What You Should Know about Government Oversight, Manufacturing Practices and Quality

This is a non-technical introduction to differences in the stringency of manufacturing for branded drugs, generic drugs, and dietary supplements. Most of this lens is based on practices in the USA, although obtaining medications in other nations is also mentioned.

This article does not attempt to develop such issues as off-label use of a prescription drug (use of the drug for purposes other than those approved by the FDA), interactions between drugs and/or supplements, or the extent to which supplements can or cannot be regarded as appropriate for particular health conditions. It's mainly about quality.

Newly Approved Drugs

When it comes to regulating medications and quality control in drug manufacturing, many countries regard the USA's Food and Drug Administration (FDA) as the model to try to emulate.

The USA FDA approves a drug for clinical use only after it is shown to be sufficiently effective and safe in clinical trials.

Being approved does not mean a drug is completely innocuous. Any drug powerful enough to have major clinical benefits is also strong enough to cause problems for some people. Clinical trials are intended to determine whether a drug will generally do what it is supposed to do, what side effects it most often causes, and whether it is especially helpful or especially troublesome in people with specific medical profiles.

Be aware that even when hundreds of people participate in clinical trials, those people cannot represent the full variety of situations in a much larger population. Some side effects (even major ones) might not appear until after the drug is approved and begins being used by many thousands of people. As additional information is learned about a new drug, the FDA may order changes in the way it is labeled and the way doctors prescribe its use.

The latest safety label changes are available at the FDA's MedWatch website.

A new drug's complete range of effects may not be known until it has been in use by the general public for years. In extreme cases where a potentially fatal or crippling side effect becomes evident, the FDA rescinds its approval and orders a drug withdrawn from the market.

Occasionally, if a prescription drug proves to be safe enough for the general public to use without a doctor's guidance, the drug may be approved for over-the-counter (OTC) sale and no longer require a prescription.

Branded versus Generic Medications

Brand Name Medications

When a company develops and seeks marketing approval for a new drug, it spends enormous amounts of time, effort, and money to determine precisely the best way to make the drug, as well as test it and run clinical trials to verify that it is safe and effective. Bringing a new prescription drug to market typically costs hundreds of millions of dollars.

For the first few years after a new drug comes on the market, the company that originally developed it enjoys a monopoly for that particular drug. During those years, the price of the drug remains relatively high–not just because it is only available from one manufacturer, but also because that manufacturer needs to recover the cost of development while it has monopoly advantage. A successfully released drug must cover not only the cost of its own development, but that of other drugs the company investigated which did not turn out well enough to be released for use.

Generic Versions of a Drug

Eventually, that company's patent for the new drug expires. When patent protection ends for a drug, other companies are allowed to introduce generic versions. These companies start out knowing the essential formula of the medication. Their development cost is only a small fraction of what the original company spent to figure out exactly what would work best. This the main reason a generic version of a drug costs so much less than the original.

The generic version of a brand-name drug must be close to the same amount of the same active ingredients. However, that does not mean it is identical. Most of the time, the generic version of the drug has approximately the same therapeutic effect as the original branded version, but not always–for some drugs, or for some patients, or both.

Why a Generic with the Same Amount of Active Ingredient can Work Differently from the Brand Name Version

A medication's effectiveness depends on more factors than just the amount of active ingredient in a dose. Consider a drug that is delivered in a pill:

  • Most of the pill is a carrier substance, not the active ingredient. A generic version of the pill need not use the same carrier substance as the brand name version. Some patients may not digest the carrier in the generic pill at the same rate as they do the carrier for the brand-name pill, or some patients may react well to one carrier but poorly to another.
  • Even if the carrier is the same substance, a generic pill may use a different proportion of carrier to active ingredient.
  • The manufacturing process may be different. If the carrier is more densely packed, for example, the carrier will dissolve more slowly and the drug will take longer to get into the bloodstream.

The exact steps used to make a pill determine many characteristics which are important to the effectiveness of the pill. For example, friability is a measure of how well the pill stays intact as it is jostled against other pills during handling. You can roughly guess how friable a batch of pills is by looking at the inside of a bottle full of the pills. Those that tend to leave dust on the inside of a container dissolve more readily in the digestive system and therefore can deliver a drug more quickly. However, those that do not leave much dust pass through packaging, shipping, handling and the human stomach more intact. When the optimum pill tends to be crumbly, like the original formulation for aspirin, sturdiness may be accomplished by applying a coating. Pills that are coated or packed very hard do not allow a drug to be absorbed as rapidly as pills that fall apart readily.

Brand Name and Generic Manufacturers have Different Primary Focuses

The original developer of the drug optimizes all aspects of the drug's manufacture and consumption to smooth the way for approval and to build up the best possible reputation while the drug is still protected by its patent.

