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Article Samples

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I have written dozens of FDA and pharmaceutical related articles over the last seven years. On this page are a few of them. Many more are available!

New Sample - Oct. 10:

Don’t Be Haunted By Your Words

How to Avoid Document Mistakes That Destroy Your Credibility and Lead to Legal Trouble

By Nancy Singer and Joseph Pickett

Nancy Singer is the creator and presenter of the 5-hour in-person seminar Dangerous Documents: Avoiding Land Mines in Your Emails and Documents. She began her career as an attorney with the United States Department of Justice where she did litigation for the Food and Drug Administration. Joseph Pickett is a freelance writer at josephmpickett.com, and the owner of the pharmaceutical webinar website Expertbriefings.com and contract lab job site Laboratoryretriever.com.

In this article, we offer advice to both FDA and industry on how to write clear, concise reports and SOPs that won’t come back to haunt them in the future.

If you think about it, an electronic document is like a diamond in your wedding ring. It is very precious.

And it lasts forever.

This is especially true in the field of health care products. These products save and enhance lives. The people and entities that regulate and manufacture these drugs and medical devices are highly visible.

That visibility is often a plus, but when things go wrong, it can be a minus.

For FDAers, you and your documents are under the intense scrutiny of:

Defense lawyers
Office of the Investigator General (OIG)
Congress
Trade associations
The media

Pharmaceutical and device firms, you do not get off easy, either. You and what you write is being closed watched by:

The competition
Federal prosecutors
State prosecutors
Plaintiffs’ lawyers
The media

Basically, people are out to get you in the health care industry. All of these entities have the power to make you look very bad.

So, it is vital to be careful when you write reports and SOPs. Or, six years later at your indictment hearing, you could have prosecutors, the media or Congress saying, “Can you believe they wrote that?”

For FDA – Lack of Specificity or Evidence in an Your EIR Statements

According to the Investigator Operator Manual (IOM) 5.10.4 Narrative Report: “All reports…should be factual, objective and free of unsupportable conclusions…capable of being used as evidence.”

Sounds simple, right?

However, all too often in my career, I have read EIRs with investigator statements like this:

Example 1

“The firm calibrates all of its manufacturing equipment every six months.”

Buzz – wrong answer!

Why? First of all, it is very vague. But there is a deeper problem. In essence, the investigator has just endorsed an unsubstantiated claim of the company! If that company has a recall down the road that injures a customer due to improper calibration, the investigator could have some unpleasant questions to answer.

This is one better way to convey the same information in the EIR:

“I reviewed the firm's SOP that states that the director of calibration will calibrate all of the manufacturing equipment every six months. (See Exhibit 1). I reviewed the firm’s calibration documentation for the calendar year 2010, and the records reflect that all of the equipment identified in the SOP have been calibrated according to the schedule.”

As you can see, this statement provides clear, concise facts about the SOP. And, it makes clear that the SOP claims are that of the company itself, and that the investigator has verified them.

Example 2

Another example from an EIR:

“The production rooms are cleaned daily.”

A lawyer could have a lot of fun with this one, such as: “If the production rooms are cleaned daily, Mr. Investigator, how can you explain the existence of rodents in the production facility?” Once again, the investigator is setting himself up as the defender of the company’s unsubstantiated policy.

A better way to say this is:

“The SOP on sanitation states that the production rooms are cleaned daily.”

Example 3

Another vague example from an EIR:

“The firm uses Yost Pest Control Services, and the firm has not had problems with pests.”

How nice of you to take the company’s side, Ms. Investigator!

Let’s try that again:

“I reviewed the firm’s pest control reports from the Yost Pest Control Services for 2010, which are attached in Exhibit 1. Out of the 10 reports that I reviewed, I did not see any reports of rodent activity.”

For FDA – Know When To Use Active and Passive Voice

IOM 5.10.4 Narrative Report Elements states: “Generally, EIRs…should be written in the first person using the active voice.”

FDA has stated: “Readers prefer active voice sentences, and we should try to use the active voice in most of our business writing…Active voice identifies the action and who is performing it. Unfortunately, much of government writing is in the passive voice….[it] becomes a habit; one we should all work to change.”

