Compliance Blog

Internal Control: Guidance to Directors” or Turnbull Guidance

2012-01-07T10:57:00.000-08:00

The Turnbull guidance or the 'Internal Control: Guidance to Directors' sets out best practice on internal control for UK listed companies, and assists them in applying section C.2 of the UK Corporate Governance Code.
The guidance was originally published in 1999. In 2004 the FRC set up a group chaired by Douglas Flint (then Group Finance Director, HSBC Holdings plc) to review the guidance and update it where necessary, in the light of experience in implementing the guidance and developments in the UK and internationally since 1999.

How Can UK Companies Comply with the FRC “Internal Control: Guidance to Directors” or Turnbull Guidance? Best Practices to Follow

Corporate Governance -UK Bribery Act

2012-01-07T10:47:00.000-08:00

Bribery is a criminal offense as per the The Bribery Act 2010(UK) and follows the benchmark set by the USForeign Corrupt Practices Act (FCPA). The Act makes bribery of foreign publicofficials an offense. It extends beyond company employees to include thirdparties acting on behalf of a company. The salient features of the Act are:

i. It covers all bribery, not only bribery cases involvingpublic officials.

ii. Itis an offense not only to give but also to receive a bribe.

iii. TheAct makes no exception for facilitation payments made to expedite routinegovernmental actions.

iv. TheAct makes failure to prevent bribery a corporate offense.

How to comply with this act by following a set of best practices. read this article in ComplianceOnline.

Corporate Governance in the Post-UK Bribery Act Era – How Can Multi-National Corporations Achieve Compliance? Best Practices to Follow

EBA Guidelines on Internal Governance

2012-01-07T10:38:00.000-08:00

In the European BankingAuthority's (EBA) new Guidelines on Internal Governance theaim is to enhance and consolidate supervisory expectations and improve the implementationof internal governance arrangements for individual institutions and the bankingsystem as a whole

It has 6 key sections .
1 -CorporateStructure and Organization
The management body should ensure that there is a suitable and transparent corporate structure. It should access how the different structures complement and interact with each other . The operational structure is inline with approved business strategy. If they are operating in a special structure not falling under jurisdiction of international banking regulations, the management body should understand the particular risk associated with it.

2- Management Body

it should have overall responsibility and it should be clear and written in documents which in turn should have been approved.
management should conduct an annual review of the effectiveness of internal governance framework and implementation.
management body should have written policy for managing conflicts
members should be engaged actively in business of the institution and should be able to make their own sound,objective and independent decisions.
management body should consider setting up various committee with members as part of the committee keeping in to account of the size and complexity of the institution ex- audit committee, remuneration,ethics and compliance committee.

3- Risk Management

the institutions should create a integrated and institution wide risk culture based on full understanding of risks it faces and how they are managed taking account of the the risk tolerance.
overall remunerationpolicy should be in line with its values, business strategy, and risk tolerance
Regular andtransparent reporting mechanisms should be established so that the managementbody is provided with reports in a timely, accurate, and meaningful manner

4- Internal Control

An institution shouldmaintain a strong and comprehensive internal control framework,including specific independent control functions with appropriate standing to fulfill their mission
There should be acomprehensive Risk Control Function and a Chief Risk Officer to ensure thateach key risk the institution faces is identified and properly managed by therelevant units and reports are submitted to the management body

5- Information systems and business continuity

An institution shouldhave effective and reliable information and communication systemscovering all its significant activities
These systems shouldbe secure, independently monitored and supported by adequate contingencyarrangements
The institution shouldalso establish a sound business continuity management

6- Transparency

Internal governance strategy and policy should be communicated to allstaff in the institution.
The internal governance framework of aninstitution should be transparent and institution should present itscurrent position and future prospects in a balanced, accurate and timely way

Federal Travel Regulation (FTR)

2011-09-12T00:49:00.000-07:00

The FTR is contained in 41 CFR Chapters 300-304. These implement statutory requirements and Executive branch policies for travel by federal civilian employees and others authorized to travel at government expense

The five chapters that form the FTR include:

41 CFR 300	General
41 CFR 301	Temporary Duty (TDY) Travel Allowances
41 CFR 302	Relocation Allowances
41 CFR 303	Payment of expenses connected with the death of certain employees
41 CFR 304	Payment from a non-federal source for travel expenses

Read Details of its requirements in ComplianceOnline

California Hazardous Waste Regulations

2011-09-12T00:29:00.005-07:00

California has unique hazardous waste regulations that include, but substantially exceed requirements of the federal Resource Conservation and Recovery Act (RCRA) regulations generally in effect in other states. It is also hard to navigate California’s hazardous waste requirements because of the dramatic differences in substantive requirements, enforced by pervasive local city and county agencies deputized as Certified Unified Program Agencies (CUPAs) and result in surprising violations and onerous penalties.

These national and international corporations did not know they were doing anything wrong because, under RCRA, most of these offenses would not be violations, and rarely are the relatively modest offenses so harshly enforced. However, due to widely-varying resources and competence, there are large gaps in compliance assurance, which inevitably leads to intervention by the state DTSC or even U.S. EPA Region 9, usually resulting in substantial penalties.

Related Trainings
Nuts and Bolts of California Environmental Regulations – Differences between U.S. EPA and State Requirements
Hazardous Waste Regulation: 10 Major Differences Between Federal RCRA and California Hazardous Waste Regulations

Google and California Online Privacy Protection Act of 2003

2011-09-12T00:20:00.002-07:00

The California Online Privacy Protection Act of 2003 or OPPA became effective on July 1, 2004, is a pioneering privacy law enacted by a state. It requires owners of commercial websites or online services to conspicuously post a privacy policy.

Applicability

OPPA applies to any website that collect personally identifiable information from California consumers.

OPPA does not apply to ISPs or similar entities that transmit such information at the request of third parties.

Google accused of OPPA non-compliance

In 2008, a New York Times reporter said in a blog post that Google might be violating OPPA since it hadn’t posted a link to its privacy policy from the homepage. Rather, the search engine’s privacy policy had been posted at the bottom of the About Google page.

Following this, privacy activists and groups sent the Google CEO a letter charging that "Google's reluctance to post a link to its privacy policy on its home page is alarming."

The company had argued that users could access its privacy policy by typing Google Privacy Policy in its search engine. A month and a barrage of criticism later, Google linked to its privacy policy from its homepage, fulfilling OPPA requirements

What is FMEA and How to Use it

2011-05-25T08:17:00.003-07:00

Failure Modes and Effects Analysis is the subject of an international standard, IEC 60812-Analysis techniques for system reliability-Procedure for failure mode and effects analysis (FMEA)

The only international standard that applies for FMEA is IEC 60812, which shows general application, but does not show the use of the tool in risk management.

An extension to the FMEA allows analysis of the criticality of a failure, such an analysis is called FMECA or Failure Mode and Effects Criticality Analysis

Most medical device companies use FMECA, although they incorrectly label it as “FMEA”

Failure Modes and Effects Analysis was developed as a tool to explore the effects of failure of components on the reliability of various products

The tool was developed as a tool for use in the field of reliability engineering to explore where more rugged components would be required to obtain desired product life

The title of the standard, Analysis techniques for system reliability-Procedure for failure modes and effects analysis (FMEA), reflects its correct use

Use of FMEA

As an input to the Risk Management process FMEA should be used to:
–Identify Effects of failures of the product design that can cause harm to people, property, or the environment

–Identify Effects of failure in the manufacturing process that can result in the product causing harm to people, property or the environment

–These safety-related effects identified in either Design FMEA or Process FMEA become Hazards in the Risk Analysis

–The Hazardous Situation that may lead to Harm must be identified during the Risk Analysis

– Sometimes the Hazardous Situation may be identified as part of the FMEA process

How to Use FMEA Properly
- FMEA may be used to identify hazards, and indicate Severity of any possible Effect

- FMEA may also be used to identify the Probability of the Hazard occurring

- We must find the Probability of the Harm occurring which may require use of Fault Tree Analysis

- Severity of the Harm usually requires input from Clinicians

- The information gathered (hazard, hazardous situation, and estimation of the severity of effect and probability of occurrence of the hazard) from FMEA is then recorded in a specific Risk Analysis document

- A document similar to that in GHTF SG3/n15r8 IMPLEMENTATION OF RISK MANAGEMENT PRINCIPLES AND ACTIVITIES WITHIN A QUALITY MANAGEMENT SYSTEM in AnnexC

-It is preferable to have a specific Risk Analysis document because of the number of other tools required to be used to perform a complete analysis , to identify hazards, and to provide the required traceability from hazard to control measure to verification of effectiveness of control

Solvency II

2011-05-25T08:12:00.000-07:00

Solvency II is a new, stronger EU-wide requirement on capital adequacy and risk management for insurers with the aim of increasing protection for policyholders. The strengthened regime should reduce the possibility of consumer loss or market disruption in insurance.

Solvency I was a minimum harmonization directive introduced in the early 1970s. It allowed for differences to emerge in the way that insurance regulation was applied across Europe leading to different regimes. It was also primarily focused on the prudential standards for insurers and did not include requirements for risk management and governance within firms.

Solvency II aims to achieve consistency across Europe on the key ideas of:

Market consistent balance sheets;
Risk-based capital;
Own risk and solvency assessment (ORSA);
Senior management accountability; and
Supervisory assessment.

The Solvency II Directive states that the new regime will go live on 1 November 2012 when it will replace the Solvency I requirements and the current regulatory regime for insurance supervision for firms in the UK. The European Commission’s (EC) proposals for the Omnibus II Directive include an amendment to the implementation date by two months to 1 January 2013.

The new regime will apply to all insurance firms with gross premium income exceeding €5m or gross technical provisions in excess of €25m. Some insurance firms will be out of scope depending on the amount of premiums they write, the value of technical provision or the type of business written.

Solvency II principles and rules apply to Lloyd’s of London syndicates in full. Due to its specific nature, some of the Solvency II requirements are being considered for their application to Lloyd’s.

European process

Solvency II is being created with a four-level process or the ‘Lamfalussy processes

Lamfalussy processes:

· European Commission adopts formal proposal for Directive/Regulation. Council and European Parliament adopt legislative act.

· European Commission requests EIOPA advice on delegated acts and implementing acts (Directives or Regulations). EIOPA drafts technical standards and European Commission adopts (Regulations or Decisions - sometimes referred to as 'binding level 3').

· EIOPA adopts ‘comply or explain’ guidelines and recommendations, carries out peer review, mediates and settles agreements, takes action in emergency situations, facilitates delegation of tasks and responsibilities, monitors and assesses market developments, undertakes economic analyses and fosters investor protection.

· Strengthened enforcement of European Union law (EIOPA and European Commission).

Sovency II Requirements:

Solvency II is split into three major requirements:

1. It covers all the financial requirements. It ensures the firms are adequately capitalized with risk-based capital. All valuations in this pillar are to be done in a prudent and market consistent manner. This pillar also includes the use of internal models which, subject to stringent standards and prior supervisory approval, enable a firm to calculate its regulatory capital requirements using its own internal model.

2. It imposes higher standards of risk management and governance within a firm’s organization and gives supervisors greater powers to challenge their firms on risk management issues. The ORSA requires a firm to undertake its own forward-looking self-assessment of its risks, corresponding capital requirements and adequacy of capital resources.

3. This aims for greater levels of transparency for supervisors and the public. There is a private annual report to supervisors, and a public solvency and financial condition report that increases the level of disclosure required by firms. Our current returns will be completely replaced by reports containing core information that firms will have to make to us on a quarterly and annual basis. This will ensure that over all, we have better and more up-to-date information on a firm’s financial position.

Process validation process

2011-03-12T20:59:00.002-08:00

Following processes to be validated are

– Aseptic filling processes
– Sterilization processes
– Clean room ambient conditions
– Sterile packaging sealing processes
– Lyophilization process
– Heat treating processes
– Plating processes
– Plastic injection molding processes
– Routine end-product tests have insufficient sensitivity to verify the desired safety and efficacy of the finished devices
– Clinical or destructive testing would be required to show that the manufacturing process has produced the desired result or product
– Routine end-product tests do not reveal all variations in safety and efficacy that may occur in the finished devices
– The process capability is unknown, or it is suspected that the process is barely capable of meeting the device specifications

Process Validation steps

1. Determine the need to validate
2. Determine what to validate (IQ, OQ, or PQ)
3. Write a validation protocol
4. Conduct the protocol and collect the data
5. Analyze the data
6. Improve the process, as warranted, based on the data and analysis
7. Prepare a report
8. Maintain the documentation as a quality record

Types of Process Validation

2011-03-12T20:44:00.002-08:00

Prospective
– Validation conducted prior to the distribution of either a new product, or product made under a revised manufacturing process, where the revisions may affect the product's characteristics.

There are three phases of prospective
validation:
– Installation qualification (Process equipment consistently operates within established limits and tolerances)
– Process performance qualification (The process is effective and reproducible)
– Product performance qualification (The finished product produced by a specified process meets all release requirements for functionality and safety)

Concurrent
– A subset of prospective validation conducted with the intention of ultimately distributing product manufactured during the validation study

Retrospective
– Validation of a process for a product already in distribution based upon accumulated production, testing and control data

In this validation there is an assumption, typically unmet, of complete records
– Customer complaints not investigated
– Investigations without adequate corrective action
– Scrap and rework not fully documented
– Inadequate process variability records

Sponser Meeting with FDA some facts

2010-12-16T04:53:00.002-08:00

There are many meetings which a sponser can have with FDA related to the product being developed and to be approved by FDA. But it can be categorized in to 3 base categories.

