Drugs

Questions and Answers on Current Good Manufacturing Practices, Good Guidance Practices, Level 2 Guidance - Equipment

  1. Many leading analytical balance manufacturers provide built-in "auto calibration" features in their balances.  Are such auto-calibration procedures acceptable instead of external performance checks? If not, then what should the schedule for calibration be? 

  2. Is there a list of CDER-approved drug manufacturing equipment?

  3. Can Total Organic Carbon (TOC) be an acceptable method for detecting residues of contaminants in evaluating cleaning effectiveness?  (updated 5/18/2005)

  4. A firm has multiple media fill failures. They conducted their media fills using TSB prepared by filtration through 0.2F m-sterilizing filter.  Investigation did not show any obvious causes. What could be the source of contamination?

  5. What are the cleaning validation requirements for potent compounds (e.g., compounds that are cytotoxic, mutagenic, or have high pharmacologic activity), and is dedicated equipment required?

  6. How do I perform cleaning validation, including for homeopathic drug products?

  7. Does equipment need to be clean enough to meet limits based on the most sensitive possible methods of residue detection or quantification?

  8. Do firms need to quantify the total amount of residue remaining on equipment surfaces after manufacturing a product (before cleaning) to support cleaning validation studies?

  9. Should laboratory glassware be included in a firm's equipment cleaning validation program?

  10. What is an acceptable level of detergent residue, and what is the basis for arriving at this level, if any?

  11. If a procedure’s ability to clean a piece of equipment made of a particular material, such as 316 stainless steel, is acceptable and validated, can that “material-specific” cleaning procedure be applied to other pieces of equipment and compounds without extensive validation?

  12. Is testing rinse solution enough to support residue determinations for cleaning validation?

  13. Does FDA prefer one type of material over another (e.g., polyvinylidene difluoride over stainless steel) for construction of recirculating loops in water for injection (WFI) systems?

 1.  Many leading analytical balance manufacturers provide built-in "auto calibration" features in their balances.  Are such auto-calibration procedures acceptable instead of external performance checks?  If not, then what should the schedule for calibration be?

The auto-calibration feature of a balance may not be relied upon to the exclusion of an external performance check (211.68).  For a scale with a built-in auto-calibrator, we recommend that external performance checks be performed on a periodic basis, but less frequently as compared to a scale without this feature.  The frequency of performance checks depends on the frequency of use of the scale and the criticality and tolerance of the process or analytical step.  Note that all batches of a product manufactured between two successive verifications would be affected should the check of the auto-calibrator reveal a problem.  Additionally, the calibration of an auto-calibrator should be periodically verified--a common frequency is once a year--using National Institute of Standards and Technology (NIST)-traceable standards or NIST-accredited standards in use in other countries.

References:

  • 21 CFR 211.68: Automatic, mechanical, and electronic equipment
  • 21 CFR 211.160(b)(4): General requirements (Lab Controls)
  • USP Chapter <41> Weights and Balances
  • See also: ASTM standard E 617: Standard Specification for Laboratory Weights and Precision Mass Standards (this standard is incorporated into the USP by reference; other widely recognized standards may be acceptable)


Date: 8/4/2004

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 2.  Is there a list of approved drug manufacturing equipment?

No.  The CGMP regulations neither approve nor prohibit specific equipment for use in manufacturing of pharmaceutical products (with the exception of asbestos and fiber-releasing filters, see 211.72).  We do not maintain a list of approved equipment.  Firms are afforded the flexibility to select equipment that best satisfies their particular needs and that is capable of meeting the relevant CGMP requirements.  Each firm is responsible for selecting all equipment used in their manufacturing process to produce quality product in accordance with CGMP. They are also responsible for selecting the appropriate intended use for the equipment's operation, and are free to modify standard equipment designs to best suit their process and that are compatible with the product under process.

The CGMPs require that equipment be of appropriate design to facilitate operations for its intended use and for cleaning and maintenance (see 211.63 and 211.67) and, that any equipment surface in contact with components, in-process materials, or drug products not be reactive, additive, or absorptive so as to "alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements" (see 211.65).

References:

  • 21 CFR 211.63: Equipment design, size, and location
  • 21 CFR 211.65: Equipment construction
  • 21 CFR 211.67: Equipment cleaning and maintenance
  • 21 CFR 211.68: Automatic, mechanical, and electronic equipment
  • 21 CFR 211.72: Filters


Date: 5/18/2005

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 3.  Can Total Organic Carbon (TOC) be an acceptable method for detecting residues of contaminants in evaluating cleaning effectiveness?

