERNALAUDIT :
Tells you the health of a quality system.
 Identify the root of a problem and plan for corrective and
preventive actions with timeline.
Achieve better allocation of resources.
Able to avoid potentially big problem
continuous improvement.
2.EXTERNALAUDIT
 The another name of this audit is known as Second Party Audit.
 These audits are usually carried out for any outsourcing operations or
suppliers.
 This is the reason in this audit customer is actually performing audit on
supplier or contractor.
 The organization has to comply may rules and regulations eg. cGMP
guidelines and thus audits of the contractors and suppliers is also having
important role in regulatory compliance.
Third party
 A customer wants an audit of your company but wants your
company to pay for it.
3.
Regulatory
Audit
These audits are carried out by regulatory bodies against relevant regulations for the
manufacture and supply of pharmaceutical products.
National regulatory bodies, such as the Medicines Control Agency (MCA) in the UK
and Food And Drug Administration (FDA) in the USA, are statutorily responsible for
carrying out such audits.
These audits may be unannounced (MCA currently performs about ten percent of
its UK inspections like this) as manufacturers are expected to be complying with
GMP at all times.
Regulatory bodies from other countries in which products are sold may also audit
companies (i.e. FDAAudits European Manufacturers).
Regulatory inspectors are extensively trained and are knowledgeable and
professional.
Failure to pass a regulatory audit can lead practical experience of GMP and receive to
restrictions on (or the withdrawal ) of a manufacturing or import/export license.
Plan and prepare
Arrange and
announce
Arrive at the site
meet and explain
purpose
Perform audit
Informal oral
report of finding
Formal report
with
recommendations
Follow up
AUDIT PLANNING:
Before
Audit
During
Audit
After
Audit
1. Before Audit
• Plan well in advance.
• Decide if there are any products or activites that you
want to exclude from the audit.
• Know your procedures and where they are located.
• Remove all absolute documentation.
• Ensure all uncontrolled documentation that you are
working with are properly stamped "uncontrolled“.
• Label all your filing cabinets and files.
• Ensures all productive material, is identified by
number and status.
• Ensure all materials are stored in authorized areas.
• Eliminate all unused ,scrap/suspect material from around machine and workstations.
• Scrap /non-confirming material must be segregated and clearly identified.
• Do not over communicate and make people nervous, the system is being tested not them.
• Be prepared for the audit team to spelt up and audit separately.
• Have an audit communication center set up.
DURING AUDIT
 Make everyone aware that the auditors are likely to ask up to six questions:
1. What is your quality policy.
2. Tell me how do you do your job.
3. Show me where your system it tells you to do this.
4. Can i see some evidences.
5. What action do you take if you have problems.
6. What training have you received to help you to do this job.
 Be punctual and respectful .
 Be honest in your answers.
 Do not brag: they are not customer. You do not have to impress them with the past
or future, just what happens now.
 Do not volunteer additional information. Just answer the question asked and stop.
Do not “ramble on”.
 Do not use terms like “usually” or “generally”. They invite further questions.
 Do not fill in space between questions. If there is a gap, let the auditor fill it.
 Do not rush or divert the auditors. They are responsible for their own schedule.
 Note any non-compliances observed in as much detail as possible.
 Do not “point fingers” at someone else in front of the auditors.
 Do not challenge or argue to excess. Make your point then stop.
 Do not be panic.
AFTER AUDIT
• Do not argue at the exist meeting.it is too late.
• Do not rush into hasty corrective action-do it
properly.
• Remain polite, even if you did not do well-it is not
the auditor fault; it is your organization that failed.
Report the successful Audit can be achieved through a formal
report that has been generated by the leader of the Audit Team
and reviewed by that individual's manager the essential
elements of the audit report should include
1. Distribution List.
2. Dates Of Audit.
3. Scope Of Audit.
4. Name Of Team Leader.
5. Name Of Other Team Members With Positions In Team Eg.
Auditor, Expert, Auditor In Training, Guest And So On.
AUDIT REPORT
6. Standards of reference used in audit.
7. Date of opening meeting with list of attendees and position
titles.
8. Date of closing meeting with list of attendees and position title.
9. General strengths.
10. General weakness.
11. Specific observations requiring corrective and or preventive
actions.
12. Request for corrective and preventive action plans for each
observation.
13. Due date for the response to the audit report.
14.Information of audit report is highly confidential therefore copies of the audit
report should be controlled.
15.Many companies use unique codes or numbering methods to control the
copies.
16.It is necessary to follow and track the corrective and preventive actions.
17.Audit is not really completely closed out until all observations have been
verified as effectively corrected.
18.Monitoring of effectiveness may take very long time (a year or more) some
auditors elect to close out the audit once the corrective and preventive actions
have been verified correctly.
Introduction of Distribution Record
 Distribution record are written data related to distribution of drug
product from the manufacturer to the distributor.
 It include wide range of document like invoice bill of lading,
customer receipt’s, internal warehouse storage and inventory record
it etc.
