From academia to entrepreneur chapter 8 about meeting regulatory requirements

From academia to entrepreneur chapter 8 about meeting regulatory requirements From academia to entrepreneur chapter 8 about meeting regulatory requirements From academia to entrepreneur chapter 8 about meeting regulatory requirements From academia to entrepreneur chapter 8 about meeting regulatory requirements From academia to entrepreneur chapter 8 about meeting regulatory requirements From academia to entrepreneur chapter 8 about meeting regulatory requirements From academia to entrepreneur chapter 8 about meeting regulatory requirements From academia to entrepreneur chapter 8 about meeting regulatory requirements From academia to entrepreneur chapter 8 about meeting regulatory requirements From academia to entrepreneur chapter 8 about meeting regulatory requirements

About Meeting Regulatory

Requirements

8

8.3.3.1 About Quality Assurance and Internal Audit 158

References 161

O U T L I N E

8.1 IMPLIED, EXPECTED, DELIVERED

Imagine one evening you feel unwell and intuition suggests that

it may be more than just the common flu You get to a night clinic and after the requisite wait the physician in attendance assesses your situa-tion as requiring immediate further treatment at the hospital When the ambulance arrives, the paramedics place you on a gurney and load you into the ambulance for the trip to the hospital In the tight cabin space you note all the medical equipment and supplies around you The EMT (emergency medical technician) places an oxygen mask on you She next dons gloves and rips open sterile packaging from which she removes a catheter to insert into your arm to start an IV line She also wraps your

free upper arm with a cuff and takes your pulse and blood pressure, not-ing the readnot-ings

Arriving at the hospital, you are received at the EMERGENCY area, examined by the medical staff and admitted as a patient The nurse hooks you up to an electronic box that displays your vital signs

contin-uously; the duty vampire (blood technologist) rips open a sterile

pack-age and inserts a sterile needle into a vein in your arm, collects your blood into color-coded vacutainers® and heads to the lab to assay the contents This is followed by the duty nurse inserting a couple more needles into your arm, connecting the hub ends to tubes that lead into semi-translucent bags containing saline and pharmaceuticals all hung

up above you, passing through pumps complete with various LED indi-cators and alarms, directing the amount of fluid and medication you receive per time period

Lying in that hospital bed in emergency undergoing treatment, your thoughts wander through the events of the past few hours Your life hung in the balance Yet with the passage of time, you grew calmer You became confident that barring the remote adverse event, you would

pull through and recover Your relief is probably founded on three

primary patient care perceptions most people have acquired from expe-rience, reinforced by your observations in the preceding episode These are:

accompanied by a good training program, on-going upgrading of skills and periodical review by superiors and peers, resulting in a high level of competence and dedication for medical services staff You are quite comfortable in accepting that these healthcare service providers from the clinic physician, the EMTs, and the doctors, nursing and

support staff, will do their best for you, the patient.

you will contribute to your full recovery because they are clinically relevant and well manufactured Your general knowledge assures your subconscious that these legal drugs have undergone a rigorous process of selection, evaluation, production and trials before they were ever used on the larger patient population

thought out, properly manufactured and they perform robustly, with beeps and alarms going off when appropriate If you were more perceptive, you probably had noticed sophistication in some units compared to others, a sign of constant upgrading by the manufacturers to match advancement in science and technology and the needs of the healthcare facility as much as budget can support

b. Finally, the array of disposables such as gloves, catheters, needles, syringes, IV line tubing, vacutainers® and other supplies used for the benefit of the patient were properly packaged, with evidence of proper sterilization, production and expiry dates Here again, you probably noted the varying designs and complexities of products that make their way into every aspect of clinical care

In essence, for you, the implied and expected of the biomed industry

for more than 50 years, the regulatory agencies of many countries and the biomed industry have interacted with each other to successfully entrench this subliminal acuity in you Let’s explore this further

8.2 GETTING TO KNOW REGULATORY

REQUIREMENTS

The implied and expected alluded to above is that generally, patients

and the public believe that medical products are properly made and

of good quality, and have passed safety and use tests that meet health

valid The gains made in regulatory compliance for biomed products since the latter half of the twentieth century have been substantive, and continue to evolve