Yes. Since the publication of the inspection guide on cleaning validation in 1993, a number of studies have been published to demonstrate the adequacy of TOC in measuring contaminant residues.

TOC or TC can be an acceptable method for monitoring residues routinely and for cleaning validation. In order for TOC to be functionally suitable, it should first be established that a substantial amount of the contaminating material(s) is organic and contains carbon that can be oxidized under TOC test conditions. This is an important exercise because some organic compounds cannot be reliably detected using TOC.

TOC use may be justified for direct surface sample testing as well as indirect (rinse water) sample testing. In either case, because TOC does not identify or distinguish among different compounds containing oxidizable carbon, any detected carbon is to be attributed to the target compound(s) for comparing with the established limit. Thus, a firm should limit 'background' carbon (i.e., carbon from sources other than the contaminant being removed) as much as possible. If TOC samples are being held for long periods of time before analysis, a firm should verify the impact of sample holding time on accuracy and limit of quantitation.

References:

  • 21 CFR 211.67: Equipment cleaning and maintenance.

  • 21 CFR 211.160(b): General requirements (Laboratory Controls)

  • USP 643 Total Organic Carbon

  • Guide to Inspections of Cleaning Validation, 1993

Contact for further information:

Brian Hasselbalch, CDER
Brian.Hasselbalch@fda.hhs.gov


Date: 5/18/2005

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 4.  A firm has multiple media fill failures. They conducted their media fills using TSB (tryptic soy broth) prepared by filtration through 0.2 micron sterilizing filter.  Investigation did not show any obvious causes.  What could be the source of contamination?

A firm recently had multiple media fill failures.  The media fill runs, simulating the filling process during production, were conducted inside an isolator.  The firm used TSB (non-sterile bulk powder) from a commercial source, and prepared the sterile solution by filtering through a 0.2 micron sterilizing filter.  An investigation was launched to trace the source of contamination.  The investigation was not successful in isolating or recovering the contaminating organism using conventional microbiological techniques, including the use of selective (e.g., blood agar) and nonselective (e.g., TSB and tryptic soy agar) media, and examination under a microscope.  The contaminant was eventually identified to be Acholeplasma laidlawii by using 16S rRNA gene sequence.  The firm subsequently conducted studies to confirm the presence of Acholeplasma laidlawii in the lot of TSB used.  Therefore, it was not a contaminant from the process, but from the media source.

Acholeplasma laidlawii belongs to an order of mycoplasma. Mycoplasma contain only a cell membrane and have no cell wall.  They are not susceptible to beta-lactams and do not take up Gram stain.  Individual organisms are pleomorphic (assume various shape from cocci to rods to filaments), varying in size from 0.2 to 0.3 microns or smaller.  It has been shown that Acholeplasma laidlawii is capable of penetrating a 0.2 micron filter, but is retained by a 0.1 micron filter (see Sundaram, et al.). Acholeplasma laidlawii is known to be associated with animal-derived material, and microbiological media is often from animal sources.  Environmental monitoring of mycoplasma requires selective media (PPLO broth or agar).

Resolution:

For now, this firm has decided to filter prepared TSB, for use in media fills, through a 0.1 micron filter (note: we do not expect or require firms to routinely use 0.1 micron filters for media preparation).  In the future, the firm will use sterile, irradiated TSB when it becomes available from a commercial supplier.  (Firm's autoclave is too small to permit processing of TSB for media fills, so this was not a viable option.)  The firm will continue monitoring for mycoplasma and has revalidated their cleaning procedure to verify its removal.  In this case, a thorough investigation by the firm led to a determination of the cause of the failure and an appropriate corrective action.

References:

  • 21 CFR 211.113: Control of microbiological contamination
  • 21 CFR 211.72: Filters
  • 21 CFR 211.84(d)(6): Testing and approval or rejection of components, drug product container, and closures
  • Sundaram, S., Eisenhuth, J., Howard, G., Brandwein, H. Application of membrane filtration for removal of diminutive bioburden organisms in pharmaceutical products and processes. PDA J. Pharm. Sci. Technol. 1999 Jul-Aug; 53(4): 186-201.
  • Kong, F., James, G., Gordon, S., Zekynski, A., Gilbert, G.L. Species-specific PCR for identification of common contaminant mollicutes in cell culture. Appl. Environ. Microbiol. 2001 Jul; 67(7): 3195-200.
  • Murray, P., Baron, E., Pfaller, M., Tenover, F., Yolken, R. Manual of Clinical Microbiology ASM Press, Sixth Edition.

