BIO 221
REGULATORY AFFAIRS COMPLIANCE IN BIOMANUFACTURING
ASSIGNMENT 8
DOCUMENTATION, QUALITY SYSTEMS AND GMP
Background
Good documentation practices are an essential feature of any biotechnology company. A
document affirms the following and contains such a statement depending on the purpose of
the document: The rules set forth in this document should apply to all personnel in a
biotechnology company involved in the holding, transportation, manufacture, testing, support,
or packaging of clinical and commercial drugs, whether temporary or regular staff.
Biotechnology companies are regulated by the Food and Drug Administration (FDA) as well as
by foreign regulatory agencies for products marketed abroad. Strict documentation rules are
set to ensure compliance with all regulatory agencies. By placing your signature on a cGMP
document, you have proven in the view of the FDA that you have completed a step. cGMP
documents and records include, but are not limited to the following: Standard Operating
Procedures (SOPs), Manufacturing Procedures (MPs), Specifications, Analytical Methods,
Validation Documents, Batch Records, Product and Sample Labels. All cGMP documents may be
reviewed by the FDA or other regulatory agencies.
Documentation Rules
1. Do
When writing in cGMP documents DO:
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Use only black, indelible, ball-point ink
Make all entries legible such that they are readable
Initial, unless a signature is required, and date all entries
Document each step before moving to the next
Write N/A, initial and date spaces if it is not appropriate to fill them in
Record numbers less than one with a zero before the decimal point
2. Do Not
When writing in cGMP documents DO NOT:
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Overwrite
Use liquid correction fluid
Backdate
Record data before the action or event has occurred
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Use ditto marks
Leave required data spaces blank
Approve, verify or review your own performance
3. Initial/Date
All entries to a cGMP document must be accompanied by the identity of the person (initials or
signature) and the date that the entry was made. This is required by the Code of Federal
Regulations (CFR) and serves as a tracking method to determine that a task was indeed
performed and who did the work.
Initials are the accepted standard method of identification. However, some operations require
a signature. For example, an “Approved By” space must be filled with a signature, not initials.
4. Recording Time
Either military time or meridian time is acceptable for recording time.
Military time: two (2) digits to indicate the hour (00 to 23) followed by two (2) digits to indicate
the minutes (00 to 59).
Examples:
0850
1750
Meridian time: One or two digits to indicate the hour (1 to 12) followed by two digits to indicate
the minutes (00 to 59), then the morning (AM) or afternoon (PM) designation.
Examples:
8:50 AM
5:50 PM
5. Corrections
No handwritten changes or corrections may be made to the printed text of an approved cGMP
document. Consult with your supervisor if you discover an error. Any changes required to an
approved cGMP document shall be implemented through the established quality system.
When making a correction to a manually recorded entry on controlled documents perform the
following steps:
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Place a single line through the incorrect entry
Initial and date adjacent to the cross-out
Enter the correct data near the original entry
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The mistake must still be legible through the cross-out
Date of correction is the date the correction was made, not the date the error was
made.
6. Performed By
Performance of a step must be documented at the time of completing the step and prior to
moving on to the next step. Do not execute a step if the manufacturing procedure is not
available for documenting necessary data at the time of execution. The following personnel
may initial and date the “Performed By” space:
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Personnel already proficient in the task performed OR
Personnel who are in training under the supervision of their qualified trainer
7. Recorded By
The “Recorded By” space is used if the operator is unable to initial and date immediately, due
to working in a confined or restricted space, such as a laminar air flow hood. This situation is
the only exception to the “Performed By” rule. Data must then be recorded by another person
watching the operation. The person recording data must initial and date the “Recorded By”
space prior to moving on to the next step.
8. Verified By
Verification shall be performed prior to moving on to the next step. Operators executing a task
cannot verify their own action. At least one other person must review documentation for
accuracy. Personnel may initial or sign and date the “Verified By” space if:
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They witnessed that a task, operation, or procedure was performed per written
instructions and accurately documented AND
They are already proficient in the task performed
9. Deviations
If you deviate from a written procedure, you must:
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Notify your supervisor
Document the deviation using the appropriate quality system
10. Missing Data
If information is not entered at the time of completing the step, the blank entry shall be marked
by an asterisk or similar notation. The use of each notation is limited to one per page.
Comments explaining the reason information is missing, along with the proper information, e.g.
date event actually occurred, shall be documented on the same page of the record. The
explanation shall be initialed and dated at the time of recording.