Type A: Critical Path (Urgent) meetings – Clinical hold, Safety Issues, Site disqualification, etc (within 30 days)
Type B: Procedural meetings – Pre-IND meeting, EOP2, pre-NDA, etc (within 60 days)
Type C: Miscellaneous meetings – CMC issues, mid-P3, early-review, mid-review, etc ( within 75 days)
Formal meetings are not the only way you communicate with the FDA: comment requests, emails, telecons with the RPMs, etc.

Why meeting FDA?

- Sponsors have the right to request a meeting with the FDA review division
- These meetings are specifically to help prescription drug approvals
–Not granted if FDA perceives that an IND is not being planned
–More for issue resolution while product development than scientific rationale
–Clarification and discussion, not “interrogation”
- Pre-submission meetings (pre-IND, EOP2, pre-NDA) meetings are considered critical by FDA compared to mid-cycle meetings (mid-P3, mid-review, etc)

Time for meeting
1. Developed “final product” idea
–Finished formulation
–Target indication(s) and population(s)
2. CMC information
–Characterization
–Manufacturing and packaging (cGMP)
–Stability studies
3. Basic non-clinical studies (GLP)
–Acute and sub-acute toxicology
–Pharmacology
–In vitro toxicity tests
4. Ready to initiate clinical studies
5. Have sufficient GMP level investigational product
6. The pre-clinical studies demonstrate MTD, NOAEL, major expected adverse events
7. Scientific rationale for mechanism of action is available
8. Clinical development plan is proposed

FCPA Act Anti-bribary provisions

2010-12-16T04:36:00.002-08:00

1977 Congress passes FCPA act to stop bribery and restore public confidence in U.S. business systems.
it has 2 sections Anti -Bribery and accounting provision.
Anti-Bribery provison is enforced by DOJ (department of justice) and it helps in Prohibiting corrupt payments (bribes) to foreign government officials, political parties, party officials and candidates in order to obtain or retain business
It has five elements of violation

1- Who comes in its purview :
–public companies filing periodic reports with SEC
–Any U.S. citizen, national or resident
- Any corporation, partnership, association, unincorporated organization & sole proprietorship with principal place of business in U.S. or organized in a U.S. state
- If a bribe occured within U.S. then it must use of U.S. mails, interstate telephone, facsimile, wire transfer or interstate or international
- If a bribe occured outside the U.S. then it is not subjected to such requirements
–Foreign companies & nationals if they cause, directly or indirectly through agents, an act in furtherance of a bribe to take place within the U.S.
–U.S. parent corporations if they authorize, direct or control questionable activity of foreign-incorporated subsidiaries
–U.S. citizen & residents employed by or acting on behalf of foreign-incorporated subsidiaries

2- Intent - Payment must be intended to cause foreign official to use his/her influence or misuse his/her position to improperly direct business to payer or some other person.
3-Payment - FCPA violation occurs if there is: A payment or authorization of a payment, An offer to pay or , A promise to pay but there is no minimum value.
4 - Recepients
FCPA applies to:
•Foreign official - Includes officer or employee of a foreign government or public international organization, regardless of rank or position
•Member of a royal family
•Official of state-owned business enterprise?
•Foreign political party or party official
•Candidate for foreign office
5 - Business Purpose
Purpose of payment must be to assist in obtaining or retaining business. However, business need not be with the foreign government, e.g. bribe is made to foreign government official to pressure a private in-country business to award a contract to a U.S. company.

Supplier Qualification Regulations

2010-12-13T04:48:00.005-08:00

There are various regulations formulated by different agencies highlight as a whole or part the supplier qualification guidelines. few are below.
ISO 13485 -
–Clause 4.6.2: Assessment of Sub-contractors–ISO 13485:2003 – Clause 7.4.1 mimics previous clause; standard adds explicit reference to “outsourced process” (4.1)

Requirements -
–Clause 7.4.1 - The type and extent of control applied to the supplier… shall be dependent upon the effect of the purchased product on… product realization or the final product.”
–The organization shall evaluate and select suppliers based on their ability to supply product in accordance with…requirements.
–Criteria for selection, evaluation, and re-evaluation shall be established.
–Records of the results of evaluations and any necessary actions arising from the evaluation shall be maintained.

FDA
–GMPs : No requirement, but sometimes “unofficially” reviewed during inspection
- 21 CFR 820.50 – Purchasing Controls: “all …product and services…”
- 21 CFR 820.50(a) - Evaluation of suppliers, contractors, and consultants

Requirements
–“…establish and maintain the requirements, including quality requirements, that must be met by suppliers, contractors, and consultants.” “including quality requirements” that must be met by the suppliers/contractors/consultants – indicates that there are requirements OTHER than those that deal solely with component acceptance
- Each manufacturer shall:
(1) Evaluate and select potential suppliers, contractors, and consultants on the basis of their ability to meet specified requirements, including quality requirements. The evaluation shall be documented.
(2) Define the type and extent of control to be exercised over the product, services, suppliers, contractors, and consultants, based on the evaluation results.
(3) Establish and maintain records of acceptable suppliers, contractors, and consultants.

Canada Device Regulations state that

For Application for a Medical Device License under Section 32 for Class II, III and IV License a copy of a quality system certificate certifying that QMS under which the device is manufactured satisfies the requirements of CAN/CSA-ISO 13485

ISO 9001

Clause 7.4.1 – Purchasing -
–The type and extent of methods to control these [purchasing] processes shall be dependent on the effect of the purchased product and/or service upon the final product and/or service.
–The organization shall evaluate and select suppliers based on their ability to supply product in accordance with…requirements.
–Criteria for selection, evaluation, and re-evaluation shall be established.
–The organization shall evaluate and select suppliers based on their ability to supply product and/or service in accordance with…requirements.
–Evaluation and selection criteria for suppliers shall be established.
–Supplier evaluations, supplier audit records, and evidence of previously demonstrated ability shall be considered when selecting suppliers and when determining the type and extent of supervision applicable to the purchased product and/or service.

Allergen Labelling

2010-12-13T04:35:00.004-08:00

The various methods of allegen labelling are as follows
- All retail products must have Allergens labelled.
- Restaurant employees must be able to control and discuss allergen presence with customers.
- Common names must be used
- The allergen may appear in bold following the ingredient containing the allergen, on the label
- The allergen and Contains statement must be of equal size and style type.

Sometimes it contains "May Contain" statements to address potential cross contamination. This type of practices should be avoided as .
- It is confusing for consumers and limits product appeal.
- It shows an inadequate allergen control program.

You should include similar allergen control program requirements in the supplier approval program for incoming ingredients as.
- Allergen labeling of incoming ingredients is a necessity for accurate product labeling.
- Allergen testing or Certificates of Analysis for newly approved ingredients is a good way to measure labeling accuracy.

http://www.fda.gov/food/labelingnutrition/FoodAllergensLabeling/GuidanceComplianceRegulatoryInformation/ucm106187.htm

What is FINRA and the guidances

2010-12-10T21:37:00.002-08:00

FINRA is Financial Industry Regulatory Authority, Inc., is a private corporation that acts as a self-regulatory organization (SRO) and established in June 2007 . It is the successor to the National Association of Securities Dealers, Inc. (NASD).
FINRA’s mission is to protect America’s investors by making sure the securities industry operates fairly and honestly.

Various guidance by FINRA

•Standards of Commercial Honor and Principles of Trade (FINRA Rule 2010)
•Communications with the Public (NASD Rule 2210)
•Guidelines to Ensure Communications With the Public are Not Misleading (IM- 2210-1)
•Recordkeeping (NASD Rule 2210(b), NASD Rule 3110 and SEC Rule 17a-4)
•Approval and Supervision (NASD Rules 2210(b) and 3010)
•Suitability: Recommendations to Customers (NASD Rule 2310) and Online Communications (Regulatory Notice 01-23)
•Conflicts of Interest (NASD Rule 2711, IM-2210-1 (6)(C) and Regulatory Notices 07-04, 04-18 and 03-44)
•Day Trading Rules (Rules 2270 and 2130)

Top 5 GCP violations

2010-12-08T03:52:00.002-08:00

- Protocol non-adherence: Failure to follow the protocol or notify the IRB of problems
- Clinical Records not well documented: They are incomplete, inaccurate or out-of-date. 483 bait
- Informed Consent problems: Incomplete, language issues, back dated, process absent or in question
- Investigational product supply chain accountability: Failure to account for each and every product/pill.
- Adverse Event collection and reporting: from severity determination to reporting errors occur

A clinical trial inspection - general procedure

2010-12-08T03:38:00.002-08:00

Review of the procedures, frequency, scope and process of the sponsor / CRO used to monitor progress
Reviewing SOPs and Monitoring Plans, interview personnel, and read trip reports
Review of items to determine that the clinical study / investigation was conducted in accordance with the signed protocol that was submitted to the FDA
An assessment of protocol deviations or violations from the approved protocol or FDA regulations and how the sponsor / CRO handled them
An Assessment of training records, SAE reporting, drug accountability,
Particular attention to both non-compliant sites and the highest enrollers
Inconsistencies such as protocol deviations, source documents not mirroring CRFs, unclear informed consents, confused Pis
Is the PI in compliance with the FDA Form 1572
Making sure the IC process was clear sans coercion
Do all subjects meet all Inclusion / exclusion criteriaIs the data reasonable and fits the sourse data
Are all IRB/IEC approvals reasonable / appropriate

to Know more attend the training

GCP violations and Site Mistakes commonly found During a FDA Investigator Site Inspection/Audit

Records FDA inspectors look for - related to Quality system

2010-12-07T07:15:00.002-08:00

The FDA’s QSR expects the manufacturer to maintain a series of documents that describe the design and production of the device. QSR allocated the information into four documents.

The Design History File (DHF) gives a history of device design. One of the design outputs is the Device Master Record (DMR).
The Device Master Record (DMR) contains all the information necessary manufacture, install, service, and maintain the device.
The Device History Record (DHR) has the objective evidence to support the device production history.
The Quality System Record (QSR) contains information that is not device specific.

A compliant Quality Management System (QMS) should be able to address these questions quickly and easily.

The list of the records that belong in the Design History File (DHF)?
Can your team relate the component specifications in the DMR to the Purchasing Data you use to obtain the components?
What are the records you must keep when you verify the component at receiving?
Which of these records must go into the DHR?
What is the list the activities that require a designated individual?
Do you have quality records that designate the individual and demonstrate training to perform the assigned responsibility?
How to assure that the designated individual, not somebody else, performed the activity before you released the product for distribution?
Some information could be in the DMR or the QSR. Does you team know how to make the decision?

What is the Definitions of the Terms Manufacturer, Authorised Representative, Distributor and Importer?

2009-09-09T05:29:00.003-07:00

As per GHTF find below the guide to know the definitions of Definitions of the Terms Manufacturer, Authorised Representative, Distributor and Importer.

1.1 Manufacturer
“Manufacturer” means any natural or legal person with responsibility for design and/or manufacture of a medical device with the intention of making the medical device available for use, under his name; whether or not such a medical device is designed and/or manufactured by that person himself or on his behalf by another person(s).
NOTES:

1. This ‘natural or legal person’ has ultimate legal responsibility for ensuring compliance with all applicable regulatory requirements for the medical device in the countries or jurisdictions where it is intended to be made available or sold, unless this responsibility is specifically imposed on another person by the Regulatory Authority (RA) within that jurisdiction.
2. The manufacturer’s responsibilities are described in other GHTF guidance documents. These responsibilities include meeting both pre-market requirements and post-market requirements, such as adverse event reporting and notification of corrective actions.
3. ‘Design and/or manufacture’, as referred to in the above definition, may include specification development, production, fabrication, assembly, processing, packaging, repackaging, labelling, relabelling, sterilization, installation, or remanufacturing of a medical device; or putting a collection of devices, and possibly other products, together for a medical purpose.
4. Any person who assembles or adapts a medical device that has already been supplied by another person for an individual patient, in accordance with the instructions for use, is not the manufacturer, provided the assembly or adaptation does not change the intended use of the medical device.
5. Any person who changes the intended use of, or modifies, a medical device without acting on behalf of the original manufacturer and who makes it available for use under his own name, should be considered the manufacturer of the modified medical device.
6. An authorised representative, distributor or importer who only adds its own address and contact details to the medical device or the packaging, without covering or changing the existing labelling, is not considered a manufacturer.
7. To the extent that an accessory is subject to the regulatory requirements of a medical device, the person responsible for the design and/or manufacture of that accessory is considered to be a manufacturer.
1.2 Authorised Representative
“Authorised representative” means any natural or legal person established within a country or jurisdiction who has received a written mandate from the manufacturer to act on his behalf for specified tasks with regard to the latter’s obligations under that country or jurisdiction’s legislation.
1.3 Distributor
“Distributor” means any natural or legal person in the supply chain who, on his own behalf, furthers the availability of a medical device to the end user.
NOTES:
1. More than one distributor may be involved in the supply chain.
2. Persons in the supply chain involved in activities such as storage and transport on behalf of the manufacturer, importer or distributor, are not distributors under this definition.
1.4 Importer
“Importer” means any natural or legal person in the supply chain who is the first in a supply chain to make a medical device, manufactured in another country or jurisdiction, available in the country or jurisdiction where it is to be marketed.

