4.5 Equipment Qualification Program

This page will address various regulatory issues related to this section of the GMP Institute framework.  Click below to view the issues that are relevant to you.

What is the significance of defects in container-closure integrity of an injectable? Can product sterility be affected?

Validation and equipment qualification; when "identical" really isn't.

Has FDA established a required number of runs to be performed during Operational Qualification (OQ) testing? If a firm qualifies one type and model of equipment, can it be used in a different process without additional qualification?

Should non-pharmaceuticals be manufactured in common equipment with active pharmaceutical ingredients (APIs)?

What are the CGMP requirements for equipment used for industrial grade products and then used for medical products?

What is the significance of defects in container-closure integrity of an injectable? Can product sterility be affected?

References:
211.63 Equipment design, size, and location;
211.110 Written procedures; deviations;
211.186 Master production and control records;
211.192 Production record review

A number of injectable pharmaceuticals have been voluntarily recalled over the last two years due to critical defects in container-closure systems. These product integrity problems included glass fractures or leaks. Product non-sterility was one of the consequences of these defects.

In the case of most recalls, investigations were not conducted in accord with 21 CFR 211.192. In some instances, while the cause of the defects was known, corrective actions were not implemented and impact on past and future batches was not determined. As a result, new lots were produced with the same serious quality problem, the defective product was shipped, and health practitioners began registering complaints with FDA and the manufacturers.

The critical defects stemmed from various causes. Rough or irregular handling during specific process steps was a common denominator in each of the recalls. Some specific examples of causes include: 

We have seen several other scenarios in which process deficiencies lead to loss of vial, ampul, or cartridge integrity.  But mechanical problems have not been the only cause identified. Investigations have also attributed problems to improper manual handling. Trays dropped by personnel after final packaging, and rough charging of vials to the processing line, have resulted in recalls. In the former case, vial integrity was lost and the product was subsequently found to be non-sterile. Contaminated water from a washing step performed by the firm after autoclaving was named as the source of the predominant water-borne bacterium contaminating the vials.

Just as the container-closure system chosen by a firm needs to be a robust one to ensure sterility and stability, there must also be compatibility with the production line on which the product will be manufactured. As cited above, incompatibility of a new container-closure with an existing line has resulted in loss of integrity. FDA requires firms to
develop consistent processes employing suitable manufacturing equipment (see 211.65 and 211.100). This equipment should be qualified to process product in a manner that assures integrity of the specific container-closure.

As a final measure, a batch manufacturing operation includes an inspection stage intended to reject defective units. It is important to be mindful that final visual/electronic inspection has its limitations. In particular, the nature (e.g., location, visibility) of a given defect may make its detection problematic. Some critical defects are difficult or impossible (e.g., hidden cracks under the crimp, etc.) to detect during the final inspection stage. This fact underscores the importance of building quality into a manufacturing operation to prevent serious defects. For each batch of a parenteral drug product, reconciliation records should document the actual quantities of defective units detected, categorized by major defect type. These results should be compared to established specifications, and an investigation triggered if results are beyond specifications. In addition, upon detection, a critical defect should be investigated. A lot should not be released for shipment in the event that it contains units lacking container-closure integrity.

Contact for further information:
Richard L. Friedman, HFD-325; phone: (301) 594-0098;
e-mail: friedmanr@cder.fda.gov 

Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 8, Number 2) June, 2000
This same text is also reprinted in Framework sections 4.1 and 7.2.

Validation and equipment qualification; when "identical" really isn't.

Reference: 
21 CFR 211.100, Written procedures, deviations; 
Guideline On General Principles of Process Validation, May, 1987

As explained in the 1987 validation guideline, the general requirement for process validation is contained in section 211.100 of the CGMP regulations which states that "[T]here shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess." 

The validation guideline addresses several general principles of equipment suitability. For example, installation qualification is described as establishing confidence that process equipment and ancillary systems are capable of consistently operating within established limits and tolerances. Installation qualification includes examination of equipment design, determination of calibration, maintenance, and adjustment requirements, and identifying critical equipment features that could affect the process and product.  Another principle is that equipment is evaluated and tested to verify that it is capable of operating satisfactorily within the required process operating limits and that actual production conditions, including "worst case" situations, are simulated. The guideline cautions that "[I]n assessing the suitability of a given piece of equipment, it is usually insufficient to rely solely upon the representations of the equipment supplier…"

The guideline further states that each specific process should be appropriately qualified and validated, noting the inherent danger in relying on perceived similarities between products, processes, and equipment.

The following case illustrates the importance of performing adequate equipment qualification on each piece of processing equipment, and the problems that may result when firms fail to verify equipment supplier representations.

A pharmaceutical firm used two blenders to produce a tablet. Both blenders were from the same equipment manufacturer, had the same model number and same design. Although one blender was older than the other, the supplier told the drug manufacturer that the units were "identical." The drug manufacturer took the claim at face value and did not include the older blender as part of its process validation.

The drug company marketed about 100 lots of tablets made using the old blender. In testing retain samples, the company found that some lots failed the content uniformity specification.

The firm's investigation traced the out of specification lots to one of the two "identical" blenders, namely the old one. The pharmaceutical firm's own investigation found the older blender to have a slightly smaller capacity and different RPM (revolutions per minute) operational characteristics when run at the same settings as the newer blender.

Subsequently, the firm recalled its total production of the product it made using the older blender. This extensive recall involved multiple strengths of product totaling approximately one half million bottles from U.S. and foreign consignees. The firm plans to qualify the old blender using production size lots.

