regulation of drug manufacturing

Food and Drug Law Institute's
Workshop on
INTRODUCTION TO
DRUG LAW AND REGULATION:
REGULATION OF DRUG MANUFACTURING
November 8-9, 2010
Park Hyatt Hotel
Washington, D.C.
1
REGULATION OF
DRUG MANUFACTURING
Presented by:
Cathy L. Burgess, Esq.
Dean R. Cirotta, MBA
Crowell & Moring LLP
1001 Pennsylvania Avenue, N.W.
Washington, D.C. 20004
202.624.2851 phone
202.628.5116 fax
[email protected]
EAS Consulting Group, LLC
1940 Duke Street, Suite 200
Alexandria, Virginia 22314
703.684.4408 phone
703.684.4428 fax
[email protected]
www.easconsultinggroup.com
2
DRUG ESTABLISHMENT
REGISTRATION
AND DRUG LISTING
3
Authority To Require Establishment
Registration And Drug Listing
• Initial Registration. § 510(c), 21 U.S.C. § 360(c);
21 C.F.R. § 207.21
• Annual Registration and Fees. § 510(b), 21 U.S.C.
§ 360(b); §§ 736(a)(2), (3), (b)(1); 21 U.S.C. § 379h
§§ (a)(2), (3), (b)(1); 21 C.F.R. § 207.21
• Semi-Annual Reports. 21 C.F.R. § 207.30; §
510(j)(2),
21 U.S.C. § 360(j)(2)
• Failure to Register, List Drugs, or File Semi-Annual
Reports. § 505(e), 21 U.S.C. § 355(e); § 301(p),
21 U.S.C. § 331(p)
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Purpose And Scope Of Establishment
Registration And Drug Listing
• Purpose. § 510; 21 U.S.C. § 360; 21 C.F.R. § 207.20
• Scope.
– Domestic Establishments. 21 C.F.R. § 207.20
– Establishments and Activities Requiring Registration.
21 C.F.R. § 207.3(a)(7-8)
– Private Label Distributors. 21 C.F.R. § 207.20(b);
Forms FDA 2656, 2657, 2658
– Foreign Drug Establishments. § 501(i), 21 U.S.C. §
360(i); 21 C.F.R. § 207.40 (66 F.R. 59138, Nov. 26,
2002)
5
Exemptions From Registration
• Pharmacies regulated by local laws; dispensing drugs at
retail.
• Practitioners’ use in professional practices.
• Research, teaching or chemical analysis and not for
sale.
• Other Classes: e.g. hospitals, clinics, farmers, common
carriers. § 510(g); 21 U.S.C. § 360(g); 21 C.F.R. §
207.10
6
Information Required for
Registration and Drug Listing
Information Required on Initial Registration of Drug
Establishments (Form FDA 2656).
21 C.F.R. §§ 207.20 - 207.35
• Purpose of Form
(registrant, distributor,
foreign)
• Report Date (current)
• Type of Owner (sole
proprietor, partnership,
corporation, etc.)
• Reason for Submission
(annual, new, private label,
name change, etc.
• Business Type (human,
veterinary)
• Name and Site Address
(street, city, state, country)
7
Information Required For
Registration And Drug Listing
Information Required on Initial Registration (continued)
• Mailing Address (if
different from Site
Address)
• Type of Ownership or
Operation (partnership,
corporation)
• Names(s) of Owner(s)
• Name and Phone
Number of submitter
• Other Establishment
Names at same site
• Signature of Authorizing
Official (must be
signed)
• Parent Company Name
8
Information Required For
Registration And Drug Listing
Amendments to Establishment
Registration 21 C.F.R. § 207.26
• Changes in ownership, structure, location or
activity--within five (5) days.
• Change in an establishment’s firm name.
• Changes in the names of officers and directors of
corporations--annual registration.
9
Information Required For Registration And
Drug Listing
Drug Product Listing (Form FDA 2657)
21 C.F.R. § 207.25
• New drugs, authority for the marketing, application number,
labeling. § 510(j)(1)(A); 21 U.S.C. § 360(j)(1)(A)
• Prescription drugs subject to § 503(b)(1), all labeling and
representative sampling of advertisements. § 510(j)(1)(B)(I);
21 U.S.C. § 360(j)(1)(B)(I)
• Quantitative listing of active ingredient(s)
§ 510(j)(1)(C); 21 U.S.C. § 360(j)(1)(C)
• Quantitative listing of all ingredients as necessary.
