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  1. Guidances | Drugs

Questions and Answers on Current Good Manufacturing Practice Regulations | Production and Process Controls

Contains Nonbinding Recommendations

  1. Do the CGMP regulations require a firm to retain the equipment status identification labels with the batch record or other file?  Assuming each major piece of equipment has a unique cleaning and use log that is adequately retained, is it acceptable to discard these quick reference equipment labels?
  2. Can containers, closures, and packaging materials be sampled for receipt examination in the warehouse?
  3. A firm has multiple media fill failures. They conducted their media fills using TSB (tryptic soy broth) prepared by filtration through a 0.2 micron sterilizing filter.  Investigation did not show any obvious causes. What could be the source of contamination?
  4. Some products, such as transdermal patches, are made using manufacturing processes with higher in-process material reject rates than for other products and processes.  Is this okay?
  5. Does CGMP require three successful process validation batches before a new active pharmaceutical ingredient (API) or a finished drug product is released for distribution?
  6. Is it generally acceptable from a CGMP perspective for a manufacturer of sterile drug products produced by aseptic processing to rely solely on ISO 14644-1 and ISO 14644-2 when qualifying its facility?
  7. In 2004, FDA issued a guidance entitled PAT—A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance that encouraged industry to modernize manufacturing through enhancements in process control.   How can I implement PAT (process analytical technology)?
  8. How do I contact CDER with questions about PAT?
  9. How do I contact CBER with questions about PAT?
  10. What is the acceptable media fill frequency in relation to the number of shifts? Normally, media fills should be repeated twice per shift per line per year. Is the same frequency expected of a process conducted in an isolator?
  11. Why is FDA concerned about human topical antiseptic drug products?
  12. What specific CGMP regulations might be useful to manufacturers of topical antiseptic drug products?
  13. How can manufacturers assess and address the risk of microbiological contamination of topical antiseptics?   
  14. Can Leptospira species penetrate sterilizing-grade filters? If so, what should manufacturers keep in mind in their ongoing lifecycle risk management efforts to ensure microbial control?
  15. FDA withdrew its draft guidance for industry on Powder Blends and Finished Dosage Units — Stratified In-Process Dosage Unit Sampling and Assessment. What were the Agency’s major concerns with this guidance?
  16. Why is FDA concerned about proper sampling of powder blends?
  17. What are some recommended innovative approaches to ensuring adequacy of mixing of powder blends?
  18. What are the Agency’s recommendations regarding in-process stratified sampling of finished dosage units?
  19. For a nonsterile compendial drug product that includes an antimicrobial preservative in its formulation, may I release and market lots of this drug product with initial out-of-specification total aerobic plate counts if these lots test within specification 2 weeks later?
  20. Do pharmaceutical manufacturers need to have written procedures for preventing growth of objectionable microorganisms in drug products not required to be sterile? What does objectionable mean anyway?
  21. For drug products formulated with preservatives to inhibit microbial growth, is it necessary to test for preservatives as part of batch release and stability testing?
  22. Is parametric release an appropriate control strategy for sterile drug products that are not terminally sterilized?
  23. Does FDA consider ophthalmic drug products to be adulterated when they are not manufactured under conditions that ensure sterility throughout their shelf life and, in the case of multidose products, that prevent harmful microbial contamination throughout their in-use period?

 1. Do the CGMP regulations require a firm to retain the equipment status identification labels with the batch record or other file?  Assuming each major piece of equipment has a unique cleaning and use log that is adequately retained, is it acceptable to discard these quick reference equipment labels?

The CGMP regulations for finished pharmaceuticals require the retention of cleaning and use logs for non-dedicated equipment, but no similar requirement exists for retaining what are intended to be quick reference or temporary status labels.  Examples of these kinds of status labels include mixing lot ###; clean, ready for use as of d/m/y; and not clean.  We see no value in the retention of such labels in addition to the required equipment log or batch record documentation.  The labels serve a valuable, temporary purpose of positively identifying the current status of equipment and the material under process.  Any status label should be correct, legible, readily visible, and associated with the correct piece of equipment.  The information on the temporary status label should correspond with the information recorded in the equipment cleaning and use log, or the previous batch record for nondedicated equipment.

Labels are merely one way to display temporary status information about a piece of equipment.  It is considered acceptable practice to display temporary equipment status information on dry-erase boards or chalkboards.  And it would be appropriate for an FDA investigator to verify that the information on a temporary status label is consistent with the log.

References:

  • 21 CFR 211.182: Equipment cleaning and use log
  • 21 CFR 211.105:  Equipment identification

 2. Can containers, closures, and packaging materials be sampled for receipt examination in the warehouse?

Yes.  Generally, we believe that sampling in a typical drug manufacturing facility warehouse would not represent a risk to the container or closure or affect the integrity of the sample results. But whether the act of collecting a sample in the warehouse violates the CGMP requirement that containers "be opened, sampled, and sealed in a manner designed to prevent contamination of their contents..." will depend on the purported quality characteristics of the material under sample and the warehouse environment. For containers or closures purporting to be sterile or depyrogenated, sampling should be under conditions equivalent to the purported quality of the material: a warehouse environment would not suffice (see 21 CFR 211.94 and 211.113(b)).  This is to preserve the fitness for use of the remaining containers or closures as well as to ensure sample integrity, if they are to be examined for microbial contamination.  At a minimum, any sampling should be performed in a manner to limit exposure to the environment during and after the time samples are removed (i.e., wiping outside surfaces, limiting time that the original package is open, and properly resealing the original package). Well-written and followed procedures are the critical elements.

