Wednesday, February 25, 2009

Pointers Inspectors look for during FDA inspection - For CAPA (QSIT)

  1. see that corrective action taken to correct existing product nonconformity or quality problems and Prevent recurrence of the problem
  2. The corrective action should Include explanations for how the firm will meet the requirements for all elements of the CAPA subsystem
  3. Gain working knowledge of the firm's CAPA procedure before beginning evaluation of this subsystem
  4. Have management provide definitions
  5. Assure that there is a method for identification and input of quality data into CAPA system, including information regarding product/quality problems that may require corrective and/or preventive action
  6. Assure the firm has procedures that describe/require input of product/quality problems into the CAPA system.
  7. Analyze product/quality problems to identify those that may require corrective action.
  8. Confirm the firm is routinely analyzing data from
    –Acceptance activities relating to component, in-process and finished device testing
    –Information obtained subsequent to distribution: complaints, service activities, returned products
    –Information relating to concessions, quality records, and other sources of quality data
  9. Determine if the firm is identifying product and quality problems that may require a preventive action
  10. Review if preventive actions have been taken regarding unfavorable trends recognized from the analysis of product and quality information.
  11. Determine if the firm is capturing and analyzing data regarding in-conformance product.
  12. Select one or two quality data sources
  13. Review records to confirm data was entered into CAPA system
  14. Determine whether data is Complete ,Accurate ,Entered into CAPA system in timely manner
  15. Determine which statistical and non-statistical techniques are used
  16. Confirm comparison of problems and trends across different data sources to establish a global, and not an isolated view, of a problem.
  17. Confirm that the full extent of a problem is captured before the probability of occurrence, risk analysis and the appropriate corrective or preventive action can be determined
  18. Review procedure for conducting failure investigations
    –Determine if the procedure includes a) Provisions for identifying failure modes b) Determining significance of failure modes c) Rationale for determining if a failure analysis should be conducted as part of the investigation
  19. Discuss with the firm their rationale for determining if CAPA is necessary for an identified trend of product/quality problems.
  20. Select failure investigation records of more than one failure mode and determine if the firm is following their failure investigation procedures.
  21. Confirm that all sampled failure modes have been captured within data summaries
  22. Determine whether the depth of investigation is sufficient to determine the corrective action necessary to correct the problem.
  23. Review incomplete failure investigations for potential unresolved nonconformances and possible distribution of nonconforming product
  24. Review records of nonconforming product where the firm concluded CAPA was not necessary.
  25. Review nonconforming product and quality concessions
  26. Review controls for preventing distribution of nonconforming products.
  27. Review records of the most recent corrective/preventive actions
  28. Determine if corrective/preventive actions for product/quality problems and changes have been documented and implemented
  29. Determine that information regarding quality problems and CAPA has been submitted for management review
  30. Confirm that there is a mechanism to disseminate CAPA information to those directly responsible for assuring product quality and the prevention of quality problems

How to be one step ahead of FDA inspectors and what to do to show what they want to check attend the training

Tuesday, February 24, 2009

Things to look while writing the response after FDA inspection

-Open with a general statement of intent to comply
-Include a commitment to compliance by top management
-Never admit to guilt or characterize 483 citations as “violations”
-Address each and all individual items on the 483
-Indicate root cause and measures taken to prevent recurrence
-Indicate date corrective action is expected to be completed
-Provide supporting evidence if 483 citation is incorrect (but, don’t be defensive)

