1. FDA cGMP Training Program
cGMP in the USA
Nicholas Buhay
Deputy Director
Division of Manufacturing & Product Quality
Office of Compliance, CDER, FDA

2. Current Good Manufacturing Practice
Introduction to
Drug
Current Good Manufacturing Practice
Of US FDA

3. An Outline Legal bases for CGMP CGMP legal principles
CGMP Implementation Tools
CGMP Resources
Overview of CGMP Requirements
Integrity of Records and Data

4. FD&C Act; 501(a)(2)(B) “A drug 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 ...”
Prohibited Acts: 301, doing or causing:
introducing or delivery for intro into IS of drug that’s adulterated (misbranded)
adulterating (misbranding) of drug in IS commerce
receipt in IS of adulterated (misbranded) drug, and delivery or proffered delivery thereof for pay or otherwise
manufacture in US Territory of drug that’s adulterated (misbranded
more...

5. FD&C Act; 501(a)(2)(B)
“to assure that such drug meets the requirements of this Act as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess.”
Reason for CGMP

6. CGMP legal principles Quality built into product
By “taking care” in making medicine
Can’t ‘test’ into product the quality
Without/Inadequate CGMP
Product(s) adulterated(defects need not be shown)
Firm and its management are responsible

7. CGMP legal principles Non-compliance = eventual problems
Superpotency/subpotency
Contamination
Misbranding
Bioavailability
Safety and efficacy

8. CGMP Legal Principles Scope Ingredients (APIs + excipients)
Finished dosage forms administered to humans/animals
OTC, Rx products
Biologics, veterinary drugs
Drugs undergoing study(IND, etc)
Manufacturers, test laboratories, packagers(including pharmacies)

9. CGMP legal principles Excluded from the CGMP requirement
Positron emission tomography, per FDAMA (own CGMP to be developed)
Drug products compounded per Section 503 Pharmacy Compounding (FDAMA)

10. CGMP Legal Principles Current = dynamic Good practices
Standards evolve over time
Good practices
Minimal standards
Not “best practices”
Unless “best” is, in fact, current minimal
C in CGMP

11. CGMP Legal Principles Feasible and valuable
No threshold for “percentage” in practice
Doesn’t have to be “predominant”
Enforceable even if nobody is doing it
Stronger case if someone is doing it

12. The CGMP Regulation CGMP for Finished Pharmaceuticals 21 CFR 210, 211
First issued: June 1963
Today’s version: September 1978
Scope
Dosage forms for human/vet/biologics
OTC, Rx, IND, NDA, Medical Gases
Not: pharmacies, ingredients, non-clinical research, etc

13. The CGMP Regulation CGMP for Finished Pharmaceuticals 21 CFR 210, 211
Substantive
Force and effect of law
Constitute major part of (not entire) CGMP
more...

14. The CGMP Regulation CGMP for Finished Pharmaceuticals 21 CFR 210, 211
Establish “what to” do, not “how to” do
Minimal standards
Maximum flexibility
Specific enough to address problems
e.g., Penicillin contamination control
Technology neutral
Scalable

15. CGMP Implementation Tools
Compliance Policy Guides
Specific actions we do related to CGMP
Examples:
Sub Chapter 410 Bulk Drugs
The regulations for finished pharmaceuticals will be applied as guidelines for bulk drugs
Sub Chapter 420 Compendial (USP)/Test Requirements Ex:USP not required for release test
Other Sub Chapters
Labeling and Repackaging
Stability/Expiration
Process Validation
Etc

16. CGMP Implementation Tools
CGMP Guidance Documents
Principles:
Not requirements
Agency “current thinking”
Detailed, technical
Expression of “How to” meet “what to” do (requirements)
Shape industry behavior
offers routes to efficiency in meeting CGMP requirement, evaluation of compliance

17. CGMP Implementation Tools
CGMP Guidance Documents (Examples)
General Principles of Process Validation
Compressed Medical Gases
Sterile Drug Products Produced by Aseptic Processing
Guideline on the Preparation of Investigational New Drug Products
more...