11. Voiding Records
On occasion, errors are made in the execution of making an in-process material such as a buffer
and all the proper documentation was completed. However, because of the error, the decision
is made to scrap the material and start all over with new in-process material. The original
document would then need to be voided and attached to the document replacing it. The
documents are voided to prevent confusion or mix-ups with the correct document. When
voiding a document do the following:
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Get supervisor and Quality Assurance (QA) approval
Write “Void” across the front of the document and include initials and date
12. Recreating and Rewriting Records
Recreating or rewriting records should be avoided; however it is sometimes necessary.
Supervisor and QA approval is required when recreating records. It is important to identify the
recreated document as “Rewrite” and to reference the sources of the information. Records can
be recreated only when:
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Record is illegible
Incorrect form or document was used
Record was irreparably damaged
13. Rounding Off Rules
The following rules apply to rounding off:
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In a series of calculations, carry the extra digits through the final result, and then round
off.
If the digit to be removed is <5, the preceding digit remains the same. For example, 1.84
rounds to 1.8.
If the digit to be removed is ≥5, the preceding digit is increased by 1. For example, 1.85
rounds to 1.9.
GLOSSARY
Approved By
Signature of a qualified individual (supervisor or designee)
indicating that the information documented is complete,
accurate, and acceptable.
Backdating
Backdating is the practice of going back to a previously
completed task that has not been properly initialed and dated
and placing the date that the task was completed on the date
line, as though filling in the date had been done in a timely
fashion. This practice is not allowed in any cGMP document.
Batch
Production
Record
Collection of records associated with the manufacture of a
specific lot of product.
Comment
Any written additions to a document for informational
purposes. All comments must be initialed and dated by the
person writing the addition and may require a verification.
Controlled
Documents
Written approved documents used in association with cGMPrelated activities to ensure compliance with US and
international regulations, as well as company standards.
Cross-out
A cross-out indicates a correction has been made. This is
accomplished by drawing a single straight ink line through
information which has been entered inadvertently or
incorrectly.
Data
The values and information generated by processing,
calculating or transcribing from the raw data. This may include
computer printouts.
Date
The date is the actual day on which information is entered or
printed on a document.
Document
A written or printed form which is used to furnish information
or provide instructions.
Identifiers
Information that serves to identify or describe something, such
as effective dates, lot number, line number, equipment
number, manufacturing or task date, product description,
container numbers, specification number and run number.
Identifiers can usually be retrieved from another source or
document.
Initials
Consist of the first letter of both the first name and the last
name, i.e. surname. Use of the middle initial is optional.
NA or N/A
Abbreviation for the phrase “Not Applicable”. It is used to
indicate that the entering of data into a space provided is not
appropriate in that particular case.
Overwriting
Overwriting refers to writing over previously recorded
information to make a change. Overwriting is never allowed on
any cGMP document.
Performed By
Initials or signature of the person executing an operation or
task. This is usually the “operator” or “analyst”.
Quarantine
The default status for raw materials and packaging components
upon receipt from the supplier and for drug products upon
completion of processing while awaiting evaluation against
identified release criteria.
Raw Data
The actual information obtained from an observation, test,
measurement or activity. This may include computer or
instrument printouts.
Recorded By
Initials or signature of a person documenting information,
results, or readings of an operation. This may be the “operator”.
Reviewed By
Initials or signature of the person examining a task, document
or record in order to confirm its accuracy and completeness,
including checking calculations.
Signature
Consists of at least the initials of the first name and the
complete last name.
Video
Corporate Quality Concepts: cGMP Documentation Practices
Q002
Corporate Quality Concepts: cGMP Documentation Practices
Standard Operating Procedures (SOPs)
SOPs are documents which detail how staff should undertake particular procedures or
processes. These procedures or processes are usually of a general nature, often being
independent of any one pharmaceutical product. Many SOPs fall into one of several general
categories, including:
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SOPs detailing step-by-step operational procedures for specific items of equipment, e.g.
autoclaves, homogenizers, freeze-dryers, pH meters, product labeling machines, etc.;
SOPs detailing maintenance/validation procedures for specific items of equipment or
facility areas, e.g. SOPs detailing CDS (cleaning, decontamination and sanitation) of
clean rooms;
SOPs relating directly to personnel, e.g. step-by-step procedures undertaken when
gowning-up before entering a clean room;
SOPs relating to testing and analysis, e.g. procedures detailing how properly to sample
raw materials or finished products for QC (quality control) analysis, SOPs relating to the
routine sampling and testing of WFI from the ring main system, etc.
