Good Manufacturing Practices and Enforcement Actions

1
Good Manufacturing Practices and Enforcement
Actions

• Dr. Timothy J. Hahn
• November 4, 2004

2
Introduction

• Good Manufacturing Practices (GMP) ensure
  quality, safety, and consistency
• GMP is the law (Code of Federal Regulations)
• Laws are upheld and enforced by the FDA.
• Enforcement is facilitated by facility inspections

3
Food and Cosmetic Act

• A drug is deemed adulterated if the methods
  used in, or the facilities or controls used for,
  its manufacture, processing, packaging, or
  holding do not conform to or are not operated or
  administered in conformity with current good
  manufacturing practice 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.

4
Food and Cosmetic Act

• A drug is deemed adulterated if the methods
  used in, or the facilities or controls used for,
  its manufacture, processing, packaging, or
  holding do not conform to or are not operated or
  administered in conformity with current good
  manufacturing practice 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.

5
Food and Cosmetic Act

• A drug is deemed adulterated if the methods
  used in, or the facilities or controls used for,
  its manufacture, processing, packaging, or
  holding do not conform to or are not operated or
  administered in conformity with current good
  manufacturing practice 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.

6
What is cGMP?

• Compliance with regulations

7
Code of Federal Regulations

• Title 21 Food and Drugs
• Chapter 1 Food Drug Administration,
  Department of Health Human Services
• Subchapter C Drugs General (contains Parts
  200-299)
• Part 211 Current good manufacturing practices
  for finished pharmaceuticals
• Subpart F Production and Process Controls
• Section 211.100 Written Procedures
  deviations
• Paragraph (b)
• Sub-paragraphs (2)
• Sub-sub paragraph (ii)

8
Code of Federal Regulations21 CFR

• Part 211 Finished Pharmaceutical
• Part 600 Biological Products
• Part 820 Medical Devices

9
What is the purpose of compliance?

• A manufacturer of a drug or biological product
  must ensure that appropriate quality systems are
  in place to provide assurance that products are
  manufactured under a state of control to ensure
  safety, identify, quality, strength, purity.

10
General Language of CFR

• suitable
• adequate
• sufficient
• appropriate
• justified
• qualified
• Exceptions For example, Part 211 Subpart J
  Records and Reports
• Defines what but not necessarily how

11
Example

• Staffing
• CFR 211.25(c)
• Training
• CFR 211.25(a)

12
Staffing

• CFR 211.25(c) There shall be an adequate number
  of qualified personnel to perform and supervise
  the manufacture, processing, packing, or holding
  of each drug product.

13
Staffing

• CFR 211.25(c) There shall be an adequate number
  of qualified personnel to perform and supervise
  the manufacture, processing, packing, or holding
  of each drug product.

14
Training

• CFR 211.25 (a) Each person engaged in the
  manufacture, processing, packing, or holding of a
  drug product shall have education, training, and
  experience, or any combination thereof, to enable
  that person to perform the assigned functions.
  Training shall be in the particular operations
  that the employee performs and in current good
  manufacturing practice as they relate to the
  employee's functions. Training in current good
  manufacturing practice shall be conducted by
  qualified individuals on a continuing basis and
  with sufficient frequency to assure that
  employees remain familiar with CGMP requirements
  applicable to them.

15
Training

• CFR 211.25 (a) Each person engaged in the
  manufacture, processing, packing, or holding of a
  drug product shall have education, training, and
  experience, or any combination thereof, to enable
  that person to perform the assigned functions.
  Training shall be in the particular operations
  that the employee performs and in current good
  manufacturing practice as they relate to the
  employee's functions. Training in current good
  manufacturing practice shall be conducted by
  qualified individuals on a continuing basis and
  with sufficient frequency to assure that
  employees remain familiar with CGMP requirements
  applicable to them.

