Inspections - Institute of Validation Technology (IVT)

AUDITING YOUR STABILITY PROGRAM
BEFORE THE FDA STEPS IN”
Christopher Smith, CQE, RAC
Vice President, Quality & Regulatory Affairs
IVT’s Forum on Stability Programs
Philadelphia, PA
December 7-9, 2010
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Objectives
• To prepare and qualify you to
successfully manage the regulatory
inspection process.
● To assure the inspection appropriately
portrays the compliance status of your
company.
● To assist you in maintaining a positive
relationship with the regulatory
Agency conducting the inspection.
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Overview
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FDA’s organization
The legal basis for inspections
The inspection process
Inspection do’s and don’ts
The close out
Criminal investigations
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Who Regulates our Industry?
• Food and Drug Administration (DHHS)
• Drug Enforcement Administration (Justice)
• Nuclear Regulatory Commission
(Independent)
• Health Care Financing Administration
(DHSS)
• Environmental Protection Agency
(Independent)
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Other Agencies
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U.S. Postal Service (Independent)
U.S. Customs Service (Treasury)
U.S. Department of Agriculture
Occupational Safety and Health Administration (Labor)
Federal Trade Commission (Independent)
Consumer Product Safety Commission (Independent)
Alcohol, Tobacco and Firearms (Treasury)
Securities and Exchange commission (Independent)
State agencies
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How Are We Regulated?
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Laws
Regulations
Guidelines
Policies
Court Decisions
Reviewer/Inspectors
• Advisory
Committees
• Our Industry
• Our Customers
• The Public
• The Press
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FDA is Organized by Product
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Center for Drug Evaluation and Research
Center for Biologics Evaluation and Research
Center for Veterinary Medicine
Center for Devices and Radiological Health
Center for Food Safety and Applied Nutrition
Center for Toxicological Research
Center for Tobacco Products (1995)
Office of Regulatory Affairs
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The FDA “Field”
• Five Regions: j Pacific, kSouthwest,
lCentral, mNortheast and nSoutheast
• 20 Districts
• 13 Labs
• 150 Resident Posts
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FDA’s Mission a Basis in Laws
• Biologics control Act (1902)
• Pure Food and Drug Act (1906)
• Federal Food, Drug and Cosmetic Act (1938)
*(NDAs, Inspections, Advertising)
• Pesticide, Food and Color Additive Amendments (1950s)
• Efficacy Amendments (1962)
*(GMPs, Record Keeping)
• Radiation Control for Health and Safety Act (1968)
• Medical Device Amendments (1976)
• Orphan Drug Act (1983)
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And More Laws
• Drug Price Competition and Patent Term Restoration Act (1984)
*(ANDAs)
• Generic Drug Enforcement Act (1992)
*(Debarment)
• User Fee Act (1992) Animal Drugs added 2003
• Dietary Supplement Act (1994)
• Food and Drug Modernization Act (1997)
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*(new user fees; no ELAs, easier mfging changes, off-label use, pharmacy
compounding, risk-based regulation)
Pharmaceutical for Children Act (2002) improved in 2003
Bioterrorism Response Act (2002) added to in 2004
Device User Fee and Modernization Act (2002)
Food Labeling Act (2004)
Minor Use/Minor Species Animal Health Act (2004)
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And a Basis in Regulations
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Recalls (21 CFR Part 7)
FOI (Part 20)
Informed Consent (Part 50)
IRBs (Part 56)
Patent Restoration (Part 60)
Foods (Parts 100 - )
GRAS Substances (Part 184)
Drug Advertising (Part 202)
Biologics (Parts 600 - )
Radiological Health (Parts 1000-)
Cosmetics (Parts 700 - )
Devices (Parts 800 - )
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Electronic Records (Part 11)
Environmental (Part 25)
GCPs (Proposed Part 54)
GLPs (Part 58)
Colors (Part 70)
Food Additives (Part 172)
Drug Labeling (Part 201)
Drug GMPs (Part 210 & 211)
NDAs/ANDAs (Part 314)
INDs (Part 312)
Drug Monographs, Standards and
Tests (Parts 330-460)
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The Law Defines a Drug
• *Articles recognized in the official USP, official Homeopathic
Pharmacopeia, or official National Formulary.
• *Articles intended for use in the diagnosis, cure, mitigation,
treatment or prevention of disease in man or other animals.
• *Articles other than food intended to affect the structure or any
function of the body of man or other animals.
• *Articles intended for use as a component of any articles above.
