It is no secret the agency has been focusing on process validation for several years now. After all, Process Validation (PV) should be considered one of the basic tenets associated with the manufacturing of finished medical devices that are safe and effective in their intended use. However, what happens when a device establishment fails to implement an effective program for process validation? The answer is FDA shows up for a cup of coffee and an inspection. The outcome of such inspections often end badly when violations of the QSR are discovered, including the failure to properly validate processes that cannot be verified through test and inspection. When the outcome of an inspection results in the issuance of a warning letter, the establishment’s Chief Jailable Officer (CJO) often talks about the “oneiric” (look-it-up) effect of receiving the prized warning letter, typically the effect can be equated to a nightmare. Can you say IQ, OQ, PQ, and PPQ? Dr. D hopes you enjoy this week’s guidance.

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FDA Warning Letter Dated – 10 April 2014

Premised on last week’s guidance and this week’s adventure, the doctor is going to assume the Minneapolis District Office of FDA has been very busy. As Dr. D stated last week, the fishing must be pretty darn good in the Great Lakes region of the United States.

This week’s warning letter is premised on a device establishment’s failure to properly validate its processes. Considering the number of processes cited in the warning letter and knowing the inspection is typically just a snapshot of the establishment’s Quality Management System (QMS), there must have been some serious issues surrounding PV. On a positive note, the offending device establishment recognized its PV shortcomings and submitted a get-well plan that was accepted by the agency. Dr. D wishes them well on their journey to recovery.

Warning letter

“Violations include, but are not limited to, the following:

1. Failure to validate processes whose results cannot be fully verified by subsequent inspection according to established procedures, which is required by 21 CFR 820.75(a).

Specifically, Process Validation, QSP-D09, Rev. 09, states that manufacturing processes must be validated when the process output cannot be fully verified. Test Method Validation, QSP-D39, Rev. 04, states that all test methods within the scope of this procedure must be validated.

The following manufacturing processes and test methods for the AMS 800 Artificial Urinary Sphincter and AMS 700 Inflatable Penile Prosthesis have not been validated or had inadequate validations.

800 Artificial Urinary Sphincter Manufacturing Processes and Test Methods

Balloon

• (b)(4) process
• (b)(4) process
• (b)(4) process
• (b)(4) test method
• (b)(4) process

Cuff

• (b)(4) process
• (b)(4) qualification
• (b)(4) process
• (b)(4) process

Pump

• (b)(4) process
• (b)(4) process
• (b)(4) process
• (b)(4) process

 

700 Inflatable Penile Prosthesis Manufacturing Processes and Test Methods

Spherical (65 and 100 mL) and Conceal Reservoirs

• (b)(4) process
• (b)(4) test method
• (b)(4) process

Cylinders (CX, LGX, and CXR)

• (b)(4) process
• (b)(4) process
• (b)(4) process
• (b)(4) test method
• (b)(4) process
• (b)(4) test method
• (b)(4) process
• (b)(4) test methods
• (b)(4) process
• (b)(4) test method

MS Pump

• (b)(4) process
• (b)(4) process
• (b)(4) test method

 

In addition, numerous manufacturing processes and test methods that require validation have not been validated for the AdVance Male Sling System, Ambicor 2-Piece Inflatable Penile Implant, Spectra Non-Inflatable 1-Piece Implant, and Y-Mesh Sacral Colpopexy System.”

Subpart G–Production and Process Controls

Sec. 820.75 Process Validation
“(a) Where the results of a process cannot be fully verified by subsequent inspection and test, the process shall be validated with a high degree of assurance and approved according to established procedures. The validation activities and results, including the date and signature of the individual(s) approving the validation and where appropriate the major equipment validated, shall be documented.

(b) Each manufacturer shall establish and maintain procedures for monitoring and control of process parameters for validated processes to ensure that the specified requirements continue to be met.

1. Each manufacturer shall ensure that validated processes are performed by qualified individual(s).
2. For validated processes, the monitoring and control methods and data, the date performed, and, where appropriate, the individual(s) performing the process or the major equipment used shall be documented.

(c) When changes or process deviations occur, the manufacturer shall review and evaluate the process and perform revalidation where appropriate. These activities shall be documented.”

Complying with the regulation

Not wanting to state the obvious but obliged to do so, device establishments must script and implement a procedure that not only governs their approach to PV but identifies their approach to monitoring, control methods applied, and the data collected. The agency’s expectation is: “Where the results of a process cannot be fully verified by subsequent inspection and test, the process shall be validated with a high degree of assurance and approved according to established procedures.”

From Dr. D’s perspective, there is nothing like the application of good old-fashion Statistical Process Control (SPC) to ensure processes remain in control; however, the processes must first be validated.

Now Dr. D is not going to lecture the readers on the appropriate approach to PV. The approaches will vary considerable depending on the product portfolio and depending upon the processes being validated. However, things to be considered and included in the written validation protocol are:

• A protocol review and approval page;
• A detailed description of the process to be validated;
• Type of testing being performed, i.e., limit versus challenge;
• Compiled list of equipment to be used;
• Training requirements (please note, validation activities should only be performed by qualified individuals;
• Data collection sheets;
• Sample size rationale;
• Type of data being collected attribute versus variables data;
• Targeted reliability/confidence level;
• Method employed for data analysis;
• Criteria for acceptance;
• Criteria for repeating validation; and
• Location of where the protocol, data, and eventual validation report will be retained.

Similar to the protocol, the outcome of the validation testing is the written report. The report is the documented evidence that a process has been properly validated. Items for consideration for inclusion into the written report include:

• A report review and approval page;
• Analysis of the data collected;
• Compiled list of equipment used (including calibration dates, as applicable);
• Use of any statistical tools to normalize data, e.g. Anderson-Darling;
• Definitive statement of pass or fail;
• Compiled list of protocol deviations and the impact such deviations had on the PV testing;
• All of the data collected (as attachments to report);
• Criteria for repeating validation; and
• A statement as to where the protocol, data, and report are retained.

A subset of the PV work is the Test Method Validation (TMV) work. Device establishments cannot create test fixtures, methods, and other tools needed to support the day-to-day activities associated with manufacturing finished medical devices without first validating the use of these tools. For example, Dr. D strongly recommends scripting a procedure that defines when an inspector should be using a micrometer versus a caliper to perform a mechanical inspection. The doctor also recommends using some common sense as having a 3-page TMV protocol for the use of a steel rule, is just insane. Don’t laugh; the doctor has witnessed this type of insanity first hand.

Takeaways

For this week’s guidance, the doctor will leave the readers with just two takeaways. One – the agency is big on PV so if your organization does not have a robust approach to PV, there is not time like the present to implement a procedure and start validating baby. Two – documented evidence is always the best defense during an FDA inspection. Your CJO will appreciate: (a) well-written protocols; (b) protocols that have been properly executed: and (c) protocols supported by a thorough analysis included in the written report. Remember one of the Dr. D’s most important mantras: “If an event or activity is not documented in writing, in the eyes of FDA it never happened.

In closing, thank you again for joining Dr. D and I hope you find value in the guidance provided. Until the next installment of DG – cheers from Dr. D. and best wishes for continued professional success.

References:

1. Code of Federal Regulation. (2013, April) Title 21 Part 820: Quality system regulation. Washington, D.C.: U.S. Government Printing Office.
2. Devine, C. (2011). Devine guidance for complying with the FDA’s quality system regulation – 21 CFR, Part 820. Charleston, SC: Amazon.
3. FDA’s enforcement page. (2014, May). FDA.gov Website. Retrieved April 25, 2014, from http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm393157.htm.