Dos and Don't during and after FDA inspections

This is a collection of facts from different experts and not the whole thing, there might be other dos and don'ts other than these applicable as per particular situation.
  • Present business card
  • Be prepared
  • Be organized
  • Be calm
  • Be professional
  • Be confident
  • Have Scribe present at all times during the interview
  • Leave as soon as interview is over
  • Listen carefully and repeat the question or ask it to be repeated, if necessary
  • Answer completely, directly and honestly
  • Speak slowly and clearly
  • Speak only for your area of expertise
  • Know your procedures
  • Examine the credentials of the inspector, and establish the purpose of the inspection (e.g., routine, for cause, or survey).
  • Immediately inform corporate management and staff that an inspection is under way, and tell these individuals what the purpose of the inspection is.
  • Work out a rough schedule for the visit so that key personnel can be made available
  • Be able to verify everything you say
  • Prepare everyone in the firm who might come into contact with the inspector.
  • Train all such individuals with the procedures to be followed during the inspection
  • make sure all understand the role of the inspection coordinator.
  • Familiarize these individuals with a list of inspection do’s and don’ts
  • Inspection co-ordinator must stay all the time with the inspectors.
  • Inspection co-ordinator should have a runner to fetch information which is not in hand or to inform other about the stage of the inspection.
  • Inspection co-ordinator should think that he/she is the company as far as investigator is concerned
  • be positive in attitude and speak with authority and confidence
  • Interact with other company employees - those working in the plant as well as those in staff groups.
  • Effectively guide questions posed by the inspector to people with both the knowledge and the verbal skills to answer them.
  • smoothly challenge inappropriate questions immediately.
  • Focus on the positive aspects of a situation rather than getting defensive about negative aspects
  • Communicate inspection results on a continuing basis.Summarize the results more formally after the inspection is complete
  • Expect what you say to be documented in FDA field notebook
  • communicate clearly that there will be full cooperation within the law
  • Give Complete responses to valid questions, be open to the investigator’s point of view
  • Have a writtent policy about responsibilities
  • Representatives of the corporate quality, regulatory affairs, and legal departments are immediately informed that an inspection is taking place and are told what the purpose of that inspection is
  • Allow copying of records and access to a copier
  • Keep a second copy and attach to the inspection coordinator’s report
  • Allow FDA to take sample and retain a copy of sample and receipt
  • Follow up to see that all written comments (e.g., 483s) and verbal comments have been addressed and resolved


  • Do not make casual conversation
  • Do not assume the investigator is your “buddy”
  • Do not guess or make up an answer
  • Do not lie
  • Do not volunteer more information than necessary to completely answer the question
  • do not answer in way that looks to be rehearsed or artifical
  • Do not make faces or jokes about company's expenses
  • Make the auditor wait for the information
  • Override a liasion decision infront of auditors
  • Do not show auditors , your computers, but under FDA inspectors can see your comupter in a proper setting with proper personnel who are familiar with your systems present with them
  • Do not speculate. Don’t be afraid to find information and give it to the investigator later
  • Do not assume to know what the investigator means
  • Ask for clarification, examples or specifies
  • Do not conduct the inspection for the investigator
  • Never question the investigator’s authority
  • Never argue or raise your voice
  • Bring several people into conference room and have several conversations going on at one time
  • Provide documents with post-it notes, etc.
  • Do not agree or volunteer to change a procedure or practice without first discussing with Management
  • Respond to questions that are improper or outside your area of expertise or authority
  • Threaten to contact the investigator’s boss if conflict develops.
  • Allow Photographs
  • do not forget to make a decision which items to be given to inspectors, which to show and retain and which is to be exclusively used by co-ordinator
  • uncontrolled interchanges between personnel and the inspector

Classification of FDA inspection

NAI - No Action Indicated
Site is in compliance. No actions or response from site necessary
VAI - Voluntary Action Indicated
Violative practices noted that do not immediately jeopardize subject safety, but require correction action. Response necessary; follow-up inspection possible
OAI - Official Action Indicated
Violations severe enough to warrant immediate administrative actions. Reinspection likely

Other Inspections
Routine GMP audits
Directed audit for a specific reason
Reinspection after a Warning Letter
Recall effectiveness check
Preapproval inspection
Special Enforcement Initiative

Top Reasons for FDA inspection

  1. Routine Inspections, Routine Surveillance, For Cause inspections
  2. Pre-approval and Post-approval
  3. Controlling product approvals for commercialization
  4. Surveillance Programs through Adverse event reports
  5. Undercover Surveillance (drug/device promotion, distribution)
  6. Consumer complaints/former employee complaints (Whistle-blower)
  7. Bioresearch Monitoring Foreign
  8. Benchmarking, Complaints and Recall related
  9. New Product/Process Being Implemented

