Gap Analysis 4d6yj

Presented By: Aris Koumandaros IVT’s 2nd Validation Week Canada, May 14 to 16, 2013 Toronto

Outline  Plan for a Successful Gap

Analysis  Assess Current Company Position  Develop an Implementation Plan for Correcting Deficiencies  Interactive Exercise

Definitions Audits versus Gap Analysis Reasons for Conducting a Gap Analysis Gap Analysis Preparation Plans

Gap Analysis & Audits Gap Analysis

Audit

 A technique that compares a

 An audit is a systematic,

company’s existing state to its desired state (as expressed by its long-term plans) to help determine what needs to be done to remove or minimize the gap. [Source: Christensen, Eldon H., Kathleen M. Coombes-Betz, and Marilyn S. Stein. The Certified Quality Process Analyst Handbook, ASQ Quality Press, 2007]

independent and documented process for obtaining audit evidence and evaluating it objectively to determine the extent to which audit criteria are fulfilled. [Source: ISO 19011:2011 Guidelines for quality and/or environmental management systems auditing]

Audit versus Gap Analysis  Audits  An independent review  Decisions based on a sample of data reviewed  Limited scope and time  Assess compliance or lack of compliance to an accepted standard

Audit versus Gap Analysis  Gap Analysis  Detailed review, identify gaps in a program  Identify opportunities for improvement, going beyond compliance  Wider scope, examining greater number of records  More collaborative, open environment

Why Audit?  Ensure compliance with company requirements  Ensure compliance with regulatory requirements  Ensure the quality system is effectively implemented

and maintained  Identify opportunities for improvement

Why Conduct a Gap Analysis?  Identify compliance issues and improve the quality

system  Proactive response  Continuous quality improvements  Reactive response to an internal or corporate audit or

regulatory audit  Response to serious regulatory findings (FDA warning letter) 

For example, conduct a gap analysis between the updated “Process Validation” procedure and the validation documentation associated with the equipment

ISO 9000 Quality Management Principles  Principle 4—Process Approach  A desired result is achieved more efficiently when activities and related resources are managed as a process  Principle 5—System Approach to

Management  Identifying, understanding, and

managing interrelated processes as a system contributes to the organization’s effectiveness and efficiency in achieving its objectives. [Source: ANSI/ISO/ASQ Q9000-2000]

Gap Analysis Process Process—A group of interrelated activities and related resources that transforms inputs into outputs

Input •Policy & Procedures •Records

Gap Analysis •Resources & Management (Inputs)

Output •Reports •CAPAs, CCRs

Gap Analysis Methodology  Assess current system &

practices  Identify weaknesses  Compare to best

practices

 Determine priorities  Risk-based prioritization of tasks  Develop an

improvement plan  CAPA, Change Control

Gap Analysis Preparation Plans  Define Objective  What do you want to achieve with the gap analysis?  Define Scope  Identifies the items & activities to be examined  Define Team  Functional & Multi-functional teams  Define Standards/Requirements  Develop a technical understanding  Develop a Checklist

Preparation for a Gap Analysis  Read policies and procedures  Determine what has been established in comparison to the requirements  Create questions, addressing 3 general conditions  Procedures established & meet requirements?  Procedures implemented?  Management adequate to procedures?  Create a sampling plan for collecting information  Training is up-to-date for personnel involved in process  Training in gap analysis process  Knowledge of documenting gaps  Know the requirements (policies, procedures, regulations)

Regulatory requirements Elements of a validation program FDA citations relating to validation

Validation Program  Extent of qualification /

validation & level of detail  Based on risk associated

with product quality and patient safety  Complexity and novelty of the systems  Considerations regarding the integrity of the data

Validation Program Prerequisites  Have a quality system in place  Investigate root causes  Assure effective corrective & preventative actions  Implement effective change control  Validation s the FDA quality systems approach  Quality System  Laboratory Controls System  Facilities & Equipment System  Materials System  Production System  Packaging & Labeling System