16
Staffing and Training

• Adequate Number
• Qualified for the Specific Task
• Education
• Training
• Experience
• or appropriate combination
• cGMP Training is sufficient

17
Staffing for Operations

• Considerations for
• Shift (1st, 2nd 3rd or rotating shift, 12 on, 12
  off)
• Weekends, Holidays
• Vacation, sick days, personal days
• Turnover
• Routine, non-routine operations
• Options for
• Overtime
• Cross training
• Compensate with schedule modifications

18
Staffing and Training

• Defined by the firm
• Must ensure processing is performed correctly
• Must be defendable during an inspection
• Must meet current GMP requirements

19
Enforcement

• Administrative
• Inspections (Biennial, Pre-approval, for cause)
• Form FDA 483 Inspection Observations
• Warning Letters
• Delay, suspension, withdrawal of product
  approvals
• Judicial
• Injunctions
• Civil Seizures
• Criminal Prosecution

20
Administrative Action

• Form 482 Notice of Inspection
• Issued to highest ranking responsible person
• Form 483 Inspectional Observations
• Citations of items deemed as non-compliant with
  cGMP
• FDA may take copies of documents with them as
  evidence
• Form 484 Receipt of Samples
• Allow FDA to take samples as evidence
• EIR Establishment Inspection Report
• Official FDA document that describes issues with
  supporting evidence.

21
Establishment Investigation ReportWhat is the
companys status?

• NAI no action indicated
• VAI voluntary action indicated
• Companys responses (explanation or corrective
  actions) to Form 483 observations were acceptable
• OAI official action indicated
• Regulatory sanctions will be recommended
• Warning Letter will be issued
• Response required within 15 working days

22
Opportunities to Understand Inspectors Concerns
and Express Position

• During initial response to an item
• At daily close-out meeting
• At follow-up discussions
• At the close-out meeting to review the Form 483
  observations
• During submission of responses to 483
  observation.
• After issue of EIR letter
• After issue of Warning Letter
• During submission of response to the Warning
  letter
• During meetings with the Agency

23
Response to a Warning Letter

• Correct the objectionable condition
• Commit to completion of a corrective action plan
• Short-term, procedural controls are recommended
  prior to completion of the action plan
• Potential Consequences
• Withdraw of product or license to distribute
  (Ultimate FDA enforcement Action)
• Proceed to Judicial Action

24
Judicial Action

• Injunction
• Stop adulterate product from reaching the market
• Requires non-compliant conditions to be corrected
• Seizure
• Civil court action used to confiscate product
• FDA files a complaint in federal court
• U.S. Marshall confiscates the material (no
  advance warning may be required)
• Criminal Prosecution

25
Consent Decree

• Defendants in an injunction proceeding my consent
  to a Decree of Permanent Injunction
• Negotiated settlement
• Fines
• Penalty charges
• Restrictions on product distribution
• Plan to correct objectionable condition
• Oversight and frequent reporting

26
Schering-Plough Consent Decree

• Four New Jersey and Puerto Rico sites
• 500 Million Fine
• Additional payments and costs
• Suspended manufacture of products
• Expert consultant hired
• Yearly inspections for 3 years

27
Current Good Manufacturing Practices

• Principles
• Quality cannot be tested into a product
• Products must be manufactured under controlled
  conditions where quality is built into the
  process.
• GMP regulations are the minimum requirements
• Current is a moving target
• Take Home Message Stay current

28
How to stay current with GMP?

• Read Warning Letters issued to other companies
  (www.fda.gov)
• Read FDA-issued Guidance Documents (www.fda.gov)
• Attend FDA/Industry seminars
• Through feedback from inspections
• Review internal control systems against the CFR
• Through internal audits

29
Schering-Plough Consent Decree Historical View
of Events related to Testing

• Barr Laboratory Federal Court Case
• Schering-Plough 483 Citations

30
Barr Laboratory

• Federal Court Case
• U.S. vs. Barr Laboratories
• Decided in February 1993
• Impacted the interpretation of GMP for
  out-of-specification test results
• Very visible case and decision!

31
What is an OOS?

• Each release test has
• A testing protocol
• Method
• Number of samples tested
• Method of data analysis
• A release specification range.
• An OOS is an out-of-specification result for a
  release test

32
The U.S. Government Alleged

• Barr discarded failing results based on an
  assumption of laboratory error
• Barr discarded failing results based on
  subsequent passing results on a retest
• Barr discarded initial results after sampling
  different parts of the batch and retesting

33
The U.S. Government Alleged (contd)

• Barr rarely performed true root cause
  investigations
• Barr conducted some investigations but did not
  document results
• The absence of documentation limited an
  evaluation of the merits of the investigation
• Barr would release product by averaging passing
  and non-passing (without an investigation)

34
Highlights of Judges Ruling

• Laboratory investigation consists of more than a
  retest
• Must conduct a thorough investigation to identify
  root cause
• Document results
• Implement corrective action
• When no root cause is found
• Cannot conduct 2 retests and average 3 results
• Cannot use a resample and assume sampling or
  preparation error.