 Maintenance of records is important to facilitate complete recall of
batch, if necessary.
DISTRIBUTION RECORDS
 The distribution record should be contain:
a. Name ,strength of the product, distribution of the doses form.
b. Name an address of the consignee.
c. Data and quantity shipped and lot of control number of the drug
product.
d. The distribution record shall we maintain in a manner.
e. So as to facilitate prompt and complete recall of the batch if necessary.
f. Prior to distribution or dispatch of batch of a drug it should be insure
that the batch has been tested, approved and release by quality control
personnel.
DISTRIBUTION PROCEDURE
 Written procedure shall be established and followed, describe in
the distribution of drug products.
 A procedure where by the oldest approved stock and product is
distribution first.
 A system by which the distribution of each lot of drug product
can be the readily determine to facilitate it’s recall if necessary.
 Distribution record must be constructed and procedure
established to facillate recall of defective product.
 Manufacturer must maintain record of the distribution
transaction involving in the process of finishing goods.
 All record should be indexed by either manufacturing batch
number of the packaging control number as the mean of
accountability until the shipment passes from the direct control of
manufacturer.
 The distribution process also include other consideration it must
be arrange so that a first in /first out of moment of product occur.
 APIs should only the release for distribution to third party after
they have the been released by the quality unit.
 API should be transported in the manner that does not adversely
affect their quality.
 A system should be in place by which the distribution of each
batch of intermediate and API can be readily determine to permit
its recall.
ELECTRONIC DATA HANDLING:
 According to 21 CFR part 11 the electronic record can be
electronics signature must control the electronic data record
security, integrity, traceability and the proper use of
electronics signature.
 A document management system consists of hardware and
software that convert paper document into the electronic
documents, manages and achieve those electronic
document and they index and store them according to
company policy.
Objective for the implementing and EDC
system in clinical trial
1. Real time data access.
2. Efficient data transfer and faster impact on marketing
of drug.
3. Overcoming the shipping of paper CRFs (case report
form) from remote areas.
4. Synergy between the serious adverse effect reporting
and the data base.
ADVANTAGES
Faster data
transfer.
Instant
data
access by
the staff.
Reduced
queries.
Installation of
software in each
PC which is
costlier.
Availability of
internet
connection is
remote where
trial is being
conduct.
Data security is
a major problem
if public internet
is being used.
DISADVANTAGES
CONTROLLED DOCUMENT UNCONTROLLED DOCUMENT
Documents shall be periodically reviewed
(recommended once/year).
QA & Document control Centre are
responsible to ensure that issued documents
are controlled, effective and implemented.
Use of electronic signatures as well as
electronic maintenance and submission, is
an acceptable substitution for paper, when
practical.
Documents that is not subjected to
amendments, changes or revisions and
not traceable.
OR
The photocopy of master copy of
controlled documents or written
procedure which shall be given to any
department or person for reference
purpose only.
Drug Master File (DMF)
 DMF is a confidential document for API (Active Pharmaceutical Ingredient)
submitted to the regulatory body for the approval process.
 In fact there is no regulations to file a DMF.
 It is not reviewed on receipt as like dossier and DMF’s are neither approved
nor disapproved.
It has
divided into
2 parts
• Open part (Applicant’s Part): Contains all the required information
related to method of manufacture and brief outline of method of
manufacture, potential impurities, manufacturing system etc.
• Closed Part (Restricted Part): Contains Confidential information on the
manufacture of API like Extraction, validation, process, solvents approved.
It has divided into 2 parts used, reactions, temperature, conditions, critical
steps in manufacture etc.
Apart from this DMF is divided into 5 types
Type I: Plant information (No more a part of
DMF)
Type II: Drug substance, drug products,
intermediates and materials used in
manufacturing.
Type III: Packaging materials.
Type IV: Excipients or additives.
Type V: FDA accepted reference information
Type I DMF
It contains information about the plant
information like
Manufacturing site.
Equipment capabilities.
Operational layout.
Corporate headquarters.
Site Address.
Type II DMF
It includes information about all the significant steps in manufacturing and control
of drug substance and intermediates
 Manufacturing sections
• Quality control
Inputs
Intermediates
and In-process
Finished drug
substance
Raw
Materials
Packing
Materials
• Validations.
• Stability data.
• Impurities.
• Packaging and labelling
Type III DMF
It contains detailed information of the packaging material used. i.e.,
 Intended use of the packing material
 Composition of the packing material.
 Name of the suppliers.
 Specifications.
 Toxicological data on the packing material
Type IV DMF
• Excipients used in the manufacture of the product.