Note that the CGMP regulations at 21 CFR 211.84 permit a manufacturer to release for use a shipment of containers or closures based on the supplier's certificate of analysis and a visual identification of the containers or closures.  Once a supplier's reliability has been established by validation of their test results, a manufacturer could perform the visual examination entirely in the warehouse.

References:

  • 21 CFR 211.84: Testing and approval or rejection of components, drug product containers, and closures
  • 21 CFR 211.94: Drug product containers and closures
  • 21 CFR 211.113(b): Control of microbiological contamination
  • 21 CFR 211.122: Materials examination and usage criteria

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

A firm had multiple media fill failures.  The media fill runs, simulating the filling process during production, were conducted inside an isolator.  The firm used TSB (nonsterile 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 shapes 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, Eisenhuth, et al. 1999). 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, J Eisenhuth, G Howard, and H Brandwein, 1999, Application of Membrane Filtration for Removal of Diminutive Bioburden Organisms in Pharmaceutical Products and Processes, PDA J Pharm Sci Technol, 53(4):186–201
  • Kong, F, G James, S Gordon, A Zekynski, and GL Gilbert, 2001, Species-Specific PCR for Identification of Common Contaminant Mollicutes in Cell Culture, Appl Environ Microbiol, 67(7):3195–3200
  • Murray, P, E Baron, M Pfaller, F Tenover, and R Yolken, 1995, Manual of Clinical Microbiology, 6th ed., Washington, DC: ASM Press 

Date: 5/18/2005

 4. Some products, such as transdermal patches, are made using manufacturing processes with higher in-process material reject rates than for other products and processes.  Is this okay?

Maybe.  It depends on the cause and consistency of the reject rate.  Many transdermal patch manufacturing processes produce more waste (i.e., lower yield from theoretical) than other pharmaceutical processes.  This should not of itself be a concern.  The waste is usually due to the cumulative effect of roll splicing, line start-ups and stoppages, roll-stock changes, and perhaps higher rates of in-process sampling.  This is most pronounced for processes involving lamination of rolls of various component layers.  Roll-stock defects detected during adhesive coating of the roll, for example, can often only be rejected from the roll after final fabrication/lamination of the entire patch, which contributes to the final process waste stream.

We expect that validated and well-controlled processes will achieve fairly consistent waste amounts batch-to-batch.  Waste in excess of the normal operating rates may need (see 21 CFR 21.192) to be evaluated to determine cause (e.g., due to increase in sampling or higher than normal component defects...or both) and the consequences on product quality assessed.  We've seen a small number of cases where unusually high intra-batch rejects/losses were due to excessive component quality variability and poorly developed processes.

References:

  • 21 CFR 211.100: Written procedures; deviations

  • 21 CFR 211.103: Calculation of yield

  • 21 CFR 211.110: Sampling and testing of in-process materials and drug products

  • 21 CFR 211.192: Production record review

5. Does CGMP regulations require three successful process validation batches before a new active pharmaceutical ingredient (API) or a finished drug product is released for distribution?

No.  Neither the CGMP regulations nor FDA policy specifies a minimum number of batches to validate a manufacturing process. The current FDA guidance on APIs (see guidance for industry ICH Q7 for APIs) also does not specify a specific number of batches for process validation. 

FDA recognizes that validating a manufacturing process, or a change to a process, cannot be reduced to so simplistic a formula as the completion of three successful full-scale batches. The Agency acknowledges that the idea of three validation batches became prevalent in part because of language used in past Agency guidance. FDA's process validation guidance now recommends a product lifecycle approach. The emphasis for demonstrating validated processes is placed on the manufacturer’s process design and development studies in addition to its demonstration of  reproducibility at scale, a goal that has always been expected. 

However, a minimum number of conformance (a.k.a. validation) batches necessary  to validate the manufacturing processes is not specified.  The manufacturer is expected to have a sound rationale for its choices in this regard.  The Agency encourages the use of science-based approaches to process validation.

In March 2004, FDA revised the Compliance Policy Guide (CPG) Sec. 490.100 on Process Validation Requirements for Drug Products and Active Pharmaceutical Ingredients Subject to Pre-Market Approval.  The CPG describes the concept that, after having identified and establishing control of all critical sources of variability, conformance batches are prepared to demonstrate that under normal conditions and operating parameters, the process results in the production of an acceptable product.  Successful completion of the initial conformance batches would normally be expected before commercial distribution begins, but some possible exceptions are described in the CPG.  For example, although the CPG does not specifically mention concurrent validation for an API in short supply, the Agency would consider the use of concurrent validation when it is necessary to address a true short-supply situation, and if the concurrent validation study conforms to the conditions identified in the CPG (see paragraph 4, a-c).

The conditions outlined in the CPG include expanded testing for each batch intended to address a short-supply situation.  Expanded testing conducted according to an established validation protocol could provide added assurance that the batch meets all established and appropriate criteria before the API is used in the finished drug product.  Additionally, confidence in the API manufacturing process may be gained by enhanced sampling (larger sample size representative of the batch) and perhaps the testing of additional attributes.  Validated analytical methods are needed for testing every batch, including validation batches.  The Agency would also expect the manufacturer to use a validation protocol that includes a review and final report after multiple batches are completed, even though the earlier batches may have been distributed or used in the finished drug product.

 References:

 6. Is it generally acceptable from a CGMP perspective for a manufacturer of sterile drug products produced by aseptic processing to rely solely on ISO 14644-1 and ISO 14644-2 when qualifying its facility?