Sections of an SOP:
Purpose
Scope
Responsibilities
References
Definitions
Precautions
Materials/Equipment
Procedure
Attachments
History
General Word of Caution
When Writing SOPs: Keep it general!
Only include what is needed so any qualified person can perform the SOP correctly and safely.
Do not list specific brand names, unless necessary (example: equipment). If possible, give
ranges of times and temperatures. No section should ever be omitted or left blank. An entry of
N/A (not applicable) may be included if there is no information to be included in a section.
Purpose: Describes why the SOP exists.
Scope: Defines to whom and to what the procedure applies.
Responsibilities: The person or people responsible for performing and updating the SOP. May
also include the person responsible for overseeing the activities of the SOP
References: Other documents which were consulted during the writing of the SOP as well as
those that should be consulted to perform the SOP. Documents may include manufacturer
manuals and other SOPs.
Definitions: Describe any words, phrases or abbreviations which are specific to the SOP.
Commonly used words, phrases or abbreviations need not be described. For example, do NOT
include pH. This is common terminology.
Precautions: Describes any hazards associated with the procedure or with materials used in
performing the procedure.
Materials and Equipment: Any and all materials and/or equipment that are needed to execute
the SOP.
Procedure: A step by step description of the procedure, organized into subgroups.
Attachments: Lists attachments by name and number. Attachments are all documents that are
necessary to perform the SOP. Typically these include diagrams and drawings.
History: Origin of document.
Steps in obtaining an SOP
1.
2.
3.
4.
SOP is written.
Effective date assigned allowing for time to train personnel.
QA (quality assurance) assigns a document number.
Circulated for review.
5. Approved and signed by QC, QA, operations, and facilities.
6. QA distributes to authorized personnel. Obsolete versions destroyed. Master copy retained.
7. Document becomes effective.
ASSIGNMENT NUMBER 8
DOCUMENTATION, QUALITY SYSTEMS AND GMP (PART 1-SOPs)
WRITING AN SOP
Introduction
You will study a generic or template SOP and an actual SOP and. These will be used to write an
SOP for use of a pH meter.
Background
Following is a generic or template SOP. It starts on the next page. On the next page after the
template, and for the next five pages, is an example of an SOP. Study both the generic/template
SOP and the SOP example.
Company Name:
Document Number:
Revision Number:
Issue Date:
Page:
Document Title:
Supersedes:
New
Document Originator / Reviser:
__________
Signature
Dept.
Date
I have reviewed this document and find it accurate and complete:
Date:
Date:
This document has been approved as a Master Document.
Date:
Quality Manager
This is an OFFICIAL COPY; a true reproduction of the MASTER DOCUMENT. It has
been checked for accuracy and approved for use.
Date:
Issued by:
1.0
PURPOSE:
1.1
2.0
SCOPE:
2.1
3.0
The purpose of this document is to describe in detail the…..
The scope of this document includes…
RESPONSIBILITIES:
3.1
It is the responsibility of the Position Title to:


4.0
5.0
6.0
REFERENCES (RELATED DOCUMENTS):
4.1
Refer to DOC# XX-XXX.
4.2
Refer to DOC#XX-XXX.
DEFINITIONS:
5.1
Definition 1 …
5.2
Definition 2…
PRECAUTIONS
6.1
Precaution 1……
6.2
Precaution 2……
7.0
MATERIALS AND EQUIPMENT:
7.1
Materials:
7.1.1 Chemical 1….. (Lot #, Product #, handling)
7.1.2 Chemical 2…..
7.2
Equipment:
7.2.1 Hardware 1…
7.2.2 Hardware 2…
8.0
PROCEDURE:
8.1
Initial Preparation:
8.1.1 Prepare a ……….
8.1.2 Add the …….
8.1.3 Filter the solution to….
8.2
Primary Steps:
8.2.1 Measure the…..
8.2.2 Adjust the pH to ……
8.2.3 Centrifuge at ___ g or _____ rpm and…
8.2.4 Resolubilize the …..
8.3
Second Treatment to remove remaining contaminants:
8.3.1 The conductivity is ….
8.3.2 Filtration to …
8.3.3 Pass the filtered solution….
6.3.4 Analyze the pass fraction by SDS-PAGE to determine….
9.0
ATTACHMENTS AND EXHIBITS:
9.1
Attachment or Form #:
Title
Number
10.0
HISTORY
A Biotechnology Company
123 Bioscience Drive
Anywhere, US 0007
Document Number: 1.23
Revision Number: 2
Effective Date:
Page 1 of 5
Title: SDS-PAGE SOP
Approvals
Preparer: _________Your Name________________________ Date ________________
Reviewer: ________His Name _______________________ Date ________________
Reviewer: ________His Name _______________________ Date ________________
1. Purpose:
1.1. To describe the appropriate operating instructions to perform SDS-PAGE analysis of
protein samples.
