Celltrion Inc, Republic of Korea, Receives Warning Letter for Microbiological/Environmental Issues

 

The U.S. Food and Drug Administration (FDA) inspected Celltrion Inc, Republic of Korea from May 22 – June 2, 2017.  On January 26, 2018 the FDA issued a Warning Letter for microbiological/environmental issues that summarizes significant violations of cGMP for finished pharmaceuticals (see 21 CFR, parts 210/211).  Several interesting observations involved microbiological and environmental issues.

During our inspection, our investigators observed specific violations including, but not limited to, the following.

1. Your firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes (21 CFR 211.113(b)). 

Poor Aseptic Behavior

On May 23, 2017, our investigator observed multiple poor aseptic practices during the set-up and filling of (b)(4)batch (b)(4).

For example, during the aseptic filling of vials, an operator used restricted access barrier system (RABS) (b)(4) to remove a jammed stopper by reaching over exposed sterile stoppers in the stopper bowl. The RABS (b)(4)disrupted the unidirectional airflow over the stopper bowl, creating a risk for microbial contamination. After the operator removed the jammed stopper, the filling line was restarted, but the affected stoppers were not cleared.

In your response, you included revised aseptic technique procedures for set-up and filling. However, your response was inadequate because you did not perform a retrospective investigation and thorough risk assessment of the effect on your product. In addition, your revised procedure FF21024 permits contamination of product-contact surfaces during set-up, followed by wiping with a disinfectant, instead of preventing sterile equipment contamination by improved design and procedures.

In response to this letter, provide:

• Your plan to assure appropriate aseptic practices and cleanroom behavior during production. Include specific steps to ensure routine supervisory oversight for all production batches. Also describe the frequency of quality assurance oversight (e.g., audit) during aseptic processing and other operations.
• A thorough risk assessment that evaluates how poor aseptic technique and cleanroom behavior such as that observed during the inspection may have affected quality and sterility of your drugs.
• A corrective action and preventive action (CAPA) plan to fully remediate any contamination hazards to sterile product contact surfaces during set-up, including improved equipment design and procedures.
• A standard operating procedure (SOP) that requires routine sterilization of your RABS (b)(4)and specifies maximum use time.
• Comprehensive identification of all contamination hazards with respect to your aseptic processes, equipment, and facilities. Provide an independent risk assessment that covers, among other things, all human interactions with the ISO 5 area, equipment placement and ergonomics, air quality in the ISO 5 area and surrounding room, facility layout, personnel flow, and material flow (e.g., RABS material transfers).
• A CAPA plan, with timelines, to address the findings of the contamination hazards risk assessment. Describe how you will improve aseptic processing operation design, control, and personnel qualification.

Comments:

A RABS system permits the aseptic filling of product when used properly.  This includes a set-up which involves no poor technique in getting the facilities ready for fill.  Once the filling is operational, no individuals should penetrate the panels.  Only sterile forceps should be used.  Parts that are removable to include the stopper rails, stopper hopper and other removal stainless parts should be terminally sterilized with either steam or dry heat.  Chemical sterilization does not permit a definite Sterility Assurance Level.

Smoke Study Deficiencies

Our investigator reviewed the smoke studies for the RABS filling and (b)(4) loading areas, and documented deficiencies. The smoke studies conducted for these ISO 5 areas lacked sufficient evaluation of dynamic conditions, including set-up and routine aseptic manipulations. For example, you did not address critical interventions such as the removal of jammed stoppers, so it was not possible to evaluate the effects of such interventions on unidirectional airflow.

In your response, you stated that you conducted two additional smoke studies. In response to this letter, provide a copy (e.g., an mpeg file) of your new smoke study recordings.

Comments:

Smoke studies within ISO Class 5 areas are being frequently sought when the FDA audits an Aseptic Filling Facility.  These studies should be initiated by individuals familiar with what the FDA desires and include smoke studies under both static and dynamic conditions as well as with critical interventions.  While one may wish to use media fills as part of this, I would urge caution until one is assured that the results are those that would be anticipated.

