1. THE FUNDAMENTALS OF QUALITY ASSURANCE AND VALIDATION
2. IMPLEMENTATION OF VALIDATION3. HOW VALIDATION GETS DONE4. THE VALIDATION MASTER PLAN5. REVALIDATION AND CHANGE CONTROL6. AUDITS
7. PROCESS VALIDATION8. VALIDATION OF PACKAGING9. RECEIPT, HANDLING AND USE OF
MATERIALS10. QUALITY ASSURANCE INVESTIGATIONS11. DOCUMENTATION RESPONSIBILITIES
OF QUALITY ASSURANCE
12. RECALL PROCEDURE13. ELECTRONIC RECORDS14. CORRECTIVE AND PREVENTIVE
ACTIONS
A central concept is that quality cannot be tested for!
◦ Testing programs are based on testing a statistically significant number of samples
However to be absolutely sure that all of your product meets specifications you would have to test everything.
◦ Testing by itself will not insure quality and is inefficient
◦ Testing is required under the GMP’s Raw materials In-process samples Final Product
◦ Quality (identity, safety, efficacy, potency, purity, stability, consistency) must be designed into the production process
◦ Begins with predetermined specifications Raw material specifications In-process material specifications Final Product Specifications
Validation – An Essential Part of GMPs!
Validation is the scientific study of a system To prove that the facility/system/equipment/method is
consistently doing what it is supposed to do (i.e., that the process is under control).
◦ We want to make decisions based on good science and not hunches and assumptions!
To determine the process variables and acceptable limits for these variables, and to set-up appropriate in-process controls.
◦ Is it ok if the wash from a chromatography column is pH 6.8 vs. 7.0 ?
Biomanufacturing is a complex process involving multiple unit operations many of which are critical to insuring patient safety
and product efficacy
InoculumSeed
FermentationProduction
FermentationHarvest
Ultrafiltration1
Chrom. 11
Ultrafiltration2
Chrom. 2
Viral Filtration
Chrom.3
Ultrafiltration3
Final Formulation/
Sterile Filtration
Sterile Fill
UPSTREAM
DOWN-STREAM
VIRAL
NON-VIRAL
Block Flow Diagram of a typical Production Process
A central concept in quality is that quality cannot be tested for. Quality must be designed and built into the production process.
Requires careful attention to raw material specifications, in process material specifications, and final product specifications.
The FDA’s definition of validation:
“Validation is a process of demonstrating, through documented evidence, that a process, procedure, method, piece of equipment, or facility will consistently produce a product or result that meets predetermined specifications and quality attributes.”
Identity
◦ 21 CFR 211.84 (d) at least one test shall be conducted to verify the identity of each component of a drug product.
◦ Chemical, biological, immunological◦ Raw materials, in-process intermediates, final products.
Safety◦ 21 CFR 600.3 (p) safety as the relative freedom from harmful effect to persons affected, directly
or indirectly, by a product when prudently administered, taking into consideration the character of the product in relationship to the condition of the recipient at the time. Activity of active ingredients Activity of the excipients or additives Activity of process related impurities
Efficacy◦ Effectiveness of the product in achieving its medicinal purpose (therapeutic, prophylactic,
diagnostic). Gathered at Phase II and Phase III trials. Potency
◦ 21 CFR 600.3 (s) specific ability or capacity of the product, as indicated by its appropriate laboratory tests or by adequately controlled clinical data obtained through the administration of the product in the manner indicated to effect the given result.
Purity◦ 21 CFR 600.3 (r) relative freedom from extraneous matters in the finished product, whether or
not harmful to the recipient or deleterious to the product. Cleaning Procedures
Stability◦ 21 CFR 211.137 (a) to assure that a drug product meets applicable standards of identity, quality,
and purity at the time of use; it shall bear an expiration date determined by stability testing. Drugs may use accelerated time studies, biologics must use real time studies.
