Groups Say GMPs for Compounding Pharmacies are Unworkable

Pharmacy groups and pharmaceutical manufacturers are at odds over the applicability of GMPs to outsourced pharmacy compounding operations. In the meantime, FDA is going full steam ahead and taking an aggressive enforcement approach to compounding pharmacies that violate GMPs, issuing 19 warning letters so far this year.

Pharmaceutical manufacturers said that drug compounding pharmacies should be subject to GMP standards similar to those of conventional drug manufacturers and that a rigorous quality environment be maintained.

Yet they pointed out that there should be a better distinction in a draft guideline between GMPs for sterile drugs that are compounded from sterile drugs and those compounded from non-sterile bulk active pharmaceutical ingredients.

Pharmacy groups went even further and said that FDA’s new guidance on GMPs for outsourcing pharmacies is not workable because it is too closely aligned to conventional pharmaceutical manufacturers and fails to take into account the different business model of compounding pharmacies.

Yet even though the regulations are not yet fully in place, FDA is aggressively enforcing drug compounding pharmacies that violate GMPs. The agency has issued 19 drug GMP warning letters to compounding pharmacies since January.

FDA’s guidance, issued on July 1, is a first step toward outlining the agency’s expectations for large-scale compounders that produce sterile drugs under the 2013 Drug Quality Safety Act.

The guidance incorporates almost all of the GMP regulations that already apply to conventional pharmaceutical manufacturers and apply them to compounding pharmacies (see box below). The deadline for submitting public comment was Sept. 1.

DQSA gave FDA stronger authority to regulate outsourcing facilities that compound sterile drugs for hospitals and health care providers. DQSA was enacted in response to the deadly fungal meningitis outbreak in late 2012 that resulted from the use of contaminated steroids compounded by the New England Compounding Center in Framingham, Mass. (Also see "What FDA Saw at Compounder Behind Fungal Meningitis Outbreak" - Pink Sheet, 29 Nov, 2012.).

Under DQSA outsourcing facilities are unlike traditional pharmacies and may compound drugs without individual prescriptions. FDA is encouraging compounders to register as outsourcing facilities to ensure they meet GMPs.

The DQSA also encouraged large-scale compounders to voluntarily register as outsourcing facilities and follow GMPs, submit to risk-based inspections, report adverse events and pay user fees. The new user fees go into effect on Oct. 1.

The agency has registered 56 pharmacies as outsourced high-volume compounders as of Sept. 22. Yet registering does not seem to inoculate compounders against regulatory actions. Of the 56 that have registered, 37 compounding facilities had received either a warning letter or a Form 483 report either before or after enactment of DQSA.

Sterility an ongoing problem

FDA investigators continue to see sterility issues and inadequate microbiological controls during inspections of compounding facilities. Some of the same problems found in these inspections seemed to mirror those found at the NECC in terms of preparing sterile products under unsanitary conditions.

According to an analysis by “The Gold Sheet” of warning letters issued so far in calendar year 2014 to drug compounders, inadequate controls in the microbiology laboratory under 21 CFR 21.113 was the top deficiency, cited in 17 warning letters.

Inadequate design and construction features under 21 CFR 211.42 was the second-most cited deficiency, and was noted in 16 warning letters.

The third most frequently observed deficiency found in inspections was inadequate sterility testing under 211.167 as well as inadequate stability testing under 211.168. These problems were found in 11 warning letters.

And the fourth most common problem was lax employee practices such as inadequate gowning in the cleanroom under 21 CFR 211.28, found in 10 warning letters.

Tailored GMPs for compounders

The interim guidance said it “reflects FDA’s intent to recognize the differences between compounding outsourcing facilities and conventional drug manufacturers, and to tailor GMP requirements to the nature of the specific compounding operations conducted by outsourcing facilities while maintaining the minimum standards necessary to protect patients form the risks of contaminated or otherwise substandard compounded drug products.”

The guidance sets GMP expectations for facility design; control systems and procedures for maintaining suitable facilities; environmental and personnel monitoring; equipment containers and closures; components; production and process controls; release testing; laboratory controls; packaging and labels; and complaint handling.

It was not FDA’s intention to subject drug compounding pharmacies to all GMPs. Janet Woodcock, director of FDA’s center for drugs, told Congress during a May 9, 2013, hearing on the drug compounding issue that FDA would not subject these facilities to all GMPs, but instead would provide separate regulations tailored specifically to them (Also see "Sterile Compounders Would Get Tailored Manufacturing Regs If FDA Gets New Authority" - Pink Sheet, 9 May, 2013.).

