GAMP Good Automated Manufacturing Practice GMP Good Manufacturing Practice
PQLI Product Quality Lifecycle Implementation (ISPES) CFR Code of Federal Regulation
QMS Quality Management System QbD Quality by Design
FS Functional Specifications VP Validation Plan
TH4 Thema4
FDA Food and Drug Administration FAT Factory Acceptance Test SAT Site Acceptance Test
CAPA Corrective And Preventive Action BCP Business Continuity Plan
NF Factory Number (unambiguous identification code of each machine)
THEMA4 CONTROL SYSTEM
21 CFR PART 11
COMPLIANCE ASSESSMENT
“Electronic Records; Electronic Signatures”
Document Rev.1
FEDEGARI AUTOCLAVI S.P.A.
S.S. 235 km.8 - 27010 Albuzzano (PV) - ITALY
+39 0382 434111 +39 0382 434150 http://www.fedegari.com
DOCUMENT REVISION LIST
Function Name Date Signature
Written and verified by: Valdation Engineer D. Martigani 12-MAR-2010
Verified by: Automation Mgr. M. Ghelfi 12-MAR-2010
Approved by: Quality System Mgr. R. Boatti 12-MAR-2010
1 12-MAR-2010 DAM D/O 110434.2 Update after critical review according to GAMP 5 0 04-OCT-2004 GIR D/O 110434.1 First issue
Revision no.
Date (dd/mmm/yyyy)
Author Document code
Revision subject
FEDEGARI has made every effort to ensure that information and data contained in this document are accurate and exhaustive.
However, it assumes no responsibility in case of errors or omissions. FEDEGARI reserves itself the right to amend, at any time and without notice, the information regarding the items described in this document. FEDEGARI reserves itself the option of amending this document at any time without notice.
DOCUMENT SECTIONS
This document is composed of the following sections
1 FOREWORD
2 DEFINITIONS
3 COMPLIANCE ASSESSMENT
NOTATIONS
In this document, these notations are used:
NOTICE
for additional notices
REFERENCE
for references to other sections
IMPORTANT NOTICE
for important notices
WARNING!!
for very important notices
INDEX
1 FOREWORD 5
1.1 OVERVIEW...6 1.2 FDA 21 CFR PART 11 “ELECTRONIC RECORDS, ELECTRONIC SIGNATURES”...6 1.2.1 Issuing 21 CFR part 11: history ...6 1.3 THEMA4 CONTROL SYSTEM COMPLIANCE WITH 21CFR PART11 ...7 1.3.1 How Thema4 complies with 21 CFR Part 11?...7 1.3.2 Scope of 21 CFR Part 11 for Fedegari systems ...7 2 DEFINITIONS 8
2.1 ELECTRONIC RECORDS (ER) ...9 2.2 ELECTRONIC SIGNATURE (ES) ...9 3 COMPLIANCE ASSESSMENT 10
SUBPART A--GENERAL PROVISIONS...12
§11.1 Scope ...12
§11.2 Implementation...13
§11.3 Definitions...14 SUBPART B—ELECTRONIC RECORDS...15
§11.10 Controls for closed systems. ...15
§11.30 Controls for open systems...18
§11.50 Signature manifestations...18
§11.70 Signature/record linking...18 SUBPART C--ELECTRONIC SIGNATURES...19
§11.100 General requirements...19
§11.200 Electronic signature components and controls. ...20
§11.300 Controls for identification codes/passwords...21
Section 1 THEMA4 CONTROL SYSTEM
1 FOREWORD
1.1 - Overview
1.2 - FDA 21 CFR Part 11 “Electronic records, Electronic Signatures”
1.3 - Thema4 control system compliance
with 21CFR Part11
1.1 Overview
The production of pharmaceuticals or medical devices is governed by specific manufacturing standards which tend to establish tests meant to ensure a certain qualitative level of the product and define a working method known as Good Manufacturing Practice.
Any automatic system working in this environment has to comply with these rules. Since the 1980s, various control bodies and technical organizations have issued guidelines regarding automatic systems used in the production and control of pharmaceuticals and medical devices.
The need for a shared approach regarding the methods for developing and managing an automatic system in the pharmaceutical field and medical devices (of which the automatic system can be an integral part or be a device in itself) led to the establishment of a study group known as GAMP (Good Automated Manufacturing Practice) Forum, which by transferring the principles of GMP focused its attention on the automatic systems used in these two particular fields.
1.2 FDA 21 CFR Part 11 “Electronic records, Electronic Signatures”
In March of 1997, the Food and Drug Administration issued the final rule providing criteria for acceptance, by the agency itself, of electronic records and signatures as equivalent to paper records and handwritten signatures executed on paper.
