Interpretation of Part 11 by the GxP Predicate Rules

Agenda

Predicate Rules Background

Predicate Rules and 21 CFR Part 11

A Few Examples of Where in the GxPs Records are Required to be Created and Maintained

Sigs Too!

How Does It Work?

Laws within the US are formulated by Congress and enter into the United States Code of Federal Regulations

Once approved by Congress and the President

The United States Code of Federal Regulations (CFR) is official record of all US Federal Law

Holds regs for the implementation of the US Acts (Laws)

The root of the US document hierarchy

Proposed regs are first published in the Federal Register for public comment

Once approved, entered in final form into the CFRhttp://www.access.gpo.gov/cgi-bin/cfrassemble.cgi?title=199821

The CFR

The Code of Federal Regulations is divided into Titles…

The two Titles relevant to Pharma are…

Title 21 Food and Drugs

Title 42 The Public Health and Welfare

Within Title 21 that we find various “Parts” e.g. 21 CFR Part 11 on ERES and 21 CFR Part 820 on Quality Systems

Title 21 and 42

Each contains chapters dealing with a wide range of food, drug and health issues

The important chapter in Title 21 is Chapter 9, the Federal Food, Drug, and Cosmetic Act (The Act)

Title 21 §393 authorizes the existence of the FDA as part of the US Department of Health and Human Services, to carry out its duties

Title 42, Public Health, contains Chapter 6A, the Public Health Service Act (PHS)

Other “Parts”

21 CFR Part 312: Investigational New Drug Application

21 CFR Part 314: Application For FDA Approval To Market New Drug

21 CFR Part 52: Obligation of Sponsors and Monitors of Clinical Investigation

21 CFR Part 54: Financial Disclosure by Clinical Investigators

21 CFR Part 50: Protection of Human Subjects

21 CFR Part 56: Institutional Review Boards

21 CFR Part 310: New Drugs

21 CFR Part 820: Quality System Regulation

http://www.access.gpo.gov/nara/cfr/cfr-table-search.html#page1

So What Are The Predicate Rules?

“The Underlying Requirements Set Forth in the US Federal Food, Drug, and Cosmetic Act (The Act),

US Public Health Service (PHS) Act,

..and FDA Regulations Under Title 21 are Referred to in the Part 11 Guidance Document as….

Predicate Rules”.

The term “predicate rules” should really only be used in relation to US regulations

However, there is creeping usage of the term to refer to both US and European higher-level regulations

Scope, 21 CFR 11.1

Records are Required by a “Predicate Rule”

Predicate Rules, not Part 11, Determine:

Record creation

Record content

Record signature requirements

Record retention period

Archiving

Original vs copy

Guidance Documents

In Addition to the Regulations in the CFR, the FDA Also Publishes a Number of Guidance Documents

To Assist in Understanding the Various Rules and Regulations

Not Binding on the Industry or Agency

Only Represent the FDA’s “Current Thinking”“Contains Non-Binding Recommendations”

What About E-Signatures?

For Electronic Signatures, the Requirements Imposed Upon Systems Not Only Come Form Pharmaceutical Regulations but From Other Legislation

Such as the ….

US E-sign Act (2000)

EU Directive 1999/93/EC on Electronic Signatures

Predicate Rules & Part 11

The Predicate RulesGLP:

21 CFR 58 Good Laboratory Practice for Non-Clinical Lab Studies

GCP:

21 CFR 310 New Drugs

21 CFR 312 Investigational New Drug Application

21 CFR 314 Applications For FDA Approval To Market A New Drug

21 CFR 510 New Animal Drugs

21 CFR 511 New Animal Drugs For Investigational Use

21 CFR 514 New Animal Drug Applications

GMP:

21 CFR 210 Current Good Manufacturing Practice In Manufacturing, Processing, Packing, Or Holding Of Drugs

21 CFR 211 Current Good Manufacturing Practice For Finished Pharmaceuticals

QSR:

21 CFR 820 Quality System Regulation

Food related "GMPs"; ‘GOOD FOOD PRACTICES’:

PART 106 Infant Formula QC Procedures

PART 110 Current Good Manu Practice in Manu, Packing and Holding Human Food

PART 113/114 Thermally Processed and Acidified Low-Acid Canned Foods

PART 123 Fish and Fishery Products

PART 129 Bottled Drinking Water

Records and Signatures Subject to Part 11

Any Record Required by FDA that is in Electronic Form

Any Electronic Signature that Appears in an FDA-required Record, Whether or Not Signature is Required

Electronic Submissions to FDA

E-Records?