Besides the guidance, FDA also issued other policies on July 1 to implement the Compounding Quality Act:

• A proposed rule that would add 25 drug products to the agency’s list of drug products that may not be compounded;
• A final guidance for individuals, pharmacies and hospitals that intend to compound drugs under the pharmacy compounding provisions of the DQSA;
• A notice seeking nominations for bulk drug substances that may be used for compounding products under Food, Drug and Cosmetic Act section 503B; and
• A notice seeking nominations for bulk drug substances that may be used for compounding products under Food, Drug and Cosmetic Act section 503A.

Good starting point

FDA received 21 comments on the guidance. Many of the comments were from compounding pharmacies, and some were from pharmaceutical manufacturers.

One comment said that the guidance is a good starting point.

Pew Charitable Trusts wrote that “this draft guidance provides a roadmap that will help outsourcing facilities understand how the agency intends for them to comply with cGMPs, and what standards are of particular importance to sterile compounding activities. This clarity is important for facilities that elect to join the new 503B regulatory category, which is voluntary, and will help support successful implementation.”

Similar GMP standards should apply

The Generic Pharmaceutical Association said that drug compounders should be held to similar standards as conventional drug manufacturers. “It is important that a rigorous cGMP environment be maintained for large-scale, non-patient-specific batch compounding given the risk of contamination to a drug product and the ramifications of that risk to patient safety and the number of patients that could be harmed by such drug product.”

The Biotechnology Organization concurred. “It is imperative that FDA ensures that any current Good Manufacturing Practices (cGMPs) for outsourcing facilities apply well established and standard industry requirements in order to ensure consistent and adequate protection of public health.”

Yet they both note that “a distinction should be made within the requirements between a sterile drug product that is compounded by the aseptic combination of licensed, commercially manufactured sterile drugs products under aseptic conditions (sterile to sterile) and sterile drug products that are compounded from non-sterile bulk APIs. The risks associated with the compounded drug differ between these two types of products, necessitating different controls.”

BIO also urged FDA not to reduce laboratory testing for incoming components.

“We believe that the alternative approach to testing should not be permitted exclusively for outsourcing facilities. These sites should be accountable for maintaining the same level of control over their contract sites as would any other pharmaceutical manufacturers.”

The guidance calls for compounding pharmacies to establish in-house laboratories to perform final release testing but would accept outside labs performing this work (see box).

Sterile held to same standard

PharMEDium said that FDA would subject pharmacies that compound with sterile drugs to the same standards as if they had started with a non-sterile API.

PharMEDium was the recipient of a warning letter on July 18, 2014, and the recipient of four untitled observations. PhARMEDium registered all four of its facilities on Dec. 11, 2013.

The company said that currently one-third of 503B registrants start with sterile FDA approved drugs, but would be held to the “stricter standards designed for starting with non-sterile API” under this draft guidance.

PharMEDium said that “much of the production of 503B registrants for traditional outsourcing is admixing and reconstituting already sterile FDA-finished drugs into FDA-finished containers as ready-to-use dosage forms for easier administration to hospitalized patients.”

They cite a recent government study that found that of hospitals utilizing outsourced compounded sterile preparations, or CSPs, sterile preparations compounded from non-sterile products represented less than 1% of CSPs used in 2012.

“A framework designed around less than 1% of production intended for hospital customers exerts too much influence over the draft guidance,” PharMEDium said. Although it is essential for cGMPs to account for this highest-risk activity when it does occur, the guidance should not default to, nor should subsequent regulations categorically require, the application of standards designed for high risk activity to the very distinct context of lower risk sterile to sterile compounding.”

PharMEDium suggests adding in language in the guidance that acknowledges the different models of compounding.

The language would state that “outsourcing facilities generally compound sterile preparations using two specific models. Sterile to sterile compounding is defined as aseptically transferring FDA approved finished drugs into FDA cleared components. This process maintains sterility through media fill validated aseptic manipulations. The second method consists of compounding sterile preparations from APIs. This process creates sterility through terminal sterilization or sterile filtration.”

Not workable

Compounding pharmacies said that the guidance is unworkable because the GMP requirements are too closely aligned to conventional pharmaceutical manufacturing and do not take into account their business model.

PharMEDium said that “the quality lapses and lack of rigorous standards that gave rise to the DQSA have been well documented. However, the other extreme – of impossible or impracticable standards for compounding – is not without its own risks. … If 503B regulatory requirements are too closely reflective of manufacturer cGMPs, cost-prohibitive, economic realities could force production into other settings associated with far less quality controls negatively impacting patient safety.”

PharMEDium notes that the “conventional” pharmaceutical manufacturing model is based upon mass-producing drugs that are sold around the world and is associated with very large-scale production, significant expiration dating, and distribution through a network of third parties.