• Compendia excipients usually not reviewed so DMF is not required
Differences between the Application
(Dossier) and DMF
Sr.N
o
APPLICATION (DOSSIER) DMF
1 Must be filed by applicant Not mandatory to file DMF
2 Comes under regulatory status No such regulations
3 Each applications and their
supplements are entered in
common database
DMF’s are entered in separate
database as per the type
4 Submitted to intended review
division
Submitted to Regulatory body
5 Review procedure is different than
that of DMF
Reviewed only when referenced
with NDA/ ANDA applications
6 Approval timeline is there No approval timeline
DMF Filing System
Step 1
•Applicants file DMF
Step 2
•Submitted to Regulatory Body
Step 3
•Information in DMF is checked (Not Reviewed) and entered into DMF
database
Step 4
•DMF number will be assign and acknowledgement letter will be sent to
DMF holder along with reminder of obligations
DMF Reviewing System
Step
1
•Applicant file NDA or AND
Step
2
•Submit dossier and quotes DMF number as a supportive
documents for drug substance
Step
3
•Applicant will send letter of Authorization (LOA)
Step
4
•Upon receiving LOA DMF will be taken for Review
Important points to be noted in DMF
 Holder: The person who submits a DMF.
 Agent: The person or company who represents the DMF holder.
 Applicant: The person or company who use the DMF for referencing in
the NDA or ANDA submission.
 Agent will be appointed by the DMF holder to file DMF and to
communicate with the regulatory body.
 Major contents of DMF are, Transmittal letter, Administrative
information of DMF holder, Technical information of the product.
 Reason to file DMF: DMF filed for API’s which acts as supportive
document while submitting NDA or ANDA.
Obligations of DMF Holder
 Should submit any changes as amendments.
 Should notify regulatory body of change in holder name or address.
 Should notify regulatory body of change in agent or representative.
 Issue LOA to each applicant who intends to use that API.
 Should submit annual report to regulatory body on the anniversary date of
DMF filing.
Symbols used in finding the status of DMF
 “A” : Active, (DMF is acceptable and up to date)
 “I” : Inactive
 “N” : Not assigned DMF number
 “P” : Pending filing review
 DMF for OTC drugs and compendia excipients are never reviewed.
 DMF cannot be registered or approved, it just entered in DMF database.
 Letter of Authorization (LOA) shall be send by DMF holder to regulatory
body (2 copies) and NDA/ANDA applicant (1 copy).
 DMF number will be assigned only when the regulatory body receives 2
copies of DMF along with the cover letter.
 If any deficiencies found in DMF it shall be communicated with the
holder and the applicant will be just notified.
 DMF shall be registered immediately but not reviewed.
 Regulatory body will issue termination letter to DMF holder when there is
no communication for 3 consecutive years (i.e., no annual report) regarding
the DMF.
 If annual report is not send, it causes delay in the review process of the
filed NDA and ANDA.
 Regulatory body shall send a reminder letter called overdue notice letter
(ONL) to DMF holder, if there is no response from the holder within 90
days, one copy will be send to federal center and the other will be
destroyed.
 Now a days DMF filing also become electronic submission and can
convert existing Paper MF’s to eCTD
COMMON TECHNICAL DOCUMENT (CTD)
 It is an essential document to be submitted to regulatory body as a supportive list of leaflets
attached with the registration applications for pharmaceuticals to get market authorization.
Mainly CTD tells about the format for the data.
1. The Common Technical Document (CTD) guidance’s have been developed for Japan,
European Union and United States.
2. Most countries have adopted the CTD format. Hence, CDSCO has also decided to adopt
CTD format for technical requirements for registration of pharmaceutical products for
human use.
3. This guidance is developed by CDSCO based on:
a. The ICH Harmonized Tripartite Guideline on “Organization of the Common Technical
Document for the Registration of Pharmaceuticals for Human Use”. M4, Step 4 version
dated January 13, 2004, and
b. Drugs & Cosmetics Act 1940 and Rules made thereunder.
4. The CTD is only a format for submission of information to CDSCO.
CTD: OVERVIEW
The CTD is organized into five modules (Module 1, 2, 3, 4, and 5)
and a diagrammatic representation of organization of the CTD is
provided in Annexure I.
It is organized into:-
Module 1: General Information
Module 2: CTD summaries
Module 3: Quality
Module 4: Nonclinical study reports
Module 5: Clinical study reports
ELECTRONIC COMMON TECHNICAL
DOCUMENT (eCTD)
eCTD is electronic Common Technical Document, an electronic format
where the information and document is submitted to regulatory body
electronically by using a software. Some of the eCTD software are
Pharm ready, Edios etc.
Requirements of eCTD:
1. Copy and paste.
2. Verifying and printing documents.
3. Document Annotation.
4. Export of information to databases.
Sr.
No.
Common Technical
Document (CTD)
Electronic Common
Technical Document
(eCTD)
1 Paper submission Electronic (Using Software)
2 Tedious and Difficult Review process Faster review process
3 Bulk and Large documents XML files storage will be in GB
4 Cross references include CTD section
number
Cross references include hyperlink and
book mark
5 CTD navigation through TOC and Volumes eCTD navigation by XML backbone
6 Paper volume- A4 Layout shall be A4 or US letter size
7 Submitted in Binders or boxes Submitted on CD or DVD or e-mail or
Portal.