To recap, selling a biomed product in a country requires you to meet the legal requirements administered by the pertinent authorities of that country as they pertain to manufacture, sale and use The biomed prod-uct must be as safe as current understanding permits, and its benefits in use shown to outweigh (preferably substantially) potential risks in using the product The intent is to protect their citizens from known or reason-ably anticipated preventable harm with a medical product that works Some of the regulatory agencies you probably will have to deal with are the Australian TGA, Health Canada, the Chinese CFDA, the EU mem-ber countries’ Health Ministries, the Japan Ministry of Health, Labor & Welfare and the US-FDA

There is a lot of information published on their websites, as well as most other countries’ health authorities’ websites, on how they accept biomed products for sale in their country How to produce, and what and how to test biomed products, to provide the vital information required in a submission compilation to regulatory authorities in support

of a biomed product for approval, follow a rigorous process Once you know one system, you will be able to recognize similarities in another

i Healthcare service providers (who are recruited and trained, not manufactured) are excluded.

Bringing a biomed product to market is a non-trivial exercise Meeting regulatory requirements is more than ticking items off a checklist to sat-isfy in a legal manner that a product intended for sale in a territory has complied with the necessary rules Do not be overwhelmed or intimi-dated by the deluge of information you have to master All the complexity behind this regulatory enigma distills down to two straightforward facts:

manufacturer and/or supplier of biomed products

for you to comply with the law The sponsoring organization (i.e your company) must satisfy and reasonably prove by various processes imposed on the manufacture, and through tests and/or scientific studies on the finished goods, that the biomed product is well

conceived, well made, works and is safe Two insights on what this entails, quality systems and the use of science-based studies will be elaborated later in this chapter The burden of proof is on the sponsor

(you), not the regulatory agency Compliance is mandatory.

Knowing, understanding and working through the extensive docu-mentation that exists for compliance and related procedures, and keep-ing updated on changes, i.e dealkeep-ing with regulatory matters, as stated in

an earlier chapter, is a fulltime job and someone other than you should

do this Your objective as a biomed runway entrepreneur is to be familiar

enough with regulatory matters to:

with regulatory matters to get your product through the regulatory submission and approval process

you control your company’s purse strings

Making a commitment to gain at least a working knowledge of regu-latory matters will go a long way to establishing your credibility as an authentic player in the “biomed club” It is an important “license” to obtain and maintain, and I urge you not to compromise on this aspect for profit To begin, let’s narrow the information you have to cope with by answering three main questions

(1) WHAT ARE YOU GETTING REGULATORY APPROVAL FOR?

The obvious answer is a medical product This is further differentiated into:

d. Others (e.g health supplements, cosmetics, depending on the

classification method)

This is the part where you deal directly with health authorities Each type of product has different requirements with regard to facility certifi-cation and mainly scientific evidence you have to provide to the regula-tory agency/authority to demonstrate your product is safe and effective For example, the FDA website posts comprehensive regulatory informa-tion on what is required for a medical device to meet compliance, such as

“quality system (QS) regulation” and “labeling requirements” Working through the documents will help you find out what you need to do

A biomed service, for example testing, is a component of this process

in that the science-based testing results performed in these facilities pro-vide the primary scientific information required by regulators to make a judgment on the product’s overall safety and effectiveness Practices

facili-ties are to perform testing

(2) WHAT ARE THE MANUFACTURING REQUIREMENTS?

The design, prototyping and manufacturing of medical devices were introduced in Chapter 3 To meet regulatory requirements, you carry out all these tasks, especially manufacturing in a certified facility, be it your own or a sub-contractor’s Some leeway can be exercised; for example the certified facility qualifies by audit the design component of a separate non-certified location The certified facility takes on the responsibility that all work performed at the satellite non-certified location conforms

to its certification Before BRASS received accreditation in 2000, a pharma client qualified BRASS by audit to perform tests for them

The type of certification depends on your target sales countries and the country of your operations For example, a manufacturing facil-ity for medical devices is required to be ISO13485 certified in Canada, while for the USA, the US-FDA QSR requirements must be met ISO9001 certification normally suffices if you are producing raw materials and

requirements that are normally variations or modifications of one or a combination of the above

You will have to get your facility to the required level based on the Standard you are conforming to, and be audited and approved by a

cer-tification granting body such as a Notified Body for the EU member

coun-tries The US-FDA does its own inspection If you use a manufacturing

ii Good Laboratory Practice.

iii Be prudent and verify with your consultant There are details in your processes or products that may require another choice.

sub-contractor, ensure that they have the necessary credentials that are

current

Pharmaceutical manufacturing follows a comparatively more

(3) WHAT ARE THE TESTING REQUIREMENTS?