FDA Guidance on Computerized Systems Used in Clinical Investigations

Computerized systems that contain data that support a marketing application
  • Case histories
  • Analytical test results (e.g., LIMS)
  • Data captured from analytical instruments
  • Electronic transcription of hardcopy source data
it Does not apply to Computerized medical devices*
Study Protocols
•Identify computerized system use within the trial process
•Computerized systems must:
–Satisfy process requirements defined in study protocol
–Have built-in error prevention
–More complicated protocols
–Some automated processes may not be defined at protocol authoring stage – unnecessary protocol revisions
•Potential Solutions
–Include only high level detail in study protocol
–Maintain detailed computerized process map outside study protocol
SOPs and System Documentation

•Specific to computerized system
–Setup/Installation instructions
–Operating manual
–Data collection and handling
–System maintenance
–Security controls
–Change control
–Disaster recovery/contingency planning
–Data collection contingencies
–Roles and responsibilities

–Guidance states “Such SOPs should be maintained either on-site or be remotely accessible through electronic files as part of the specific study records, and the SOPs should be made available for use by personnel and for inspection by FDA.”
Potential Solutions
–Considerations for which SOPs are implemented at the site
For detailed description on this topic please attend the training

Sunday, February 22, 2009

FDA expectation from you during Design Control portions of Inspections

Subsystems interacting with The Design Control Process
  • Management Controls
  • Production and Process Controls
  • Corrective and Preventive Action
  • Document and Record Control
  • Labeling and Packaging Control
  • Risk Management
  • Change Control


Design control requirements

Your Firm must have a 21 CFR 820.30 compliant design control process prior to submitting a 510(k), as well as during IDE and PMA data collection. FDA WILL LOOK AT THIS!!!! In the last year several client firms have had FDA heavily examine whether or not their design control was compliant prior to a submission taking place.

Concepts of Design Control

  • Design and Development Plan
  • Design Input & Output
  • Design Review
  • Design Verification
  • Design Validation
  • Design Transfer
  • Design Changes
  • Design History File (DHF)

Risk Management Process ISO 14971

For more detailed explanation attend the training click here

what is FDA 482 and FDA 484 and other form used in FDA inspection

Forms Commonly Used During FDA Inspections
FDA 482 - Notice of of Inspection
FDA 483 - List of Observations
FDA 484 - Receipt for Samples
FDA 463 - Affidavit
Special purpose affidavits
Various special purpose forms
EIR - Establishment Inspection Report

FDA 482 - called Notice of inspection

  • FDA Investigators must formally identify themselves by presenting credentials
  • FDA issues a FDA 482- to Inspection Coordinator/Executive Manager
  • A copy shall be obtained for the Inspection File
  • Firm can not copy FDA credentials

FDA 484- Request for Samples

FDA inspectors can collect samples from the site but they have to issue a receipt of samples.

Items not requiring a FDA 484

  • Items or Materials Examined but not removed
  • Labels or Promotional Material
  • Photographs
  • Records

what are Firm’s Inspectional Policies during fda inspections

  • Cameras or recording devices are strictly prohibited
  • Maintain Documentation Integrity-GXP documentation shall not be defaced
  • All Documentation given to FDA shall be first stamped- “Confidential” or “Proprietary” Information
  • Employees shall not sign any documented presented by FDA or an Official
  • Affidavits or other official FDA documents shall be courteously refused

Saturday, February 21, 2009

FDA inspection - Effective SOP for participants duty

Following are key points need to be followed to have a successful FDA inspection.

following people play major role in FDA inspections and hence the roles and responsibilities must be defined well and informed.


  • Maintains a Current Inspection Contact List
  • Actively in Contacting Key Personnel
  • Trained on FDA Inspection SOP
  • Does notReview - FDA credentials, Accept FDA 482, Leave FDA Investigators Unattended, Keep FDA Investigators Waiting

–Inspection Coordinator

  • Responsible for Managing the FDA Inspection
  • First Person to be Notified upon FDA arrival
  • Appoints other members of the Inspection Team
  • Actively involved in all Topics
  • Calls Time Outs-when needed
  • Should be Escort for Lead FDA Investigator
  • Be Present at all Times


  • One per FDA Investigator
  • With Assigned FDA personnel At All Times
  • Broad Knowledge
  • Answers Questions Appropriately
  • Refers to the Inspection Coordinator


  • One Scribe per FDA Investigator
  • Accuracy in Note Taking -Questions, Responses ,Documents Requested/Received
  • With Assigned FDA personnel At All Times
  • Generally a Non-Speaking Role
  • Must be Knowledgeable to Understand Discussion
  • Will Transcribe Notes Daily-Record of Inspection