This rule was codified as 21 CFR Part 11 Electronic records; Electronic Signatures; Final Rule.
1.2.1 Issuing 21 CFR part 11: history
• 1991 : Request from industry to FDA to accommodate paperless systems to GMP
• July 1992 : FDA announces the intention to use ER/ES
• August 1994 : Issue of the first draft of the proposed rule
• March 1997 : Issue of the final rule
• August 2003 : Issue of “Guidance for Industry” - Electronic Records; Electronic Signatures - Scope and Application
1.3 Thema4 control system compliance with 21CFR Part11
The Thema4 process controller used by Fedegari Autoclavi S.p.A. in its pharmaceutical machines (dry- and moist-heat sterilizers, washing machine, pass box, ..) is the natural evolution of the well-established and reliable Thema3 controller, which has been on the market since 1995.
Thema4 process controller was developed following GAMP approach (GAMP 4 in the Conception and Project initial phases and the next Operation phase of its product life cycle and now, that the system is in the maturity of its Operational life, following the guide line GAMP 5).
1.3.1 How Thema4 complies with 21 CFR Part 11?
Thema4 has a well-structured software program which offers an extensive set of “instruments” (i.e.
variable parameters) that end user can customize (according to its own SOPs) for achieving and “easy and configurable” compliance to “part 11”.
In this way we can state that Thema4 has built in a native compliance with 21 CFR part 11.
The following sections describe how this requirements for a proper management of electronic records and signatures in regulated industries have been interpreted and satisfied by Thema4 computerized control system.
1.3.2 Scope of 21 CFR Part 11 for Fedegari systems
Section 2 THEMA4 CONTROL SYSTEM
2 DEFINITIONS
2.1 - Electronic Records (ER)
2.2 - Electronic Signature (ES)
2.1 Electronic Records (ER)
ELECTRONIC RECORD - ER
(as specified in the “Guidance for Industry” of August 2003)Records that are required to be maintained under predicate rule requirements and that are maintained in electronic format in place of paper format.
Records that are required to be maintained under predicate rules, that are maintained in electronic format in addition to paper format, and that are relied on to perform regulated activities.
2.2 Electronic Signature (ES)
ELECTRONIC SIGNATURE – ES
(as defined in 21 CFR Part 11 § 11.3.(b).(7) )Electronic signature means a computer data compilation of any symbol, or series of symbols, executed, adopted or authorised by an individual to be the legally binding equivalent of the individual’s hand-written signature.
Section 3 THEMA4 CONTROL SYSTEM
3 COMPLIANCE ASSESSMENT
21 CFR PART 11 ELECTRONIC RECORDS;
ELECTRONIC SIGNATURES
DESCRIPTIONS, COMMENTS AND NOTES ON THE COMPATIBILITY OF
THE THEMA4 CONTROL SYSTEM WITH RULE 21 CFR PART 11
Subpart A--General Provisions 11.1 Scope.
11.2 Implementation.
11.3 Definitions.
Subpart B--Electronic Records 11.10 Controls for closed systems.
11.30 Controls for open systems.
11.50 Signature manifestations.
11.70 Signature/record linking.
Subpart C--Electronic Signatures 11.100 General requirements.
11.200 Electronic signature components and controls.
11.300 Controls for identification codes/passwords.
Hereinafter 21 CFR Part 11 is referenced as “Rule.
Comments to Rule (written in italics)
Notes regarding non-applicability on the on the part of the system supplier (written in bold).
Description of the manner in which the system complies with the Rule (written in normal font).
Subpart A--General Provisions
§11.1 Scope
(a) The regulations in this part set forth the criteria under which the agency considers electronic records, electronic signatures, and handwritten signatures executed to electronic records to be trustworthy, reliable, and generally equivalent to paper records and handwritten signatures executed on paper.
(b) This part applies to records in electronic form that are created, modified, maintained, archived, retrieved, or transmitted, under any records requirements set forth in agency regulations. This part also applies to electronic records submitted to the agency under requirements of the Federal Food, Drug, and Cosmetic Act and the Public Health Service Act, even if such records are not specifically identified in agency regulations. However, this part does not apply to paper records that are, or have been, transmitted by electronic means.
(c) Where electronic signatures and their associated electronic records meet the requirements of this part, the agency will consider the electronic signatures to be equivalent to full handwritten signatures, initials, and other general signings as required by agency regulations, unless specifically excepted by regulation(s) effective on or after August 20, 1997.
(d) Electronic records that meet the requirements of this part may be used in lieu of paper records, in accordance with Sec. 11.2, unless paper records are specifically required.