Validation Program Prerequisites (cont.)  Principles for quality assurance involved in

validation  Quality, safety, effectiveness must be designed and

built into the product  Quality cannot be tested into the finished product  Each step of a manufacturing process must be controlled to ensure the finished product meets specifications

 Adequate personnel with the required experience,

knowledge and training

Regulatory Requirements (FDA)  Part 211 Subpart D – Equipment  Sec. 211.68 Automatic, mechanical, and electronic equipment  Part 211 Subpart F – Production and Process

Controls  Sec 211.100 Written procedures; deviations  Sec 211.110 Sampling and testing of in-process

materials and drug products  Sec 211.113 Control of microbiological contamination

 Part 211 Subpart I – Laboratory Controls  Sec 211.165 Testing and release for distribution

Regulatory Requirements Health Canada  C.02.004, Premises

 C.02.014, Quality Control

 C.02.005, Equipment

 C.02.015, Quality Control

 C.02.007, Sanitation

 C.02.018, Finished Product

 C.02.009, Raw Material

Testing  C.02.024, Records  C.02.027, Stability  C.02.029, Sterile Products

Testing  C.02.011, Manufacturing Control  C.02.012, Manufacturing Control

Elements of a Validation Program  Equipment Qualification

 Aseptic Operations

 Utilities Qualification  Computerized System



Validation  Process Validation  Cleaning Validation

  

Qualification Analytical Methods Validation Sterilization Validation Filter Validation Integrity Closure Testing Validation

Quality Systems Model  Management Responsibilities  Validation plans, procedures, personnel  Resources  Qualification/validation, training  Manufacturing Operations  Define critical parameters, data collection, addressing deviations  Evaluation Activities  Trends, risk management, CAPA

[Source: FDA, Quality Systems Approach to Pharmaceutical CGMP Regulations, 2006]

SOPs

Records

Training

Validation Equipment/Systems  Quality System  Document Management System  Complaints System  Change Management System  Laboratory Systems  LIMS  HPLC  Materials Systems  SAP  Dispensary Systems

 Production System  MRP II  Sterile Filtration  Packaging/Labeling Systems  Artwork Systems  Packaging Equipment  Facilities/Equipment Systems  Building Automation System  Purified Water System

Validation Documentation  Validation Policy  Validation Planning  Validation Master Plans  Validation Plans  Specifications  Requirements Specification  Functional Specifications  Technical Specifications

Validation Documentation (cont.)  Validation / Qualification

Protocols & Reports  Facilities, Utilities, Equipment  Computerized Systems Validation  Cleaning Validation  Process Validation  Test Method Validation  Sterilization Validation  Filter Validation  Standard Operating Procedures & Work Instructions  Operational  Cleaning  Maintenance

Revalidation Program  Sterilization &         

Depyrogenation processes Steam-in-Place Equipment Qualification Computer Validation Utilities Environmental Validation Aseptic Processes Analytical Test Methods Process Validation Cleaning Validation

Maintaining the Validated State  Change Control Management  Preventative Maintenance  Calibration  Corrective & Preventative Action Plans  Statistical Process Controls  Management Reviews

Systematic approach to determining gaps in a validation program FDA citations related to validation

Techniques for Assuring a Complete Gap Analysis  Include all system elements

 Examine all functions at all

elements  Use checklists to assure that requirements are reviewed

Gap Analysis Approaches  “Horizontal” gap analysis  Assessment of one system/process across several functional groups  “Vertical” gap analysis  Assessment of each function (department) and conduct gap analysis of all processes in each function

Developing Checklists  Develop questions based on the

requirements  Open questions; closed questions

 Aid in documenting assessment of

current practices  Adequacy, suitability,

effectiveness, compliance

 Possible answers to each question  Meets requirements; does not meet requirements; partial requirement met; not applicable

“I have six honest serving men. They help in all I do. Their names are: Where, What and When, How, Why, and Who.” --Rudyard Kipling

Checklist Question Examples  Does the company have a Validation    

Master Plan (VMP)? Does the document meet the company requirements for layout and format? Does the creation, review, approval and control of the VMP comply with the procedure for master GMP documents? Does the VMP clearly state the requirements for validation documentation management? Does the VMP provide details of the overall expected timescales and activities associated with validation of equipment, utilities and systems?