No.  It is generally not acceptable from a CGMP perspective for a manufacturer of sterile drug products produced by aseptic processing to rely solely on ISO [International Organization for Standardization] 14644-1 Part 1: Classification of Air Cleanliness (14644-1) and ISO 14644-2 Part 2: Specifications for Testing and Monitoring to Prove Compliance with ISO 14644-1 (14644-2) when qualifying its facility. Rather, a manufacturer of sterile drug products produced by aseptic processing should use these ISO standards in combination with applicable FDA regulations, guidance, and other relevant references to ensure a pharmaceutical facility is under an appropriate state of control. Consequently, appropriate measures augmenting ISO’s recommendations (e.g., with microbiological data) would likely be expected for a firm to meet or exceed CGMP in a pharmaceutical facility.

Please understand that 14644-1 and 14644-2 have superseded Federal Standard 209E, Airborne Particulate Cleanliness Classes in Cleanrooms and Clean Zones (Federal Standard 209E).  In November 2001, the U.S. General Services Administration canceled Federal Standard 209E.

Although 14644-1 and 14644-2 are not FDA regulations or FDA guidance, the Agency believes that they are useful in facilitating the international harmonization of industrial air classification for nonviable particle cleanliness in multiple industries (e.g., computer, aerospace, pharmaceutical).  As such, FDA adopted these particle cleanliness ratings in the 2004 guidance for industry Sterile Drug Products Produced by Aseptic Processing–Current Good Manufacturing Practice.  However, due to the unique aspects of producing sterile drug products by aseptic processing (e.g., microbiological issues), an aseptic processing manufacturer should not rely solely on 14644-1 and 14644-2 when qualifying its facility. 

References:

 7. In 2004, FDA issued a guidance entitled PAT - A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance that encouraged industry to modernize manufacturing through enhancements in process control.   How can I implement PAT (process analytical technology)? 

The objective of FDA's PAT program is to facilitate adoption of PAT.  In our 2004 guidance, we discuss FDA's collaborative approach to promote industry uptake of new and beneficial technologies that modernize manufacturing operations and enhance process control.  FDA recognizes that firms should be encouraged to promptly implement new systems that improve assurance of quality and process efficiency.  Accordingly, our approach to PAT implementation is risk based and includes multiple options:

(1) PAT can be implemented under the facility's own quality system. CGMP inspections by a PAT-certified investigator can precede or follow PAT implementation.

(2) As another quality system implementation option, FDA invites manufacturers to request a preoperational review of their PAT manufacturing facility and process (see ORA Field Management Directive No.135).

(3) A supplement (Changes Being Effected (CBE), CBE-30, or Prior Approval Supplement (PAS)) can be submitted to the Agency prior to implementation, and, if necessary, an inspection can be performed by a PAT-certified investigator before implementation.  This option should be used, for example, when an end product testing specification established in the application will be changed. 

(4) A comparability protocol can be submitted to the Agency outlining PAT research, validation and implementation strategies, and time lines. Following collaborative review of the general strategy outlined in the comparability protocol, the regulatory pathway can include implementation under the facility's own quality system, a preoperational review, CGMP inspections (either before or after PAT implementation), a combination of these, or another flexible approach.

Manufacturers should evaluate and discuss with the Agency the most appropriate option for PAT implementation (see questions 8 and 9, below).

References:

 8. How do I contact CDER with questions about PAT?  

Manufacturers should contact the Office of Pharmaceutical Quality and/or the appropriate review division in CDER to discuss applicability of PAT to CDER-regulated products.

Contact for further information:
CDER Key Officials

Date Revised: 6/18/2015

 9. How do I contact CBER with questions about PAT?  

Manufacturers should contact the appropriate review division in CBER to discuss applicability of PAT to CBER-regulated products.

Contact for further information:
CBER Key Staff Directory

Date Revised: 9/16/2013

 10. What is the acceptable media fill frequency in relation to the number of shifts? Normally, media fills should be repeated twice per shift per line per year. Is the same frequency expected of a process conducted in an isolator?

A firm's justification for the frequency of media fills in relation to shifts should be risk based, depending on the type of operations and the media fill study design. For closed, highly automated systems run on multiple shifts, a firm with a rigorous media fill design may be justified to conduct a lower number of total media fill runs. Such a program can be appropriate provided that it still ensures performance of media fills for each aseptic processing line at least semiannually. The 2004 guidance for industry on Sterile Drug Products Produced by Aseptic Processing states that "[A]ctivities and interventions representative of each shift, and shift changeover, should be incorporated into the design of the semi-annual qualification program."  In addition, the EU Annex 1, Manufacture of Sterile Medicinal Products, states that "Normally, process simulation tests should be repeated twice a year per shift and process."

Certain modern manufacturing designs (isolators and closed vial filling) afford isolation of the aseptic process from microbiological contamination risks (e.g., operators and surrounding room environment) throughout processing. For such closed systems,1 if the design of the processing equipment is robust and the extent of manual manipulation in the manufacturing process is minimized, a firm can consider this information in determining its media fill validation approach. For example, it is expected that a conventional aseptic processing line that operates on two shifts be evaluated twice per year per shift and culminate in four media fills. However, for aseptic filling conducted in an isolator over two shifts, it may be justified to perform fewer than four media fill runs per year, while still evaluating the line semiannually to ensure a continued state of aseptic process control. This lower total number of media fill runs would be based on sound risk rationale and would be subject to reevaluation if contamination issues (e.g., product nonsterility, media fill failure, any problematic environmental trends) occur.

l This does not apply to RABS (restricted access barrier systems).