Predicate Rules Apply?

High Risk?

Audit

Remediation Plan

NOT Part 11 Records

No

No

No

Part 11 Decision Flow Chart

Importance of Predicate Rules

21 CFR 11 Interpretation Always via Predicate Rules

GMP, GLP, GCP

Draft Guidance Places Increased Emphasis on Predicate Rule Interpretation

Not all e-records produced by a company are Part 11 records

Documented assessment

Read predicate rules and understand where records and signatures are required

How Will Investigator Evaluate Compliance With Part 11 During an Inspection for Another Purpose?

An investigator will look at records to evaluate compliance with the predicate rule. At the same time, the investigator may check compliance with Part 11 for adequacy of recordkeeping.

Understanding Predicate Rules

Some Requirements for Signatures are Explicit:

“signature or initials”

“handwritten, full signature”

Others are Implicit:

“approved”

“authorized”

Part 11 Guidance Document Predicate Rule Reference: Triggering Part 11

Under narrow interpretation, FDA considers Part 11 to be applicable to the following records or signatures in electronic format:

Records that are required to be maintained under predicate rule requirements and that are maintained in electronic format in place of paper format. On the other hand, records (and any associated signatures) that are NOT required to be retained under predicate rules, but that are nonetheless maintained in electronic format, are NOT part 11 records.

We recommend that you determine, based on the predicate rules, whether specific records are Part 11 records. We recommend that you document such decisions.

Guidance Document Predicate Rule Reference: Time Stamps

“Persons must still comply with all applicable predicate rule requirements related to…

…documentation of….

…date, time, or sequencing of events…

…and requirements for ensuring that changes to records do not obscure previous entries.”

e.g., § 58.130(e)

11 Guidance Document Predicate Rule Reference: e-Signatures

“Electronic signatures that are intended to be the equivalent of handwritten signatures, initials, and other general signings required by predicate rules. Part 11 signatures include electronic signatures that are used, for example, to document the fact that certain events or actions occurred in accordance with the predicate rule (e.g. approved, reviewed, and verified).”

“….must still comply with all applicable predicate rule requirements for validation (e.g., 21 CFR 820.70(i)).”

“We suggest that your decision to validate computerized systems, and the extent of the validation, take into account the impact the systems have on your ability to meet predicate rule requirements.”

Part 11 Guidance Document Predicate Rule Reference: Validation

“The system [must meet] all applicable predicate rule requirements before the effective date.”

“The system [must] currently meet all applicable predicate rule requirements.”

“If a system has been changed since August 20, 1997, and if the changes would prevent the system from meeting predicate rule requirements, Part 11 controls should be applied to Part 11 records and signatures…”

Part 11 Guidance Document Predicate Rule Reference: Legacy Systems

Part 11 Guidance Document Predicate Rule Reference: Copies of Records

“All records held by you are subject to inspection in accordance with predicate rules (e.g., §§ 211.180(c), (d), and 108.35(c)(3)(ii)).”

“Persons must still comply with all applicable predicate rule requirements for record retention and availability (e.g., §§ 211.180(c),(d), 108.25(g), and 108.35(h)).”

“We suggest that your decision on how to maintain records be based on predicate rule requirements and that you base your decision on a justified and documented risk assessment and a determination of the value of the records over time.”

“Persons must still comply with all predicate rule requirements, and the records themselves and any copies of the required records should preserve their content and meaning.”

“As long as predicate rule requirements are fully satisfied and the content and meaning of the records are preserved and archived, you can delete the electronic version of the records.”

Part 11 Guidance Document Predicate Rule Reference: Record Retention

21 CFR Part 211 cGMP

§211.182 – Equipment Cleaning and Use Log

§211.184 – Component, Drug Product Container, Closure and Labeling Records

§211.186 – Master Production and Control Records

§211.188 – Batch Production and Control Records

§211.192 – Production Record Review

§211.194 – Laboratory Records

§211.196 – Distribution Records

§211.198 – Complaint Files

21 CFR Part 211 cGMP

For Finished Pharmaceuticals

Covers Use of Computers

§211.68; Automatic, mechanical and electronic electronic equipment

Covers Use of Records

§211.180 – 211.198; Records and reports

§211.194 : Order of Signing

Laboratory Records

(7) The initials or signature of the person who performs each test and the date(s) the tests were performed.