Possible Quality Tools  Checklists  Flowcharts  Matrix diagrams  Pareto Analysis  Histograms

Gap Analysis Results  Classification of gaps  Critical  Major  Minor  Validation Requirement Matrix  Demonstrates regulatory requirements met  Tracking system for gaps  CAPA system

CAPA Concepts  Remedial corrections of an

identified problem  Root cause analysis with corrective action  Preventive action

CAPA Process  Analyze process  Investigate  Identify corrective and

preventative actions  Validate corrective and preventative actions  Implement corrective and preventative actions  Evaluate effectiveness

Aftermath of a Gap Analysis  Documenting results of the gap

analysis

 Final report  Worksheet

 Report Format  Executive Summary  Objective  Scope  Responsibilities  Gap Analysis Design  Results & Discussion  Conclusion  Recommendation

Barriers to a Successful Gap Analysis  Insufficient management    

involvement Inadequate resources to perform the task Inappropriate assignment of personnel Unreasonable schedule Inadequate follow-up to CAPA plans

FDA Warning Letter Citation “Plans were put in place 12/1/94 to validate the processes in the Chemical Manufacturing Operations (CMO)... However, the CMO production summary indicates that since 1/98 CMO routinely manufactured most of the major products scheduled for validation. Our investigators spoke with selected of management and the CMO validation staff about the number of projects scheduled versus the number of employees in that Department. The Department currently has seven employees... This department is responsible for all process, cleaning, equipment validation, validation change controls, and all the corresponding reports, data and protocols. This seems like an inadequate number of trained employees... We feel that the lack of adequate staff to perform validations has likely contributed to the slow progression of validation activities over the past few years...”

FDA Inspectional Observation “Your firm’s CAPA procedure allows corrective and preventive actions to remain uninitiated for prolonged periods of time. For example, CAPA 12307 was opened on 10/8/09 as a preventive action to identify gaps in your firm’s previously executed equipment cleaning validations. A Cleaning Validation Gap Analysis status report identifying deficiencies in these cleaning validations was issued in April 2010. This report recommended that a Master Cleaning Program be written... On 2/2/11, 10 months after the cleaning validation deficiencies were identified, another CAPA, 37944, was opened to create a Cleaning Validation Master Plan (CVMP)... The CVMP... was approved in July 2011, more than 15 months after cleaning validation deficiencies were identified.”

Management Review of a Validation program  Review effectiveness of the validation

program    

Internal & corporate audits Investigations Change controls Annual product reviews

 Review gap analysis  Follow-up on CAPAs  Ensure timely actions taken  Review metrics  % critical/major/minor gaps  % requirements met

FDA Citations Related to Validation  Part 211 Subpart B – Organization

and Personnel  Sec. 211.22 Responsibilities of

quality control unit

 Part 211 Subpart D – Equipment  Sec. 211.63 Equipment design, size, and location  Sec. 211.67 Equipment cleaning and maintenance  Sec. 211.68 Automatic, mechanical, and electronic equipment

FDA Citations Related to Validation  Part 211 Subpart J – Records and

Reports  Sec. 211.192 Production record

review  Sec. 211.194 Laboratory records

 Part 211 Subpart C – Buildings and

Facilities  Sec. 211.42 Design and construction

features  Sec. 211.46 Ventilation, air filtration, air heating and cooling

FDA Citations Related to Validation  Part 211 Subpart E – Control of

Components and Drug Product Containers and Closures  Sec. 211.94 Drug product

containers and closures

 Part 211 Subpart I– Laboratory

Controls  Sec. 211.160 General

requirements  Sec. 211.165 Testing and release for distribution

FDA Citations Related to Validation  Part 211 Subpart F – Production

and Process Controls  Sec. 211.100 Written procedures;

deviations  Sec. 211.110 Sampling and testing of in-process materials and drug products  Sec. 211.111 Time limitations on production  Sec. 211.113 Control of microbiological contamination