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 211.84(c)(3), which states that "Sterile equipment and aseptic sampling techniques shall be used when necessary."
  • 21 CFR 211.113(b), which states that "Appropriate written procedures, designed to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed. Such procedures shall include validation of all aseptic and any sterilization process."
  • FDA Guidance for Industry, 2004, Sterile Drug Products Produced by Aseptic Processing
  • EU Annex 1, 2003, Manufacture of Sterile Medicinal Products

Date: 12/3/2009

11. Why is FDA concerned about human topical antiseptic drug products?

FDA has identified several incidents of objectionable microbial contamination of topical antiseptic drug products (e.g., alcohol pads or swabs used to prepare the skin prior to an injection).   Microbial contamination may be caused by substandard manufacturing practices, and the Agency is concerned about safety risks, such as from infection, associated with this contamination.

Date: 12/21/2011

12. What specific CGMP regulations might be useful to manufacturers of topical antiseptic drug products?

Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act requires all drugs to be manufactured in conformance with CGMP.  The CGMP regulations in 21 CFR parts 210 and 211 for finished pharmaceuticals apply equally to over-the-counter (OTC) and prescription (Rx) drug products (see Compliance Policy Guide Sec. 450.100).

The CGMP regulations provide the minimum legal requirements for conducting reliable operations (see 21 CFR part 211).  Some relevant CGMP regulations, with a brief description, are given below:

Manufacturing Design and Control: CGMP Requirements and Recommended Guidance for Manufacturers

  • Design manufacturing facilities (§ 211.42) and processes (see below) to prevent microbial contamination: 
    • For nonsterile drug products, establish control procedures to monitor output and validate processes to include bioburden testing (§§ 211.110(a)(6)), 211.111) and establish and follow written procedures designed to prevent the introduction of objectionable microorganisms (§ 211.113(a)). 
    • For sterile drug products, establish and follow written procedures designed to prevent microbial contamination (§ 211.113(b)). See the guidance for industry Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice.
  • Conduct process validation studies to ensure acceptable output (e.g., with topical antiseptics, particularly product microbiological quality) (§ 211.110(a)).  Implement and validate needed changes when deficient manufacturing steps, equipment, or raw materials may be adversely affecting process control. See the guidance for industry Process Validation: General Principles and Practices.
  • Ensure that operating procedures will consistently produce a quality product (§ 211.100).  Review and evaluate any deviations or discrepancies documented during manufacturing and testing to determine if a product lacks assurance of sterility (for sterile antiseptics) or may be contaminated with objectionable microorganisms (for nonsterile antiseptics).  Document and implement any corrective actions deriving from the evaluation (§ 211.192).
  • Ensure that all equipment, including water systems, operates consistently and is clean, sanitary, and suitable for its intended use (§§ 211.63, 211.65, 211.67, and 211.68). 
  • Establish and follow in-process bioburden testing procedures to help monitor in-process control, including understanding the bioburden challenge to a final sterilization process (§ 211.110(a)(6)).  

Components, In-Process Materials, Containers or Closures, and Finished Product Testing: CGMP Requirements for Manufacturers

  • Establish appropriate written testing standards/specifications and sampling plans for components, in-process materials, containers or closures, and finished products (§ 211.160).
  • Establish procedures for testing and approval or rejection of components, drug product containers, and closures (§ 211.80).  Test each lot of a drug product component and container or closure, including those that may be vulnerable to microbiological contamination (§ 211.84)(d)(4-5), including applicator material (e.g., cotton pads) and water used as an ingredient in the product.
  • Conduct appropriate microbiological tests before a batch disposition decision is made.  Test each batch of a sterile product for sterility (§ 211.167).  Test each batch of a non-sterile product to ensure absence of objectionable microorganisms (§ 211.165(b)).

Management

The CGMP regulations require that the management of a manufacturing facility maintains a well-functioning quality system, which includes an effective quality unit vested with the responsibilities and authorities required under CGMP (§ 211.22). See ICH guidances for industry Q9 Quality Risk Management and Q10 Pharmaceutical Quality System.

References:

  Date: 12/21/2011  

13. How can manufacturers assess and address the risk of microbiological contamination of topical antiseptics?    

Because there are potentially many different root causes of product contamination by microorganisms, it is imperative that manufacturers perform a manufacturing risk assessment to understand manufacturing failure modes and implement prevention measures.

In addition, any risk assessment approach should be informed by an understanding of the microbial contamination vulnerabilities of the concerned product.  For example, some product considerations for manufacturers include, but are not limited to:

  • Determine the types of microbes that might survive or thrive in your products. Provide additional controls and testing based on the output of the risk assessment to ensure product quality.
  • Ensure that your microbial recovery methods are capable of detecting the types of microbes that may affect product quality.
  • Evaluate risk of contamination from components, including during component production, storage, or due to the intrinsic risk from source materials. Consider all possible sources of microbial contamination, including the following:
    • Components or products stored in open bins can be at risk for contamination by spore-forming microbes, such as Bacillus cereus, as well as by Serratia species and other worrisome airborne microbes (see the FDA news release and Morbidity and Mortality Weekly Report, referenced below). Manufacturing areas exposed to windy or poor HVAC conditions may increase the potential for this environmental contamination risk.
    • Some materials, especially from natural sources, may have high or objectionable intrinsic bioburden.
    • Water quality can pose a significant risk, as most antiseptics include water as a key ingredient.  Contaminated purified water has been the root cause of multiple recalls of antiseptics, including instances of antiseptics contaminated with Burkholderia (previously Pseudomonas) cepacia, an opportunistic pathogen.
    • Unsanitary practices or sources.
    • When manufacturing in areas with high humidity, molds can be of special concern.

References:

Date: 12/21/2011

14. Can Leptospira species penetrate sterilizing-grade filters? If so, what should manufacturers keep in mind in their ongoing lifecycle risk management efforts to ensure microbial control?