(e) Computer systems (including hardware and software), controls, and attendant documentation maintained under this part shall be readily available for, and subject to, FDA inspection.
Items (c) and (d) define the purpose of this Rule unequivocally: except for any specified exceptions, the FDA will consider “electronic signatures” and “electronic records” as fully equivalent to handwritten ones, provided that they comply with the prescriptions of this rule.
As FDA specifies in the “Guidance for Industry” about the “Scope and Application”
of part 11 (issued on August 2003) the rule shall apply with respect to records required to be maintained under predicate rules when persons choose to use records in electronic format in place of paper format.
If the regulated organization uses paper records to demonstrate the compliance with applicable predicate rules part 11 does not apply.
§11.2 Implementation.
(a) For records required to be maintained but not submitted to the agency, persons may use electronic records in lieu of paper records or electronic signatures in lieu of traditional signatures, in whole or in part, provided that the requirements of this part are met.
(b) For records submitted to the agency, persons may use electronic records in lieu of paper records or electronic signatures in lieu of traditional signatures, in whole or in part, provided that:
(1) The requirements of this part are met;
and
(2) The document or parts of a document to be submitted have been identified in public docket No. 92S-0251 as being the type of submission the agency accepts in electronic form.
This docket will identify specifically what types of documents or parts of documents are acceptable for submission in electronic form without paper records and the agency receiving unit(s) (e.g., specific center, office, division, branch) to which such submissions may be made.
Documents to agency receiving unit(s) not specified in the public docket will not be considered as official if they are submitted in electronic form; paper forms of such documents will be considered as official and must accompany any electronic records. Persons are expected to consult with the intended agency receiving unit for details on how (e.g., method of transmission, media, file formats, and technical protocols) and whether to proceed with the electronic submission.
Section 11.2 repeats and limits the preliminary information given in 11.1(d):
electronic records and signatures can always be used, fully or partially, instead of paper ones, so long as they comply with the prescriptions of this Rule, in the case of documents that are required only to be maintained but not submitted to the FDA.
The supplier of the system, in any case, cannot define what the user intends to manage as “electronic record” or with which “electronic records” and criteria the user intends to associate the “electronic signature”. These choices and their implementation are the exclusive responsibility of the user of the system.
The Thema4 control system allows to make all the documents that it can generate compliant to this Rule.
§11.3 Definitions.
(a) The definitions and interpretations of terms contained in section 201 of the act apply to those terms when used in this part.
(b) The following definitions of terms also apply to this part:
(1) Act means the Federal Food, Drug, and Cosmetic Act (secs. 201-903 (21 U.S.C.
321-393)).
(2) Agency means the Food and Drug Administration.
(3) Biometrics means a method of verifying an individual’s identity based on measurement of the individual’s physical feature(s) or repeatable action(s) where those features and/or actions are both unique to that individual and measurable.
(4) Closed system means an environment in which system access is controlled by persons who are responsible for the content of electronic records that are on the system
(5) Digital signature means an electronic signature based upon cryptographic methods of originator authentication, computed by using set of rules and a set of parameters such that the identity of the signer and the integrity of the data can be verified.
(6) Electronic record means any combination of text, graphics, data, audio, pictorial, or other information representation in digital form that is created, modified, maintained, archived, retrieved, or distributed by a computer system.
(7) Electronic signature means a computer data compilation of any symbol or series of symbols executed, adopted, or authorized by an individual to be the legally binding equivalent of the individual’s handwritten signature.
(8) Handwritten signature means the scripted name or legal mark of an individual handwritten by that individual and executed or adopted with the present intention to authenticate a writing in a permanent form. The act of signing with a writing or marking instrument such as pen or stylus is preserved. The scripted name or legal mark, while conventionally applied to paper, may also be applied to other devices that capture the name or mark.
(9) Open system means an environment in which system access is not controlled by persons who are responsible for the content of electronic records that are on the system.
“Electronic record” characteristic shall be applied not only to so-called “process reports”
but also to any data item or combination of data stored in the system (system configuration, operating programs, calibration data, et cetera).
Choosing what to manage as “electronic record” is not part of the duties of the system supplier and can be done only by the user (as FDA specifies in the
“Guidance for Industry” about the
“2.Definition of Part 11 Records”.
Thema4 allows the user to treat as “electronic records”
(ER) that comply with the provisions of this Rule all the data, parameters, et cetera that can be programmed by the user and contribute significantly to the management or safety of the system.
For Thema4 controller ERs are:
• Process data (Report)
• Recipes
• Configuration data
• Audit trail
Subpart B—Electronic Records
§11.10 Controls for closed systems.