FDA Warning Letter (21 CFR 211.22)  There were numerous and significant discrepancies in the

Process Validation Report, which was approved by Quality. For example, the results documented in the report conflicted with the sterilization cycle descriptions outlined in the report.  The “Validation Policy” procedure was not followed when a change was made to the manufacturing process. A planned deviation changed the tank mixer speeds and mixing times used to make the batch of suspension product. The Validation Department did not determine if the modification was major or minor as per procedure. In addition, the Validation Department did not address the need to do additional testing to assure the product was equivalent to that made by the validated process.

FDA Warning Letter (21 CFR 211.22)  An investigation of the test procedure for the impurity test

method conducted by the Quality Control Director revealed that the procedure was unreliable and concluded that the method should be revalidated. Despite this finding, the Quality Control Director did not implement any corrective actions to remedy this deficiency. Your QCU was aware of these issues and took no corrective and preventative action with respect to the product on the market.  There was inadequate oversight of the media fill process. Furthermore, the responsibility section of the “Validation of Aseptic Manufacturing and Filling Process Using the PST” procedure makes no mention of the quality control unit having an active role in the oversight of media fill studies.

FDA Warning Letter (21 CFR 211.22)  Your quality procedure (i.e., Responsibility of the

Quality Group) states that the Quality Group shall have the responsibility and authority to direct all operational groups with respect to compliance with all CGMP requirements. However, your Quality Group:  Failed to establish valid test methods for raw materials

and drug products that assure components and drug products conform to appropriate standards of identity and strength prior to release.  Approved the validation of test method even though the ruggedness and robustness elements do not meet the acceptance criteria.

FDA Warning Letter (21 CFR 211.63)  You have not qualified the performance of manufacturing

equipment, including a lack of installation qualification, operation qualification and performance qualification of your autoclave, laminar flow hood, compounding equipment and fillers.  Your firm failed to ensure your water system was of

adequate design. Your firm also has not performed a formal validation of the purified water system, although you collected data that indicates your firm is now apparently producing purified water of adequate quality for your products.

FDA Warning Letter (21 CFR 211.63)  The calibration of thermocouples (TCs) used during the

validation of your terminal steam sterilizers is not performed before or after the autoclave cycles... The calibration of these TCs provides assurance of an accurate reading of the temperature in the sterilizer.  Our review of the equipment qualifications for multiple automated Tablet Testing System (TTS) machines, used to conduct in-process tablet testing (weight, hardness and thickness) revealed that performance qualification was not conducted to ensure the accuracy of the machine at the various available speed settings.

FDA Warning Letter (21 CFR 211.63)  The re-qualification of the... did not have clearly

defined acceptance criteria. In addition, there was no discrepancy report to explain why equipment drawings, equipment schematics, equipment manuals, and purchase orders were not available, what steps had been taken in an attempt to obtain these materials, and why the re-qualification was acceptable without this information.

FDA Warning Letter (21 CFR 211.67)  No documented evidence exists to demonstrate the

effectiveness of cleaning methods and agents used in cleaning of all production equipment and utensils to ensure that residues have been reduced to acceptable levels. Cleaning validation is limited to only glassware. Additionally, your firm failed to conduct investigation(s) of out of specification results obtained during the cleaning validation for lyophilization trays. There is no cleaning validation for screens or wire electrodes that have product during lyophilization.

FDA Warning Letter (21 CFR 211.67)  Your firm lacked adequate evaluation of possible migration

of potent compounds throughout the facility. Specifically, the cleaning validation study... was inadequately performed in that recovery studies have not been performed on material coupons (samples of materials used for wall coverings, countertops, ceiling, and stainless steel) to demonstrate the ability to recover cytotoxic products from surfaces and equipment used in production as required by the protocol... Also, the sampling records failed to show time of sampling, and the area cleaning records failed to show the time of cleaning. Finally, the sampling locations were not defined and evaluated as possible worst case locations.