Consistency◦ The ability of the product and/or process to reliably possess specified quality attributes on an
ongoing basis. 3 consecutive batches of product meeting predetermined specifications is accepted as proof that a process is consistent. However, in NDA data from up to twenty batches may be submitted.
Validating the performance of unit operations, analytical methods, and critical process points (sterilization, viral inactivation, cleaning procedures) is essential in ensuring that the process generates a quality product.
Assumptions concerning virus inactivation resulted in ten deaths and 200 children becoming paralyzed, from a supposedly “inactivated” polio vaccine.
Assumptions about sterilization caused severe infections among burn victims given supposedly sterile solutions.
Validation eliminates assumptions and relies on experimental proof!
Validation does not replace testing, but it does reduce the testing burden for raw materials, in-process materials, and final product
Validation itself is a process that evolves with the product.
Validation requirements for production of pre-clinical material much less stringent then for phase III clinical material.
Critical operations: raw materials, analytical methods, viral clearance, sterilization, cleaning.
Some operations are more critical than others. ◦ Viral filtration, sterilization, cleaning, analytical
methods.
◦ These operations will require greater validation efforts then less critical operations (media blending).
How critical is the system being validated to final product quality?
◦ Media blending systems for cell growth vs. final fill & finish operations
Demonstrating that the device which fills, labels, and caps the final product will require more extensive validation then the blenders used to prepare media for bioreactors.
Validation of complex devices can take years!
Proceeds in stages with new facilities / equipment.
Planning for validation should start with the design process.
Leaving validation to the last minute is asking for trouble.
Starts with Design & Receipt:◦ Does the equipment meet the needs (is the autoclave big
enough?)◦ Do you have the manuals, spare parts, can you plug it in? ◦ Is it installed properly (drain lines, vents, etc)
Does it work? ◦ Does the autoclave reach the necessary temp. and
pressure? ◦ Can the autoclave sterilize your equipment (worse case
situation)? How does it work in the manufacturing process?
◦ Can it handle production quantities? ◦ Will failure compromise product quality?
What parameters are critical to sterilization?
◦ Temperatures, pressures, time, pore size (filtration), radiation dosage, chemical concentration.
Must demonstrate that your autoclave reaches the temperatures, pressures, and times necessary for sterilization.
Must demonstrate that items representing real world samples achieve those conditions (20 ft of 1 ½ hose; a 20 L carboy; a 500 ml bottle).
Must challenge with worse case scenario (may take place in pilot plant if scalability demonstrated).
21 CFR 211 Subpart F –Production and Process Controls 211.100 –Written procedures; deviations (a) Requires written procedures for production and process control designed to assure that products
possess the quality attributes that they purport or are represented to possess. (b) Requires that any deviations from written production and process control procedures be
recorded and justified. 211.101 – Change in of components 211.103 – Calculation of yield 211.105 – Equipment identification 211.110 – Sampling and testing of in-process materials and drug products “Requires that control procedures be established to monitor the output and validate the
performance of those manufacturing processes that may be responsible for causing variability of in process material and drug product.”
211.111 – Time limit on production 211.113 – Control of microbiological contamination “Requires that sterilization processes be validated” 211.115 – Reprocessing21 CFR 211 Subpart H- Holding and Distribution 211.165 – Testing and release for distribution “Requires that the accuracy, sensitivity, specificity, and reproducibility of test methods employed
by the firm shall be established and documented. Such validation and documentation may be accomplished in accordance with 21 CFR 211.194 (a)(2)”
21 CFR 211 Subpart I- Laboratory Controls21 CFR 211 Subpart J – Record and Reports21 CFR 820 Quality Systems Regulations
Sec. 211.113 Control of microbiological contamination.
(a) Appropriate written procedures, designed to prevent objectionable microorganisms in drug products not required to be sterile, shall be established and followed.
(b) Appropriate written procedures, designed to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed. Such procedures shall include validation of any sterilization process.