2. Scope:
2.1. Applies to confirming the presence and purity of two recombinant human proteins (tPA
and HSA) produced and purified in the laboratory of A Biotechnology Company.
3. Responsibilities:
3.1. It is the responsibility of the Supervisor to ensure that this SOP is performed as
described and to update the procedure when necessary.
3.2. It is the responsibility of the technicians to follow the SOP as described and to inform
the Supervisor about any deviations or problems that may occur while performing the
procedure.
4. References:
4.1. Invitrogen Novex Gel instructions
4.2. Novex XCell II Mini-Cell Gel Box Operation SOP
4.3. Gel Documentation Instrument SOP
5. Definitions:
5.1. tPA is tissue plasminogen activator.
5.2. HSA is human serum albumin.
6. Precautions:
6.1. Acrylamide is a neurotoxin. Always wear protective gloves when handling the
polyacrylamide gels.
6.2. Fixative solution is flammable – keep away from sparks and flames. Dispose in Fixative
Hazardous Waste bottle
6.3. GelCode Blue is harmful. Dispose in GelCode Blue Hazardous Waste bottle.
7. Materials:
7.1. Protein Samples
7.2. Protein Standard, 4mg/ml: (2– 8C refrigerator)
7.3. Invitrogen Molecular Weight Marker (2– 8C refrigerator)
7.4. NOVEX Precast Gel Box and Accessories
7.5. Power Supply for Protein Electrophoresis
7.6. NuPAGE 4-12% Bis-Tris Gels (1.0mm x 10 well), 2– 8C refrigerator
7.7. NuPAGE MOPS SDS Running Buffer (20X), room temperature
7.8. NuPAGE Antioxidant, 2– 8C refrigerator
A Biotechnology Company
123 Bioscience Drive
Anywhere, US 0007
Document Number: 1.23
Revision Number: 2
Effective Date:
Page 2 of 5
7.9. NuPAGE SDS Sample Buffer (4X), room temperature
7.10. Reducing Agent (10X), -20C freezer
7.11. Graduated cylinders (1L and 100ml)
7.12. P20, P100 or P200 Micropipettor and tips, including gel loading tips
7.13. Microfuge Tubes
7.14. Microfuge
7.15. Boiling Water Bath
7.16. Staining Trays
7.17. Infors HT Labotron mini rotary shaker
7.18. Gel Fixative Solution
7.19. Pierce GelCode Blue Staining Reagent, 2– 8C refrigerator
7.20. Light Box
7.21. Gel Documentation Instrument
8. Procedure:
8.1. Prepare Running Buffer and Staining Solutions
8.1.1. 1L NuPAGE MOPS SDS Running Buffer (1X) (if needed)
8.1.1.1.Place 50ml NuPAGE MOPS SDS Running Buffer (20X) in a 1 Liter
graduated cylinder.
8.1.1.2. Gently add 950ml deionized water by running it down the side of the
cylinder to make 1 liter of 1X NuPAGE MOPS SDS Running Buffer.
8.1.1.3. Add a stir bar and gently stir. NOTE: SDS is a detergent and will
foam if mixed vigorously. We do not want bubbles.
8.1.2. 200ml NuPAGE MOPS SDS Running Buffer (1X) plus antioxidant (if needed)
8.1.2.1. Separate 200ml of 1X NuPAGE MOPS SDS Running Buffer into a
500ml Erlenmeyer flask.
8.1.2.2. Add 500µl of NuPAGE Antioxidant.
8.1.2.3. Add a stir bar and gently stir. NOTE: SDS is a detergent and will
foam if mixed vigorously. We do not want bubbles.
8.1.3. 500ml Fixative Solution (if needed)
8.1.3.1. In a 500ml Wheaton bottle, mix together:
250ml 100% Methanol
215ml deionized water
35ml glacial acetic acid
8.1.3.2. Store at 2– 8C
8.2. Dilute Protein Standards (if needed).
8.2.1.1. Dilute the appropriate protein standard(s) with water to a final
concentration of 1mg/ml
8.2.1.2. Label tube with protein name, 1mg/ml, [date], [initials]. Store on ice
until ready to use.