§ 510(j)(1)(C); 21 U.S.C. § 360(j) (1)(C)
• Over-the-counter drugs, label, package insert, sampling of any
other labeling. § 510(j)(1)(C); 21 U.S.C. § 360(j)(1)(C)
• Drug Listing Number using the National Drug Code (NDC).
21 C.F.R. § 207.35
10
Information Required For
Registration And Drug Listing
Updating Drug Listing Information.
21 C.F.R. § 207.30
• Updates semi-annually, in June and December
• Information to be submitted in the updates:
– Drugs not on a previously submitted list;
– Drugs that have been discontinued;
– Reintroduction of discontinued drugs;
– Material change in previously submitted
information; and
– No changes; no report.
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Public Inspection Of Registrations
And Drug Listings; 21 C.F.R. § 207.37;
510(f), 21 U.S.C. § 360(f)
• Registration of Drug Establishment (Form FDA 2656) is
publicly available at Drug Listing Branch, CDER and FDA
District Offices. (21 C.F.R. § 207.37)
• Types of Information Available for Public Disclosure
include:
– List of all drug products
– List of all drug products by labeled indications or
pharmacological category
– Drug products listed by manufacturer
– List of active ingredients
– Discontinued drugs, newly marketed drugs and drugs
for which marketing is resumed
– Labeling
– Advertising
12
Public Inspection Of Registrations
And Drug Listings; 21 C.F.R. § 207.37;
510(f), 21 U.S.C. § 360(f)
Information Not Available for Public
Disclosure
• Basis for determination not subject to drug provisions
of the Act.
• Drug product’s inactive ingredients. §502(e)(i)(A)(iii)
• Drugs containing a particular inactive ingredient.
13
Adulteration/Misbranding
and
GMPs
14
Adulterated Drugs
(21 U.S.C. § 351)
Drug is deemed adulterated if:
• contains any filthy or decomposed substance
(FDCA § 501(a)(1), 21 U.S.C. § 351(a)(1));
• prepared, packed or held under unsanitary
conditions (FDCA § 501(a)(2)(A),
21 U.S.C.§ 351(a)(2)(A);
• methods used do not conform to good
manufacturing practices (FDCA § 501 (a)(2),
21 U.S.C. § 351 (a)(2)(b), 21 CFR Part 210 &
211);
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Adulterated Drugs (21 U.S.C. § 351)
• container composed of poisonous or deleterious
substance may cause contents to be injurious to
health
(FDCA § 501 (a)(3), 21 U.S.C. § 351 (a)(3));
• contains an unsafe coloring additive (§ 501 (a)(4),
21 U.S.C. § 351 (a)(4));
• strength, quality or purity falls below compendial
standards § 501 (b), 21 U.S.C. § 351 (b));
• strength or purity falls below what it purports to
possess
(§ 501 (c), 21 U.S.C. § 351 (c));
• mixed or packaged to reduce quality or strength
(§ 501 (d), 21 U.S.C. § 351 (d)).
16
MISBRANDING of DRUG PRODUCTS
(21 U.S.C. § 331)
A drug is deemed misbranded if:
• labeling is false or misleading (FDCA § 502 a),
21 U.S.C. § 352(a));
• label fails to bear the name and place of business,
an accurate statement of contents, weight, measure
or numerical count (FDCA § 502(b), 21 U.S.C. §
352(b));
• labeling required is not prominently displayed
and understandable (FDCA § 502(c),
21 U.S.C. § 352(c));
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DEEMED MISBRANDED - continued
• labeling does not contain the established name and names
and quantities of active ingredients
(FDCA § 502(e), 21 U.S.C. § 352(e);
• labeling does not prominently display the established name
at least half as large as the proprietary name
(FDCA § 502(e)(1)(B), 21 U.S.C. § 352(e)(1)(B));
• labeling doesn’t bear adequate directions for use
(FDCA § 502(f), 21 U.S.C. § 352(f));
• not packaged or labeled as prescribed in the official
compendium
(FDCA § 502(g), 21 U.S.C. § 352(g)).
18
Misbranding Of Drug Products
• Reference to Registration or Registration Number
denoting FDA’s approval of firm or products.
21 C.F.R. § 207.39
• Manufacture in a Non-Registered Establishment.