Persons who use closed systems to create, modify, maintain, or transmit electronic records shall employ procedures and controls designed to ensure the authenticity, integrity, and, when appropriate, the confidentiality of electronic records, and to ensure that the signer cannot readily repudiate the signed record as not genuine. Such procedures and controls shall include the following:
Thema4 is a closed system according to the definition of 11.3 b (4) and has access controls and procedures that are designed in compliance with the provisions of Subpart C of this Rule.
(a) Validation of systems to ensure accuracy, reliability, consistent intended performance, and the ability to discern invalid or altered records.
The Thema4 control system is subjected by the supplier to a full pre-validation, aimed at demonstrating and documenting its compliance with the functional specifications and its operating reliability.
Validation activities follow what specified in validation plan. A Validation Package is available if required.
Thema4 Life Cycle is carried out according to GAMP guideline.
The pre-validation performed by the supplier cannot replace the validation that must be performed by the user and under the user’s responsibility: it can only facilitate, support and shorten user validation activities.
(b) The ability to generate accurate and complete copies of record in both human readable and electronic form suitable for inspection, review, and copying by the agency. Persons should contact the agency if there are any questions regarding the ability of the agency to perform such review and copying of the electronic records.
All the ERs generated by the system are stored as
“electronic documents” (files), which can be copied, printed and displayed in “human readable” form by virtue of the resources of the system.
The system produces hard copies in its own format.
(c) Protection of records to enable their accurate and ready retrieval throughout the records retention period.
ERs managed by Thema4 (process data, sterilization cycles, configuration data, user accounts, ..) can not be modified, but only deleted.
For each ER, Thema4 produce a back-up copy of the modified or deleted ER, allowing the retrieval of the unaltered form.
Prior to every use by means of the system resources, the conformity (exactness and completeness) of the stored data is checked by means of integrity check routines (based on CRC 32 algorithm).
Back-up and Restore of ERs (user selectable) can be executed by different media. These operation are password controlled.
In any case, assurance of the protection of the electronic records can be given only by the user with a proper use of the system’s features.
(d) Limiting system access to authorized individuals.
No one can access the functions of the system that allow to create, modify, transmit or delete ERs unless he has been authorized to do so beforehand in the manner described in the comments to Subpart C of the present Rule.
In order to take into account the various requirements of users, the Thema4 offers various selectable modes for controlling access to the system. All these modes are compatible with the provisions of Subpart C of this Rule.
(e) Use of secure, computer-generated, time-stamped audit trails to independently record the date and time of operator entries and actions that create, modify, or delete electronic records. Record changes shall not obscure previously recorded information. Such audit trail documentation shall be retained for a period at least as long as that required for the subject electronic records and shall be available for agency review and copying.
Thema4 generates and updates automatically an Audit Trails file.
This means that every activity aimed at creating, modifying or deleting ERs by means of the resources of the system (including the back-up and restore procedures) is logged in a specifically provided electronic document that can be read independently of the system (file stored in readable form).
This document is time-stamped, stored, retained and integrity checked in the same manner as the ERs.
The ERs can be copied and inspected.
It is the user’s responsibility to determine how to make them available to the FDA.
(f) Use of operational system checks to enforce permitted sequencing of steps and events, as appropriate.
Where appropriate, the Thema4 allows to perform certain operations only if other operations that are considered preliminary have been performed beforehand. For example, no document can be stored or printed unless its “conformity” has been checked by means of the CRC 32 algorithm.
Moreover no change in any electronic record can be used is the file has not been saved.
(g) Use of authority checks to ensure that only authorized individuals can use the system, electronically sign a record, access the operation or computer system input or output device, alter a record, or perform the operation at hand.
The access to the system is controlled by two components code: one is “public” and assigned by the organization, the other one is secret and known only to the relevant user. The “first access” secret code shall be changed by the owner in order to “activate”
the user account.
Customizable password parameters are available to comply with several password policies and procedures.
The management of authorizations and the checking of all the operations that might be performed manually are under the responsibility of the user of the system.
(h) Use of device (e.g., terminal) checks to determine, as appropriate, the validity of the source of data input or operational instruction.
The transmission of information (input) and the execution of commands (operational instruction) to the Thema4 system can occur only between the components of the system, which recognize each other on the basis of a specific communications protocol, recognizing and refusing unauthorized data sources.
(i) Determination that persons who develop, maintain, or use electronic record/electronic signature systems have the education, training, and experience to perform their
(i) Determination that persons who develop, maintain, or use electronic record/electronic signature systems have the education, training, and experience to perform their