A Biotechnology Company
123 Bioscience Drive
Anywhere, US 0007
Document Number: 1.23
Revision Number: 2
Effective Date:
Page 3 of 5
8.3. Prepare Protein Samples and Protein Standards
(Do NOT perform this step with the Molecular Weight Marker)
8.3.1. For all the samples and the standards, combine the following in a sterile 1.5ml
microfuge tube: 25ul 4x sample buffer
10ul 10x reducing agent
65ul sample
8.3.2. Mix gently with a pipette by aspirating and dispensing at least 3 times
8.3.3. Boil for 3-5 minutes.
8.3.4. Remove from boiling water bath.
8.3.5. Pulse all samples and standards in a microfuge for 30 seconds.
8.4. Prepare Novex Precast Gel Box
8.4.1. Assemble gel box according to its SOP.
8.4.2. Place 200ml NuPAGE MOPS SDS Running Buffer (1X) plus antioxidant in the
upper buffer chamber (small chamber between 2 gels or the gel and buffer dam)
8.4.3. Fill the lower buffer chamber with approximately 600ml of 1X NuPAGE
MOPS-SDS Running Buffer (large chamber).
8.4.4. Rinse gel wells with micropipettor and buffer from upper buffer chamber.
8.5. Load Samples
8.5.1. Using a micropipettor and disposable tips, load 10ul of the Molecular Weight
Marker into one well and up to 50µl of each sample into separate wells.
8.5.2. Load any empty wells with 15µl of diluted 4X Sample Buffer.
8.5.3. Record order of samples and volumes loaded.
8.6. Run NOVEX NuPAGE MOPS SDS Precast Gel Box
8.6.1. Plug electrophoresis chamber into the gel electrophoresis power supply.
8.6.2. Run gel at 200V for 40 – 60 minutes.
8.6.3. Turn off the power supply when the dye reaches 1cm from the bottom of the gel.
8.7. Stain and Photodocument the NOVEX NuPAGE MOPS SDS Precast Gel
8.7.1. Disassemble gel box per SOP and remove gel from plastic cassette.
8.7.2. Rinse gel box well with DI water. Do not use brushes on the gel box, they scratch
the surface. Do not immerse top of gel box or electrical components.
8.7.3. Place gel in staining tray.
8.7.4. Wash gel 3 times for approximately 5 minutes with DI water at room
temperature on a shaker.
8.7.5. Add enough Fixative solution to cover the gel completely and fix for
approximately 15 minutes at room temperature on a shaker.
8.7.6. Discard Fixative Solution into the Fixative Hazardous Waste bottle.
A Biotechnology Company
123 Bioscience Drive
Anywhere, US 0007
Document Number: 1.23
Revision Number: 2
Effective Date:
Page 4 of 5
8.7.7. Wash gel 3 times for a minimum of 5 minutes with DI water at room
temperature on a shaker.
8.7.8. Add about 50ml of GelCode Blue and stain for 1-24 hours at room temperature
on a shaker.
8.7.9. Decant GelCode Blue into GelCode Blue Hazardous Waste bottle.
8.7.10. Wash gel with DI water for 15 minutes to overnight on a shaker
8.7.11. Remove gel from staining tray and place on visible light box
8.7.12. Identify the protein standards and samples and estimate their molecular
weights. See Molecular Weight Diagram.
9. Attachments:
9.1. Molecular Weight Marker Diagram
10. History:
Name
John Smith
A Person
Her Name
Date
2002
2005
2007
Amendment
Initial Release
Changed Coomassie stain to GelCode Blue Stain
Put into SOP 2005 format
A Biotechnology Company
123 Bioscience Drive
Anywhere, US 0007
Attachment: Molecular Weight Maker Diagram
Document Number: 1.23
Revision Number: 2
Effective Date:
Page 5 of 5
Assignment 8 is an SOP Exercise
Go to the following web page which describes the operation of a pH meter:
http://www.umd.umich.edu/casl/natsci/slc/slconline/PHM/operate.html
Imagine that you are examining the pH meter under laboratory conditions. From the operation of
the pH meter and using the above generic or template SOP and the example SOP as guides, write
an SOP for operation of the pH meter. This is to be used to check the pH of buffers for the
production of a biopharmaceutical. Write up the SOP as if it was the genuine document. Use the
format in the generic/template SOP for the preparer and reviewers’ signatures and acceptance of
the SOP. This would make the document the best possible and would indicate approval by two
reviewers, acceptance by the Quality Manager, and final issuance by the Company. Leave the
signature spaces blank.