Friday, April 28, 2023

Sterile drug manufacturing facility audit considerations

Sterile drug products / Injectable dosage form manufacturing facility audit.

The questionnaire is intended to cover the manufacture of all sterile drug products, including sterile bulk drugs, ophthalmic and ophthalmic dosage forms, Small Volume Parenteral (SVP) products, Large Volume Parenteral ( LVP) products, and any other drug products required to be sterile.

This article will help you for conducting inspections of manufacturers of sterile bulk and finished dosage form drug products to determine compliance with the Food, Drug, and Cosmetic Act and
the Good Manufacturing Practice Regulations (GMPs), Title 21, CFR Parts 210 and 211
Inspections of sterile product manufacturing firms are performed as either Full Inspections or Abbreviated inspections. In the Abbreviated Inspection, coverage are directed to key
points in the major systems affecting the production of the sterile drug product. If the information collected indicates that the firm's practices are in compliance with CGMPs, the
inspection may be concluded at this point. When questionable practices are observed in areas outside of the systems delineated under this option, the investigator is urged to expand the inspection to cover these areas to his/her satisfaction.

The full Inspection option involves an in depth inspection of key manufacturing systems and processes and their validation in order to maintain surveillance over the firm's activities.

Consider using a team approach in conducting these inspections, utilizing investigators familiar with these processes, and chemists, microbiologists, and engineers, as appropriate.

Investigators or team members should be well qualified in sterile product production experience and preferably have completed formal training courses in parenteral drug manufacture, sterilization methods, procedures and equipment. Microbiologists involved should have experience in sterility/pyrogen testing and some experience in sterile product inspections

Determine if changes have occurred by comparing current operations against the EIR for the previous full inspection. The following type of changes are typical of those that would warrant the Full Inspection Option

1.New potential for cross-contamination arising through change in process or product line.

2. Use of new technology requiring new expertise, significantly new equipment or new facilities

3.Review the firm's complaint file, annual product reviews, etc. and determine if the pattern of complaints as well as the firm's records of internal rejection or reworking of batches warrant expanding the inspection to the pu11 Inspection Option to look for weaknesses in the firm's processes, systems or controls

4. If no significant changes have occurred and no violative conditions are observed, the Abbreviated Inspection Option are considered adequate.

5. If significant changes have occurred, or if violative or potentially violative conditions are noted, the inspection are expanded to the Full Inspection Option to provide appropriate coverage.

Inspection is performed for the firm's manufacturing facility including a review of a representative number of Master and Batch Production Records (minimum of 5 batches) on products manufactured by the firm. Products that appear in the firm's inspectional history of previous problems should be included. A brief inspection of the laboratory should include a spot check of a limited number of test records (at least 10) to assure that batches are being subjected to adequate testing for conformance to specifications

Special note should be taken of the firm's packaging and labeling controls. Any observation of inadequate controls will indicate that a Full inspectional Option should be performed. If the following type of procedures are encountered, in-depth inspectional coverage should be given
to the firm's Labeling systems:

The use of labels which are similar in size, shape, and color for different products.
The use of cut labels which are similar in appearance without some type of 100 percent electronic verification system for the finished product.
If the use of gang printing of cut labels is not minimized as required by current regulations.
If the firm has had more than one mislabeling recall in the past two years.
If the firm fills product into unlabeled containers which are later labeled under multiple private labels.
The inspection will focus on the major systems that impact on the safety and effectiveness of all sterile products manufactured by the firm:

Sterilization procedures applied to the drug product; components; container/closures; product contact equipment and surfaces
1.water systems  (preparation of water for injection)
2.air handling
3.environmental monitoring
4.handling of incoming components
5.packaging and labeling
7.lyophilization (where applicable)

It is suggested that one drug product be selected and followed throughout; if the firm utilizes more than one type of drug product sterilization process, one drug product representing each
type of sterilization process should be selected.
When selecting a drug product for review, drugs that are listed in the firm's complaint files should be considered.

Drug product information collected is as follows:
A. Name of Selected Drug
B. Dosage Size
C. Strength
D. itch sizes
E. Number of batches per year

What type of sterile drug products are manufactured by this firm:
F. Small Volume Parantral
G. Large Volume Parantral
H. Ophthalmics
I. Sterile Otics
J. Sterile Bulk
K. Other (identify)
Indicate whether any of these products are lyophilized.

The inspections are done on separate sections for each unique drug product and sterilization process investigated.


Documentary or physical samples are collected, including in-process samples where possible, to document any suspected adulteration and misbranding problems encountered during the inspection.

If microbiological contamination is suspected, document where possible the conditions which could contribute microbiological contamination to the product both by collecting records and
physical samples taken aseptically at points where such contamination might occur, such as from the water for injection WFI system. Products found positive on initial sterility testing should also be
considered for sampling. Physical samples should not be collected if the estimated level
of microbial contamination is low.
Collect samples for particulate matter contamination where inspectional observations indicate poor manufacturing practices have possibly contributed to the introduction of particulate
matter into these products or where finished product controls are inadequate to assure rejection of such units.

Sample Size
(determining sample sizes for endotoxin and sterility evaluation)


Routine chemical analyses
Sterility Testing:
Other microbiological examinations
Salmonella Serotyping
Chemical cross-contamination analyses by mass spectrometry (MS)
Particulate Matter in Injectables

1. Samples are to be examined for compliance with applicable specifications. Check analyses will be by the official method, or when no official method exists, by other validated procedures.

2. The presence of cross-contamination must be confirmed by a second method. Spectroscopic methods, such as MS, NMR, UVvisible, or infrared are preferred. However, a second
chromatographic method may be employed, provided the chromatographic mechanisms are different (e.g., ion-pairing vs. conventional reverse phase HPLC).

3. Sterility testing methods should be based on USP and the Sterility Analytical Manual Other microbiological examinations should be based on appropriate sections of USP

Part 1 Inspection and facility audit questionnaire for sterile dosage form

Part 2 Sterile drug manufacturing facility audit questionnaire

Part 3 Sterile drug / Injectable dosage form manufacturing facility inspection questionnaire

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