警告信相关内容原文：

3. Your firm failed to establish and follow adequate written procedures for cleaning and maintenance of equipment (21 CFR 211.67(b)).

You have not demonstrated that your cleaning procedures are adequate to prevent cross-contamination between the OTC drug products and nondrug products manufactured at your facility. Your firm utilizes (b)(4) filling lines during manufacturing of your drug products, which are shared among multiple drug products and cosmetics. Our investigator observed inadequate cleaning and maintenance of these filling lines and associated equipment. Specifically:

Inadequate Cleaning Validation

The cleaning validation protocol for your (b)(4) Tube Filler, line (b)(4) stated that it was “representative of all filling machines used in the production department” at your firm. However, filling lines (b)(4) do not use identical equipment, and you failed to provide evidence or scientific justification for how the cleaning of (b)(4) Tube Filler, line (b)(4) is representative of your other filling lines.

Also, this cleaning validation protocol incorporated (b)(4) sunscreen drug products, stating they “are considered to be the worst case scenario due to the nature of the formula and the amount of active material (i.e., (b)(4)) in the product.” However, you failed to provide scientific justification for why these products are considered “worst case” and how they are representative of all drug products manufactured at your firm. We note that your firm manufactures other OTC sunscreen drug products with higher percentages of the active ingredient (b)(4), and other topical drug products with different active ingredients (for example, acne creams and pain-relief balms and lotions).

In your response, your firm committed to completing cleaning validation for your other filling lines and assessing if other drug products are “worst case” and, if required, performing additional validation studies. In addition, you stated that you would review products made on lines (b)(4), including a risk assessment, and that you will document your justification for selecting the (b)(4) as being representative. Your response is inadequate because you did not provide adequate details about your corrections, and you did not discuss whether equipment will still be used in the manufacturing of drug products before the completion of these corrections.

Inadequate Documentation and Verification of Equipment Cleaning

You failed to appropriately document and verify the cleaning of your filling line equipment before use, as required by your procedure. For example, on your batch record for (b)(4), Batch (b)(4), your production staff and quality representative confirmed by signature that the previous batch of (b)(4), Batch (b)(4), was cleared and the associated filling equipment was cleaned and ready for use. However, there is no entry on your equipment maintenance log sheet that documents the use and cleaning of your filling line equipment for (b)(4), Batch (b)(4). Instead, the log sheet notes the previous use and cleaning was for “(b)(4), Batch: (b)(4).”

In your response, your firm committed to investigating the missing entries for the batches noted by our investigator and to performing retraining. Your response is inadequate because you have not provided details about expanding your investigation into ensuring that all drug products manufactured were documented, and how you are assured that all associated equipment was appropriately cleaned. In addition, you do not discuss why your firm had signed off these activities in your batch records as being complete, despite the missing entries on your log sheets.

Lack of Purified Water (PW) System Sanitization

According to your firm’s PW system sanitization procedure, your PW system will be sanitized (b)(4). However, you could not provide evidence to show that your water system had been sanitized within (b)(4) of the time of the FDA inspection.

In your response, you stated that your quality department will continue to sanitize your PW system on a (b)(4) basis and will open a deviation into the quality department’s failure to log sanitizations properly. Your response was inadequate because you did not provide evidence that the PW system was sanitized appropriately during that time period, nor did you discuss what impact a lack of sanitization has on the quality of PW used in both the manufacturing of your drug products and the cleaning of manufacturing equipment.

In response to this letter, provide the following:

• A comprehensive, independent retrospective assessment of your cleaning effectiveness to evaluate the scope of cross-contamination hazards. Include the identity of residues, other manufacturing equipment that may have been improperly cleaned, and an assessment whether cross-contaminated products may have been released for distribution. The assessment should identify any inadequacies of cleaning procedures and practices, and encompass each piece of manufacturing equipment used to manufacture more than one product.

• A CAPA plan, based on the retrospective assessment of your cleaning program, that includes appropriate remediations to your cleaning processes and practices, and timelines for completion. Provide a detailed summary of vulnerabilities in your process for lifecycle management of equipment cleaning. Describe improvements to your cleaning program, including enhancements to cleaning effectiveness; improved ongoing verification of proper cleaning execution for all products and equipment; and all other needed remediations.

• Appropriate improvements to your cleaning validation program, with special emphasis on incorporating conditions identified as worst case in your drug manufacturing operation. This should include but not be limited to, identification and evaluation of all worst case:

  o drugs with higher toxicities
  o drugs with higher drug potencies
  o drugs of lower solubility in their cleaning solvents
  o drugs with characteristics that make them difficult to clean
  o swabbing locations for areas that are most difficult to clean
  o maximum hold times before cleaning

In addition, describe the steps that must be taken in your change management system before introduction of new manufacturing equipment or a new product.

• A summary of updated standard operating procedures (SOPs) that ensure an appropriate program is in place for verification and validation of cleaning procedures for products, processes, and equipment.

• 作者：Shengyi
  来源：拾西
  公众号日期：2022年9月28日