8 Compiled electronically with volumes, tabs
and slip sheets and then printed to paper.
Compiled electronically with documents in
folders
Regulated Market Non- 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.
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, some Asian countries.
Being said since these countries do not have specific
monitoring authorities, they depend on other
regulated countries.
THANK YOU!

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Documentation in pharmaceutical industry

  • 1. UNIVERSITY OF CHEMICAL TECHNOLOGY, CHHATRAPATI SAMBHAJINAGAR. PHARMACEUTICAL QUALITY ASSURANCE DEPARTMENT ~ POOJA HARKAL Documentation in Pharmaceutical Industry
  • 2. Technical Documentation Documentation is the Essential and crucial part in any of the company. In pharma we can say “If it is not documented, it has not done”. Documentation is an evidence to show or to prove that the things have done accordingly. Quality assurance documents are the heart of the company. Technical documents are  Master Formula Record (MFR).  Batch Manufacturing Record (BMR).  Drug Master File (DMF) While registering the Indian product in overseas market RA team should be carefully check, verify all the documents for the genuinity, quality and uniformity from batch to batch and to avoid delay in the approval process.
  • 3. Documentation flow chart Batch Manufacturing Record Scale up batch Master Formula Record Formulation and development
  • 4. Master Formula Record (MFR):  MFR is a master document which contains detailed information about the product, process etc. MFR is prepared by the Formulation and Development team which is called technology transfer. By this master document BMR and BPR prepared.
  • 5. MASTER BATCH RECORD 1. Master Batch Record also known as MFR (Master Formula/Mfg Record). 2. It should be available for each product, batch and pack size. 3. It is a master document for any pharmaceutical product. 4. It contains all information about the manufacturing process for the product. 5. It is prepared by the research and development team of the company. 6. It is used as reference standard for preparing batch manufacturing record (BMR) by manufacturing units. 7. It plays an important in consistency for each batch manufacturing.  Responsible Department : Primary Responsibility : Formulation Research and Production Department Secondary Responsibility : QA Department
  • 6. Content of Master Batch Record 1. Product details: Name, address, logo of the manufacturing company. Product name. Dosage form. Brand name. Generic name. Product code. Product description. Label claim of all ingredients used. Batch size. Pack size. Shelf life. Storage conditions
  • 7. 2. Flow chart: • Steps involved in the manufacturing process and flow chart representing the material movement from dispensing to the finished product to packaging and to the store. 3. Equipment: • List of equipment required for the manufacture of the product with the capacity 4. Special instructions: • Warnings and precautions related to manufacturing process should be clearly mentioned. • Quantity to be added should be mentioned. • Time interval and overages to be added to be mentioned clearly. • Name of the ingredient with tests and specification limit as per IP, BP and USP. 5. Calculations: • Quantity to be added to get 100% final product. • It can be done by using water content or LOD to get 100% potency.
  • 8. 6. Manufacturing process:  It should include all the steps involved the manufacturing process like sifting, milling, granulation, mixing, blending, lubricating, compression, coating, filling, if necessary filtration with environmental conditions such as temperature, humidity, storage to be maintained with time. 7. Packaging process:  Details of packaging materials used.  Line clearance, batch reconciliation of the packing material. 8. Yield:  It includes theoretical yield, Practical yield and acceptance limit of the batch
  • 9.
  • 10.  Master Batch Record Packaging details : • There have to be authorized packaging instructions • Name. • Description of dosage form. • Pack sizes- Number, dose volume. • A total list of all Packaging materials required for standard batch size with reference to the specifications of the packaging material • Specimens of all packaging material. • Line clearance instructions. • Description of packaging operations. • In process controls.
  • 11. BATCH MANUFACTURING RECORD Once the Master formula is prepared, pilot batch will be started to validation and BA/BE studies, upon getting the report from the pilot batch BMR will be prepared which will be used for commercial batch manufacturing. a. The "Batch Manufacturing Record" is the necessary quality and GMP documentation for tracing the complete cycle of manufacturing batch or lot. b. The batch manufacturing record should be checked before issuance to assure that it is the correct version and a legible accurate reproduction of the appropriate master production instruction. c. Before any processing begins, a check should be performed and recorded to ensure that the equipment and workstation are clear of previous products, documents, or materials not required for the planned equipment is clean and suitable for use. d. These records should be numbered with a unique batch or identification number and dated and signed when issued.
  • 12. Batch Manufacturing Record Content : 1. Name of the product, Batch number, revision number, effective date. 2. Product details like Type of the product, dosage, shape of the drug. 3. Batch size and Total number of tablets or capsules. 4. Pack size and packaging Instructions. 5. Storage instructions. 6. Production batch record issuance. 7. Signed & issued by QA 8. Signed for completion by production 9. Bill of materials: It is a list of all raw material ingredients that are required involving more materials appear in the final product.