To get away from passive voice, EIR statements by the investigator should include answers to the following:

Who
What
When
Where
How and
Challenge each observation by asking “so what?” (regarding its significance)

If you use the passive voice, it can be difficult to write in the first person and to answer those questions.

In passive voice, the subject is acted upon. Statements usually are wordy, contain the verb “to be,” and can hide the actor. We want the document to specify who the actor was. So down the road, it is clear who did what.

Example 1:

Passive: “Six records were reviewed, and discrepancies were found in each record.”

In active voice, the subject performs the action.

Active: “I reviewed six records and found discrepancies in each record.”

Example 2:

Passive: “The 483 was annotated by the firm.”

No good. This statement does not answer who, what or when. FDA is going to want to know these things if something goes wrong at the firm someday.

Active: “At the end of the inspection, the firm’s VP QA, Joe Yates, annotated each of the items on the 483.”

Better. Now if the firm does not follow up on the corrective items, FDA knows to whom it needs to speak.

Example 3

Passive: “A list of all batches of SAP drugs manufactured since the last inspection was provided.”

Active: “I asked Mr. Bates to provide a list of all batches of SAP drugs manufactured from Jan-June 2010. He provided the list that is attached to this report as Exhibit 4.”

However, there are times when you do want to use passive voice, such as when the actor is:

Unknown: The office was built in 2006.
Unimportant: The Bates’ response to the 483 was mailed on June 10, 2010.
Better left unsaid (tact): Your form was written incorrectly.

Here are some other examples of acceptable passive voice:

“The previous inspection was classified as VAI.”

“No 483 was issued.”

“The inspection of this Class II device manufacturer was conducted on Nov. 23, 2009.”

For Industry - Problems With Passive Voice

We also want to use active voice in most industry documents. This way, it is clear in, say, 5 years, who did what and when.

IOM 5.3.6.2 states that “in order to establish relationships between violative conditions and responsible individuals, the following types of information would be useful:”

What orders were issued? When, by whom, to whom, and on whose authority and instructions?
What follow-up was done to see if orders were carried out? When, by whom, and on whose authority and instructions?
Who decided corrections were not complete and satisfactory?

Let’s apply this to a typical CAPA documentation. The company should state:
What happened
Why it happened
What they did about it
Why the solutions were effective
How to make sure it does not happen again

However, oftentimes, the company uses the passive voice in the CAPA report. This can tell what happened without revealing the responsible parties.

Examples 1-3

“Complaints were received.”

“The investigation took place.”

“The corrective action was taken.”

These vague statements can result in the reader of the document (say an FDAer or an attorney) not understanding the root cause of the failure, as well as the compliance story.
Again, we need to understand five years later what the story was, after everyone at the company who was involved may no longer be around.

Example 4

CAPA report states: “2% of the brakes on the hospital beds fail to hold.”

What it should say: “Based on the investigation, the root cause for the brakes of the hospital beds failing to hold is that the operator is not using the correct settings on the new manufacturing equipment to test the brakes. This is the third time the incident has happened by three different operators.”

For Industry - SOP Habit to Avoid – Sloppy Writing

Also on the industry side, company employees are often guilty of other types of poor writing that can cause trouble, too.

Example 1

This is an example a statement I might see in an industry document:

“The purpose of this study was to ensure that the coating material #234 will not affect the leak and tear resistance of the latex gloves.”

The problem here is the company employee has injected bias into the statement. This should be rewritten to be completely neutral:

“The purpose of the study was to determine whether the coating material #234 will affect the leak and tear resistance of the latex gloves.”

Example 2

“If there is not more than one positive test of sterility in the 10 tests, the selected sterilization dose is substantiated.”

The sentence explains the criteria for what a substantiated dose is, but there is no reference.

Example 3

“The raw data collected is located in Appendix 1. The official data for this study can be found in the mechanical test report.”

What is the difference between raw data and official data? Why not just say ‘data’?

Example 4

“This report tested the accuracy of the glucose monitor readings.”