§ 502(o) 21 U.S.C. § 352(o)
• Drugs Not Included in Drug Listing. § 502(o);
21 U.S.C. § 352(o); 21 U.S.C. § 510(j)
19
Regulation of Drug Manufacturing
Current Good Manufacturing Practices (cGMPs)
History
• First Regulations - June 20, 1963 (28 FR 6385)
• Now codified as 21CFR parts 210 through 226
• Major revisions to regulations
January 15, 1971 (36 FR 601)
September 29, 1978 (43 FR 45014)
January 20, 1995 (60 FR 4087)
December 8, 2008 (73 FR 51919)
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Regulation of Drug Manufacturing
Current Good Manufacturing Practice (cGMP)
Principles:
(1) Quality, safety, and effectiveness must be
designed and built into a product;
(2) Quality cannot be inspected or tested into a
finished product; and
(3) Each step of the manufacturing process
must be controlled to maximize the likelihood
that the finished product will be acceptable.
21
Regulation of Drug Manufacturing
Current Good Manufacturing Practice
(cGMP)
Regulations
 Drugs Generally
21 CFR Parts 210 and 211
 Blood and Blood Components
21 CFR Part 600 et seq.
 Note: For Blood Establishments, Parts 210
through 226 and Parts 600 through 680
supplement rather than supersede each other.
22
Regulation of Drug Manufacturing
Current Good Manufacturing Practice (cGMP)
Case Law
United States v. Barr Labs, Inc. 812 F. Supp. 458
(D.N.J. 1993)
 Established cGMP Standards for industry
23
Regulation of Drug Manufacturing
Current Good Manufacturing Practice (cGMP)
Guidance
 Proposed cGMP regulations (May 3, 1996,
Based on Barr Labs decision; Withdrawn
December 4, 2007)
 Draft Guidance on OOS Results (Based on
Barr Labs decision)
 Guidelines for Quality Assurance in Blood
Establishments (July 11, 1995)
 Guidance on OOS Results (October 2006)
24
Regulation of Drug Manufacturing
Current Good Manufacturing Practice (cGMP)
Pharmaceutical cGMPs for the 21st Century
• Risk Based Model for Prioritizing Sites for Manufacturing
Inspections
• Science Based Regulation of Product Quality
• Guidance on Quality Systems Approach to
Pharmaceutical cGMPs (September 2006)
http://www.fda.gov/cder/guidance/7260fnl.htm
• Amendments to Current Good Manufacturing Practice
Regulations for Finished Pharmaceuticals. (73 FR 51919)
Effective December 8, 2008
25
FDA Inspections
26
Statutory Authority to Conduct
Establishment Inspections
•
•
•
•
•
•
•
Section 704 21 U.S.C. §374; 21 U.S.C. §360(h)
Reasonableness of the Inspection (time, limits, manner)
Frequency of Inspections 21 U.S.C. §360(h)
Consent Unnecessary
Search Warrant Unnecessary
Miranda Warnings Unnecessary
Inspection Warrants
27
Scope of Inspection
FDA Authority To Inspect
FDA may not inspect:
• Financial data.
• Sales data other than shipping figures.
• Pricing data.
• Personnel data other than information establishing
the qualifications of technical and professional
personnel.
• Certain research data except to the extent such
information may be required to be made available for
inspection or submitted to FDA for particular
products.
28
Scope of Inspection
FDA Authority To Inspect
• No general subpoena authority, but in certain civil
proceedings FDA may issue a subpoena for
production of evidence and records.
• If FDA initiates an enforcement action, records are
available under the rules of discovery.
• During a criminal investigation the Justice
Department can subpoena records relevant to an
ongoing grand jury investigation.
29
Scope of Inspection
• FDA’s Authority to Inspect Records of Interstate Shipment
by Common Carriers and Recipients
– Section 703
– If requested in writing
• Sample Types
– Official sample
– Documentary sample (DOC sample)
– 301(k) sample
– Post-seizure sample
– Investigational sample (INV sample)
– Induced sample
30
Scope of Inspection
• What FDA is Not Expressly Authorized to Obtain, but
May Attempt to Obtain
– In-plant photographs
• Not specifically authorized
* Dow Chemical Co.