  • 13. 10.Reference documents i.e., SOP’s such as Dispensing of the product, temperature and humidity monitoring, material weighing, cleaning procedure, use, operation and cleaning of the equipment. 11.List of raw material along with quantity required. 12.Equipment description, calibration certificate etc. 13.Area clearance- step by step cleaning of the equipment and area. 14.Production procedure- Instruction for each step of the production from dispensing to dispatch. 15. Calculation of yield. Yield =Weight of tablets × 100 Weight of raw materials Finished product Yield = No. of goods produced in process+Rejects+Samples+Returned × 100 No. of goods received at the start of procedure
  • 14. 16. Post production review- Complete batch has been reviewed for the completeness and accuracy in the entries for Good Documentation Practices. 17. Product release- the product should comply with the finished goods specifications and released to market Responsibility : • Primary Responsibility : QA/ QC/ Production Officer • Secondary Responsibility : QA/ QC/ Production Manager
  • 15. BMR format should contain following parts: 1. Batch record : First page of the BMR has all records about the batch as batch no., batch size, composition MFR, weight of drug, shelf life, storage condition, manufacturing date, expiry date. 2. General instruction for mfg. : Health and safety instruction to the operation and be followed during the mfg. process regarding the material and equipment used during mfg. 3. Equipment cleaning record : Check list of the cleaning of all equipment is prepared. Those are used in manufacturing of the batch including the previous product batch and date of cleaning. 4. Bills of materials : list of the raw materials should have the quantity of the material with that AR number. Weight of the material should be verified by QA.
  • 16. 5. Manufacturing Process : Should be written step by step in easy language. Milling, Shifting, Drying, Compression, Coating and Packing having all instruction with process time should be written. 6. Yield : Yield of batch should be calculated at the end of every stage to calculate the process loss. Final yield should be calculated at the end of manufacturing that should not be less than 99%. 7. Abbreviations : list of used in document should be made to understand the BMR easily. 8. History of changes : At the end of document should have a list of the changes in the document including the revision no. and date of change.
  • 17.
  • 18. Documentation of Completion of each Significant step in the BMR should include: • Specific identification of each batch, including weights, measures, and batch numbers of raw materials, intermediates, or any reprocessed materials used during manufacturing. • Signatures of the persons performing and directly supervising or checking each critical step in the operation.
  • 19. • In-process and laboratory test results. • Actual yield at appropriate phases or times. • Any deviation noted, its evaluation, and investigation conducted (if appropriate) or reference to that investigation (if stored separately). • Results of release testing. • Production and quality control records should be reviewed as part of the approval process of batch release. • Any divergence or failure of a batch to meet its specifications should be thoroughly investigated.
  • 20. Following Attachments Required To Be Attached To BMR Before Submitting The Completed BMR To Quality Assurance : Equipment clean record status label. Equipment clean record. Raw materials dispensed weighing slip. Intermediate raw material sealed. Transfer note for finished goods to F.G. store. Raw material issue order (P.R). IPQC-In Process Test Request Cum Report. Excess material requisition (S.R.). Deviation note if any. Certificate of Analysis (COA). Finish product dispatched data.
  • 21. CONCLUSION • Master batch records provide the product's overall description and detailed manufacturing and testing instructions. • Batch manufacturing record (BMR) is an important document for chemical and process manufacturers. • It tells users how to produce a batch of a given product, then records the entire production process, from start to finish. • It is a complete specification for manufacturing a specific batch size in a specific plant at a specific time.
  • 22. Introduction Of Quality Audit : Quality audit Is defined as a “Systematic and independent examination of manufacturer quality system to determine whether activities and related results comply with planned arrangement are implemented effectively and we suitable to achieve objective.” Quality audit means a systematic examination of a quality system. Quality audits are typically performed at defined intervals. Any failure in their proper implementation may be published publicly and may lead to a revocation of quality certification.
  • 23. • To check out the compliances of activities and results of quality systems; with the procedures of quality systems. • To investigate that whether the working procedures are implemented effectively or not. • Also to evaluate that implemented procedures are suitable or not, in order to achieve the objectives of quality systems. • Basically this quality audit is carried out by internal / external quality auditors or audit team. • This quality audit programs are effective means of evaluating the compliance with the objectives of quality system. • Also it provides the feedback to the management, as a part of continuous improvement program. • We can also evaluate the particular process or activity, whether it is going as per plan or not. And if any deviation is occurring then corrective action can be taken to bring the process on normal. Objectives Of Quality Audit Planning:
  • 24. Aims of quality audit plan: To access the company's performance on the fact. To obtained unbiased information about company. To know factually if company is at risk. To evaluate manufacturers compliance with GMP. To identify the deficiency and faults to make improvements in quality. To investigate the root cause of any quality related problem. To educate and trained the people within organization. To make the supplier aware of any quality related problem in their supplies.