A fully validated process is “locked in” Any change outside of the validated space
invalidates process
Change must be evaluated for effect on patient safety and product efficacy
Validated Production Process
Δ
Monitor
Monitor
Revalidate
ValidateOr
Revalidate
Specific protocols (SOP’s) that provide detailed information on what is to be validated.
Validation Protocols consist of: ◦ A description of the process, equipment, or
method to be validated.◦ A description of the validation method.◦ A description of the sampling procedure
including the kind and number of samples.◦ Acceptance criteria for test results. ◦ Schedule or criteria for revalidation.
Validation Protocols may consist of multiple SOP’s each describing specific steps in the validation process
Starts with Design & Receipt:◦ Does the equipment meet the needs (is the autoclave big
enough?)◦ Do you have the manuals, spare parts, can you plug it in? ◦ Is it installed properly (drain lines, vents, etc)
Does it work? ◦ Does the autoclave reach the necessary temp. and
pressure? ◦ Can the autoclave sterilize your equipment (worse case
situation)? How does it work in the manufacturing process?
◦ Can it handle production quantities? ◦ Will failure compromise product quality?
Installation Qualification (IQ)A process used to document that the piece of equipment was supplied and installed properly and that appropriate utilities, i.e., electrical, steam, gas, etc. are available to operate the equipment according to the manufacturers specifications.
Operational Qualification (OQ)A process designed to supply the documented evidence that a piece of equipment operates as it is intended through all anticipated operational ranges.
Performance (Process) Qualification (PQ)Verifies that a process / piece of equipment performs as it is intended to in the manufacturing process and produces product (in process or final) meeting predetermined specifications.
Example of a protocol for the IQ component of validating apH meter
As with all other SOP’s this document will contain an Objective, Scope, and ResponsibilitySection.
Name and description of equipment, including model numbers
Identification, including model and serial numbers Location of the equipment Any utility requirements, i.e. electrical voltage,
steam or water pressure, etc. Any safety features of the equipment, including
alarms, interlocks, or relief valves. That all documentation, including manufacturers
contact information, spare parts inventory, operational manual, and installation drawings are available on site.
Example of a protocol for the OQ component of validating apH meter
As with all other SOP’s this document will contain an Objective, Scope, and ResponsibilitySection.
O
Example of a protocol for the OQ component of validating anautoclave
As with all other SOP’s this document will contain an Objective, scope, and responsibilitySection.
Objective Responsibility Equipment required (Calibration verification
& Traceability) SOP(s) used Equipment Identification Parameters measured (Specifications) Documentation
Ideally validation takes place prior to actual production runs, however in some cases validation may take place as product is produced, or past production runs may be used to provide validation data.
Prospective Validation
Concurrent Validation
Retrospective Validation
IQ
OQ
Calibration
PQ protocol approval
PQ protocol execution
Data Analysis
Validation Report
Approve Conclusions
Are systems
qualified?
NoCalibrations Correct ?
Data Analysis
Qualify systemCalibrate system
No
Yes
Yes
Approval
UserRequirementsSpecification
(URS)
FunctionalSpecification
Detail Design
Implement/Build
InstallationQualification
OperationalQualification
PerformanceQualification
Related to
Related to
Related to
37
Project PlanAgreed by team membersDetails phases, activities, and milestones Gantt Chart most commonly used
ID Task Name Start Finish DurationJan 2003
1/12 1/19
1 15d1/31/031/13/03Design
5 5d3/28/033/24/03Obtain Funding
6 15d4/18/033/31/03Construct
7 10d5/2/034/21/03Commission
10d6/5/035/23/03Validate
2 10d2/14/032/3/03Prepare Quality Plan
3 5d2/21/032/17/03Prepare URS
4 20d3/21/032/24/03Prepare Project JustificationDocument
Feb 2003 Mar 2003 Apr 2003 May 2003
1/26 2/2 2/9 2/16 2/23 3/2 3/9 3/16 3/23 3/30 4/6 4/13 4/20 4/27 5/4 5/11
9
8
1d6/6/036/6/03Turnover - Project Complete
Putting it all together
39
GoodEngineering
Practice
TheCompliance
Pyramid
Organizations must define an approach towards validation
◦ What is to be validated ◦ How is it to be validated◦ Who is to validate it ◦ Who is to approve the validation◦ When it must be revalidated
Regulatory agencies (FDA, EMEA, WHO, etc) identify minimum components of validation.