Media Fill Deficiencies

Our investigator observed multiple deficiencies related to the validation of your aseptic processes.

1. Our review of your media fill batch records found that your firm rejected integral vials. For example, during simulation of a power failure at the capping station, your firm rejected integral vials filled and stoppered prior to the power outage. The practice is inappropriate and contrary to your firm’s media fill procedure (b)(4) 2205 Media Fill Plan for Sterile Injectable Products.

Clear and specific SOPs for line clearance (i.e., intervention type and quantity of units removed) enable consistent production practices and assessment of these practices during media fills. Where procedures lack specificity, there is insufficient justification for exclusion of units from the media fill batch. You should not remove more units during a media fill intervention than would be cleared during a production run. To ensure a valid assessment, it is critical that media fill studies accurately simulate these and other worst-case conditions encountered during commercial production.

1. Your procedure (b)(4) 2205 did not specify that all personnel authorized to enter the aseptic processing rooms during manufacturing should participate in a media fill at least once a year.

Comments:

All personnel should participate in a media fill at least once each year.  Where Companies have problems is when they assume that each individual needs to participate in every “worst case scenario”.  This is not required and when placed within a SOP will guarantee a citation since it is almost impossible for an individual to perform all of these manipulations with only one fill.

1. You lacked adequate procedures for training and qualifying personnel to examine media filled units following incubation, and you did not specify how they are to conduct this inspection. Furthermore, you did not keep adequate records that document which personnel performed the examinations.

Comments:

SOPs are required to guide personnel for training and qualification of media filled units following incubation.  A series of positive and negative units should be included as part of this training.

In your response, you included revised media fill procedures, and indicated that you performed an additional media fill. However, you did not adequately address the vials that were erroneously removed and the impact on the accuracy of past media fill results. You also failed to perform a full assessment of your media fill program. For example, you did not conduct a thorough assessment of the training and qualifications of personnel to determine whether they can reliably examine media fill units.

In response to this letter:

Provide a retrospective assessment of all media fills since January 2014. List all media fills conducted, fill date, number of units runs, number of vials rejected, number of units incubated, and number of positive units. Describe the circumstances under which any integral media fill vials were removed from each media fill batch. Explain in detail why they were rejected. Provide the final, signed summary report prepared by your firm for each media fill.

Describe how you revised SOPs to specify when units must be rejected during commercial operations. Provide your full CAPA to ensure that units can be rejected in media fills only if appropriate and consistent with corresponding production SOPs.

Provide a comprehensive independent review of your media fill program.

List all batches processed during power outages since January 2015. Describe actions taken after the power failures to restore appropriate aseptic processing conditions. If you permitted continuation of batch production, describe how many units you rejected and the criteria you used to accept units following the power failure. Also, provide the related investigation report and an assessment of suitability of any batch that may have been exposed to a loss of environmental control in the aseptic processing facility.

3. Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas (21 CFR 211.42(c)(10)(iv)).

Your environmental monitoring program for the aseptic processing (ISO 5) area was deficient.

For example, your SOP FF21017 Environmental monitoring in operation for fill and finish process lacked active air monitoring in ISO 5 areas during operations. In your response, you provided your updated procedures that include monitoring during manufacturing operations.

In response to this letter, describe the status of improvements you made to your environmental monitoring program and an assessment of CAPA effectiveness to ensure your program can reliably evaluate whether your aseptic processing environment remains in a state of control. 

Additional Guidance on Aseptic Processing

See FDA’s guidance document Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice (September 2004) to help you meet CGMP requirements when manufacturing sterile drugs using aseptic processing, at http://www.fda.gov/downloads/Drugs/…/Guidances/ucm070342.pdf.

 Comments:

Both active and passive airborne environmental monitoring is currently required for products that are sold in the United States.  Likewise, a product manufactured within the U.S., but planned for marketing outside of the U.S., must also have passive settling plates within the fill ‘n finish area.