In light of this case study, during your audits of a firm's process validation, it would be appropriate to determine if the firm's validation protocol includes equipment qualification for all units of significant equipment, even where multiple units are supposedly "identical." Moreover, as explained in the validation guideline, the validation should reflect production size lots.

Contact for further information: Michael J.Verdi, HFD-301, 301-594-2456; e-mail: verdim@cder.fda.gov

Has FDA established a required number of runs to be performed during Operational Qualification (OQ) testing? If a firm qualifies one type and model of equipment, can it be used in a different process without additional qualification?

Reference: 
21 CFR 211.100, Written procedures; deviations; 
May 1987, Guideline on General Principles of Process Validation

Installation Qualification (IQ), Operational Qualification (OQ), and Performance Qualification (PQ), along with other similar terms, are commonly used in the pharmaceutical industry to discuss the generally accepted concept that a firm should qualify equipment and systems as part of validating a manufacturing process. The FDA Guideline on General Principles of Process Validation does not use the term Operational Qualification. It defines Installation Qualification as establishing confidence that process equipment and ancillary systems are capable of consistently operating within established limits and tolerances. This includes IQ and OQ. The FDA Guideline also defines Process Performance Qualification as establishing confidence that the process is effective and reproducible.

The guideline states that "it is important that equipment qualification simulate actual production conditions, including those which are 'worst case' situations," and that "tests and challenges should be repeated a sufficient number of times to assure reliable and meaningful results."

Regarding the first question, the often-cited "three consecutive batch" recommendation is intended for process validation rather than for equipment qualification. FDA has not recommended any specific number of "runs" for equipment qualification, but expects multiple tests to simulate actual operating ranges and to establish consistency.

As to the second question, FDA expects Installation Qualification on each piece of equipment to document that it is installed correctly and operates consistently according to established limits and tolerances. Operational Qualification should also be performed for each different use of the equipment or system to document the suitability for that use, but would not be required for additional pieces of the same type/model of equipment when used in the same process. Process Performance Qualification would also not be required for each piece of the same type/model of equipment used in the same process, provided installation qualification has been performed.

Contact for further info: John Dietrick, HFD-325, 301-594-0098; e-mail: dietrickj@cder.fda.gov

Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 7, Number 1) March, 1999.
This same text is also reprinted in Framework section 6.3.

Should non-pharmaceuticals be manufactured in common equipment with active pharmaceutical ingredients (APIs)?

Reference: 
FD&C Act, Section 501(a)(2)(b); 
WHO Good Practices for the Manufacture and Quality Control of Drugs, June 1993

FDA has not specifically addressed this issue in a formal document. However, a fundamental tenet of current good manufacturing practice is that equipment does not contaminate the drugs -- that is, alter drug safety, quality or purity beyond established specifications. If you encounter instances in which non-pharmaceuticals are made in the same equipment as APIs, consider this basic tenet, and evaluate the suitability of using common equipment on a case by case basis.

Some non-pharmaceuticals pose unacceptable risks of cross-contamination and product mix-ups, and should therefore not normally be manufactured in common equipment with APIs. In some cases, in addition to separate equipment, it would be appropriate to use a separate facility for pharmaceutical chemical manufacturing. 

This separation is an internationally recognized concept. For example, the World Health Organization (WHO) Guide to Good Manufacturing Practices discusses the use of separate facilities for the production of certain "non-pharmaceutical products." It adds that "the production of technical poisons, such as pesticides and herbicides," should not take place on the "premises used for the manufacture of pharmaceutical products." 

As a general principle, the risks posed by unanticipated mix-ups or cross-contamination should be considered with particular emphasis on chemicals: (1) Known to pose any acute or long term toxicity concerns; or, (2) of incompletely characterized toxicity. Toxicological assessments normally include information such as acute data (e.g., LD50 determinations) using different routes of administration, mutagenicity, carcinogenicity, teratogenicity, sensitization, and irritation. Investigators should be aware that lack of toxicological assessments is not uncommon.

These risks are influenced by the nature and intended use of the drug products that will incorporate the API. For example, those risks may be of greater concern when the APIs will be used in dosage forms intended for: (1) Large doses, (2) long term therapy; (3) treating open wounds; (4) injection; or, (5) inhalation. 

Even when an API manufacturer considers these issues, and determines that the non-pharmaceutical is "harmless" and can be made in common equipment with APIs, it is important that the manufacturer still follows CGMPs for APIs. 

Contact for further info: Richard L. Friedman, HFD-322, 301-594-0095; e-mail: friedmanr@cder.fda.gov

Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 6, Number 2) June 1998.
This same text is also reprinted in framework section 4.3. 

What are the CGMP requirements for equipment used for industrial grade products and then used for medical products?

Reference: 
21 CFR 211.67(a, b, & c) Equipment cleaning and maintenance,
211.100(a) Written Procedures; and 
211.25(a) Training

Equipment, i.e., hoses, temporary vessels, etc. used in the delivery of a medical drug product is considered an integral part of the drug delivery system and as such is a regulated under the drug CGMPs. Any equipment used for medical use is required to be cleaned, maintained, and sanitized at appropriate intervals to prevent contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official requirements in the delivery of a medical product.

Detailed written procedures should be established, and records maintained of the cleaning, sanitizing, and inspection. Another vital CGMP requirement is the assurance that all personnel involved with the equipment on the medical side are adequately trained to perform their designated function.

Problems arise from the contaminants that may be introduced while being used for industrial grade products. Equipment used for industrial products must be qualified prior to being used for medical product, i.e., should be tested for any contaminant that the equipment may have come in contact with, before a medical drug product is introduced.

Contact for further info: Duane Sylvia, HFD-325, 301594-0095, e-mail: sylviad@cder.fda.gov .