–Document Support

  • Final QA Check on ALL Documentation
  • Maintains a Complete Record of All Docs Sent to FDAOrganizes and Stages Documents
  • Coordinates Runners
  • Makes Copies of Documents for FDA
  • Stamps Copies- “Confidential” or “Proprietary Information

–Subject Matter Expert

  • Expert Knowledge of Specific Areas of Operation’“On Call”
  • Articulate and Knowledgeable
  • Knows when to speak and when not to speak
  • Redirects Questions to the Inspection Coordinator

Good Cell Culture Practices, GCCP, in Non Clinical In Vitro Safety Studies

Basic In Vitro Non Clinical Testing regulations
-21 CFR 58 - GLP
-40 CFR 162 - FIFRA
-40 CFR 792 - TSCA
-ENV/MC/Chemical (98) 17 Section No. 1-15
-21 CFR 210/ 211; 820

Alternative Animal Studies Expansion
Replace, reduce, and refine
-Modeling of in vitro systems to correlate with in vivo data
-Identification of cell line
-Qualification of test model
.Within a lab
.Data is reproducible and designed for specific cellular outcome
-Validation of model
.Inter lab studies

GCCP In Vitro NonClinical Safety Testing

In Vitro Safety Studies Examples
-USP Elution Assay
-3D dermal tissue models
-CaCo 2 cells
In Situ Safety Studies
-Viral/ Gene / Receptors markers

Increased in vitro models for toxicity
Increased submission of data from in vitro models for xenobiotic toxicity profiles
Increased use of cells lines
Controlling variation between laboratories using similar models
Acceptance of data; harmonization

Thursday, February 19, 2009

Overview of ISO 19011

- ISO 19011 provides guidance on the principles of auditing, managing audit programs, conducting QMS audits, as well as guidance on the competence of QMS auditors.
- It is applicable to all organizations needing to conduct internal or external audits or to manage an audit program.

ISO 19011 Basics

General Clauses:
1 Scope
2 Normative reference
3 Terms and definitions
Guidance Clauses:
4 Principles of Auditing
5 Managing an audit program
6 Audit activities
7 Competence and evaluation of auditors
ISO 19011: Basics

Audit activities:
6.2 Initiating the audit
6.3 Document review
6.4 Preparing for on-site audit
6.5 Conducting On-site audit
6.6 Audit Reporting
6.7 Completing the Audit
6.8 Audit Follow-up

Basics of Japanese Medical Device GCP (JGCP)

JPAL Laws, Ordinances and Notifications (relevant to GCP audits & the foreign manufacturer)

The Pharmaceutical Affairs Law (Law No. 145 Established as of August 10, 1960; Law No. 87 Revised as of July 26, 2005)MHLW Ministerial Ordinance No. 36 Clinical Tests for Medical Devices (hereinafter referred to as "Medical Device GCP" or “JGCP”)
YAKUSHOKUKIHATSU No. 0720005 Administration of Good Clinical Practice for Medical Devices
YAKUSHOKUKIHATSU No. 070720 Essential documents for criteria concerning clinical tests for medical devices
YAKUSHOKUHATSU No. 0720004 Criteria for Clinical Trials for Medical Devices
YAKUSHOKUHATSU No. 0331006 Handling of clinical study data based on clinical study that is carried out in a foreign country
MHLW Administrative Correspondence from June 23, 2006 Q&A on the Handling of Tests Records from Clinical Studies on Medical Devices Conducted Overseas

JGCP Basics

A. Ministry Ordinance 36 issued in 2005
B. Based on ICH6 and closely aligned with ISO 14155
C. Parallels the Drug GCP (MHLW Ordinance 28)
D. 6 Chapters, 79 Articles
- Chapter 1. General Provisions
- Chapter 2. Criteria for Preparations for Clinical Trial
- Chapter 3. Criteria for Clinical Trial Management
- Chapter 4. Clinical Trial Criteria
- Chapter 5. Criteria for Reevaluation Documents, Etc.
- Chapter 6. Criteria for Sponsoring Clinical Trial, Etc.
E.Audit requirement discussed mostly in Articles 21, 31 & 42

- JGCP requirements have many similarities to those the US and Europe.
- Largely due to MHLW participation in ICH and the ICH Guideline for GCP (E 6)
- Closely aligned with ISO 14155 Parts 1 & 2
- Basic functions of the Sponsor, Investigators, Informed Consent, Record Retention, and IRB’s are nearly identical to requirements currently in place for the US.