(8) The initials or signature of a second person showing that the original records have been reviewed for accuracy, completeness and compliance with established standards.

Evaluate Systems Carefully:

What is a signature versus identification of action

Two signatures only required for each test

Order of signing is important: technical control for system

§211.100: Written Procedures; Deviations

(a)…. These written procedures, including and changes shall be drafted, reviewed and approved by the appropriate organizational units and reviewed and approved by the quality control unit.

(b)… Any deviation from the written procedure shall be recorded and justified.

No Stated Requirement for a Record of the Paper Procedure

Defined Sign-offs Required for the Final Procedure

Deviations: No Stated Requirement for Signatures or Initials

Part 211: Record Requirements

§211.188 Batch Production & Control Records

Batch production and control records shall be prepared for each batch of drug product produced and shall include complete information relating to the production and control of each batch

§211.194(a) Laboratory Records

Laboratory records shall include complete data derived from all tests necessary to assure compliance with established specifications and standards

§ 211.68: Record Requirements

For Automatic, Mechanical and Electronic Equipment

(a) Automatic, mechanical, or electronic equipment or other types of equipment, including computers, or related systems that will perform a function satisfactorily, may be used in the manufacture, processing, packing, and holding of a drug product.

If such equipment is so used, it shall be routinely calibrated, inspected, or checked according to a written program designed to assure proper performance. Written records of those calibration checks and inspections shall be maintained.

Record Integrity: §211.68(b)

(b) Appropriate controls shall be exercised over computer or related systems to assure that changes in master production and control records or other records are instituted only by authorized personnel. Input to and output from the computer or related system of formulas or other records or data shall be checked for accuracy.

The degree and frequency of input/output verification shall be based on the complexity and reliability of the computer or related system.

Record Back-up: §211.68(b)

A backup file of data entered into the computer or related system shall be maintained except where certain data, such as calculations performed in connection with laboratory analysis, are eliminated by computerization or other automated processes.

In such instances a written record of the program shall be maintained along with appropriate validation data.

Hard copy or alternative systems, such as duplicates, tapes, or microfilm, designed to assure that backup data are exact and complete and that it is secure from alteration, inadvertent erasures, or loss shall be maintained.

Retention Period: §211.180

a) Any production, control, or distribution record that is required to be maintained in compliance with this part and is specifically associated with a batch of a drug product shall be retained for at least 1 year after the expiration date of the batch or, in the case of certain OTC drug products lacking expiration dating because they meet the criteria for exemption under § 211.137, 3 years after distribution of the batch.

(b) Records shall be maintained for all components, drug product containers, closures, and labeling for at least 1 year after the expiration date or, in the case of certain OTC drug products lacking expiration dating because they meet the criteria for exemption under § 211.137, 3 years after distribution of the last lot of drug product incorporating the component or using the container, closure, or labeling.

§211.68(b): Risk

Computerised Systems “Changes to Records Made by Authorized Personnel”

Many firms use a help desk to co-ordinate change requests for GXP systems

Help desk software needs to be validated: e- records

Risk assessment: what is the impact on product safety, efficacy and quality?

Direct?

Indirect?

Record Inspection: §211.180(c)

All records required under this part, or copies of such records, shall be readily available for authorized inspection during the retention period at the establishment where the activities described in such records occurred. These records or copies thereof shall be subject to photocopying or other means of reproduction as part of such inspection. Records that can be immediately retrieved from another location by computer or other electronic means shall be considered as meeting the requirements of this paragraph.

Record Archival: §211.180(d)

Records required under this part may be retained either as original records or as true copies such as photocopies, microfilm, microfiche, or other accurate reproductions of the original records. Where reduction techniques, such as microfilming, are used, suitable reader and photocopying equipment shall be readily available.

21 CFR Part 58 GLP

Subpart J—Records and Reports

§58.185 Reporting of Non-clinical Lab Study Results

§58.190 Storage and Retrieval of Records and Data

§58.195 Retention of Records

Raw Data

Definition of ER from Part 11

Broad scope

Predicate Rules Define Application to ER

Narrow scope

FDA Guidance to Clarify

Industry Coalition Seeks to Define “Raw Data” as NOT Being ER

Raw Data: 21 CFR Part 58

FDA Says “Raw Data” Available for Inspection Requires Integrity as Electronic Records

(k) Raw data means any laboratory worksheets, records, memoranda, notes, or exact copies thereof, that are the result of original observations and activities of a non-clinical laboratory study and are necessary for the reconstruction and evaluation of the report of that study.