Manufacturers’ batch sizes can range from 10,000 to 250,000 units per batch, or more. Moreover, it is associated with highly routine processes designed to ensure perfect uniformity of output, and features the creation of sterile and non-sterile drugs from non-sterile raw materials.

PharMEDium asserts that Congress created the 503B category to respond to health care providers’ needs for commercially unavailable customized formulations of one or more existing drugs for prompt shipment and use.

“Compared to conventional manufacturing, batches are small, shipped directly to domestic health care customers that administer the drug to their patients in a healthcare setting, and are intended for only short-term storage before administration. This type of production should only use non-sterile raw starting materials/API in limited circumstances when they are completely unavailable in finished drug form.”

Pentec Health concurred. “Several portions of the draft guidance are unclear, unnecessary or overly burdensome for compounding outsourcing facilities regulated under Section 503B of the Food, Drug and Cosmetic Act. Striking the proper regulatory balance is of particular concern to compounding pharmacies that, like Pentec, have yet to decide whether or not to register as 503B entities.” The company provides renal nutritional products to patients outside of the hospital setting.

Too closely resemble pharma GMPs

Advanced Pharma concurred that the guidelines “are too rigid and too closely resemble the expectations of drug product manufacturers.”

The firm said it’s apprehensive about the ability of outsourcing to continue to meet the demands of hospitals and other healthcare facilities if the guideline is put into effect.

“Imposing the same expectations of the 21 CFR Parts 210 and 211 regulations may limit the supply of compounded drugs from outsourcing facilities and cause market shortages that affect patient safety and cause a vacuum that will generate secondary markets that may not necessarily be in compliance with the guidelines being proposed.”

The company urged FDA to adopt USP standard <797> as the standard for making sterile products for outsourcing pharmacies.

“Currently most compounding outsourcing pharmacies have worked diligently to comply with current USP <797>. As the agency is already aware the USP chapter provides guidelines for compounding sterile products based on risk levels (low, medium and high risk CSPs).”

“We are proposing that the agency issue the guidance in two chapters. The first for those products that are made using sterile components throughout the process (sterile to sterile compounding) and a second chapter for those products that are made using non-sterile components in any part of the process (non-sterile to sterile compounding). By having clear and precise sets of guidance, compounding outsourcing facilities would be better able to meet both sets of expectations.”

The USP <797> is a national standard for the process, testing and verification of compounded sterile preparations – not GMP requirements enforceable by FDA. It provides guidance on preventing microbial contamination in compounded sterile products. Yet USP <797> was not meant to apply to large scale compounding operations.

Follow USP <797>

The guidance also incorporates many of the GMP provisions related to batch release to compounding pharmacies.

Yet to ease some of the sterility testing requirements, FDA said that it will waive such testing for batches consisting of fewer than 10 units. However, this must be compounded pursuant to a prescription for a single patient and the unit is labeled with a beyond use date not to exceed 24 hours at USP controlled room temperature, is not refrigerated more than three days, and has not been frozen more than 45 days.

Pentec Health, said the sterility testing requirements for small batches are still too strict for compounding pharmacies. They make patient-specific formulations that are compounded in batches of 10 or fewer dosage units.

Pentec said that “FDA has rightly recognized the importance of creating exemptions to sterility testing for compounded products produced in very small batches, as onerous testing requirements would unnecessarily increase compliance costs for 503B entities. However, Pentec believes that the limited conditions under which FDA proposes to make the exception available impose too stringent of a standard on 503B entities and do not reflect the actual risks associated with most compounding activities.”

Pentec said that pharmacies should continue to follow the USP standard <797>, which sets sterility standard for low, medium and high risk compounded formulations that are made in small batches.

USP <797> imposes sterility requirements for high-risk compounded products produced in groups of more than 25 under certain temperature conditions.

Central Admixture Pharmacy Services also said that the sterility requirements were too strict. They said that “limiting BUD to three days refrigerated conditions imposes a much more stringent standard than those imposed by USP Chapter 797 for low and medium risk compounded sterile preparations.”

IACP: two standards

The International Academy of Compounding Pharmacists said that the guidance creates an un-level playing field because it creates two standards of GMPs, one for compounding pharmacies that choose to register and one for those that do not.

“At the present time, the FDA’s website lists 51 registered 503B outsourcing facilities. Under this proposed guidance document, those 51 facilities will be expected to comply with all cGMPs cited by the agency. At some point in the future, unspecified by FDA, potentially less stringent cGMPs may be created that are unique to outsourcing facilities. That introduces the potential for two distinct classes of 503B facilities: currently registered entities who are expected to comply with cGMPs as they exist today and future registered entities whose level of compliance may be less stringent based upon some revised standard.”