This statement also injects bias. A better way is:

“This report includes the test results of the accuracy of the glucose monitor readings.”

Conclusion

The federal government has been trying for years to encourage the use of plain, clear language in government documents. In 1998, President Clinton directed agencies to write all documents in concise language. OMB also formed a group called the Plain Language Action Network (www.plainlanguage.gov). Vice President Gore even created the “No Gobbledygook” Award, which FDA won on four occasions!

The government wants all of us to use clear language, as in the examples cited above, so we can keep health care products safe and reliable for the future. Hopefully, by following some of these tips, both FDA and industry can produce clearer and more concise documents in the future.

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September 2011 Medical Product Website Copy:

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Dingell Discussion Draft to Require Inspections Before Drugs

The Food and Drug Administration Globalization Act of 2008, by House Energy and Commerce Committee Chairman John Dingell (D-MI), would require “an initial inspection before…any drug, active pharmaceutical ingredient, Class II or III device, or device part to such a device” is sold in the U.S., according to a discussion draft issued April 17.

According to the draft, this section requires domestic and foreign drug and device establishments to be inspected every two years. Current law requires only domestic drug and device establishments to be inspected every two years.

FDAers already have concerns with the sweeping nature of the measure. CDER Director Janet Woodcock, M.D., testified before the committee May 1: “FDA cannot rely on inspection as its primary means of ensuring product safety. Any legislation should build in safety measures to address risks throughout a product’s life cycle and focus efforts on preventing problems first, and then using risk-based interventions to ensure preventive approaches are effective, coupled with a rapid response as soon as a problem is detected.”

Double Bracket: “Any legislation should build in safety measures to address risks throughout a product’s life cycle and focus efforts on preventing problems first…”

Besides, Woodcock said, FDA is attempting to ramp up foreign inspections under its existing authority, but that is not the sole answer to increased safety.

Regarding inspections, she did note FDA conducted more foreign inspections in FY 2007 than any other in the agency’s history. For example, in FY 2007, FDA conducted 332 inspections of foreign drug manufacturers, compared to 260 in FY 2004, 266 in FY 2005, and 212 in FY 2006.

“We plan to conduct 500 in FY 2009,” she promised. “While inspections are an important component of the agency’s systematic approach to ensuring the safety of imported medical products, they alone cannot fully address these challenges.”

The proposed legislation also contains a section that states that a drug should only enter the United States through a port of entry that is located in a metropolitan area with a federal testing laboratory, less the party offering that drug for import provides documentation demonstrating compliance with applicable requirements pertaining to identity, strength, quality, purity, approval, listing, labeling, and
registration.

Another section of the proposed legislation states: “A drug shall be deemed adulterated if, upon request, the manufacturer of the ingredient and of each drug that contains that ingredient does not have adequate documentation to establish where the ingredient was made, that the ingredient is not adulterated or misbranded, that the ingredient will perform in accordance with specifications, and is not

contaminated.”

Regarding regulation of import activities, Woodcock added: “Our Action Plan for Import Safety calls for increased FDA and Customs and Border Protection (CBP) cooperation, including the development of interdepartmental procedures for clearing and controlling shipments at ports-of-entry, co-locating FDA and CBP at locations to improve coordination and efficient use of resources, and greater import information sharing between FDA and CBP through new technology applications,” she testified.

The next part of the draft calls for FDA to “assess and collect an annual registration fee for domestic and foreign drug and device establishments for the purpose of defraying the costs of inspecting establishments registered to ensure that such establishments are in compliance with requirements of this Act.”

Woodcock commented in her testimony: “While FDA is supportive of user fee programs in which regulated industry provides funding for additional performance and efforts or programs designed to recoup the costs of regulatory actions resulting from findings of violations (such as re-inspections), [we] will carefully review any proposed user fee program to ensure that it is being assessed against identifiable recipients of special benefits derived from federal activities beyond those received by the general public.”

Added Rep. Frank Pallone (D-NJ) during the May 2 hearing: “FDA’s need is so great, there is going to be a need for user fees in addition to whatever is appropriated.”