In the event that exact transcripts of raw data have been prepared (e.g., tapes which have been transcribed verbatim, dated, and verified accurate by signature), the exact copy or exact transcript may be substituted for the original source as raw data.

Raw data may include photographs, microfilm or microfiche copies, computer printouts, magnetic media, including dictated observations, and recorded data from automated instruments.

Records Storage and Retrieval: §58.190

(a) All raw data, documentation, protocols, final reports, and specimens (except those specimens obtained from mutagenicity tests and wet specimens of blood, urine, feces, and biological fluids) generated as a result of a non-clinical laboratory study shall be retained

(b) There shall be archives for orderly storage and expedient retrieval of all raw data, documentation, protocols, specimens, and interim and final reports. Conditions of storage shall minimize deterioration of the documents or specimens in accordance with the requirements for the time period of their retention and the nature of the documents or specimens. A testing facility may contract with commercial archives to provide a repository for all material to be retained. Raw data and specimens may be retained elsewhere provided that the archives have specific reference to those other locations

(c) An individual shall be identified as responsible for the archives

(d) Only authorized personnel shall enter the archives

(e) Material retained or referred to in the archives shall be indexed to permit expedient retrieval

GLP Raw Data

Bottom Line:

Apply risk analysis to evaluate the importance of ‘raw data’

Document how the data is being controlled to ensure integrity based upon its value to the integrity of the ER it supports

i.e. Save data records in a normal manner

Save checksum of data records as ER

Equipment Design: §58.61

Equipment used in the generation, measurement, or assessment of data …. shall be of appropriate design and adequate capacity to function according to the protocol and shall be suitability located for operation, inspection, cleaning and maintenance

Note similar requirements for 21 CFR 211.63

Appropriate Design:

Write a user requirements specification

Adequate Capacity:

Design – liaison with IT and/or supplier

Incorporate in a design document or URS

Suitably Located:

Read and follow the supplier’s instructions

Documented evidence of installation (IQ/OQ)

21 CFR Part 820 QSR

§820.180 – General Requirements

§820.181 – Device Master Record

§820.184 – Device History Record

§820.186 – Quality System Record

§820.198 – Complaint Files

21 CFR Part 820 QSR

21 CFR Part 820 – Quality Systems Regulation

Covers the use of computers in devices

§820.30 Design controls

§820.70 Production and Process Controls

Covers records for device development

Subpart M, §820.180 – 820.198

Automated Processes: 820.70(i)

When computers or automated data processing systems are used as part of production or the quality system, the manufacturer shall validate computer software for its intended use according to an established protocol.

All software changes shall be validated before approval and issuance.

These validation activities and results shall be documented

Wide Scope:

Systems for QMS and device production

Intended Use:

Write a user requirements specification

Established Protocol:

CSV policy, validation plan and testing scripts

Changes Approved:

Change control SOP & authorization signatures

Record Requirements: §820.30(a)(1)

Each manufacturer of any Class III or Class II device, and the Class I devices ….. shall establish and maintain procedures to control the design of the device in order to ensure that specified design requirements are met

If Electronic, Records within and About the Equipment Must Meet Part 11 Requirements

Record Requirements: §820.180(i)

When computers or automated data processing systems are used as part of production or the quality system, the manufacturer shall validate computer software for its intended use according to an established protocol.

All software changes shall be validated before approval and issuance

These validation activities and results shall be documented

Record Retention Period : §820.180(b)

All records required by this part shall be retained for a period of time equivalent to the design and expected life of the device, but in no case less than 2 years from the date of release for commercial distribution by the manufacturer.

Record Archival : §820.180

All records required by this part shall be maintained at the manufacturing establishment or other location that is reasonably accessible to responsible officials of the manufacturer and to employees of FDA designated to perform inspections.

Such records, including those not stored at the inspected establishment, shall be made readily available for review and copying by FDA employees.

Such records shall be legible and shall be stored to minimize deterioration and to prevent loss

Those records stored in automated data processing systems shall be backed up.

Summary

Predicate Rules Rule!!

You Must Be Familiar With What Records and Signatures Are Required By the Applicable Predicate Rules

Part 11 Is Triggered By

Predicate Rule Requirements

High Risk

Electronic Decision Making

Incorporate a Risk Analysis

Document Your Justification

Thank You For Your Attention!

Questions……………………?