Guidance document on the management of design and process changes

2009-09-09T05:16:00.002-07:00

To ensure that good quality assurance practices are used for the design of medical devices and that they are consistent with quality system requirements worldwide, the Food and Drug Administration revised the Current Good Manufacturing Practice (CGMP) requirements by incorporating them into the Quality System Regulation, 21 CFR Part 820. An important component of the revision is the addition of design controls.
Because design controls must apply to a wide variety of devices, the regulation does not prescribe the practices that must be used. Instead, it establishes a framework that manufacturers must use when developing and implementing design controls. The framework provides manufacturers with the flexibility needed to develop design controls that both comply with the regulation and are most appropriate for their own design and development processes.
This guidance is intended to assist manufacturers in understanding the intent of the regulation. Design controls are based upon quality assurance and engineering principles. This guidance complements the regulation by describing its intent from a technical perspective using practical terms and examples.
You can download the guidance here - Design Control Guidance For Medical Device Manufacturers

In the last GHTF STEERING COMMITTEE MEETING last October a discussion started regarding the potential need for a guidance document on the management of design and process changes . It was decided that there is no consolidated approach to how changes are assessed by the regulatory jurisdictions. Hence in coming days the user group 1 of the GHTF is assigned to create the guidance document.

Medical Device Supply Chain - Managing the long chain as per FDA regulations

2009-09-09T03:56:00.005-07:00

with the recession looming large on all businesses Medical device Manufacturers are focussing more on outsourcing the manufacturing and services function to low cost destinations. But with the benefit of low cost also comes lots of problems related to regulations and management. As the supply chain becomes longer and more diverse it becomes more difficult to control. But the company is reponsible for any kind of problem happening with the devices and ultimately will be held responsible for its failure. Hence it is very important to have a concrete process for the supplier selection, evaluation and management. The FDA has formulated many regulations for medical devices that define the requirements for supplier selection, management, and control. ISO 13485 includes similar requirements. In February 2009, the Global Harmonization Task Force (GHTF) released a guidance document on controlling products and services from suppliers. This guidance document has become the global de facto standard for supplier management.

As part of their Quality Management System (QMS) requirements, manufacturers must evaluate, select, and monitor suppliers. As the supply chain becomes longer and more diverse, the methods of control become more difficult and the expectations of regulators become more stringent.

The best approach implements specific actions:
· Create clear requirements for supplier
· Evaluate potential suppliers against the criteria
· Create cross-functional multi-discipline teams that remain active beyond the selection process
The team approach, often called a commodity team or supplier team, is one of the most effective methods for supplier selection and management. The team needs to understand the requirements, implement the best practices in the GHTF document, and work with suppliers.

There is a webinar on this conducted by Complianceonline in Oct 30. Click on the link below to view the complete agenda.
http://www.complianceonline.com/ecommerce/control/trainingFocus?product_id=701462&channel=pblog

Download the GHTF Document -
Quality Management System – Medical Devices – Guidance on the Control of Products and Services Obtained from Suppliers

Compliance with the New Draft Guidance on Process Validation

2009-07-13T05:15:00.007-07:00

FDA have released a draft Guidance document titled "Guidance for Industry - Process Validation: General Principles and Practices .The following categories of drugs are within the scope of this guidance: Human drugs Veterinary drugs Biological and biotechnology products Finished products and active pharmaceutical ingredients (API or drug substance)The drug constituent of a combination (drug and medical device) product The following categories of products are not covered by this guidance: Type A medicated articles and medicated feed Medical devices Dietary supplements Human tissues intended for transplantation regulated under section 361 of the Public Health

The draft guidance can be found at http://www.fda.gov/OHRMS/DOCKETS/98fr/FDA-2008-D-0559-gdl.pdf

Article - FDA's New Process Validation Guidance Recommends Team Approach

http://www.thephantomwriters.com/free_content/db/h/fda-process-validation-guidance.shtml

Webinar on this topic - http://www.ispe.org/cs/webcasts/process_validation

Manage a Medical Device Recall Efficiently and Effectively

2009-07-13T05:05:00.005-07:00

Medical device recalls are very common now days. It is an action taken to address a problem with a medical device that violates FDA law. Recalls occur when a medical device is defective, when it could be a risk to health, or when it is both defective and a risk to health. It might be worrisome for people who are using a medical device and suddenly the recall is announced, here it might be logical to remove the device but it is not always need to be done. But it is essential for doctors to inform their patients what are the risks of removing it VS using a faulty device.

Attend a webinar on How to Manage a Medical Device Recall Efficiently and Effectively hosted by Complianceonline and available at price $199

Webinar Implementing GLP in Contracting Laboratories

2009-07-13T04:45:00.003-07:00

It must be understood that in contract laboratories the GMP or GLP compliance lies with the study sponser, and hence it becomes necessary to know what are the roles and responsibilities of key Management, Supervisors, Scientists, Principal Investigators, Regulatory, QAU and other personnel in GLP facilities, contract laboratories.

Here are some webinars to refer.
http://www.gmptrainingsystems.com/files/u2/pdf/GLP_1.pdf
http://www.complianceonline.com/ecommerce/control/trainingFocus/~product_id=700870

webinar Related to Electronic Health Records (EHRs)

2009-07-13T04:21:00.003-07:00

Using Electronic Health Records and Claims Databases for Rapid-Response Pharmacovigilance Studies

WEBINAR: ELECTRONIC HEALTH RECORDS SYSTEMS at $99
Leveraging EHR Stimulus Funding During Contract Negotiation

Complaint Handling - How FDA and ISO Regulations effect

2009-07-13T04:02:00.009-07:00

Compliant handling is one of the most important customer feedbacks which can never be missed. Many warning letters cite wrong way handling of compliant as one of the main reasons of receiving warning. But it is confused by most of the manufacturers do not know how to document customer feedback, what constitutes a complaint and non-compliant feedback, and what do with "non-complaint" feedback. Some companies merey just implement the compliant management software with out knowing the rules and processes and end of hurting more to them selves. It is imperative to know what ISO and FDA regulations effect the compliant handling process.
Here is a webinar by ComplianceOnline on Complaint Handling in Compliance with FDA and ISO Regulations which gives and over view of solutions to the above problems mentioned.

Customer compliant software -

http://www.mastercontrol.com/white_papers/customer-complaint-software/customer-complaint-handling.html

http://www.lynksoftware.com/

www.etq.com/complaint

http://www.sparta-systems.com/solutions/customer-complaints/index.shtml

http://www.metricstream.com/solutions/complaints_management.htm

Risk Based CAPA system - closed loop

2009-07-13T03:40:00.006-07:00

Expectations for meaningful, results driven CAPA activities are increasing among regulatory agencies world wide. Almost 60-70 % of warning letters are related to CAPA. EU’s ISO 14971 and the FDA’s QSIT and Q9, underscore this increased emphasis. Growing high-profile field problems indicate that QA / CAPA activities are not yet fully utilizing the power of current risk management tools. The billions of dollars spent by industry annually on quality / GMP are not providing the product safety or efficacy seemingly promised. And for most companies, the fixes are not rocket-science, but proper up-front risk-based, closed-loop CAPA as an integral part of Quality Management Systems planning, implementation and execution.
The essential component of a closed loop CAPA system is how you re organize and distribute the scare resource for those activities which has higher opportunity cost and high value.
You can attend a webinar hosted by ComplianceOnline and available at discounted rate

Federal preemption case for medical device

2009-07-13T03:18:00.001-07:00

In the United States, Federal preemption refers to the displacement of state law by Federal law

Federal pre-emption is the notion that, if the U.S. Food and Drug Administration (FDA) approves a medical device, injured patients should not be able to sue product manufacturers by alleging defective warnings.

There is a classic case of Riegel v. Medtronic in regards to the federal preemption

Reportable Food Registry Draft Guidance

2009-07-10T04:04:00.002-07:00

The RFR is scheduled for implementation on September 8, 2009, and applies to all FDA-regulated categories of foods, including dietary supplements. Only infant formula is exempt from the RFR requirements.

The RFR requires a responsible party to file a report through an FDA internet portal when there is reason to believe that an adulterated food (other than infant formula) will cause serious adverse health consequences or death to humans or animals. "Responsible party" is defined as the person who submits the registration information to FDA for a food facility that manufactures, processes, packs, or holds food for human or animal consumption in the United States. Federal, state, and local government officials may also use the portal to report information that may come to them about such foods.

Submit electronic comments on the draft guidance to http://www.regulations.gov/.

Find out what are its implecations and loopholes click the link below

http://www.kelleydrye.com/resource_center/client_advisories/0475

Drug establishment registration and drug listing Regulation

2009-07-10T03:54:00.002-07:00

From June 1, 2009 FDA is no longer accepting paper submissions for drug establishment registration and listing unless a waiver is granted.

Both information were been submitted using a paper-based format, i.e., Form FDA 2656 (Registration of Drug Establishment/Labeler Code Assignment), Form FDA 2657 (Drug Product Listing), and Form FDA 2658 (Registered Establishments' Report of Private Label Distributors). But now FDA will not accept anything on paper and would rather accept fully compliant electronic submission.

Also by Jan 1, 2010 starting 1 January 2010. Some regulatory authorities in Europe have implemented all electronic review environments ahead of this deadline and are refusing to accept paper submissions for review. Many authorities are receiving the eCTD files with full of error and non compliant submissions and finding difficulty in navigating through it.

Section 510 of the Act and 21 CFR part 207, subject to certain limited exceptions, require establishment owners and operators (registrants) upon first engaging in the manufacture, preparation, propagation, compounding, or processing of drugs, (including human drugs, veterinary drugs, and biological drug products 4 ) to register their establishments and submit listing information for all drugs in commercial distribution. Registrants are also required to submit registration information for their establishments on or before December 31 of each year.

At the time of registration, registrants must also submit required listing information. Additionally, registrants are required to update listing information in June and December of each year to include information for drugs that have not been previously listed. Certain changes to information for previously listed drugs must also be submitted every June and December.

Purpose of this regulation

FDA intends to update these documents regularly to reflect the evolving technology and user experience.

Receipt of timely and accurate information will enhance FDA’s efforts to help ensure the integrity of the drug supply and protect public health.

The electronic drug establishment registration and drug listing system will permit FDA to electronically populate the Agency’s listing databases and the NDC Directory and will, therefore,improve the inclusiveness and accuracy of these databases.

To read details about this regulation please refer following links

Trainings-

http://www.complianceonline.com/ecommerce/control/trainingFocus?product_id=700719

http://www.raps.org/personifyebusiness/ConferencesTraining/PreparingComplianteCTDsAdvanced/tabid/1108/Default.aspx

Regulations doc
www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072339.pdf

Unique Device Identification

2009-07-09T01:01:00.003-07:00

UDI stands for a unique serial number given to each medical device. In this scenario, each identical device would be assigned its own serial number which becomes easy to track it through out its life cycle.

On Feb. 12, the U.S. Food and Drug Administration convened a public workshop on development of a unique device identification system for medical devices under the FDA Amendments Act of 2007, which mandates the UDI.

As part of the FDA Amendments Act of 2007 (“FDAAA”), FDAAA does not mandate a specific type of device identifier, but a unique device identifier (“UDI”) must be placed on the device label, unless an alternative location is specified, or unless FDA has exempted the device or group of devices from the UDI system. The UDI must adequately identify the device throughout its distribution and use, and may need to include information such as the lot or serial number, if required by FDA.

It is expected to be coming out in late 2009 and later with a final rule in 2010. There are many discussions going on how to implement it, which devices come under its purview and how it can affect the different sectors.

There are very common concerns are below
1. What all devices or particular type of devices should be subject to the? Which types of devices or particular devices should be excempted?

2. What are set criteria to uniquely identify a device?

3. What should be the UDI's components? (For example, should the lot or serial number be required?)

4. Where should the UDI be placed?

5. How should the UDI be presented? Should FDA mandate a particular technology or permit different standards to be used depending on the type of device?

6. How should the UDI database be developed and maintained?

7. What is the magnitude of the problem to be addressed by the establishment of a UDI system?

Once this rule come it may change the lot of sectors using the device like HME sector along with it will help in better post marketing surveillance.

Click on the below link which contains lot of good suggestion given by America's Health Insurance Plans (AHIP) which also details about post marketing surveillance aspects.
The FDA should develop standards requiring the linking of medical device identifiers to adverse event reporting. The use of identifiers should also be required in all investigational and research studies involving medical devices. In addition, the FDA should take steps to incorporate the UPN into any databases that collect and maintain information about medical devices.
http://www.fda.gov/ohrms/dockets/dockets/06n0292/06n-0292-c000019-01-vol8.pdf
There is a conference scheduled for UDI details present in the link below.