35
Highlights of Judges Ruling (contd)

• An OOS result can be
• Disregarded when laboratory error is documented
• Not disregarded when due to process error
• Additional retesting
• May be performed if scientifically justified
• May not be used to test a product into compliance
• A firm should have
• a procedure to govern the retesting program.
• a predetermined testing protocol prior to
  performing a retest.

36
Current Expectations

• Perform a root cause investigation
• Document investigations
• Implement corrective actions
• Rationale for retesting much be scientifically
  justified
• Do not average passing and failing results,
  unless justified
• Establish a procedure to govern retesting

37
Schering-Plough 483 Citations

• Location
• Manati, Puerto Rico (PR)
• Manati, PR
• La Piedras, PR
• Manati, PR
• La Piedras, PR
• Manati, PR

• Form 483 Issue Date
• March 28, 2000
• December 14, 2000
• February 16, 2001
• February 16, 2001
• June 5, 2001
• June 16, 2001

Issues include insufficient process validation,
failure to follow procedures, insufficient root
cause investigations, insufficient corrective
actions, and inappropriate responses to
out-of-specification results
38
Observations from December 14, 2000

• Uniformity of assay is not always
  representative of the lot being tested. For
  example, one of the units...tested for release
  testing was replaced with another unit when the
  analyst noticed it was not sealed properly. An
  adequate investigation was not conducted and
  what corrective and preventive actions should be
  implemented.

39
Observations from December 14, 2000

• The analytical laboratory is instructed in Doc
  No. 145.188.01 in the event of an
  Out-of-Specification test result for the
  Uniformity of Spray Content that is attributed
  to a possible clogged actuator, to clean
  actuator with methanol and water. However, the
  product insert provided instructsto clean the
  actuator with cold water. The result of the
  retest after the cleaning was within
  specification and was reported as the final
  result.

40
Observations from March 28, 2000

• The procedure Retest/Resample for
  out-of-specifications (OOS) or out-of-guidelines
  (OOG) Results and Analytical Laboratories
  Investigations do not define the step that the
  analyst should perform when the re-injection of
  samples do not confirm the original results. As
  explained by laboratory management the decision
  on what to do in these cases is made on a case to
  case basis and according to the supervisor and
  analyst judgment.

41
Observations from March 28, 2000

• At least in four (OOS) laboratory investigations
  the laboratory practice was to retest only the
  individual (OOS) results, at least in duplicate,
  in a run different from the original one. The
  results obtained are averaged and added to the
  original results as individual values.

42
Observations from March 28, 2000

• Failure to always perform adequate analytical
  laboratory investigations into the cause of
  product out-of-specification (OOS) and atypical
  results
• no data to support conclusion
• firm failed to conduct a linearity test in
  order to demonstrate that the equipment was
  suitable at the specific range of the absorbances
  obtained.

43
Observations from Feb 16, 2001

• Your laboratory failure investigations are
  inadequate in that you re-test without any
  scientific justification until passing results
  are obtained and/or fail to take corrective
  actions to prevent recurrence of the possible
  assigned cause.
• Six specific examples cited.
• No evidence to support this conclusion
• No scientific justification

44
Observations from June 5, 2001

• Your Out of Specification (OOS) laboratory
  investigations system is inadequate in that
• After your laboratory obtained an OOS value, they
  performed the re-testing without justification
  documented.
• Your laboratory investigations fail to support
  the conclusion and/or assignable cause, which
  invalidated the original analytical data and
  validated the data obtained during re-testing.

45
Observations from June 5, 2001

• These investigations do not have analytical data
  to demonstrate the validity of this assignable
  cause. During the inspection, your laboratory
  performed a study to prove this assignable cause
  and they found that this assignable cause
  previously used to invalidate data is not valid.

46
Observations from June 13, 2001

• In the following three recent laboratory
  investigations, you concluded that extraneous
  peaks in sample chromatography were the result of
  contaminated glassware.
• failed to indicate why the glassware for all 10
  samples was presumed to be contaminated while the
  glassware for the standard preparations was not.
• your conclusion was that the presence of the
  extra peak was due to glassware contamination
  introduced by new flasks, even though you
  conducted a special testing of new glassware that
  resulted in chromatography results with any
  extraneous peaks.

47
Current Good Manufacturing Practices

• Principles
• Quality cannot be tested into a product
• Products must be manufactured under controlled
  conditions where quality is built into the
  process.
• GMP regulations are the minimum requirements
• Current is a moving target
• Take Home Message Stay current