FDA Warning Letter (21 CFR 211.67)  Your cleaning validation was limited to the cleaning

process of a plastic 55-gallon drum used in the manufacture of Hydroquinone Skin Lightening Formula. You have not established an adequate rationale, including determining whether this product is the most difficult product to clean. The validation also does not include other equipment used in the manufacture and packing of this product.  Layers of chemical powders were observed covering the lids of mixing tanks and equipment. Cleaning procedures have not been validated to assure the adequacy in preventing contamination.

FDA Warning Letter (21 CFR 211.67)  Cleaning validation involved testing for residues of the

cleaning compound but not for residues of the various products for which the beakers, stir bars, and homogenizer had been used.  Disposable silicone tubing sets are cleaned with isopropyl alcohol and distilled water between uses and then reused to fill liquid oral drug products. There is no documentation that your firm performed studies to ensure, for example, that this cleaning procedure (a) is sufficient to effectively remove residues of the drug product from the tubing and (b) does not adversely affect the quality of the tubing for its re-use.

FDA Warning Letter (21 CFR 211.68)  The process control computer monitoring system that

is used to monitor various production and processing operations (e.g., operation conditions, equipment and component status, historical trending of collected data) is not validated to the current corporate standards.  Your firm’s laboratory analysts have the ability to access and delete raw chromatographic data located on the ... used to conduct HPLC testing. Due to this unrestrictive access, there is no assurance that laboratory records and raw data are accurate and valid.

FDA Warning Letter (21 CFR 211.68)  Your firm’s custom software for your Master Batch

Production record, referred to as the “I-131 Database”, has not been validated. This software is responsible for generating the batch production record, performing calculations to produce varying concentrations of drug product, and generating label information for customer vials.  The accuracy of calculations performed by the Spectrophotometer has not been verified.

FDA Warning Letter (21 CFR 211.68)  The initial qualification for the Cutting and Packaging Machine was

completed on June 7, 2007. Approximately 25 major and minor changes were implemented between June 14, 2007, and July 15, 2010, before your approval of the re-qualification report for the equipment.  The data acquisition system for the UV/Visible spectrophotometers allows your analysts to modify, overwrite, and delete original raw data files. The spectrophotometers are used for dissolution testing of finished product, stability samples, and process and method validation studies. All laboratory personnel were given roles as Managers, which allowed them to modify, delete, and overwrite results files. This system also does not include an audit trail or any history of revisions that would record any modification or deletion of raw data files. Your laboratory computer system lacks necessary controls to ensure that data is protected from tampering, and it also lacks audit trail capabilities to detect data that could be potentially compromised.

FDA Warning Letter (21 CFR 211.192)  You failed to investigate environmental monitoring data

recorded in your aseptic processing suite, which failed to meet your established limits... You have not investigated the cause of the environmental monitoring results that exceeded the limits on your “Performance Qualification Data HVAC Validation” and “Routine Environmental Monitoring” worksheets, nor have you justified your assessment of the product impact caused by those excursions.  Your investigation regarding the media fill failures for eye wash aseptic filling suite is inadequate because it was attributed solely to improper aseptic techniques during the filling operation without scientific justification to this conclusion.

FDA Warning Letter (21 CFR 211.192)  Low OOS assay results for... were noted in mixing samples

during process validation of... A clearly assignable cause for the OOS result was not found. Your firm prepared samples again and retested the lot. Only the ing retest results were reported.  Out-of-limit (OOL) results obtained during the in-process fill weight examination for validation batches were not investigated. Specifically, you reported 31 in-process fill weight OOL results for validation batch..., while reporting 11 and 3 OOL results for batches..., respectively... In addition, the batch record does not contain any evidence that you evaluated the in-process results to determine the impact of the out-of-limit fill weight results in product quality.