FD&C Act Sec 201 (g)
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Definition Covers Many Products
• All biologics are drugs
• Some drugs are also biologics
• Some drugs are also cosmetics
• Some drugs are also foods
• Some drugs are also medical devices
And today recognize “combination” products
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A Prohibited Act
• “The introduction or delivery for
introduction into interstate commerce
of any food, drug, device, or cosmetic
that is adulterated or misbranded” is
specifically prohibited by Section 301(a)
of the FD&C Act.
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Misbranded
• A drug is misbranded if it is “dangerous to health when
used in the dosage, or manner, or with the frequency or
duration prescribed, recommended or suggested on the
label thereof.”
In general a product is misbranded if the label or
accompanying labeling is false or misleading, or if it fails
to include information required by law.
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Adulterated
• “A drug or device shall be deemed
adulterated if. . .the methods used in, or the
facilities or controls used for its
manufacture, processing, packing, or holding
do not conform to or are not operated or
administered in conformity with current
Good Manufacturing Practice. . ..”
• FD&C Act Sec 501 (a)
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GMPs
• The drug GMPs (21 CFR Part 210-211) are the
minimum current methods to be used in, and
the facilities and controls to be used for the
manufacture, processing (includes testing),
packaging (includes labeling) and holding of a
drug (bulk and finished) to assure it meets
the requirements for safety, identity, quality,
purity, strength and other characteristics it
is represented to possess.
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Methods of Enforcement
• Product Review
• Deficiency Letters
• Inspections
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FDA 4832
Warning Letters
Suspension of Approvals (Press Coverage)
Recalls
Import Detentions
Seizures
Injunctions
Prosecutions
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The FDA Inspection
• The overall objective of an FDA inspection is
to determine compliance with appropriate
GxPs and regulatory requirements.
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Scope of Inspection Authority
• FDA has the authority to inspect ALL
companies that manufacture, process, pack or
hold FDA-regulated products, including
contract testing laboratories, animal testing
labs, clinical study sponsors, monitors and
investigators and Institutional Review Boards.
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FDA’s Authority
• The FDA may inspect records, files,
papers, processes, controls and facilities
bearing on whether drugs are adulterated
or misbranded. FDA is permitted to have
access to and to copy and verify such
records.
• FDA inspections DO NOT require advance
notice, a warrant or consent.
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Don’t Say No
• It is a criminal offense to refuse an FDA
inspection.
• FDA may conduct inspections:
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At reasonable times
Within reasonable limits
In a reasonable manner
With reasonable promptness
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Items Not within FDA Authority
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Financial Data
Sales Data
Pricing Data
Personnel Data (other than qualifications)
“Research” Data
Records pertaining to the practice of
medicine or pharmacy (unless connected
to an application)
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Reasons for Inspection
• Routine (GMP)
• Pre-Approval (PAI)
• “For Cause”
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Adverse Events
Complaints
Recalls, Seizures, etc.
Congressional Oversight
Public Health Emergency
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Setting the Tone
• Auditors should be impressed with the
organization from the very start; i.e.,
professional, organized, responsive,
cooperative and concerned with patient
safety.
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What to Expect
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A prepared Investigator
Notice of Inspection (FDA form 482)
Investigator Credentials (badge)
Purpose of inspection
Requests for tours
Requests for documents
Requests for interviews
Requests for samples
Lots of questions
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Inspection Vs Criminal Investigation
• Upon arrival to conduct a routine audit, the
FDA representative must issue a Notice of
Inspection and state the purpose of the
inspection.
• If the FDA representative does not issue a
482, or is evasive regarding the purpose for the
visit, a criminal investigation may be underway.
…… more about this later……
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Do’s and Don’ts
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Be prepared
Be honest
Answer the question, but don’t volunteer
Never say “never”
Don’t argue
Be positive and confident
Don’t guess or speculate
Communicate clearly
Take corrective actions
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Do’s and Don’ts
• Avoid extraneous conversations and discussions
regarding issues.
• Never leave an auditor unescorted.
• Provide a neutral workplace for the conduct of
interviews and a place to review documents. If
possible, this should be away from operations
and should not require access through
operational areas.
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Do’s and Don’ts
• If you do not know the answer to a question, DO NOT
SPECULATE! Tell the auditor you do not know the
answer, write the question down and tell the auditor
you will provide a timely answer to the question.
• If you do not understand the question, ask for
clarification before answering it. It may be helpful to
repeat the question as you understand it and have it
acknowledged by the auditor before answering.