For a medical device, testing normally applies to the end product that

is in final fully assembled packaged form (some devices require assem-bly by the end user) The class of the device and the level and duration

of contact with the body determines what safety tests are to be done The ISO10993 provides a table that you can use to determine what types of

nor-mally performed under GLP (Good Laboratory Practice – it is a regula-tion) Others include sterility assurance and endotoxin limits verification, bioburden and package integrity

The testing regime for pharmaceuticals is more elaborate and strin-gent, as most drugs go inside the body Furthermore, drugs have been regulated much longer than medical devices and more is known and

applied The chemistry has to be verified and how the drug behaves in

vivo assessed There are also requisite phases of clinical (human) trials Working through the three questions helps define and direct you to the necessary information you require for your matter at hand (that is already considerable), relieving you of having to handle the more routine and non-relevant (to you) aspects

Understanding the information you require may be challenging for

a novice since there is a lot to cover, but it is surmountable For a

error Alternatively, you hire a consultant from the get-go to guide you through the process It is wise to do a combination of both The simple stuff is obvious to do You are familiar with the country you set up your enterprise in, and have settled on the intended countries of sale You also know what you are going to make, a pharmaceutical, bio-pharmaceuti-cal, medical device, etc Therefore, you can obtain and familiarize your-self with the regulations of the countries of interest, including the specific requirements for your product type

You follow this up by attending the many courses conducted by con-sulting companies and some regulatory agencies (some you may have to pay) on regulatory related topics For example, the US-FDA has several free online courses that you can access You will gain a general knowl-edge in these matters from these activities The next step is when you

iv Good Manufacturing Practice.

v Ensure the regulatory authority you are submitting to accepts this.

consider bringing in a consultant For a facility, a consultant will assist you to bring your operations to the required level to pass certification audit For medical devices testing, I recommend where possible work-ing with a regulatory consultwork-ing organization (known as CROs –

con-tract research organizations) with testing capability or vice versa This

normally optimizes costs as well as workflow The consultant on your project will be motivated to get on top of the testing component to move your regulatory paperwork along as they have access to their own tests experts This is a reasonable and efficient approach

8.2.1 Regulatory Affairs

The pharmaceutical industry is comparatively mature For a pharma and/or bio-pharma start-up, the hiring of a Regulatory Affairs (RA) pro-fessional may be more appropriate due to the intense level of compliance required Regulatory Affairs is a profession particular to biomed, specifically

to pharmaceutical, biotech, medical devices and functional foods “The RA professional in a company is the interface between the organization and its products and regulatory authorities Their role is to ensure their company keeps up with changes in regulations and laws, and that their company com-plies in the markets they serve Compliance is over all aspects, from devel-opment, manufacture, testing, marketing, registration and licensing of the company’s regulated products” You may consider training an existing staff,

or be on the lookout for a trained professional with the requisite experience Some smaller medical device outfits I know have a combined RA/QA (quality assurance – to be discussed later) position Realize that the two functions are different, and preferably, the positions should be staffed separately

Regulatory submission and compliance is a serious matter A good RA professional that interacts well with the regulatory agency contacts and with personnel in their own organization tasked with duties in this area will facilitate a smooth progress before, during and after the approval process

8.2.2 Industry Feedback

Before leaving this section, you should note that as new regulations

or revisions to existing regulations are being prepared, industry is nor-mally granted opportunities to review proposals and provide feedback The manner in which this is conducted is again country dependent This

is an important practice as it provides industry a channel to share their opinions on impending regulations that affect a business’s operations, finances and revenue Consider participation where possible, as regula-tions impact your business and you should know what is forthcoming to incorporate into your work plan

You should also think of being active in Standards work, either as a national representative or on a committee in a trades/technical group or association For example, the ISO has technical committees on Standards for various aspects You will obtain an insight into how representatives from government, agencies, industry and academia interact to derive or revise a Standard Your scientific input could be another channel you can contribute to better biomed products

Finally, realize Standards and Regulations are subject to interpreta-tions that in practice rely on human beings who are reasonable people

8.3 ABOUT QUALITY SYSTEMS

Manufacturing and testing (M&T) precedes regulatory submission M&T are the two sources that provide much of the vital information you put in your submission that is reviewed by the health authorities The manner these facilities have to operate to meet certification and/

or accreditation criteria, as well as other associated requirements stipu-lated by respective health authorities, are extensive and time consum-ing Books, training courses and consultancies abound to address these important matters