FDA is aware of a report of Leptospira licerasiae contamination in cell cultures (see Chen, Bergenvin, et al. 2012). There is no indication that this bacterium ultimately contaminated either the finished drug substance or drug product.  This bacterium has been found to pass through 0.1 µm pore size rated sterilizing-grade membrane filters.  While this specific species was the identified contaminant in this case, other Leptospira species also are capable of passing through 0.1 µm pore size rated filters (see Faine 1982). Compendial microbiological test methods typically used in association with upstream biotechnology and pharmaceutical production are not capable of detecting this type of bacteria.  Whether this apparently rare contamination risk may be more widespread is unknown, and we are sharing this information so that manufacturers can consider whether this hazard may be relevant to their operations. 

Leptospira are Gram-negative aerobic spirochetes that are flexible, highly motile, and spiral-shaped with internal flagella.  The bacteria measure 1μm in diameter and 10-20 μm in length. Leptospira are obligate aerobes that use oxygen as the electron receptor and long-chain fatty acids as a major source of energy. While some of the Leptospira are harmless fresh-water saprophytes, other species are pathogenic and can cause leptosporosis, a significant disease in humans and animals (Ricaldi, Fouts, et al. 2012; Matthias, Ricaldi, et al. 2008; Bharti, Nally, et al. 2003).   Based on current information, Leptospira contamination does not appear to occur frequently, and purification steps that follow cell culture in a typical biotechnology operation would be expected to prevent carryover to the finished drug substance.  Testing of bulk drug substances produced in the reported cases did not detect the Leptospira species, and no evidence of deleterious effects on in-process product were observed in the known case study.  However, we are providing this communication to alert manufacturers that these types of bacteria can potentially:  

  • Penetrate sterilizing-grade membrane filters
  • Be present in the manufacturing site environment
  • Impact in-process production (e.g., production yields, impurity levels, process performance)
  • Go undetected due to the limitations of current compendial bioburden tests in detecting this microbial genus

As a general principle, manufacturers should use sound risk management and be aware of unusual microbiota reported in the literature that may impact their manufacturing processes (e.g., cell culture biotechnology, conventional sterile drug manufacturing).     Manufacturers should assess their operations, be aware of potential risks, and apply appropriate risk management based on an understanding of possible or emerging contamination risks (see section 18.3 in ICH guidance for industry Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients). As appropriate, preventive measures should be implemented during the product and process lifecycle.      To illustrate, if leptospiral contamination is considered possible, or has occurred, risk mitigation procedures and practices for this microorganism should include at least the following:   

(1) Review of available published articles from the scientific literature and technical reports by related industry organizations that may provide further understanding on how to mitigate this contamination hazard.

(2) Use of molecular or nonconventional microbial monitoring methods at appropriate intervals to detect microbial flora that may exist in processing steps or in the immediate environment, but are not readily detected by current routine methods.  Such expanded testing should be used to modify the strategy (e.g., timing, frequency, types of tests) of detection and control in the event of newly identified risk posed by the viable, but not easily cultured, microorganism.  

Examples include: a.  Use of specialized media such as Ellinghausen McCullough Johnson Harris (EMJH) medium (Ellinghausen and McCullough 1965) or other suitable media (Rule and Alexander 1986).  It should be noted that these bacteria typically grow very slowly.  b.  Use of validated polymerase chain reaction (PCR) methods (e.g., as an investigative tool) for rapid screening and detection of spirochete bacteria. c.  Consideration of special stain techniques or other means to identify the presence of Leptospira (Frank and Kohn 1973).


(3) Use of conventional approaches. Firms should continue to properly employ basic, standard microbiology laboratory practices to detect contamination. For example, the laboratory should ensure that microscopic examination is part of its routine cell culture process control program, as it provides an important means of detecting microbial contaminants that may not readily grow on conventional media.

(4) Implementing such quality risk-management measures into the initial design (i.e., preventive actions) and promptly implementing an appropriate corrective action plan in response to newly identified contamination sources, throughout the life cycle of the product.

   References: 

  • FDA Guidance for Industry, 2001, ICH Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients
  • Chen, J, J Bergenvin, R Kiss, G Walker, T Battistoni, P Lufburrow, H Lam, and A Vinther, 2012, Case Study: A Novel Bacterial Contamination in Cell Culture Production—Leptospira licerasiae, PDA J Pharm Sci Technol, 66(6):580–591
  • Faine, S (ed.), 1982, Guidelines for the Control of Leptospirosis, Geneva: World Health Organization
  • Ricaldi, JN, DE Fouts, JD Selengut, DM Harkins, KP Patra, et al., 2012, Whole Genome Analysis of Leptospira licerasiae Provides Insight into Leptospiral Evolution and Pathogenicity, PLoS Negl Trop Dis, 6(10):e1853
  • Matthias, MA, JN Ricaldi, M Cespedes, MM Diaz, RL Galloway, et al., 2008, Human Leptospirosis Caused by a New Antigenically Unique Leptopspira Associated with a Rattus Species Reservoir in the Peruvian Amazon, PLoS Negl Trop Dis, 2(4):e213
  • Bharti, AR, JE Nally, JN Ricaldi, MA Matthias, MM Diaz, et al., 2003, Leptospirosis: A Zoonotic Disease of Global Importance, Lancet Infect Dis, 3:757–771
  • Ellinghausen, HC, and WG McCullough, 1965, Nutrition of Leptospira pomona and Growth of 13 Other Serotypes: Fractionation of Oleic Albumin Complex (OAC) and a Medium of Bovine Albumin and Polysorbate 80, Am J Vet, 26:45–51
  • Rule Pl, and AD Alexander, 1986, Gellan Gum as a Substitute for Agar in Leptospiral Media, J Clin Microbiol, 23(3):500–504
  • Frank S, and J Kohn, 1973, J Amer Med Technology, July–Aug

Date: 12/20/2012

15. FDA withdrew its draft guidance for industry on Powder Blends and Finished Dosage Units—Stratified In-Process Dosage Unit Sampling and Assessment.  What were the Agency’s major concerns with this guidance?