“Industry standards” (the c in cGMP) can increase validation requirements.
New & Novel processes / equipment require greater scrutiny then established processes / equipment.
Validation requirements increase as a product moves through development (phase I, phase II, phase III).
The Validation Master Plan
◦ A high level document that outlines the organizations philosophical approach to validation and revalidation. The validation master plan becomes a guideline by which individual validation protocols are developed and implemented.
◦ May contain a flow chart or other diagram of the validation process
Is the initial validation for a piece of equipment the end? ◦ No! ◦ Periodic revalidation may be necessary
depending on the criticality of the equipment◦ Changes need to be evaluated for their impact
on validation◦ Deviations from specifications may require
revalidation◦ Revalidation should be spelled out in Validation
Master Plan
Changes that require revalidation
Software changes; Controllers Site changes; Operational changes Change of source of material Change in the process Significant equipment change Production area changes Support system changes
Must assess impact of changes on FDA compliance and validation state.
Change control is a formal process defined in company SOP on how process/equipment changes are evaluated.
Any change that takes place outside the change control process can jeopardize product quality (patient safety).
VMP should contain change control statement
Policy and procedure
Risk assessment
Authorization
Failure to properly document changes to the
system means invalidation of the process
I. IntroductionII. What is an Audit?
III. What is an Internal Audit?IV. What is an External Audit?V. The Quality Systems ApproachVI. Example of a Quality AuditVII. Medical Device RegulationsVIII.Detecting Potential ProblemsIX. The Audit Program
QUARANTINE
APPROVEDEXPERIMENTAL
REJECTED
COLOR CODING FOR QUARANTINE SYSTEM
CHAPTER THIRTEEN
Purpose
To understand the requirements that apply to records that are created, maintained, archived, retrieved or transmitted in electronic form.
21CFR – Part 11Electronic Records; Electronic Signatures
Electronic Record Inspection
Record-keeping requirements Relevant procedures System security System validation DeficienciesCorrective actionsTechnical personnel training
Trustworthy Reliable Generally paper equivalent Legally binding
21CFR 11.1
Digital Signature (21CFR 11.3(b)(5))- an electronic signature based upon cryptographic methods of originator authentication, computed by using a set of rules and a set of parameters such that the identity of the signer and the integrity of the data can be verified.
Electronic Record (21CFR 11.3(b)(6))- any combination of text, graphics, data, audio, pictorial, or other information representation in digital form that is created, modified, maintained, archived, retrieved, or distributed by a computer system.
Electronic Signature (21CFR 11.3(b)(7))- a computer data compilation of any symbol or series of symbols executed, adopted, or authorized by an individual to be the legally binding equivalent of the individual's handwritten signature.
Handwritten Signature (21CFR 11.3(b)(8))- the scripted name or legal mark of an individual handwritten by that individual and executed or adopted with the present intention to authenticate a writing in a permanent form. The act of signing with a writing or marking instrument such as a pen or stylus is preserved. The scripted name or legal mark, while conventionally applied to paper, may also be applied to other devices that capture the name or mark
Meta Data- Data about data- Gives factual information based on the raw data
Biometrics- Means of identifying individuals based on measurement of the individual’s physical features. Those physical features must be unique to that individual and they must be measurable.
Hybrid Systems - Semi-automated systems using both
electronic and paper-based records Most batch records
Laboratory data, e.g. from chromatography
Legacy System - A system in use and already compliant
with existing standards or regulations prior to the advent of new standards or regulations.