A company that makes generic versions of drugs is more motivated by keeping costs down. In the case of a drug that works best in a crumbly pill, a company making a generic version might want to make the pills more durable to minimize losses due to breakage, even though that makes them also not work as well.

Drugs versus Dietary Supplements

Manufacture of Medications

Both brand-name and OTC drugs are subject to stringent quality control and traceability requirements. Drug manufacturing still requires more human involvement than many other kinds of manufacturing, but it is rigidly controlled. Some elements of the process described below vary from company to company, such as use of pallets. Many factories are much more automated now than they used to be, but the automation mimics manual steps from the original methods.

Each drug has a master recipe specifying each amount, temperature, processing time, and so on in the manufacturing process. No detail is left out of the recipe. When a batch of drug is to be made, a complete copy of the recipe and containers holding the specified amounts of the ingredients are placed on a pallet. The pallet and everything on it goes through the manufacturing line from start to finish together. At each step, the person who performs that step fills in blanks or initials steps to certify temperatures, pressures, run times, and so on. At especially important steps, a supervisor must also initial or sign. This recordkeeping is so thorough that it may take 48 hours to make the drug, and 140 hours to do all the associated recordkeeping. When all of the records were kept on paper, the final paper record for a single batch of drug could weigh four to seven pounds. (Nowadays the record may be digital and may be stored on a computer.)

After the batch is complete, it cannot be released until the records of its manufacture have been reviewed in detail and verified as satisfactory. If even one detail of the recordkeeping is not right, even if someone merely forgot to initial a single blank and the drug itself is correct, the entire batch of the drug must be destroyed.

If all is well, the drug goes to market and the record of how it was made is archived. That record must be easily retrievable for years in case any adverse reports are associated with that batch. Adverse reports may be due to undesirable effects of the drug, or may be due to tampering after the batch is sent to market.

Manufacture of Supplements

Dietary supplements, on the other hand, are not subject to anything resembling that degree of quality control. They are not subject to FDA approval before they can be marketed. They are not required to achieve a standard amount of active ingredient, as is required for both branded and generic drugs. The extensive safety checks imposed on drug manufacturing are not imposed on the packaging of supplements. Lots are not required to be traceable to a detailed step by step, item by item record of their manufacture.

There are moves underway to at least require supplements to deliver the amount of active ingredient stated on the label. Such a requirement is not yet in place as of this writing.

Implications for You as a Patient

Chances are that whenever your doctor prescribes a drug for you, your health insurer prefers that you choose the generic version of the drug if one is available.

For many medications, generic versions are about as effective as the original branded versions. However, some medications are notorious for having such a delicate interaction with patients that trouble often results from switching between major brand names or between branded and generic versions.

Thyroid hormone pills are an excellent example, which I am familiar with because a close relative has to take them. A patient whose thyroid gland has been removed or is underperforming needs thyroid pills to keep the amount of thyroid hormones in the bloodstream at the right level. Too much can cause lasting damage, and can be especially dangerous to the heart. Too little leaves the patient literally without enough energy–the patient is exhausted and can gain weight rapidly. Getting the balance right is tricky. The doctor must repeatedly run tests and adjust dosage until everything is just right, and then the doctor must test again on a regular basis in case anything shifts. The balance is so delicate that getting pills from a different manufacturer requires repeating the entire balancing act, virtually as though the prescription is being taken for the first time.

Even when you are taking something that is not as delicate as thyroid pills, sometimes you as a patient may fare best on the branded version or on a generic from a particular manufacturer. It may be because you respond well to the carrier substance in their capsules, the friability of their tablets… any of the myriad details of manufacture. When you realize you are faring noticeably better when the medicine comes from a particular manufacturer, tell both your pharmacist and your doctor. The doctor can write prescriptions in a way that specifies the manufacturer, and the pharmacist can make sure you get it from the right source even if your doctor forgets to write the prescription in the right way.

Occasionally, though, you may find that none of the generic versions work very well for you, whereas the brand-name version does. In that case, you will need your doctor's or your pharmacist's help to explain to the insurer that this specific prescription must always be filled with the brand-name version, despite higher cost. If the insurer tries to insist that generics are the same, you now know that is not precisely true, and sometimes the difference can be important.

Note: Some states have laws that force your pharmacist to substitute a generic (without being required to tell you or your doctor) unless your doctor writes the prescription in a specific way. If you are taking a medication that only works well for you when it is a particular brand, check whether you live in a state with such a law.

With dietary supplements, you now also know that the rules for manufacturing are much looser than for making drugs. You must depend upon the manufacturer to resist any temptation to cut corners on quality control in order to gain a price advantage.

With supplements, it is safest to always buy a brand you trust. Saving a few cents by getting a bargain brand you do not know well may get you less effective doses, or in rare instances may get you part of a bad batch. When someone reports a problem with a prescription or OTC medication, the entire batch can be recalled from the market in a few days. In the 1980s, a single bad batch of one supplement severely affected an estimated 3,000 people in the USA before it was recalled. (One of the affected patients was a classmate of my sister.) Supplements can be helpful, but even after diligent investigation of their effects, they should be used with greater caution than drugs due to the variability of their potency.