Compounding Guidance Mirrors GMPs

The guidance incorporates many GMP requirements that apply to conventional drug manufacturers for drug compounders. The following is a description of the GMPs that compounders will be expected to follow.

Facilities should not use dirty filters

The guidance said that manufacturers must comply with the requirements set under 211 CFR 211.42 for design and construction features as well as 211.56 for sanitation procedures.

It said that “certain elements of facility design are considered critical to ensuring the quality of compounded drug products. For example, all processing and controlled areas must be clean and free of visible signs of filth, dirt, mold or mildew, insects, and inappropriate items or debris.”

In addition, the guidance states, outsourcing facilities should not use damaged, dirty or discolored HEPA filters, and drugs should only be made in ISO 5 or better air quality.

Alarms needed to detect excursions

The guidance states that manufacturers should also follow the requirements laid out in 211.42 which require manufacturers to have separate or defined areas to make sterile drugs to prevent contamination or mix-ups with other drug products.

There should also be pressure differential limits and built-in alarms to detect excursions. It said that “monitoring for pressure differentials, humidity, and temperatures should occur during production, and prompt action should be taken to correct inappropriate conditions.”

If powder drugs are handled procedures should also be established to manage cross-contamination risks, particularly if the powder is cytotoxic or highly sensitizing. For penicillin or beta-lactam products, there should be a separate facility or physically separate space as set under 211.42 (d).

For environmental and personnel monitoring, FDA expects manufacturers to follow CFR 211.42 to monitor environmental conditions in aseptic processing areas, as well as 211.113(b) and 211.28(a), which require personnel sanitation practices and gowning to be both acceptable and qualified for the operations performed.

Containers critical to compounders

FDA also expects manufacturers to follow most of the requirements set forth under 211 Subpart E on control of components and drug product containers and closures, including 211.65, 211.67, 211.80, 211.82, 211.84, 211.87, 211.94 and 211.113.

The guidance states that “a number of equipment and container/closure controls are considered critical to ensuring the quality of compounded drug products and are expected to be implemented by outsourcing facilities.”

Yet to minimize the burden of testing, FDA is seeking public comment on whether to have an alternative approach to reduce the burden of testing incoming components.

These alternative approaches, said FDA, “would enable an outsourcing facility to have confidence in the quality of incoming components without periodic laboratory testing following initial qualification testing to confirm the information in the supplier’s certificate of analysis (CoA).”

Under this approach, FDA would not take action if the supplier submits to FDA a drug master file and FDA has reviewed the DMF and issued a letter to the DMF holder stating that FDA has no further comments.

The DMF would contain the following information: a description of the testing performed before its release and shipment; a description of the packaging and labeling to ensure package integrity; and examples of testing records, such as chromatographs and spectrographs.

Proper gowning necessary

FDA expects manufacturers to follow GMPs governing personnel, including 211.21, 211.25, 211.28, production and process controls, including 211.100, 211.111 and 211.113 and records and reports including 211.188 on batch production and control records and 211/192 on production record review.

Regarding 211.25 on personnel qualification, for example, it states that introductory training on aseptic techniques, cleanroom behavior, gowning and procedures covering aseptic manufacturing area operations must be established before an individual can enter the aseptic manufacturing area.

Alternative approaches to lab testing

For laboratory controls, FDA expects manufacturers to follow Section 211.160 on laboratory controls as well as 211.194 on laboratory records.

To ease this requirement, FDA is also seeking public comment on a possible alternative approach that would minimize the need for outsourcing facilities to establish an in-house laboratory to perform final release testing, while providing confidence about the accuracy of testing performed by a third party.

For example, a laboratory interested in performing testing for outsourcing facilities could submit a drug master file containing the following information: a description of the procedures for the conduct and documentation of each test to be conducted; a description of how the methods and equipment for each test were found to be suitable for their intended use and capable of producing valid results; and a description of the records to be maintained at the laboratory or provided to the outsourcing facility.

Upon receipt of a letter from an outsourcing facility stating its intention to use the laboratory, FDA would review the DMF. If the review did not identify any questions regarding the content of a DMF, FDA would issue a letter to the DMF holder stating that FDA has no further comments.

Exemption for small batches

The guidance also incorporates some of the requirements under 21 CFR 211.165 on testing and release for distribution. 211.167, 211.22 and 211.160.

It exempts manufacturers from conducting sterility testing for batches consisting of fewer than 10 dosage units. Yet these batches cannot sit out more than 24 hours at USP controlled room temperature and cannot be refrigerated more than three days.