  FDA’s major concern was that sections V and VII of the withdrawn draft guidance no longer represented the Agency’s current thinking, as explained below.    Section V (Exhibit/Validation Batch Powder Mix Homogeneity) recommended that at least 3 replicate samples be taken from at least 10 locations in the powder blender, but that only 1 of the 3 replicates be evaluated to assess powder blend uniformity. The Agency currently recommends that all replicate samples taken from various locations in the blender be evaluated to perform a statistically valid analysis. This analysis can demonstrate that variability attributable to sample location is not significant and that the powder blend is homogenous. Statistical tools are available to ascertain both the number of replicates and the number of sampling locations across the blender that should be analyzed to conduct a valid analysis.     Section VII (Routine Manufacturing Batch Testing Methods) acceptance criteria designated to the Standard Criteria Method and the Marginal Criteria Method were based upon the limits published in the United States Pharmacopeia (USP) General Chapter <905> Uniformity of Dosage Units. However, the procedures and acceptance criteria in General Chapter <905> are not a statistical sampling plan and so the results of the procedures should not be extrapolated to larger populations. Therefore, because the procedure and acceptance criteria prescribed in section VII provided only limited statistical assurance that batches of drug products met appropriate specifications and statistical quality control criteria, FDA no longer supports their use for batch release.  Currently, there are several standard statistical practices that, if used correctly, can help to ensure compliance with CGMP regulations, including 21 CFR 211.110, 21 CFR 211.160, and 21 CFR 211.165.  

References:   

Date: 8/6/2013

16.  Why is FDA concerned about proper sampling of powder blends?

  The CGMPs require that all sampling plans be scientifically sound and representative of the batch under test (see 21 CFR 211.160(b)). Further, in-process testing of powder blends to demonstrate adequacy of mixing is a CGMP requirement (21 CFR 211.110).  Between- and within-location variability in the powder blend is a critical component of finished product quality and therefore should be evaluated. Drug product manufacturers need to use a science- and risk-based sampling approach to ensure (a) adequacy of blend mixing and (b) that sampling of the blend is done at a suitable juncture in the manufacturing process. The sampling and analysis needs to ensure that no differences exist between locations in a blend that could adversely affect finished product quality. Traditional sampling using a powder-thief may have drawbacks and limitations, such as causing disturbance to the powder bed, powder segregation, or other sampling errors.  However, powder-thief sampling remains widely used and provides reliable results in many cases. The Agency encourages firms to adopt more innovative approaches to ensuring adequacy of mixing (see, e.g., the guidance for industry PAT—A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance).  If a manufacturer proposes to use a thief sampling method, the reliability of the method should be evaluated as part of analytical methods development.  

References:

    Date: 8/6/2013  

17. What are some recommended innovative approaches to ensuring adequacy of mixing of powder blends?

  Innovative approaches to consider include, but are not limited to: (a) PAT real-time monitoring and feed-forward controlling of the powder blending process (see the guidance for industry PAT—A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance) and (b) use of statistical process control tools to monitor the powder blending process and to maintain a state of control.     When a manufacturer decides to implement PAT or other process-monitoring and control techniques for powder blend homogeneity assessment, its decision should be supported with appropriate data and rationale using a science- and risk-based approach.  For example, the effective sample size of powder examined by PAT probes has to be estimated such that the scale of scrutiny of the PAT powder blending monitoring can be justified (Wu, Tawakkul, et al. 2009). The number of PAT probes and their locations also have to be justified. If a scientifically sound PAT monitoring and control strategy is established, it can facilitate the assessment of (a) variability across locations within the powder bed (El-Hagrasy, Morris, et al. 2001), (b) variability over time of one location, and (c) potential correlation between the powder sample and the unit dosage form.   

References:

  • FDA Guidance for Industry, 2004, PAT—A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance
  • Wu, H, M Tawakkul, M White, and M Khan, 2009, Quality-by-Design (QbD): An Integrated Multivariate Approach for the Component Quantification in Powder Blends, International Journal of Pharmaceutics, 372(1-2):39–48
  • El-Hagrasy, A, H Morris, F D’Amico, et al., 2001, Near-Infrared Spectroscopy and Imaging for the Monitoring of Powder Blend Homogeneity, Journal of Pharmaceutical Sciences, 90(9):1298–1307

Date: 8/6/2013

18. What are the Agency’s recommendations regarding in-process stratified sampling of finished dosage units?

  Stratified sampling is recommended to be used when the population is known to have several subdivisions (i.e., locations), which may give different results for the quality characteristics measured.  The Agency expects that no significant differences should exist between in-process locations that could affect finished product quality.  Between- and within-location variability is a critical component of finished product quality and therefore should be evaluated.  Please refer to ASTM E2709 and ASTM E2810 for further guidance on establishing acceptance criteria for a stratified sampling plan.   References: 

  • ASTM Standard E2709, 2014, Standard Practice for Demonstrating Capability to Comply with an Acceptance Procedure, West Conshohocken, PA: ASTM International
  • ASTM Standard E2810, 2011, Standard Practice for Demonstrating Capability to Comply with the Test for Uniformity of Dosage Units, West Conshohocken, PA: ASTM International

Date: 8/6/2013 

19. For a nonsterile compendial drug product that includes an antimicrobial preservative in its formulation, may I release and market lots of this drug product with initial out-of-specification total aerobic plate counts if these lots test within specification 2 weeks later?