But at the center of all the activity common to manufacturing and

QS can be inferred from the effort put in by the organization that can be garnered from its attitude, workflow processes, well thought out intra- and inter-organizational activities that produce a biomed product that is generally better rather than just meeting what is required The organiza-tion must also continually strive to manufacture products that testify to its integrity throughout the products’ lifecycle What will be emphasized

is that regardless of what system you adopt or follow, the three critical aspects for a robust quality system are:

maintenance of the QS to the required level as the defining attribute for the organization

under the QS For example, how you purchase, install, qualify and use, service and maintain a piece of equipment must be specified How you handle, check, store and bring raw materials to the

production line; how you clean the facility, etc are all activities

covered by the QS It does not take much imagination to conclude that this is a humongous task to initiate from scratch, fully implement in

vi An alternate term is QMS – Quality Management System.

a new facility, and maintain Only by people performing the tasks as trained and responsibly can this be achieved, i.e people matter

as adapt to changes when requirements are revised Continuity is the only recourse

Without these three factors being met well, whatever is implemented

is just procedural Even though the facility may obtain accreditation and/or certification, they may not reveal the true state of affairs in the facility Consider the following excerpt from the medical devices sector

“Medical devices that met standards have been recalled Quality sys-tems that were said by internal audits to be in compliance with FDA regulations or ISO quality standards received serious questions after external auditing Devices meeting standards or produced by quality systems felt to be in compliance have put patients at risk by failing at critical moments Something more than just meeting standards and

What does this imply? Despite knowing the requirements, and checks being in place, things are not so straightforward How can it be improved? Let’s look at these three factors in greater detail

8.3.1 Is Management on Board?

All quality systems rely on the management taking the lead This is realistic, as true compliance can only be achieved from the top down Without management behind the QS to allocate the necessary human resources and funds, a quality system will not be properly developed and maintained Paying for HR time to prepare documented procedures, controls and checks, and to properly outfit a facility to the level required

is costly Furthermore, the effort cannot stop or diminish in importance once the certification and accreditation has been obtained Lapsing into paying transient attention to QS in order to pass subsequent mandated audit inspections can occur Only management can provide sustained enthusiasm Management’s leadership must be earnest Otherwise, staff will not take the QS seriously This is the reason why all known quality systems have this management emphasis

Ultimately, a good QS is an attitude to want to do things right, from management down to the staff on the production floor, in the lab doing the tests, right down to the persons clearing the trash and cleaning the lab Clients and others interacting with your organization must get this

“feel” that your company “walks the talk”

Your customers’ audit teams are not going to be impressed by the number of document revisions you perform, necessary though they may

be They search for other subtle noticeable traces such as in the type of

equipment you purchase (the GLP and GMP compliant types are good indicators of commitment), the frequency and how well you carry out your internal checks, calibrations, etc that are all down in your proce-dures, recorded and available to be reviewed by your clients’ auditors Even your staff’s work attitudes can be revealing Former employees do talk about their training and how work was performed

Auditors from accreditation and certification bodies are more likely

to note how many times you sat in meetings on internal management reviews (minutes of these meetings that are reviewed during an audit would indicate your attendance) Even if you only just sat in for the meeting, you had to make time to attend, and that says much about your interest in your company’s QS The other notable role you can participate

in is to be an internal auditor for some or most of the formal operational

requires active involvement and will be noticed

Word gets around and the prevailing attitude of your organization towards the QS will come out You cannot hide Build a QS you can be proud of Nurture and permeate the culture throughout your organization

8.3.2 People Matter

Regardless of what quality system you settle on, ultimately, people are the prevailing factors who determine the quality and performance of an operation in a facility to produce or test medical products Personnel are involved from the onset of product development through to production, testing and product release They must have the appropriate academic background and must be properly trained for the job in order to perform their assigned duties well All training performance indicators should be clearly specified, and proper staff training procedures with records must be maintained Staff attitude is the most important criteria for the good imple-mentation of processes and procedures that quality systems rely on, i.e.:

Conversely:

Every employee has a responsibility to the company to ensure that his or her responsibilities are met, thus assuring a quality product is produced

viii This presupposes you are competent scientifically in the areas being evaluated.

vii You have to train and be qualified as an internal auditor I was the IQA (Internal Quality Auditor) for BRASS in its first 6 years of operations.