  • 25. Internal Audit External Audit Regulatory Audit Types of Audit :  The other names of this type of audit are first party audit or self audit.  The auditors and the process or product being audited belongs to same company.  Self audit helps to achieve goals of pharmaceutical industry in a professional way by advising them in improvement of any procedure related to the quality of the product. 1.Internal audit
  • 26. BENEFITS OF INTERNALAUDIT : Tells you the health of a quality system.  Identify the root of a problem and plan for corrective and preventive actions with timeline. Achieve better allocation of resources. Able to avoid potentially big problem continuous improvement.
  • 27. 2.EXTERNALAUDIT  The another name of this audit is known as Second Party Audit.  These audits are usually carried out for any outsourcing operations or suppliers.  This is the reason in this audit customer is actually performing audit on supplier or contractor.  The organization has to comply may rules and regulations eg. cGMP guidelines and thus audits of the contractors and suppliers is also having important role in regulatory compliance. Third party  A customer wants an audit of your company but wants your company to pay for it.
  • 28. 3. Regulatory Audit These audits are carried out by regulatory bodies against relevant regulations for the manufacture and supply of pharmaceutical products. National regulatory bodies, such as the Medicines Control Agency (MCA) in the UK and Food And Drug Administration (FDA) in the USA, are statutorily responsible for carrying out such audits. These audits may be unannounced (MCA currently performs about ten percent of its UK inspections like this) as manufacturers are expected to be complying with GMP at all times. Regulatory bodies from other countries in which products are sold may also audit companies (i.e. FDAAudits European Manufacturers). Regulatory inspectors are extensively trained and are knowledgeable and professional. Failure to pass a regulatory audit can lead practical experience of GMP and receive to restrictions on (or the withdrawal ) of a manufacturing or import/export license.
  • 29.
  • 30. Plan and prepare Arrange and announce Arrive at the site meet and explain purpose Perform audit Informal oral report of finding Formal report with recommendations Follow up
  • 31. AUDIT PLANNING: Before Audit During Audit After Audit 1. Before Audit • Plan well in advance. • Decide if there are any products or activites that you want to exclude from the audit. • Know your procedures and where they are located. • Remove all absolute documentation. • Ensure all uncontrolled documentation that you are working with are properly stamped "uncontrolled“. • Label all your filing cabinets and files. • Ensures all productive material, is identified by number and status. • Ensure all materials are stored in authorized areas.
  • 32. • Eliminate all unused ,scrap/suspect material from around machine and workstations. • Scrap /non-confirming material must be segregated and clearly identified. • Do not over communicate and make people nervous, the system is being tested not them. • Be prepared for the audit team to spelt up and audit separately. • Have an audit communication center set up. DURING AUDIT  Make everyone aware that the auditors are likely to ask up to six questions: 1. What is your quality policy. 2. Tell me how do you do your job. 3. Show me where your system it tells you to do this. 4. Can i see some evidences. 5. What action do you take if you have problems. 6. What training have you received to help you to do this job.
  • 33.  Be punctual and respectful .  Be honest in your answers.  Do not brag: they are not customer. You do not have to impress them with the past or future, just what happens now.  Do not volunteer additional information. Just answer the question asked and stop. Do not “ramble on”.  Do not use terms like “usually” or “generally”. They invite further questions.  Do not fill in space between questions. If there is a gap, let the auditor fill it.  Do not rush or divert the auditors. They are responsible for their own schedule.  Note any non-compliances observed in as much detail as possible.  Do not “point fingers” at someone else in front of the auditors.  Do not challenge or argue to excess. Make your point then stop.  Do not be panic.
  • 34. AFTER AUDIT • Do not argue at the exist meeting.it is too late. • Do not rush into hasty corrective action-do it properly. • Remain polite, even if you did not do well-it is not the auditor fault; it is your organization that failed.
  • 35. Report the successful Audit can be achieved through a formal report that has been generated by the leader of the Audit Team and reviewed by that individual's manager the essential elements of the audit report should include 1. Distribution List. 2. Dates Of Audit. 3. Scope Of Audit. 4. Name Of Team Leader. 5. Name Of Other Team Members With Positions In Team Eg. Auditor, Expert, Auditor In Training, Guest And So On. AUDIT REPORT
  • 36. 6. Standards of reference used in audit. 7. Date of opening meeting with list of attendees and position titles. 8. Date of closing meeting with list of attendees and position title. 9. General strengths. 10. General weakness. 11. Specific observations requiring corrective and or preventive actions. 12. Request for corrective and preventive action plans for each observation. 13. Due date for the response to the audit report.
  • 37. 14.Information of audit report is highly confidential therefore copies of the audit report should be controlled. 15.Many companies use unique codes or numbering methods to control the copies. 16.It is necessary to follow and track the corrective and preventive actions. 17.Audit is not really completely closed out until all observations have been verified as effectively corrected. 18.Monitoring of effectiveness may take very long time (a year or more) some auditors elect to close out the audit once the corrective and preventive actions have been verified correctly.
  • 38.
  • 39. Introduction of Distribution Record  Distribution record are written data related to distribution of drug product from the manufacturer to the distributor.  It include wide range of document like invoice bill of lading, customer receipt’s, internal warehouse storage and inventory record it etc.  Maintenance of records is important to facilitate complete recall of batch, if necessary.