Medications Obtained Outside the USA

Bringing Medications from Abroad Into the USA

For obvious reasons, both the pharmaceutical industry and FDA want USA residents to buy all their medications in the USA. Drug manufacturers want the higher prices they command here, and the FDA wants control. Technically, for you as an individual patient, importing medications from outside the USA is illegal.

Despite the law, some USA patients routinely buy prescription medications outside the USA. In some instances, a drug that requires a prescription in the USA is available OTC in other countries. As an example, antibiotics can be bought in Mexico without a prescription. In many instances, drugs are less expensive (even dramatically less expensive) outside the USA, even where a prescription is still required. Lastly, some drugs are available in other countries that are not available in the USA at all.

There are some special circumstances in which the FDA does not object, when:

  • The intended use [of the drug] is unapproved and for a serious condition for which effective treatment may not be available domestically [in the USA] either through commercial or clinical means;
  • There is no known commercialization or promotion to persons residing in the U.S. by those involved in the distribution of the product at issue;
  • The product is considered not to represent an unreasonable risk; and
  • The individual seeking to import the product affirms in writing that it is for the patient's own use (generally not more than 3 month supply) and provides the name and address of the doctor licensed in the U.S. responsible for his or her treatment with the product or provides evidence that the product is for the continuation of a treatment begun in a foreign country/area.

If you fit these special circumstances, that does not guarantee you will be able to bring foreign medications into the USA. Customs officers at the border are not FDA agents and may not acknowledge the exception.

Remarks about Medications Obtained Outside the USA

Many nations do not impose quality control as stringent as in the USA, so a medication of the same name may not be of the same quality. In some nations, there is an elevated risk of getting counterfeit, contaminated or otherwise faulty medication. The FDA recommends that when buying medications outside the USA, a patient should buy only those that are approved for sale in the USA. This is often feasible, since many medications for sale "across the border" are actually manufactured in the USA. Price caps in other nations can lead to a large price difference on opposite sides of the border even when the drug comes from the same batch at the same factory.

When a medication is not approved for use in the USA and medical attention becomes needed due to complications from using the drug, it may not be possible to trace the batch in which the drug was made. That can delay necessary care.

Both patients and health insurers want to limit costs. Some health insurers are beginning to reimburse their patients for prescriptions bought in Canada, where quality control is widely regarded as good. But getting the medications back into the USA can be problematic. The federal government has been cracking down more heavily on attempts to bring medications back into the USA from abroad, in some instances stopping entire busloads of pensioners at the border to confiscate any medications they bought outside the country. Expect more battles of wills between federal attempts to prohibit importation and insurers or state governments attempting to reduce health care costs by allowing medications to be imported.

Mail order delivery of medications ordered from outside the USA is an area of increasing contention. The FDA regards it as a violation of interstate commerce laws. The government began cracking down on it several years ago.

Traveling Internationally with Medications

Whenever traveling internationally, you should keep all medications in their original containers with their original labels, regardless of whether they are prescription or OTC drugs. For prescription drugs, you should carry a copy of the prescription (or better yet, an original) also. If your medications are lost or ruined, getting a new prescription written in another country can be a lot of bother. Having your doctor's prescription with you will make that easier.

Other Countries Have Drug Laws Too

If a medication obtained or carried in another nation is regarded by that nation as illegal, and that other nation notices you possess it, that nation's laws and legal system apply.

For USA citizens, this can be an especially rude shock in Mexico, where the legal system is quite unlike the USA's. Before crossing a border, it is best to find out whether the medications and amounts you carry are legal on both sides of the border, and whether you are legally required to carry a prescription also.

Disclaimer

I am not a medical professional and am not trying to give you medical advice. I am passing along what I learned while consulting for a couple of major pharmaceutical manufacturers. My aim is to explain in understandable terms the differences in regulatory and quality control for prescription drugs, OTC drugs and dietary supplements.

Years ago, I did a lot of this as a volunteer in a forum for people with chronic illnesses. For more technical detail and a more thorough explanation, please see definitive medical and scientific publications. There is no substitute for the help of a doctor and a pharmacist you trust. Your pharmacist knows much more about this than your doctor.

For your safety, it is best if you get all your medications from one pharmacy and keep the pharmacist aware of everything you are taking–all the prescriptions, OTC medicines, dietary supplements, and foods with special characteristics that could affect how any of those work (such as aged or fermented foods, grapefruit, grapefruit juice, orange juice, apple juice, pomegranate juice).

Before international travel, please check current laws for all the countries involved in your itinerary, including your own, to make sure you will not inadvertently carry a supplement or medicine (prescription or OTC) across a border into a country where it is illegal.