18. CGMP Implementation Tools
CGMP Guidance Documents
Investigating Out of Specification Test Results for Pharmaceutical Production
Manufacturing, Processing or Holding of Active Pharmaceutical Ingredients

19. CGMP Implementation Tools
CGMP Compliance Programs –Instructions to FDA inspectors
Drug Manufacturing Inspections Program
Systems-based assessment of site
Preapproval Inspection Program
Points to inspect
Laboratory support
Regulatory approaches

20. CGMP Implementation Tools
CGMP Guides to Inspection of….
Help field investigators apply CGMP
Uncover need for CGMP changes
Specific to topics (e.g., cleaning validation)

21. CGMP Resources Internet WWW site by DMPQ http://www.fda.gov/cder/dmpq
CGMP regulations and ongoing changes
Preamble to the CGMP regulation
Division subject contacts
Medical gases
Active pharmaceutical ingredients
Human Drug CGMP Notes/Policy
etc.

22. Overview of CGMP requirements in the regulation
CGMP Regulations
21 CFR 210
Status of the regulations
Applicability of the regulations
Definitions
Batch
Lot
In-process material
Quality control unit
Representative sample
etc

23. Overview of CGMP requirements in the regulation
CGMP Regulations
21 CFR 211
Subpart A General Provisions
Subpart B Organization an Personnel
Subpart C Buildings and Facilities
Subpart D Equipment
Subpart E Control of Cmpnts/Cntr/Closures
Subpart F Production and Process Controls
Subpart G Packaging and Labeling Controls
more...

24. Overview of CGMP requirements in the regulation
CGMP Regulations
21 CFR 211
Subpart A General Provisions
this is minimum CGMP

25. Overview of CGMP requirements in the regulation
CGMP Regulations
21 CFR 211
Subpart B Organization and Personnel
There shall be a quality control unit
quality control unit responsibility to approve/reject

26. Overview of CGMP requirements
CGMP Regulations
21 CFR 211
Subpart C Buildings and Facilities
buildings shall be….suitable
operations to be in specifically defined areas….separate…. Or such other control systems for ….operations as are necessary to prevent contamination or mix-ups…. (see list, includes aseptic processing)
“separate” facilities for penicillin
building….shall be….clean and sanitary

27. Overview of CGMP requirements
CGMP Regulations
21 CFR 211
Subpart D Equipment
surfaces ….shall not be reactive, additive, or absorptive
Equipment….shall be cleaned, maintained and sanitized….

28. Overview of CGMP requirements
CGMP Regulations
21 CFR 211
Subpart E Control of Components, Containers and Closures
containers and closures ….handled in a manner to prevent contamination.
Testing or examination of c/c/c’s
test to identify each component
tests on components for conformance with specs
test c/c/c’s microscopically, for adulterants, microscopically

29. Overview of CGMP requirements
CGMP Regulations
21 CFR 211
Subpart F Production and Process Controls
written procedures for production and process control
formulated not less than 100 %
portions of components identified, examined by a 2nd person before dispensed for use in manufacture
sampling and testing of in-process materials and products, some specified
time limits
reprocessing allowed, but controlled

30. Overview of CGMP requirements
CGMP Regulations
21 CFR 211
Subpart G Packaging and Labeling Controls
examination, approval of labels, labeling
strict control over labeling issue, and return to stock
written procedures, physical separation of labeling operations
examination of materials before use
inspection of facilities immediately before
tamper resistant packaging (for OTC products)
expiration dating

31. Overview of CGMP requirements
CGMP Regulations
21 CFR 211
Subpart H Holding and Distribution
Subpart I Laboratory Controls
Subpart J Records and Reports
Subpart K Returned and Salvaged Drug Products

32. Overview of CGMP requirements
CGMP Regulations
21 CFR 211
Subpart H Holding and Distribution
quarantine before release
store under appropriate conditions

33. Overview of CGMP requirements
CGMP Regulations
21 CFR 211
Subpart I Laboratory Controls
establish specs, standards, sampling plans, test procedures
calibration, of laboratory equipment
test each batch of drug product
adequate acceptance criteria
validate test methods
conduct stability program
more....

34. Overview of CGMP requirements
CGMP Regulations
21 CFR 211
Subpart I Laboratory Controls
Special tests
sterility and pyrogenicity
ophthalmic ointments for foreign/abrasive particles
controlled release products for rate of release
keep reserve samples
test non-penicillin products for penicillin when reasonable possibility of exposure to presence of penicillin

35. Overview of CGMP requirements
CGMP Regulations
21 CFR 211
Subpart J Records and Reports
keep records, make available for inspection
conduct annual review of each drug product for changes to specs, control procedures
keep equipment cleaning and use log
keep component, container, closure and labeling records more....