  • 40. DISTRIBUTION RECORDS  The distribution record should be contain: a. Name ,strength of the product, distribution of the doses form. b. Name an address of the consignee. c. Data and quantity shipped and lot of control number of the drug product. d. The distribution record shall we maintain in a manner. e. So as to facilitate prompt and complete recall of the batch if necessary. f. Prior to distribution or dispatch of batch of a drug it should be insure that the batch has been tested, approved and release by quality control personnel.
  • 41. DISTRIBUTION PROCEDURE  Written procedure shall be established and followed, describe in the distribution of drug products.  A procedure where by the oldest approved stock and product is distribution first.  A system by which the distribution of each lot of drug product can be the readily determine to facilitate it’s recall if necessary.  Distribution record must be constructed and procedure established to facillate recall of defective product.  Manufacturer must maintain record of the distribution transaction involving in the process of finishing goods.
  • 42.  All record should be indexed by either manufacturing batch number of the packaging control number as the mean of accountability until the shipment passes from the direct control of manufacturer.  The distribution process also include other consideration it must be arrange so that a first in /first out of moment of product occur.  APIs should only the release for distribution to third party after they have the been released by the quality unit.  API should be transported in the manner that does not adversely affect their quality.  A system should be in place by which the distribution of each batch of intermediate and API can be readily determine to permit its recall.
  • 43. ELECTRONIC DATA HANDLING:  According to 21 CFR part 11 the electronic record can be electronics signature must control the electronic data record security, integrity, traceability and the proper use of electronics signature.  A document management system consists of hardware and software that convert paper document into the electronic documents, manages and achieve those electronic document and they index and store them according to company policy.
  • 44. Objective for the implementing and EDC system in clinical trial 1. Real time data access. 2. Efficient data transfer and faster impact on marketing of drug. 3. Overcoming the shipping of paper CRFs (case report form) from remote areas. 4. Synergy between the serious adverse effect reporting and the data base.
  • 45. ADVANTAGES Faster data transfer. Instant data access by the staff. Reduced queries. Installation of software in each PC which is costlier. Availability of internet connection is remote where trial is being conduct. Data security is a major problem if public internet is being used. DISADVANTAGES
  • 46. CONTROLLED DOCUMENT UNCONTROLLED DOCUMENT Documents shall be periodically reviewed (recommended once/year). QA & Document control Centre are responsible to ensure that issued documents are controlled, effective and implemented. Use of electronic signatures as well as electronic maintenance and submission, is an acceptable substitution for paper, when practical. Documents that is not subjected to amendments, changes or revisions and not traceable. OR The photocopy of master copy of controlled documents or written procedure which shall be given to any department or person for reference purpose only.
  • 47. Drug Master File (DMF)  DMF is a confidential document for API (Active Pharmaceutical Ingredient) submitted to the regulatory body for the approval process.  In fact there is no regulations to file a DMF.  It is not reviewed on receipt as like dossier and DMF’s are neither approved nor disapproved. It has divided into 2 parts • Open part (Applicant’s Part): Contains all the required information related to method of manufacture and brief outline of method of manufacture, potential impurities, manufacturing system etc. • Closed Part (Restricted Part): Contains Confidential information on the manufacture of API like Extraction, validation, process, solvents approved. It has divided into 2 parts used, reactions, temperature, conditions, critical steps in manufacture etc.
  • 48. Apart from this DMF is divided into 5 types Type I: Plant information (No more a part of DMF) Type II: Drug substance, drug products, intermediates and materials used in manufacturing. Type III: Packaging materials. Type IV: Excipients or additives. Type V: FDA accepted reference information
  • 49. Type I DMF It contains information about the plant information like Manufacturing site. Equipment capabilities. Operational layout. Corporate headquarters. Site Address.
  • 50. Type II DMF It includes information about all the significant steps in manufacturing and control of drug substance and intermediates  Manufacturing sections • Quality control Inputs Intermediates and In-process Finished drug substance Raw Materials Packing Materials • Validations. • Stability data. • Impurities. • Packaging and labelling
  • 51. Type III DMF It contains detailed information of the packaging material used. i.e.,  Intended use of the packing material  Composition of the packing material.  Name of the suppliers.  Specifications.  Toxicological data on the packing material Type IV DMF • Excipients used in the manufacture of the product. • Compendia excipients usually not reviewed so DMF is not required
  • 52. Differences between the Application (Dossier) and DMF Sr.N o APPLICATION (DOSSIER) DMF 1 Must be filed by applicant Not mandatory to file DMF 2 Comes under regulatory status No such regulations 3 Each applications and their supplements are entered in common database DMF’s are entered in separate database as per the type 4 Submitted to intended review division Submitted to Regulatory body 5 Review procedure is different than that of DMF Reviewed only when referenced with NDA/ ANDA applications 6 Approval timeline is there No approval timeline
  • 53. DMF Filing System Step 1 •Applicants file DMF Step 2 •Submitted to Regulatory Body Step 3 •Information in DMF is checked (Not Reviewed) and entered into DMF database Step 4 •DMF number will be assign and acknowledgement letter will be sent to DMF holder along with reminder of obligations
  • 54. DMF Reviewing System Step 1 •Applicant file NDA or AND Step 2 •Submit dossier and quotes DMF number as a supportive documents for drug substance Step 3 •Applicant will send letter of Authorization (LOA) Step 4 •Upon receiving LOA DMF will be taken for Review
  • 55. Important points to be noted in DMF  Holder: The person who submits a DMF.  Agent: The person or company who represents the DMF holder.  Applicant: The person or company who use the DMF for referencing in the NDA or ANDA submission.  Agent will be appointed by the DMF holder to file DMF and to communicate with the regulatory body.  Major contents of DMF are, Transmittal letter, Administrative information of DMF holder, Technical information of the product.  Reason to file DMF: DMF filed for API’s which acts as supportive document while submitting NDA or ANDA.