* Acri Wholesale Grocery Co
– Affidavits from individuals
– Interview of employees
• FDCA does not expressly authorize investigators
to interview a company’s employees; with/without
company’s counsel:
* Managerial employees
* Non-managerial employees
31
Scope of Inspection
• Limitations to the Scope of Inspection
– Retail pharmacies
– Licensed practitioners
– Research, teaching, or chemical analysis
– Exempted by regulation
32
Procedure for Conducting Inspections
• Investigation Operations Manual
(www.fda.gov/ora/inspect_ref/iom/IOMTC.html)
• Present Credentials and Notice of Inspection
• Inspectional Observations (Form FDA 483)
• Discussion with Management
• Establishment Inspection Report
33
Procedure for Conducting Inspections
How FDA prepares for Inspections
•
and
Review of FDA inspection procedures
compliance policy guides.
•
Review of a firm’s most recent
Establishment
Inspection Reports (EIRs) and responses to
483s and Warning Letters.
34
Refusal to Permit Entry or Inspection;
Refusal to Permit Access
to or Copying of Records
• Prohibited Acts
•
Administrative Inspection
Warrant
35
Reasons for
Food and Drug Administration (FDA)
Administrative Inspections
•
•
•
•
Routine
For Cause
Follow Up to Warning Letter or Enforcement Action
Complaints from Consumers, Industry, and Current or
Former Employees
• Recall Effectiveness Check
• Pre-Approval Inspection
• Special Enforcement Initiative
36
Scope of Inspection
Scope of FDA Inspections
• The scope of the inspection depends on “the
information desired, or upon the violations
suspected or likely to be encountered.”
37
Regulation of Drug Manufacturing
FDA Authority To Inspect
FDA may inspect and copy:

records, files, papers, processes, controls and
documents related to a facility’s bearing on
whether drugs are adulterated, misbranded or
otherwise violative.
38
Scope of Inspection
Pre-Approval Inspections
CDER’s Role
• Review data in applications(s)
• Establish specifications for manufacture and
control based on data
39
Scope of Inspections
Pre-Approval Inspections
Districts’ Role:
• Assure cGMP compliance
• “Data audit” – verify authenticity and
accuracy of data submitted
• Report other data or information with
impact on cGMP compliance
• Verify compliance with application
commitments
40
Scope of Inspections
Pre-Approval Inspections
Inspection Teams (Investigators, Analysts, Engineers,
etc.)
Areas Covered:
• Manufacturing (Dosage form, bulk drug/API, GMP)
• Reprocessing (if in application)
• Laboratory (Equipment and Procedures qualified and validated,
raw data)
• Components (API-supplier, source of bio-batch, clinical batch)
41
Scope of Inspections
Pre-Approval Inspections
Areas Covered (cont.):
• Buildings and Facilities (impact on other products,
structure – e.g., cross-contamination)
• Equipment (cleaning validated)
• Packaging and Labeling Controls (accountability, past
mix-ups, recalls)
• Stability (data audit)
• Process Validation (including pre-approval and
commercial batches.
42
Scope of Inspections
Pre-Approval Inspections
Field Recommendations:
• Approve (NAI, VAI)
• Withheld approval (OAI - with reasons why)
• Delay approval pending pre-approval inspection
43
Scope of Inspections
Pre-Approval Inspections
“Show Stoppers”
• Application misrepresents date or conditions relating
to pre-approval batches
• Inconsistencies and/or discrepancies raising
significant questions about the validity of records
• Pre-approval batches not made in cGMP compliance
•
44
Failure to report adverse findings or test data without
adequate justification
Procedure for Conducting Inspections
How FDA Prepares For Inspections
Selection of team and designation of team leader
•
The team leader:
–
Plans the inspection
–
Schedules and coordinates team
member
–
pre-inspection preparations
Assesses progress of the
–
Coordinates preparation of
inspection
investigation
45
Procedure for Conducting Inspections
FDA Inspection Goals
• To determine a firm’s compliance with FDA
rules and regulations.
• To obtain evidence to support legal action
when violations are found, or to obtain specific
information as directed by counsel.
46
Procedure for Conducting Inspections
What To Do Before An Inspection
•
•
•.
