During the hosting of a recent seminar, I was asked to share my opinion on the most under-rated and/or misunderstood Federal law or regulation under 211 CGMP for Finished Pharmaceuticals. With over a thousand site audits, and remediation projects under my belt, my response was ‘21 CFR Part 211.68 Automatic, mechanical, and electronic equipment’.
This regulation encompasses more than what the three subsections imply. This statute, in my opinion, is one of the most important statutes, which encompasses more than it appears.

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§211.68 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.

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(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. 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.

 

(c) Such automated equipment used for performance of operations addressed by §§ 211.101(c) or (d), 211.103, 211.182, or 211.188(b)(11) can satisfy the requirements included in those sections relating to the performance of an operation by one person and checking by another person if such equipment is used in conformity with this section, and one person checks that the equipment properly performed the operation.

 

This regulation comprises of three (3) subsections, which address both instrumentation and Computerized Systems. 21 CFR Part 211.68 addresses Instrumentation and Computers in one statute. Some feel that the references are too vague, however, the regulation is written to allow companies to decide how to address the statute, based upon their own specific risk and applicability to the regulations.

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21 CFR Part 211.68 addresses both Instrumentation, and Computerized systems, however, what it does not emphasize is what it means to properly assess ‘direct’ and ‘indirect’ impacts and risk assessments associated with instrumentation and computerized systems.

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The first subsection focuses on Instrumentation, which, could have in itself, been isolated as a single statute, or tied back to Equipment under 211.58 Maintenance or 211.67 Equipment cleaning and maintenance. This regulation states that instruments must be calibrated. The question I hear is ‘what’ instruments should be calibrated? My response is in order to properly assess applicability you must; 1) Conduct a complete inventory of all instruments, and 2) conduct risk assessments for each inventory item. Based upon risk, the determination will then be made for calibration requirement which would assess the instrument calibration requirement, to determine 1) applicability, and 2) frequency (if required based on applicability).

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The second subsection focuses on Computerized systems. This section is what I called redundant, as the predicate rule for this statute would be ‘21 CFR Part 11 Electronic Records; Electronic Signatures’. However, it is noted that you will not see an FDA observation pertaining to Part 11, as the governance for electronic systems failures would be found within FDA Part 211.68, when the QC operations includes, consists of, or utilizes data to support operations, decisions, or other indirect actions which may affect, or have an affect on, products, directly and/or indirectly.

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And the third subsection states that if you use computerized systems or calibrated instruments as part of any process, you can negate the necessity of having a secondary verification if subsection a) and b) are validated.

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Many FDA 483’s and ‘Warning Letters’, are written, with this statute in mind, however, there are other governing statutes which could be cited, i.e., Subpart C Buildings and Facilities, and/or Subpart D Equipment

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Your comments are welcomed:  jcuspilich@auditing.com