  No. 21 CFR 211.113(a) requires appropriate written procedures to be established and followed during manufacturing to prevent objectionable microorganisms in drug products not required to be sterile.   Additionally, the second paragraph of USP General Chapter <51> Antimicrobial Effectiveness Testing reads:   Antimicrobial preservatives should not be used as a substitute for good manufacturing practices, solely to reduce the viable microbial population of a nonsterile product, or control the presterilization bioburden of a multidose formulation during manufacturing.   Drug manufacturers should not rely on antimicrobial preservatives to reduce initial out-of-specification plate counts to within-specification levels and then market the product. Section 211.165(f) mandates that drug products failing to meet established standards or specifications be rejected. The initial test results exhibiting out-of specification levels of microbes are not disqualified even if subsequent test results are within specifications. In such cases, FDA still expects the manufacturer to reject the drug product based on the initial results.   It is also not acceptable for manufacturers to allow an inappropriately long time (e.g., weeks) to pass before testing the product, which might permit the preservative to reduce levels of microbes possibly introduced during manufacture and thus avoid out-of-specification test results.   Finally, drug manufacturers should review their manufacturing process to determine procedures or equipment that might introduce contaminating microorganisms into the process or product.  

References: 

  • 21 CFR 211.113: Control of microbiological contamination
  • 21 CFR 211.165: Testing and release for distribution
  • USP 38–National Formulary (NF) 33 (2015) General Chapter <51> Antimicrobial Effectiveness Testing
  • USP 38–NF 33 (2015) General Chapter <61> Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests
  • USP 38–NF 33 (2015) General Chapter <62> Microbiological Examination of Nonsterile Products: Tests for Specified Microorganisms

Date: 6/11/2015

20. Do pharmaceutical manufacturers need to have written procedures for preventing growth of objectionable microorganisms in drug products not required to be sterile? What does objectionable mean anyway?

  Yes, CGMP regulations do require these written procedures. 21 CFR 211.113(a) specifies that appropriate written procedures be established and followed to prevent growth of objectionable microorganisms in drug products not required to be sterile. Even though a drug product is not sterile, a firm must follow written procedures that proactively prevent introduction and proliferation of objectionable microorganisms. 21 CFR 211.165(b) states that “[t]here shall be appropriate laboratory testing, as necessary, of each batch of drug product required to be free of objectionable microorganisms” before it is released for distribution.   The meaning of the term objectionable needs to be evaluated on a case-by-case basis by each drug manufacturer. The primary meaning relates to microbial contaminants that, based on microbial species, numbers of organisms, dosage form, intended use, patient population, and route of administration, would adversely affect product safety. Microorganisms may be objectionable for several reasons; for example, they:

  • Are a known human pathogen
  • Adversely affect product stability
  • React with, or potentially damage the integrity of, the container closure system (for example, fermentation that creates gaseous pressures sufficient to rupture a product container/closure)
  • Interfere with analytical methods or active ingredient bioavailability

  Establishing production time limits is an example of a control to prevent growth of objectionable microorganisms. Per 21 CFR 211.111, time limits for the completion of each phase of production, when appropriate, must be established and followed. For example, if a firm finds it necessary to hold a bulk topical or liquid product for several months until it is filled, the firm might establish a holding time limit to help prevent objectionable microbial buildup. Validation and control over microbial content of purified water systems used in certain topical products are also examples of such procedures (see FDA guidance, referenced below).

References:  

  • 21 CFR 211.113: Control of microbiological contamination
  • 21 CFR 211.165: Testing and release for distribution
  • 21 CFR 211.111: Time limitations on production
  • FDA Guidance for Industry, 2011, Process Validation: General Principles and Practices

  Date: 6/11/2015

21. For drug products formulated with preservatives to inhibit microbial growth, is it necessary to test for preservatives as part of batch release and stability testing?

  Yes. Two types of tests are generally used. Initially, firms perform antimicrobial preservative effectiveness testing to determine a minimally effective level of preservative. Once that level has been determined, firms may establish appropriate corresponding analytical test specifications. Firms may then apply the analytical tests for preservative content at batch release and throughout the shelf life of lots on stability.   

References:

  • 21 CFR 211.165: Testing and release for distribution 
  • 21 CFR 211.166: Stability testing
  • USP 38–NF 33 (2015) General Chapter <51> Antimicrobial Effectiveness Testing

Date: 6/11/2015

22. Is parametric release an appropriate control strategy for sterile drug products that are not terminally sterilized?

No. Parametric release is only appropriate for terminally sterilized drug products. Although both terminally sterilized and aseptically processed drug product batches are required to meet the sterility test requirement (see 21 CFR 211.167(a)) before release to the market, there are inherent differences between the production of sterile drug products using terminal sterilization and aseptic processing. 

Products that are terminally sterilized are rendered sterile in their final, sealed units by sterilizers. Discrete physical parameters (e.g., temperature, pressure, and time) are continuously measured and controlled with robust precision and accuracy during processing. Additionally, parametric release incorporates a sterilization load monitor that is integral to satisfying the requirement for a sterility test (see § 211.167(a)) by confirming that the load has been exposed to the prescribed physical conditions. This allows manufacturers to couple adherence to sterilization cycle parameters with a load monitor to determine thermal lethality, thereby directly confirming sterility and substituting for the sterility test. 