•
Evaluate Relationship with FDA
Assess Systems, Procedures and Controls
Review Company Performance
Establish Team & Plan
47
Procedure for Conducting Inspections
What To Do During An Inspection:
The Team Approach
• The Daily Record
• Entry and Observation: What is allowed
• Access to Documents
– Types of documents
– Reasonable access
– Provide what is requested
– Keep good records; keep copies
48
Procedure for Conducting Inspections
Closing the Inspection
The Team Approach
• The Exit Meeting - A Critical Part of the Inspection
• Presentation of Form FDA 483 – written report of
the Inspection Observations
• Discussion of a Reply
49
Procedure for Conducting Inspections
After the Inspection
• Report to Regulatory Affairs and Senior Management
• Response to Form FDA 483 is critical
– Provide tangible evidence that you are correcting
problems
– Allocate necessary resources to make corrections
– Address major quality system or safety issues first
– Demonstrate that you understand issues and what
corrections are necessary
• Follow-Up
50
Establishment Inspection Reports
• Establishment Inspection Report (EIR) –
– report written by the investigators that
summarizes all the findings from the
inspection.
– Investigators submit EIR to the District Office
for a classification decision
Establishment Inspection Reports
District Classifications
•
No Action Indicated (NAI) No objectionable conditions or practices were found
during the inspection (or the significance of the documented objectionable conditions
found does not justify further action).
•
Voluntary Action Indicated (VAI) Objectionable conditions were found and
documented but the District and/or Center is not prepared to take or recommend any
of the regulatory (advisory, administrative, or judicial) actions listed below since the
objectionable conditions do not meet the threshold for regulatory action. The district
may use an Untitled Letter, Regulatory Meeting or other communication with
responsible individuals to inform the establishment of findings that should be
corrected. A written response by the establishment may be an option, but is not
necessary. Any corrective action is left to the establishment to take voluntarily.
•
•
Official Action Indicated (OAI) Objectionable conditions were found and one of the
regulatory actions listed below should be recommended. Includes voluntary recalls
where the district has decided conditions warrant regulatory (advisory, administrative,
or judicial) action. Typically, an OAI classification should be made only if a FDA-483
has been issued and the documented evidence supports the action recommended.
Establishment Inspection Reports
District Classifications
•
Referred to State (RTS) Referred to State, local, or other federal
office. This classification can be used only when either there is no federal
jurisdiction over the apparent violation in question or it is determined that
State action is the most efficient method of obtaining the establishment’s
compliance with applicable Federal Laws, Regulations or Administrative
requirements.
•
Referred to Center (RTC) This “District Decision Type” can only be used
when the objectionable conditions or apparent violations noted constitute a
compliance area for which no clear policy has been established or
significant technical issues exist which require Center review and
decision. An RTC classification should be made only if a FDA-483 has
been issued.
Field Alert Reports (FAR)
• 21 CFR 314.81(b)(1)(i) and (ii); NDAs and
ANDAs
(Effective May 23, 1985)
• Any incident that causes the drug product or
its labeling to be mistaken for, or applied to,
another article
54
FAR - Required Reporting
21 CFR 314.81(b)(1)(ii)
•
•
•
•
Bacterial contamination
Significant chemical, physical or other change
Product deterioration
Out-of-specification batch(es)
55
FAR - Reporting Requirements
• Applicant holders are required to submit
NDA/ANDA Field Alert reports on drug
products manufactured or distributed within
or outside the U.S.
• U.S. Office/Agent - responsible for reporting
to FDA district office where registered/located
• Notify the district office within 3 working days
56
FAR - Reporting Requirements
• Information may be provided by telephone or other rapid
communication means, with prompt written follow-up
• Form FDA 3331
• Internet Availability of Form 3331 - Word Format
http://www.fda.gov/opacom/morechoices/fdaforms/cder.html
or
http://forms.psc.gov/forms/MSWFDA/FDA-3331.doc
57
FAR - Timeframe: 3 Working Days
• Starts
– Firm becomes aware of a reported problem
• Complaint
• Internal testing
58
FAR - Firm Reporting
• FAR Required
– Further investigation required
– Corrective action initiated
• e.g., Formulation revision, labeling change
– Product Recall
• FAR Not Required
– Problem is resolved within 3 working days
• e.g., Analytical lab error
59
FAR - Regulatory Actions
• Warning Letter
– When appropriate
• Significance
• Previously cited
• Concurrence with headquarters
• Withdrawal of Approval - CFR 314.81(d)
60
FAR - Impact on Public Protection
• Recalls
(types 21 CFR Section 7.3)
• Corrective Actions
• Discontinuation
61
Regulation of Drug Manufacturing
Further Action by FDA
• Warning Letters
• Adverse Publicity
• FDA “Requested” Recalls (21 CFR §7.45)
• Suspension or Withdrawal of Product Approval
• Impact on Award of Government Contracts
• Seizures
• Injunctions
• Criminal Prosecutions
62
Thank You
63