The UID Conference is the industry gathering to help medical device manufacturers, distributors and hospitals prepare for the impending FDA UDI Rule. The FDA UDI Rule will establish a single device identification system that is consistent, unambiguous, standardized, and globally harmonized. FDA intends to issue the Final Rule in 2010

http://www.udiconference.com/

Elements of Obama's healthcare reform plan

2009-06-29T06:43:00.002-07:00

Obama expects to see a healthcare bill by end of 2009. The most important factor is to be discussed is increased insurance access for the under and uninsured.Reports from wasignton D. C suggest that a serious effort will be under way through out the summer to craft bill and get it to the President's desk for signature before end of the year.
I found a good report on these developments from Pharmavoice.
click on the link to read the full article

Voice of the Customer Executive Management

2009-06-29T05:51:00.002-07:00

I found a new keyword ExecutiVOC™
ExecutiVOC™ is a process of executive management of VOC that reduces product development risk by providing oversight, direction and guidance at key points or milestones of the VOC process.. Through ExecutiVOC™, the process of executive oversight of VOC is demonstrated. ExecutiVOC™ is a process of executive management that reduces product development risk by providing oversight, direction and guidance at key points or milestones of the VOC process.

To know more about it attend the webinar by ComplianceOnline
Product Success during the Development Process through ExecutiVOC™

Acceptance Sampling as a tool

2009-06-26T06:55:00.003-07:00

Statistical procedure used in quality control. Acceptance sampling involves testing a batch of data to determine if the proportion of units having a particular attribute exceeds a given percentage. The sampling plan involves three determinations: (1) batch size; (2) sample size; and (3) maximum number of defects that can be uncovered before rejection of the entire batch. This technique permits acceptance or rejection of a batch of merchandise or documents under precisely specified circumstances.

Acceptance sampling is a valuable tool often used (and misused) in the manufacturing sector. The most common methods employ standards so you can look up a sampling plan. The user has many choices, and needs to understand their impact on cost and risk. This seminar explains how to apply Z1.4 and c=0 plans.

To know more about it click on the link below
Understanding Attribute Acceptance Sampling including Z1.4 and c=0 Plans

Steam-In-Place (SIP) strategy

2009-06-26T06:26:00.003-07:00

One of the most common methods for creating a sterile bioprocessing environment is the use of heat in the form of steam to eliminate unwanted organisms. Steam-In-Place (SIP) is a good sterilization method and involves sterilizing by means of steam the interior of pipes, vessels, process equipment, and associated fittings, without disassembly.
Steam-in-Place (SIP) can be a critical element in any startup and commissioning project. However, the full range of SIP strategies are not always thoroughly understood, and thus many manufacturers miss important elements of these techniques.
To know more about the application of SIP, about • Bioburden reduction• Saturated steam conditions: Temperature/pressure relationship• Autoclaves, vessels, filters and transfer lines• Empty- and full-vessel SIP• Proper use of Tempilstik®
Attend the webinar
Effective Steam-in-Place Strategies to Consider before Qualifying a Facility

How Green Is Your Plant?

2009-06-26T06:19:00.005-07:00

While the automotive, chemical, cosmetic industries have made strides in reducing their carbon impact, the pharmaceutical and biopharmaceutical industries have lagged behind. It has been estimated that organizations can reduce their Carbon Footprints by as much as 20 per cent through the implementation of lean processes. By applying operational excellence techniques, a strategy can be developed to assist pharmaceutical manufacturing and supply chain operations to achieve more “Green Operations”. By adopting a focused practice to inventory wastewater, hazardous and solid waste streams, and energy consumption a facility’s carbon footprint can be determined. Efforts can them be focused on key waste generating areas such as gowning, facility cleaning, equipment cleaning and process operations. Not only will these efforts reduce the environmental impact of manufacturing operations, but they will ultimately reduce costs. Risk management and Quality-by-Design approaches will enable firms to better understand cleaning cycles, optimize them and reduce water, chemical, time and energy requirements. More efficient cleaning cycles result lower these resource demands and reduce the Carbon Footprint of these waste generating operations.Such strategies can help manufacturing achieve “Green Operations” in the face of mounting pressure for more environmentally friendly corporate citizenship drug manufacturing costs.

You can attaend this webinar to know how to develop a strategy for it
How Green Is Your Plant? – Determining the Carbon Footprint of Your Operations

Records covered in 21 CFR part 11 for clinical data

2009-06-20T01:16:00.002-07:00

click on the image to enlarge it

Compliance Quiz test your knowledge

2009-06-18T03:44:00.002-07:00

http://www.caci.com/cacihealth/rapid_assessment_quiz.shtml
http://searchdatamanagement.techtarget.com/generic/0,295582,sid91_gci1322417,00.html
http://www.infinisource.net/Infinisource/Benefit_Resources/COBRA_Quiz.aspx

Residual Solvent Analysis According to USP <467>

2009-06-16T06:01:00.000-07:00

•“ Residual solvents in pharmaceuticals are defined as organic volatile chemicals that are used in the manufacture of drug substances and impurities or excipients, or in the preparation of drug products
•Residual solvents refers to the amount not removed during the purification of the product
•Residual solvents are one of the three main types of impurities in pharmaceutical articles (other two: organic and inorganic impurities)
•Residual solvents need to be controlled (ICH, USP, EP) and control is enforced (e.g., FDA)
USP Requirements

•All drug substances, excipients, and drug products (dosage forms) are subject to relevant control of residual solvents, even when no test is specified in the individual monograph
•Acceptable limits depend on solvent classification(toxicity, consistent with risk based approach)
•USP incorporates ICH Q3C classification and evaluation system and EP procedures
•Requirements aligned with ICH Q3C
•Testing is to be performed only for solvents “likely to be present”
–Used or produced in the final manufacturing step
–Used in previous steps and not removed by validated procedure
–Important for suppliers to disclose solvents (and manufacturing process)
•Limits for acceptable concentrations listed in the chapter are for drug products NOT for its components
•Quantitative or limit tests
•The concentration in the drug product may be
–Calculated from the contributions of components
–Determined experimentally; mandatory if:
–Solvents are used in its manufacture
–Cumulative calculation exceeds limits
•Manufacturers of drug products may rely on data provided by the suppliers of components
•The procedures described in this general chapter are to be applied whenever possible.Otherwise other methods can be used
Main changes to previous USP revision

•Title change: From “Organic Volatile Impurities (OVI)” to residual solvents
•Largely refer to ICH QC3 terminology, solvent categories and acceptance criteria
•Widely harmonized with EP
•Individual test procedures in Monographs replaced by general chapter <467>
•Finished product testing may not be necessary (testing of APIs and excipents may be enough)

Off Label promotion

2009-06-16T05:48:00.002-07:00

Offlabel promotion is - the use of medical device for an indication not approved by FDA.
Company Responsibilities
Company has the responsibility for promotion, marketing and labelling of medical device. The FDA many monitor company's practices and enforce regulations when necessary. enforcement may include criminal and civil actions
Labelling
All medical devices distributed by company must contain the required labeling On product ,On packaging and In manuals

Product Nomenclature
The company medical device may fit into a specific product description used by the FDA.
Company personnel should not refer to the medical device by nomenclature other than that used by the FDA.
It is recognized that individuals not employed by the company may refer to the device with nomenclature different than that used by the FDA
Sales Effort
Efforts of sales personnel should focus on market opportunities, potential customers and physicians who will utilize the medical device for indications that are approved for use by the FDA. Sales training and meetings should only address indications that are approved for use by the FDA.
Example of off label promotion cases
Schering-Plough Example of An Off-Label Case
U. S. Department of Justice investigation into sales, marketing and clinical trail practices and programs. The government claimed:
Schering salespeople were trained how to win off-label sales and were paid for doing so.
Tactics included "illegal remuneration" to doctors for "sham advisory boards" and "lavish entertainment“.
Aggregate settlement amount of $435 million:
One count of conspiracy to make false statements to the government. Criminal fine of $180 million.
$225 million to resolve civil aspects of the investigation.
Schering required to sign an addendum to an existing corporate integrity agreement

CGMP guidance for Phase I Investigational Drugs

2009-06-16T05:31:00.003-07:00

This guidance got approved in July , 2008

This Replaces guidance issued in 1991 “Preparation of Investigational New Drug Products for the manufacture of phase I investigational drugs” . However the 1991 guidance still applies to the manufacture of investigational new drugs(human and animal) used in phase II and phase III clinical trials
This guideline is intended to help in applying current good manufacturing practice (CGMP) required under section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) in the manufacture of most investigational new drugs (IND) used in phase I clinical trials.

This guidance describes an approach to
•Implementation of manufacturing controls that are appropriate for phase I clinical trial stage of development
•Product quality differences
−Between investigational drugs and commercial manufacture
–Among the various phases of clinical trials
•FDA's CGMP for the 21 Century initiative
– Where applicable, manufacturers are also expected to implement manufacturing controls that reflect product and manufacturing considerations, evolving process and product knowledge, and manufacturing experience .
Scope

This guidance applies to phase I investigational drugs for human use that are
•manufactured in small or large-scale environments
•typically designed to assess tolerability, or feasibility, for further development of a specific drug or biological product
•new drug and biological products including finished dosage forms used as placebos

- Investigational drugs used in phase I studies described in 21 C.F.R. § 312.21 of FDA’s IND regulations are EXEMPTED from the Current Good Manufacturing Practice (“CGMP”) requirements in 21 C.F.R. Part 211
- This exemption does not apply to an investigational drug for use in a phase I study once the investigational drug has been made available for use by or for the sponsor in a phase II or phase III study, or the drug has been lawfully marketed
- The exempted phase I drugs are, however, still required to meet statutory (as opposed to regulatory) requirements for CGMP

This guidance DOES NOT apply to phase I investigational drugs for human use that are
−Human cell or tissue products regulated solely under § 361 of the Public Health Service Act
−Clinical trials for products subject to the device approval or clearance provisions of the FD&C Act
−Investigational products manufactured for phase II and phase III clinical trials
−Previously approved products that are being used in phase I clinical trials (e.g. for a new indication)
−Positron Emission Topography (PET) drugs that are subject to § 501(a)(2)(C) of the FD&C Act and/or the new PET CGMP in 21 CFR part 212 when finalized

What is design validation and what are rules applied

2009-06-16T05:00:00.004-07:00

Design Validaiton is a requirement of regulators prior to placing a product on the market. It is considered the last step of the Design Control process prior to transfer of the design to manufacturing. However, it is intimately tied to Process Validation a portion of Production Controls. Companies must assure that they are properly conducting Design Validation with products from a validated production process to avoid audit/inspection observations, and the risk of placing a violative product on the market.

Find below the regulations to look out for design validation as stated in http://www.fda.gov/

I. REQUIREMENTS
§ 820.30(g) Design validation.
Each manufacturer shall establish and maintain procedures for validating the device design.
Design validation shall be performed under defined operating conditions on initial production units, lots, or batches, or their equivalents.
Design validation shall ensure that devices conform to defined user needs and intended uses and shall include testing of production units under actual or simulated use conditions.
Design validation shall include software validation and risk analysis, where appropriate.
The results of the design validation, including identification of the design, method(s), the date, and the individual(s) performing the validation, shall be documented in the Design History File.
Cross-reference to ISO 9001:1994 and ISO/DIS 13485 section 4.4.8 Design validation.

II. DEFINITIONS
§820.3(y) Specification means any requirement with which a product, process, service, or other activity must conform.
§ 820.3(z) Validation means confirmation by examination and provision of objective evidence that the particular requirements for a specific intended use can be consistently fulfilled.

Process Validation means establishing by objective evidence that a process consistently produces a result or product meeting its predetermined specifications.

Design Validation means establishing by objective evidence that device specifications conform with user needs and intended use(s).
§820.3(aa) Verification means confirmation by examination and provision of objective evidence that specified requirements have been fulfilled.

III. DISCUSSION AND POINTS TO CONSIDER
Whereas verification is a detailed examination of aspects of a design at various stages in the development, design validation is a cumulative summation of all efforts to assure that the design will conform with user needs and intended use(s), given expected variations in components, materials, manufacturing processes, and the use environment.

VALIDATION PLANNING. Planning for validation should begin early in the design process. The performance characteristics that are to be assessed should be identified, and validation methods and acceptance criteria should be established. For complex designs, a schedule of validation activities and organizational or individual responsibilities will facilitate maintaining control over the process. The validation plan should be reviewed for appropriateness, completeness, and to ensure that user needs and intended uses are addressed.

VALIDATION REVIEW. Validation may expose deficiencies in the original assumptions concerning user needs and intended uses. A formal review process should be used to resolve any such deficiencies. As with verification, the perception of a deficiency might be judged insignificant or erroneous, or a corrective action may be required.

VALIDATION METHODS. Many medical devices do not require clinical trials. However, all devices require clinical evaluation and should be tested in the actual or simulated use environment as a part of validation. This testing should involve devices which are manufactured using the same methods and procedures expected to be used for ongoing production. While testing is always a part of validation, additional validation methods are often used in conjunction with testing, including analysis and inspection methods, compilation of relevant scientific literature, provision of historical evidence that similar designs and/or materials are clinically safe, and full clinical investigations or clinical trials.
Some manufacturers have historically used their best assembly workers or skilled lab technicians to fabricate test articles, but this practice can obscure problems in the manufacturing process. It may be beneficial to ask the best workers to evaluate and critique the manufacturing process by trying it out, but pilot production should simulate as closely as possible the actual manufacturing conditions.

Validation should also address product packaging and labeling. These components of the design may have significant human factors implications, and may affect product performance in unexpected ways. For example, packaging materials have been known to cause electrostatic discharge (ESD) failures in electronic devices. If the unit under test is delivered to the test site in the test engineer's briefcase, the packaging problem may not become evident until after release to market.