36. Overview of CGMP requirements
CGMP Regulations
21 CFR 211
Subpart J Records and Reports
have SOP for master production and control record, maintain record
use batch production and control records for manufacture, keep records
records to be reviewed/approved by qual control unit
complete data derived from all tests necessary to assure compliance
more....

37. Overview of CGMP requirements
CGMP Regulations
21 CFR 211
Subpart J Records and Reports
distribution records, with lot numbers(except medical gases)
complaint files

38. Problem Applications for approval [AIP]
Drug Regulatory Program depends heavily on the reliability (i.e. truthfulness, completeness and accuracy) of data & information in records
Applications for approval [AIP]
Manufacturing Controls documentation [non-AIP]
Historical experience with broad scale unreliability of data in records or in conduct related to records
In the late 80's, several FDA employees were found to have taken illegal gratuities ranging from thousands of dollars to eating lunch at a fast food restaurant which was paid for by company representatives (lied about it) in exchange for moving certain applications ahead of previously submitted applications in the agency’s cue. Examples of wrongful acts committed by Industry appear on Pages 2 -5 of the handouts that I have given you. These are examples of inaccurate and unreliable data submitted by applicants to FDA. These findings became known as the Generic Drug Scandal. The Application Integrity Policy is one of a number of changes that resulted from the scandal (along with the inception of the preapproval inspection program as we know it today).
The Fraud Policy (fraud, untrue statements of material facts, bribery and illegal gratuities, final policy) was published in Sept We no longer refer to the policy as the fraud policy since the term fraud has a specific legal definition which includes proving intent. Intent does not need to be proven in AIP cases.
Also, as a result of the Generic drug Scandal, CDER requested in-depth inspections of most of the large generic drug manufacturers and found that submission of unreliable or inaccurate data to applications (data integrity problems) was a significant problem that was extant. The AIP policy was created to deal with the data integrity problems.

39. Data and records that are not acceptable or are misleading
What are some characteristics of data that lack integrity?
Untrue, made up, false, no source in an event
Omission of significant data from the submission that is determined to be material to the review process. Data that is not submitted, but should have been
Inaccurate (e.g. First data failed specs, retest data passes specs, no lab investigation, but retest data is submitted to the application.)

40. Records Must be True
All data and information in records submitted to FDA & supporting documents in the possession of the applicant are accurate & true representations of -
Actual tests performed & the test results
Actual manufacturing & quality control steps & procedures associated with the development and manufacture of the submission batch (clinical/pilot or biobatch)
any other actions and conditions associated with the application

41. Wrongful Acts
Any act or conduct that subverts the integrity of the review process, including, but not limited to the following:
submitting fraudulent applications
offering or promising a bribe or illegal gratuities
making an untrue statement of a material fact (e.g. false statement, a misstatement or an omission of a fact)
submitting unreliable data which results from system-wide or firm-wide behavior
The first two wrongful acts are the most serious instances and are handled in a similar way. These kinds of things were prevalent when the scandal first broke(around 1989 and 1990), but presently, when data integrity problems are found they fit into the third and fourth category. Materiality isn't an issue with the first two wrongful acts
The untrue statements and unreliable data definitions in the 3rd and 4rth bullets include the ADDITIONAL requirement that the finding be "material" or "important" to the review process.

42. Wrongful Acts (continued)
An untrue statement of material fact is a false statement, a misstatement or an omission of a fact that is important in the review process.
System-wide incompetence is also a wrongful act
When an untrue statement of material fact or system-wide incompetence is found, several steps are required to the invoke the AIP including:
Documentation of a pattern or practice of wrongful acts.
Ensuring that the untrue statements are material facts.
These kinds of findings are seen today, often in only one application.
Additional investigation is needed to determine the depth of the problem and to ensure a pattern or practice.
An example of an untrue statement would be repeated retesting without determining the cause of the original failure and submitting only good results. General incompetence is self explanatory, for example grossly inadequate SOPs, employees that lacked the training needed to do a competent job, etc.
In both cases, unreliable data reaches the reviewer and in both cases the act raises significant question regarding the reliability of the data.
Generally, after findings are documented and submitted, the center Office of Compliance will request a materiality review.