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Do’s and Don’ts
• Either have on site or know where to quickly acquire the
following:
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Current organizational charts
Development reports
Method validation records
Process validation records
Computer validation records
Equipment qualification records
Laboratory raw data
SOPs
Employee training records
Complaint, investigation, failure files
NDA, ANDA, IND and other regulatory documents
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Developing an Inspection Procedure
• One of the main keys to success of surviving an
FDA inspection is PREPARATION.
• Have an SOP that addresses basic assignments,
locations, Company policies (e.g. cameras), etc.
• Train upon, practice and audit against this SOP.
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A Procedure Should Contain
Receptionist responsibilities
Conference room locations
General conduct for employees
How you would like to handle the inspection
List of key contacts
Safety and other rules for auditors
Procedures for tours
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And
Attendance at daily debriefings
Procedures for providing documents
Accessibility of auditors
Use of cameras
Address 2nd and 3rd shifts and weekends
Use of computers
Procedures for affidavits
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Documents
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Have them available
Have them organized
Originals vs copies
Confidentiality
Make duplicates of any record
photocopied for the Investigator
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Interviews
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Have the “right” person
Always be clear
You don’t need to volunteer information
If approached outside of work, you have
no obligation to speak with an
Investigator and you have the right to
have an attorney or other representative
with you.
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Affidavits
• An affidavit is a “statement of purported
facts.”
• If an FDA Investigator presents you with an
affidavit:
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DON’T SIGN IT
DON’T INITIAL IT
DON’T READ IT
DON’T LISTEN TO THE INSPECTOR READ IT TO
YOU
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Recording Devices
• Generally, the use of recording devices should
be discouraged.
• However, in a spirit of cooperation, the
Company should determine it’s policies
regarding the use of recording devices and
include the policies in the inspection SOP.
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Photographs
• Pictures should not have extraneous
information in the background.
• Limit the scene to the information requested;
similar to the logic for limiting the answering of
questions.
• Photographs of the same scene from the same
angle as the Investigator should be taken by
the company audit team as well.
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Recording
• If the Investigator requests the use of a tape
recorder, get clearance from your senior
management and/or legal department. Secure a
duplicate tape recorder, if possible, and make an
identical recording.
• If the Investigator requests the use of a video
recorder, respond as above.
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Observations
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FDA may issue a Form 483
Think about who you want at close out meeting
Know to whom the 483 should be issued
Seek corrections of any mistakes on it
Seek notations of observations addressed
Seek to delete confidential information
Make sure you are clear about each observation
You do not have to make commitments at the close out
meeting
• Always respond in writing – now in 15 days!
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Wrap-Up Meetings
• Confirm the Company’s commitment to compliance.
• Have appropriate management from the organization and
all individuals who directly participated in the inspection
attend the meeting.
• Take detailed notes of the comments made by all parties
at the meeting.
• Ask questions about any observations or findings which
are not clear. Don’t be afraid to discuss the
observations for clarity and accuracy.
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Wrap-Up Meetings
• To the degree you can, take corrective actions
immediately and provide documentation of the
correction to the Investigator.
• Do not admit that any observations or findings are a
violation of law.
• Remain calm, attentive and responsive. Remember,
that the FDA auditor will write a report which will
draw conclusions about the tone and attitude of your
communication.
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Ethics
• Have a policy!
• Adhere to it at all times.
• Do not offer any auditor gratuitous items of
value at any time.
• FDA must provide you a receipt (FDA 484) for
any materials or product samples collected
during the course of the inspection.
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Ethics
• Do not, by your words or actions, give an auditor any
reason to feel they are being placed in an awkward
position by undue influence of any type.
• Do not offer free lunches or dinners during the
inspection process (there is some leeway outside of
US).
• Meetings with the Agency, under the venue of the
Agency, should be conducted per the ethics and
protocol of the Agency.
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Office of Criminal Investigations
• Special Agents who have full police
enforcement powers, including arrest
powers and the authority to carry
firearms.
• Generally limited to investigations of
“crimes of intent” involving the FD&C Act
and related statutes.
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Office of Criminal Investigations
Typical OCI investigations include:
• Counterfeiting of FDA-regulated products
• Intentional violations of the FD&C Act
• Tampering and tampering-related extortion
• Illegal re-entry of imported goods detained or
refused entry into the U.S. by FDA
• Investigations of deliberate criminal acts, subterfuge
or criminal activity
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Inspection Vs Criminal Investigation
• FDA believes a serious violation of the
law has been committed.