Billy Tauzin, president of the Pharmaceutical Research and Manufacturers of America (PhRMA), noted during his testimony that having a secure drug supply chain is as important as increased foreign inspections.

“Our current system is by and large a ‘closed’ distribution system and even with such a system, from time to time counterfeit and tainted products surface, and the public health could be placed at risk. Domestic challenges thus remain great. These challenges would, however, be multiplied exponentially by the added complexities and burdens of an expanded international supply of drugs from various wholesalers and pharmacies,” he stated.

Tauzin said that Congress “should reject proposals, such as proposals to legalize prescription drug importation, which would further strain and compromise the FDA’s ability to protect Americans from potentially dangerous counterfeit medicines and maintain the current ‘closed’ distribution system.”

The PhRMA president had praise for a related bill, H.R. 5839, “The Safeguarding America’s Pharmaceuticals Act of 2008,” sponsored by Rep. Stephen Buyer (R-IN), which calls for anti-counterfeiting technologies for prescription medicines based initially on the potential risks posed by counterfeiting and diversion of such products.

He stated: “It is important to recognize that any requirement to apply electronic technologies to prescription drug products will necessarily need to be applied using a phased approach, both in terms of the scope of products selected, and phased across all partners in the prescription drug supply chain.”

In PhRMA’s view, any legislative or regulatory requirements to authenticate products and pass pedigree information should be uniform, should apply to all parties in the pharmaceutical supply chain, and should recognize the recent federal requirement 20 for a standardized numerical identifier, Tauzin said.

AdvaMed President and CEO Stephen Ubl testified regarding the user fees in the discussion draft that inspections are a core function of FDA and funding should come from appropriations, not industry fees. The draft legislation would impose an additional facility registration fee and a $10,000 importer registration fee.

“Many of our members, particularly small companies, do not have foreign facilities, yet through their fees they would effectively subsidize inspection of foreign companies exporting their products to the U.S.,” Ubl said.

Meanwhile, the Senate on May 22 passed an amendment to a war funding bill that earmarked an additional $48.5 million to CDER and related field activities in the Office of Regulatory Affairs and $23.5 million to the Center for Biologics.

The Senate supplemental appropriations bill also would add $26 million to the CDC’s budget, of which at least $5 million must go to responses to outbreaks of communicable diseases, including genetic sequencing of those who potentially have been exposed to such diseases.

FDA won't scrap Part 11, will continue to refine guidance based upon industry feedback

FDA will not eliminate CFR Part 11 guidance, as some industry comments on the docket have requested, because to do so would effectively cede control of the policy to Department of Justice (DOJ) lawyers. This is the last thing the industry needs, reported John Murray, CDRH software compliance expert, at the Regulatory Affairs Professionals Society (RAPS) Conference in Washington, D.C. on Oct. 13.

"As long as we have control of Part 11, FDA and the industry can approach it in our own way. Otherwise, we'll be waiting around for DOJ to decide what an electronic record is," Murray stated.
Murray also said the biggest problem he has seen with Part 11 in the field is people not even realizing they are using a computer system for recordkeeping. "Management control is the number one problem with software, before even validation. [A company] is using a computer for recordkeeping and [they] don't even know it. How do you know the data is valid? It's a really big problem."

Further, he noted: "Companies don't know what computerized systems they have in their building. They don't know what kind of records they keep. It blows my mind. These systems cost lots of money. Companies spend millions on these things, but how do they know they actually work without validating them?"

Additionally, Murray announced that FDA is working on a draft guidance for cybersecurity for medical devices. "We intend to publish it as level 2 guidance in final form," he said.
He also stressed the importance of following Part 11 if you are maintaining records in accordance with a predicate rule. "Look, it doesn't matter to FDA if you use paper, plastic or rock to keep records. Carving in stone doesn't matter. But if you are keeping records in an electronic format to comply with a predicate rule, you must have some sort of system in place that proves the records are accurate."

The guidance released for Part 11 in August 2003 states: "We will enforce all predicate rule requirements, including predicate rule record and recordkeeping requirements."