FDA Warning Letter (21 CFR 211.194)  Your firm has not evaluated the HPLC method used in

assaying Cetylpyridinium Chloride in Tech 2000 Dental Rinse, to assure that it meets proper standards of accuracy and reliability, or that the test method was verified under actual conditions of use. Identification and assay methods for Cetylpyridinium Chloride Topical Solution are contained in the current revision of the United States Pharmacopoeia.

FDA Warning Letter (21 CFR 211.42)  There is no documentary evidence of in-situ air pattern

analysis (e.g., smoke studies) conducted at critical areas to demonstrate unidirectional airflow and sweeping action over and away from the product under dynamic conditions. Your firm failed to demonstrate that the appropriate design and controls are in place to prevent turbulence and stagnant air in the critical area. It is essential that you evaluate airflow patterns for turbulence that can act as a channel for air contamination. The studies should be well documented within written conclusions, and should include an evaluation of the impact of aseptic manipulations (e.g., interventions) and the equipment design.

FDA Warning Letter (21 CFR 211.42)  Your firm’s cleaning validation studies demonstrate the

selected cleaning agent is not effective on spore forming microorganisms. However, spore forming microorganisms have been detected in the environmental monitoring samples, personnel monitoring samples, and sterility test samples of final product.  Disinfectant effectiveness studies against representative microorganisms and/or specific in-house isolates were not conducted for cleaning agents used in your facility to disinfect production areas, including aseptic areas.

FDA Warning Letter (21 CFR 211.42)  For parenteral operations, smoke studies were not

conducted to demonstrate unidirectional airflow and sweeping action over and away from the product under dynamic conditions during numerous aseptic operations in classified areas of the vial filling facility. For example:  Various manual operations performed with the... such as

dispensing sterile API and connecting equipment to this... were not included in smoke studies.  Other significant manual aseptic activities that can affect airflow, including opening and closing the fill equipment access s during routine aseptic filling operations, were not evaluated in smoke studies.

FDA Warning Letter (21 CFR 211.46)  API products sold as dry powders are manufactured in

a suite... solution drug product is manufactured. There have been no studies showing whether contamination of the solution drug product by the dry powders cannot occur when doors to the manufacturing suites are opened at the same time. The air handling system, including the air filters and filter combinations, have not been qualified to demonstrate that the drug product does not become contaminated with the dry powders. There are no diagrams showing the flow of air through the rooftop vents, fans, and air return units.

FDA Warning Letter (21 CFR 211.94)  Your unfilled vial depyrogenation process has not been

demonstrated to provide a 3-log reduction in bacterial endotoxins for 3cc and 10cc vials, which represent all vial sizes that are aseptically filled in your facility. You have never performed quantitative recovery studies from 3cc and 10cc vials. Additionally, you did not document that the applied endotoxin solution was allowed to air dry. Therefore, you have not demonstrated that the worst-case conditions were challenged to validate depyrogenation of all vial sizes that are aseptically filled at your facility.

FDA Warning Letter (21 CFR 211.160)  Your firm failed to prove that the methods used to perform

the bacteriostasis and fungistasis tests on Povidone-Iodine Gel Swab Sticks are equivalent to or better than the USP methods. The test methods used to evaluate the inhibitory effects of the Povidone-Iodine on the ability of the ... to microbial growth lacked the requirements to use... as part of the validation test as well as adequate incubation times and temperatures.  The validation data for several laboratory methods was incomplete or unavailable (i.e. total viable aerobic count for the API, total viable aerobic plate count of raw materials, and bacterial endotoxin testing for... However, you approved the validation for these methods without the complete data in place.

FDA Warning Letter (21 CFR 211.160)  During cleaning validation of the ... the specification

was a maximum of ... micrograms per swab and the result was 41.9 micrograms per swab . The cleaning validation was not repeated and the cleaning procedure was not changed until after the inspection.  The biological indicators are not stored in accordance with the manufacturer’s requirements for temperature and relative humidity.