• An FDA Investigator may consider a
reluctance to cooperate with a request
as a refusal.
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Office of Criminal Investigations
• IF AN OCI AGENT ARRIVES,
CALL LEGAL COUNSEL
IMMEDIATELY!
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So Far We’ve Discussed
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The FDA and its legal mandate and mission
The laws and regulations
Some things to do to be prepared for an audit
Some things to do during an audit
Some things to do after the audit
Let’s get more specific about audits of stability
operations…………………..
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Criticality of Stability Operations
• Stability issues are in the top 10 reasons for
product recalls
• Stability issues are commonly cited in nonapproval letters
• Stability operations are typically a window to
the quality of many other operations
(laboratory, manufacturing, metrology, quality
systems)
• Stability operations are standard audit fare
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Operational Excellence
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Can you make these statements:
– “We store the right quantity of the right lots in
the right storage conditions, the first time, every
time according to an approved protocol.”
– “Samples are stored in well controlled,
continuously monitored, qualified storage
chambers under a perpetual inventory system.”
– “We pull the right quantity of the right lots from
the right storage conditions at the right time,
every time.”
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Procedural Excellence
• Do your SOPs “mistake-proof” your program:
– Protocol generation and approval
– Determining quantities for storage
– Sample set-up
– Sample pulls
– Inventory control
– Chamber qualification
– Chamber monitoring
– Facilities
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Protocol Generation and Approval
• Supporting documentation identifying:
– Regulatory status (US, EU, Global, R&D, Marketed,
Rx, OTC, Large Molecule, Medical Device, etc.)
– Batch selection, batch numbers
– Dosage forms, delivery systems, packaging
– Storage conditions and timepoints
– Test methods and specifications
– Sample requirements
– Bracketing and/or matrixing rationale
– Statistical evaluation
• Required signatures (change control)
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Determining Quantities for Storage
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Number and type of tests
Dosage form
Packaging (unit dose, multi-dose, primary, secondary)
How shared within labs (sub-dividing, multiple
analysts, microbiology, etc.)
Available supply and cost of materials
Storage conditions
Number of timepoints per storage condition
Surplus pulled per timepoint
Back-up/retention samples
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Sample Set-Up
• Define storage labeling
– Bin or box for storage or individual labels?
– Recommend don’t over-label (watch leachables!).
– Pre-label timepoint and/or storage condition on each sample? Possibly
but does it add value?
• Prevent co-mingling with other products or labels
– Staging area clearance is critical.
• Prevent co-mingling with other lots
– One lot per staging area at a time.
• Pre-storage approval
– Have count and labeling second-checked.
• Storage verification
– Have chamber placement second-checked.
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Sample Calendar and Pulls
• Define month and/or year
• Define pull windows (account for
weekends/holidays)
• Define “system” (manual or electronic?)
• Use a “pick list”
• One lot, one storage condition at a time
• Individual samples prevents mix-ups
• Define how you will transfer to lab
(conditions?).
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Inventory Control
• Document sample receipt
• Document study set up with a record for each
study (lot, strength, package, condition,
position)
• Maintain transaction history (set, pulls,
transfers)
• Decide on physical inventory control (how
often? statistical sample or complete
inventory?)
• Use of bar codes or other e-tools can help
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Chamber Qualification
• DQ = design qualification (user requirements)
• IQ = installation qualification (specs, critical
components, utility requirements, size,
weight)
• OQ = operational qualification (testing
functionality, mapping)
• PQ = performance qualification (monitoring
use)
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Chamber Monitoring
• Determine frequency of data capture
– Electronic (every few seconds) (may be computer
captured)
– Circle chart (continuous)
– Combination of above
• Temp, %RH, Light Specs
– Rounding rules?
• Don’t forget calibration of devices used for
monitoring!
• Alarms
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Facilities
• Risks
– Flooding (from above AND below)
– Weather
– Explosion
• Access
– Physical security (guards, keys)
– Electronic security (cameras, swipe cards)
• Maintenance
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In Summary
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Understand FDA’s mission
Know the law and regulations
Be prepared
Be cooperative, honest, responsive, clear
Follow-up on commitments
Remember – stability is a common area for
audits
• Practice operational excellence
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Christopher Smith, CQE, RAC
Vice President, Quality & Regulatory Affairs
AAIPharma Services Corp.
Wilmington, NC 28405
(910) 254-7691
[email protected]
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