 
Date: 5/18/2005

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5.  What are the cleaning validation requirements for potent compounds (e.g., compounds that are cytotoxic, mutagenic, or have high pharmacologic activity), and is dedicated equipment required?

 
Separation or dedication of equipment and facilities for the manufacture of potent compounds is not specifically required by CGMP regulations. However, manufacturers should identify drugs with such risks and define the controls necessary to eliminate risk of product cross-contamination in nondedicated equipment and facilities. Such controls include proper cleaning, cleaning validation, and other contaminant controls. Firms must validate that cleaning procedures are adequate to ensure that cross-contamination does not occur. CGMP regulations establish requirements to guide development and execution of cleaning validation plans.
 
In designing a facility, firms should carefully evaluate manufacturing processes to determine the best procedural controls and floor plan—optimizing the flow of materials, equipment, and people—to help prevent product contamination.
 
References:
  • 21 CFR 211.42: Design and construction features
  • 21 CFR 211.67: Equipment cleaning and maintenance
 

Date: 6/8/2015

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6.  How do I perform cleaning validation, including for homeopathic drug products?

21 CFR 211.67(a) requires that any equipment, including dedicated and multipurpose equipment, is “cleaned, maintained, and, as appropriate for the nature of the drug, sanitized and/or sterilized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements.” You must therefore ensure that residues (e.g., active ingredients, cleaning agents) are adequately removed from product contact surfaces of all equipment during product changeovers and/or between production campaigns, depending on the types of materials and surfaces in use.

Cleaning procedures should be well-documented and consistent for their intended use. Cleaning validation programs should provide assurance that residues are effectively removed from product contact surfaces, and manufacturers should select test methods that demonstrate their effectiveness. FDA does not provide extensive guidance on conducting cleaning validation but does recommend consulting guidelines published by various trade and professional associations for additional information (e.g., International Society for Pharmaceutical Engineering, Parenteral Drug Association).
 
Reference:
  • 21 CFR 211.67: Equipment cleaning and maintenance


Date: 6/8/2015

 

7.  Does equipment need to be clean enough to meet limits based on the most sensitive possible methods of residue detection or quantification?
 
No. CGMPs require that equipment be cleaned to prevent contamination that “would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements” (see 21 CFR 211.67). The preamble to the CGMP regulations (see 43 FR 45014) indicates that this phrase was added because absolute cleanliness for multiuse equipment is neither valuable nor feasible in many circumstances. The degree of cleanliness needed, therefore, cannot depend on the method of detection because improvements in method sensitivity would necessitate ever-lower limits and ever-increasing wash cycles. Equipment should be as clean as can be reasonably achieved to a residue limit that is documented to be safe, causes no product quality concerns, and leaves no visible residues. Contamination that is reasonably avoidable and removable is never considered acceptable.
 
References:


Date: 6/8/2015

8.  Do firms need to quantify the total amount of residue remaining on equipment surfaces after manufacturing a product (before cleaning) to support cleaning validation studies?
 
No. In validating original cleaning procedures, firms need not quantify the level of chemical contamination remaining after manufacturing a product and before cleaning. Firms must, however, ensure that they validate proposed cleaning procedures as for routine use and should not pre-clean or otherwise attempt to make it easier for the procedures being validated to meet their cleaning objectives.
 
For example, batches significantly smaller than full-scale would not offer sufficient assurance that the cleaning procedure could reliably remove residues to acceptable levels after full-scale production. The material being cleaned should be manufactured at a similar scale and manner as during validation. Also, firms should sample equipment that is stored uncleaned for a longer time than validated to demonstrate that their cleaning procedures are effective.
 
Once equipment surfaces are cleaned by validated procedures, firms generally are not expected to analytically examine them after each cleaning. (Manual cleaning methods may be an exception to this general rule because of inherent variability in operator compliance and abilities.) However, a residue-monitoring program whose frequency and methods have been determined by risk assessment is recommended.
 