Also, Murray talked at length about the phrase "exercise enforcement discretion" found in the guidance. "[This phrase] means that you should never see a Part 11 citation by itself [on a 483]."
I could get in a Winnebago and drive for a day and cite 20 companies for Part 11 violations. Part 11 violations have to be attached to predicate rules. There should be no independent part 11 violations," Murray noted.

The guidance states: "For those records that remain subject to part 11, we intend to exercise enforcement discretion with regard to part 11 requirements for validation, audit trails, record retention, and record copying in the manner described in this guidance and with regard to all part 11 requirements for systems that were operational before the effective date of part 11 (also known as legacy systems)."

Part 11 applies if a firm uses electronic records to perform regulated activities, Murray noted, even if a firm generates a paper record with it. He cited this example: "I inspected a company with a complaint handling system that they said used a computer to only generate their paper records. They said they did all their complaint-handling by paper, so they would not need to comply with Part 11. They said, 'we just type it in there and print them out and put them in these binders.'"

The binders, Murray noted, were bound in beautiful brown leather, with 'FDA' embossed in gold on the cover.

"But in the inspection, we discovered they never took those beautiful binders off the shelf in their complaint-handling process. Another employee told us they did all of that on the computer." This means, of course, that the firm has to comply with Part 11 in that situation, Murray said.

Murray also emphasized Part 11's new narrowed scope. "I must get 1,000 phone calls about what records are subject to Part 11 requirements," he said.

The guidance states: "Under the narrow interpretation of the scope of part 11, with respect to records required to be maintained under predicate rules or submitted to FDA, when persons choose to use records in electronic format in place of paper format, part 11 would apply. On the other hand, when persons use computers to generate paper printouts of electronic records, and those paper records meet all the requirements of the applicable predicate rules and persons rely on the paper records to perform their regulated activities, FDA would generally not consider persons to be "using electronic records in lieu of paper records."

Murray also noted the importance of firms training providing regulatory training to their IT staff. "Most software people have no regulatory training. There needs to be one common training program for regulatory affairs people, consultants, IT people, investigators, etc."

The need for regulatory training for all employees, including IT staff, was revealed, he said, in his recent review of 20 software books. "Every reference to 'risk management' related to marketing and time to market, not public health and safety," he said.

At the end of the presentation, an audience member asked if Murray prefers Linux to Microsoft Windows, the latter being a closed system. "Linux is a good option, but the notion that it is much better than Windows is a religious belief, not a scientific one. I've never seen an operating system that is flawless," he said.

He also noted: "Laser eye surgery equipment runs on a Windows operating system. This is a scary thought, isn't it? But it works fine because the risk has been identified and the system has been validated. We know Windows doesn't always work, so we have to deal with that."
The complete August 2003 Part 11 guidance is at: http://www.fda.gov/cder/guidance/5667fnl.htm.

International collaboration playing vital role in new PAT guidance

There are strong signs that the new PAT (Process Analytical Technology) guidance is drawing significant international backing, as international regulators are beginning to form PAT teams in Canada, Europe and Japan, and the guidance is gaining support from the ASTM International Technical Committee E55: Pharmaceutical Applications of Process Analytical Technology.

ASTM International's support of the PAT guidance, issued in September as part of FDA's Final report "Pharmaceutical cGMPs for the 21st Century - A Risk-Based Approach," is particularly important, because "[the organization] provided an excellent process to identify and develop standards in a timely manner using technical expertise in all relevant disciplines from the pharmaceutical community and other industrial sectors," the FDA guidance document notes.

The document also states that the E55 committee has been tasked with developing standards related to process analytical technology, with a primary focus on process understanding and control. Three subcommittees of E55 include PAT system management, PAT system implementation & practice and PAT terminology. "The PAT Team is represented on E55 committees with a goal to ensure that standards developed are aligned with the PAT guidance and acceptable to FDA."