Validation should include simulation of the expected environmental conditions, such as temperature, humidity, shock and vibration, corrosive atmospheres, etc. For some classes of device, the environmental stresses encountered during shipment and installation far exceed those encountered during actual use, and should be addressed during validation.
Particular care should be taken to distinguish among customers, users, and patients to ensure that validation addresses the needs of all relevant parties. For a consumer device, the customer, user, and patient may all be the same person. At the other extreme, the person who buys the device may be different from the person who routinely uses it on patients in a clinical setting. Hospital administrators, biomedical engineers, health insurance underwriters, physicians, nurses, medical technicians, and patients have distinct and sometimes competing needs with respect to a device design.

VALIDATION DOCUMENTATION. Validation is a compilation of the results of all validation activities. For a complex design, the detailed results may be contained in a variety of separate documents and summarized in a validation report. Supporting information should be explicitly referenced in the validation report and either included as an appendix or available in the design history file.

Overview of ISO 14971

2009-05-02T23:51:00.002-07:00

It has 9 clauses.
Clause -1 - Scope
It covers all medical devices including IVDs.
It applies to all phases of product life cycle.
It does not
-define acceptable risk
-Apply to clinical decision making
-Does not require quality system
Clause -2 - Definition
- Clause provides definitions of terms
- there are new terms and definitions
- To provide uniformity among standards many definitions are harmonized with other standards and also with Guide 51 which is used by ISO and IEC for common definitions
- Clause also contains updated definitions from ISO 9000:2005
Definition changes

-in vitro diagnostic medical device– “medical device intended by the manufacturer for the examination of specimens derived from the human body to provide information for diagnostic, monitoring, or compatibility purposes”

- life-cycle– “all phases in the life of a medical device, from the initial conception to final decommissioning and disposal”
- Post-production – new term – “part of the life-cycle of the product after the design has been completed and the medical device has been manufactured”
- Use error – “act or omission of an act that results in a different medical device response than intended by the manufacturer or expected by the user” – from IEC 62366
Clause -3 -General Requirements
- Sub-clause 3.2 “Management responsibilities” expands description of requirements and indicates that documentation created in the process and the risk management review can be part of the quality system documentation.
-Sub-clause 3.3 indicates in a Note that risk management activities can be performed by “representative of several functions, each contributing their specialist knowledge”
-Does not require a single individual be assigned the total responsibility for risk management
-Personnel assigned these activities must have proper training, background, education and experience
- Sub-clause 3.4 describes the Risk management plan
- Requirements unchanged
-In response to many comments in ISO 14971 voting process, extensive notes added to provide explanations and references to additional information in Annex D and Annex F

- Sub-clause 3.5 has been revised to include the traceability requirement removed from Clause 8 Risk management report
- Risk management report for complex devices was getting unwieldy
- Note indicates the Risk management file can be in any form or medium (such as electronic files)
Clause -4 - Risk Analysis
- Clause 4 covers Risk Analysis and Risk Estimation
- Sub-clause 4.1 re-titled to “Risk analysis process” from “Risk analysis procedure”
- New Notes point to informative annexes with additional information
- Sub-clause 4.2 Note 1 indicates “misuse is intended to mean incorrect or improper use of the medical device”
- Sub-clause 4.3 title changed to “Identification of hazards”
- Note points to E.2 and H.2.4 for guidance in hazard identification
- Sub-clause 4.4 title changed to “Estimation of the risk(s) for each hazardous situation”
- This is a new emphasis in Second Edition, from idea that harm cannot occur unless a Hazardous Situation leads to an exposure to a hazard
- Extensive notes used to explain this Subclause
Clause -5 - Risk Evaluation
- Evaluation requirement is in reference to “Hazardous situation” instead of “Hazard”
- Evaluation is comparison of Risk to Acceptability Criteria established in Risk Management Plan
Clause -6 - Risk Control
Sub-clause 6.1 removed requirement to reduce residual risk associated with each hazard to acceptable
- Addressed under “Residual Risk”
Sub-clause 6.2 Title changed to “Risk Control Option Analysis”
- Extensive Notes provide information and reference including use of other standards as part of option analysis
- Sub-clause 6.3 Implementation of risk control measure(s)
- Indicates that verification of effectiveness of risk control measures may include validation activities
- Sub-clause 6.4 Residual risk evaluation
- adds Note to Annex J for information on disclosing residual risk
- Sub-clause 6.5 Risk/benefit analysis
-Adds note referring to Annex D.6 for more information on Risk/benefit analysis
- Sub-clause 6.6 title changed to “Risks arising from risk control measures”
- Includes introduction of new hazards or hazardous situations
- Adds requirement that these new risks or increased risks be managed with process in sub-clauses 4.4 to 6.5
- Sub-clause 6.7 Completeness of risk control
- Changes “hazard” to “hazardous situation”
- Changes “The results of this assessment…” to “The results of this activity…”

Clause -7 - Evaluation of overall Residual risk acceptability
Clause 7 title changed to “Evaluation of overall residual risk acceptability”
- Adds requirement for deciding what information to disclose on overall residual risk
- Add reference to Annex D.7 on Overall residual risk
-Adds reference to Annex J on disclosure of residual risk
Clause -8 - Risk Management report
- Clause 8, removed the traceability requirement from the Risk management report to the Risk Management File (see Sub-clause 3.5)
- Adds requirements for responsibility for review and documentation of review that demonstrates
-“the risk management plan has been appropriately implemented;
-the overall residual risk is acceptable;
-appropriate methods are in place to obtain relevant production and post-production information.”

Clause - 9 - Production and post production process

- The Title was changed to “Production and post-production information” to emphasize that there is information available during production which is important to Risk Management
- Adds a requirements for systems collecting and reviewing device information

FDA/IEC Software Standard 62304

2009-05-02T23:31:00.002-07:00

IEC- The International Electrotechnical Commission (IEC) is a worldwide organization for standardization comprising all national electrotechnical committees (IEC National Committees). The object of IEC is to promote international co-operation on all questions concerning standardization in the electrical and electronic fields.

FDA has approved IEC 62304 as recognized software development standard, allowing submissions stipulating conformance to 62304
How FDA plays with it

FDA uses QSIT in regard to auditing this area.
By standardizing to 62304, companies can eliminate confusion during compliance audits, and especially show FDA personnel how the development happens for your S/W
By adopting the standard, all staff will be on the same development platform, thus easing audits and lessening FDA Form 483’s and Warning Letters or worse.

Basic Assumptions
SOUP=software of unknown provenance (acronym)
SOUP is a SOFTWARE ITEM that is already developed and generally available and that has not been developed for the purpose of being incorporated into the MEDICAL DEVICE (also known as “off-the-shelf software”) or software previously developed for which adequate records of the development PROCESSES are not available
AUDIT TOOLS—REMEMBER FDA TIGHTLY AUDITS THIS UNDER 820.70(i) AND YOUR FIRM MUST CONTROL ALL SOUP VIA DESIGN, CHANGE PURCHASING AND DOCUMENT CONTROLS

Software safety classification

a) The MANUFACTURER shall assign to each SOFTWARE SYSTEM a software safety class (A, B, or C) according to the possible effects on the patient, operator, or other people resulting from a HAZARD to which the SOFTWARE SYSTEM can contribute.
The software safety classes shall initially be assigned based on severity as follows:
Class A: No injury or damage to health is possible
Class B: Non-SERIOUS INJURY is possible
Class C: Death or SERIOUS INJURY is possible

This standard does not specify an organizational structure for the MANUFACTURER or which part of the organization is to perform which PROCESS, ACTIVITY, or TASK. This standard requires only that the PROCESS, ACTIVITY, or TASK be completed to establish compliance with this standard.

This standard does not prescribe the name, format, or explicit content of the documentation to be produced. This standard requires documentation of TASKS, but the decision of how to package this documentation is left to the user of the standard.

This standard does not prescribe a specific life cycle model. The users of this standard are responsible for selecting a life cycle model for the software project and for mapping the PROCESSES, ACTIVITIES, and TASKS in this standard onto that model.

For the purposes of this standard:
· “shall” means that compliance with a requirement is mandatory for compliance with this standard
· “should” means that compliance with a requirement is recommended but is not mandatory for compliance with this standard
· “may” is used to describe a permissible way to achieve compliance with a requirement
·“establish” means to define, document, and implement
·REMEMBER—FDA DEFINES ESTABLISH THE SAME WAY
Compliance

Compliance with this standard is defined as implementing all of the PROCESSES, ACTIVITIES, and TASKS identified in this standard in accordance with the software safety class.

NOTE 1 This assessment could be carried out by internal or external audit{FDA expects this}

NOTE 2 Although the specified PROCESSES, ACTIVITIES, and TASKS are performed, flexibility exists in the methods of implementing these PROCESSES and performing these ACTIVITIES and TASKS.

NOTE 3 Where any requirements contain “as appropriate” and were not performed, documentation for the justification is necessary for this assessment.

NOTE 4 The term “conformance” is used in ISO/IEC 12207 where the term “compliance” is used in this standard.

Ref -
ISO 14971, Medical devices – Application of risk management to medical devices.
FDA expects ISO 14971 style r/m..although they cannot require it. By adopting thus standard, you now must comply to ISO 14971. ISO 13485:2003 also require ISO 14971
Make sure and study all of the definitions in the standard

Software Development plan

The MANUFACTURER shall establish a software development plan (or plans) for conducting the ACTIVITIES of the software development PROCESS appropriate to the scope, magnitude, and software safety classifications of the SOFTW ARE SYSTEM to be developed.
The s/w DEVELOPMENT LIFE CYCLE MODEL shall either be fully defined or be referenced in the plan (or plans).
AUDIT TOOL—INVESTIGATE DHF CONTENT FOR REQUIREMENT TRACES, MATRICES AND INTER-RELATIONSHIPS BETWEEN DEPARTMENTS

The plan shall address the following:

a) the PROCESSES to be used in the development of the SOFTW ARE SYSTEM
b) the DELIVERABLES (includes documentation) of the ACTIVITIES and TASKS;
c) TRACEABILITY between SYSTEM requirements, software requirements,
SOFTWARE SYSTEM test, and RISK CONTROL measures implemented software
AUDIT TOOL—PARSE APART THE DHF, SHOWING ALL PROCESSES IN USE,V/V FOR OTS S/W AND TRACE MATRICES

Security best practices under HIPAA

2009-04-24T02:25:00.001-07:00

- Document Everything – look through the rule, pick out each standard and each implementation specification and create a chart that briefly describes how you are addressing each.
- Require and use strong passwords – teach your staff andcoworkers how to create them
- Limit systems access to those who absolutely need it for their jobs
- Create written policies and procedures detailing the requirements
- Provide regular (annual) training
- Audit your own compliance
- Check state law for breach/incident notice requirements
- Be afraid. These rules apply to the smallest medical practices and the largest healthsystems and health plans
- Information Security is a hot topic. New lawsare being passed constantly.
- HIPAA may not provide for a private right of action but novel legal arguments are beingtested
- A major breach in your information securitycan be a public relations disaster.
- The media will be quick to report an inappropriate release of significant amounts of PHI

What is Protected Health Information (PHI)?

2009-04-24T02:12:00.002-07:00

Individually identifiable information collected ormaintained by a Covered Entity
- Can be oral or written
- Can be in any medium (electronic, printed, recorded)
- Includes simple demographic data
– just the fact that someone is your patient/plan member is PHI
- It’s still PHI if someone could reasonably figure out who the individual subject is.
- Sometimes a judgment call but best to be conservative

As per HIPAA guidelines following may receive PHI about an individual.
- The individual (must disclose)
- Anyone who has been authorized by the individual
- Anyone who is the individual’s Personal Representative
- Governed by state law but typically guardians, agents underPowers of Attorney, estate executors,
- Parent of an unemancipated minor EXCEPT if the minor has the ability to consent to the treatment (typically relates tomental health, substance abuse treatment and other sensitiveissues such as abortion and birth control.
- State law governs here. Know your state’s laws regardingPowers of Attorney, guardianships and executorships.
- Providers involved in the treatment of theindividual
- State and Federal agencies performing healthoversight activities (CE is permitted, but not required, to disclose unless state law requiresdisclosure).
- Other CEs when the disclosure is necessary tofacilitate Treatment, Payment or Health Care Operations

Invitro device and 510K related information resource

2009-04-17T06:39:00.002-07:00

- Medical Device Guidance Documents - [http://www.fda.gov/cdrh/guidance.html ]
- CDRH Databases - [http://www.fda.gov/cdrh/databases.html ]
- Code of Federal Regulations - [http://www.fda.gov/cdrh/devadvice/365.html ]
- International Information - [http://www.fda.gov/cdrh/international/ ]
- Consumer Information - [http://www.fda.gov/cdrh/consumer/index.html ]
- Overview of Regulations - http://www.fda.gov/cdrh/devadvice/overview.html
- Is Your Product Regulated? - http://www.fda.gov/cdrh/devadvice/31.html
- Classify Your Medical Device - http://www.fda.gov/cdrh/devadvice/313.html
- How to Market Your Medical Device - http://www.fda.gov/cdrh/devadvice/3122.html
- Does Your Product Emit Radiation? - http://www.fda.gov/cdrh/devadvice/311.html
- Registering Your Establishment -http://www.fda.gov/cdrh/devadvice/341.html
- Listing Your Medical Device -http://www.fda.gov/cdrh/devadvice/342.html
- PMN = Premarket Notification 510(k) -http://www.fda.gov/cdrh/devadvice/314.html
- Device Exemptions 510(k) but with GMP - http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpcd/315.cfm
- Investigational Device Exemption (IDE) http://www.fda.gov/cdrh/devadvice/ide/index.shtml - Premarket Approval (PMA) Class III Devices http://www.fda.gov/cdrh/devadvice/pma/
- Quality System (QS) Regulation for Good Manufacturing Practices (GMP) http://www.fda.gov/cdrh/devadvice/32.html
- Device Labeling Requirements http://www.fda.gov/cdrh/devadvice/31.html
- Medical Device Reporting (MDR) http://www.fda.gov/cdrh/devadvice/351.html
- Device Recalls Corrections Removals http://www.fda.gov/cdrh/devadvice/51.html
- Importing Medical Devices into the U.S. http://www.fda.gov/cdrh/devadvice/391.html
- Exporting Medical Devices from the U.S. http://www.fda.gov/cdrh/devadvice/39.html

Four Basic Factors to Microbial Kill

2009-04-16T07:19:00.002-07:00

EO Concentration

Commonly 400 and 700 mg/l
As EO concentration increases at a given temp and RH,
–microbial inactivation (kill) rate increases
Killing concentration required at the site where the microbes (BI’s) are located

Water Vapor (Humidity)

Required for EO to react with the critical cell molecules
• Generally measured as Relative Humidity

Temperature

Kill rate increases with temperature
–D-value decreases (time) with temperature
–Exponential function
For each 10°C (18°F) rise in temperature, the spore inactivation rate will generally double

Time

Amount of kill increases with exposure (EO gas dwell) time
90 percent of surviving microbes are killed for each D-value time in gas dwell

D Value ?