  • 56. Obligations of DMF Holder  Should submit any changes as amendments.  Should notify regulatory body of change in holder name or address.  Should notify regulatory body of change in agent or representative.  Issue LOA to each applicant who intends to use that API.  Should submit annual report to regulatory body on the anniversary date of DMF filing. Symbols used in finding the status of DMF  “A” : Active, (DMF is acceptable and up to date)  “I” : Inactive  “N” : Not assigned DMF number  “P” : Pending filing review
  • 57.  DMF for OTC drugs and compendia excipients are never reviewed.  DMF cannot be registered or approved, it just entered in DMF database.  Letter of Authorization (LOA) shall be send by DMF holder to regulatory body (2 copies) and NDA/ANDA applicant (1 copy).  DMF number will be assigned only when the regulatory body receives 2 copies of DMF along with the cover letter.  If any deficiencies found in DMF it shall be communicated with the holder and the applicant will be just notified.  DMF shall be registered immediately but not reviewed.
  • 58.  Regulatory body will issue termination letter to DMF holder when there is no communication for 3 consecutive years (i.e., no annual report) regarding the DMF.  If annual report is not send, it causes delay in the review process of the filed NDA and ANDA.  Regulatory body shall send a reminder letter called overdue notice letter (ONL) to DMF holder, if there is no response from the holder within 90 days, one copy will be send to federal center and the other will be destroyed.  Now a days DMF filing also become electronic submission and can convert existing Paper MF’s to eCTD
  • 59. COMMON TECHNICAL DOCUMENT (CTD)  It is an essential document to be submitted to regulatory body as a supportive list of leaflets attached with the registration applications for pharmaceuticals to get market authorization. Mainly CTD tells about the format for the data. 1. The Common Technical Document (CTD) guidance’s have been developed for Japan, European Union and United States. 2. Most countries have adopted the CTD format. Hence, CDSCO has also decided to adopt CTD format for technical requirements for registration of pharmaceutical products for human use. 3. This guidance is developed by CDSCO based on: a. The ICH Harmonized Tripartite Guideline on “Organization of the Common Technical Document for the Registration of Pharmaceuticals for Human Use”. M4, Step 4 version dated January 13, 2004, and b. Drugs & Cosmetics Act 1940 and Rules made thereunder. 4. The CTD is only a format for submission of information to CDSCO.
  • 60. CTD: OVERVIEW The CTD is organized into five modules (Module 1, 2, 3, 4, and 5) and a diagrammatic representation of organization of the CTD is provided in Annexure I. It is organized into:- Module 1: General Information Module 2: CTD summaries Module 3: Quality Module 4: Nonclinical study reports Module 5: Clinical study reports
  • 61. ELECTRONIC COMMON TECHNICAL DOCUMENT (eCTD) eCTD is electronic Common Technical Document, an electronic format where the information and document is submitted to regulatory body electronically by using a software. Some of the eCTD software are Pharm ready, Edios etc. Requirements of eCTD: 1. Copy and paste. 2. Verifying and printing documents. 3. Document Annotation. 4. Export of information to databases.
  • 62. Sr. No. Common Technical Document (CTD) Electronic Common Technical Document (eCTD) 1 Paper submission Electronic (Using Software) 2 Tedious and Difficult Review process Faster review process 3 Bulk and Large documents XML files storage will be in GB 4 Cross references include CTD section number Cross references include hyperlink and book mark 5 CTD navigation through TOC and Volumes eCTD navigation by XML backbone 6 Paper volume- A4 Layout shall be A4 or US letter size 7 Submitted in Binders or boxes Submitted on CD or DVD or e-mail or Portal. 8 Compiled electronically with volumes, tabs and slip sheets and then printed to paper. Compiled electronically with documents in folders
  • 63. Regulated Market Non- 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. 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, some Asian countries. Being said since these countries do not have specific monitoring authorities, they depend on other regulated countries.

Editor's Notes

  1. Electronic data capture