FDA Warning Letter (21 CFR 211.165)  Your firm failed to validate the specificity of the test

procedures used to analyze finished product stability samples to ensure that the methods are stability-indicating. For example, your firm determined the content of salicylic acid in... stability samples by titration. Your firm has not demonstrated the specificity of the method for degradation products. The method may not allow you to detect the presence of degradation products that may indicate deterioration of the drug product.  Your firm employs a microbial limits test for Total Aerobic Count (TAC) and Total Yeast and Mold (TYM) that differs from the compendial procedure outlined in USP <61> and has not validated the altered method.

FDA Warning Letter (21 CFR 211.165)  Failure to use fully validated computer spreadsheets to

calculate analytical results for in-process and finished product testing. For example, the computer spreadsheets used to calculate analytical results for... have not been validated.

FDA Warning Letter (21 CFR 211.100)  Lot #79298AF00 was one of the batches included in the process

validation study for this product. This lot was not produced using the manufacturing process discussed in the validation study protocol. Lot #79298AF00 was subjected to several reconditioning steps, due to particulate contamination, that were not listed in the master batch record. Some of the actions taken with respect to this lot, such as the hand pouring of the granules from a drum ... were steps that were performed for the production of the two additional lots used in the validation study.  Three initial process validation batches failed the dissolution test specification... Your investigation concluded that the dissolution results were affected by the order in which the excipient... was added during the... process. Appropriate process design studies were not conducted to scientifically establish the correct order of adding excipients... to ensure proper dissolution of the drug product.

FDA Warning Letter (21 CFR 211.100)  Your manufacturing process, has not been validated for repeated

changes to the drying time parameter of the oven dryers in the... granulation. The changes were implemented in an attempt to ensure granulation is not too dry without establishing a minimum specification and without an assessment of product quality.  You conducted validation with batches of 1,550,000 tablets. For subsequent lots, you scaled up to 2,400,000 tablets, then 3,500,000 tablets... The manufacturing instructions in all Master Batch Records had identical blending times of... even though the batch size was increased... Your firm failed to provide validation protocols that evaluated the impact of the increasing batch sizes on product quality. You failed to conduct a study to demonstrate at what point each batch size is uniformly blended. You have not conducted any analysis comparing data between your validation batches.

FDA Warning Letter (21 CFR 211.100)  Written procedures do not define how process validation

will be conducted or documented.  No written validation plan or written validation protocols were available at the time of the inspection.  Your firm has failed to validate a number of procedures and processes used in the manufacture of your drug products. Specifically, your firm does not have data to that the mixing times used for bulk drug products are adequate to produce homogeneity. Further, you have not provided any data to demonstrate that your bulk drug products can be stored for extended periods of time under ambient conditions without altering their identity, strength, quality, and purity.

FDA Warning Letter (21 CFR 211.100)  The process validation conducted for Fentanyl

Transdermal System is inadequate in that your final process validation report failed to include and evaluate the impact of all the combined deviations that occurred during process validation. The report failed to include such deviations as (1) the discovery of brown particles in a laboratory sample of Fentanyl Adhesive Mass Solution, (2) aborting the cutting/packaging operations during the first process validation lot due to a broken cutting and packing machine, and (3) setting of the IR gauge value below specification during the coating process for the first validation lot.

FDA Warning Letter (21 CFR 211.110)  During the process validation... your firm failed to

reject tablets that were Out-of-Specification (OOS) for hardness.  Your firm does not have data to the temperature range of... used during the granulation process... During the validation studies for the granulation process, your firm established a temperature range of... Your process validation study does not provide any data to the process range allowed in the Master Batch Records.