Determined to prove predictable logarithmic death kinetics of challenge microorganisms (BIs) or natural bioburden
“Decimal” Reduction Time - Measure of the biological organism’s resistance to the sterilant
Time in minutes necessary to reduce (kill) a microbial population by one logarithm or 90%
A Simple D-Value Calculation
Time

-----------------------------

Log of Starting Population – Log of Final Population

Best practices in supplier Quality

2009-04-15T09:05:00.004-07:00

Best Practice #1: Push Quality Upstream
• Deploy a web-based system and make it available to outsourcedmanufacturers
• They collect quality data and enter real-time into the quality system
• Quality data is instantly available to OEM quality engineers
• Process metrics are calculated by the system and pushed to quality
engineers every few hours
• Benefit: Engineers spend more time on working with
outsourced-manufacturers to improve process quality rather
than data collection and reporting

Examples -
Large Golf Manufacturer
• Sources components and clubs from dozens of suppliers worldwide.
• Also assembles clubs at multiple facilities around the world
• Process capability monitoring critical to keeping cost of poor quality

.low in an outsourced operation
• Benefits of implementing a web-based QMS at outsourced-manufacturer
• Data converted into information in a timely manner.
• Information is made available to all relevant parties while the
information is still fresh, thus enabling timely action.
• Engineers can address issues and take corrective action in time and
even before the lots reach the warehouse
• Cpk improved over 70% in 18 months

Best Practice #2: Streamline Audits

Other Audit Best Practices
• Clearly defined processes and metrics, so audit can discover unambiguous
process quality issues
• Audit process must incorporate the results of previous audits to track progress
against previous nonconformities
• There is a well defined process for root cause analysis and corrective actions
• Corrective and Preventive Actions are reported formally to all stakeholders

Best Practice #3: Live Supplier Scorecard

Key Metrics
• PPM of Components
• # of Corrective Actions Last Quarter
• Average Response and Resolution time for CAR
• # RMAs Processed per month
• MRB Inventory Levels
• Performance against benchmark

Best Practice #4: Closed-loop QMS

Stand Alone modules
• No Closed Loop Feedback
• No integrated process dashboard
Integrated closed-loop QMS
• Information flows easily from one module
to another
• Powerful drill down and drill across of analytics.

Best Practice #5: Calculating Cost of Poor Quality

COPQ 5% to 30% for most manufacturing companies
• Average COPQ is 20% for a manufacturer
• 1% for a six sigma company
• Over 25% for a three sigma company
• F50 company saved $1B/year in going from COPQ of 9+% to under 5%.

-Charge backs for additional cost incurred by the OEM due to
• Non-conforming components and materials
• Late deliveries from suppliers
• Introduce discipline and accountability

Best Practice #6: Build Business Case for QMS

Supplier Quality System is strategic to an OEM that outsources manufacturing
• VPs of Quality want to upgrade their Quality Systems but
can’t convince others about the investment
• Strategically linking quality with company objectives
• Defining before and after process maps
• Quantifying the value of infrastructure upgrade
• Getting buy-in from stakeholders

Framework for Defining Business Value

Savings From
• Cost Recovery
• Reduced Scrap
• Reduced Rework
• Reduced Inspections
• Reduced MRB Inventory
• Reduced Line Shutdowns
• Improved Equipment Utilization
• Reduced Warranty Recalls, Returns

What is OOS and how to avoid it ?

2009-04-15T08:51:00.002-07:00

An OOS result is generated when a drug product undergoing release testing or stability testing fails to meet an expected result or specification. When this happens, the FDA requires a valid reason must be determined to invalidate the OOS result and therefore an investigation into the cause of the OOS result must be conducted.

OOS Related Inspection Questions
•Show me a list of OOS results from the last 6 months?
•What is the procedure for OOS situations?
•Are SOPs followed?
•Are initial investigations made in a timely manner?
•Are full investigations made in a timely manner (where necessary)?
•Are investigations documented properly?
•Are investigation findings subject to proper review?
•Does the procedure include root cause analysis, impact analysis, and corrective actions and preventive actions?

Avoid Analytical Instrument Related OOS

•Regular method re-validation
•Instrument qualification (initial, after changes, after repairs etc)
•Operator qualification
•Qualification of reference material and reagents(stability, purity, accuracy)
•Preventive maintenance for equipment and computer hardware (seal, lamps)- based on usage
•Trend charts of critical instrument and method parameters

Avoid Product Related OOS

•Process analytical technology
–Get a good understanding of the process
–Uncover and fix critical process parameters
–Reduces process variability
–Can interfere in production process based on results of intermediate steps
•Setting meaningful specifications
–Set specifications based on mature process not on pilot results or ‘tentative’ registration specifications
–Update specifications based on experience and statistical evaluations

JGCP Audit Requirements

2009-04-09T02:11:00.003-07:00

1 -Per Article 2, Audit is defined as “an investigation conducted by a sponsor or postmarketing sponsor, or one that a sponsor-investigator appoints a designated person
to determine whether the clinical trial or postmarketing clinical trial is conducted according to this Ministerial Ordinance (No. 36) and the protocol or postmarketing protocol
to ensure the reliability of the technical documents collected by the clinical trial or postmarketing clinical trial.”

2- When the sponsor-investigator appoints an individual within the same medical institution to conduct the audit, said individual must be a third party who is not involved in the clinical trial.
3 -The sponsor-investigator may also appoint a third-party organization outside of the medical institution to conduct the audit.

4-Article 21, Clause 6:
"Procedures concerning auditing plan and duties" refer to a plan and procedure that the sponsor-investigator prepares to guarantee that the audit is properly conducted.

5 -This documentation must include:
+ Selection of the auditor (including the qualifications for the auditor)
+ Name of the auditor who will audit the clinical trial
+ Specific methods of auditing

+ Handling of auditing report and audit certificate.

6- Article 31. Audit (by sponsor)
- The sponsor shall prepare an audit plan as well as the operating procedures for the related duties, and conduct audits in accordance with the audit plan and the operating procedures.
- Auditor to be independent of those in charge of medical device development or monitoring.
- Audit report to document the matters confirmed in the audit and an audit certificate to verify that the audit has been conducted. Submit report and certificate to the sponsor.

7 -Article 42. Audit (sponsor-investigator)
-The sponsor-investigator shall prepare an audit plan as well as the operating procedures for the related duties, and conduct audits in accordance with the audit plan and the operating procedures.
-Auditor shall not be engaged in the clinical trial at the medical institution where the clinical trial is conducted (including its preparation and management) or in monitoring.
-Audit report to document the matters confirmed in the audit and an audit certificate to verify that the audit has been conducted. Submit report and certificate to the sponsor-investigator and the head of the medical institution.

8 -An audit on individual clinical trials shall be conducted by deciding on:
+ the subject of the audit, i.e. medical institution and other facilities engaged in the clinical trial
+ the timing of the audit taking into account the
* importance of the clinical trial for application to the regulatory authorities
* number of subjects
* type and complexity of the clinical trial
* level of risk posed by the clinical trial to subjects,
* various issues discovered through monitoring.

9 -The auditor is required to
+ visit the medical institution and other facilities engaged in the clinical trial as necessary
+ directly access the source documents to confirm that the clinical trial is being properly conducted and the reliability of the data is fully ensured.

Japan good clinical practice rules

2009-04-09T02:09:00.002-07:00

Ministry Ordinance 36 issued in 2005
Based on ICH6 and closely aligned with ISO 14155
Parallels the Drug GCP (MHLW Ordinance 28)
6 Chapters, 79 Articles
- Chapter 1. General Provisions
- Chapter 2. Criteria for Preparations for Clinical Trial
- Chapter 3. Criteria for Clinical Trial Management
- Chapter 4. Clinical Trial Criteria
- Chapter 5. Criteria for Reevaluation Documents, Etc.
- Chapter 6. Criteria for Sponsoring Clinical Trial, Etc.
Audit requirement discussed mostly in Articles 21, 31 & 42
JGCP requirements have many similarities to those the US and Europe.
Largely due to MHLW participation in ICH and the ICH Guideline for GCP (E 6)
Closely aligned with ISO 14155 Parts 1 & 2
Basic functions of the Sponsor, Investigators, Informed Consent, Record Retention, and IRB’s are nearly identical to requirements currently in place for the US.

JPAL Laws, Ordinances and Notifications

2009-04-09T02:09:00.001-07:00

The Pharmaceutical Affairs Law (Law No. 145 Established as of August 10, 1960; Law No. 87 Revised as of July 26, 2005)MHLW Ministerial Ordinance No. 36 Clinical Tests for Medical Devices (hereinafter referred to as "Medical Device GCP" or “JGCP”)
YAKUSHOKUKIHATSU No. 0720005 Administration of Good Clinical Practice for Medical Devices
YAKUSHOKUKIHATSU No. 070720 Essential documents for criteria concerning clinical tests for medical devices
YAKUSHOKUHATSU No. 0720004 Criteria for Clinical Trials for Medical Devices
YAKUSHOKUHATSU No. 0331006 Handling of clinical study data based on clinical study that is carried out in a foreign country
MHLW Administrative Correspondence from June 23, 2006 Q&A on the Handling of Tests Records from Clinical Studies on Medical Devices Conducted Overseas

FDA Guidance on Computerized Systems Used in Clinical Investigations

2009-04-09T01:52:00.003-07:00

Scope of this guidance

Computerized systems that contain data that support a marketing application
–Case histories
–Analytical test results (e.g., LIMS)
–Data captured from analytical instruments
–Electronic transcription of hardcopy source data
it Does not apply to:
–Computerized medical devices

Study Protocols
•Identify computerized system use within the trial process
•Computerized systems must:
–Satisfy process requirements defined in study protocol
–Have built-in error prevention

•Challenges
–More complicated protocols
–Some automated processes may not be defined at protocol authoring stage – Unnecessary protocol revisions

SOPs and system documentations

•Specific to computerized system
–Setup/Installation instructions
–Operating manual
–Validation
–Data collection and handling
–System maintenance
–Security controls
–Change control
–Backup/Restore
–Disaster recovery/contingency planning
–Data collection contingencies
–Training
–Roles and responsibilities

•Challenges
–Guidance states “Such SOPs should be maintained either on-site or be remotely accessible through electronic files as part of the specific study records, and the SOPs should be made available for use by personnel and for inspection by FDA.”

Source Documentation and Retention
•Original observations entered directly in computer = source document
•Investigator must retain source data, or a copy
•If source data not generated and stored at clinical site, a copy must be provided to clinical site or a designated site
–Copies must be made contemporaneously with data entry

•Challenges
–Does contemporaneous mean simultaneous?
•Initial impressions from FDA = Yes
•Often not logical and sometimes demonstrably impossible
•CDISC eSDI guidance on Electronic Source Data within Clinical Trials: “as soon as possible after the event to which it refers
–FDA’s concern: If Investigator does not retain a copy of the source data, the records can be modified and original data obscured
–Although Investigator may be able to remotely access data at Sponsor site, it is not under his/her control
–No longer acceptable to just send investigator copy of data at end of study

Access control

–Individual accounts
–Limit log-in attempts and record failed attempts
–Work only under own password/account
–Do not share password
–Password aging
–Procedural or automatic log-offs or lock-outs
–The system should not allow an individual to log onto the system to provide another person access to the system*

•Challenges
–“The system should not allow an individual to log onto the system to provide another person access to the system”
–How does the system control this?
•Should you not allow concurrent logins?
•Should you require periodic user checkpoints in the system?
•Does “system” include both the computerized application and procedural controls?