Reference:
 

Date: 6/8/2015

9.  Should laboratory glassware be included in a firm's equipment cleaning validation program?
 
No. FDA does not expect laboratory glassware to be included in the processing equipment cleaning validation program. Glassware must, of course, be clean, and CGMP regulations consider laboratory equipment to be included within the scope of 21 CFR 211.67. Cleanliness is best assessed by inspecting laboratory procedures for the following:
  • Use of nondedicated glassware and other equipment
  • Method validation (e.g., ruggedness)
  • Absence of extraneous or interfering data in the results of sample analyses
 
Laboratory cleaning procedures may include repetitive rinses with the solvent used to prepare the analyte, followed by oven drying. The equipment need not be swabbed or otherwise tested to ensure removal of potentially contaminating residues. A firm may elect to sample its glassware for residual contamination to exclude or explore the possibility of interference in the case of particularly sensitive analyses or difficult-to-clean compounds.
 
The possibility of carryover contamination affecting a method’s performance or integrity of the results is generally considered of low risk to the product and consumers, with the exception of potent compounds. Contaminated laboratory equipment, however, should not be a frequent excuse for rejecting or discarding aberrant results. Glassware that is not properly cleaned can make it difficult to determine if the source of aberrant analytical results is related to the unclean glassware or residues from manufacturing equipment. We expect firms to maintain laboratory equipment in a clean and sanitary manner to provide confidence in the analytical results.
 
Reference:
  • 21 CFR 211.67: Equipment cleaning and maintenance
 

Date: 6/8/2015

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10.  What is an acceptable level of detergent residue, and what is the basis for arriving at this level, if any?

 
It is the firm’s responsibility to establish acceptance limits and to be prepared to provide the basis for those limits to FDA. Thus, there is no universal standard for levels of detergent residue. Residues must not exceed their established acceptance limits and must not adversely alter drug product safety, efficacy, quality, or stability (see references below).
 
References:


Date: 6/8/2015

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11.  If a procedure’s ability to clean a piece of equipment made of a particular material, such as 316 stainless steel, is acceptable and validated, can that “material-specific” cleaning procedure be applied to other pieces of equipment and compounds without extensive validation?

 
No. In establishing an effective cleaning procedure for a particular piece of equipment, firms must consider its material of construction/fabrication, exact design, conditions of use, and, in particular, the specific substances that could contaminate the equipment. Therefore, to demonstrate proof of cleaning for a given piece of equipment, firms should have data that relate to all of these factors.
 
References:

Date: 6/8/2015

12.  Is testing rinse solution enough to support residue determinations for cleaning validation?
 
No. For cleaning validation, rinse samples alone would not be acceptable; firms should also measure the residue or contaminant on the equipment surface using a direct method (if feasible). One disadvantage of rinse samples is that the rinse solvent may not remove the residue or contaminant. Rinse samples are capable of sampling large surface areas, particularly ones that are difficult to access; therefore, some firms use both swab and rinse samples during the course of their cleaning validation. This is acceptable if the rinse solvent has been demonstrated to dissolve residues of concern and is otherwise suitable for use on the surfaces to be sampled.
 
For routine equipment cleaning after validation, a residue-monitoring program whose frequency and methods have been determined by risk assessment is recommended to demonstrate that the validated process continues to consistently clean the equipment.
 
The purpose of cleaning validation is to demonstrate that a particular cleaning process will consistently clean the equipment to a predetermined standard; the sampling and analytical test methods should be scientifically sound and should provide adequate scientific rationale to support the validation.
 
References:

Date: 6/8/2015

13.  Does FDA prefer one type of material over another (e.g., polyvinylidene difluoride over stainless steel) for construction of recirculating loops in water for injection (WFI) systems?
 
No. There is no official agency preference for one material over another. Whatever material a firm selects for its WFI system must be suitable for its intended use. This holds true for virtually all production equipment.
 
When evaluating the suitability of a WFI system’s piping, consider the surface texture or finish of the piping’s interior wall (e.g., smoothness, waviness), its ability to resist high temperatures and pressures, and its ability to withstand sterilizing and sanitizing agents and procedures.
 
Equipment surfaces that are in contact with components, in-process materials, or drug products must not be reactive, additive, or absorptive so as to alter the drug product’s safety, identity, strength, quality, or purity beyond its official or established requirements.
 
References:
  • 21 CFR 211.65: Equipment construction
  • 21 CFR 211.67: Equipment cleaning and maintenance
 
Date: 6/8/2015

 

Date created: August 4, 2004, updated June 8, 2015

Page Last Updated: 06/19/2015
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