FDA Warning Letter (21 CFR 211.110)  The manufacturing process does not include in process controls

to monitor and confirm that the filtration step is effective. We note that your complaint investigation for particulate matter in two bottles of... concluded that “the subject particles present in the complaint sample are inert organic sediment,” and you have not provided ing documentation to confirm the conclusion.  Your process validation, which consists of compounding, vial washing/depyrogenation, filling, capping, sterilization, and visual inspection resulted in a high vial rejection rate . Additionally, a lack of non-viable particle (NVP) monitoring with out-of-limit (OOL) results was reported, as well as fill weight discrepancies. This is all an indication of deficient process controls in a non-validated manufacturing process.

FDA Warning Letter (21 CFR 211.111)  Your firm has not validated your bulk or process hold

times assigned for most products... The assigned... hold time limits for solutions and... day limits for suspensions are largely uned. Your firm also lacks data to the adequacy of your process hold times even though some of your products contain... that are known to be absorbed by your hoses.  Your firm has failed to provide a justification for the hold times... used in current batch records for sterile ophthalmic eye drop products.

FDA Warning Letter (21 CFR 211.113)  Your firm has failed to conduct a media fill representative

of the different packaging configurations of your drug products for the past two years. Your firm has been using a volume of... for media fills; however, commercial products are available in... In addition, you have not established maximum aseptic fill duration.  Your firm’s qualifications of the Getinge Model 4300 autoclave and the Grieve CLE-500 oven are inadequate in that you have not qualified this equipment with representative loads. Your firm’s practice is to qualify the equipment using minimum loads as opposed to actual loads during routine operation (e.g., Grieve CLE-500 oven was qualified to depyrogenate glass vials using... tray when the actual load is a maximum of 60 trays).

FDA Warning Letter (21 CFR 211.113)  You have not conducted bacterial filtration retention

validation for all of your aseptically filled products.  Your firm failed to adequately document air flow (smoke) studies to demonstrate unidirectional airflow under dynamic conditions. Your firm’s air flow patterns procedure lacked specific acceptance criteria. Your airflow study documentation included hand drawings that provided insufficient information to determine whether HEPAfiltered air used in the manufacturing area (and sterility test laboratory) robustly sweeps away particles and maintains unidirectional airflow protection under dynamic production conditions.

FDA Warning Letter (21 CFR 211.113)  Your firm’s purified water system that provides water for

the production of liquid and semisolid drug products has not been validated to show that it produces water that meets the necessary specifications for objectionable microorganisms with sufficient consistency to justify the sampling frequency employed.  Steam sterilization cycles for the... lack adequate validation. There was no justification provided for selection of the worst case maximum load for the PREVAC1 used for sterilization of aseptic manufacturing equipment loads and terminally sterilized drug product equipment loads. Furthermore, a minimum load was not established.

Closing Remarks  Going beyond traditional

internal audits

 Identify all deficiencies to

be corrected on a systemic level

 Planning the gap analysis

is the key to a successful validation program  Leads to continuous

improvements

 Practice is the path to

improvement

 Review lessons learned

Questions?  Before Proceeding to the

Group Exercises...

Thank you for your attendance!  Information:

[email protected]  LinkedIn:

http://ca.linkedin.com/in/ariskoumandaros  Next Step: Interactive Exercises

Section 1 : Group Discussions Section 2: Gap Analysis—Equipment Qualification Program

Group Discussion  Validation Requirements on Like-for-Like

Changes  During review of the maintenance records as part of the

gap analysis, you noted the following like-for- like changes (same model replacement):  Replacement of the vacuum pump in the Sterilizing Autoclave  Replacement of the water distribution pump in the RO Water

System  Replacement of Mixer Motor

 As per company policy, like-for-like changes do not

require revalidation. Is this a gap?  What is the extent of validation required, if any, in the above situations?

Gap Analysis: Equipment Qualification Program Purpose: This gap analysis is intended to assess the company’s current equipment qualification program as compared to regulatory requirements and identify gaps between the company’s current practice and the expectations of regulatory agencies.  Identify the scope (and what is not in scope) of the gap

analysis.  Develop a gap analysis checklist. (Consider a minimum of 5 questions based on the scope of this gap analysis).