JGCP Audit Requirements

- Per Article 2, Audit is defined as “an investigation conducted by a sponsor or postmarketing sponsor, or one that a sponsor-investigator appoints a designated person to determine whether the clinical trial or postmarketing clinical trial is conducted according to this Ministerial ordinance (No. 36) and the protocol or postmarketing protocol to ensure the reliability of the technical documents collected by the clinical trial or postmarketing clinical trial.”
- When the sponsor-investigator appoints an individual within the same medical institution to conduct the audit, said individual must be a third party who is not involved in the clinical trial.
- The sponsor-investigator may also appoint a third-party organization outside of the medical institution to conduct the audit.
- Article 21, Clause 6:
"Procedures concerning auditing plan and duties" refer to a plan and procedure that the sponsor-investigator prepares to guarantee that the audit is properly conducted.
- This documentation must include:
+ Selection of the auditor (including the qualifications for the auditor)
+ Name of the auditor who will audit the clinical trial
+ Specific methods of auditing
+ Handling of auditing report and audit certificate

Article 31. Audit (by sponsor)
1. The sponsor shall prepare an audit plan as well as the operating procedures for the related duties, and conduct audits in accordance with the audit plan and the operating procedures.
2. Auditor to be independent of those in charge of medical device development or monitoring.
3. Audit report to document the matters confirmed in the audit and an audit certificate to verify that the audit has been conducted. Submit report and certificate to the sponsor

Article 42. Audit (sponsor-investigator)
1. The sponsor-investigator shall prepare an audit plan as well as the operating procedures for the related duties, and conduct audits in accordance with the audit plan and the operating procedures.
2. Auditor shall not be engaged in the clinical trial at the medical institution where the clinical trial is conducted (including its preparation and management) or in monitoring.
3. Audit report to document the matters confirmed in the audit and an audit certificate to verify that the audit has been conducted. Submit report and certificate to the sponsor-investigator and the head of the medical institution.

An audit on individual clinical trials shall be conducted by deciding on:
+ the subject of the audit, i.e. medical institution and other facilities engaged in the clinical trial
+ the timing of the audit taking into account the
* importance of the clinical trial for application to the regulatory authorities
* number of subjects
* type and complexity of the clinical trial
* level of risk posed by the clinical trial to subjects,
* various issues discovered through monitoring.

The auditor is required to
+ visit the medical institution and other facilities engaged in the clinical trial as necessary
+ directly access the source documents to confirm that the clinical trial is being properly conducted and the reliability of the data is fully ensured.
Note: “When a serious noncompliance to the GCP Ordinance is found, the regulatory authorities may request access to the audit report.”

Wednesday, February 18, 2009

Pre Approval Inspection and things to look for

Following are the key things you should look for pre approval inspection.

  1. Deviations, OOS, product failures
  2. Investigations and CAPA’s
  3. Label control
  4. QA oversight
  5. Management oversight
  6. Drug Safety and Pharmacovigilance projects
  7. Process, shipping cleaning method
  8. Vendor and contractor qualification and oversight

Deviations gives the indication of break down in one or all of the following:Equipment, processes, SOP’s, training, culture, QA or management oversight
Product failures are indicators of one or more of the following:Equipment, processes, SOP’s, training, culture, QA or management oversight as well as testing, specifications and change control

Investigations contain following things

  • Depth of root cause analysis
  • asking all the questions
  • is the documentation Adequate
  • A recurring theme and if so why“Super investigation” initiation
  • Adequate time allocated Investigation completed in a timely manner
  • Management awareness of issues


  • Point issue versus holistic solution
  • Logical and encompassing CAPA’s
  • CAPA effectiveness – evidence
  • Adequate time allocated
  • Recurring issues – is the CAPA a cut and paste
  • SOP rewrite and training do not solve all problems
  • Management awareness of issues – did they act in a timely fashion