Records and Documents - Protection - Controls - Archiving Access Control - Limited access - Authority checks - ID & Password loss - Breach prevention practices Audit trails - Secure time and date stamp - Technical requirements
System Performance - Operation and use checks - Location check - Device check Electronic Signature - Unique - Linked to records - Actions Training Change Controls &
Procedures Computer Validation Written policies FDA inspection-ready
Closed System RequirementsAccess is controlled by the person responsible for the content of the record
21CFR 11.10
Open System RequirementsAccess is not controlled by the person responsible for the record’s content
21CFR 11.30
Maintained in electronic format in place of paper format
Maintained in electronic format in addition to paper format and relied upon to perform regulatory activities
Submitted to the FDA in electronic format Affecting electronic signatures intended to
be the equivalent of handwritten signatures
Provide measures to assure: - Distinct identification components - Limited access by authorized persons - Genuine owner use - Detection of unauthorized use - Prompt reporting of use - Breach controls
Provide controls: - Distribution - Revision - Access - Use
NetworkSystem
PC
PC
PCExternal
PC
Procedures to ensure accurate retrieval throughout retention:
- Limited access - Secure data - Printable data - Archived audit trail - Meta data storage - Preferred XML file format - Data migration plan
Batch records Maintenance records Laboratory records Training Procedures Financial Legal Other predicate rule documents
•Use the same retention times as used for
hardcopy documents.•Test the system
periodically.
Identification Password Individual accountability and responsibility
Biometrics - Thumb scan - Retina scan - Voice recognition Without biometrics - ID Code - Password
Confirms log-in authorization for the transaction
21CFR 11.10(g)
Data File orSystem Access
Authority C
heckAuthority Check
Provide periodic checks, recalls and revisions Unique Lock out Time out ID and password inactivation Prevent alterations Unauthorized use detection and reporting Breach reporting and investigation Audit trail continuity
Security: unique to one identified individual Legally binding equivalent of hand-written
signature FDA certification of electronic signature
21CFR 11.100
Limited Access Authorized Individuals Qualified Persons Security Individual Accountability Consequences of Violation
Management
Design Controls Production &Process Controls
Corrective & Preventive Actions
MaterialControls
Equipment &Facility ControlsRecords,
Documents, &Change Controls
Controls
Corrective Action
Action taken to eliminate the causesof an existing non-conformity, defect
or other undesirable situation inorder to prevent recurrence.
[ISO 8402]
“Correction” refers to repair, rework, or adjustment and relates to the
disposition of an existing non-conformity
“Corrective action” relates to the elimination of the causes of non-conformity [ISO 8402]
• Correction: Devices returned because of out-of-box failures are repaired and put back into inventory• Corrective action: Defective components damaged by ESD
(electrostatic discharge) during assembly caused out-of-box failures. ESD controls instituted; operators are
trained in ESD controls
Action taken to eliminate the cause of a potential non-conformity, defect, or other undesirable situation in order to prevent occurrence [ISO 8402]
SPC (Statistical Process Control) charts indicate process is drifting toward upper limit for diameter of injection molded part. Investigation determines cause of drift is wear to mold. Replace mold, and verify/validate that process yields parts meeting specifications.
Correct (“correction”) nonconforming product and other quality problems
Prevent recurrence (“corrective action”) of nonconforming product and other quality problems
Eliminate the cause of potential (“preventive action”) nonconforming product and other quality problems
1. ID existing problems (Corrective Actions) – Quality data sources are identified– Data from sources are analyzed
2. ID potential problems (PreventiveActions)– Quality data sources are identified– Data from sources are analyzed
3. Data challenge– Complete– Accurate– Timely
4. Statistical and non-statistical techniques– Detect recurring quality problems– Results of analyses
» compared across different data sources
» identify and develop extent of problems
5. Appropriate action taken6. Actions
– Were effective– Were verified or validated– Do not adversely affect the finished device, pharmaceutical or biologic
7. Actions– Implemented– Documented
8. Information dissemination– Individuals directly responsible for
» assuring product quality» prevention of quality problems
– Management review