Overall, the guidance points out the importance of building quality into products from the start, which fits hand-in-glove with FDA's focus on risk-based approaches. The guidance states: "Quality cannot be tested into products; it should be built-in or should be by design. Increased emphasis on building quality into products allows more focus to be placed on relevant multi-factorial relationships among material, manufacturing process, environmental variables, and their effects on quality."

Chris Watts, a compliance officer from CDER's Office of Pharmaceutical Science, who spoke at the RAPS Conference on Oct. 12 in Washington, D.C., said: "Quality by design means we statistically identify what is critical to the performance of the product. PAT can give you a one percent increase in efficiency, which has meant 1 billion dollars in savings to some firms."

The guidance document states that quality is built into pharmaceutical products through a comprehensive understanding of:

· The intended therapeutic objectives; patient population; route of administration; and pharmacological, toxicological, and pharmacokinetic characteristics of a drug;
· The chemical, physical and biopharmaceutic characteristics of a drug;
· Design of a product and selection of product components and packaging based upon the chemical, physical and biopharmaceutic characteristics of a drug; and
· The design of manufacturing processes using principles of engineering, material science, and quality assurance to ensure acceptable and reproducible product quality and performance throughout a product's shelf life.

Watts also said that PAT is a critical concept in the overall GMP final report. "PAT is a risk-based regulation, a non-impeding regulation and a consistent regulation. Success is based upon a broad cooperation between industry, academia and FDA."

In addition: "It is very important that regulators are on same page of reviewing applications. In terms of the PAT initiative, FDA has a team approach to inspections. It's a two-way street: Compliance officers and investigators have input in how we review scientific principles. It's eliminating inconsistencies between field offices and Centers," he stated.

The FDA final report also documents how the agency is beginning to update its current thinking on validation under a Cross-Agency Process Validation workgroup. It was led by CDER's Office of Compliance Coordinating Committee with participation from CDER, CBER, ORA and CVM.

In March, FDA began this process by issuing a compliance policy guide (CPG) called "Process Validation Requirements for Drug Products and Active Pharmaceutical Ingredients Subject to Pre-Market Approval."
At the PDA/FDA Joint Regulatory Conference recently, Brian Hasselbatch, senior compliance officer at CDER, said the CPG manual "is the repository for all agency compliance policy that has been agreed to by the centers." He also noted that "the purpose of the CPG manual is to provide a convenient and organizing system…for internal guidance."

According to the guidance, "the CPG stresses the importance of rational experimental design and ongoing evaluation of data. The document also notes that achieving and maintaining a state of control for a process begins at the process development phase and continues throughout the commercial phase of a product's life-cycle."

Hasselbatch also noted that the scope of the current enforcement policy "does not address the methods and controls designed to ensure product sterility." Also, "it does not address products approved by a BLA or recombinant protein drug products submitted in an NDA."

For current enforcement policy for APIs, Hasselbatch said to "refer to the Guidance for Industry, Q7A, GMP Guidance for APIs, issued in August 2001."

Next steps for process validation guidance, Hasselbatch concluded, is to revise the 1987 Guidance on Principles of Process Validation.

New guidance aims to provide regulatory relief developed through the use of comparability protocol

The guidance for comparability protocols, released with the agency's Final Report "Pharmaceutical cGMPs for the 21st Century - A Risk-Based Approach," was developed to identify options for a systematic risk-based approach to the review process for post-approval manufacturing changes.

According to the guidance, "a comparability protocol is a comprehensive, detailed, written plan that describes the specific tests and studies, analytical procedures, and acceptance criteria to be achieved to demonstrate the lack of adverse effect for a specified type of CMC change that may relate to the safety or effectiveness of the drug product."

The guidance also notes that the Changes Without Prior Review Working Group determined that "a reduced reporting category can be justified when a comparability protocol provides evidence that an applicant has a scientific and technological understanding of the drug, manufacturing process, controls, proposed change and potential effect of that change on the product quality."

A comparability protocol is beneficial because it could allow an applicant to implement a CMC change without waiting for prior approval from FDA. It could therefore place a product in distribution sooner than without a protocol.

"A comparability protocol may also provide a means to facilitate process improvement and/or process optimization. In some cases, a comparability protocol may provide a means to prevent or mitigate drug supply disruptions or shortages," the guidance states.