Document control as per ISO 13485

2009-04-08T05:09:00.003-07:00

Document control is

•Required by both FDA (in Federal, Food, Drug, and Cosmetic Act) and European Community (in ISO 13485)
•Has always been a requirement, from 1976 (GMPs) and 1996 (ISO)
•Cited regularly by both FDA inspectors and notified body auditors as deficient
•Often ignored by upper management as an area for possible streamlining
Requirements of FDA

1>Sec. 820.40(a) Document approval and distribution
–Approval
•…designate an individual(s) to review for adequacy and approve …all documents.
–Approval - date and signature(s) - shall be documented.
–Distribution
•Documents …shall be available at all [necessary] locations
•All obsolete documents shall be promptly removed from all points of use or otherwise prevented from unintended use.

2>Sec. 820.40(b) Document changes
–Changes to documents shall be reviewed/approved by an individual(s) in the same function/organization that performed the original review/approval, unless designated otherwise.
–Approved changes shall be communicated to the appropriate personnel in a timely manner.
–Each manufacturer shall maintain records of changes to documents. Change records shall include: •a description of the change
•identification of the affected documents
•the signature of the approving individual(s)
•Approval date
•Effectivity date

ISO 13485 requirements

•Clause 4.2.3 - Control of Documents
–A documented procedure shall be established
a) review and approve documents prior to issue
b) review and update as necessary and re-approve
c) ensure that changes and current revisions are identified
d) ensure that relevant versions of applicable documents are available at points of use
e) ensure that documents remain legible/identifiable
f) ensure that documents of external origin are identified and their distribution controlled
g) prevent unintended use of obsolete documents, and apply suitable identification if retained
–Changes to documents must be reviewed/approved either by original approving function or another designated one that has access to pertinent information upon which to base its decisions.

Fatures of a document control system

1.Requester of change red-lines documents and completes change request
2.Requester submits red-lined documents and change request to Document Control
3.Document Control supervisory personnel reviews red-lined documents and change request to assure completeness and accuracy
4.Document Control personnel incorporates changes into current documents
5.Document Control personnel distributes revised documents for review/approval
6.Approval of document package
7. Distribution of new documents to appropriate work areas
8. Work areas either destroy obsolete versions or return them to Document Control

How to Streamline a document control process

1.Requester of change red-lines documents and completes change request
•If MS Word document, use Tools/Track Changes/ Highlight Changes
2.Requester submits red-lined documents and change request to Document Control
•Via e-mail
3.Doc Control supervisory personnel reviews red-lined documents and change request
4.Document Control personnel incorporates changes into current documents
•Tools/Track Changes/Accept or Reject Changes
5.Document Control personnel distributes revised documents for review/approval
•Via e-mail
6.Approval of document package
•In Outlook, New Message/Options/Voting and Tracking Options/Use Voting Buttons
7.Distribution of new documents to appropriate work areas
•Document Control scans originals
•Puts them in appropriate directory
8.Little or no need for destruction/return of obsolete versions

USE error and medical device recall

2009-04-08T04:48:00.002-07:00

FDA's definition of USE error though the word USE error is not used officially.

“Act or omission of an act that results in a different outcome than intended by the manufacturer or expected by the USER, which may result from a mismatch situation between USER, man-machine interface, task and/or environment.” AAMI HE74:2001
Many research suggests that the frequency and consequences of medical device use errors may far exceed those arising from device failures

•A study of patients 65 and older found that those who couldn’t understand basic written medical instructions were much more likely to die within six years than those who had no problems. The difference in death rates “was much higher than we expected.”
Ref - Dr. David Baker, Chief of General Internal Medicine at Northwestern University’s Feinberg School of Medicine, 2007
•Most people have difficulty understanding pharmaceutical label instructions, regardless of their cultural background and level of education.
Ref - Mining Complex Clinical Data for Patient Safety Research, George Hripcsak, M.D., 2002

•Recent FDA reports show that more than 1/3 of medical device incident reports involve use error, and More than 1/2 the recalls due to design problems can be traced to design of the user interface. Hence design of user interface and the labelling is one of the main causes of recall.
To get out of the problem FDA suggests manufacturers go for Human Factor Engineering and also follow the guidance documents provided as below.

•Guidance on Medical Device Patient Labeling: Final Guidance for Industry and FDA Reviewers
•Do It By Design: An Introduction to Human Factors in Medical Devices
•Human Factors Principles for Medical Device Labeling
•ANSI/AAMI HE75: Human factors design principles for medical devices (adopted by the FDA later part of 2008)
http://marketplace.aami.org/eseries/scriptcontent/docs/Preview%20Files/HE48preview.pdf

Human Factors Engineering - Medical Device

2009-04-08T04:45:00.002-07:00

HFE is a scientific discipline concerned with the understanding of interactions among human and other elements of a system
it is Also called:
•Usability engineering
•Customer-centric design
•User-centered design
- A series of FDA standards and guidelines intended to ensure:
-“Each manufacturer shall establish and maintain procedures to ensure that the design requirement related to a device are appropriate and address the intended use of the device, including the needs of the users and patients.” (QSR paragraphs c, f, and g of Section 820.30)
-Ability to use a device safely and effectively is a primary “user need”
-Includes hardware, software and labeling

Cleaning validation and Labelling Requirement for reusable medical devices

2009-04-08T04:16:00.004-07:00

FDA regulatory requirements as follows

- Most of the complex medical device instruments require premarket notification [510(k) or even a PMA (premarket approval)
- 510(k) and PMA Guidance Documents include requirements for reprocessing instructions for the user:
-Detailed cleaning instructions, including disassembly.
-Detailed disinfection & sterilization instructions with specific sterilization parameters.
-Expected end of life & how this can be determined by user.
-Roles and Responsibilities
-21CFR 820.30 Design Controls
-21 CFR 820.70 Production & Process Controls
-21CFR 820.75 Process Validation

EU Regulatory Requirements

-European Medical Device Directive, MDD 93/42/EEC.
-Annex I, Essential Requirements
para 7,8, & 13.6 (h)
-ISO 13485:2003
-7.3 Design & Development
-7.5.1.2.1 Cleanliness of Product

Instructions for USE need to be developed as follows

- Start with determining intended use.
- Consider intended use during design.
- Obtain FDA guidance documents.
- Obtain & review consensus standards.
- Develop validation protocol.

Determine Intended USE

The Center for Disease Control & Prevention (CDC) recommends disinfection or sterilization based on three end use categories (CDC, 1985):
1>Critical Items
Devices in direct contact with blood or areas of the body not usually in contact with contaminants. Examples include biopsy forceps, endo cavity probes, and implants. Sterilization is required for these devices.
2>Semi-critical items
These devices are non-invasive and normally contact intact mucous membranes. Examples include endotracheal tubes, specula. High level disinfection is a minimum process requirement for these device.
3>Non-critical Items
Devices not in contact with patient, or only with intact skin, such as blood pressure cuffs, hospital beds, crutches, etc. High, intermediate, and/or low level disinfection is recommended

Intended USE during design
1 -Cleaning ports -Ease of use.
2- Minimize hard to reach areas.
-Narrow lumens
-Dead ends, rough surfaces, luer locks
-Crevices, hinges, areas between insulation and device
3-Compatibility with cleaning agents & sterilants.
-Ethylene Oxide
-Gamma Radiation
-Hydrogen Peroxide
-Chemical disinfectants & sterilants
4-Ease of disassembly & reassembly.
-The easier to do so, the more likely a thorough job.
-Disassembly/reassembly instructions are often lost/misplaced

Obtain FDA guidance documents
Labeling for reprocessing reusable medical devices.
- FDA - Guidance document for washers and washer-disinfectors intended for reprocessing reusable medical devices. June 2, 1998
- FDA - Labeling reusable medical devices for reprocessing in health care facilities: FDA reviewer guidance. April 1996.
- FDA - Questions and answers for the FDA reviewer guidance: Labeling reusable medical devices for reprocessing in health care facilities. September 1996.
- 510(k) guidance for specific devices
www.fda.gov/cdrh/guidance.html

Obtain and Review consesus standards

1>ANSI/AAMI ST81:2004 - Sterilization of medical devices-Information to be provided by manufacturers for reprocessing of resterilizable medical devices.
2>AAMI TIR-12:2003 Designing, testing, and labeling reusable medical devices for healthcare facilities: a guide for medical device manufacturers.
3>AAMI TIR-30:2003 – A compendium of processes, materials, test methods, and acceptance criteria for cleaning reusable medical devices.
4>AAMI ST:2004 – Information provided by manufacturers for the processing of resterilizable medical devices
5>ISO/TS 15883-5:2005 – Washer-disinfectors – Part 5: Test soils and methods for demonstrating cleaning efficacy of washer-disinfectors.

Develop validation protocol

1>Cleaning is the most important activity.
-Often inadequate, hard to confirm cleaning efficacy.
-Definition of cleaning is the removal of visible contaminants. The manufacturer must design the test to demonstrate that a soiled device can be rendered free from contamination to the degree that the device is free of soil. The accepted endpoints depend on the degree of disinfection recommended. FDA has guidance documents on validating sterilization processes8.
-Cleaning must be validated as well as sterilization.
2>Organic material works as a shield to Ethylene Oxide, steam, other sterilants.
-Blood & tissue
-Carbohydrates, fat
-Fluids introduced during medical procedures

Salient Features of cleaning validation

-Reusable devices must be designed to function safely & effectively following multiple cleaning/disinfection/sterilization cycles.
-Most devices composed of cleaning and sterilant tolerant materials will withstand more than 100 cycles
- Testing should be designed to address not only cleaning & sterilization efficacy, but also bio-compatibility & functional performance.
- Not just the sterilization cycles, but the simulated soils added, disassembly must also occur after cycles
-The cleaning process must remove blood, protein, fat, carbohydrates, endotoxins, microorganisms from all joints, lumens, crevices.
-Test soils have been developed to test the efficacy of cleaning as well as testing methods in AAMI TIR 303 .
-No single test soil is appropriate for all medical devices.
-Depends on contact points, mucosa, intact skin, blood pathways, etc.
-For example, intravascular devices should be tested with whole blood and serum.
-Simulated blood or body fluids may be formulated using a mixture of calf serum, dry milk powder, and a 1:1 rabbit blood/saline mixture (Miles, 1991).
-One method proposed by AAMI is to add Geoacillus stereothermopilis spores @ about 104 to 105 organisms.
-The soiled device is then cleaned according the given directions and the remaining spores are recovered & enumerated.
-The recovery technique must be validated prior to determining the efficacy of cleaning.
-Cleaning efficacy can then be determined by subtracting the spores recovered from the device after cleaning from the spores recovered from a control sample (soiled w/o cleaning).
-Ensure the cleaning procedure can be duplicated in the health care facilities.
-A good benchmark bioburden reduction level should show at least a three log reduction. This was demonstrated as possible for flexible endoscopes (Alfa, et. Al, 1999)
- Markers such as protein & carbohydrates can be used to evaluate the cleaning effectiveness.
-Blood cells contain hemoglobin which can be tested from extracts of the device. (Alfa, et. Al, 1999)
-Endotoxins (gram negative bacterial cell wall molecule) are found in tap water & can cause systemic pyrogenic reactions.
-Endotoxin levels extracted from a device can be analyzed by various methods. (ANSI/AAMI ST 72)
-The phenol-sulfuric acid assay can be used to measure both mono and poly saccharides.
-The bicinchonic acid (BCA) protein assay is a highly sensitive reagent for the photometric determination of protein.

Risk Management for Bio-Pharma ICH Q8 and ICH Q9

2009-03-26T04:58:00.004-07:00

ICH Q9 elements of risk management

Risk Identification -> Risk Assessment ->Risk Mitigation -> Risk Communication

How to identify risk

•Theoretical analysis
-Science, engineering, or math
•Based on experiments
-Structured or unstructured experiments
-Edge of failure or validation
•Statistically derived
-Trend analysis

FMEA and HACCP

FMEA salient features

•How can the process fail?
-Power outage stops mixing
-Wrong valve open sends product to drain
•How can each mode be made less likely to occur, and less harmful if it does occur?
-Back-up power, UPS
-Feedback or automation control

ICH Q8 design space

Risk AssessMent

Risk can be reduced by

•Risk mitigation—two strategies
•Reduce the severity (building codes for earthquake resistance; testing)
•Reduce the probability (stop sign at intersection of two roads; training)

HACCP concepts for Food processors

2009-03-22T01:17:00.003-07:00

The 7 principles applied to HACCP are
- Conduct a Hazard analysis
-Establish CCPs
-Establish critial limits
-Establish a monitoring system
-Establish corrective action
-Verification
-Record keeping

5 prelim steps to support the HACCP model
- Create the HACCP team
-Describe the products
-Identify the final users
-Create a flowchart of production process
-Verify the flow chart

Building requirements for a Food Audit

2009-03-22T01:02:00.003-07:00

Building and Grounds should have -
-Lights clean and protected
-Glass, metal and brittle plastic control
-Wooden items eliminated
-Adequate lighting in production and storage areas
-Floor surfaces clean no water, good condition
-Doors pest proof
-Dock doors have buffers
- Walls in good repair no entry points for pests or harborage
-Personal item storage
-18 inch perimeter and 14 inches between rows
-Outside areas clean no standing water or weeds, litter
-Pallet storage clean and adequate
-Pallets maintained broken pallets removed
-Dumpster/cull area clean, covered
-Backflow prevention
-floor drains adequate

Third party audit in food facility

2009-03-22T00:41:00.002-07:00

The difference between Regulatory and third party audit is at one side regulatory audits are concerned with compliance with code but thrird party audits go beyond codes and evalute the management of food safety systems. A facility can fail in third party audit though it is in compliance with regulatory requirements.
Here are list of general food safety requirements which is must for third party audits.