In contrast, aseptic processes do not subject the final, sealed drug product to a sterilization cycle, and monitoring the sterility hazards to drugs manufactured throughout aseptic manufacturing operations relies on indirect measurements. Sterilization processes (e.g., filtration) for the drug occur before further manipulations that are performed in Class 100 (ISO 5) environments where transient events can present microbial contamination risks during the manufacturing process. Consequently, indirect measurements used in aseptic processing provide limited information to conclude whether a batch is sterile. Even contemporary aseptic operations conducted in closed RABS and isolators can experience sterility and media fill failures, despite the substantial robustness of these technologies over traditional cleanroom and open RABS operations. The sterility test is therefore an essential element to monitor the state of control of an aseptic operation, and it is the last step in a series of fundamental, required controls that collectively contribute to the minimum assurance that a given manufacturing operation produced a drug that meets its sterility claim. The sterility test also protects patients by potentially preventing the distribution of an aseptically processed drug product batch posing serious safety concerns that would not otherwise be readily detected. 

All quality control tests, including the sterility test, have limitations. Although the sterility test may not exhaustively assess batch sterility, the sterility test is, nonetheless, a critical component of a comprehensive control strategy that is designed to prevent microbiological contamination of drug products purporting to be sterile (21 CFR 211.113(b)). Innovations in sterility testing (e.g., rapid microbiological methods, genotyping) and the integration of these innovations into manufacturing operations may further improve prompt operational feedback, which can result in significant batch release efficiencies while ensuring equivalent or better ability to detect nonsterility compared with the compendial method. FDA encourages the use of beneficial testing innovations in conjunction with advanced manufacturing technologies (e.g., robotic isolators) to enhance process design and improve both microbial detection and identification. 

References: 

Date: 8/11/2023

23. Does FDA consider ophthalmic drug products1 to be adulterated when they are not manufactured under conditions that ensure sterility throughout their shelf life and, in the case of multidose products, that prevent harmful microbial contamination throughout their in-use period?

Product sterility is a critical quality attribute (CQA) for ophthalmic drug products.2 Recent cases of microbially contaminated ophthalmic drug products leading to serious injury and death, as well as recent recalls, highlight the importance of product sterility.3 Manufacturers of drug products, including sterile products offered or intended for ophthalmic use, must comply with CGMP requirements in 21 CFR parts 210 and 211. Failure to comply with these requirements will cause affected products to be deemed adulterated under section 501(a)(2)(B) of the FD&C Act.

Sterile drug products must meet specific CGMP requirements for personnel, buildings and facilities, materials, production and controls, and testing, as appropriate, to ensure product sterility at the time of manufacture and throughout the product’s shelf life. FDA has published guidance4 to provide clarity on how manufacturers can meet CGMP requirements in 21 CFR parts 210 and 211 when manufacturing sterile drug and biological ophthalmic products using aseptic processing. Some of the relevant regulations and guidance applicable to products for ophthalmic use are summarized below.

  • Per 21 CFR 211.113(b), there must be appropriate written procedures designed to prevent microbiological contamination that must be established and followed, including the validation of aseptic and sterilization processes.
  • Per 21 CFR 211.94(b), drug product container closure systems must provide adequate protection against foreseeable external factors in storage and use that can cause deterioration or contamination of the drug product.
    • As explained in guidance for industry Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice, a container closure system that does not maintain adequate container integrity after it is sealed is unsuitable for sterile products, and safeguards should be implemented to strictly preclude shipment of product that may lack container closure integrity and lead to product nonsterility. Such safeguards could include ensuring suitability and incoming quality of container closure systems, including dose delivery mechanisms, and ensuring that manufacturing equipment for container closure systems is fit for purpose. Validation of container closure system integrity should demonstrate no penetration of microbial contaminants or chemical or physical impurities.5
  • Per 21 CFR 211.160, 211.165, and 211.166, there must be appropriate testing to demonstrate conformance to product specifications. When preservatives are used to maintain sterility of ophthalmic products in multidose containers,6 manufacturers should (1) demonstrate that the preservatives have sufficient bactericidal and fungistatic activity to inhibit growth of microorganisms over the product’s shelf life and during use; and (2) test drug products at release and throughout the product’s shelf life to confirm they have a sufficient amount of the preservatives to maintain sterility.7
  • Per 21 CFR 211.167, there are special testing requirements for products purporting to be sterile and/or pyrogen free, specifically use of appropriate laboratory testing to determine conformance to requirements for sterility. This includes testing for microbial contamination and pyrogens or bacterial endotoxins (e.g., release and stability testing of the drug product in the commercially marketed container closure system).

FDA assesses compliance with these and other applicable CGMP requirements through facility inspections under section 704(a)(1) of the FD&C Act, records requests under section 704(a)(4) of the FD&C Act, and other oversight tools. Manufacturers can find additional insight in the guidance for industry Submission Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products, which, although focused on application submission, includes information about the efficacy of sterilization processes.

1 As defined in guidance for industry Quality Considerations for Topical Ophthalmic Drug Products (December 2023).

2 See 21 CFR 200.50(a)(1).

3 See FDA’s alerts and warnings about eye drops at https://www.fda.gov/drugs/buying-using-medicine-safely/what-you-should-know-about-eye-drops.

4 See FDA’s 2004 guidance for industry Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice.

5 This is consistent with USP General Chapter <771> Ophthalmic Products–Quality Tests.

6 Liquid ophthalmic products in multidose containers should contain one or more suitable and harmless substances that will inhibit the growth of microorganisms; see 21 CFR 200.50(b). See also USP General Chapter <51> Antimicrobial Effectiveness Testing.

7 USP General Chapter <51> Antimicrobial Effectiveness Testing.

References:

Date: 5/22/2024

Contact for further information:

CDER-OPQ-Inquiries@fda.hhs.gov

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