Future changes the agency is considering in the guidance include:

· Change ICH Q8 to describe the suggested contents for the 3.2.P.2 Pharmaceutical Development section of a regulatory submission in the ICH M4 Common Technical Document (CTD) format. The intent is to provide sponsors of drug applications an opportunity to present knowledge gained during development of a product.
· Under the Manufacturing Subcommittee of the Advisory Committee for Pharmaceutical Science (ACPS), form a working group to identify specific steps needed to move towards the desired state.
· Consider ACPS recommendations on regulatory flexibility for postapproval changes (e.g., reduce the need for prior review) for modifying the draft Comparability Protocol Guidance (for small molecules only).
Currently the agency is finalizing the guidance to incorporate the agency's new risk-based approach to ensure reductions in post approval manufacturing changes and to ensure that appropriate manufacturing science is incorporated in the decision-making processes.

New aseptic processing guidance revised after receiving more than 1,800 comments from industry experts, FDAer reports

The new aseptic processing guidance released in September titled "Sterile Drug Products Produced by Aseptic Processing-Current Good Manufacturing Practice," replaced the 1987 "Guideline on Sterile Drug Products Produced by Aseptic Processing," after taking into account more than 1,800 comments from industry experts, reported Center for Drugs compliance officer Richard Friedman at the PDA/FDA Joint Regulatory Conference recently in Washington, D.C.

While many comments lauded the new guidance as flexible and science-based, other comments requested changes, including revisions specifying "a need for clear expectations during inspections and a need for 483s based on appropriate science and best practices," Friedman said.

Some comments also noted that the new aseptic processing guidance should not apply to terminally sterilized products, and detection of microbial contamination on a critical site should not necessarily result in batch rejection. Another comment stated that several definitions should be added to the guidance glossary, including 'shift' and 'certification.'

One of the key aspects of the new guidance, Friedman noted, is Section IX, Validation of Aseptic Processing and Sterilization. Regarding process simulations, the guidance states: "An aseptic processing operation should be validated using a microbiological growth medium in place of the product. This process simulation, or media fill, normally includes exposing the microbiological growth medium to product contact surfaces of equipment, container closure systems, critical environments, and process manipulations to closely simulate the same exposure that the product itself will undergo."

But Friedman noted: "Where the technology is such that the possibility of contamination is higher, a larger number of units, generally at or approaching the full batch size should be considered. For isolators, a lower number of units as a proportion of the overall operation can be used."

He also stressed the need for "sound rationales to support your design of process simulations. They should be adequate to mimic commercial production and accurately assess the potential for commercial batch contamination. Also, media fill acceptance criteria should be based on PQRAI recommendations and survey findings," he said.

The new guidance also emphasizes that "a media fill program should incorporate the contamination risk factors that occur on a production line, and accurately assesses the state of process control." Some of the issues a media fill program should address include:

· Factors associated with the longest permitted run on the processing line that can pose contamination risk;
· Representative number, type, and complexity of normal interventions that occur with each run, as well as nonroutine interventions and events;
· Lyophilization, when applicable;
· Aseptic assembly of equipment;
· Number of personnel and their activities;
· Representative number of aseptic additions or transfers;
· Shift changes, breaks, and gown changes (when applicable);
· Type of aseptic equipment disconnections/connections;
· Aseptic sample collections;
· Line speed and configuration;
· Weight checks;
· Container closure systems;
· Specific provisions in written procedures relating to aseptic processing

A written batch record, which documents production conditions and simulated activities, should be prepared for each media fill run, the guidance continues. Also, "the firm's rationale for the conditions and activities simulated during the media fill should be clearly defined. Media fills should not be used to justify practices that pose unnecessary contamination risks."

Next steps for the aseptic processing guidance, Friedman said, include a revision of the sterile process inspection compliance program 7356.002a, more investigator training and a continued effort to communicate and reach out to industry.

The new aseptic processing guidance document can be read in its entirety at: http://www.fda.gov/cder/guidance/5882fnl.htm.