43. Pattern or Practice
Pattern- More than one instance of errors or acts involving the subject matter important to the evaluation of an application
Practice- An act or process of doing something affecting subject matter important to the evaluation of an application
A practice can be one or more acts or processes. A pattern or practice can occur in one or more applications.
Basically, a practice is doing something that affects the data that is important to the evaluation of an application. A pattern is doing it more than once in the same application or in more than one application.
This can also include basic incompetence, for example repeatedly making math errors that aren't caught by the applicant’s reviewing official that results in unreliable data going to an application. Inadequate training, supervision and SOPs will also likely be found
If problems are found in one application, it is usually necessary to expand the inspection to include a representative number of other applications.
The RPM indicates that it is still possible to invoke the AIP if only one application is involved, however, it may be more appropriate to use the review process to deal with a single application, e.g. find a pending application unapprovable. The review process will generally not be adequate if problems are very serious and SOPs are totally inadequate or if the firm will not properly train or even remove employees that are responsible for the original unreliable date.

44. If submitted to an Application
The AIP procedures broadly define the term, “application” to include, but not be limited to, any application, amendment, supplement or other submission made by an applicant.
“Submitted” is an understandable term and includes documents received by the review branch.
Wrongful acts also include omissions of data and/or information that should have been submitted to an application.
DON'T READ SLIDE
On the surface, submitted seems like an understandable term.
But it may be appropriate to expand this to include instances when an application is submitted that contains false date and is subsequently withdrawn by a firm or where a submission is prepared and reviewed and ready to be mailed.
There is legal concept of "moral equivalency" and these examples may be considered the same as submitted to the application.

45. Food, Drug, and Cosmetic Act Section 505(e) (excerpt below)
Numbered Part 5
The Secretary shall, after due notice and opportunity for hearing to the applicant,withdraw approval of an application with respect to any drug under this section, if the Secretary finds….
(5) that the application contains any untrue statement of a material fact

46. TO INVOKE AIP
Documentation of a pattern or practice of wrongful conduct that raises significant questions about the reliability of data submitted to an application wrongful acts pattern or practice unreliable data

47. Restore FDA’s Confidence in Data???
Cooperation with investigators
Identification of involved individuals
Credible internal review & actions
Problem analysis/identify all instances of wrongful acts
Use of impartial auditor/Outside consultant
Audit Plan, audits, audit reports
Other measures as FDA deems appropriate

48. Restore FDA’s Confidence in Data
Corrective Action Operating Plan:
Analysis of audit findings
Implementation of auditor recommendations
Actions taken to correct fraud/wrongful acts, e.g.
Withdraw applications & recall products
Timetable
Identification of persons assigned to complete and verify corrective actions
Comprehensive ethics program
Procedures for monitoring effectiveness of the plan
Training in the requirements of the Act and 18 USC 1001

49. Corrective Actions Plan Evaluation
Monitor applicant’s actions/inquiries during internal review
Inspection to assess actions taken by applicant to determine if
Internal Review performed adequately
Corrective Action Operating Plan implemented adequately
Submit recommendation to CDER to remove site from the policy
Expect a long time to pass before restoration

50. Overview of CGMP requirements
CGMP Regulations
21 CFR 211
Subpart K Returned and Salvaged Drug Products
if conditions cast doubt returned product shall be destroyed unless proved ok by test, examination, investigation
salvage only if evidence from tests and inspection show all standards met

51. Input for CGMP Changes Establishment inspections
Industry changes/problems
Defect reports/complaints/recalls
Litigation
Agency application reviews
Trade/scientific literature
Citizen petitions

52. Management of CGMP Regulatory Program
FDA/CDER
OC/Division of Manufacturing and Product Quality
maintenance of the regulation
definitive interpretation
manage guidance development
develop, operate, evaluate programs
train FDA/outreach to industry
CGMP not NDA or firm specific

53. We Have Discussed Legal bases for CGMP CGMP legal principles
CGMP Implementation Tools
CGMP Resources
Overview of CGMP requirements
Integrity of Records and Data

54. Nicholas Buhay E-mail: buhay@cder.fda.gov Deputy Director
Division of Manufacturing
and Product Quality, HFD-320
Center for Drug Evaluation and Research
Phone:
Fax:
Montrose Metro Centre II Room 438
11919 Rockville Pike
Rockville, MD 20852

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