Label Control

  • Largest reason for recall
  • Processes for master labeling control must be adequate
  • Label control on production floor must be defined and followed
  • Labelers and packaging lines must be validated
  • Process history must support operations

QA Oversight/Mgt Oversight

  • Very clear in Warning Letters but sometimes hidden in 483’s
  • QA disposition lots not a committee
  • QA’s role in stopping production
  • QA reporting relationship –org charts must represent real life
  • Discretionary budget
  • QA’s voice at the right table
  • Does the senior person on site know what is going on
  • This could be the CEO
  • Does the head person hear the good and the bad news and from whom

Validation (Proc, Ship, Clean & QC )

  • Is it a living discipline? Or is it a paper hurdle?
  • Is validation a one time activity?
  • Development reports must support validation which supports batch records
  • Validation is not a development activity
  • Validation must support what you claim for your process
  • Methods used, in compendial, must be valid
  • Deviations in the reports must be addressed

For detailed explanation of above points i would recommend the training.

Preparing for FDA Pre-Approval Inspections

Tuesday, February 17, 2009

What are the guidance documents that govern MDDs?(Microbial Data Deviation Investigations)

Regulatory and Guidance Documents
•2006 FDA Guidance for Industry - Investigating Out of Specification (OOS) Test Results for Pharmaceutical Production.
•USP 31 <1117> Best Microbiological Practice

•Addressed in PMF Newsletter (Sutton and Settineri) (Sutton) (Settineri)
•Addressed in PDA Draft Technical Report
Points to Consider When Investigating Microbiological Data Deviations (MDD) (Formerly known as the Micro OOS Task Force)

•Tangentially addressed in FDA Aseptic Processing Guidance albeit it is focused on sterile products.

Concepts of Design Control

•Design and Development Plan
•Design Input & Output
•Design Review
•Design Verification
•Design Validation
•Design Transfer
•Design Changes
•Design History File (DHF

When do we need 510(K)

510(K) is required under following conditions.

  1. Introducing a device into commercial distribution for the first time
  2. Different intended use for a device already in commercial distribution
  • Indicated by claims made for a device in labeling/advertising
  • Note: Prescription use to over-the-counter use is a major change in intended use

3. Change to a device that could significantly affect its safety or effectiveness

  • Burden is on you to decide whether a modification “could significantly affect safety or effectiveness.”
  • If no submission, justification should be recorded in your change control records

510(K) is not required under following conditions.

•Device is not marketed or commercially distributed
–Example: clinical trials (regulated by 21 CFR 812)
•Distributor of another firm's U.S.-manufactured device
•Device is not manufactured by your company, but is marketed or commercially distributed by your company
–Labeling shall reveal connection with manufacturer: "Manufactured for Life-Tech" or "Distributed by Life-Tech"
•For repackager or relabeler, if labeling or condition of the device is not significantly changed
–Labeling must be same as 510(k): indications for use, warnings, contraindications
•Device in commercial distribution before 5/28/76
–Must be documented
Related Training -

ASTM E 2500 – 07, What is it? - salient features

•“A risk-based and science-based approach to the specification, design, and verification of manufacturing systems and equipment that have the potential to affect product quality and patient safety.”
•“The overall objective is to provide manufacturing capability to support defined and controlled processes that can consistently produce product meeting defined quality requirements.”
this is Approved June 1, 2007
–An ASTM Standard
–A voluntary consensus standard
–It has legal relevance
•The term “Validation” appears only 1 time
–“quality”, (not Quality Assurance or Quality Unit) appears 44 times
–“expert” appears 21 times
–“critical” appears 20 times
•The terminology implies knowledge of what’s important to your system

What ASTM E 2500 Applies To
Pharmaceutical and biopharmaceutical manufacturing systems:
  • Facility equipment
  • Process equipment
  • Supporting utilities
  • Process monitoring and control systems
  • Automation Systems that have the potential to affect product quality and patient safety
    Attend the detailed training to know following areas. Click here
  • Review of how these ASTM and ICH approaches can simplify the qualification process.
  • Documentation of design.
  • Risk mitigation by design review and operational practices.
  • The role of subject matter experts.
  • Use of risk management techniques to drive the extent of systems verification and level of documentation detail.
  • Acceptability of well-managed changes to systems.