- GMP signeage is present in key locations
-Production and storage areas should be free from pests and any areas 20ft around it should be free from recurring pests.
-Pest control equipments are located away from infected area and monitered every month
-Pest control equipments should have barcodes.
-Ingreditents and products should be packaged and care to be taken to avoid cross contamination
-Storage racks should allow free passage of air
-On hold products should be segregated and properly identified
-Ingredietnts , products and packaging should be rotated in FIFO
-Equipments designed to prevenet condensation, dust or spillage
- Complete enclosure of packaging and processing areas.
-Raw ingredients should be examined before usage
-Unit and carton packaging should be coded for production day
- Bathrooms adequate in number, design and number, and stocked
-Hand washing stations adequate in number, design and number and stocked
-Warm water available for hand washing
- Single service containers not re used for food
-Reusable containers marked for purpose
-Infected employees are restricted or excluded, wounds bandaged
- Hair nets, beard nets, restraints
-Jewelry confined to a wedding band
-Clean outer garments
-Smoking, eating, drinking controlled
- No items in upper pockets
- No equipment should have provisional repairs using tape, cardboard, string, wire
-Temporary repairs should have date stamps.
- Equipment cleaning should have - Surfaces cleanable ,Clean items used for storage ,Protection of food during cleaning ,Cooler coils, fan guards clean ,Stored equipment protected , Safety equipment for sanitation crew ,Cleaning equipment color coded or identified for use ,Excess lubricants removed

Food Recall - Each Teams responsibility

2009-03-21T00:46:00.004-07:00

There are many steps in each recall where multiple teams are involved and hence it is very important that each team exactly knows what to do and when to do. Here is a snap shot of all teams involved and at what stpe what need to be done.

Notification of a recall
Sales and Quality Team - These 2 teams generally receive the call

Initial risk assessment - Quality team does the initial risk assessment

Assembling recall team - The admin dept assembles all people who should be involved in the recall process.

Information gathering - Following teams are involved in this step
- Admin - Coordinate all team
- Production -Review ingredient lot numbers used. Check production records.
- Warehouse - Track ingredients and finished products. Check for rework, damaged goods.
- Quality - Check micro and lab results.
- Maintenance - Review all Work Orders, repairs during problem period
- HR - Check for staffing issues and levels.
- Legal - Contact insurance. Work with PR.
- PR - Develop communication plan
- Sales - Ensure customer contact info correct. Finalize customer notice with Legal.
Notification to CFIA
- Admin and Quality team generally calls and informs the authorities
- Legal - team reviews the wording of communication
- PR develops the initial communication to customers.
Customer Notification
- Admin team's duty is to ensure all teams has resources.
- HR works with PR to communicate the staff
- Legal team deals with contacts by consumers, customers and lawyers.
- PR team communicates with public, shareholders and staff.
- Sales team Faxes and calls to customers.

Product Retrieval and storage
- Warehouse team arranges for trucking. Calculates % product retrieved.Secure the goods in - - warehouse (class 3) or in locked trucks (class 1&2)
- Sales team co-ordinates with warehouse.

Investigate the problem
- Warehouse gets the sample of product.
- Quality team analyzes and Gather data
Dispose of product
Warehouse ensures products are destroyed or hire third party.

Food Recall steps and recall plan components

2009-03-21T00:27:00.003-07:00

Steps of food recall
Notification of camplaint --->Initial risk assessment ----> Assemble recall team -->Gathering of information --> Determine risk level ---> Regulatory body communication --->customer notification --->Retrieve products --->Store faulty products --->Investigate the root cause -->Dispose the product

Recall team comprise of
-Plant Manager
-Production manager
-Quality manager
- Warehouse manager
-Sales Manager
-Human Resource
- PR, Legal and consultants
Components of a Recall Plan
The manual should include
-Responsibility of the tracebility co-ordinator and all teams
-Customer notification procedure
-Contact list details about all regulatory and gov people
-Description of product code identification
-How to handle product return
-Classification of Hazard level
-How to track customer complaint
-Description of test method used for traceability
-Maintenance of customer records
But you should create a Mock recall and prepare your teams for the actual recall.

Pointers Inspectors look for during FDA inspection - For CAPA (QSIT)

2009-02-25T05:04:00.005-08:00

see that corrective action taken to correct existing product nonconformity or quality problems and Prevent recurrence of the problem
The corrective action should Include explanations for how the firm will meet the requirements for all elements of the CAPA subsystem
Gain working knowledge of the firm's CAPA procedure before beginning evaluation of this subsystem
Have management provide definitions
Assure that there is a method for identification and input of quality data into CAPA system, including information regarding product/quality problems that may require corrective and/or preventive action
Assure the firm has procedures that describe/require input of product/quality problems into the CAPA system.
Analyze product/quality problems to identify those that may require corrective action.
Confirm the firm is routinely analyzing data from
–Acceptance activities relating to component, in-process and finished device testing
–Information obtained subsequent to distribution: complaints, service activities, returned products
–Information relating to concessions, quality records, and other sources of quality data
Determine if the firm is identifying product and quality problems that may require a preventive action
Review if preventive actions have been taken regarding unfavorable trends recognized from the analysis of product and quality information.
Determine if the firm is capturing and analyzing data regarding in-conformance product.
Select one or two quality data sources
Review records to confirm data was entered into CAPA system
Determine whether data is Complete ,Accurate ,Entered into CAPA system in timely manner
Determine which statistical and non-statistical techniques are used
Confirm comparison of problems and trends across different data sources to establish a global, and not an isolated view, of a problem.
Confirm that the full extent of a problem is captured before the probability of occurrence, risk analysis and the appropriate corrective or preventive action can be determined
Review procedure for conducting failure investigations
–Determine if the procedure includes a) Provisions for identifying failure modes b) Determining significance of failure modes c) Rationale for determining if a failure analysis should be conducted as part of the investigation
Discuss with the firm their rationale for determining if CAPA is necessary for an identified trend of product/quality problems.
Select failure investigation records of more than one failure mode and determine if the firm is following their failure investigation procedures.
Confirm that all sampled failure modes have been captured within data summaries
Determine whether the depth of investigation is sufficient to determine the corrective action necessary to correct the problem.
Review incomplete failure investigations for potential unresolved nonconformances and possible distribution of nonconforming product
Review records of nonconforming product where the firm concluded CAPA was not necessary.
Review nonconforming product and quality concessions
Review controls for preventing distribution of nonconforming products.
Review records of the most recent corrective/preventive actions
Determine if corrective/preventive actions for product/quality problems and changes have been documented and implemented
Determine that information regarding quality problems and CAPA has been submitted for management review
Confirm that there is a mechanism to disseminate CAPA information to those directly responsible for assuring product quality and the prevention of quality problems

How to be one step ahead of FDA inspectors and what to do to show what they want to check attend the training http://www.complianceonline.com/ecommerce/control/trainingFocus/~product_id=700788&channel=blog

Things to look while writing the response after FDA inspection

2009-02-24T02:56:00.001-08:00

-Open with a general statement of intent to comply
-Include a commitment to compliance by top management
-Never admit to guilt or characterize 483 citations as “violations”
-Address each and all individual items on the 483
-Indicate root cause and measures taken to prevent recurrence
-Indicate date corrective action is expected to be completed
-Provide supporting evidence if 483 citation is incorrect (but, don’t be defensive)

Dos and Don't during and after FDA inspections

2009-02-24T02:13:00.004-08:00

This is a collection of facts from different experts and not the whole thing, there might be other dos and don'ts other than these applicable as per particular situation.
Dos

Present business card
Be prepared
Be organized
Be calm
Be professional
Be confident
Have Scribe present at all times during the interview
Leave as soon as interview is over
Listen carefully and repeat the question or ask it to be repeated, if necessary
Answer completely, directly and honestly
Speak slowly and clearly
Speak only for your area of expertise
Know your procedures
Examine the credentials of the inspector, and establish the purpose of the inspection (e.g., routine, for cause, or survey).
Immediately inform corporate management and staff that an inspection is under way, and tell these individuals what the purpose of the inspection is.
Work out a rough schedule for the visit so that key personnel can be made available
Be able to verify everything you say
Prepare everyone in the firm who might come into contact with the inspector.
Train all such individuals with the procedures to be followed during the inspection
make sure all understand the role of the inspection coordinator.
Familiarize these individuals with a list of inspection do’s and don’ts
Inspection co-ordinator must stay all the time with the inspectors.
Inspection co-ordinator should have a runner to fetch information which is not in hand or to inform other about the stage of the inspection.
Inspection co-ordinator should think that he/she is the company as far as investigator is concerned
be positive in attitude and speak with authority and confidence
Interact with other company employees - those working in the plant as well as those in staff groups.
Effectively guide questions posed by the inspector to people with both the knowledge and the verbal skills to answer them.
smoothly challenge inappropriate questions immediately.
Focus on the positive aspects of a situation rather than getting defensive about negative aspects
Communicate inspection results on a continuing basis.Summarize the results more formally after the inspection is complete
Expect what you say to be documented in FDA field notebook
communicate clearly that there will be full cooperation within the law
Give Complete responses to valid questions, be open to the investigator’s point of view
Have a writtent policy about responsibilities
Representatives of the corporate quality, regulatory affairs, and legal departments are immediately informed that an inspection is taking place and are told what the purpose of that inspection is
Allow copying of records and access to a copier
Keep a second copy and attach to the inspection coordinator’s report
Allow FDA to take sample and retain a copy of sample and receipt
Follow up to see that all written comments (e.g., 483s) and verbal comments have been addressed and resolved

Don’ts

Do not make casual conversation
Do not assume the investigator is your “buddy”
Do not guess or make up an answer
Do not lie
Do not volunteer more information than necessary to completely answer the question
do not answer in way that looks to be rehearsed or artifical
Do not make faces or jokes about company's expenses
Make the auditor wait for the information
Override a liasion decision infront of auditors
Do not show auditors , your computers, but under FDA inspectors can see your comupter in a proper setting with proper personnel who are familiar with your systems present with them
Do not speculate. Don’t be afraid to find information and give it to the investigator later
Do not assume to know what the investigator means
Ask for clarification, examples or specifies
Do not conduct the inspection for the investigator
Never question the investigator’s authority
Never argue or raise your voice
Bring several people into conference room and have several conversations going on at one time
Provide documents with post-it notes, etc.
Do not agree or volunteer to change a procedure or practice without first discussing with Management
Respond to questions that are improper or outside your area of expertise or authority
Threaten to contact the investigator’s boss if conflict develops.
Allow Photographs
do not forget to make a decision which items to be given to inspectors, which to show and retain and which is to be exclusively used by co-ordinator
uncontrolled interchanges between personnel and the inspector

Classification of FDA inspection

2009-02-24T02:10:00.002-08:00

NAI - No Action Indicated
Site is in compliance. No actions or response from site necessary
VAI - Voluntary Action Indicated
Violative practices noted that do not immediately jeopardize subject safety, but require correction action. Response necessary; follow-up inspection possible
OAI - Official Action Indicated
Violations severe enough to warrant immediate administrative actions. Reinspection likely

Other Inspections
Routine GMP audits
Directed audit for a specific reason
Reinspection after a Warning Letter
Recall effectiveness check
Preapproval inspection
Special Enforcement Initiative

Top Reasons for FDA inspection

2009-02-24T02:04:00.001-08:00

Routine Inspections, Routine Surveillance, For Cause inspections
Pre-approval and Post-approval
Controlling product approvals for commercialization
Surveillance Programs through Adverse event reports
Undercover Surveillance (drug/device promotion, distribution)
Consumer complaints/former employee complaints (Whistle-blower)
Bioresearch Monitoring Foreign
Benchmarking, Complaints and Recall related
New Product/Process Being Implemented

FDA Guidance on Computerized Systems Used in Clinical Investigations

2009-02-24T01:02:00.002-08:00

Scope
Computerized systems that contain data that support a marketing application

Case histories
Analytical test results (e.g., LIMS)
Data captured from analytical instruments
Electronic transcription of hardcopy source data

it Does not apply to Computerized medical devices*
Study Protocols
•Identify computerized system use within the trial process
•Computerized systems must:
–Satisfy process requirements defined in study protocol
–Have built-in error prevention
•Challenges
–More complicated protocols
–Some automated processes may not be defined at protocol authoring stage – unnecessary protocol revisions
•Potential Solutions
–Include only high level detail in study protocol
–Maintain detailed computerized process map outside study protocol
SOPs and System Documentation

•Specific to computerized system
–Setup/Installation instructions
–Operating manual
–Validation
–Data collection and handling
–System maintenance
–Security controls
–Change control
–Backup/Restore
–Disaster recovery/contingency planning
–Data collection contingencies
–Training
–Roles and responsibilities

•Challenges
–Guidance states “Such SOPs should be maintained either on-site or be remotely accessible through electronic files as part of the specific study records, and the SOPs should be made available for use by personnel and for inspection by FDA.”
•Potential Solutions
–Considerations for which SOPs are implemented at the site
For detailed description on this topic please attend the training
http://www.complianceonline.com/ecommerce/control/trainingFocus/~product_id=700842&channel=blog